Physical Activity,
and the Preventionof Cancer:a Global Perspective
The most definitive review of the science to date,
and the most authoritative basis for action toprevent cancer worldwide.
u Recommendations based on expert
judgements of systematic reviews of theworld literature.
u The result of a five-year examination by apanel of the world’s leading scientists.
u Includes new findings on early life, bodyfatness, physical activity, and cancer
survivors.
u Recommendations harmonised withprevention of other diseases and promotionof well-being.
u A vital guide for everybody, and theindispensable text for policy-makers andresearchers.

Food, Nutrition, Physical Activity, and thePrevention of Cancer: a Global Perspective

Food, Nutrition,

World
CancerResearch Fund

AmericanInstitute forCancer Research

Food, Nutrition,
Physical Activity,
World
CancerResearch FundSECOND EXPERT REPORT

American Institutefor Cancer Research

World Cancer
Research Fund

Wereld Kanker
Onderzoek Fonds

World Cancer
Research Fund
Hong Kong

Fonds Mondial
de Recherche
contre le Cancer

www.wcrf.org

www.aicr.org

www.wcrf-uk.org

www.wcrf-nl.org

www.wcrf-hk.org

www.fmrc.fr

ER HARD FINAL.indd 1

AmericanInstitute forCancer Research

World Cancer
Research FundInternational

and the Preventionof Cancer:a Global Perspective

30/10/07 10:07:25

Food, Nutrition,
P h y s i c a l A c t i v i t y, a n d t h e
P re v e n t i o n o f C a n c e r :a Global Perspective

Please cite the Report as follows:
World Cancer Research Fund / American Institute for Cancer Research.
Food, Nutrition, Physical Activity, and the Prevention of Cancer: a Global Perspective.
Washington DC: AICR, 2007

First published 2007 by the American Institute for Cancer Research1759 R St. NW, Washington, DC 20009© 2007 World Cancer Research Fund International
All rights reserved

Readers may make use of the text and graphic material in this Reportfor teaching and personal purposes, provided they give credit toWorld Cancer Research Fund and American Institute for Cancer Research.
ISBN: 978-0-9722522-2-5
CIP data in process
Printed in the United States of America by RR Donnelley

Food, Nutrition,
P h y s i c a l A c t i v i t y, a n d t h e
P re v e n t i o n o f C a n c e r :a Global Perspective

A project ofWorld Cancer Research FundInternationalP re f a c e
I am very grateful to the special group of distinguished scientists who made up the Paneland Secretariat for this major review of the evidence on food, nutrition, physical activity
and cancer. The vision of WCRF International in convening this Panel and confidence inletting a strong-willed group of scientists have their way is to be highly commended.
In our view, the evidence reviewed here that led to our recommendations provides a
wonderful opportunity to prevent cancer and improve global health. Individuals andpopulations have in their hands the means to lead fuller, healthier lives. Achieving thatwill take action, globally, nationally, and locally, by communities, families, andindividuals.
It is worth pausing to put this Report in context. Public perception is often that experts
disagree. Why should the public or policy-makers heed advice if experts differ in theirviews? Experts do disagree. That is the nature of science and a source of its strength.
Should we throw up our hands and say one opinion is as good as another? Of course not.
Evidence matters. But not evidence unguided by human thought. Hence the process thatwas set up for this review: use a systematic approach to examine all the relevant evidence
using predetermined criteria, and assemble an international group of experts who, having
brought their own knowledge to bear and having debated their disagreements, arrive atjudgements as to what this evidence means. Both parts of the exercise were crucial: thesystematic review and, dare I say it, the wisdom of the experts.
The elegance of the process was one of the many attractions to me of assuming the roleof chair of the Panel. I could pretend that it was the major reason, and in a way it was, but
the first reason was enjoyment. What a pleasure and a privilege to spend three years in
the company of a remarkable group of scientists, including world leaders in research on
the epidemiology of cancer, as well as leaders in nutrition and public health and thebiology of cancer, to use a relatively new methodology (systematic literature reviews),
supported by a vigorous and highly effective Secretariat, on an issue of profoundimportance to global public health: the prevention of cancer by means of healthy patternsof eating and physical activity. It was quite as enjoyable as anticipated.
Given this heady mix, the reasons why I might have wanted to take on the role of Panelchair were obvious. I did question the wisdom of WCRF International in inviting me to doit. Much of my research has been on cardiovascular disease, not cancer. What I described
as my ignorance, WCRF International kindly labelled impartiality.
WCRF also appreciated the parallels between dietary causes of cardiovascular diseaseand cancer. There is a great deal of concordance. In general, recommendations in thisReport to prevent cancer will also be of great relevance to cardiovascular disease. The only
significant contradiction is with alcohol. From the point of view of cancer prevention, thebest level of alcohol consumption is zero. This is not the case for cardiovascular disease,
where the evidence suggests that one to two drinks a day are protective. The Panel
therefore framed its recommendation to take this into account.
The fact that the conclusions and recommendations in this Report are the unanimousview of the Panel does not imply that, miraculously, experts have stopped disagreeing. The
Panel debated the fine detail of every aspect of its conclusions and recommendations withremarkable vigour and astonishing stamina. In my view, this was deliberation at its best. If
conclusions could simply fall out of systematic literature reviews, we would not haveneeded experts to deliberate. Human judgement was vital; and if human, it cannot be
infallible. But I venture to suggest this process has led to as good an example of evidencebased public health recommendations as one can find.
Throughout the Panel’s deliberations, it had in mind the global reach of this Report.
Most of the research on diet and cancer comes from high-income countries. Butiv

noncommunicable diseases, including cancer, are now major public health burdens inevery region of the world. An important part of our deliberations was to ensure theglobal applicability of our recommendations.
One last point about disagreement among experts: its relevance to the link between
science and policy. A caricature would be to describe science as precise and policy-makers
as indecisive. In a way, the opposite is the case. Science can say: could be, might be,some of us think this, and some think that. Policy-makers have either to do it or not
do it — more often, not. Our effort here was to increase the precision of scientificjudgements. As the Report makes clear, many of our conclusions are in the ‘could be’
category. None of our recommendations is based on these ‘could be’ conclusions. All are
based on judgements that evidence was definite or probable. Our recommendations, wetrust, will serve as guides to the population, to scientists, and to opinion-formers.
But what should policy-makers do with our judgements? A year after publication ofthis Report, we will publish a second report on policy for diet, nutrition, physical activity,
and the prevention of cancer. As an exercise developing out of this one, we decided toapply, as far as possible, the same principles of synthesis of evidence to policy-making.
We enhanced the scientific panel that was responsible for this Report with experts innutrition and food policy. This policy panel will oversee systematic literature reviews onfood policy, deliberate, and make recommendations.
The current Report and next year’s Policy Report have one overriding aim: to reduce
the global burden of cancer by means of healthier living.
Michael MarmotvContents
P re f a c e

iv

Contentsvi

Acknowledgementsviii

S u m m a ryxiv

I n t ro d u c t i o n

xxii■ PA RT O N E B A C K G R O U N D

1Chapter 1

4

1.1
1.2
1.3
1.4

Food systems and diets throughout history
Foods and drinks, physical activity,
body composition
Migrant and other ecological studies
Conclusions

Chapter 2
2.1
2.2
2.3
2.4
2.5
2.6

5
11
22
25

T h e c a n c e r p ro c e s s

30

Basic concepts and principles
Cellular processes
Carcinogen metabolism
Causes of cancer
Nutrition and cancer
Conclusions

31
32
36
37
41
46

Judging the evidence48

Chapter 3
3.1
3.2
3.3
3.4
3.5
3.6

I n t e r n a t i o n a l v a r i a t i o n s a n d t re n d s

Epidemiological evidence
Experimental evidence
Methods of assessment
Causation and riskComing to judgement
Conclusions

49
52
55
57
58
62

■ PA RT T W O E V I D E N C E A N D J U D G E M E N T S

63Chapter 4

66

Foods and drinks

4.1
4.2

Cereals (grains), roots, tubers and plantains
Vegetables, fruits, pulses (legumes), nuts,
seeds, herbs, spices
4.3 Meat, poultry, fish and eggs
4.4 Milk, dairy products
4.5 Fats and oils
4.6 Sugars and salt
4.7 Water, fruit juices, soft drinks and hot drinks
4.8 Alcoholic drinks
4.9 Food production, processing, preservationand preparation
4.10 Dietary constituents and supplements
4.11 Dietary patterns

Chapter 5

Physical activity

Chapter 6

G ro w t h , d e v e l o p m e n t , b o d ycomposition

6.1
6.2
6.3

vi

Body fatness
Growth and development
Lactation

67
75
116
129
135
141
148
157
172
179
190

Chapter 7

Cancers244

7.1 Mouth, pharynx and larynx
7.2 Nasopharynx
7.3 Oesophagus
7.4 Lung
7.5 Stomach
7.6 Pancreas
7.7 Gallbladder
7.8 Liver
7.9 Colon and rectum
7.10 Breast
7.11 Ovary
7.12 Endometrium
7.13 Cervix
7.14 Prostate
7.15 Kidney
7.16 Bladder
7.17 Skin
7.18 Other cancers

245
250
253
259
265
271
275
277
280
289
296
299
302
305
310
312
315
318

Chapter 8
Chapter 9

D e t e rm i n a n t s o f w e i g h t g a i n ,o v e rw e i g h t , o b e s i t y

322

C a n c e r s u rv i v o r s

342

C h a p t e r 1 0 F i n d i n g s o f o t h e r re p o r t s

348

10.1 Method10.2 Interpretation of the data
10.3 Nutritional deficiencies
10.4 Infectious diseases
10.5 Chronic diseases other than cancer
10.6 Cancer
10.7 Conclusions

349
350
350
351
352
355
358

C h a p t e r 1 1 R e s e a rc h i s s u e s

360■ PA RT T H R E E R E C O M M E N D AT I O N S

365

Chapter 12 Public health goals andp e r s o n a l re c o m m e n d a t i o n s

368

12.1 Principles
12.2 Goals and recommendations
12.3 Patterns of food, nutrition andphysical activity

369
373
391

APPENDICES

395

A p p e n d i x A P ro j e c t p ro c e s s

396

A p p e n d i x B T h e f i r s t W C R F / A I C R E x p e rt R e p o rt

398

Appendix C WCRF global network

400

G l o s s a ry

402

R e f e re n c e s

410

Index

506

198
210
211
229
239

CHAPTER BOXES

Box 4.6.1
Box 4.6.2■ PA RT O N E B A C K G R O U N D
Chapter 1
Box
Box
Box
Box 1.1
Box
Box
Box
Box 1.2
Box
Box
Box
Box
Box
Box
Chapter 2

I n t e r n a t i o n a l v a r i a t i o n s a n d t re n d s
EgyptSouth Africa
China
Measurement of food supply
and consumption
India
Japan
UK
Measurement of cancer incidence
and mortality
PolandSpain
USA
MexicoAustralia
Brazil

6
8
10
13
14
16
18
18
20
22
24
26
27
28

Sugar, sugars, sugary foods and drinks
Salt and salty, salted and salt-preserved
foods
Box 4.6.3 Chemical sweeteners
Box 4.6.4 Refrigeration
Box 4.7.1 High temperature, and irritant drinks
and foods
Box 4.7.2 Contamination of water, and of foods
and other drinks
Box 4.8.1 Types of alcoholic drink
Box 4.9.1 Food systems
Box 4.9.2 ‘Organic’ farming
Box 4.9.3 Regulation of additives andcontaminants
Box 4.9.4 Water fluoridation
Box 4.10.1 Food fortification
Box 4.10.2 Functional foods
Box 4.10.3 Levels of supplementation
Chapter 5
Box 5.1
Box 5.2

Nutrition over the life course
Oncogenes and tumour suppressor genes
Mechanisms for DNA repair
Body fatness and attained height
Energy restriction

34
35
37
39
46

Box 6.2.1
Box 6.2.2
Chapter 7

Chapter 3
Box 3.1
Box 3.2
Box 3.3
Box 3.4
Box 3.5
Box 3.6
Box 3.7
Box 3.8

Box 4.1.1
Box 4.1.2
Box 4.1.3
Box 4.1.4
Box 4.2.1
Box 4.2.2
Box 4.2.3
Box 4.2.4
Box 4.3.1
Box 4.3.2
Box 4.3.3
Box 4.3.4
Box 4.3.5
Box 4.4.1
Box 4.5.1

150
150
159
173
174
175
176
182
182
183

Physical activity
Energy cost and intensity of activity
Sedentary ways of life

200
201

G ro w t h , d e v e l o p m e n t , b o d y c o m p o s i t i o n
Sexual maturity
Age at menarche and risk ofbreast cancer

232
232

Cancers

Judging the evidenceIssues concerning interpretation of
the evidenceDose-response
Forest plots
Systematic literature reviews
Experimental findings
Effect modification
Energy adjustment
Criteria for grading evidence

50
52
53
54
55
56
57
60

■ PA RT T W O E V I D E N C E A N D J U D G E M E N T S
Chapter 4

143
143
144

T h e c a n c e r p ro c e s s
Chapter 6

Box 2.1
Box 2.2
Box 2.3
Box 2.4
Box 2.5

142

Foods and drinks
Wholegrain and refined cereals andtheir products
Foods containing dietary fibre
Glycaemic index and load
Aflatoxins
Micronutrients and other bioactive
compounds and cancer risk
Phytochemicals
Preparation of vegetables and nutrient
bioavailability
Foods containing dietary fibre
Processed meat
Nitrates, nitrites and N-nitroso
compounds
Foods containing iron
Heterocyclic amines and polycyclicaromatic hydrocarbons
Cantonese-style salted fish
Foods containing calcium
Hydrogenation and trans-fatty acids

Box 7.1.1
Box 7.2.1
Box 7.5.1
Box 7.8.1
Box 7.13.1
Chapter 8
Box 8.1
Box 8.2
Box 8.3
Box 8.4
Chapter 9
Box 9.1

69
69
69
70

Box 9.2

Cancer incidence and survival
Epstein-Barr virus
Helicobacter pylori
Hepatitis viruses
Human papilloma viruses
D e t e rm i n a n t s o f w e i g h t g a i n ,o v e rw e i g h t , o b e s i t y
Energy density
Fast foodBody fatness in childhood
Television viewing

Conventional and unconventional
therapies
Use of supplements by cancer survivors
F i n d i n g s o f o t h e r re p o r t s

78
79

Chapter 11

R e s e a rc h i s s u e s

79
80
117

■ PA RT T H R E E R E C O M M E N D AT I O N S

119
120
131
137

324
325
326
331

C a n c e r s u rv i v o r s

Chapter 10

118
118

246
251
266
278
303

Chapter 12

Public health goals and personalre c o m m e n d a t i o n s

Box 12.1
Box 12.2
Box 12.3
Box 12.4
Box 12.5

Quantification
Making gradual changes
Height, weight and ranges of BMI
When supplements are advisable
Regional and special circumstances

345
346

371
372
375
387
392

vii

F O O D , N U T R I T I O N , P H Y S I C A L A C T I V I T Y, A N D T H E P R E V E N T I O N O F C A N C E R : A G L O B A L P E R S P E C T I V E

Acknowledgements
Panel
Sir Michael Marmot
MB BS MPH PhD FRCP FFPH
Chair
University College London
UK
Tola Atinmo PhD
University of Ibadan, Nigeria
Tim Byers MD MPH
University of Colorado Health
Sciences Center
Denver, CO, USA
Junshi Chen MD
Chinese Centre for Disease
Control and Prevention
Beijing, People’s Republic of
China
Tomio Hirohata MD
DrScHyg PhD
Kyushu University
Fukuoka City, Japan
Alan Jackson CBE MD FRCPFRCPCH FRCPath
University of Southampton
UK
W Philip T James CBE MD
DSc FRSE FRCPInternational Obesity Task
Force
London, UK
Laurence N Kolonel MD PhD
University of Hawai’i
Honolulu, HI, USA

Jim Mann DM PhD FFPH
FRACP
University of Otago
Dunedin, New ZealandHilary J Powers PhD RNutr
University of Sheffield, UK

World Health Organization(WHO)
Geneva, Switzerland
Denise Coitinho PhD
Ruth Bonita MD
Chizuru Nishida PhD MA
Pirjo Pietinen DSc

K Srinath Reddy MD DM MSc
Institute of Medical Sciences
New Delhi, India

Panel observers

Additional
members for policy
panel

Elio Riboli MD ScM MPH
Was at: International Agency
for Research on Cancer(IARC), Lyon, France
Now at: Imperial College
London, UK

Food and Agriculture
Organization of the United
Nations (FAO)
Rome, Italy
Guy Nantel PhD
Prakash Shetty MD PhD

Barry Popkin PhD MSc BSc
Carolina Population Center,
University of North Carolina,
Chapel Hill, NC, USA

Juan A Rivera PhD
Instituto Nacional de Salud
Publica
Cuernavaca, Mexico

International Food Policy
Research Institute (IFPRI)
Washington DC, USA
Lawrence Haddad PhD
Marie Ruel PhD

Arthur Schatzkin MD DrPH
National Cancer InstituteRockville, MD, USA

International Union of
Nutritional Sciences (IUNS)Mark Wahlqvist MD AO

Jacob C Seidell PhD
Free University Amsterdam
The Netherlands

Mechanisms Working GroupJohn Milner PhD

David E G Shuker PhD FRSCThe Open University
Milton Keynes, UK

Methodology Task ForceJos Kleijnen MD PhD
Gillian Reeves PhD

Ricardo Uauy MD PhD
Instituto de Nutricion y
Tecnologia de los Alimentos
Santiago, Chile

Union Internationale Contre
le Cancer (UICC)
Geneva, Switzerland
Annie Anderson PhD
Curtis Mettlin PhD
Harald zur Hausen MD DSc

Shiriki Kumanyika PhD MPH
University of Pennsylvania
Philadelphia, PA, USA

Walter C Willett MD DrPH
Harvard School of Public
Health
Boston, MA, USA

Claus Leitzmann PhD
Justus Liebig University
Giessen, Germany

Steven H Zeisel MD PhD
University of North Carolina
Chapel Hill, NC, USAviii

Robert Beaglehole ONZMFRSNZ DSc
Chair 2003
Was at: World HealthOrganization (WHO)Geneva, Switzerland
Now at: University of
Auckland, New ZealandUnited Nations Children’s
Fund (UNICEF)
New York, NY, USA
Ian Darnton-Hill MD MPH
Rainer Gross Dr Agr

Jane Wardle PhD MPhil
University College London, UK
Nick Cavill MPH
British Heart Foundation
Health Promotion
Research Group
University of Oxford, UK

A C K N O W L E D G E M E N T S

Systematic
Literature Review
Centres
University of Bristol, UK

Rajendra Persad ChM FEBU
FRCS
United Bristol Healthcare
Trust & Bristol Urological
Institute, UK

Carlos A Gonzalez PhD MPH
MDCatalan Institute of Oncology
Barcelona, Spain
Vittorio Krogh MD MSc
Istituto Nazionale Tumori
Milan, Italy

George Davey Smith
FMedSci FRCP DSc
University of Bristol , UK

Massimo Pignatelli MD PhDFRCPath
University of Bristol, UK

Jonathan Sterne PhD MSc
MAUniversity of Bristol, UK

Jelena Savovic PhD
University of Bristol, UK

Sylvie Menard ScD
Istituto Nazionale Tumori
Milan, Italy

Steve Thomas MB BS PhD
FRCS
University of Bristol, UK

Eugenio Mugno ScD
Istituto Nazionale Tumori
Milan, Italy

Tim Whittlestone MA MD
FRCS
United Bristol Healthcare
Trust, UK

Valeria Pala ScD
Istituto Nazionale Tumori
Milan, Italy

Chris Bain MB BS MS MPH
University of Queensland
Brisbane, Australia
Nahida Banu MB BS
University of Bristol, UK
Trudy Bekkering PhD
University of Bristol, UK

Luisa Zuccolo MSc
University of Bristol, UK

Sabina Sieri ScD
Istituto Nazionale Tumori
Milan, Italy

Rebecca Beynon MA BSc
University of Bristol, UK
Margaret Burke MSc
University of Bristol, UK
David de Berker MB BS MRCP
United Bristol Healthcare
Trust, UK
Anna A Davies MSc BSc
University of Bristol, UK
Roger Harbord MSc
University of Bristol, UK
Ross Harris MSc
University of Bristol, UK
Lee Hooper PhD SRD
University of East Anglia
Norwich, UK
Anne-Marie Mayer PhD MSc
University of Bristol, UK
Andy Ness PhD FFPHM MRCP
University of Bristol, UK

Istituto Nazionale
Tu m o r i M i l a n , I t a l yFranco Berrino MD
Istituto Nazionale Tumori
Milan, Italy
Patrizia Pasanisi MD MSc
Istituto Nazionale Tumori
Milan, Italy
Claudia Agnoli ScD
Istituto Nazionale Tumori
Milan, Italy
Silvana Canevari ScD
Istituto Nazionale Tumori
Milan, Italy
Giovanni Casazza ScD
Istituto Nazionale Tumori
Milan, Italy
Elisabetta Fusconi ScD
Istituto Nazionale Tumori
Milan, Italy

Johns Hopkins
U n i v e r s i t y, B a l t i m o re ,MD, USA
Anthony J Alberg PhD MPH
University of South Carolina
Columbia, SC, USA
Kristina Boyd MS
Johns Hopkins University
Baltimore, MD, USA
Laura Caulfield PhD
Johns Hopkins University
Baltimore, MD, USA
Eliseo Guallar MD DrPH
Johns Hopkins University
Baltimore, MD, USA
James Herman MD
Johns Hopkins University
Baltimore, MD, USA

Karen Robinson MSc
Johns Hopkins University
Baltimore, MD, USA
Xuguang (Grant) Tao MD
PhD
Johns Hopkins University
Baltimore, MD, USA

University of Leeds, UK
David Forman PhD FFPH
University of Leeds, UK
Victoria J Burley PhD MSc
RPHNutr
University of Leeds, UK
Janet E Cade PhD BSc
RPHNutr
University of Leeds, UK
Darren C Greenwood MSc
University of Leeds, UK
Doris S M Chan MSc
University of Leeds, UK
Jennifer A Moreton PhD MSc
University of Leeds, UK
James D Thomas
University of Leeds, UK
Yu-Kang Tu PhD MSc DDS
University of Leeds, UK
Iris Gordon MSc
University of Leeds, UK
Kenneth E L McColl FRSE
FMedSci FRCP
Western Infirmary
Glasgow, UK
Lisa Dyson MSc
University of Leeds, UK

Genevieve Matanoski MD
DrPH
Johns Hopkins University
Baltimore, MD, USAix

F O O D , N U T R I T I O N , P H Y S I C A L A C T I V I T Y, A N D T H E P R E V E N T I O N O F C A N C E R : A G L O B A L P E R S P E C T I V E

London School of
H y g i e n e & Tr o p i c a l
Medicine, UKP e n n S t a t e U n i v e r s i t y,
University Park,
PA , U S AAlan D Dangour PhD MSc
London School of Hygiene &Tropical Medicine, UK

Terryl J Hartman PhD MPH
RDPenn State University,
University Park, PA, USA

Shefalee Mehta MSc
London School of Hygiene &Tropical Medicine, UK
Abigail Perry MSc
London School of Hygiene &Tropical Medicine, UK
Sakhi Kiran Dodhia MSc
London School of Hygiene &Tropical Medicine, UK
Vicki Pyne MSc
London School of Hygiene &Tropical Medicine, UK

U n i v e r s i t y o f Te e s s i d e ,UK
Carolyn Summerbell PhD
SRD
University of Teesside
Middlesbrough, UK
Sarah Kelly PhD
University of Teesside
Middlesbrough, UKLouisa Ells PhD
University of Teesside
Middlesbrough, UK
Frances Hillier MSc
University of Teesside
Middlesbrough, UK
Sarah Smith MSc
University of Teesside
Middlesbrough, UK
Alan Batterham PhD
University of Teesside
Middlesbrough, UK
Laurel Edmunds PhD
University of Teesside
Middlesbrough, UK
Vicki Whittaker MSc
University of Teesside
Middlesbrough, UK
Ian Macdonald PhD
University of Nottingham, UK

xDavid Mauger PhD
Penn State College ofMedicine,
University Park, PA, USA
Lindsay Camera MS
Penn State College ofMedicine,
University Park, PA, USA
M Jenny Harris Ledikwe PhD
Penn State University,
University Park, PA, USA
Linda Kronheim MS
Penn State University,
University Park, PA, USA
Keith R Martin PhD MTox
Penn State University,
University Park, PA, USA
Tara Murray
Penn State University,
University Park, PA, USA
Michele L Shaffer PhD
Penn State College ofMedicine,
University Park,
PA, USA

Dina M Gifkins MPH
The Cancer Institute of New
JerseyNew Brunswick, NJ, USA
Marjorie L McCullough RD
ScD
American Cancer Society
New York, NY, USA

Wa g e n i n g e n U n i v e r s i t y,
The Netherlands
Pieter van ‘t Veer PhD
Wageningen University
The Netherlands
Ellen Kampman PhD
Wageningen University
The Netherlands
Marije Schouten PhD
Wageningen University
The Netherlands
Bianca Stam MSc
Wageningen University
The Netherlands
Claudia Kamphuis MSc
Wageningen University
The Netherlands
Maureen van den Donk PhD
Wageningen University
The Netherlands
Marian Bos MSc
Wageningen University
The Netherlands

Anouk Geelen PhD
Wageningen University
The Netherlands
Evelien Smit MSc
Wageningen University
The Netherlands
Salome Scholtens MSc
Wageningen University
The Netherlands
Evert-Jan Bakker PhD
Wageningen University
The Netherlands
Jan Burema MSc
Wageningen University
The Netherlands
Marianne Renkema PhD
Wageningen University
The Netherlands
Henk van Kranen PhD
National Institute for Healthand the Environment (RIVM)
Bilthoven, the Netherlands

Narrative review
authors
Liju Fan PhD
Ontology Workshop
Columbia, MD, USA
Luigino Dal Maso ScD
Aviano Cancer Center
Italy
Michael Garner MSc
University of Ottawa
Ontario, Canada

Kim Spaccarotella PhD
Rutgers, The State Universityof New Jersey, New
Brunswick, NJ, USA

Akke Botma MSc
Wageningen University
The Netherlands

K a i s e r P e rm a n e n t e ,Oakland, California, USA

Simone Croezen MSc
Wageningen University
The Netherlands

Frank M Torti MD MPH
Wake Forest University,
Comprehensive Cancer Unit
Winston-Salem, NC, USA

Mirjam Meltzer MSc
Wageningen University
The Netherlands

Christine F Skibola PhD
University of California,
Berkeley, CA, USA

Elisa V Bandera MD PhD
The Cancer Institute of New
JerseyNew Brunswick, NJ, USA
Lawrence H Kushi ScD
Kaiser Permanente
Oakland, California, USA
Dirk F Moore PhD
The Cancer Institute of New
JerseyNew Brunswick, NJ, USA

Fleur Schouten MSc
Wageningen University
The Netherlands
Janneke Ploemacher MSc
Wageningen University
The Netherlands
Khahn Le MSc
Wageningen University
The Netherlands

A C K N O W L E D G E M E N T S

Methodology
Task Force
Martin Wiseman FRCPFRCPathChair
Project Director
WCRF International
Sheila A Bingham PhD
FMedSci
MRC Dunn Human Nutrition
Unit
Cambridge, UK
Heiner Boeing PhD
German Institution of Human
Nutrition
Berlin, Germany
Eric Brunner PhD FFPH
University College London,UK
H Bas Bueno de Mesquita MD
MPH PhD
National Institute of Public
Health and the Environment(RIVM)
Bilthoven, the Netherlands
David Forman PhD FFPH
University of Leeds, UK
Ian Frayling PhD MRCPath
Addenbrookes Hospital
Cambridge, UK
Andreas J Gescher DSc
University of Leicester, UK
Tim Key PhD
Cancer Research UK
Epidemiology Unit,
University of Oxford
Oxford, UK
Jos Kleijnen MD PhD
Was at: University of York, UK
Now at: Kleijnen Systematic
Reviews, York, UK
Barrie Margetts MSc PhD
MFPH
University of Southampton,
UK
Robert Owen PhD
German Cancer ResearchCentreHeidelberg, Germany

Gillian Reeves PhD
Cancer Research UK
Epidemiology Unit,
University of Oxford
Oxford, UK
Elio Riboli MD ScM MPH
Was at: International Agency
for Research on Cancer(IARC), Lyon, France
Now at: Imperial College
London, UK
Arthur Schatzkin MD DrPH
National Cancer InstituteRockville, MD, USA
David E G Shuker PhD
The Open University
Milton Keynes, UK

Mechanisms
Working Group

Peer reviewers andother contributors

John Milner PhD
ChairNational Cancer InstituteRockville, MD, USA

David S Alberts MD
Arizona Cancer Center
Tucson, AZ, USA

Nahida Banu MBBS
University of Bristol, UK

Chris Bain MBBS MPH
University of Queensland
Brisbane, Australia

Xavier Castellsagué Pique
PhD MD MPH
Catalan Institute of Oncology
Barcelona, Spain

Amy Berrington de Gonzalez
DPhil MSc
Johns Hopkins University
Baltimore, MD, USA

Sanford M Dawsey MD
National Cancer InstituteRockville, MD, USA

Sheila A Bingham PhD
FMedSci
MRC Dunn Human Nutrition
Unit
Cambridge, UK

Michael Sjöström MD PhD
Karolinska InstituteStockholm, Sweden

Carlos A Gonzalez PhD MPH
MDCatalan Institute of Oncology
Barcelona, Spain

Pieter van ‘t Veer PhD
Wageningen University
The Netherlands

James Herman MD
Johns Hopkins University
Baltimore, MD, USA

Chris Williams MD
Cochrane Cancer Network
Oxford, UK

Stephen Hursting PhD
University of North Carolina
Chapel Hill, NC, USA
Henry Kitchener MD
University of Manchester, UK
Keith R Martin PhD MTox
Penn State University
University Park, PA, USA
Kenneth E L McColl FRSE
FMedSci FRCP
Western Infirmary
Glasgow, UK
Sylvie Menard ScD
Istituto Nazionale Tumori
Milan, Italy
Massimo Pignatelli MD PhD
MRCPath
University of Bristol, UK
Henk van Kranen PhD
National Institute of Public
Health and the Environment(RIVM)
Bilthoven, the Netherlands

Diane Birt PhD
Iowa State University
Ames, IA, USA
Steven Blair PED
University of South Carolina
Columbia, SC, USA
Judith Bliss MSc
The Institute of Cancer
Research
Sutton, UK
Cristina Bosetti ScD
Istituto di Recherche
Farmacologiche “Mario
Negri”
Milan, Italy
Paul Brennan PhD MSc
International Agency for
Research on Cancer (IARC)
Lyon, France
Johannes Brug PhD FFPH
Institute for Research in
Extramural Medicine(EMGO),VU University Medical Centre
Amsterdam, the Netherlands
Eric Brunner PhD FFPH
University College London,UK
H Bas Bueno de Mesquita MD
MPH PhD
National Institute of Public
Health and the Environment(RIVM)
Bilthoven, the NetherlandsxiF O O D , N U T R I T I O N , P H Y S I C A L A C T I V I T Y, A N D T H E P R E V E N T I O N O F C A N C E R : A G L O B A L P E R S P E C T I V E

Noel Cameron BEd MSc
Loughborough University, UK
Moira Chan-Yeung MBBS
FRCP FACP
University of Hong Kong
China
Robert Clarke DSc PhD
Lombardi Comprehensive
Cancer Center, Georgetown
University
Washington DC, USA
Steven K Clinton MD PhD
The Ohio State University
Columbus, OH, USA
Karen Collins MS RD
Nutrition Advisor
AICR

Elizabeth TH Fontham DrPHLouisiana State University of
Public Health
New Orleans, LA, USA
Terrence Forrester MB BS DM
FRCP
University of the West Indies
Kingston, Jamaica
Teresa Fung ScD RD MSc
Simmons College andHarvard School of Public
Health
Boston, MA, USA
John Garrow MD PhD FRCP
University of London, UK
Glenn Gibson PhD
University of Reading, UK

Brian Cox MBChB PhD
FAFPHM
University of Otago
Dunedin, New Zealand

Ian Gilmore MD PRCP
Royal College of Physicians
London, UK

Cindy Davis PhD
National Cancer InstituteRockville, MD, USA

Vay Liang W Go MD
University of California
Los Angeles, CA, USA

Diana Dyer MS RD
Ann Arbor, MI, USA

Per Hall MD PhD
Karolinska Institutet
Stockholm, Sweden

Jonathan Earle MB BCh FCAP
Memorial Sloan Kettering
Cancer Center
New York, NY, USA
Alison Eastwood MSc
University of York, UK
Ibrahim Elmadfa PhD
University of Vienna
Austria
Dallas English PhD MSc
University of Melbourne
Victoria, Australia
Michael Fenech PhD MSc BSc
Commonwealth Scientific andIndustrial Research
Organization (CSIRO)
Adelaide, Australia
Justin Fenty MSc
University of Nottingham, UK
Lynn Ferguson DSc DPhil MSc
Univerity of Auckland
New Zealandxii

Laura Hardie PhD
University of Leeds, UK
Peter Herbison MSc
University of Otago
Dunedin, New ZealandVictor Kipnis PhD
National Cancer InstituteRockville, MD, USA
Paul Knekt PhD
National Public HealthInstitute
Helsinki, Finland
Thilo Kober PhD
Cochrane Haematological
Malignancies Group
Cologne, Germany
Suminori Kono PhD MD MSc
Kyushu University
Fukuoka, Japan
Nancy Kreiger PhD MPH
Cancer Care Ontario andUniversity of Toronto
CanadaPetra Lahmann PhD
University of Queensland
Brisbane, Australia
Fabio Levi MD MSc
Institut Universitaire deMédecine Sociale etPréventive
Lausanne, Switzerland
Ruth Lewis MSc
Cardiff University, UK
Albert B Lowenfels MD
New York Medical College
New York, NY, USA

Melvyn Hillsdon PhD
University of Bristol, UK

Graham A MacGregor FRCPSt George’s University of
London, UK

Edward Hurwitz DC PhD
University of Hawai’i
Honolulu, HI, USA

Geoffrey Marks PhD MS
University of Queensland
Brisbane, Australia

Susan Jebb PhD
MRC Human Nutrition
Research
Cambridge, UKJohn Mathers PhD DipNutr
University of Newcastle, UK

Stanley B Kaye MD FRCP
FMedSci
The Institute of Cancer
Research
Sutton, UK
Tim Key PhD
Cancer Research UK
Epidemiology Unit,
University of Oxford
Oxford, UK

Sam McClinton MD FRCSNHS Grampian
Aberdeen, UK

Tony McMichael MB BS PhD
FAFPHM
The Australian National
University
Canberra, Australia
Dominique Michaud ScD
Harvard School of Public
Health
Boston, MA, USA
Anthony B Miller MD FRCP
FACE
University of Toronto
CanadaSidney Mirvish PhD
University of Nebraska
Omaha, NE, USA
Max Parkin MD
International Agency for
Research on Cancer (IARC)
Lyon, FranceCharlotte Paul MB ChB PhD
University of Otago
Dunedin, New Zealand
John Reilly PhD
University of Glasgow, UK
Richard Rivlin MD
Strang Cancer ResearchLaboratory
New York, NY, USA
Andrew Roddam DPhil
Cancer Research UK
Epidemiology Unit
University of Oxford
Oxford, UK
Leo Schouten MD PhD
Nutrition and Toxicology
Research Institute Maastricht
The Netherlands
Jackilen Shannon PhD MPH
RD
Oregon Health and Science
University
Portland, OR, USA

Fiona Mensah
University of York, UK

Keith Singletary PhD
University of Illinois
Urbana, IL, USA

Margaret McCredie PhD
University of Otago
Dunedin, New Zealand

Rashmi Sinha PhD
National Cancer InstituteRockville, MD, USA

A C K N O W L E D G E M E N T S

Rachael Stolzenberg-Solomon
PhD MPH RD
National Cancer InstituteBaltimore, MD, USA
Boyd Swinburn MB ChB MD
Deakin University
Melbourne, Australia
Peter Szlosarek MRCP PhD
St Bartholomew’s Hospital
London, UK
Paul Talalay MD
Johns Hopkins University
Baltimore, MD, USA
Margaret Thorogood PhD
University of Warwick, UK
Stewart Truswell MD DSc
FRCP
University of Sydney
Australia
Paolo Vineis MD MPH
Imperial College
London, UK
Steven Waggoner MD
Case Comprehensive Cancer
CenterCleveland, OH, USA
Christopher P Wild PhD
University of Leeds, UK
Anthony Williams DPhil FRCPFRCPCHSt George’s University of
London, UK
Frederic M Wolf PhD MEd
University of Washington
Seattle, WA, USA
Jian-Min Yuan MD PhD
University of Minnesota,
Minneappolis, MN, USA
Maurice Zeegers PhD MSc
University of Birmingham, UK

WCRF/AICR Report
Executive Team
Marilyn Gentry
President
WCRF Global Network
Kelly Browning
Chief Financial Officer
WCRF Global Network
Kate Allen PhD
Director
WCRF International
Kathryn L Ward
Senior Vice-President
AICR
Deirdre McGinley-Gieser
WCRF International

Kate Coughlin BSc
Science Programme Manager
WCRF International
Cara James
Associate Director for
Research
AICR
From 2003 to 2005
Jennifer Kirkwood
Research Administration
Assistant
WCRF International
From 2003 to 2004
Anja Kroke MD PhD MPH
Consultant
University of Applied Sciences
Fulda, Germany
2002

Jeffrey R Prince PhD
Vice-President for Education
and Communications
AICR

Kayte Lawton
Research Administration
Assistant
WCRF International
From 2006 to 2007

Secretariat

Lisa Miles MSc
Science Programme Manager
WCRF International
From 2002 to 2006

Martin Wiseman FRCPFRCPathProject Director
WCRF International
Geoffrey Cannon
Chief Editor
WCRF International
Ritva R Butrum PhD
Senior Science Advisor
AICR
Greg Martin MB BCh MPH
Project Manager
WCRF International
Susan Higginbotham PhD
Director for Research
AICR
Steven Heggie PhD
Project Manager
WCRF International
From 2002 to 2006
Alison Bailey
Science Writer
Redhill, UK
Poling Chow BSc
Research Administration
Assistant
WCRF International

Sarah Nalty MSc
Science Programme Manager
WCRF International
Edmund Peston
Research Administration
Assistant
WCRF International
From 2004 to 2006

Ivana Vucenik PhD
Associate Director for
Research
AICR
Joan Ward
Research Administration
Assistant
WCRF International
From 2001 to 2003
Julia Wilson PhD
Science Programme Manager
WCRF International

Art & production
Chris Jones
Design and Art Director
Design4Science Ltd
London, UK
Emma Copeland PhD
Text Editor
Brighton, UK
Rosalind Holmes
Production Manager
London, UK
Mark Fletcher
Graphics
Fletcher Ward Design
London, UK
Ann O’Malley
Print Manager
AICR
Geoff Simmons
Design & Production Manager
WCRF UK

Serena Prince
Research Administration
Assistant
WCRF International
From 2004 to 2005
Melissa Samaroo
Research Administration
Assistant
WCRF International
From 2006 to 2007
Elaine Stone PhD
Science Programme Manager
WCRF International
From 2001 to 2006
Rachel Thompson PhD
RPHNutr
Review Coordinatorxiii

F O O D , N U T R I T I O N , P H Y S I C A L A C T I V I T Y, A N D T H E P R E V E N T I O N O F C A N C E R : A G L O B A L P E R S P E C T I V E

Summary
Introduction
This summary provides an abbreviated version of the full
Report. It highlights the wealth of information and data
studied by the Panel and is designed to give readers an
overview of the key issues contained within the Report,
notably the process, the synthesis of the scientific evidence,and the resulting judgements and recommendations.
T h e f i r s t a n d s e c o n d R e p o rt s
Food, Nutrition and the Prevention of Cancer: a global perspective, produced by the World Cancer Research Fund
together with the American Institute for Cancer Research,has been the most authoritative source on food, nutrition,and cancer prevention for 10 years. On publication in 1997,
it immediately became recognised as the most authoritativeand influential report in its field and helped to highlight theimportance of research in this crucial area. It became thestandard text worldwide for policy-makers in government
at all levels, for civil society and health professional organisations, and in teaching and research centres of academic
excellence.
Since the mid-1990s the amount of scientific literature on
this subject has dramatically increased. New methods ofanalysing and assessing evidence have been developed,
facilitated by advances in electronic technology. There ismore evidence, in particular on overweight and obesity andon physical activity; food, nutrition, physical activity, andcancer survivors is a new field. The need for a new report
was obvious; and in 2001 WCRF International in collaboration with AICR began to put in place a global process inorder to produce and publish the Report in November 2007.
H o w t h i s R e p o rt h a s b e e n a c h i e v e d
The goal of this Report is to review all the relevant research,using the most meticulous methods, in order to generate acomprehensive series of recommendations on food, nutrition, and physical activity, designed to reduce the risk ofcancer and suitable for all societies. This process is also thebasis for a continuous review of the evidence.
Organised into overlapping stages, the process has been
designed to maximise objectivity and transparency, separating the collection of evidence from its assessment andjudgement. First, an expert task force developed a method
for systematic review of the voluminous scientific literature.
Second, research teams collected and reviewed the literature based upon this methodology. Third, an expert Panel
has assessed and judged this evidence and agreed recommendations. The results are published in this Report andxivsummarised here. A more detailed explanation of thisprocess is given in Chapter 3 and the research teams andinvestigators involved are listed on pages viii–xi.
This Report is a guide to future scientific research, cancer
prevention education programmes, and health policy
around the world. It provides a solid evidence base forpolicy-makers, health professionals, and informed andinterested people to draw on and work with.

Overview of the second expert Report
This Report has a number of inter-related general purposes.
One is to explore the extent to which food, nutrition, physical activity, and body composition modify the risk of cancer, and to specify which factors are most important. To theextent that environmental factors such as food, nutrition,and physical activity influence the risk of cancer, it is a preventable disease. The Report specifies recommendations
based on solid evidence which, when followed, will be
expected to reduce the incidence of cancer.
P a r t 1 — B a c k g ro u n dChapter 1 shows that patterns of production and consumption of food and drink, of physical activity, and of bodycomposition have changed greatly throughout humanhistory. Remarkable changes have taken place as a resultof urbanisation and industrialisation, at first in Europe,
North America, and other economically advanced countries, and increasingly in most countries in the world.
Notable variations have been identified in patterns of cancer throughout the world. Significantly, studies consistently
show that patterns of cancer change as populations migratefrom one part of the world to another and as countries
become increasingly urbanised and industrialised. Projections indicate that rates of cancer in general are liable
to increase.
Chapter 2 outlines current understanding of the biologyof the cancer process, with special attention to the ways inwhich food and nutrition, physical activity, and body composition may modify the risk of cancer. Cancer is a diseaseof genes, which are vulnerable to mutation, especially overthe long human lifespan. However, evidence shows that
only a small proportion of cancers are inherited.
Environmental factors are most important and can be modified. These include smoking and other use of tobacco;
infectious agents; radiation; industrial chemicals and pollution; medication; and also many aspects of food, nutrition,
physical activity, and body composition.

S U M M A R Y

Chapter 3 summarises the types of evidence that thePanel has agreed are relevant to its work. No single study
or study type can prove that any factor definitely is a causeof, or is protective against, any disease. In this chapter,building on the work of the first report, the Panel showsthat reliable judgements on causation of disease are basedon assessment of a variety of well-designed epidemiological and experimental studies.
The prevention of cancer worldwide is one of the mostpressing challenges facing scientists and public healthpolicy-makers, among others. These introductory chaptersshow that the challenge can be effectively addressed andsuggest that food, nutrition, physical activity, and bodycomposition play a central part in the prevention of cancer.
P a rt 2 — E v i d e n c e a n d J u d g e m e n t s
The judgements made by the Panel in Part 2 are based on
independently conducted systematic reviews of the literature commissioned from academic institutions in the USA,UK, and continental Europe. The evidence has been meticulously assembled and, crucially, the display of the evidence was separated from assessments derived from that
evidence. Seven chapters present the findings of thesereviews. The Panel’s judgements are displayed in the formof matrices that introduce five of these chapters, and in thesummary matrix on the fold-out page inside the back cover.
Chapter 4, the first and longest chapter in Part 2, is concerned with types of food and drink. The judgements of the
Panel are, whenever possible, food- and drink-based,reflecting the most impressive evidence. Findings on
dietary constituents and micronutrients (for example foods
containing dietary fibre) are identified where appropriate.
Evidence on dietary supplements, and on patterns of diet,is included in the two final sections of this chapter.
Chapters 5 and 6 are concerned with physical activity
and with body composition, growth, and development.
Evidence in these areas is more impressive than was thecase up to the mid-1990s; the evidence on growth anddevelopment indicates the importance of an approach tothe prevention of cancer that includes the whole life
course.
Chapter 7 summarises and judges the evidence asapplied to 17 cancer sites, with additional briefer summaries based on narrative reviews of five further body systems and cancer sites. The judgements shown in thematrices in this chapter correspond with the judgements
shown in the matrices in the previous chapters.
Obesity is or may be a cause of a number of cancers.
Chapter 8 identifies what aspects of food, nutrition, andphysical activity themselves affect the risk of obesity andassociated factors. The judgements, which concern the biological and associated determinants of weight gain, overweight, and obesity, are based on a further systematic
literature review, amplified by knowledge of physiologicalprocesses.
The relevance of food, nutrition, physical activity, andbody composition to people living with cancer, and to theprevention of recurrent cancer, is summarised in Chapter 9.
Improved cancer screening, diagnosis, and medical services
are, in many countries, improving survival rates. So thenumber of cancer survivors — people living after diagnosisof cancer — is increasing.
The Panel agreed that its recommendations should also
take into account findings on the prevention of other chronic diseases, and of nutritional deficiencies and nutritionrelated infectious diseases, especially of childhood. Chapter
10, also based on a systematic literature review, is a summary of the findings of expert reports in these areas.
The research issues identified in Chapter 11 are, in theview of the Panel, the most promising avenues to explore inorder to refine understanding of the links between food,nutrition, physical activity, and cancer, and so improve theprevention of cancer, worldwide.
P a rt 3 — R e c o m m e n d a t i o n s
Chapter 12, the culmination of the five-year process, presents the Panel’s public health goals and personal recommendations. These are preceded by a statement of theprinciples that have guided the Panel in its thinking.
The goals and recommendations are based on ‘convincing’ or ‘probable’ judgements made by the Panel in the chapters in Part 2. These are proposed as the basis for public
policies and for personal choices that, if effectively implemented, will be expected to reduce the incidence of cancer
for people, families, and communities.
Eight general and two special goals and recommendations are detailed. In each case a general recommendation
is followed by public health goals and/or personal recommendations, together with further explanation or clarification as required. Chapter 12 also includes a summary of theevidence, justification of the goals and recommendations,and guidance on how to achieve them.
The process of moving from evidence to judgements andto recommendations has been one of the Panel’s main
responsibilities, and has involved discussion and debate
until final agreement has been reached. The goals and recommendations here have been unanimously agreed.
The goals and recommendations are followed by thexv

F O O D , N U T R I T I O N , P H Y S I C A L A C T I V I T Y, A N D T H E P R E V E N T I O N O F C A N C E R : A G L O B A L P E R S P E C T I V E

Panel’s conclusions on the dietary patterns most likely toprotect against cancer. In order to discern the ‘big picture’ ofhealthy and protective diets, it is necessary to integrate avast amount of detailed information. The Panel used a
broad, integrative approach that, while largely derived fromconventional ‘reductionist’ research, has sought to find patterns of food and drink consumption, of physical activity,and of body fatness, that enable recommendations designed
to prevent cancer at personal and population levels.
The goals and recommendations are designed to be generally relevant worldwide and the Panel recognises that innational settings, the recommendations of this Report will
be best used in combination with recommendations, issued
by governments or on behalf of nations, designed to prevent
chronic and other diseases. In addition, the Panel cited
three specific cases where the evidence is strong enough tobe the basis for goals and recommendations, but which currently are relevant only in discrete geographical regions:maté in Latin America, Cantonese-style salted fish in thePearl River Delta in Southern China, and arsenic contaminating water supplies in several locations. Further details on
nutritional patterns and regional and special circumstances
can be found in section 12.3.
The main focus of this Report is on nutritional and otherbiological and associated factors that modify the risk of cancer. The Panel is aware that as with other diseases, the riskof cancer is also modified by social, cultural, economic, andecological factors. Thus the foods and drinks that people
consume are not purely because of personal choice; likewise
opportunities for physical activity can be constrained.
Identifying the deeper factors that affect cancer risk enables
a wider range of policy recommendations and options to be
identified. This is the subject of a separate report to be published in late 2008.
The public health goals and personal recommendations of
the Panel that follow are offered as a significant contribution towards the prevention and control of cancer throughout the world.

xvi

The Panel’s recommendations
The Panel’s goals and recommendations that follow are
guided by several principles, the details of which can befound in Chapter 12. The public health goals are forpopulations, and therefore for health professionals; therecommendations are for people, as communities, families,
and individuals.
The Panel also emphasises the importance of not smoking
and avoiding exposure to tobacco smoke.
Format
The goals and recommendations begin with a general statement. This is followed by the population goal and the personal recommendation, together with any necessary
footnotes. These footnotes are an integral part of therecommendations. The full recommendations, including
further clarification and qualification, can be found in
Chapter 12.

S U M M A R Y

RECOMMENDATION 1

RECOMMENDATION 2

B O D Y FAT N E S SPHYSICAL ACTIVITY

Be as lean as possible withint h e n o rm a l r a n g e1 o f b o d y w e i g h t

B e p h y s i c a l l y a c t i v e a s p a rt o f e v e ry d a y l i f e
PUBLIC HEALTH GOALSPUBLIC HEALTH GOALS
The proportion of the population that is sedentary1
to be halved every 10 years

Median adult body mass index (BMI) to be
between 21 and 23, depending on thenormal range for different populations2Average physical activity levels (PALs)1 to be above 1.6

The proportion of the population that is overweightor obese to be no more than the current level,or preferably lower, in 10 years

PERSONAL RECOMMENDATIONS
Be moderately physically active, equivalent
to brisk walking,2 for at least 30 minutes every day

PERSONAL RECOMMENDATIONS
As fitness improves, aim for 60 minutes or moreof moderate, or for 30 minutes or more ofvigorous, physical activity every day2 3

Ensure that body weight throughchildhood and adolescent growth projects3 towards thelower end of the normal BMI range at age 21

Limit sedentary habits such as watching television
Maintain body weight within
the normal range from age 21
1

Avoid weight gain and increases inwaist circumference throughout adulthood
1‘Normal range’ refers to appropriate ranges issued by national governments or
the World Health Organization
2
To minimise the proportion of the population outside the normal range
3‘Projects’ in this context means following a pattern of growth (weight andheight) throughout childhood that leads to adult BMI at the lower end of thenormal range. Such patterns of growth are specified in International Obesity
Task Force and WHO growth reference charts

Justification
Maintenance of a healthy weight throughout life may be
one of the most important ways to protect against cancer.
This will also protect against a number of other common
chronic diseases.

Weight gain, overweight, and obesity are now generally
much more common than in the 1980s and 1990s. Rates ofoverweight and obesity doubled in many high-income countries between 1990 and 2005. In most countries in Asia andLatin America, and some in Africa, chronic diseases including obesity are now more prevalent than nutritional deficiencies and infectious diseases.
Being overweight or obese increases the risk of some cancers. Overweight and obesity also increase the risk of conditions including dyslipidaemia, hypertension and stroke, type2 diabetes, and coronary heart disease. Overweight in childhood and early life is liable to be followed by overweight
and obesity in adulthood. Further details of evidence andjudgements can be found in Chapters 6 and 8. Maintenanceof a healthy weight throughout life may be one of the mostimportant ways to protect against cancer.

The term ‘sedentary’ refers to a PAL of 1.4 or less. PAL is a way of representing
the average intensity of daily physical activity. PAL is calculated as total energy
expenditure as a multiple of basal metabolic rate2
Can be incorporated in occupational, transport, household, or leisure activities
3
This is because physical activity of longer duration or greater intensity is more
beneficial

Justification
Most populations, and people living in industrialised andurban settings, have habitual levels of activity below levels
to which humans are adapted.

With industrialisation, urbanisation, and mechanisation,
populations and people become more sedentary. As withoverweight and obesity, sedentary ways of life have been
usual in high-income countries since the second half of the20th century. They are now common if not usual in mostcountries.
All forms of physical activity protect against some cancers, as well as against weight gain, overweight, and obesity; correspondingly, sedentary ways of life are a cause of
these cancers and of weight gain, overweight, and obesity.
Weight gain, overweight, and obesity are also causes ofsome cancers independently of the level of physical activity.
Further details of evidence and judgements can be found in
Chapters 5, 6, and 8.
The evidence summarised in Chapter 10 also shows thatphysical activity protects against other diseases and thatsedentary ways of life are causes of these diseases.

xvii

F O O D , N U T R I T I O N , P H Y S I C A L A C T I V I T Y, A N D T H E P R E V E N T I O N O F C A N C E R : A G L O B A L P E R S P E C T I V ERECOMMENDATION 3RECOMMENDATION 4

F O O D S A N D D R I N K S T H AT
PROMOTE WEIGHT GAIN

PLANT FOODSEat mostly foods of plant origin

L i m i t c o n s u m p t i o n o f e n e rg y - d e n s e f o o d s1
Av o i d s u g a r y d r i n k s 2

PUBLIC HEALTH GOALSPUBLIC HEALTH GOALS

Population average consumption of non-starchy1
vegetables and of fruits to be at least 600 g (21 oz) daily2

Average energy density of diets3 to be lowered
towards 125 kcal per 100 g

Relatively unprocessed cereals (grains) and/or pulses(legumes), and other foods that are a natural source of
dietary fibre, to contribute to a population averageof at least 25 g non-starch polysaccharide daily

Population average consumption of sugary drinks2
to be halved every 10 years

PERSONAL RECOMMENDATIONSPERSONAL RECOMMENDATIONS
Eat at least five portions/servings(at least 400 g or 14 oz) of a variety2 of
non-starchy vegetables and of fruits every day

Consume energy-dense foods1 4 sparingly
Avoid sugary drinks2

Eat relatively unprocessed cereals (grains)
and/or pulses (legumes) with every meal3

Consume ‘fast foods’5 sparingly, if at all
1

Energy-dense foods are here defined as those with an energy content of morethan about 225–275 kcal per 100 g
2This principally refers to drinks with added sugars. Fruit juices should also be
limited
3This does not include drinks
4
Limit processed energy-dense foods (also see recommendation 4). Relatively
unprocessed energy-dense foods, such as nuts and seeds, have not been shownto contribute to weight gain when consumed as part of typical diets, and theseand many vegetable oils are valuable sources of nutrients
5
The term ‘fast foods’ refers to readily available convenience foods that tend to
be energy-dense and consumed frequently and in large portions

Justification
Consumption of energy-dense foods and sugary drinks isincreasing worldwide and is probably contributing to theglobal increase in obesity.

This overall recommendation is mainly designed to preventand to control weight gain, overweight, and obesity.
Further details of evidence and judgements can be found in
Chapter 8.
‘Energy density’ measures the amount of energy (in kcal
or kJ) per weight (usually 100 g) of food. Food supplies thatare mainly made up of processed foods, which often contain
substantial amounts of fat or sugar, tend to be more energydense than food supplies that include substantial amountsof fresh foods. Taken together, the evidence shows that it is
not specific dietary constituents that are problematic, somuch as the contribution these make to the energy densityof diets.
Because of their water content, drinks are less energydense than foods. However, sugary drinks provide energy
but do not seem to induce satiety or compensatory reduction in subsequent energy intake, and so promote overconsumption of energy and thus weight gain.

xviii

Limit refined starchy foods
People who consume starchy roots or tubers4
as staples also to ensure intake of sufficientnon-starchy vegetables, fruits, and pulses (legumes)
1This is best made up from a range of various amounts of non-starchy vegetables
and fruits of different colours including red, green, yellow, white, purple, andorange, including tomato-based products and allium vegetables such as garlic
2
Relatively unprocessed cereals (grains) and/or pulses (legumes) to contributeto an average of at least 25 g non-starch polysaccharide daily
3
These foods are low in energy density and so promote healthy weight
4
For example, populations in Africa, Latin America, and the Asia-Pacific region

Justification
An integrated approach to the evidence shows that mostdiets that are protective against cancer are mainly made up
from foods of plant origin.

Higher consumption of several plant foods probably protects
against cancers of various sites. What is meant by ‘plantbased’ is diets that give more emphasis to those plant foods
that are high in nutrients, high in dietary fibre (and so in nonstarch polysaccharides), and low in energy density. Nonstarchy vegetables, and fruits, probably protect against somecancers. Being typically low in energy density, they probably
also protect against weight gain. Further details of evidence
and judgements can be found in Chapters 4 and 8.
Non-starchy vegetables include green, leafy vegetables,
broccoli, okra, aubergine (eggplant), and bok choy, but not,for instance, potato, yam, sweet potato, or cassava. Nonstarchy roots and tubers include carrots, Jerusalem artichokes, celeriac (celery root), swede (rutabaga), and turnips.
Continued on next page

S U M M A R Y

RECOMMENDATION 5RECOMMENDATION 6ANIMAL FOODS

ALCOHOLIC DRINKS

L i m i t i n t a k e o f re d m e a t 1 a n d

L i m i t a l c o h o l i c d r i n k s1

a v o i d p ro c e s s e d m e a t 2

PUBLIC HEALTH GOAL

PUBLIC HEALTH GOAL

Proportion of the population drinking
more than the recommended limits to be
reduced by one third every 10 years1 2

Population average consumption of red meat
to be no more than 300 g (11 oz) a week,
very little if any of which to be processed

PERSONAL RECOMMENDATIONPERSONAL RECOMMENDATION

If alcoholic drinks are consumed,
limit consumption to no more than two drinks a day
for men and one drink a day for women1 2 3People who eat red meat1
to consume less than 500 g (18 oz) a week,
very little if any to be processed2
1

2‘Red meat’ refers to beef, pork, lamb, and goat from domesticated animals
including that contained in processed foods‘Processed meat’ refers to meat preserved by smoking, curing or salting, oraddition of chemical preservatives, including that contained in processed foods

Justification
An integrated approach to the evidence also shows thatmany foods of animal origin are nourishing and healthy if
consumed in modest amounts.

People who eat various forms of vegetarian diets are at low
risk of some diseases including some cancers, although it is
not easy to separate out these benefits of the diets fromother aspects of their ways of life, such as not smoking,drinking little if any alcohol, and so forth. In addition, meatcan be a valuable source of nutrients, in particular protein,iron, zinc, and vitamin B12. The Panel emphasises that thisoverall recommendation is not for diets containing no meat— or diets containing no foods of animal origin. The
amounts are for weight of meat as eaten. As a rough conversion, 300 g of cooked red meat is equivalent to about
400–450 g raw weight, and 500 g cooked red meat to about
700–750 g raw weight. The exact conversion will dependon the cut of meat, the proportions of lean and fat, and themethod and degree of cooking, so more specific guidance is
not possible. Red or processed meats are convincing or
probable causes of some cancers. Diets with high levels ofanimal fats are often relatively high in energy, increasing
the risk of weight gain. Further details of evidence andjudgements can be found in Chapters 4 and 8.

Recommendation 4, continued from page xviii

The goals and recommendations here are broadly similar
to those that have been issued by other international andnational authoritative organisations (see Chapter 10). They
derive from the evidence on cancer and are supported byevidence on other diseases. They emphasise the importance1

This recommendation takes into account that there is a likely protective effectfor coronary heart disease2Children and pregnant women not to consume alcoholic drinks
3
One ‘drink’ contains about 10–15 grams of ethanol

Justification
The evidence on cancer justifies a recommendation not todrink alcoholic drinks. Other evidence shows that modest
amounts of alcoholic drinks are likely to reduce the risk ofcoronary heart disease.

The evidence does not show a clear level of consumption of
alcoholic drinks below which there is no increase in risk of
the cancers it causes. This means that, based solely on theevidence on cancer, even small amounts of alcoholic drinks
should be avoided. Further details of evidence and judgements can be found in Chapter 4. In framing the recommendation here, the Panel has also taken into account theevidence that modest amounts of alcoholic drinks are likely
to protect against coronary heart disease, as described in
Chapter 10.
The evidence shows that all alcoholic drinks have thesame effect. Data do not suggest any significant difference
depending on the type of drink. This recommendation
therefore covers all alcoholic drinks, whether beers, wines,
spirits (liquors), or other alcoholic drinks. The importantfactor is the amount of ethanol consumed.
The Panel emphasises that children and pregnant womenshould not consume alcoholic drinks.

of relatively unprocessed cereals (grains), non-starchy vegetables and fruits, and pulses (legumes), all of which contain
substantial amounts of dietary fibre and a variety of
micronutrients, and are low or relatively low in energy density. These, and not foods of animal origin, are the recommended centre for everyday meals.

xix

F O O D , N U T R I T I O N , P H Y S I C A L A C T I V I T Y, A N D T H E P R E V E N T I O N O F C A N C E R : A G L O B A L P E R S P E C T I V ERECOMMENDATION 7RECOMMENDATION 8

P R E S E R VAT I O N , P R O C E S S I N G ,P R E PA R ATIOND I E TA R Y S U P P L E M E N T S
Aim to meet nutritional needst h ro u g h d i e t a l o n e 1

L i m i t c o n s u m p t i o n o f s a l t1
A v o i d m o u l d y c e re a l s ( g r a i n s ) o r p u l s e s ( l e g u m e s )PUBLIC HEALTH GOAL
PUBLIC HEALTH GOALS

Maximise the proportion of the population achieving
nutritional adequacy without dietary supplements

Population average consumption of salt fromall sources to be less than 5 g (2 g of sodium) a day

PERSONAL RECOMMENDATION

Proportion of the population consuming more than 6 gof salt (2.4 g of sodium) a day to be halved every 10 years
Minimise exposure to aflatoxinsfrom mouldy cereals (grains) or pulses (legumes)

Dietary supplements are not recommended
for cancer prevention
1

This may not always be feasible. In some situations of illness or dietary
inadequacy, supplements may be valuable

PERSONAL RECOMMENDATIONS
Avoid salt-preserved, salted, or salty foods;
preserve foods without using salt1
Limit consumption of processed foods with added salt
to ensure an intake of less than 6 g (2.4 g sodium) a day
Do not eat mouldy cereals (grains) or pulses (legumes)
1

Methods of preservation that do not or need not use salt include refrigeration,
freezing, drying, bottling, canning, and fermentation

Justification
The strongest evidence on methods of food preservation, processing, and preparation shows that salt and salt-preserved
foods are probably a cause of stomach cancer, and that foods
contaminated with aflatoxins are a cause of liver cancer.

Salt is necessary for human health and life itself, but at levels very much lower than those typically consumed in mostparts of the world. At the levels found not only in highincome countries but also in those where traditional diets
are high in salt, consumption of salty foods, salted foods,
and salt itself is too high. The critical factor is the overall
amount of salt. Microbial contamination of foods and drinks
and of water supplies remains a major public health problem worldwide. Specifically, the contamination of cereals(grains) and pulses (legumes) with aflatoxins, produced bysome moulds when such foods are stored for too long inwarm temperatures, is an important public health problem,and not only in tropical countries.
Salt and salt-preserved foods are a probable cause ofsome cancers. Aflatoxins are a convincing cause of liver cancer. Further details of evidence and judgements can befound in Chapter 4.

xx

Justification
The evidence shows that high-dose nutrient supplements
can be protective or can cause cancer. The studies that
demonstrate such effects do not relate to widespread use
among the general population, in whom the balance ofrisks and benefits cannot confidently be predicted. A general recommendation to consume supplements for cancer
prevention might have unexpected adverse effects.
Increasing the consumption of the relevant nutrients
through the usual diet is preferred.

The recommendations of this Report, in common with its
general approach, are food based. Vitamins, minerals, andother nutrients are assessed in the context of the foods anddrinks that contain them. The Panel judges that the bestsource of nourishment is foods and drinks, not dietary supplements. There is evidence that high-dose dietary supplements can modify the risk of some cancers. Although somestudies in specific, usually high-risk, groups have shown evidence of cancer prevention from some supplements, thisfinding may not apply to the general population. Their levelof benefit may be different, and there may be unexpected
and uncommon adverse effects. Therefore it is unwise torecommend widespread supplement use as a means of cancer prevention. Further details of evidence and judgements
can be found in Chapter 4.
In general, for otherwise healthy people, inadequacy of
intake of nutrients is best resolved by nutrient-dense dietsand not by supplements, as these do not increase consumption of other potentially beneficial food constituents. The
Panel recognises that there are situations when supplements
are advisable. See box 12.4.

S U M M A R Y

SPECIAL RECOMMENDATION 1

SPECIAL RECOMMENDATION 2

BREASTFEEDINGC A N C E R S U R V I V O R S1

M o t h e r s t o b re a s t f e e d ; c h i l d re n t o b e b re a s t f e d 1

F o l l o w t h e re c o m m e n d a t i o n s
f o r c a n c e r p re v e n t i o n 2

PUBLIC HEALTH GOAL
RECOMMENDATIONS
The majority of mothers to breastfeed
exclusively, for six months2 3All cancer survivors3 to receive nutritional carefrom an appropriately trained professional

PERSONAL RECOMMENDATION
If able to do so, and unless otherwise advised,
aim to follow the recommendations for
diet, healthy weight, and physical activity2

Aim to breastfeed infants exclusively2
up to six months and continue
with complementary feeding thereafter3
1

1

Breastfeeding protects both mother and child‘Exclusively’ means human milk only, with no other food or drink, includingwater3
In accordance with the UN Global Strategy on Infant and Young Child Feeding
2

Justification
The evidence on cancer as well as other diseases showsthat sustained, exclusive breastfeeding is protective for themother as well as the child.

This is the first major report concerned with the preventionof cancer to make a recommendation specifically on breastfeeding, to prevent breast cancer in mothers and to prevent
overweight and obesity in children. Further details of evidence and judgements can be found in Chapters 6 and 8.
Other benefits of breastfeeding for mothers and theirchildren are well known. Breastfeeding protects against
infections in infancy, protects the development of theimmature immune system, protects against other childhood
diseases, and is vital for the development of the bond
between mother and child. It has many other benefits.
Breastfeeding is especially vital in parts of the world wherewater supplies are not safe and where impoverished families do not readily have the money to buy infant formulaand other infant and young child foods. This recommendation has a special significance. While derived from the evidence on being breastfed, it also indicates that policies andactions designed to prevent cancer need to be directed
throughout the whole life course, from the beginning oflife.

Cancer survivors are people who are living with a diagnosis of cancer, including
those who have recovered from the disease2
This recommendation does not apply to those who are undergoing active
treatment, subject to the qualifications in the text
3
This includes all cancer survivors, before, during, and after active treatment

Justification
Subject to the qualifications made here, the Panel has
agreed that its recommendations apply also to cancer survivors. There may be specific situations where this advice
may not apply, for instance, where treatment has compromised gastrointestinal function.

If possible, when appropriate, and unless advised otherwise
by a qualified professional, the recommendations of thisReport also apply to cancer survivors. The Panel has madethis judgement based on its examination of the evidence,
including that specifically on cancer survivors, and also on
its collective knowledge of the pathology of cancer and its
interactions with food, nutrition, physical activity, and bodycomposition. In no case is the evidence specifically on cancer survivors clear enough to make any firm judgements orrecommendations to cancer survivors. Further details ofevidence and judgements can be found in Chapter 9.
Treatment for many cancers is increasingly successful,and so cancer survivors increasingly are living long enoughto develop new primary cancers or other chronic diseases.
The recommendations in this Report would also be expected to reduce the risk of those conditions, and so can also berecommended on that account.

xxi

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I n t ro d u c t i o n
The proposals that cancer might be preventable, and that
food, nutrition, physical activity, and body composition
might affect the risk of cancer, were first made before
science emerged in its modern form in the 19th and 20th
centuries. Throughout recorded history, wise choices offood and drink, and of habitual behaviour, have been
recommended to protect against cancer, as well as otherdiseases, and to improve well-being.
Reports such as this, which incorporate systematic
examination of all relevant types of research, differ fromancient, historical, and even relatively recent accounts, anddescriptive studies of the type detailed in Chapter 1, notonly in the quantity and quality of evidence, but also in thereliability of the judgements and recommendations thatderive from it.
T h e p u r p o s e o f t h i s R e p o rtThis Report has been commissioned and resourced by theWorld Cancer Research Fund (WCRF) International and its
sister organisation the American Institute for Cancer
Research (AICR), who provided the Secretariat that has
supported the Panel responsible for the Report. Panelmembers, observers, review centres, and other contributors
are listed on the preceding pages. The five-year project thathas resulted in this Report follows a previous five-year
project that resulted in the first WCRF/AICR reportpublished in 1997, which was the responsibility of theformer distinguished international multidisciplinary panel
chaired by Professor John Potter.
This Report has two overall general purposes. The first is
to summarise, assess, and judge the most comprehensive
body of evidence yet collected and displayed on the subjectof food, nutrition, physical activity, body composition, andthe risk of cancer, throughout the life-course. The second
purpose is to transform the evidence-derived judgements
into goals and personal recommendations that are areliable basis for sound policies and effective actions at
population, community, family, and individual level, inorder to prevent cancer, worldwide.
W h a t i s a l re a d y k n o w n

The Panel is aware of the general consensus shared byscientists, health professionals, and policy-makers on therelationships between food, nutrition, physical activity,
body composition, and the risk of cancer.
This consensus, based on the findings of a rapidly
growing mass of increasingly well-designed
epidemiological and experimental studies and otherrelevant evidence, emerged in the early 1980s. Thus: ‘It isxxiiabundantly clear that the incidence of all the common
cancers in humans is determined by various potentiallycontrollable external factors. This is surely the most
comforting fact to come out of cancer research, for itmeans that cancer is, in large part, a preventable disease’.1
This is the conclusion of a report on diet and theprevention of cancer published a quarter of a century
before this Report.
Since the early 1980s, relevant United Nations agencies,
national governments, authoritative non-governmentalorganisations, and researchers and other experts in thefield have agreed that food and nutrition, physical activity,and body composition are individually and collectively
important modifiers of the risk of cancer, and taken
together may be at least as important as tobacco.
By the mid-1990s the general consensus became more
solidly based on methodical assessment of the totality of
the relevant literature. Thus: ‘It is now established thatcancer is principally caused by environmental factors, ofwhich the most important are tobacco; diet and factors
related to diet, including body mass and physical activity;and exposures in the workplace and elsewhere.’ This
statement introduces the recommendations made in thefirst WCRF/AICR report.
Expert reports may be accompanied by guidebooks
written for general readers. Thus: ‘A healthy eating
strategy… is an important part of protecting yourself
against a long list of diseases. These include heart disease,stroke, several common cancers, cataract formation, otherage-related diseases, and even some types of birth defects.
When combined with not smoking and regular exercise, thiskind of healthy diet can reduce heart disease by 80 per
cent, and stroke and some cancers by 70 percent, comparedwith average rates’.2 This is a conclusion of a book written
by a member of the Panel responsible for this Report.
Some general judgements are now well known and not amatter for serious debate. Cancer in general, and cancers
of different types and sites, are agreed to have various
causes, among which are inherited genetic predisposition
and the increasing likelihood that cells will accumulate
genetic defects as people age. This is discussed in moredetail in Chapter 2. Also, people die less frequently fromnutritional deficiencies, infectious diseases, predation, andaccidents, whereas chronic diseases including cancer —which are more common in older people — become morecommon.
However, cancer is not an inevitable consequence ofageing, and people’s susceptibility to it varies. There isabundant evidence that the main causes of patterns of

I N T R O D U C T I O N

cancer around the world are environmental. This does
indeed mean that at least in principle, most cancer ispreventable, though there is still discussion about therelative importance of various environmental factors.
But what are these environmental factors, what is theirrelative importance, and how may they vary in different
times in the life-course and in different parts of the world,and how might they interact with each other? Many
thousand epidemiological and experimental studies havelooked for answers. Some answers are now agreed to beunequivocal. Thus, smoking is the chief cause of lungcancer. Alcohol is also an established carcinogen inhumans, as are types of radiation such as those used in
medical treatments and as released by nuclear weapons
and accidents. Certain infectious agents are undoubtedly acause of some cancers.
The need for a new initiative

Many questions, particularly in the field of food, nutrition,
and associated factors, remain. Some are fundamental. Do
statements such as those quoted above remain valid? Do
they apply worldwide? Have the reviews and reports so far
published overlooked key findings? How do the large
prospective studies, meta-analyses, pooling projects, andrandomised controlled trials undertaken and publishedsince the mid-1990s impact on earlier conclusions andrecommendations? Are there areas in this field that havebeen neglected? Is entirely new evidence coming to light?
Questions such as these led to the commissioning of thisReport by WCRF/AICR in 2001. The Panel responsible for
the Report first convened in 2003, and has met twice ayear until 2007. The terms of reference accepted by the
Panel at its first meeting were to:• Judge the reviews of the scientific and other literature
prepared for the Panel by the assigned review teams• Devise a series of dietary, associated, and otherrecommendations suitable for all societies, designed toreduce the risk of cancer• Evaluate the consistency between such
recommendations and those designed to prevent otherfood-related diseases.
The Panel believes that these terms of reference have been
fulfilled. The public policy implications of therecommendations made in this Report are the subject of afurther report, to be published in late 2008.

S p e c i a l f e a t u re s o f t h i s R e p o r t

This Report in part adapts and builds on the work of theprevious WCRF/AICR report. It also has central featuresthat are new. It is not simply an ‘update’ of the previous
report. Since the mid-1990s a substantial body of relevant
literature has been published in peer-reviewed journals.
Further, the executive officers of WCRF/AICR, its
Secretariat, and the Panel responsible, decided at theoutset that developments in scientific method since themid-1990s, notably in systematic approaches tosynthesising evidence, and as enabled by the electronic
revolution, have been so remarkable that a whole newprocess was justified.
Systematic literature reviews
This process (described in Appendix A) has involved
systematic literature reviews (SLRs), which have been usedas the main basis for the Panel’s judgements in this Report.
These are described in more detail in Chapter 3. They were
undertaken by independent centres of research and review
excellence in North America and Europe, to a common
agreed protocol, itself the product of an expert
Methodology Task Force. As a result, the judgements of the
Panel now are as firmly based as the evidence and the stateof the science allow. Some are new. Some are different
from those previously published. Findings that may at firstreading seem to repeat those of the first report are in fact
the result of an entirely new process.
Rigorous criteria to assess evidence
The criteria used in this Report to assess the evidence
presented in the SLRs and from other sources are more
precise and explicit than, and in some respects different
from and more stringent than, those used in the previous
report. During its initial meetings, the Panel reviewed andagreed these criteria before embarking on the formal
evidence review. More details are given in Chapter 3.
Nevertheless, readers and users of this Report should be
able to see how and why the development of scientificmethod and research since the mid-1990s has resulted inconclusions and recommendations here that sometimes
vary from, sometimes are much the same as, andsometimes reinforce those of the previous Report.
Graphic display of Panel judgements
The Panel has retained the matrix technique of displaying
its judgements, which introduce the chapters and chapter
sections throughout Part 2 of this Report. This technique,pioneered in the first report, has been adapted by thexxiiiF O O D , N U T R I T I O N , P H Y S I C A L A C T I V I T Y, A N D T H E P R E V E N T I O N O F C A N C E R : A G L O B A L P E R S P E C T I V EWorld Health Organization in its 2003 report on diet,nutrition, and the prevention of chronic diseases. Some
members of the expert consultation responsible for the
WHO report, including its chair and vice-chair, have served
as members of the Panel responsible for this Report.
In further adapting the format of the matrices used in
the first report, the Panel was careful to distinguishbetween evidence strong enough to justify judgements ofconvincing or probable causal relationships, on which
recommendations designed to prevent cancer can bebased, and evidence that is too limited in amount,consistency, or quality to be a basis for public and personal
health recommendations, but which may nevertheless insome cases be suggestive of causal relationships.
Food-based approach
Since the 1990s a broad food- and drink-based approach tointerpreting the evidence on food, nutrition, and the risk ofcancer has increasingly been used, in contrast to theoverwhelming research emphasis on individual foodconstituents. The previous report included three chaptersshowing the findings on dietary constituents (including‘energy and related factors’, notably physical activity),
foods and drinks, and food processing (meaningproduction, preservation, processing, and preparation), inthat order.
This Report has taken a food-based approach, as shown
throughout Chapter 4, more closely reflecting the nature of
the evidence. Thus many findings on dietary constituentsand micronutrients, when their dietary sources are fromfoods rather than supplements, are here identified as, forexample, findings on ‘foods containing dietary fibre’ or‘foods containing folate’. Findings on methods of foodprocessing are, wherever possible, shown as part of theevidence on the associated foods, so that, for example,
meat processing is integrated with the evidence on meat.
The evidence and judgements focused on cancer are
summarised and displayed in Chapter 7.
Physical activity
The scope of the work of this Panel is wider than that ofthe previous panel. The previous report judged that theevidence that physical activity protects against cancer ofthe colon was convincing. Since then evidence on physicalactivity (and physical inactivity, especially when thisamounts to generally sedentary ways of life) has become
more impressive. Correspondingly, the review centres wererequested specifically to examine the literature on physicalactivity (and inactivity) as well as on foods and drinks. The
results of this work, and the Panel’s judgements, are shownin Chapter 5.
Body fatness
As with physical inactivity, the evidence that body fatness— including degrees of fatness throughout the range ofbody weight, from underweight and normal to overweight
and obesity, as well as any specific effect of weight gain —directly influences risk of some cancers has also become
more impressive. The previous report judged that thexxivevidence that greater body fatness (there termed ‘highbody mass’) is a convincing or probable cause of cancers of
the endometrium, breast (postmenopausal), and kidney.
For this Report, the commissioned SLRs not only included
the evidence linking body fatness directly with cancer, but
a separate review was also commissioned specifically on
the biological and associated determinants of body fatness
itself. The evidence and the Panel’s judgements, which
include assessment of the physiology of energy
metabolism, are summarised in Chapters 6 and 8.
The Panel is aware that weight gain, overweight, andobesity, and their antecedent behaviours, are criticallydetermined by social, cultural, and other environmental
factors. This is one topic for the separate report on policy
implications to be published in late 2008.
Cancer survivors
There are increasing numbers of cancer survivors — people
who have at some time been diagnosed with cancer. Whatshould those people living with cancer do? Particularly
since the 1990s, this question is being asked increasingly,
as more and more people are diagnosed with and treatedfor cancer, and are seeking ways in which they can add totheir medical or surgical management to help themselves
to remain healthy. Are the circumstances of people whohave recovered from cancer any different from those ofpeople who are free from cancer? Questions such as these
are addressed in Chapter 9.
Life-course approach
Unlike this Report, the reviews conducted for the firstreport did not consider the literature on food and nutritionin the first two years of life. Increasingly, evidence isaccumulating on the importance of early life-events onlater health. Evidence and judgements on the impact ofbirth weight and adult attained height on cancer risk arepresented in Chapter 6, though the detailed processes
underpinning these associations with cancer risk are notyet clear. Findings on the relationship between not beingbreastfed and later overweight and obesity in children arereported in Chapter 8, and on lactation and lower breast
cancer risk in the mother are reported in Chapter 7. Thesefindings form part of a general ‘life-course’ approachsummarised in Chapter 2, reflecting an appreciation of theimportance of the accumulation of nutritional and otherexperiences throughout life, as well as genetic endowment,
in influencing susceptibility to disease.
Goals and recommendations
The Panel’s recommendations are set out in Chapter 12
and in abbreviated form in the Summary, on the preceding
pages.
The previous report agreed 14 recommendations. This
Report makes eight general and two special
recommendations for specific target groups. These are set
out in more detail than in the previous report. As before,
principles that guide the goals and recommendations are
set out. The recommendations themselves are displayed inboxes and are accompanied by text that justifies them, andI N T R O D U C T I O N

by practical guidance. The recommendations are addressedto people, as members of communities and families andalso as individuals.
Recommendations and options addressed to UN andother international organisations, national governments,
industry, health professional and civil society organisations,and the media are set out in the separate report on policy
implications, to be published in late 2008.

scale this represents over 3 to 4 million cases of cancer thatcan be prevented in these ways, every year.
In many of its forms, cancer is a disease that can cause
great suffering and claims many lives. The overallcommitment of scientists and other professionals
committed to disease prevention, as exemplified by thisReport, is to reduce the rates not just of cancer, but of all
diseases, so that more people enjoy good health until they
eventually die in old age.

A note of caution

The Panel is confident that its findings are soundly based,
and that its recommendations, when translated into
effective public policy programmes and personal choices,
will reduce the risk of cancer. That said, the available
evident is imperfect. The Panel’s conclusions derive fromthe best evidence now available, which reflects past andrecent research priorities mostly in high-income countries,
though synthesised and judged in as meticulous andrigorous way as possible. What is here is therefore an
incomplete picture.
The tendency of reports such as this is to consider
diseases in isolation. In the case of this Report, therelationship of weight gain, overweight, and obesity on therisk of some cancers is so clear that determinants of thesefactors have also been considered. But the Panel agrees, asevident in Chapters 10 and 12, that many chronic diseases,
including type 2 diabetes and its precursors, cardiovasculardiseases and their precursors, and also perhaps otherdiseases of the digestive, musculoskeletal, and nervous
systems, are to a large extent caused by environmental
factors, including inappropriate food and nutrition,
physical inactivity, overweight and obesity, and associatedfactors. Following from this, future reports should consider
the promotion of health and the prevention of disease as awhole.

R e f e re n c e s
National Research Council. Diet, Nutrition and Cancer. Washington
DC: National Academy of Sciences, 1982
2.
Willett W. Summary. In: Eat, Drink, and Be Healthy. The Harvard
Medical School Guide to Healthy Eating. New York: Free Press, 2003
3.
Doll R, Peto R. The causes of cancer: quantitative estimates of
avoidable risks of cancer in the United States today. J Natl Cancer Inst
1981;66:1191-308.
1.

H o w m u c h c a n c e r i s p re v e n t a b l e ?

As shown in its title, the purpose of this Report is toprevent cancer. The term ‘prevention’ needs definition. It
does not mean the elimination of cancer. It means
reduction in its occurrence, such that at any age fewer
people have cancer than otherwise would be the case.
If all factors are taken into account, cancer is mostly apreventable disease. The authors of a landmark study
published in the early 1980s concluded: ‘It is highly likelythat the United States will eventually have the option of
adopting a diet that reduces its incidence of cancer byapproximately one third, and it is absolutely certain that
another one third could be prevented by abolishingsmoking.’3 Cancers of some sites, notably of the colon, aregenerally agreed to be greatly or mostly affected by foodand nutrition.
Since then, authoritative estimates of the preventabilityof cancer by means of food and nutrition and associatedfactors have been in broad agreement with the ‘around one
third’ figure. The estimate of the previous WCRF/AICR
Report was that cancer is 30 to 40 per cent preventable
over time, by appropriate food and nutrition, regularphysical activity, and avoidance of obesity. On a globalxxv

Part 1

> V } À Õ  `Chapter 1
International variations and trends

4

Chapter 2
The cancer process

30

Chapter 3
Judging the evidence48

BACKGROUNDP A R T

1

Introduction to Part 1

This Report has a number of inter-related general purposes. One is to explore
the extent to which food, nutrition, physical activity, and body composition
modify the risk of cancer, and to specify as far as possible the importance ofspecific factors. To the extent that environmental factors such as food,nutrition, and physical activity influence risk of cancer, it is a preventabledisease. The Report specifies recommendations based on solid evidence
which, when followed, will be expected to reduce the incidence of cancer.
Part 1 of the Report begins with two chapters summarising the first lines ofevidence from observations of human populations, and from experimental
and basic science, pointing to the conclusion that cancer is preventable. The
third chapter summarises the types of evidence that are relevant in
identifying the causes of cancer, and explains the process used by the Panelto assess the strength of this evidence and to come to judgement.
Chapter 1 shows that patterns of production and consumption of food anddrink, of physical activity, and of body composition have changed greatly
throughout different periods of human history. Remarkable changes havetaken place as a result of urbanisation and industrialisation, at first in
Europe, North America, and other economically advanced countries, andincreasingly in most countries in the world.
With the establishment of reliable records in the second half of the 20th
century, notable variations have been identified in patterns of cancer
throughout the world. Some cancers, such as those of the upper
aerodigestive tract, stomach, liver, and cervix, are more common in lower
income countries; others, such as those of the colorectum, breast, ovary,
endometrium, prostate, and lung, are more common in higher income
countries.
More significant, as shown in Chapter 1, are studies consistently showingthat patterns of cancer change as populations migrate from one part of theworld to another and as countries become increasingly urbanised andindustrialised. Projections indicate that rates of cancer in general are liable
to increase.
Chapter 2 outlines current understanding of the biology of the cancer
process, with special attention given to the ways in which food andnutrition, physical activity, and body composition may modify it.
Cancer is a disease of genes, which are vulnerable to beneficial or harmful
mutation, especially over the long human lifespan. Nutritional factors areimportant in determining the likelihood of some mutations, as well as inchanging the functions of genes even without mutation. However, both
epidemiological and experimental evidence shows that only a small
proportion of cancers are inherited. Environmental factors are most2

important and can be modified. These include smoking and other use of
tobacco; infectious agents; radiation; industrial chemicals and pollution;
medication — and also many aspects of food, nutrition, physical activity, andbody composition. Essentially this is good news. It means that healthy
environments can stop cancer before it starts. The evidence also indicates thatsuch environments, including the factors that are the subject of this Report,
may be able to check the cancer process after it has started.
The third chapter summarises the types of evidence that the Panel has agreed
are relevant to its work. No one study can prove that any factor definitely is a
cause of or is protective against any disease. Also while some study designs
are more reliable than others, they often cannot be used to answer many typesof question; so no one kind of study, however careful its methods, can everproduce definitive results. In this chapter, building on the work of the firstreport, the Panel shows that all study designs have strengths and weaknesses,
and that reliable judgements on causation of disease are based on assessmentof a variety of well designed epidemiological and experimental studies.
The judgements made by the Panel in Part 2 of this Report are based on
independently commissioned and conducted systematic reviews of theliterature. This has ensured that the evidence has been assembled using
methods that are as meticulous as possible, and that the display of theevidence is separated from assessments derived from this evidence, which are
made in Part 2.
The prevention of cancer worldwide is one of the most pressing challenges
facing scientists and public health policy-makers, among others. These
introductory chapters show that the challenge can be effectively addressed.
They also suggest that food and nutrition, physical activity, and bodycomposition all play a central part in the prevention of cancer.

3

P A R T

C H A P T E RI•

B A C K G R O U N D

1International variations
and trends
The first lines of evidence suggesting that cancer isa largely preventable disease have come fromstudies noting variations in cancer incidence acrosstime and place. The most impressive initial evidence
showing that patterns of cancer are altered byenvironmental factors, and are not mainly
genetically determined, comes from studies
describing changes in the rates of different cancers
in genetically identical populations that migratefrom their native countries to other countries. Suchstudies consistently show that changes in the rates
of some of the most common cancers, including
those of the stomach, colorectum, breast, andprostate, can be remarkable, even over one or two
generations.
This first introductory chapter summarises current
knowledge of the variations in food, nutrition,
physical activity, body composition, and cancer indifferent parts of the world. This assessment
provides strong circumstantial evidence that
continues to prompt systematic studies includinginterventions of various types, and also reports suchas this, which collect and judge the available
evidence. Such systematic work has already led theUnited Nations and other international bodies,
national governments, and authoritative
independent organisations to be confident thatmost cancers are largely preventable.
Patterns of food and drink, of physical activity,and of body composition have changed remarkably
throughout human history. With industrialisation
and urbanisation, food supplies usually become
more secure, and more food is available for
consumption. In general, diets become more energy
dense, containing fewer starchy foods, more fats
and oils, sugars, and additives, and often more
alcoholic drinks. At the same time, patterns ofphysical activity change: populations become
increasingly sedentary, their need for energy fromfood drops, and rates of overweight and obesity
increase.
These changes correlate with changes in thepatterns of cancer throughout the world. Middleand low-income regions and countries within Africa,
Asia, and Latin America have generally experienced
comparatively high rates of cancers of the upper4

aerodigestive tract (of the mouth, pharynx, larynx,
nasopharynx, and oesophagus), and of the stomach,liver (primary), and cervix. Rates of some cancers,
especially stomach cancer, are now generally
decreasing.
In contrast, high-income countries, and urbanised
and industrialised areas of middle- and low-income
regions and countries, have higher rates ofcolorectal cancer and of hormone-related cancers (ofthe breast, ovary, endometrium, and prostate). Lungcancer is now the most common type in the world
because of the increase in tobacco smoking andexposure to environmental tobacco smoke. Rates ofthese cancers, some of which may have been
historically rare, are increasing.
Globally, the number of people with cancer is
projected to double by the year 2030, with most of
this increase likely to occur in middle- and lowincome countries. Such an increase would only
partly be accounted for by the projected rise in thesize and average age of the global population. This
makes the task of cancer prevention all the moreurgent and important.

C H A P T E R

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I N T E R N AT I O N A L

V A R I AT I O N SThis chapter outlines the historic, recent, and current variations and trends in food, nutrition, physical activity, overweight and obesity, and in patterns of cancer.
People’s diets reflect the times and situations in which theylive. It is only relatively recently in history that urban–industrial ways of life have evolved, with many or most people
living in towns and cities rather than in the countryside. In
much of Africa and Asia, most people still live in rural communities, and peasant–agricultural and urban–industrial
ways of life still coexist in most countries. Such patternschange very rapidly as countries become increasingly
urbanised and industrialised.
The different food systems and diets that are part of thesediverse ways of life affect people’s levels of physical activity,
their body composition and stature, their life expectancy, andpatterns of disease, including cancer. With the move tourban–industrial ways of life, populations have become taller
and heavier, their life expectancy has increased, and they areusually adequately nourished (although poverty, and evendestitution, remains a major problem in most big cities). On
the other hand, urban populations are at increased risk ofchronic diseases such as obesity, type 2 diabetes, coronary
heart disease, and also some cancers.
This chapter also summarises some available informationon eight common cancers, irrespective of any recognised links
to food, nutrition, and physical activity; these factors are dealt
with later in the Report. Four are endemic in middle- and lowincome countries: cancers of the oesophagus, stomach, liver,and cervix. Four are endemic in high-income countries, andare in general increasing in middle- and low-income countries:
cancers of the lung, colon and rectum, breast, and prostate.
Information on the trends and projections of levels of physical activity, and overweight and obesity, is summarised.
Descriptive epidemiology, including studies of changing disease patterns in migrant populations, is covered. These studies can generate hypotheses about relationships between food,nutrition, physical activity, and the risk of cancer. However,they serve mainly as a foundation for studies that provide
stronger evidence.
The 12 national examples provided throughout this chapter summarise some of the trends in foods and drinks, obesity, physical activity, and cancer in countries around the world.
These are Egypt and South Africa (Africa); China, India, andJapan (Asia); the UK, Poland, and Spain (Europe); the USA,
Brazil, and Mexico (the Americas); and Australia (AsiaPacific).1-47

A N D

T R E N D S

1.1 Food systems and diets: historical andcurrent
Throughout history, food systems, and thus human diets,
have been and are shaped by climate, terrain, seasons, location, culture, and technology. They can be grouped into threebroad types: gatherer–hunter, peasant–agricultural, andurban–industrial. These and other food systems (for example, pastoralist, the semi-mobile farming of herds of large
animals such as sheep and cattle) have their roots in history. All have coexisted in recent millennia with the exceptionof industrial food systems, which are the consequence of theindustrial revolution that began in Europe in the late 18th
century. These systems still exist in the world today.
1.1.1 Gatherer–hunter
Since the emergence of Homo sapiens around 250 000 years
ago, gatherer–hunter food systems have taken different
forms, depending on the environments in which people lived.
These systems still exist in parts of the world that are remotefrom cities and roads. They supply diets that usually include
moderate amounts of starchy foods, and which are high indietary fibre and low in sugar, mostly from fruits andhoney.48 Methods of food preparation include pulverising,
drying, and roasting. These diets are usually high in foodsof animal origin (ranging from large animals to insects, andalso fish and other seafood, depending on location), andthus in animal protein. It is sometimes thought thatgatherer–hunter diets are high in fat, which is not the casebecause wild animals are lean. Recent analyses suggest thatgathered food generally provides rather more dietary bulk
and energy than hunted food.49
People in gatherer–hunter societies are necessarily physically active, and are often tall and usually lean (only chiefs,
or old or incapacitated people might be overweight orobese). The diets of food-secure gatherer–hunter societies
may be diverse and high in micronutrients.50 51 Diets areliable to become monotonous and deficient in various nutrients, as well as in energy, when food supplies are chronicallyinsecure, or at times of acute food shortage. It is sometimes
claimed that gatherer–hunter food systems generate diets towhich the human species is best adapted.48 However, life
expectancy in gatherer–hunter societies is and has been usually relatively low.
Evidence of cancer has occasionally been found in humanand other fossil and ancient remains.52 Historically, cancer

5

P A R TI•

B A C K G R O U N D

Egypt
In 2004 Egypt had a population of just over74 million. Nearly the whole population
lives within the Nile Valley and the Nile
Delta, less than 4 per cent of the country’s

total area. Egypt has a lower-middle-income
economy, with a gross domestic product of
4274 international dollars per person (figure1.3). Life expectancy at birth is 66 years for

Non-communicable causes of death

Egypt

men and 70 for women (figure 1.1).46
Chronic diseases account for 83.6 percent of deaths, while infectious diseases,
maternal, perinatal, and nutritional condi-

Age-standardised rates of common cancers

Egypt

Age-standardised rate per 100 000

Per cent of deaths

40
Cardiovascular disease
Men

Women

30

24

Cancer20

2

58

Respiratory disease10

7

Data from World Health Organization46

of any type seems to have been uncommon among gatherer–hunter peoples, if only because their average life
expectancy was low. In modern gatherer–hunter societies,
the incidence of cancer rises after contact with industrialised
and urbanised ways of life, which usually involve shifts inpatterns of diet and physical activity.53 These points generally also apply to pastoralist societies.
1.1.2 Peasant–agricultural
In recent millennia, and until very recently in history, almost
all human populations have been rural and mostly peasant–agricultural, and the majority still are in most regions ofAsia, many regions of Africa, and some parts of Latin
America. Peasant–agricultural food systems involving the cultivation of wheat may have first developed around 9000
years ago in the ‘Fertile Crescent’ of the Middle East, including the region between the Tigris and Euphrates rivers (within modern Iraq). These systems also developed
independently in Asia, with rice as the staple food, and in
the Americas, with corn (maize) as the staple.54 The key factor in these systems is land settlement, itself determined by
the cultivation and breeding of crops and also animals, birds,
and fish for human consumption and use.55 In and around
Egypt, people began to make bread from wheat about 6000
years ago.56
Typically, diets derived from these systems are plant-based:
they are high or very high in cereals (grains), complemented with animal sources of protein. These diets are therefore
high in starchy foods and usually in dietary fibre (unless the6

Bladder

CervixBreast

Liver

Lung

0
Other

Bladder9

Diabetes

Data from International Agency for Research on Cancer20

cereals are refined). They include varying amounts of foodsof animal origin, and of vegetables and fruits, depending on
relative food security. Surplus food is stored for consumption in winter and during hard times, and methods of foodpreparation also include fermentation, used for foods as well
as for the production of alcoholic drinks (see chapters 4.8
and 4.9).
The dominant indigenous cereal crop varies in different
parts of the world: wheat is grown in the Middle East; barley, rye, and oats in colder, northern climates; millet and ricein Asia; maize (corn) in the Americas; and sorghum and teffin Africa. Indigenous staple crops also include roots andtubers such as cassava (manioc), yams, potatoes, and also
plantains. Pulses (legumes) are also farmed to ensure agricultural and nutritional balance; and other crops such as
vegetables and fruits are also cultivated. Birds and animals
are domesticated and bred for food, and fish and seafood
contribute to the diets of communities living beside water.57
As with gatherer–hunters, the diets of peasant–agricultural societies may be diverse and high in micronutrients.
Again, when food supplies are chronically insecure, or attimes of acute food shortage (including times of war), dietsare liable to become monotonous and deficient in various
nutrients, as well as in energy.
Peasant–agricultural societies are necessarily physically
active, although not constantly so: the main times of intensive physical work include building field systems, sowing,
harvesting, and storing. The level of energy balance and ofphysical activity varies greatly, depending in part on how dif-C H A P T E R

1•

I N T E R N AT I O N A L

tions account for 12.2 per cent; 4.2 per centof deaths are due to injuries. The first figure gives a breakdown of deaths caused bychronic diseases.46
Bladder cancer is the most common typeof cancer in men, followed by cancers of thelung and liver.20 In women, the dominant
cancers include those of the breast, cervix,
and bladder (for age-standardised rates ofthese cancers, see the second figure).20 The
high incidence of bladder cancer is likely tobe related to bilharzia, a parasitic infectionof the bladder.20 There is also a high incidence of hepatitis C virus, a cause of livercancer.20 Also see box 7.8.1 It is predictedthat there will be a 3.5-fold increase in livercancer by 2030.12
For the period 1991–1994, 46 per cent of
men and 48 per cent of women between
the ages of 20 and 44 were classified as
sedentary.46 In 2003, women aged 15–49
had a mean body mass index (BMI) of 28.6.
In teenagers (13–19 year olds), average BMI
was 23.9; women in their 30s had a mean
BMI of 29.0, while those over 45 had a BMI
of 31.3. In total, 77.3 per cent of women
aged 15–49 had a BMI of over 25. In 1992,

V A R I AT I O N S

A N D

T R E N D S

23.5 per cent of all women had a BMI ofover 30. By 2000, this figure had risen to 41
per cent.46 Fewer data are available formen, but in 1994, the mean BMI for men
aged
20–44
was
26.6,
risingto 28.4 for men over 45. In 2002, among
all men, 45 per cent had a BMI of between
25 and 29.99 and 20 per cent had a BMI ofover 30.15 See figure 1.4 for projections of
the proportions of men and women predicted to have a BMI of 30 or more in2015.46
The average amount of available foodenergy rose between 1964 and 2004, fromaround 2240 to 3290 kcal/person per day(9400 to 13 800 kJ/person per day).1 Early
dietary studies in Egypt demonstrated that
corn bread was the staple food and that
protein intake was about 100 g/day.15
People from higher-income households
consumed more dairy products and thosefrom urban households consumed a wider
variety of foods. Between 1950 and 1990,
there was a shift towards a dependence on
wheat rather than other cereals (grains),
and a sustained rise in the consumption ofmeat, fish, and dairy products.15

ficult it is to cultivate the land. The degree of physical activity and so of body mass in peasant–agricultural communities depends mostly on relative food security.58
People in these societies who are prosperous, especiallythose who own land farmed by others, may quite often
become overweight or obese. But in general, and largely
because of the nature of their dietary staples, peasant–agriculturalists are usually short and lean. This is still evident inrural peasant communities whose food systems remain traditional: for instance, in Africa, Latin America, and in Asia,
notably India and China.58
Agriculture enabled the development of towns and thencities: throughout the world, walled, urban settlements
became surrounded by fields cultivated by peasants. These
people subsisted on the food they produced, and the surplus
fed the community living within the walls. In times of war,
the fortified settlement became a refuge for the farmers. This
crowding of populations into towns and cities caused a sharp
rise in the rates of infectious diseases, mostly notably among
infants and young children, pregnant and lactating women,
and infirm and old people.59
The average life expectancy of peasant–agriculturists
in general is probably a little longer than that ofgatherer–hunters, with a greater percentage of people
surviving into what would be regarded as late-middle andold age.
The prevalence and incidence of various cancers in traditional rural societies is often uncertain, even following theestablishment of cancer registers in many countries: records

Consumption of sugars and oils increased
substantiallyandpulses(legumes)decreased in importance.15 Since the 1970s,
consumption of all major food groups has
increased. However, between 1990 and1994 there was a 20 per cent decrease intotal household food consumption, because
subsidies were removed and food pricesrose sharply.15 A national study in 1981
found that only 24 per cent of urban and
15 per cent of rural households ate readymade foods, and meat was eaten more frequently in urban households comparedwith rural households.15 A repeat survey in1998 found that poultry had become themain source of animal protein and that
wheat bread was the most popular type,although homemade wheat-maize bread
was common in rural areas. Another study
highlighted differences in dietary fat
intake: in urban women, 27.5 per cent of
dietary energy came from fat (mainly asvegetable oil) compared with 22.5 per centin rural women.15 Between 1981 and 1998,
people increasingly ate meals away fromhome (20.4 per cent of all meals in 1981
compared with 45.8 per cent in 1998).15

are less reliable than those kept in urbanised societies. But
there is reasonable evidence that relatively common cancers
in peasant–agricultural societies include those causally
associated with chronic infections, such as cancers of thestomach, liver, and cervix.60
1.1.3 Urban–industrial
Indigenous or traditional peasant–agricultural systems havecoexisted with urban–industrial food systems in most countries since the creation and growth of cities, and the beginning of the ‘industrial revolution’. This movement started inEurope in the 18th century, and then spread to North
America and elsewhere. Britain is one exception to this coexistence: it was the first country to become mostly urban, withhired workers replacing peasants on increasingly large andrelatively mechanised farms. The Americas are anotherexception: settlers, mostly from Europe, displaced native
populations and developed mechanised agricultural systems.61 In continental Europe, some balance between ruraland urban ways of life has been preserved. Throughout theMediterranean coastal regions, and in the Middle East, modern food systems have deep, historical roots.62 In most of
Africa and Asia, including countries with large cities, thebasic economies and cultures have remained predominantly
rural, but this is changing.63
Urban–industrial food systems have characteristics distinct
from peasant–agricultural and gatherer–hunter systems.
Their original purpose was to ensure reliable and adequate
supplies of food of an agreed minimum nutritional quality

7

P A R TI•

B A C K G R O U N DSouth Africa
In 2001 South Africa had a population ofnearly 47.5 million.3 The country has a middle-income economy, with a gross domestic
product of 8506 international dollars perperson (figure 1.3), which masks extreme
socioeconomic inequalities.46 Life expectancy at birth is 47 years for men and 49 for

Non-communicable causes of death

women (figure 1.1).46
Chronic diseases account for 53.9 per centof deaths, while infectious diseases, maternal,
perinatal, and nutritional conditions accountfor 40.2 per cent; 5.9 per cent of deaths are
due to injuries. The figure below gives a breakdown of deaths caused by chronic diseases.46

South Africa

The most common cancers in men arethose of the prostate, lung, oesophagus,
colorectum, and bladder.20 Since HIV and
AIDS became epidemic, Kaposi’s sarcoma
has become more common in both men
and women. For women, the most common
cancers are those of the cervix, breast,

Age-standardised rates ofcommon cancers

South Africa

Age-standardised rate per 100 000

Per cent of deaths

45
Cardiovascular disease

13

40
Men

35
Cancer

7

Women

30
25

51

10

Respiratory disease

20
15
10

20

Diabetes

5

Data from World Health Organization46

to entire populations. Technology has been the main driving
force behind these systems. For instance, various food-preservation techniques were developed as part of the industrial
revolution, and there has been further innovation since thattime. These include bottling, canning, refrigeration, andpackaging; the extensive use of sugar and salt; and technologies that suppress, convert, or eliminate perishable qualities in fresh foods (see chapters 4.6 and 4.9). The clearingof land to rear cattle and sheep, and the development of railways, refrigeration, and other technologies, have made meat,
milk, and their products cheap and plentiful all year round.
Sugar derived from cane is the most profitable edible cash
crop, and sugars and syrups made from cane, beet, and now
also corn are used to sweeten and preserve breakfast foods,
baked foods, desserts, soft drinks, and a vast array of othermanufactured products.64 65 Steel roller mills, invented in the1870s, separate the components of wheat and enable production of uniform quality white bread, which has becomea staple food.66 Hydrogenation, which converts oils to hardfats (see chapter 4.5), has made margarine a basic item offood, and provides ingredients used in the manufacturing ofmany processed foods.67 Perhaps the most remarkablechange following the industrialisation of food systems has
been the precipitate drop in breastfeeding.68 At various times,
urban–industrial food systems have been adjusted in
response to the then current knowledge of nutrition and pub-

8

Lung

Oesophagus

Colorectum

CervixBreastBladder

Colorectum

Kaposi's
sarcoma

Oesophagus

Lung

Other

Prostate

0

Data from International Agency for Research on Cancer20

lic health recommendations, notably when food security has
been threatened by wars.69
Urban–industrial food systems generate relatively energydense diets. These are fairly high in meat, and milk and theirproducts, and in total fats, hardened fats, processed starches and sugars, salt, baked goods, soft drinks, and often also
alcoholic drinks. These diets are relatively low in bothdietary fibre and starchy staple foods, other than products
made from wheat, which has become the dominant cereal
in most countries outside Asia and Africa. Recent advances
in food technology have further altered patterns of food production and consumption, particularly in high-income
countries. Patterns of production and consumption ofvegetables and fruits and fish vary between different
urban–industrial food systems, depending on factors such as
climate and geographical location.70
Efficient urban–industrial food systems can ensure theconstant supply of food to all sections of the population,even to the lowest-income and marginalised groups. In higher-income countries and regions, this, together with basic
public health initiatives, has helped to greatly reduce rates
of nutritional deficiencies and other diseases, which people
are more vulnerable to if they have inadequate food supplies.
As a result of these food systems, people have become generally taller and heavier.
Since the industrial revolution, as populations have moved

C H A P T E R

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I N T E R N AT I O N A L

V A R I AT I O N S

colorectum, lung, and oesophagus (for agestandardised rates of these cancers, see thesecond figure).20 Diseases of poverty andchronic diseases coexist, but it is predictedthat by 2010, deaths from AIDS will accountfor twice as many deaths as those from allother causes combined.5 41
For the period 2002–2003, 44 per cent of
men and 49 per cent of women aged 18–69
were classified as sedentary (figure 1.6).46
Some regional studies suggest that young
women who did not finish school have lowlevels of physical activity.24 There is a lack ofphysical education in schools, and poor
environment and high crime rates prevent
leisure activity outside school.24
In 1998 men aged 15–24 had an average
body mass index (BMI) of 21.1; for those
aged 35–65, average BMI remained constant at around 25. Just 7.8 per cent of men
aged 25–34 had a BMI of over 30 comparedwith 17.3 per cent of men aged 45–54. In
the same year, women aged 15–24 had an
average BMI of 23.7; for those aged 35–64,
average BMI remained constant at around
29. In women aged 25–34, 27 per cent had
a BMI of over 30 compared with 45 per centof women aged 45–64.46 Although undernutrition remains a problem among ruralchildren, obesity and associated diseases are

Figure 1.1

Asia-PacificNorth America

90

AfricaAsia

EuropeLatin
America

80
70
60
50
40
30
20
10

Data from World Health Organization46

BrazilMexicoUSA

PolandUK

Spain

Australia

India

China

Japan

South Africa

Egypt

0

Men

T R E N D S

also prevalent. There has been a misconception of ‘benign obesity’: being thin is
associated with HIV and AIDS, and moderately overweight women are thought of as
attractive and affluent.24 Overall, in 1998,
21.1 per cent of men and 25.9 per cent of
women had a BMI of at least 25; 10.1 percent of men and 27.9 per cent of women
had a BMI of at least 30. See figure 1.4 forprojections of the proportions of men andwomen who will have a BMI of 30 or morein 2015.
The average amount of available foodenergy rose between 1964 and 2004, fromaround 2700 to 3000 kcal/person per day(11 400 to 12 600 kJ/person per day). In thesame period, sugar consumption dropped
from 420 to 370 kcal/person per day (1800
to 1500 kJ/person per day).1 The National
Food Consumption survey of 1999 foundthat stunting was the most common nutritional disorder, affecting almost one fifth ofchildren aged 1–9, with the lowest levels inurban areas. There was a similar pattern forunderweight, where 10 per cent of children
aged 1–3 consumed less than half of theirsuggested daily dietary needs, and 26 percent consumed less than two thirds.25 In
rural areas, adults from lower-income
households were shorter and had a lower

Life expectancy at birth

Years

A N D

Women

BMI, and commonly consumed foods weremaize, sugar, tea, milk, and brown bread.
Urban households ate less maize porridge
but more vegetables and fruits, animalbased products, and fats and oils. It was
only in urban areas that fruits and milk
appeared in the top 10 list of foods anddrinks consumed by more than 85 per centof people. In men, alcoholic drinks made asignificant contribution to dietary energy(10–14 per cent). People living in rural areas
obtained a higher proportion of total
dietary energy from carbohydrates, whereas the most urbanised populations derived
one third of their energy from animal foods
high in protein.
Urbanisation is generally accompanied
by an improvement in micronutrient
intakes, but this way of life is also associated with increases in overweight and obesity.44 Other studies have suggested shifts
towards a Western dietary pattern in people living in both urban and rural areas, typified by a decrease in starchy foods anddietary fibre consumption, and an increasein fat. They have also shown that half ofthe population does not eat the locally
recommended four portions of fruits
and vegetables each day, while a quartereats none.10

from rural to urban areas, there have been rapid and profound changes in both the nature and quality of their foods
and drinks, and the patterns of diseases they suffer.71
Urban–industrial food systems have evidently improved people’s strength and health in early life. They are also a factor
in the doubling of average life expectancy since 1800, andthe increase in global population from around 1 billion in1800 to 6.5 billion in 2006.72 The range of current life
expectancy in selected countries is illustrated in figure 1.1.
In the second half of the 20th century, attention focusedon the apparent ill-effects of these food systems on people,
mostly in later life. By the 1980s, it was generally agreed thatthese industrialised diets increase the risk of some chronic
diseases, usually of later life, which had become common or
epidemic in higher-income industrialised countries. These
included obesity, type 2 diabetes, and coronary heart disease.
At the same time, in examining patterns of both diet and cancer across the world, and among migrants, it was increasingly thought that these diets were partly responsible forsome cancers, notably those of the colon and rectum, breast,
ovary, endometrium, and prostate.73-75
In the last decades of the 20th century, the demographic,
nutritional, and epidemiological transitions that had, until
then, largely been apparent only in higher-income countries
became global. Since the 1990s, and outside Europe, North
America, and other high-income countries, economic glob-

9

P A R TI•

B A C K G R O U N D

China
In 2004 China had a population of over 1.3
billion. The one-child policy introduced in1979 has reduced annual population
growth to 1.07 per cent. The United Nations
estimates that the population will haveincreased to nearly 1.5 billion by 2025.46 The
country has a lower-middle-income economy, with a gross domestic product of 5581
international dollars per person (figure

2004 found that there has been a shift
towards nutrition-related chronic diseases
such as type 2 diabetes, cancer, and cardiovascular disease.14
Stomach cancer is the most common typeof cancer in men, although it has declined
slightly since 1980.20 Lung cancer has risen
steadily over the same period.20 Liver cancer
has risen since 1990, although levels are now1.3). Life expectancy at birth is 70 years formen and 74 for women (figure 1.1).46
Chronic diseases account for 78.9 per centof deaths, while infectious diseases, maternal, perinatal, and nutritional conditions
account for 11.7 per cent; 9.3 per cent ofdeaths are due to injuries.46 The figure
below gives a breakdown of deaths causedby chronic diseases.46 A study published in

Non-communicable causes of death

China

Age-standardised rates of common cancers

China

Age-standardised rate per 100 000
Per cent of deaths

45
Cardiovascular disease

2

10

Men

35

Women

30
Cancer

25
20

44

22

40

Respiratory disease

15
10

Data from World Health Organization46

alisation is thought to be the single main force shifting
populations from the countryside into cities, changing thedominant food systems from peasant–agricultural tourban–industrial, and transforming patterns of disease. Thisphenomenon includes the unprecedented and accelerating
movement of money, goods, and ideas. All this has been
made possible by new international, political, and economic policies, by the creation of supranational regulatory bodies such as the World Trade Organization, and by theelectronic revolution.76-78
People’s levels of physical activity have also changed dramatically as a result of the move from peasant–agricultural
to urban–industrial ways of life. In 1950, the UN ‘referenceman’ weighing 65 kg (143 lbs) was estimated to be in energy balance at an average of 3200 kilocalories (kcal)/day(13398 kilojoules [kJ]/day); the ‘reference woman’ weighing
55 kg (121 lbs) was estimated to be in energy balance at 2300
kcal/day (9630 kJ/day). Today in the USA, average weights
are much higher, yet the figure for the ‘reference person’ (menand women combined) is taken to be 2000 kcal/day (8374kJ/day) for the purposes of nutrition food labelling. The reason for this drop in human energy requirements is because
three of the four settings for physical activity — occupational, household, and transport — (see Chapter 5) have become
increasingly mechanised. Energy-dense food systems, essen-

10Oesophagus

Liver

Lung

BreastStomachColorectum

Liver

Oesophagus

Lung

Other

5
0
StomachDiabetes

22

Data from International Agency for Research on Cancer20

tial to sustain young populations that walk or cycle to workthat is physically demanding, are unsuitable for ageing populations who sit for most of the day, even if they engage insome recreational physical activity.
There is some evidence that these very recently introduced
urban–industrial food systems have lowered the rates ofnutritional deficiencies and infectious diseases of early life
in middle- to low-income countries and regions. But theapparent impact on the rates of chronic diseases in theseareas is of increasing public health concern. In most of theseregions, with the exception of sub-Saharan Africa, childhood
overweight, obesity, and type 2 diabetes have become common and, in some countries, epidemic.70
The Panel emphasises that there is no reason to think thaturban–industrial food systems are intrinsically harmful. They
were first developed using relatively crude technologies, andat a time when something was known of their positive
impact on growth and strength, but little of their long-term
impact on health. Since then, many new technologies havebeen developed, and there is a clearer understanding thatsome methods of preserving and processing food are beneficial, whereas others are a factor in increasing the risk of
disease. Future developments can ensure universal foodsecurity, avoid earlier mistakes, and reduce the risk of chronic diseases, including cancer.

C H A P T E R

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I N T E R N AT I O N A L

stabilising.20 The incidence of cancer of theoesophagus has remained stable since the1980s and cancers of the colorectum are also
relatively common.20 For women, the mostcommon cancers are those of the lung,stomach, and breast, which have risen
steadily since the 1980s; of the liver, which
has risen since 1990; and of the oesophagus.
For age-standardised rates of these cancers,
see the second figure.20
For the period 2002–2003, 10 per cent of
men and 12 per cent of women aged 18–69
were classified as sedentary (figure 1.6).46
These figures are likely to increase, with further urbanisation and greater use of vehicles for transport. Between 1980 and 2003,
the number of cars produced in China
quadrupled to more than 2 million.84
In 1997 men aged 24–64 had an average
body mass index (BMI) of around 25; just 2.1
per cent of men aged 20–74 had a BMI ofover 30. In the same year, women aged
25–29 had an average BMI of 22.2, andthose aged 35–64 had a BMI of around 25.
Just 3.7 per cent of women had a BMI ofover 30.46 In 2002, 18.9 per cent of men andwomen aged 18 and above had a BMI ofover 25, and 2.9 per cent of them had a BMI
of over 30. See figure 1.4 for projections of
the proportions of men and women who
will have a BMI of 30 or more in 2015.
The average amount of available foodV A R I AT I O N S

A N D

T R E N D S

energy rose between 1964 and 2004, fromaround 1850 to 2940 kcal/person per day(7760 to 12 290 kJ/person per day). This islargely due to an increase in the availability of fats and oils, meat, and sugar.1 The
1957–1962 famine was followed by a liberalisation of food production. Economic
growth has reduced poverty and Chinese
diets now are influenced by the Western
pattern: cereals (grains) and lower-fat mixed
dishes are being replaced with animal foodsand edible fats.14 Recent national nutritional surveys show that energy intake from animal sources increased from 8 per cent in1982 to 25 per cent in 2002, and that energy from fat, particularly among people living in urban areas, increased from 25 to 35
per cent over the same period.84 Intake of
cereals (grains) has also decreased substantially since the mid-1980s among urban andrural populations, with a larger decrease in
the consumption of coarse grains comparedwith refined varieties. The biggest drop in
cereal intake has been among people in thelowest-income groups. Vegetable and fruit
intakes have decreased since 1989, although
they are highest in urban populations. Fat
intake is also increasing and many adults
obtain 30 per cent or more of their overall
energy intake from fat.14 Regional variations also exist: for example, the dietary pattern around the city of Hangzhou is very

1.2 Foods and drinks, physical activity,
body composition
1.2.1 Foods and drinks
Substantial changes have occurred in the patterns of foods
and drinks supplied and consumed throughout the world,
and these changes are becoming increasingly rapid. Also see
Chapter 4.
Economic development is generally accompanied byquantitative and qualitative changes in food supplies andtherefore in diets. This ‘nutrition transition’ may reduce therisk of some dietary deficiencies and improve overall nutrition. But it can also be accompanied by adverse shifts in thecomposition of diets, for instance, with a greater proportionof energy coming from fats and oils, and added sugars. Over
recent years, such dietary changes have been rapid in the
middle- and low-income countries of Asia, Africa, the Middle
East, and Latin America.63 79 80
The Food and Agriculture Organization (FAO) of the UN
records global differences in the availability of food crops andcommodities (box 1.1). These data provide information on
the average amounts of food available for consumption,rather than actual food consumption. Animal products havetraditionally made up a small proportion of food availability in low-income countries; most dietary energy comes fromvaried, resulting in a diet low in saturated
fatty acids and high in n-3 polyunsaturated
fatty acids; people there eat green, leafy
vegetables with almost every meal.26 The
incidence of nutrition-related diseases anddeaths from these diseases are lower in thisregion than in other parts of China.
Snacking contributes minimal energy
intake to Chinese diets (0.9 per cent).
However, snacking and eating food awayfrom home are increasing among children
from middle- and high-income groups.
Foods commonly eaten away from homeinclude cereals (grains), vegetables andfruits, meat, eggs, and fish. Between 1991
and 1997, the proportion of children from
low-income households eating foods awayfrom home did not change, but there wasan increase among children from higherincome groups, with a 10 per cent increasein the consumption of foods from animal
sources eaten away from home. Eating foodprepared away from home accounted for 15
per cent of total energy intake for all
Chinese children during this period.27
Despite these statistics, only 10 per cent ofChinese children and young people consumed any snacks during the study period,
and there was little evidence then that they
consumed significant amounts of softdrinks, although this is now changing
rapidly.

plant sources such as roots and tubers, cereals (grains), andfruits.
However, this pattern is changing, with proportionallymore dietary energy available for consumption now comingfrom animal sources. Since the 1960s, estimates for animal
sources for low-income countries have risen from around
160 to 340 kcal/day (670 to 1400 kJ/day). During the same
period, estimates of the energy available for consumption
from plant sources have also risen, from 1900 to 2340
kcal/day (7900 to 9800 kJ/day) (figure 1.2). There havebeen similar changes in the availability of both animal andplant sources of energy in high-income countries. However,in these cases, the proportion of energy from animal sources
is much greater: around one third or 940 kcal/day (3900kJ/day).81 The proportion of dietary energy available from
cereals (grains) has remained constant at around 50 per
cent, though dietary energy available from cereals (grains),
in particular rice and wheat, have decreased slightly in lowincome countries. This trend is likely to continue until the2030s in middle- and low-income countries.81
Large variations exist across the world in the amounts offat available for consumption. The highest availability is in
Europe and North America; the lowest is in Africa. The quantity of available fat in diets has increased globally since the1960s, with the exception of sub-Saharan Africa.81 These

11

P A R T

Figure 1.2

Changes in available energy from animaland plant food sources

Figure 1.3

Low income

Middle income•

B A C K G R O U N D

Gross domestic product per capita, 2004

International $kcal

IAsia-PacificHigh income

North America

40 0003500
low income

transition

35 0003000

AfricaAsia

EuropeLatin
America

30 0002500
25 0002000
20 0001500

15 0001000

10 000500

5000

1977–79

1987–89

1997–99

Data from Food and Agriculture Organization1

BrazilMexicoUSA

PolandSpain

UK

Australia

India

China

Japan

Egypt

Animal

Plant

Total

Animal

Plant

Total

Animal

Plant

Total

1967–1969

South Africa

00Data from World Health Organization46

Food energy from animal and plant food sources in selected low-,
middle-, and high-income countries, 1967–1999

Current gross domestic product per capita for selected countries ininternational dollars

changes are accounted for by an increase in the availability
and consumption of plant oils in lower-income countries.82
Palm oil intake is increasing in South-East Asia, and olive oil
is now consumed widely in Europe and not just in
Mediterranean countries.
Analysis of food balance sheet data suggests that available
energy for consumption has increased steadily on a worldwide basis. Since the 1960s, this has increased globally byapproximately 450 kcal/person per day (1900 kJ/person perday), and by more than 600 kcal/person per day (2500kJ/person per day) in low-income countries.81 Regional differences exist. For example, there has been little change in
sub-Saharan Africa, and in Asia the amount of available energy has risen dramatically: in China by almost 1000 kcal/person per day (4200 kJ/person per day). These data need to
be interpreted with caution, as they do not relate directly toenergy consumption (box 1.1). Global average available
energy is predicted to rise from around 2800 kcal/person perday (11700 kJ/person per day) (1997–1999 average) to
2940 (12 300 kJ) in 2015, and to 3050 (12 800 kJ) in 2030.
Again, see box 1.1.
With increasing socioeconomic status, the proportion ofenergy in diets from staples such as cereals (grains) and roots
and tubers declines, whereas the proportion of energy fromfats and oil, and animal protein (including from meat, milk,
and eggs) increases. For example, in China, energy intake
from foods of animal origin has increased significantly: theaverage Chinese adult now consumes more than 1300

kcal/day (5400 kJ/day) from these foods.83 In low-income
countries between the 1960s and 1990s, consumption ofmeat rose by 150 per cent, and of milk and dairy products
by 60 per cent. By 2030, it is predicted that consumption ofanimal products could rise by a further 44 per cent, with thebiggest contribution coming from poultry. If stocks of fish canbe maintained, fish consumption is likely to rise by 19–20
kg/person in the same period. Owing to decreases in the costof these foods in real terms, low-income countries have higher levels of meat and fat consumption at much lower levelsof gross domestic product (GDP) than was the case in countries that underwent socioeconomic transition in the 1960s
and 1970s. Figure 1.3 shows the GDP of selected countries.
According to food consumption surveys, only a minority of
the world’s adult population consumes the commonly recommended minimum daily amount of vegetables and fruitsof 400 g/person. Low-income countries have the lowest
intakes of vegetables and fruits, and vegetables are generally more readily available than fruits.43 In India, for example,
levels of vegetable and fruit intake have remained static at
120–140 g/day. Australia, Japan, and North America havehigh levels of intake, for example 300 g/day in Australia. In
Europe, average consumption is between 250 and 350 g/day— often much higher in Mediterranean countries, forinstance 550 g/day in Spain — and Scandinavian countries
have particularly high fruit intakes.43 Countries in Europe,
Latin America, North America, and South-East Asia have seen
an increase in the availability of vegetables and fruits for con-

12

C H A P T E R

Box 1.1

1•

I N T E R N AT I O N A L

V A R I AT I O N S

A N D

T R E N D S

Measurement of food supply and consumption

The data here on energy, foods, and drinks
are taken from food balance sheets compiled by the Food and Agriculture
Organization of the United Nations. These
are statistical data on the production,
trade, and use of agricultural commodities
for all countries. Food balance sheets are
the most common and widely used data
sets for food supply estimates. A food balance sheet provides estimates of the foodavailable for human consumption, and an
overall picture of a country’s food supply
during a specified period of time, which
can be compared between countries.
It follows that these estimates of availability are not measures of consumption.
They record information about the supplyof food (production, imports, stockchanges, and exports) and about how it isused (as feed and seed, in processing, andwastage, as well as food). The amounts offoods and drinks recorded on these balance sheets are expressed ‘per person’ (inkg/person per year or kcal/person per day).
The estimates in food balance sheetsthat need to be treated with most caution

are those of energy. Balance sheets overestimate food consumption in high-income
countries, where substantial amounts offood are wasted or fed to pets. They
underestimate consumption in countries
that are not dominated by urban–industrial food systems, and where many people
grow their own food, raise animals, orgather wild food such as fungi and berries.
It follows that balance sheet data showing
increases in food energy over time tend toreflect economic development and greateruse of money, rather than actual increases
in availability.
The accuracy of a food balance sheet
also depends on the reliability of theunderlying statistics of supply, use, andpopulation. Also, the data do not take into
account regional differences, so the information may not be representative of theentire country. In countries where there is
wide variation in income and food access,for example, the overall supply picture provided by the balance sheet is of limited use.
In such cases, food balance sheets can becomplemented with national nutrition

sumption since the 1960s. In contrast, in eastern and central Africa, availability has decreased since the mid-1980s.
Studies in children suggest that their eating patterns varyaround the world. For instance, children living in the USA
and the Philippines consume one third of their daily energy
away from home, and snacks provide one fifth of their dailyenergy. In contrast, children living in Russia and China eatvery little food away from the home. Snacks provide about
16 per cent of dietary energy for Russian children, but
account for only 1 per cent in Chinese children.2
A US study showed that between 1977 and 2001, consumption of sweetened drinks increased by 135 per cent.
During the same period, milk consumption decreased by 38
per cent, resulting in an overall daily increase of 278 kcal
(1164 kJ) from drinks.31
1.2.2 Overweight and obesity
There have been rapid changes in rates of overweight andobesity throughout the world since the 1980s, at the sametime as the urbanisation and industrialisation of middle- andlow-income countries. Such countries often experience thedual burden of nutritional deficiencies and chronic diseases.
Also see Chapters 6 and 8.
The most recent estimates suggest that in 2002 there were
1 billion overweight or obese people worldwide, with
Chinese people accounting for approximately one fifth. The
example of China is remarkable. Historically, China, which
is classed as a lower-middle-income economy by the World
Bank, had a lean population. But the prevalence of underweight adults has decreased and the numbers of people whosurveys or household income/expenditure
surveys.
Household income/expenditure surveys,
such as the World Bank’s Living Standards
Measurement Study, look at multiple
aspects of household welfare and behaviour, and collect data on the quantities offood purchased by a representative sampleof households. These surveys provide
detailed information about foods consumed in and away from the home over alimited time period, and can be used to
document differences in regional, geographical, or household socioeconomic
characteristics. While these surveys are
generally more useful than food balance
sheets for assessing household consumption, they are less readily available. Balance
sheets are often available for a large number of countries and for most years.
Food balance sheets, household income/expenditure surveys, and methods of assessing individual dietary intakes (see Chapter3) all provide information on food supply
and consumption, and they have different
purposes, uses, and limitations.

are either overweight or obese have risen considerably. In
2002, there were 184 million overweight and 31 million
obese people in China, out of a population of 1.3 billion.14
The prevalence of overweight and obesity among 7–18 year
olds increased substantially between 1985 and 2000.84
Between 1989 and 1997, one study estimated that the proportion of overweight and obese men in China rose from 6.4
to 14.5 per cent, and in women from 11.5 to 16.2 per cent.85
Another study, in nine Chinese provinces, found thatbetween 1989 and 2000 there was a 13.7 per cent increasein the proportion of men, and a 7.9 per cent increase in the
proportion of women, who were overweight or obese.
During the same period, there was an average 2 per centdecrease in the number of men and women who were classified as underweight.86
The World Health Organization MONICA Project monitored 10 million adults in 21 countries over a 10-year period in the 1980s and 1990s. During this time, the mean bodymass index (BMI) increased in most populations, with thelargest increases in regions of Australia and the USA. Overthe course of the project, the overall average BMI increasedby 1.5.87 However, average BMI decreased in Russia andCentral Europe, and in certain regions of Italy and
Switzerland. The UK has one of the highest rates of excess
weight in Europe. This has increased threefold since 1980;
in 2003, 65 per cent of men and 56 per cent of women were
overweight, with 22 per cent of men and 23 per cent of
women classified as obese.88
Historically, food insecurity, undernutrition, and underweight, and their likely contribution to infection, have been

13

P A R TI•

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India
In 2004 India had a population of over 1.1
billion, growing at a rate of about 1.2 percent a year; it was the next country after

China to reach the 1-billion mark.46 India
has a low-income economy, with a grossdomestic product of 1830 international

Non-communicable causes of deathIndia

dollars per person (figure 1.3). Life
expectancy at birth is 61 years for men and63 for women (figure 1.1).46

Age-standardised rates of common cancers

India

Age-standardised rate per 100 000
Per cent of deaths

35
Cardiovascular disease

Men

Women

25

13

3

30

Cancer

20
15

12

57

Respiratory disease

10
5

1.2.3 Physical activity
Changes in degrees of physical activity throughout the world
have also been rapid since the 1970s, as paid and household

14

Figure 1.4

Oesophagus

Oral

BreastOesophagus

Projected increases in obesity

Per cent of adults with BMI ≥30

Projections based on
adults aged 30 –100

70

60

50

40

30

20

10

2002 men

2002 women2015 men

Australia

MexicoBrazilUSA

Poland

Spain

UK

Japan

India

0
China

the main nutrition-related public health issues in middle- andlow-income countries. This is no longer the case. Thus,
surveys of women between 1992 and 2000 found that
overweight exceeds underweight in most middle- and lowincome countries, including those in North Africa and the
Middle East, Central Asia, China, and Latin America. Indeed,
there has been a disproportionate increase in, and prevalenceof, obesity among the lowest-income groups in most countries. It is more likely that people will be overweight if they
live in urban areas compared with rural areas, and countries
with a higher GDP have a greater ratio of overweight tounderweight women.89 North Africa and the Middle East are
two areas of the world with middle- and low-income countries that are experiencing very high rates of overweight andobesity, often higher in women than in men.82
The rise of overweight and obesity since the mid-1970s has
been much faster in lower-income countries.63 In Europe andthe USA, the prevalence has risen relatively slowly, by
0.3–0.5 per cent each year; but the figures are two- to fourfold higher in many low-income countries.90 Projections fromexisting data suggest that by 2015, levels of obesity could
be as high as 50 per cent in the USA, between 30 and 40
per cent in the UK and Australia, and more than 20 per centin Brazil.46 See figure 1.4. It is estimated that more than 12
million adults in England will be obese by 2010, while 25
per cent of children who live in households with obese parents will become obese themselves.88

Data from International Agency for Research on Cancer20

Egypt

Data from World Health Organization46

Lung

Oral

Other

Cervix0
Pharynx

DiabetesSouth Africa

152015 women

Data from World Health Organization46

Projected increases in obesity (BMI of above 30 kg/m2) inselected countries, 2002–2015

C H A P T E R

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I N T E R N AT I O N A L

Chronic diseases account for 58.1 percent of all deaths, while infectious diseases,
maternal, perinatal, and nutritional conditions account for 32.9 per cent; 9 per centof deaths are due to injuries.46 The first figure gives a breakdown of deaths caused bychronic disease.46
Common cancers in men include those of
the oral cavity and pharynx.20 Althoughthese cancers have declined since the late1970s, the incidence remains high.20 Cancersof the oesophagus and lung have also
decreased slightly in the same period.20 In
women, cancer of the cervix is the most common type, and has been since the 1970s;
breast cancer has increased steadily during
this time.20 Cancers of the oral cavity andoesophagus have declined slightly since thelate 1970s (for age-standardised rates ofthese cancers, see the second figure).20
For the period 2002–2003, 10 per cent of
men and 16 per cent of women aged 18–69
were classified as sedentary (figure 1.6).46
In 2000 men aged 20–24 had an average
body mass index (BMI) of 20.7, while those

V A R I AT I O N S

A N D

T R E N D S

aged 40–54 had an average BMI of 23.6.46
For men aged 20–70, 25.4 per cent had a
BMI of over 25.46 Women aged 20–24 had
an average BMI of 20.9, rising to an average of 24 at age 30; and women aged
30–69 also had a BMI of around 24.46 In
total, 35.8 per cent of women aged 20–70
had a BMI of over 25.46 A review from 2002
established that the prevalence ofpreschool obesity was about 1 per cent, but
stunting remained a problem in over halfof all children.39 Obesity has been uncommon in India and varies with socioeconomic
status, being more common in high-income
households. In the 1970s, 2.1 per cent of
men and 2.9 per cent of women had a BMI
of 25 or more, while less than 0.5 per centof men and women had a BMI of 30 ormore.46 By 1998 these figures had risen: 4.4
per cent of men and 4.3 per cent of women
had a BMI of 25 or more.46 See figure 1.4
for projections of the proportions of men
and women who will have a BMI of 30 ormore in 2015.46
The average amount of available foodwork has become increasingly mechanised, and vehicles areused more often for transport. Occupational and household
physical activity has reduced dramatically in high-income
countries. Also see Chapters 5, 6 and 8.
There is as yet no globally accepted, quantified definitionof physical inactivity, or of the extent to which populations
or people should be physically active. In 2002, the WHO
recommended a minimum of 30 minutes moderate-intensity physical activity most days; it found that at least 60 per
cent of the world’s population fails to achieve this level ofphysical activity.91
The proportion of people employed in agriculture canreflect the level of work-related activity undertaken in acountry, and there may be a linear relationship between thetwo.91 Thus, it is likely that, compared with high-income
countries, transport-related and occupational and household
physical activity is higher in low-income countries.
Transport-related physical activity (cycling, walking) is higher in those countries with the lowest gross domestic product and low car ownership, and this differs little between
men and women.
Data on physical activity in Africa are limited. Several studies are available for South Africa, but these cannot be used
to predict or generalise about activity levels across the entire
continent. Some small regional studies have been performed,
in Ethiopia, for example, which provide useful local information, but they are not nationally representative.
Data from Europe, where recreational physical activity
accounts for a greater proportion of total activity, suggestthat approximately half of all walking and cycling trips areless than 3 km. Therefore, almost half of European adults doenergy rose between 1964 and 2004, fromaround 2050 to 2470 kcal/person per day(8580 to 10 360 kJ/person per day).1
Recently, though, there have been large
increases in the consumption of animal
products, fats, and sugars. The proportionof energy from fat has increased each year,
although within India there are differences:for higher-income groups, 32 per cent ofenergy comes from fat, compared with
17 per cent in lower-income groups.39
Since 1975 there has been a reduction in
cereal (grains) consumption, particularlycoarse grains, although this has not affected overall energy consumption. This isprobably due to large increases in intakesof fats and animal protein, and also of milk
and milk products. In lower-income households, fat comes mainly from vegetable
foods, with very little consumption of animal fats, whereas in the highest-income
households, the majority of fat is from animal sources. India is a major producer ofvegetables and fruits, much of which areexported.

not do enough physical activity getting from one place toanother.91 In Europe, people living in more northerly regions
such as Scandinavia have higher levels of activity than thoseliving further south, for example, in Mediterranean countries. Women tend to exercise less than men and this difference is greatest in southern European countries.42
A study conducted in 1953 demonstrated that more thanhalf of US school children failed a minimum standard of

Figure 1.5

Projected levels of inactivity in selected
regions in 2020

Insufficient

Inactive

Africa

45–55

10–20

USA/Canada

35–50

17–30

Latin America

25–45

17–47

Middle East

30–42

15–30

Europe

30–60

15–40

India/Bangladesh

30–42

14–25

New Zealand/Australia/Japan

48–56

15–20

China

40

15–22

Data from Bull et al93

Percentage of adults projected to have insufficient levels ofphysical activity or to be inactive in 2020 in selected regions

15

P A R TI•

B A C K G R O U N D

JapanIn 2004 Japan’s population was just over
128 million, with 79 per cent living in urban
areas.46 The country has a high-income
economy, with a gross domestic product of

30 039 international dollars per person (figure 1.3). Life expectancy at birth is 79 years
for men and 86 for women (figure 1.1).46
Chronic diseases account for 78.7 per

Non-communicable causes of deathJapancent of all deaths, while infectious diseases,
maternal, perinatal, and nutritional conditions account for 10.5 per cent; 10.8 percent of deaths are due to injuries. The firstAge-standardised rates of common cancers

Japan

Age-standardised rate per 100 000
Per cent of deaths

70
Cardiovascular disease2

14
Cancer

6

60

Men

Women

50

37

40
30

Respiratory disease20
10

Data from World Health Organization46

fitness, compared with less than 10 per cent of European
children.92 Another study in 2001 found that only 0.2 percent of US adults were physically active in both occupational
and transport settings, compared with 29 per cent of Chinese
adults.91 In the USA, while socioeconomic status has a large
impact on whether someone participates in recreational
physical activity, there are only small differences between
men and women, and activity levels decline with age. Similar
trends exist for men and women and for socioeconomic status in Australia.42
A number of factors will affect levels of physical activity infuture. Economic development has the effect of reducing levels of occupational, household, and transport physical activity. It reduces the amount of physical activity in theworkplace, often because of a shift from agriculture to manufacturing and service industries. Improved public transportin middle- and low-income countries reduces transportrelated activity. Similarly, as people gain more disposable
income, they are more likely to own a car, which means thatthey will make fewer journeys by bicycle or foot. Recreational
activity is the only area in which physical activity may
increase as economies develop and countries become increasingly urbanised and mechanised, although people may notnecessarily use their leisure time for active pursuits.91
Other factors constrain physical activity in cities, such as
personal safety: crime rates are often high and it may beunsafe to walk, jog, or cycle in the streets. Furthermore, cityand town planning may not encourage people to be active— for example, people can only walk, run, ride, and play if

16

Lung

CervixStomachBreastColorectum

Pancreas

Oesophagus

Liver

Prostate

Other

Lung

0
StomachDiabetes

Colorectum

44

Data from International Agency for Research on Cancer20

Figure 1.6

Sedentary behaviour in adults in selected
countries (age 18–69)
Per cent of adults classified as sedentary
Men

Women

Brazil

28

31

China

10

12

India

10

16

Mexico17

18South Africa

44

49

Spain

27

33

Data from World Health Organization46

Sedentary behaviour is defined as less than 30 minutes ofmoderate physical activity (equivalent to brisk walking) on fewer
than 5 days/week, or less than 20 minutes of vigorous physicalactivity (equivalent to running) on fewer than 3 days/week. Also
defined in terms of ‘metabolic equivalents’ (METs) as achieving
less than 60 MET–hours/week of any combination of activity on
fewer than 5 days/week (also see chapter 5.2)

there are sidewalks/pavements, parks, or other areas where
they can move around freely and safely. Cultural and religious customs may also limit activity levels, particularly for
women.
By 2020 it is predicted that more adults will be physicallyC H A P T E R

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I N T E R N AT I O N A L

figure gives a breakdown of deaths causedby chronic diseases.46
In men, cancer of the stomach is the mostcommon type of cancer. This is followed bycolorectal, lung, liver, and prostate cancers,which have increased since the 1960s.
Cancer of the oesophagus has remained
steady since the 1960s, although the incidence of cancer of the pancreas has
increased since then.20 In women, breast
cancer is the most common type and its incidence has risen since the 1970s.20 Colorectal
cancer is the next most common type, andthis has also increased. Stomach cancer incidence has decreased since the 1960s, but
the rate remains high; lung cancer has risen
steadily since the 1960s.20 The incidence ofcancer of the cervix increased during the
1960s and remained high in the 1970s, but
has since declined (for age-standardised
rates of these cancers, see the second figure). 20 However, the total numbers of newcancer cases and cancer deaths are set torise because Japan has an ageing population. Cancer has been the leading cause ofdeath in Japan since 1981 and projections

V A R I AT I O N S

A N D

T R E N D S

indicate that in 2015 almost 900 000 people
will develop cancer and 450 000 will die
from cancer.47
Regional studies suggest that 68–70 per
cent of men and 70–82 per cent of women,
aged 20–70, are physically inactive.
In men there has been a steady increasein body mass index (BMI) since the mid1970s. In 2002, 17.5 per cent of men aged
20–29 and around 30 per cent of those
aged 30–60 had a BMI of over 25. Only 7 percent of women aged 20–29, 19 per cent of
those aged 40–49, and 25.6 per cent of
those aged 50–59 had a BMI of over 25. See
figure 1.4 for projections of the proportionsof men and women who will have a BMI of
30 or more in 2015.
The average amount of available foodenergy rose between 1964 and 2004, fromaround 2570 to 2760 kcal/person per day(10 780 to 11 540 kJ/person per day). Meat
consumption also increased during thistime.1 Steamed rice was the staple food
until 1950, and accounted for 80 per cent ofenergy intake before 1935. Dietary intake
of cereals (grains), almost all rice, has

inactive.91 Clearly, levels of physical activity will vary in different areas and countries around the world. In Europe, forexample, the former Soviet Union states and countries ineastern Europe are at the lower end of the estimates, withwestern European countries at the higher end. Indeed, thesefigures are expected to rise further in western Europe and it
is estimated that 50–60 per cent of adults will not be sufficiently physically active by 2020. Also see figure 1.5. The percentage of adults currently classified as sedentary in selectednational examples is shown in figure 1.6. Using different definitions, the amount of adults (aged over 16 years) classified as sedentary for the UK are 60 per cent of men and 66
per cent of women. For the USA 52 per cent of men and 65
per cent of women (aged over 18 years) are classified as
sedentary.46
1.2.4 Cancer
Patterns of cancer and trends, incidence, and projections vary
greatly in different parts of the world. Also see Chapter 7.
In 2002 there were more than 10 million new cases of cancer (excluding non-melanoma skin cancers) recorded worldwide, and nearly 7 million cancer deaths. By 2020 thesefigures are estimated to rise to over 16 million new cases,
with 10 million deaths. There may be more than 20 million
new cases of cancer in 2030.93 Indications suggest that, atthat time, 70 per cent of cancer deaths will be in low-income
countries.
This projected increase is accounted for by a combinationof factors: the projected increase in global population; andecreased, from 75 per cent of energy inthe 1940s to 41.3 per cent in 2000. Energy
from fat increased from 6.9 per cent in 1949
to 25 per cent in 1988, and to 26.5 per centin 2002. Total fat intake has increased significantly following the country’s economic growth, from 15 g/person per day in the
1940s to 59 g in 1983, remaining at aroundthis level in 2002. The percentage of energy in diets from protein has risen from 12.4
per cent in the 1940s to 15.9 per cent in2000. However, there has been a larger
increase in the percentage of protein fromanimal sources: from 18.6 per cent in the
1940s to more than 50 per cent in 2000. In
2002, people were continuing to eat more
green and yellow vegetables, with people
over 50 tending to eat the most vegetables.
Fruit intake peaked in 1975 and has sincedecreased and stabilised. In 2002, Japanesediets did not provide the recommended
intake of calcium: although consumption ofmilk and dairy products had increased, consumption of fish and shellfish had declined
slightly. Salt intake remained high, at over
12 g/person per day. 23

ageing world population; improved screening, detection, andtreatment, which increases the number of people living witha diagnosis of cancer (see Chapter 9); the projected increases in tobacco smoking in many countries; and the increasein the number of people with HIV/AIDS in some countries.
The global age-adjusted incidence of cancer is also likely toincrease. Also see box 1.2.
Globally, the most commonly diagnosed cancers (excluding all types of skin cancer) are those of the lung, colon andrectum, and breast, with lung cancer being the leading causeof cancer death.94 95 Geographical and socioeconomic differences exist for the most common cancers. In low-income
countries, the most prevalent cancers include those of which
infectious agents are a major cause, while in high-income
countries, they include hormone-related cancers. In highincome countries, and among men, prostate cancer is themost common type, followed by cancers of the lung, stomach, and colon and rectum. In low-income countries, andamong men, lung cancer is the most common type, followedby cancers of the oesophagus, stomach, and liver. Breast cancer is the most common type among women living in highincome countries, followed by cancers of the lung, colon andrectum, and endometrium. Breast cancer is also the most frequent type among women living in low-income countries,
followed by cancers of the lung, stomach, and cervix.94 96
1.2.4.1 Oesophagus

Oesophageal cancer is the seventh most common type ofcancer worldwide, with more than 460 000 new cases record-

17

P A R TI•

B A C K G R O U N D

UKIn 2001 the UK population was nearly 60
million.30 The UK is a high-income economy,
with a gross domestic product of 31 300
international dollars per person (figure1.3). Life expectancy at birth is 76 years formen and 81 for women (figure 1.1).
Chronic diseases account for 84 per centof all deaths, while infectious diseases,
maternal, perinatal, and nutritional conditions account for 11 per cent; 4.9 per centing steadily since the 1960s, is now decreasing, and stomach cancer incidence has
declined since the 1960s.20 In women, breast
cancer is the most common type, andalthough rates were fairly constant during
the 1960s and 1970s, they have risen steadily since then.20 The incidence of colorectal
cancer has remained steady since the1960s.20 Lung cancer rose from the 1960s to
1980s, and has remained steady sinceof deaths are due to injuries. The first figure below gives a breakdown of deaths
caused by chronic diseases.46
Prostate cancer is the most common cancer type in men and has increased steadily
since the 1970s.20 Lung cancer incidence
peaked in the 1960s, remained high until
the mid-1980s, and is now declining.20
Colorectal cancer has risen steadily since1960.20 Bladder cancer, which had been ris-

Non-communicable causes of deathUK

Age-standardised rates of common cancers

UK

Age-standardised rate per 100 000
Per cent of deaths

90
80
Cardiovascular disease

16

Men

70

Women

60

1

Cancer

8

50
40

42
Respiratory disease

30
20
10

Diabetes

Endometrium

Lung

Ovary

BreastColorectum

Bladder

Data from International Agency for Research on Cancer20

Data from World Health Organization46

Increases in BMI

Stomach

Other

Lung

Prostate0Colorectum

33

UK

ed in 2002. Because it has a poor survival rate, it is the fifth
most common
cause
ofBMI
cancerresponsiblefor ≥30
nearlyPer cent adults
with
25–29.9death,
Per cent
adults with BMI
000 deaths in 2002.
39050
Incidence rates vary widely between countries. Studies
40
suggestthat cancer of the oesophagus is 100 times

more common in parts of China than in Europe andNorth America.94 97 Other areas of high risk include southernand eastern Africa, south-central Asia, and some countries
in South America.
Geographical variability of exposure to established car-30
20 1.2Box

Measurement of cancer incidence and mortality

10 cancer registers were established incer. These rates are usually expressed as theAfternumber of new cases (or deaths) each year
various countries in the second half of the
0 century, descriptive studies showedfor every 100 000 people.
20th
1980
2003
1980
2003
Cancers
are not usually diagnosed until
reliably for (UK)the first timethat rates and(England)(UK)(England)they produce symptoms, so there is a peritrends of different cancers vary, sometimes
Men
od of time Women
between the first stages of cansubstantially across different countries.
cer development and its identification. This
This variation suggested that cancer is notfrom Department
of Health48
and Rosenbaum
et al49
length of time can vary greatly, and there
justData
geneticallyinherited
andthat different
are also considerable differences in survival
cancers have different causes.
times and how types of cancer respond to
Many countries publish annual incidence
treatment.
and mortality rates for cancer. The inciMany countries and international agendence rate refers to the number of newcies track mortality statistics with causes
cancer cases reported; the mortality rateof death, and national or regional cancer
refers to the number of deaths from can-18

registries prepare cancer-incidence statistics. With types of cancer where survival ishigh, cancer mortality statistics will notreflect occurrence rates. But globally, it
is easier to obtain statistics for mortality
than for incidence, so these are often used
for comparisons between populationgroups.
It can also be difficult to compare cancer incidence globally: not all countries andregions are covered by cancer registries,
and these organisations may use different
definitions and collect different data, both
geographically and over time.

C H A P T E R

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I N T E R N AT I O N A L

then.20 Cancer of the ovary has increasedslightly since the 1960s, and rates of cancerof the endometrium have remained thesame since the 1960s (for age-standardised
rates of these cancers, see the second figure).20 The incidence of childhood cancer
has been rising at an average rate of 1.1
per cent each year and, between 1978 and1997, the age-standardised incidence
increased from 120 to 141 cases/million children.22 Children in the British Isles have thehighest rates of skin cancer in Europe.11
In 2003, 64 per cent of men and 76 percent of women aged 16–69 were classified
as sedentary.46 A study to examine exercise
patterns in adults in 1991 and again in 1999
found that only 4 in 10 adults had managed to meet and maintain the current recommended level of activity, or to increase
their level. During the study period, themajority either reduced their activity levelor maintained it below the recommended
level, and 15 per cent of the sample wasinactive, both in 1991 and 1999.33
In the UK, body mass index (BMI) has
risen steadily since the mid-1970s. For the
proportions of men and women in 1980
and in 2003 with a BMI of between 25 and
29.9, or of over 30, see the figure on thispage. Also see figure 1.4 for projections of
the proportions of men and women who
will have a BMI of 30 or more in 2015.
The average amount of available
food energy rose between 1964 and 2004,

V A R I AT I O N S

Data from World Health Organization46

A N D

Data from InteT R E N D S

from around 3280
Increases in BMIUK
to 3480 kcal/person
per day (13 730 to
Per cent adults with BMI 25–29.9
Per cent adults with BMI ≥30
14 570kJ/person
50
1
per day). Consumption of pasta, rice,40
cereals(grains),30
yogurt, soft drinks,
savoury snacks, and20nuts has increased
since the mid-1980s.
10Over the same period, intakes of fish0
and fish dishes and
1980
1980
2003
2003
(UK)
(UK)
(England)(England)eggs and egg dishes
have decreased.19
Men
Women
Large studies suggest that fat intake
Data from Department of Health48 and Rosenbaum et al49
has decreased because people now
consume less whole
portions of vegetables and fruits. Instead,milk, butter, and red meat, and more vegmen ate an average of 2.7 portions while
etables and fruits.35 Men surveyed between
women had 2.9.19 The survey also showed2000 and 2001 were more likely to eatthat vegetable and fruit consumption was
foods containing fats, oils, and sugars, as
particularly low in young adults, and thatwell as meat and meat products, and soft
people from low-income households wereand alcoholic drinks.
less likely to eat fruit and yogurt.19 It
In the same survey, and compared withappears that more-educated adults put
older men and all women, young men weredietary guidelines into practice, reducing
more likely to eat savoury snacks and softthe amount of fat in their diets and increasdrinks, and less likely to eat eggs, fish, anding the amount of vegetables and fruits
fruit.19 Women ate more fruit, although
they eat.3
only 13 per cent of men and 15 per cent of
women ate the recommended five daily

cinogens can explain some of these differences. In highincome countries, alcohol and smoking tobacco are the main
carcinogenic agents, whereas chewing tobacco is more common in India. Pockets of high incidence occurring in partsof China and in the Caspian littoral of Iran may be due togeneral nutritional deficiencies. Incidence of adenocarcinoma of the lower third of the oesophagus is steadily increasing in the USA and Europe, which is likely to be linked to
an increasing incidence of acid reflux from the stomach due
to obesity.94 95 Also see chapter 7.3.
1.2.4.2 Lung

Lung (pulmonary) cancer has been the most common typeof cancer in the world since 1985, with around 1.35 million
new cases recorded in 2002. It is also the most common
cause of cancer death. In 2002, 1.2 million people died fromlung cancer.
Between 1985 and 2002, the estimated number of lungcancer cases worldwide rose by 51 per cent, and the number of cases in middle- and low-income countries has
increased steadily over recent years. Previous estimates indicated that the majority of lung cancer cases occurred inhigh-income countries (almost 70 per cent in 1980); almost
half were predicted to occur in middle- and low-income
countries in 2005.94 95 The USA and Europe have the highest numbers of lung cancer cases for both men and women,
but the incidence appears to have peaked, and may now
be declining in the USA and in parts of northern Europe. Itis, however, still increasing in southern and eastern Europe.
Men are more likely to develop lung cancer than women,
almost certainly because, on average, they smoke more than
women. Worldwide, 1 billion men and 250 million womencurrently smoke tobacco. It is estimated that throughout the20th century, 100 million people died from tobacco use.93
Also see chapter 7.4.
1.2.4.3 Stomach

Stomach (gastric) cancer is now the fourth most common
type of cancer worldwide, with around 925 000 new cases
recorded in 2002. It is the second most common cause ofdeath from cancer, with around 700 000 deaths annually.
Until about the mid-1980s, stomach cancer was the mostcommon type in the world. Since then, rates have fallen substantially in all high-income countries, and overall rates are19

P A R TI•

B A C K G R O U N D

PolandIn 2004 Poland had a population of around38.5 million. The country has an upper-middle-income economy, with a gross domestic
product of 12647 international dollars perperson (figure 1.3).46 Life expectancy atbirth is 71 years for men and 79 for women(figure 1.1).46
Chronic diseases account for 88.2 percent of all deaths, while infectious diseases,
maternal, perinatal, and nutritional condi-

Non-communicable causes of death

Polandtions account for 3.9 per cent; 7.9 per centof deaths are due to injuries. The first figure gives a breakdown of deaths caused bychronic diseases.46
Lung cancer is the most common type of

Age-standardised rates of common cancers

PolandAge-standardised rate per 100 000
Per cent of deaths

90
Cardiovascular disease

2
3

80
Men

70

11

Women

60
Cancer50
40

Respiratory disease30

20

Data from World Health Organization46

now about 15 per cent lower than in 1985.94-96
Stomach cancer is now much more common in Asia thanin the USA or Europe. Indeed, 42 per cent of cases occur in
China alone.94 97 High-risk areas are China, Japan, eastern
Europe, and Central and South America. Low-risk areas are
South-East Asia, northern and eastern Africa, the USA, andAustralia and New Zealand. In most countries, incidence has
dropped by about 15 per cent compared with 1985.
The bacterium Helicobacter pylori is an established causeof stomach cancer. Reduction in stomach cancer rates can be
explained partly by reduced exposure to H pylori and partly by increased use of refrigeration to preserve foods.94 97 Also
see chapter 7.5.
1.2.4.4 Liver

Liver (hepatic) cancer is the sixth most common type of cancer worldwide, with around 625 000 new cases recorded in
2002. The poor prognosis makes it the third most common
cause of cancer death, with around 600 000 deaths in 2002.
In most countries, the incidence of liver cancer is stable
and there is little difference in survival rates between highand low-income countries. More than 80 per cent of cases
occur in middle- and low-income countries. Areas with ahigh incidence are China (55 per cent of all new cases), subSaharan Africa, and eastern and south-eastern Asia.
Incidence is lower in high-income countries and in Latin
America, although Japan and areas of southern Europe haveintermediate incidence levels.94 96

Ovary

Lung

Endometrium

CervixBreastColorectum

Bladder

Stomach0
Prostate

Other

10
Lung

Diabetes

20

30

Colorectum

55

Data from International Agency for Research on Cancer20

Exposures to the hepatitis B and C viruses are known toincrease the risk of developing liver cancer; 85 per cent ofcases in low-income countries are attributed to exposures tothese two viruses. Also see chapter 7.8.
1.2.4.5 Colon and rectum

Colorectal cancer (of the colon or rectum) is the third mostcommon type of cancer worldwide, with just over 1 million
new cases recorded in 2002. Mortality is approximately halfthat of the incidence, and nearly 530 000 deaths wererecorded in 2002, making it the fourth most common causeof death from cancer.
There is a large geographical difference in the global distribution of colorectal cancers. Incidence varies up to 25-foldbetween countries with the highest rates (the USA, Australia
and New Zealand, and in parts of Europe) and those withthe lowest rates (in Africa and Asia). Intermediate levels
occur in South America.
Incidence of colorectal cancer may be stabilising in partsof northern and western Europe, and possibly declining
gradually in the USA. Elsewhere, however, the incidence isincreasing rapidly, particularly in Japan and in middle- andlow-income countries.94 96
As shown in 1.3, the incidence of colorectal cancer increases quickly when people migrate from low- to high-risk areasof the world. Indeed, the incidence rate is higher in Japanesepeople born in the USA than in white people born in theUSA. Also see chapter 7.9.

C H A P T E R

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I N T E R N AT I O N A L

cancer in men and age-adjusted incidence
has remained stable since the 1970s.20 The
incidence of colorectal cancer has increased
since 1990, and both prostate and bladdercancers have increased slightly since the1970s.20 Stomach cancer incidence peaked in
the late 1970s and has declined steadily since.
Breast and colorectal cancers are the mostcommon types in women and their rates
have risen steadily since the 1970s.20 Cancerof the cervix has remained steady since themid-1970s, whereas cancers of the lung,ovary, and endometrium have increased inthis period (for age-standardised rates ofthese cancers, see the second figure).20
In 1996, 31 per cent of men and 32 percent of women aged 15–75 were classified
as sedentary.46
In 1996 men aged 15–29 had an average
body mass index (BMI) of 23.1.46 This rose to
25.9 for men aged 30–44, while those aged
45–75 had a BMI of between 26 and 27.46
Only 2.4 per cent of men aged 15–29 had a
BMI of over 30, rising to 10.8 per cent of
those aged 30–44, and 17.5 per cent of 45–59
year olds.46 In the same year, women aged
15–29 had an average BMI of 21.2.46 WomenV A R I AT I O N S

A N D

T R E N D S

aged 30–44 had a BMI of 24.1, while those
aged 45–59 had a BMI of 26.7.46 Only 1.5 percent of women aged 15–29 had a BMI ofover 30, rising to 22.5 per cent of those aged
45–59, and 23.7 per cent of women aged
60–74.46 In a study of adults in Warsaw, theaverage adult BMI remained stable between
1983 and 1993 at approximately 27.46 Overall
in 1996, 10.3 per cent of men and 12.4 percent of women had a BMI of 30 or more.46
See figure 1.4 for projections of the proportions of men and women who will have a
BMI of 30 or more in 2015.46
The average amount of available foodenergy rose between 1964 and 2004, fromaround 3310 to 3520 kcal/person per day(13 850 to 14 730 kJ/person per day). The
amount of energy available from sugars
and meat increased during this period,
while the energy available from animal fatsfell substantially.1 In 1989 Poland began thetransition from a centrally planned to amarket economy. This resulted in dramaticincreases in food prices, and although thetransition gave people a better choice offoods, there was a decline in food demand
and alterations in dietary patterns.37

1.2.4.6 Breast

Breast cancer is the most common type of cancer in women,
and the third most common cancer overall. Incidence rates
are increasing in most countries, with an estimated 1.15 million new cases recorded in 2002. Breast cancer is the sixth
most common cause of death from cancer overall. However,
it is the second most common cause of cancer death inwomen, with just over 410 000 deaths recorded in 2002.
The incidence of breast cancer is highest in high-income
countries (although not in Japan) and more than half of allcases occur in these countries. Although breast cancer has
been less common in women living in low-income countries,
age-adjusted incidence is increasing, and the rates ofincrease are often greater in these countries.
Globally, estimates indicate that breast cancer incidence
has increased by 0.5 per cent annually since 1990. However,certain cancer registries, such as those in China and otherparts of Asia, are recording annual increases in incidence ofup to 4 per cent. Rates are low in Africa, with the lowest incidence in central Africa.94 96
Migrant studies show that breast cancer rates change when
women move to a new country. See 1.3. Also see chapter
7.10.
1.2.4.7 Cervix

Cancer of the cervix is the second most common type of cancer among women, and the eighth most common cancer
overall, with around 500 000 new cases recorded in 2002.

Tobacco smoking and alcoholic drink consumption are underlying factors in overallmortality trends in eastern Europe. An
analysis of national household budget andindividual dietary surveys carried out in the
1990s found that, each day, the average
person ate around 300 g of dairy products
and the same amount of cereals (grains)
and roots and tubers, although consumption of pulses (legumes) was very low.38 A
study of students found that women ate
meat and drank beer less frequently thanmen, and they ate more fruit and drankmore milk.8 Another local study, in Warsaw,
reported decreases in intakes of total energy, dietary cholesterol, and dietary animal
fats, and an increase in vegetable oil intake
between 1984 and 2001.45 Another study
found that between 1990 and 2000, theproportion of men eating fruit each day
increased from 36 to 42 per cent. Levels of
intake were stable in women, with around
60 per cent eating fruit every day. In contrast, over the same decade, only 22–23 percent of men limited their fat intake,although more women did during this period (an increase from 23 to 45 per cent).40

Cervical cancer is the seventh most common cause of deathfrom cancer overall, and the third most common in women,
and was responsible for nearly 275 000 deaths in 2002.
Over 80 per cent of cases occur in low-income countries.
Areas with the highest incidence rates are sub-Saharan Africa,
the Caribbean, Central and South America, and south-central and South-East Asia. Incidence rates are lowest in Europe,
the USA, Japan, China, and Australia and New Zealand.
The incidence has dropped substantially in high-income
countries following the introduction of cervical screening
programmes. The major established cause of cervical cancer
is infection with certain subtypes of human papilloma
viruses (HPV). Other cofactors (parity, contraception, HIV
infection, and smoking) can also modify the risk of thiscancer in women infected with HPV.94 96 97 Also see
chapter 7.13.
1.2.4.8 Prostate

Prostate cancer is the third most common type of cancer inmen, and the sixth most common cancer overall, with nearly 680 000 new cases recorded in 2002. The majority of cases
are diagnosed in men over the age of 65, and this cancer
accounted for just over 220 000 cancer deaths in 2002. This
made it the eighth most common cause of death from cancer overall, and the sixth most common in men.
Prostate cancer is more common in high-income countries,
but the incidence remains low in Japan. Incidence rates havebeen influenced by screening programmes, which increase21

P A R TI•

B A C K G R O U N D

Spain
In 2004 Spain had a population of over
43 million. The country has a high-income
economy, with a gross domestic product of
24 325 international dollars per person (fig-ure 1.3).46 Life expectancy at birth is 77 years
for men and 83 for women (figure 1.1).46
Chronic diseases account for 87.4 per centof all deaths, while infectious diseases,

Non-communicable causes of deathSpainmaternal, perinatal, and nutritional conditions account for 5.5 per cent; 6.9 per centof deaths are due to injuries. The first figure
below gives a breakdown of deaths due

Age-standardised rates of common cancers

Spain

Age-standardised rate per 100 000

Per cent of deaths

60
Cardiovascular disease

19

Cancer

35

3

Women

40
30

Respiratory disease

10

Men

50

20
10

Diabetes

33

Data from World Health Organization46

diagnosis rates. This has resulted in a huge increase in thenumber of recorded cases in the USA in recent years,
although the incidence in several high-income countries has
declined since the 1990s. Prostate cancer incidence isincreasing rapidly in low-income countries, particularly in
Latin American countries (such as Costa Rica, Colombia,
and Ecuador) and in China. Again, this may partly be due
to increased awareness and screening.
Mortality from prostate cancer is lower (5.8 per cent ofcancer deaths in men),94 and may give a better indicationof actual disease patterns.97 Even so, mortality is approximately 10 times more common in the USA and Europe
than in Asia. Also see chapter 7.14.

1.3 Migrant and other ecological studies
Ecological studies (also called correlation studies) examine the relationships between environmental factors anddisease outcomes, often in different countries, at an aggregate level (see chapter 3.1.2). These provided the first systematically gathered evidence suggesting that the principal
causes of cancer are environmental, and that food, nutrition, and physical activity are among these factors. Early
studies showed strong correlations among countries
between, for instance, dietary fat intake and breast cancer rates.98
While not providing strong evidence for causation, suchstudies generated hypotheses for possible links between

22

Cervix

Ovary

Colorectum

Endometrium

BreastOral

Bladder

Prostate

Lung

Other

Colorectum0

Data from International Agency for Research on Cancer20

Mortality from stomach and colorectal
cancer in European migrants to Australia

Figure 1.7

Stomach cancer

Colon cancer

Rectal cancer

Length ofresidence(years)Country oforigin

<16

>16

<16

>16

<16

>16

Yugoslavia

2.22

1.23

0.47

0.66

0.46

1.34

England

1.47

1.24

0.99

1.04

1.23

1.04

Scotland

1.84

1.46

1.47

1.24

1.05

1.08

Ireland

1.77

1.21

0.62

1.06

1.17

1.18

Poland

1.69

1.71

1.02

1.14

0.43

1.34

Greece

1.35

1.15

0.36

0.69

0.34

0.7

Italy

1.43

1.49

0.37

0.7

0.48

0.8

Australia

1.0

1.0

1.0

1.0

1.0

1.0

Data from McMichael et al102

Relative risk of death from cancer of the stomach, colon, andrectum in European migrants to Australia (1962–1976) comparedwith people born in Australia

specific nutritional factors and cancers at particular sites,
and for the general proposition that patterns of cancer might
be altered as a result of changing patterns of eating andother ways of life. Part 2 of this Report explores the degree

C H A P T E R

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to chronic diseases.46
Lung cancer is the most common cancer
type in men and incidence rates haveincreased dramatically since the 1970s.20
Rates of colorectal, prostate, bladder, andoral cancers have risen since records began
in the 1970s.20 Breast cancer is the mostcommon type in women and the rate has
doubled since the 1970s.20 Colorectal cancer
is the next most common type, which has
seen a steady rise during this period.20
Cancers of the endometrium and cervix
have remained steady since the 1970s, but
cancer of the ovary has risen (for age-standardised rates of these cancers, see the second figure).20
A survey in 1997 found that 76 per centof adults aged 16 and over did no regularexercise during their leisure time29; 46 percent of adults were classified as sedentary,with only 7 per cent of adults recording any
physical activity each week.29
Between 1994 and 1997, men aged
25–34 had an average body mass index(BMI) of 25, while those aged 35–44 had a

Figure 1.8

V A R I AT I O N S

Cancer among female Iranian migrants
to British Columbia, Canada

Ardabilprovince(Iran)

BreastColorectal

Kermanprovince(Iran)T R E N D S

BMI of 26, and 45–75 year olds had a BMI
of 27.46 In total, 35 per cent of men aged
25–64 had a BMI of over 27, and 12.2 percent had a BMI of over 30.46 Women aged
25–34 had an average BMI of 23, while
those aged 35–44 had a BMI of 25, and
45–74 year olds had a BMI of between 27
and 28.46 Overall, 25.7 per cent of women
aged 25–64 had a BMI of over 27, and 12.1
per cent had a BMI of over 30.46
Over the period 1977–1993, the proportion of people with energy-intensive jobs
halved. In children aged 6–7, there has
been a marked increase in obesity and overweight, higher even than in US children of
the same age. Obesity in adolescents is also
among the highest in the world.29 Between
1990 and 2000, 45 per cent of men and 32.2
per cent of women had a BMI of 25 ormore, and 13.4 per cent of men and 15.8
per cent of women had a BMI of 30 ormore. See figure 1.4 for projections of the
proportions of men and women who will
have a BMI of 30 or more in 2015.46
The average amount of available foodAge-standardised incidence in women per 100 000
CancerA N D

Iranianmigrants to
BritishColumbia

BritishColumbia
general

7.6

16.9

68.5

81.4

Not done

5.9

11.6

26.6

Data from Yavari et al104

Age-standardised incidence of breast and colorectal cancer isincreased in Asian migrants to Canada compared with source
population

Figure 1.9

energy rose between 1964 and 2004, fromaround 2700 to 3480 kcal/person per day(11 330 to 14 590 kJ/person per day), duelargely to an increase in the availability ofsugars and meat.1 The Mediterranean-style
diet is often seen as the healthiest in
Europe, but Spanish diets have recently
shifted towards being high in fat and dairy
products, with only moderate amounts ofvegetables. Dairy and fruit intakes are thehighest in Europe, but so is the proportionof energy in diets from fat.29 Between 1964
and 1990, consumption of plant-based
foods decreased from 1289 to 995 g/person
per day. In the same period, intakes of cereals (grains), pulses (legumes), and potatoes
all halved. While consumption of other vegetables remained stable, fruit intake doubled to 327 g/person per day. Consumptionof animal products increased from 407 to
743 g/person per day due to a large
increase in the amounts of meat, poultry,
milk, and dairy products in people’s
diets, although intakes of animal fats
decreased.29

Incidence of colorectal cancer in Asian
migrants to USA and their descendants

Ethnicity

Birth place

Men

Women

White

USA

89.9

64.3

Chinese

USA

66.9

40.9

China

87.8

44.7

USA

142.5

90.1

Japan

69.3

63.5

Japanese

Filipino

Incidence rate per 100 000 people

USA

57.2

14.2

Philippines

44.4

25.7

Data from Flood et al106

Age-standardised incidence of colorectal cancer is increased in thedescendants of Japanese migrants to the USA

to which such hypotheses are upheld or refuted by the totality of the relevant published literature, including more robust
observational and also experimental types of study.
The most compelling evidence, suggesting that the maincauses of cancers of most sites are environmental (due to factors that people are exposed to) rather than geneticallyinherited comes from studies of migrant populations.
There are many migrant populations. Examples include

people who have migrated from eastern Asia to theAmericas; from the Indian subcontinent to Africa and theUK; from Europe to Australia; and from Africa to the
Caribbean, and then to the UK. All of these population movements are accompanied by marked changes in patterns of
diet, physical activity, and disease.
Migrations from Japan to the USA, from the Caribbean to
the UK, and from European countries to Australia have been23

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USAIn 2004 the USA had a population of almost
300 million. The country has a high-income
economy, with a gross domestic product of
39 901 international dollars per person (figure 1.3), which masks socioeconomic
inequalities.46 Life expectancy at birth is 75
years for men and 80 for women (figure1.1).46
Chronic diseases account for 84.7 percent of all deaths, while infectious diseases,
maternal, perinatal, and nutritional conditions account for 6.7 per cent; 8.6 per centof deaths are due to injuries. The first figure below gives a breakdown of deaths
caused by chronic diseases.46

the second figure below).20
In 2003, 22 per cent of men and 27 percent of women aged 20–65 were classified as sedentary; physical inactivity was
more prevalent among people with a low
income.91
In 2002 men aged 20–24 had an average
body mass index (BMI) of 26.2, while those
aged 25–29 had a BMI of 27, and men aged
30–65 had a BMI of between 27 and 29.46
While 19.7 per cent of men aged 20–24 had
a BMI of over 30, this rose to 23.6 per centof those aged 30–34, and 30 per cent of
40–44 year olds.46 Women aged 20–24 had
an average BMI of 26.2, while those aged

Prostate cancer is the most common typeof cancer in men and the incidence rate has
more than doubled since the 1970s.20 Lungcancer peaked in the early 1980s and hassince declined slightly.20 Rates of colorectal
and bladder cancer have remained stable,
although melanoma has increased steadily.20 Breast cancer is the most common typein women, followed by lung cancer, andboth have increased since the 1970s.20 Overthe same period, the incidence of cancers of
the colon and rectum and of the ovary haveremained stable, while cancer of theendometrium has decreased slightly (forage-standardised rates of these cancers, see

Non-communicable causes of deathUSA

Age-standardised rates of common cancers

USA

Age-standardised rate per 100 000
Per cent of deaths
140
Cardiovascular disease

120

Women

Men

100

18

Cancer

4

41

80
60

Respiratory disease

8

40
20

Diabetes

29

studiedin somedetail, as have movements of populations
Increases
in BMI
USA
from rural to urban areas within countries. Both types of
migration
Per cent result in dietary changes, which are followed,
45 one or two generations, by changes in disease patwithinterns. Patterns of cancer among migrant groups often change
40
faster than they do among people who remain in their homecountryor among people native to the host country.
35
In the 1980s, one study demonstrated that breast cancer
30
incidenceincreased almost threefold in first-generation
Japanese women who migrated to Hawaii, and up to five25
fold in the second generation. Colorectal cancer incidence
increasedalmost fourfold in the first generation but did not20
increase further with subsequent generations.99 In this same15
the incidence of stomach cancer dropped bypopulation,
almosthalf in the first generation, and dropped further in10
the second generation.99
5
Anotherstudy, published in 1980, of European migrants
to Australia demonstrated a reduction in the death rate from
024

1971–74

Ovary

Colorectum

Endometrium

Lung

BreastBladder

Melanoma

Data from International Agency for Research on Cancer20

Data from World Health Organization46

1906–62

Lung

Other

Colorectum

Prostate

0

1976

Men

1988–94

1999–2000

Women
BMI 25–29.9

BMI 25–29.9

BMI 30+

BMI 30+stomach cancer, which corresponded to the length of timethe migrants stayed in Australia. However, their risk of colorectal cancer increased proportionally to the length of theirstay.100 See figure 1.7. A later study demonstrated thatdeaths from breast cancer among Italian migrants toAustralia were half that of Australian-born women during
the first five years after emigrating. However, after 17 years,
Italian migrants had similar death rates (due to breast cancer) to women born in Australia.101
Following migration, the incidence of certain cancers may
increase, whereas the incidence of other cancers may
decrease. Thus among Iranian immigrants to Canada, inwomen, breast cancer incidence rate increased fourfold, andcolorectal cancer incidence rate doubled; but there was adramatic decrease in cancers of the stomach and oesophagus in both sexes.102 See figure 1.8.
Another study showed that breast cancer incidence
increased threefold within one generation in Polish migrants

Data from World Health Organization46

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25–29 had a BMI of 27.4, and 30–65 year
olds had a BMI of between 28 and 30.46
While 23.1 per cent of women aged 20–24
had a BMI of over 30, this rose to 30.9 percent of women aged 25–29, and to morethan 40 per cent of those aged 55–64.46 The
obesity epidemic began earlier in the USA
than in other high-income countries.
Between 1906 and 1962, 10.4 per cent of
men and 15 per cent of women had a BMI
of 30 or more.46 By 1999/2000, these figures
had increased to 27.7 per cent of men and
34 per cent of women (see figure).46 In 2002
a US health survey found that almost 75 percent of people were trying to prevent
weight gain.106 See figure 1.4 for projections of the proportions of men andwomen who will have a BMI of 30 or morein 2015.46
The average amount of available foodenergy rose between 1964 and 2004, fromaround 2930 to 3750 kcal/person per day(12 250 to 15 690 kJ/person per day).1
Between 1977 and 1996, the average proportion of meals eaten in restaurants or
fast-food outlets rose from 9.6 to 23.5 per
cent, and fast food now accounts for 20 per
cent of dietary energy.2
Vegetable and fruit intakes haveincreased since the 1980s across all income
levels, and people now eat more fresh andfrozen vegetables and fruits than canned.
Potatoes are commonly eaten. Bananas
are the most popular fruit.34 More than
80 per cent of men and 70 per cent of
women aged 20–64 fail to eat the recommended five daily portions of vegetables

V A R I AT I O N S

A N D

Data from InteT R E N D S

and fruits. Between
Increases in BMI
USA
1970 and 2000,
average population
Per cent
consumptionof45
meat and poultry
per person increas40
ed by 11 per cent:people ate less beef
35
but more poultry.16
30
Analysis of national
food surveys de25
monstrated
that
between 1977 and20
2001, people consumed more sweet15
ened drinks and lessmilk. The portion
10
sizes of sweetened5
drinks increased andtheycontributed0
more energy to
1906–62
1971–74
1976
1988–94
1999–2000
diets: an increase
from 50 to 140
Men
Women
kcal/person per day
BMI 25–29.9
BMI 25–29.9(210 to 600 kJ/perBMI 30+
BMI 30+son per day). During
the same period,
fruit drinks increasData from World Health Organization46
ed from 20 to 45
kcal/person per day(80 to 190 kJ/person
and they consumed one third of their total
per day); energy intake from milk dropped
energy away from home.2 Energy from softfrom 140 to 100 kcal/person per day (600 to
drinks, fast foods, and salty snacks doubled
410 kJ/person per day), with the largest
between 1977 and 1996, and soft drinks
drop in milk consumption among those
now provide 8.5 per cent of total energy inaged 2–18.31 Another study revealed that 93
young people’s diets.2
per cent of young people ate snack foods

to the USA.103 Japanese, Chinese, and Filipino people who
migrate to the USA have a higher risk of colorectal cancer
than their counterparts who do not migrate. One study ofUS-born Japanese men demonstrated incidence rates of colorectal cancer twice as high as Japanese men born in countries other than the USA or Japan and 60 per cent higher
than in white people born in the USA (figure 1.9).104
Data from more recent migrant studies show that cancer
incidence rates generally become similar to those of the
adopted country in second-generation immigrants.17 105 Thisis illustrated in first-generation immigrants to Sweden,
where the incidence of all cancers was 5 and 8 per cent lower
for men and women, respectively, compared with native
Swedes.17 By the second generation, however, the incidence
was only marginally below the figures for people native toSweden.105
Correlation studies, and migrant studies in particular,
prove that the main determinants of patterns of cancer areenvironmental and suggest that patterns of food, nutrition,and physical activity are important among these causes.
Migrants share a common genetic background, as do theirparents and children: the genetic pool of any population does
not change within a generation or two. But as shown in
Chapter 2, different patterns of environmental exposure canand do alter patterns of DNA damage and gene expression,and so cancer, in a relatively short time.

1.4 Conclusions
Between the early 2000s and 2030, the global absolute number of cancer cases is projected by UN agencies to double,
most of all in the middle- and low-income countries of Africa
and Asia. Some of this increase can be attributed to theContinued on page 29

25

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MexicoIn 2004 Mexico had a population of over
107 million. The country has an upper-middle-income economy, with a gross domestic product of 10 158 international dollars
per person (figure 1.3). Life expectancy atbirth is 72 years for men and 77 for women(figure 1.1).46
Chronic diseases account for 72.4 percent of all deaths, while infectious diseases,
maternal, perinatal, and nutritional conditions account for 16.5 per cent; 16.49 percent of deaths are due to injuries. The first
figure below gives a breakdown of thedeaths caused by chronic diseases.46
Prostate cancer is the most common typeof cancer in men, followed by lung, stomach, and colorectal cancers. Cancer of thecervix is the most common type in women,
followed by cancers of the breast, stomach,and ovary (for age-standardised rates ofthese cancers, see the second figure
below).20 Women living in rural areas havea higher risk of cancer of the cervix compared with those living in urban areas.32
Stomach cancer incidence has risen since1980, and this increase is more evident inmen.20In 2002–2003, 17 per cent of men and 18
per cent of women aged 18–69 were classified as sedentary (figure 1.6).46
Between 1995 and 1999, the prevalenceof overweight and obesity in children rosefrom 13.6 per cent to 19.5 per cent.18
Geographically, the highest prevalence ofoverweight and obesity is in Mexico Cityand in the northern region. Across thecountry as a whole, girls are more likely to

be overweight or obese.18 One fifth ofschool-age children are overweight orobese, and the risk of body fatness rises if
their mother has a school education andhigher socioeconomic status.18 Men aged
20–29 had an average body mass index(BMI) of 25.2, while those aged 30–39 had
a BMI of 26.9, and men aged 40–59 had a
BMI of 27.5. While 11.8 per cent of men
aged 20–29 had a BMI of over 30,46 thisrose to 20.9 per cent of 30–39 year olds.46
Around 25 per cent of men aged between
40 and 69 had a BMI of over 30. Women
aged 20–29 had an average BMI of 25.6.46
This rose to 27.9 for those aged 30–39, andto 29 for women aged 40–69. While 16.7
per cent of women aged 20–29 had a BMI
of over 30, this rose to 29.6 per cent of
those aged 30–39. Around 40 per cent of
women aged 40–59 had a BMI of over 30.46
See figure 1.4 for projections of the proportions of men and women who will havea BMI of 30 or more in 2015.46
The average amount of available foodenergy rose between 1964 and 2004, fromaround 2470 to 3150 kcal/person per day(10 350 to 13 1780 kJ/person per day).1
In 1999, micronutrient deficiencies remained a problem.36 Undernutrition was
more prevalent in the indigenous population, in people of lower socioeconomic
status, and in rural areas and the south.
One in five children under the age of 5
years was stunted, and 2 per cent wereclassified as suffering from wasting. Ratesof stunting and wasting were three times
higher in rural than urban areas, and wereNon-communicable causes of death

Mexicohigher in the south of the country than thenorth.
Folate intakes were lower in urban
areas, in the north of the country, and in
Mexico City, compared with the south andin rural areas.7 This demonstrates regional
differences in diets, particularly in theamounts of green, leafy vegetables people
eat. Preschool children in the north and in
Mexico City had the highest intakes of fat
and the lowest intakes of dietary fibre.
Children in the south, those indigenous tothe country, and those of lower socioeconomic status had higher intakes of dietary
fibre and starchy foods, the lowest fat
intakes, and the highest risk of inadequate
micronutrient intakes for vitamin A, vitamin C, folate, calcium, iron, and zinc.7 In
women, there was a risk of inadequate vitamin A, vitamin C, and folate intake.
Consumption of starchy staple foods andintakes of folate, calcium, and iron weresignificantly higher in rural women compared with those living in urban areas.
Saturated fatty acid consumption was
lower in the south, reflecting the greater
contribution of beans and cereals (grains)in diets.6 Women in urban areas, and thoseof higher socioeconomic status, consumed
more cholesterol, saturated fatty acids, andtotal fat.6 Across the country as a whole,dietary fibre consumption was found to beinadequate, but intakes were higher incentral and south Mexico, mainly because
people’s diets contained beans and cereals(grains), although their intake of vegetables and fruits was low.

Age-standardised rates of common cancers

MexicoAge-standardised rate per 100 000

Per cent of deaths

30
Cardiovascular disease28

31

Cancer

25

Men

Women

20
15

Respiratory disease5

Data from World Health Organization46

Data from International Agency for Research on Cancer20

Ovary

StomachBreastCervix

Other

Colorectum

0
Stomach8

Diabetes
Lung

18

Prostate

16

26

10

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V A R I AT I O N S

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T R E N D S

Australia
In 2004 the population of Australia wasover 20 million. The country has a highincome economy, with a GDP of 31 454
international dollars per person (figure1.3).46 Life expectancy at birth is 78 years
for men and 83 for women (figure 1.1).46
Chronic diseases account for 86.9 percent of all deaths, while infectious diseases,
maternal, perinatal, and nutritional conditions account for 4.7 per cent; 8.4 per centof deaths are due to injuries. The first figure below gives a breakdown of the deaths
due to chronic diseases.46
In men, prostate cancer is the most common type and rates have doubled since the1970s. Colorectal cancer has increased andlung cancer has declined slightly. There has
been a large increase in the incidence of
melanoma and a slight increase in bladdercancer. In women, breast cancer is the mostcommon type and the rate has increased
since the 1970s. Colorectal cancer is thenext most common type, although this hasremained stable. There has been a large
increase in melanoma, and lung cancer has
doubled since the late 1970s, although cancer of the endometrium has remained stable (for age-standardised rates of thesecancers, see the second figure below).20
In 2001, 30 per cent of men and 32 percent of women aged 15–75 were classified
as sedentary.46
In the same year, men aged 18–24 had
an average body mass index (BMI) of 24.3,
while those aged 25–29 had a BMI of 25.3,
and men aged 30–75 had a BMI of
between 26 and 27.5.46 Of men aged
18–24, 34.3 per cent had a BMI of over 25.46

sumption was decreasing in adolescents,
although the intake of milk products was
declining only among girls. Fewer adolescents ate cereals (grains) compared withother age groups, although cereals andcereal products contributed 34–37 per centof their total dietary energy. Cereal products
contributed the greatest amount of food byweight to adults’ diets, followed by milk andmilk products, then pulses (legumes). Fruitconsumption increased with age, whereas
intakes of cereals (grains), milk, meat, andpoultry decreased. Adults in the Northern
Territory consumed more meat, poultry,
game, and alcoholic drinks, and less vegetables and fruits, than people living inother areas. Men were slightly more likely
to eat food away from home (64 per cent)compared with women (57 per cent).
Almost one third of adults thought thatthey should be eating more fruit, and 25 percent thought they should eat fewer high-fat
foods.4 Fruit and vegetable consumption
was highest in 18–39 year-olds, with 40–50
per cent consuming a combination of atleast one portion of fruit and three portionsof vegetables each day, although thisamount then declined steadily with age.
Only 37.6 per cent of children (12–17 yearolds) ate this quantity of vegetables andfruits and, in total, 37.2 per cent of people
over the age of 12 failed to eat this amount.
A study of people aged 20–75 living inQueensland found that 63 per cent of participants drank too much alcohol, 40 per
cent were not sufficiently physically active,
and less than half ate the recommended levels of fruits and vegetables.13

This rose to 43.8 per cent of those aged
25–29, and to between 50 and 70 per centof men aged 30–75.46 Between 17 and 20
per cent of men aged 35–69 had a BMI ofover 30.46 The average BMI of women aged
18–24 was 22.8.46 This rose to 24.9 for
women aged 30–34, and those aged 40–75
had a BMI of between 25 and 27.1.46 The
proportion of women with a BMI of over 25
increased with age: 19.9 per cent of women
aged 18–24, and 34–55 per cent of those
aged 30–75. Overall, between 15 and 20 per
cent of women aged 30–75 had a BMI ofover 30.46 There has been a steady increasein BMI since 1980, when 40.6 per cent of
men and 20.2 per cent of women had a BMI
of 25 or more, and 9.3 per cent of men and
8 per cent of women had a BMI of 30 ormore.46 In 2000, 48.2 per cent of men and29.9 per cent of women had a BMI of 25 ormore, and 19.3 per cent of men and 22.2
per cent of women had a BMI of 30 ormore.46 See figure 1.4 for projections of the
proportions of men and women who will
have a BMI of 30 or more in 2015.46
The average amount of available foodenergy remained stable between 1964 and2004: around 3130 and 3120 kcal/person perday (13100 and 13 070 kJ/person per day),respectively.1 The most recent National
Nutritional Survey in 1995 found that 90 per
cent of the people surveyed ate cereals(grains) or cereal products, and milk or milk
products, the day before the interview.
However, half of the men and one third of
the children had not eaten fruit, and 20 per
cent of children had not eaten vegetables
the day before the interview. Fruit con-Non-communicable causes of death

Australia

Age-standardised rates of common cancers Australia
Age-standardised rate per 100 000

Per cent of deaths

90
Cardiovascular disease

17

80
Men

70

Women

60
Cancer

3
7

50
40

39
Respiratory disease30
20

Data from World Health Organization46

Lung

Endometrium

Melanoma

BreastColorectum

BladderLung

0Melanoma

Other

10
Prostate

Diabetes

Colorectum

35

Data from International Agency for Research on Cancer20

27

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BrazilIn 2004 Brazil had a population of over 185
million. The country has a middle-income
economy, with a gross domestic product of
8140 international dollars per person (figure 1.3), which masks extreme socioeconomic inequalities.46 Life expectancy atbirth is 67 years for men and 74 for women(figure 1.1).46
Chronic diseases account for 75.3 percent of all deaths, with infectious diseases,
maternal, perinatal, and nutritional conditions accounting for 16.2 per cent; 8.5
per cent of deaths are due to injuries. The
first figure below gives a breakdown ofdeaths caused by chronic diseases.46
Prostate cancer is the most common type ofcancer in men. This is followed by lung, stomach, colorectal, and bladder cancers. Breast
cancer is the most common type in women,
followed by cancers of the cervix, colorectum,
stomach, and lung (for age-standardised ratesof these cancers, see the second figure
below).20 Age-standardised mortality rates forchildhood cancers have declined since 1980
and there has been a decrease in mortality
from oral and pharyngeal cancers since theearly 1980s.9 These figures may represent

improved provision of healthcare rather thanchanges in incidence.
In 1997, 28 per cent of men and 31 percent of women aged 18–69 were classified
as sedentary (figure 1.6).46
In 1997 men aged 20–65 had an average
body mass index (BMI) of between 23 and25.46 Just 2.1 per cent of men aged 20–24
had a BMI of over 30, rising to 9.1 per centof 30–34 year olds, 11.4 per cent of 40–44
year olds, and 12.3 per cent of men aged
50–54.46 Women aged 20–39 had an
average BMI of between 22.5 and 24.9,
while from age 40 onwards, average BMI
remained between 25 and 27.46 Just 5.2
per cent of women aged 20–24 had a BMI
of over 25, rising to 17.4 per cent of those
aged 40–44, and 25.5 per cent of women
aged 60–64.46 The proportion of men andwomen with a BMI of 30 or more has
increased steadily since the mid-1970s.46 In
1975, just 2.1 per cent of men and 6 percent of women had a BMI of 30 or more;this rose to 6.4 per cent and 12.4 per centin 1996/7.46 See figure 1.4 for projectionsof the proportions of men and women
who will have a BMI of 30 or more in

Non-communicable causes of death

Brazil2015.46 In 1975, for every obese woman,approximately another two were underweight. Between 1975 and 1989, theprevalence of underweight almost halved,
while the prevalence of obesity doubled;so by 1997 there were two obese womenfor every underweight woman.28
The average amount of available foodenergy rose between 1964 and 2004, from
2313 to 3157 kcal/person per day (9684 to
13 218 kJ/person per day), largely due to anincrease in the availability of meat andoils.1 In one study, people living in urban
areas ate more vegetables and fruits thanthose living in rural areas; intake increased
with age, schooling, and income. However,
only 41 per cent of adults reported eating
fruit every day and 30 per cent reported
daily vegetable intake.21 Wasting andstunting in children due to undernutrition
have decreased rapidly since 1975,
although it remains a major problem in
the north-eastern region of the country.
Obesity among children is low, but thosefrom higher income households in the economically developed south-eastern region
are more likely to be overweight.28

Age-standardised rates of common cancers

BrazilAge-standardised rate per 100 000

Per cent of deaths

60
Cardiovascular disease

15
Cancer

6

50

Men

Women

40
30

48

Respiratory disease

11

20
10

Diabetes

20

Data from World Health Organization46

28

Data from International Agency for Research on Cancer20

Lung

StomachCervixColorectum

BreastBladder

Colorectum

Lung

StomachProstate0
Other

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A N D

T R E N D SContinued from page 25
general projected increase in global population; to ageing
populations; and to improved surveillance, detection and, inthe case of prostate cancer, screening and diagnosis.
Nevertheless, at the global level, a real, age-adjusted, population-adjusted increase in cancer rates is projected. These
projections show that any global ‘war on cancer’ is not being
won. It follows that soundly based policies and effective programmes to prevent cancer — which is to say, to decrease
the risk of cancer — need not be accompanied by a decreasein the overall numbers of people suffering and dying fromcancer.
This ominous prospect should be put in context. First, bothactual numbers and also age-adjusted rates of some cancers
are decreasing in high-income countries, and rates of stomach cancer are generally decreasing worldwide. Second, theremarkable differences in the numbers of different cancers,
and in their incidence over time, show that most cancer is,
at least in principle, preventable. Third, the theme of thisReport, correlations between changes in patterns of diet,physical activity, body composition, and changes in patternsof cancer provide evidence that these factors are important
modifiers of cancer risk.
Furthermore, as shown in Part 2 of this Report, overall theevidence is a reliable basis for recommendations designed toprevent cancer. The evidence shows that, together with exposure to tobacco smoke, key aspects of food and nutrition,
physical activity, and body composition are or may be causes of important cancers of some sites. Unlike tobacco, the evidence also shows that other aspects protect against a numberof common cancers. This indicates that many cancers arepreventable not only in principle, but potentially also inpractice.

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2The cancer process
Food and nutrition modify the risk of cancers at alarge number of sites. This means that some foods
and drinks, dietary constituents (or their balance indiets), and methods of food production, processing,preservation, and preparation influence thedevelopment of some cancers. More recently,
evidence has accumulated about the effects ofphysical activity and body composition on the risk ofa number of cancers, suggesting that bioenergetics
is another factor determining cancer risk and tumour
behaviour.
Since the mid-1990s, great progress has been madein understanding the cancer process, and whichinternal and external factors modify cancer risk.
Mapping of the human genome has enabled theestablishment and development of new disciplines
devoted to understanding biological processes at
the most basic level, including those that prevent
cancer, those that cause cancer, and those thatmodify its behaviour.
Evolution in living organisms depends on theaccumulation of adaptations as a result of changes
in the expression of the genetic information carriedin DNA. Even with no changes in the DNA,
alterations in how the message in the genetic code istranslated can lead to functional changes. More
importantly, the DNA itself is susceptible tomutation — changes in the genetic code itself — as aresult of damage from external causes such asradiation or simply due to the process of
metabolism. Such mutations are the essential basis
for human evolution, by producing adaptations thatare beneficial in particular environmental
circumstances. At the same time, some mutations
can contribute to the harmful changes in cells thateventually lead to cancer.
The integrity of the genetic information isprotected by many systems that prevent DNA
damage, or remove or repair damaged DNA if it
occurs. Imperfections in these systems limit theability to block all damage and allow both helpful
and harmful mutations to occur. Cancers result whensufficient mutations have accumulated, mostpresenting at an age that was rarely reached in theevolutionary past of human beings. The
development of cancer may be seen as a corollary of30

the ability of humans to evolve and adapt.
Ultimately it is both the genetic information(genotype) and its expression that control thecharacteristics (or phenotype) of an individual. Any
exposure during the life course that affects the
genotype or its expression may also have an effecton the phenotype. At any point in time, thephenotype is related not only to the genotype but
also to a host of environmental factors, including
nutritional exposures. This accumulated metabolic
experience may begin during maternal and early life,and proceed throughout a person’s lifetime.
The purpose of this second introductory chapter is
to summarise current knowledge and thinking on the
biology of the cancer process, with special reference
to food and nutrition, physical activity, and bodycomposition. In Part 2 of this Report, epidemiologicaland mechanistic evidence is summarised, and thePanel’s assessments and judgements are made,based on a balance of all relevant evidence.

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P R O C E S SThis chapter summarises the wealth of biological evidence
that documents the ability of food and nutrition, physicalactivity, and body composition to influence several stages ofthe process of the development of cancer.
Nutrients and food constituents have effects that can either
inhibit several events that lead to cancer, or contribute tocancer development, by altering DNA itself, or by altering
how the genetic message in DNA is translated. Physicalactivity and variations in body composition also appear toinfluence cancer risk. Indeed, overall dietary patterns can
indirectly influence cell growth by way of changes in general metabolic, regulatory, and endocrine effects.
The normal functioning of all biological processes, including those of the human body, depends on the availability of
substrate and nutrients. Good nutrition — defined as appropriate provision of food and nutrients from the level of thewhole organism to the cellular and intracellular level — isneeded for normal structure and function. When a person is
not suitably nourished, either through under- or overnutrition, this impacts on the tissue microenvironment, compromising both structure and function.
Understanding the mechanisms underlying cancer development is central to improving its prevention and treatment.
The main body of this Report comprises the Panel’s judgements on a series of systematic literature reviews (SLRs) on
evidence linking food, nutrition, and physical activity to cancer. All evidence on the mechanisms of the cancer process isalso based on rigorous review criteria. However, the evidence
presented in this chapter is a summary of this literature, andthe references cited are illustrative examples only. Full detailsof the methods used for the reviews are contained in the SLR
specification manual. The full SLRs and this manual are contained on the CD included with this Report.

2.1 Basic concepts and principles
2.1.1 Cancer
Cancer is a group of more than 100 diseases characterised byuncontrolled cellular growth as a result of changes in thegenetic information of cells. Cells and tissues are complex systems with critical stages and checkpoints to ensure normal
growth, development, and function. Normally the division, differentiation, and death of cells are carefully regulated. All cancers start as a single cell that has lost control of its normal
growth and replication processes.

Human adults are made up of around 1013 (or10 000 000 000 000) cells, which are renewed and replaced
constantly. About 5–10 per cent of cancers result directlyfrom inheriting genes associated with cancer, but the majority involve alterations or damage accumulated over time to
the genetic material within cells. The causes of damage areboth endogenous (internal) and exogenous (environmental).
Food, nutrition, and physical activity are important environmental factors in the development of cancer.
Cancer can also be seen as a group of diseases that affects
many different tissues and types of cell, and can be definedby their tissue of origin. Approximately 85 per cent of adultcancers develop from the epithelial cells of the inner andouter linings of the body and are called carcinomas. Cancers
of glandular tissue such as the breast are called adenocarcinomas; cancers from bone and muscle derived from mesoderm cells (embryonic cells that grow to form muscle, blood,bone, and connective tissue), are called sarcomas.
Each type of cancer has different characteristics, but one
feature of all these diseases is unregulated cell growth and/or
cell death. Apart from haematological cancers such as
leukaemias, this results in a tumour or mass, and cancerous
cells often invade the surrounding tissue. Spread of cancer
cells from the primary site to other parts of the body is called
metastasis. Benign tumours do not invade or metastasise.
Malignant tumours do not remain localised but can invade
and/or metastasise.
2.1.2 Genetic material
The genetic material of mammalian cells is composed of double-stranded DNA made from four organic bases — cytosine,
guanine, adenine, and thymine — within a helical spine
comprising deoxyribose (a sugar) and phosphate. The combination of a base with phosphate and deoxyribose is calleda nucleotide. Humans have 3 billion base pairs in the DNA
code that encode approximately 30 000 different genes.
The nucleus of a cell contains DNA, and the informationin the code is ‘read’ to generate proteins in the cytoplasm of
the cell. This is achieved by transcribing the DNA into RNA,and then translating the information in RNA to synthesise
protein. For transcription, the two DNA strands separate andan intermediary, complementary copy of the DNA is madefrom mRNA (which differs slightly in structure from DNA
and is single stranded). For translation, the RNA leaves thenucleus and binds to an organelle in the cytoplasm called theribosome. The RNA nucleotides encode for 21 different

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components in terms of thedose (quantity), timing, andduration of exposure required
to bring about effects. To unravel the contribution of nutrition
to cancer, the biologicalprocesses underpinning cancer
development need to be understood. Extensive evidence exists
for nutritional factors in several processes related to cancer
development (figure 2.2).
However, because of the complexity of the process, it is notpossible to conclude that modifying any one, or more, of
these processes influences
cancer risk.
The recent expansion ofknowledge in molecular biology has allowed new techniques
to be developed to explain
The genetic message in the DNA code is translated into RNA, and then into protein synthesis,
these mechanisms. Nutriand so determines metabolic processes. Research methods called ‘-omics’ address these different
genomics is a new field withstages.
profound implications in cancer
prevention and therapy, since itamino acids, with the ribosome moving along the RNA molseeks to clarify the impact of nutrition in the maintenanceecule and translating the genetic code into a sequence ofof genome stability, and to dissect out the influence of genoamino acids that build into a protein.
type in determining our response to diet. Nutrigenomics is
The normal metabolic processes in cells are controlled by
the study of nutritional influences on the phenotypic variproteins, each of which is a product of a single gene from theability of individuals based on genomic diversity (figure 2.1).
DNA in the nucleus. Although each cell in the body contains
This determines the sequence and functions of genes, andexactly the same genes, cells from different organs have difstudies single nucleotide polymorphisms (SNPs), and ampliferent structures and functions because there is a process offications and deletions within the DNA sequence as modiregulation that determines which genes are expressed; thatfiers of the response to foods and beverages and theiris, which genes are turned on and which are not (see 2.2.2).
constituents. Nutritional epigenomics is another key deterThis differential gene expression varies not only from tissueminant of gene expression patterns. It includes non-coding
to tissue but also from time to time over the course of a permodification of genes (such as methylation, changes in hisson’s life, from embryonic and fetal stages onwards (box 2.1).
tone homeostasis, miRNA, and DNA stability) in response
Gene expression is regulated by promoter regions of genes into nutrition. Nutritional transcriptomics is the study of gene
the DNA, as well as by epigenetic factors — those that alter
expression patterns at the RNA level, and it can identify
gene expression without changing the nucleotide sequencecommon nutritional response elements in gene promoters(see 2.2.3). The availability of nutrients within the immedithat can be modulated by diet. Proteomics studies the proate environment influences these processes (figure 2.1).
teins that can be expressed by a cell, many of which can be
influenced by nutrition. Metabolomics studies the range of
2.1.3 Nutrigenomics and cancer
metabolic processes in a cell and metabolic regulation in
Unravelling links between diet and cancer is complex, as
cells or tissues, which again are heavily influenced by food,thousands of dietary components are consumed each day; anutrition, and physical activity.
typical diet may provide more than 25000 bioactive foodconstituents.1 Assessing intakes of some constituents is difficult due to wide variations in the amounts of bioactive com2.2 Cellular processes
ponents within a particular food.2 3 Dietary constituentsmodify a multitude of processes in both normal and cancer
The role of nutrition in cancer depends on how it impacts
cells.4 5
on fundamental cellular processes including the cell cycle
The response is further complicated since a single, bio(figure 2.3; also see 2.5.1). To understand cancer biology,
active food constituent can modify multiple steps in theit is important first to understand normal cellular processes.
The integrity of tissues and organs depends on a regulated
cancer process. Likewise, many of these processes can bebalance between cell proliferation and death, and approinfluenced by several food components. Normal and cancer
priate cell differentiation. This regulation is controlled bycells also differ in their responses to bioactive food32

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several types of genes including oncogenes and tumour suppressor genes (box 2.2), and factors in the cellular environment that influence their expression. Maintenance of the
DNA sequence and structure as cells divide is essential: several cellular mechanisms exist to ensure this is achieved.

process called phosphorylation. A regulated process of phosphorylation and dephosphorylation is necessary for theappropriate initiation, transmission, and cessation of signals.

2.2.2 Gene expression
Gene expression is the process by which the information
within a gene is ‘turned on’ or ‘turned off’. The information
2.2.1 Cell signalling
Cells detect and respond to external stimuli and send mess- is used to create the associated proteins and modify theages to other cells through a molecular mechanism known amounts produced. Also see figure 2.1.
Transcription factors are proteins involved in the regulaas cell signalling.
Cells within a tissue normally communicate with each tion of gene expression and carry the signal from theother through a network of locally produced chemicals called cytoplasm to the nucleus. They bind to the promoter regions
cytokines (including some growth factors). Cell proliferation of genes and have the effect of either switching geneis a tightly controlled and coordinated process, and is stim- expression on or off. There are also nuclear receptors, suchulated by growth factors. These soluble proteins can be pro- as retinoic acid receptors, that function as transcription
duced locally, either from the same cell (autocrine), or from factors by binding directly to specific DNA sequences.
Some so-called ‘housekeeping’ genes are expressed bydifferent cells (paracrine), or as hormones (endocrine) produced by a distant tissue and transported in the blood. almost all cell types. These genes generally encode proteins
Growth factors bind to specific receptors on the cell surface that participate in basic cell functions such as metabolicand transmit a signal into the cell, which is relayed to the pathways and synthesis, and processing of DNA, RNA, or pronucleus. In the nucleus, genes are switched on to produce teins. Other genes have more restricted expression, andthe proteins necessary for cell division.
are expressed only in specific cell types, and/or stages ofGetting the growth signal from the outside of the cell to development.
the nucleus requires a series of steps. The shape of the recepGene expression can also be influenced by changes outside
tor changes when the growth factor binds to it, which caus- the DNA of genes. DNA is closely organised and tightly packes part of the receptor to become activated, usually by a aged in the nucleus of cells. To achieve this, DNA is spooledaround proteins called histones. Histone structure canbe modified either, like DNA
itself, by methylation, or
more commonly by acetylation (addition of an acetylgroup). Acetylation anddeacetylation (removal) are
mediated by the enzymes
histone acetyl transferase(HAT) and histone deacetylase (HDAC), respectively.
HATs relax the packaged
DNA structure, which is associated with enhanced transcription, whereas HDACs
stabilise the structure withhigher levels of packaging,and so suppress transcription. Butyrate, produced in
the colon by bacterial
fermentation of non-starchpolysaccharide(dietary
fibre), diallyl disulphidefrom garlic and other allium
vegetables, and sulphoraphane, a glucosinolate from
cruciferous vegetables, canbehave as histone deacetylase inhibitors,16 and act tomaintain DNA stability orenhance transcription.
Food, nutrition, obesity, and physical activity can influence fundamental processes shown here,
Micro RNAs (miRNAs) are
which may promote or inhibit cancer development and progression.

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Box 2.1•

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Nutrition over the life course

The best understanding of the impact ofendogenous and exogenous factors on thecancer process will come from studies of
the whole life course, and particularly ofcritical periods within it.
Early nutritional exposure is an important determinant of phenotypic expression
during later life and is likely to affect vulnerability to chronic diseases, including
cancer.6 During pregnancy, the nutrient
demands of the fetus have to be satisfied.
Although the mother’s dietary intake isimportant in maintaining her own nutrient
reserves, it is her nutrition status on entering pregnancy that determines her capacity to deliver appropriate nutrients to thefetus. Any stress that modifies her nutritional state, either by changing appetite oraltering nutrient demand, can impact on
the availability of nutrients to the fetus.7 In
experimental models, pregnant rats fed a
low-protein diet resulted in overexposureof the fetus to maternal glucocorticoids.
This led to a permanent alteration inhormonal status and metabolic responses in
the offspring.8 9 These effects were attributed to differential methylation of certain
glucocorticoid genes and could be mitigated by maternal folic acid supplementation.4
Lower birth weight, followed by exposure to periods of rapid rates of growth,
possibly due to energy-dense diets, is associated with development of metabolic
syndrome during adult life.6 This is the clustering of several cardiovascular risk factors
including hypertension, abdominal obesity, insulin resistance, and type 2 diabetes.
Type 2 diabetes has been associated withincreased prevalence of some cancers, andrisk of cancer shows a graded relationshipwith glycated haemoglobin (a measure ofblood glucose control) throughout the normal range.10 Metabolic syndrome may also
increase cancer risk,11 suggesting that the

RNA molecules that do not encode proteins; instead theyfunction as negative regulators of gene expression. Somemutations in miRNAs have been associated with human cancers, and they can function as oncogenes or tumour suppressor genes (box 2.2). miRNAs are short, single-stranded
RNA molecules of approximately 22 nucleotides. For
instance, to silence (turn off) genes, they may bind to complementary mRNA sequences and degrade them before they
have been translated. Profiling miRNA signatures within cancer cells may aid the diagnosis, classification, and treatmentof cancer. For example, a certain miRNA that is downregulated in lung cancer is associated with decreased survival.17
Research on the interactions between nutrition and non-coding RNA molecules is at an early stage but is potentially relevant to cancer.
2.2.3 Epigenetic regulation
Gene expression can also be altered without changing the
DNA sequence. This is called epigenetic modulation.
Methylation of DNA — the addition of a methyl group(CH3) — plays a role in gene silencing. Methylation occurs
only to cytosine residues located next to guanine bases in the
DNA sequence. These CpG dinucleotide sequences are foundthroughout the genome; in about half of all genes, clustersof CpG sequences, so-called ‘CpG islands’, are located in the
promoter region that normally functions to promote expression of the gene. Transcription factors cannot bind to thesesites when methylated and so the gene is silenced. For active
genes, the CpG islands in the promoter regions are generally not methylated.
Controlled DNA methylation also provides a mechanism
for cell differentiation. In normal cells, genes may be permanently silenced so that they can no longer be expressed,
in a way that is transmitted into daughter cells during cell

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metabolic disturbances associated withthis syndrome promote genetic instability.
Growth and development are dependent
on the supply of adequate energy andnutrients to match a person’s needs. Famine
exposure in women affects breast dysplasia
later in life: girls exposed to famine before
the age of 10 years have less dysplasia inlater life, whereas those exposed after 18
years of age have more dysplasia than nonexposed women. This illustrates the importance of timing of nutrition during key
stages of development.12
Greater body fatness later in life islinked to development of metabolic syndrome and related health problems,
including insulin resistance. The inflammatory state associated with obesity also
promotes cancer.13 In contrast, energy
restriction (box 2.5) delays the onsetof many age-related diseases, including
cancer.

division (see 2.5.1), so maintaining the particular structural and functional characteristics of the cells of specifictissues.
Dietary constituents contribute to epigenetic modulationof promoter regions in both normal and malignant cells. For
example, dietary folate and other methyl-donors such as
choline, methionine, and betaine are essential for DNA
synthesis and epigenetic regulation of DNA. Appropriate
gene expression is maintained by appropriate patterns ofmethylation; folate is an important determinant of normal
methylation. In addition, dietary constituents such as genistein, which do not provide methyl groups, have also beenreported to modify DNA methylation.
Imbalances or lack of specific dietary constituents may
potentially increase the risk of cancer by inducing an imbalance in DNA precursors, leading to altered DNA synthesis
and repair, and may impair appropriate patterns of DNA
methylation, with consequences for gene expression. For
example, inadequate folate availability means cells tend toincorporate uracil into DNA in place of thymine. Global
hypomethylation of DNA is an early epigenetic event in cervical carcinogenesis, and the degree of hypomethylation
increases with the grade of cervical cancer.18 19 Global
hypomethylation of DNA and site-specific hypermethylation
may also be relevant in colorectal cancer.20 A host of bioactive food constituents from alcohol to zinc has beenreported to influence DNA methylation patterns.
Nevertheless, it remains to be determined how importantthese changes are in the overall cancer process. The potential cancer-protective effects of green, leafy vegetables (seechapter 4.2) are often attributed to their folate content.
Folates function as a coenzyme in the metabolism of singlecarbon compounds for nucleic acid synthesis and amino acidmetabolism.

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2.2.4 Differentiation
Cells become specialised to perform their particular function
through a process known as differentiation.
Although each cell within the body contains the entire
genome with the same genes, only some genes are active inany one cell at any one time. Gene expression controls thesubset of genes expressed and the timing of expression, andthis distinguishes one cell type from another by determining their particular structure and function.
Hundreds of different cell types arise from one fertilised
egg during development; this is achieved by proliferationand differentiation of stem cells. Stem cells are unspecialised
but can give rise to different specialised cell types. A small
population of cells within the tumour mass of several formsof human cancer, which have both the properties of stem
cells and also the characteristics of transformed cells, may
be important for the development of these tumours. As yet,
our understanding of cancer stem cells is basic, although theconcept was proposed as early as 1875.22 Several groups have
now isolated and identified cancer stem cells in bothhaematopoietic and epithelial cancers, including cancers of thebreast,23 brain,24 25 ovary,26 prostate,27 colon,28 and stomach.29
It is clear that subtle changes in exposure to bioactive foodconstituents can have a profound effect on the differentiationof these cells.
In early embryos, proliferation of embryonic stem cells
increases the total number of cells. As the organism develops, cells differentiate and become specialised to their particular function. Transcription factors specific to that cell type
turn on genes for that particular lineage of cells, so determining its structure and function.
At various stages of differentiation, cells become sensitive

Box 2.2

to different growth factors. In the cancer process, one characteristic of cells that are accumulating DNA damage is thatthey become de-differentiated and undergo epithelialmesenchymal transition (EMT), characterised by loss ofcell adhesion and increased cell mobility. In addition, during differentiation, other genes can be silenced by chromatin
modification, including DNA methylation and histone modifications such as methylation and acetylation (see 2.2.2).
Stem cells are found among differentiated cells in almost
all adult tissues, where they maintain and regenerate tissues.
Examples include haemopoietic stem cells for continuous
generation of red and white blood cells, and stem cells inthe basal layer of the epidermis and at the base of hair follicles in the skin, which can give rise to keratinocytes andhair follicles. Cellular differentiation also continues in solid
tissues such as mammary tissue, which during pregnancy differentiates for later milk production. A systematic review has
shown that long-chain n-3 polyunsaturated fatty acids(PUFAs) in fish oils promote differentiation of colonic epithelial cells.30 31 Vitamin D and retinoic acid may also promote
differentiation of cells.
2.2.5 DNA damage and repair
Each time a cell divides into two new daughter cells, there
is potential for an error in replication of the DNA (see 2.5.1).
These mutations result in non-functioning genes or in proteins with altered amino acid sequences that can change cellfunction.
DNA is continuously exposed to damage from products ofnormal intracellular metabolism, including reactive oxygen
species, hydroxyl radicals, and hydrogen peroxide; and also
to damage from external factors such as ultra-violet (UV)

Oncogenes and tumour suppressor genes

Oncogenes and tumour suppressor genes
are present in all cells, and in their normal,
non-mutated form contribute to the regulation of cell division and death. In cancer,
both types of gene are often mutated, andthese alterations contribute to the cancer
process. The combined effect of activationof oncogenes and inactivation of tumour
suppressor genes is an important driver ofcancer progression.
Oncogenes increase the rate of transformation from a normal to a cancerous cell.
Oncogene function is changed by mutation
so that the protein product is produced
either in greater quantities or has increased
activity. The normal, non-mutated form ofan oncogene is called a proto-oncogene.
More than 100 oncogenes have been
identified, including ERBB2 in breast andovarian cancers, members of the Ras family
in cancers of the lung, colorectum, and pancreas, and MYC in lymphomas. Amplification of the ERBB2 gene occurs in around30 per cent of breast cancers, and RAS muta-

tions occur in approximately 30 per cent of
all human cancers (and in 75–90 per cent ofpancreatic cancers).
Tumour suppressor genes prevent excessive growth of a cell, either by controllingcell proliferation or by controlling DNA
repair and genomic stability. Mutation of atumour suppressor gene results in the lossof function of the protein product.
Common tumour suppressor genes include p53 and the retinoblastoma (Rb) gene.
The p53 gene was the first tumour suppressor gene to be identified, and is considered to be the guardian of the genome.14
Under normal circumstances, p53 is involved
in several processes such as cell proliferation, DNA repair, apoptosis, and angiogenesis. p53 is activated by cellular stresses that
could facilitate tumour development such as
hypoxia, lack of nucleotides, and in particular, DNA damage.
In response, p53 can either halt the cell
cycle to allow DNA repair, or induce apoptosis. It can bind to the promoter regions ofapproximately 300 different genes, thereby
having an important regulatory role in various molecular pathways. The p53 pathway
is altered in most cancers, and the mutatedprotein product cannot protect the
genome, allowing mutations to accumulate.
In the absence of a functional Rb gene,
the retinoblastoma protein pRb is not madeand its inhibitory role of inactivating cell
cycle transcription factors is absent. This
leads to increased, uncontrolled proliferation, and thereby increased risk of further
mutations. More than 2000 inactivating
mutations of p53 have been identified inhuman tumours. Both p53 and pRb can also
be inactivated by the human papilloma
virus. Development of lung cancer is associated with loss of function of both genes. LiFraumeni syndrome, a result of a germ line
mutation in p53, leads to inherited
susceptibility to a wide range of cancers.
Patients with Li-Fraumeni syndrome havea 25-fold increased risk of developing cancer
compared with the general population.15

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light, as well as other environmental factors including food,nutrition, and physical activity (see 2.4). There are several
mechanisms for DNA repair (box 2.3), a vital defence inmaintaining cellular integrity and preventing a cell beingtransformed from normal to cancerous.
Various studies suggest that nutritional status and/or certain food constituents may influence DNA repair. Data fromobservational studies suggest that severe malnutrition can
impair DNA repair.34 Nucleotide excision repair has beenfound to be lower in adults with the lowest intakes offolate.35 Studies of healthy adults consuming kiwi fruits,36
cooked carrots,37 or supplements of coenzyme Q10 (an important cofactor in metabolism)38 have demonstrated improved
DNA repair in vitro. Selenium induces base-excision repair
in vitro via p53 activation in cultured fibroblasts.39
Evidence exists that some dietary components can modify
DNA damage and gene expression in exfoliated colonocytes.
For example, the amount of single-strand breaks in exfoliated colorectal mucosal cells was significantly lower inhealthy individuals consuming a vegetarian diet comparedwith a diet high in meat.40 Similarly, DNA damage in exfoliated lung epithelial cells can be influenced by dietary components. Consumption of a lycopene-rich vegetable juice wasassociated with significantly decreased damage to the DNAof lung epithelial cells in healthy volunteers.41
Defects in any of the DNA repair mechanisms can predispose to cancer. Several inherited conditions link such defects
to cancer incidence. For example, patients with hereditary
non-polyposis colorectal cancer have defective mismatch
repair (see chapter 7.9.2).
Although the processes of cell development, signalling,
and DNA repair are tightly controlled, errors will occur during the trillions of cell divisions that occur over a lifetime.
This may result in inappropriate proliferation or failure ofdamaged cells to die. These changes could provide thealtered cell with a growth advantage over the normal cells
in the tissue. If additional alterations occur, this can resultin a cell with the potential to become cancerous.

2.3 Carcinogen metabolism
The chance of carcinogenesis occurring and then progressing is modified by many factors, including food and nutriion. Dietary constituents that modify carcinogenesis include
selenium, allyl sulphur, sulphuraphane, and isoflavonoids.
Most dietary carcinogens require activation to produce
reactive intermediates that bind to and damage DNA. Phase
I and phase II metabolising enzymes in the liver and in othertissues are involved in this process. These are enzymes thatcatalyse the metabolic detoxification of xenobiotics, drugs,
and carcinogens produced through aerobic metabolism, andthus protect cells against oxidative stress and reactive electrophilic carcinogen metabolites.
Metabolic activation of carcinogens is generally catalysedby the cytochrome P450 (CYP) family of phase I enzymes
through oxidation, which usually makes the molecule morewater soluble. Some of the intermediates formed during thisprocess may be carcinogenic, and can bind to DNA, forming

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DNA adducts. These adducts distort the structure of DNA anddisrupt its replication, potentially causing mistranslation.
They can also break the DNA strand, which can result inmutations or deletions of genetic material.
In addition to P450 enzymes, other systems such as peroxidases (including the cyclooxygenases) and certain transferases, such as N-acetyltransferase and sulphotransferase,
can influence carcinogen bioactivation.42-44
Competing with this metabolic activation of carcinogens
is the detoxification process catalysed by a second group of
enzymes, known as phase II enzymes.45 They catalyse conjugation reactions, producing molecules that can be excreted in bile or urine. Examples include acetyltransferases,
glutathione-S-transferases (GSTs), UDP-glucuronyltransferases, NAD(P)H:quinone oxidoreductase, and sulphotransferases. The induction of phase II enzymes is mediatedby the antioxidant response element, which is located in the
promoter region of specific genes.46
Each of these enzymes represents a potential target for
dietary components to influence carcinogen activation.
Specificity in response is evident since isothiocyanates from
cruciferous vegetables have been shown to induce expressionof phase II detoxification enzymes without affecting expression of phase I enzymes.
The carcinogenic properties of polycyclic hydrocarbons,aromatic amines, N-nitroso compounds, and aflatoxins
result from the metabolism of these compounds, which
produces carcinogenic by-products. Metabolising enzyme
activity can be modulated by dietary factors. The enzyme
CYP3A4 participates in the metabolism of over half ofall pharmaceutical agents, and is especially sensitive to
dietary effects. For example, interactions have been reported between grapefruit juice, red wine, garlic, and various
drugs.47 Food–drug interactions involving CYP1A2, CYP2E1,
glucuronysyltransferases, and GSTs have also been
documented.48
The activity of phase I and II enzymes, and thus carcinogen metabolism and cancer development, varies between
individuals. SNPs in several phase I and phase II enzymes
have been shown to modulate cancer risk.49 50 There is somedifficulty in synthesising this evidence and some studies may
give false positive results. Nevertheless, the literature shows
tantalising evidence that relates genetic diversity to these
enzymes in various processes linked to cancer development.
Some specific examples of SNPs in cancer are listed below.
GSTs are involved in the metabolism of environmental carcinogens and reactive oxygen species. People who lack these
enzymes may be at higher risk for cancer because of areduced capacity to dispose of activated carcinogens.51 As
shown in chapter 4.1, aflatoxins — produced by moulds that
contaminate certain types of foods such as cereals (grains)and peanuts — are carcinogens that are activated by phase
I enzymes in the liver into reactive DNA metabolites thatcause DNA adducts. However, the number of adducts andtherefore the potency of aflatoxin B are influenced by otherenzymes such as GSTs, which eliminate carcinogens before
they can bind to DNA. Individuals with low expression of
GSTs are also at higher risk for colorectal cancer; however,a diet high in isothiocyanates (derived from glucosinolates

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Mechanisms for DNA repair

Mammals have five types of DNA repair system32 33:• Direct reversal corrects rather than removes damaged DNA
bases.
• Base-excision repair corrects DNA damage caused by reactive
oxygen species, deamination, and hydroxylation arising from
cellular metabolism and spontaneous depurination.
• Nucleotide-excision repair removes lesions that distort thestructure of the DNA helix, such as pyrimidine dimers andDNA adducts.
• Homologous recombination and non-homologous endjoining repair double-strand breaks. Homologous
recombination is used when a second identical DNA copy isavailable, for example after replication; non-homologous
end-joining re-links the ‘broken’ ends of a double-strand
break.
• DNA mismatch repair detects and repairs copying errors
made during replication.

in cruciferous vegetables) can ameliorate this.52
Epidemiological evidence supports the idea that individuals possessing these genotypes are predisposed to a number of cancers, including those of the breast, prostate, liver,and colon53; it also shows that nutrition influences cancer
risk. Thus, an SNP in the methylenetetrahydrofolate reductase (MTHFR) gene appears to influence folate metabolism
by reducing MTHFR activity, and is associated with a reduction in the risk of developing colorectal cancer.54 Certain
SNPs in the N-acetyltransferase gene alter the activity of the
enzyme (involved in the metabolic activation of heterocyclic
amines from meat cooked at high temperatures), and may
also increase the risk of colon cancer.
Again, as described in chapter 4.3, people whose diets arehigh in red and processed meat and who also carry an insert
variant in CYP2E1, a key activating enzyme of many nitrosamines, have a greater risk of rectal cancer.55 Consumptionof cruciferous vegetables protects against lung cancer in individuals lacking the GSTM1 gene.56 In addition, genes thatpredispose to obesity may promote obesity-related cancers(box 2.4).
Dietary components can either be, or be activated into,
potential carcinogens through metabolism, or act to prevent
carcinogen damage. For instance, as summarised in chapter
4.3, high intake of red meat may result in more absorptionof haem iron, greater oxidative stress, and potential for DNA
damage.57 58 In addition, iron overload can also activate
oxidative responsive transcription factors and inflammationin the colon.59 Red meat consumption is also associated withthe formation of N-nitroso compounds. This increases thelevel of nitrogenous residues in the colon and is associatedwith the formation of DNA adducts in colon cells.60
Cruciferous vegetables contain glucosinolates, which aretransformed by food preparation into isothiocyanates (ITCs),
which alter the metabolism of carcinogens. Indoles and ITCs,
two major glucosinolate breakdown products, attenuate theeffects of polycyclic aromatic hydrocarbons and nitrosamines
via induction of GSTs and inhibition of cytochrome P450
isoenzymes, respectively.

Human intervention studies with cruciferous vegetables
have demonstrated induction of GSTs by consumption ofBrussels sprouts and red cabbage varieties, but not withwhite cabbage and broccoli. The particular isoform of the
enzyme induced may protect against bladder cancer.
Cruciferous vegetables also affect drug metabolism inhumans, and red cabbage leads to specific changes in thepatterns of meat-derived urinary mutagens. ITCs may also
protect against mutations formed by tobacco carcinogens.61
In a variety of animal studies, certain dietary components
have shown a reduction in experimentally induced cancers.
Rats fed ITCs developed significantly fewer oesophageal
cancers due, in part, to inhibition of cytochrome P450mediated bioactivation of the carcinogen. Dietary indole-3carbinol inhibited spontaneous occurrence of endometrial
adenocarcinoma and preneoplastic lesions in rats.62
Flavonoids (polyphenolic compounds found in plantfoods) may also alter carcinogen metabolism. Quercetin has
been shown to inhibit the expression of cytochrome P450
and phase I enzymes, and may reduce tobacco carcinogenactivation.63
Exposure of vulnerable populations to excess amounts of
dietary constituents, irrespective of whether they are nutrients or not, may actually increase the risk of cancer. In
one example, consumption of beta-carotene supplementsin smokers was associated with increased incidence of lungcancer.64 For most dietary components, there will be an
upper threshold beyond which people may be exposed toadverse effects. There are also concerns regarding excessive
supplementation with folic acid, iron, copper, iodide, andselenium.65

2.4 Causes of cancer
A number of different types of exogenous (environmental)
factors are known causes of cancer. These include some
aspects of food and nutrition that are established as carcinogenic by the International Agency for Research on
Cancer, although it is difficult to estimate the proportion ofcancers directly attributable to these.74 Known causes of cancer include tobacco smoking and its use, infectious agents,
medication, radiation, and industrial chemicals, and also
some factors within the scope of this report — carcinogenic
agents in food and drink.
Sometimes the extent to which cancer in general, or specific cancers, may be modified by any factor, are calculated,and some of these figures are given here. However, these estimates should be treated with some caution. First, they are estimates, and cannot be exact, and so are best given as ranges.
Second, individual causes of cancer often interact with one
another to increase or decrease risk, or are modifiers or precursors of others; and some act together to produce a multiplicative effect. This point is particularly important with foodand nutrition, which may have a substantial effect on the riskof a cancer with environmental causes other than food, nutrition, and physical activity. Third, it is sometimes assumed thatonce all factors that decrease (or increase) risk are added
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should add up to 100 per cent. This is not so. Reasonable estimates for a number of separate or interactive factors may add
up to well over 100 per cent because of the interactions.
2.4.1 Endogenous causes
2.4.1.1 Inherited germ line mutations

As mentioned, only a minority (5–10 per cent) of cancers arelinked to single inherited genes. Such inherited alterations
are termed germ line mutations, and are passed on from egg
or sperm DNA. Individuals with inherited germ line mutations will not definitely get cancer but have an increased riskof developing cancer compared with the general population.
Often mutations in tumour suppressor genes (box 2.2)
increase the chance of developing cancer at a young age.
These include retinoblastoma (a rare cancer of the eye), LiFraumeni syndrome, multiple endocrine neoplasia type 1,
and kidney cancer in Von Hippel-Lindau disease. Mutationsin the BRCA1 and BRCA2 (breast cancer susceptibility) genes
cause 5–10 per cent of all breast cancer cases. These genes
normally produce DNA repair proteins. Patients with thesyndrome familial adenomatous polyposis coli have a predisposition to colorectal cancer due to mutations in the adenomatosis polyposis coli tumour suppressor gene.75 Other
common cancers, including those of the ovary, prostate, pancreas, and endometrium, may be related to inherited mutations, but only in a small percentage of cases.
The other type of genetic mutation — somatic genechanges — develops during the life course. Such somatic
mutations are not passed on to offspring. This DNA damage
is caused by exposure to external factors such as radiationor carcinogens, or harmful products of normal aerobic
metabolism.
2.4.1.2 Oxidative stress

Reactive oxygen species generated through normal oxidative
metabolism have the potential to cause extensive DNA damage. The body has several mechanisms, which can scavenge
reactive oxygen species to prevent such damage occurring,or block the effects.
Reactive oxygen species cause oxidative damage to DNA.
During repair (see 2.2.5), the damaged, oxidised bases are
excreted in the urine. Levels of urinary 8-hydroxy-2'deoxyguanosine, an oxidative DNA damage adduct, can beused as an indicator of oxidative DNA damage in humans
and rodents. Antioxidants can scavenge reactive oxygen
species. Vitamins C and E can donate electrons to free radicals and block their damaging activity. Dietary constituents
such as ITCs and polyphenols can also activate the signalling
pathways that lead to activation of the antioxidant response
element (see 2.3), and upregulation of the expression ofdetoxifying enzymes.
2.4.1.3 Inflammation

Inflammation is a physiological response to infection, foreign
bodies, trauma, or chemical or other irritation, and in theacute phase can be helpful. However, chronic inflammation
can result in DNA damage and cancer promotion.
Chronically inflamed tissue is infiltrated with a variety of
inflammatory cells that produce a wide variety of bioactive

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chemicals. These include cytokines, growth factors, reactive
oxygen and nitrogen species, cyclooxygenase, and lipoxygenase products. A chronic inflammatory environment canincrease proliferation and differentiation, inhibit apoptosis(programmed cell death), and induce angiogenesis (generation of new blood vessels). Chronic inflammatory conditions, such as Barrett’s oesophagus and ulcerative colitis,
predispose to cancer. In Barrett’s oesophagus, reflux of acidcan cause the cells lining the gullet to undergo EMT, andsome areas can develop dysplasia and ultimately cancer.
Around 1 per cent of people with Barrett’s oesophagus willdevelop oesophageal cancer (this is between 30 and 125
times higher than the general population). Also see chapter
7.3.2. Approximately 5 per cent of patients with ulcerative
colitis, a form of irritable bowel disease, will develop coloncancer. Also see chapter 7.9.2. Epidemiological and experimental evidence has demonstrated that long-term use ofnon-steroidal anti-inflammatory drugs can inhibit cancer
development in a number of tissues including colon,
oesophagus, and breast.76
Cancer induced by inflammation may be susceptible tonutritional influences. Thus, dietary constituents could be
involved in generation of reactive oxygen species, could
influence antioxidant defences, or could suppress the inflammatory process. For example, the glucocorticoid receptor
pathway and the vitamin D receptor are capable of suppressing inflammation.
The immune system can be divided into innate and adaptive responses. Innate immunity provides initial defences.
Adaptive immunity develops later and involves activation oflymphocytes and their differentiation into effector and memory cells. The ‘immune surveillance’ hypothesis proposes thatboth the innate and adaptive immune systems constantly
survey for and eliminate newly formed cancer cells, and that
onset and progression of cancer are kept under control by
the immune system.77 Immunosurveillance requires that theimmune system recognises something different about cancer
cells compared with normal cells within the same tissue –often different proteins (termed tumour antigens) that are
expressed on the surface of a cancer cell.
This recognition of ‘altered self’ allows the immune system to generate a response to these tumour antigens. They
can be proteins that are only expressed by cancer cells, andnewly expressed during cancer development; or proteins thathave become mutated during the cancer process and so are
different from the non-mutated protein; or proteins
expressed due to differentiation of cancer cells (termed differentiation antigens); or proteins that are normally
expressed by cells but that are expressed at much higher levels by cancer cells. Evasion of immunosurveillance is sometimes referred to as a further hallmark of cancer78 (see 2.5),
although the evidence remains speculative.
Specialised mucosal cells form the interface between theinside and outside of the body.79 These are normally an efficient barrier against pathogens. The gut barrier consists ofgut-associated lymphoid cells that can sense pathogens, andparticipate in innate and adaptive responses.80 The functionof these cells is dependent on nutrition.81 82 For example, n3 PUFAs can enhance immunity, whereas high concentrations

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Box 2.4

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Body fatness and attained heightAs shown in Chapter 6, the overall evidence
that body fatness is a cause of a number ofcancers is convincing. Some of the mechanisms by which body fatness increases therisk of cancer are well understood.
Obesity influences the levels of a number of hormones and growth factors.66
Insulin-like growth factor 1 (IGF-1), insulin,
and leptin are all elevated in obese people,
and can promote the growth of cancer
cells. In addition, insulin resistance isincreased, in particular by abdominal fatness, and the pancreas compensates by
increasing insulin production. This hyperinsulinaemia increases the risk of cancers of
the colon and endometrium, and possiblyof the pancreas and kidney.13 Increased
circulating leptin levels in obese individuals are associated with colorectal67 andprostate cancers.68
Sex steroid hormones, including oestrogens, androgens, and progesterone, arelikely to play a role in obesity and cancer.
Adipose tissue is the main site of oestrogensynthesis in men and postmenopausal
women,13. The increased insulin and IGF-1
levels that accompany body fatness resultin increased oestradiol in men andwomen,13 and may also result in higher
testosterone levels in women (extreme
obesity can lead to polycystic ovary disease). Increased levels of sex steroids arestrongly associated with risk of endometrial and postmenopausal breast cancers,69
70
and may impact on colon and other cancers. As shown in Chapter 6, body fatness
probably protects against premenopausal
breast cancer; this may be because obese
women tend to have anovulatory menstrual cycles and thus reduced levels ofoestrogen.
Obesity is characterised by a low-grade
chronic inflammatory state, with up to 40
per cent of fat tissue comprising macrophages. The adipocyte (fat cell) produces
pro-inflammatory factors, and obese individuals have elevated concentrations ofcirculating tumour necrosis factor (TNF)-

of n-6 unsaturated fatty acids can have a suppressive effect.83
Various factors have been shown to modulate both inflammation and immunity, including vitamins A and E, copper,
selenium, zinc, PUFAs, and epigallocatechin-3-gallate(EGCG) from green tea.84 Zinc deficiency can lead to abnormalities in adaptive immune responses.85
Immune status and chronic inflammation may explain patterns of cancer in different parts of the world. Cancers caused
by infectious agents, such as those of the liver and cervix (seechapter 7.8 and 7.13) are more common in low-income
countries, where undernutrition may impair people’s
immune responses. Undernutrition, with deficiencies in specific micronutrients such as vitamin A, riboflavin, vitamin
B12, folic acid, vitamin C, iron, selenium, and zinc, suppresses most immune functions and may fail to control
chronic inflammation.86 87 By contrast, hormone-related
cancers such as those of the breast and prostate are morecommon in developed countries.
The cytokine IL-6 can act as a pro- or anti-inflammatory
cytokine. In cancer, IL-6 can either stimulate proliferation orexert anti-tumour effects by enhancing both innate andadaptive immunity.88 Dietary phytoestrogens, such as soy
isoflavones, downregulate IL-6 gene expression and thus
potentially influence the development of hormone-related
cancers.89
Circulating levels of IL-6 increase (up to 100-fold)following exercise; this reduces chronic inflammation
by reducing pro-inflammatory mediators and elevating
anti- inflammatory mediators.90 Regular moderate andoccasional vigorous physical activity has been associatedwith enhanced immunity,91 but prolonged and intense
physical activity can cause immune suppression thatalpha,13 interleukin (IL)-6, and C-reactive
protein, compared with lean people,71
as well as of leptin, which also functions
as an inflammatory cytokine.72 Suchchronic inflammation can promote cancer
development.
Also as shown in Chapter 6, factorsthat lead to greater adult attained height,
or its consequences, are a cause of a number of cancers. Adult height is related to
the rate of growth during fetal life andchildhood. The number of cell divisions
in fetal life and childhood, health andnutrition status in childhood, and age ofsexual maturity can alter the hormonal
microenvironment, and affect circulatinglevels of growth factors, insulin, andoestrogens.
Taller people have undergone more cell
divisions stimulated by IGF-1 and pituitaryderived growth hormone,73 and there is
therefore more potential for error during
DNA replication, which may result incancer development.

cannot be counteracted by nutritional supplements orantioxidants.83 Physical activity does not increase pro-inflammatory cytokines, but instead increases anti-inflammatory
mediators.
Chronic consumption of alcohol alters both innate andadaptive immunity. Heavy drinkers are more vulnerable toinfections and, as shown in chapter 4.8, to liver cancer.92 One
possible mechanism is alteration in hepatic metabolism
resulting in functional iron deficiency that impairs immune
function.93-95
2.4.1.4 Hormones

Lifetime exposure to oestrogen — increased by early menarche, late menopause, not bearing children, and late (over30) first pregnancy — raises the risk of, and may be seen asa cause of, breast, ovarian, and endometrial cancers inwomen. The reverse also applies: a reduction in lifetime
exposure to oestrogen due to late menarche, early menopause, bearing children, and early pregnancy may reduce therisk of hormone-related cancers. Age at menarche andmenopause are influenced by nutrition, with high-energy
diets leading to early puberty and late menopause, and lowenergy diets delaying puberty and advancing menopause.
The oral combined contraceptive pill (containing bothoestrogen and progesterone) has been estimated to halve therisk of ovarian cancer, if taken for 5 years or more.96 This
protective effect can last for up to 15 years after women stoptaking these oral contraceptives.97 Using any type of oral
contraceptive may also have a slight protective effect against
bowel cancer.98 In contrast, combined oral contraceptives
can cause a slight and transient increase in breast cancer risk,
but only for the duration of use.99 There may also be an

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increase in the risk of cervical cancer, although this is partly related to sexual behaviour.100
Studies of women taking oestrogen-only hormone replacement therapy have suggested that the risk of endometrial
cancer is doubled after 5 years of use,101 and the risk of ovarian cancer rises by 25 per cent after the same length of use.97 102
However, use of hormone replacement therapy thatcombines oestrogen and progesterone does not increase ovarian cancer risk and may even protect against endometrial
cancer.102 97 101

Approximately 1 in 4 cancers in low-income countries are
estimated to be attributable to infection. In 2002, this represented some 1.9 million cancers or close to 1 in 5 of allcancers worldwide104. Inadequate nutrition or dietary imbalances can lead to immunodeficiencies and increased susceptibility to infections.
Dietary factors may influence host susceptibility to theviral infection or persistence of the infection. For example,
high folate intake is thought to reduce the susceptibility toand the persistence of human papilloma virus.107

2.4.2 Exogenous causes

2.4.2.3 Radiation

2.4.2.1 Tobacco use

Both ionising radiation and UV radiation damage DNA andact as carcinogens. This includes radiation used in X-ray
radiographs and in the treatment of cancer. In 1982, thevarious forms of radiation were calculated to account for
3 per cent of all cancer deaths.74
Ionising radiation can cause DNA damage, both directly
by causing breaks in the DNA strands, and indirectly by interacting with water molecules and generating reactive oxygen
species that damage DNA.
Although sunlight causes DNA damage, it also induces
production of vitamin D. One of its metabolites, 1-25-hydroxyvitamin D, has antiproliferative and pro-differentiation
effects in some cells mediated through the vitamin D
receptor.
Exposure to ionising radiation comes from cosmic radiation (air travel increases exposure), natural radioactivity
present in rocks and soil, medical exposure through X-rays,
or atomic radiation from weapons and nuclear accidents.
Ionising radiation increases the risk of various cancers, inparticular leukaemias, and breast and thyroid cancers.
UV light from sunlight or sunlamps is divided into threebands of wavelengths: UVA, UVB, and UVC. UVB is the mosteffective carcinogen and is absorbed by bases in the DNA,causing characteristic patterns of DNA damage. UVA damages DNA through generation of reactive oxygen species.
UVC in sunlight is absorbed by ozone in the atmosphereand does not reach the surface of the earth. UV radiation
causes both malignant melanoma and non-melanoma skincancer.
It has been difficult to separate the effects of nutrients on
DNA damage from those on repair, at least in animal or
human studies. There is some evidence that vitamin C andcarotenoids can protect DNA against oxidative damage insome experimental settings.108

Tobacco causes an estimated 20 per cent of all cancer deaths,
and an estimated total of 1.2 million in 2002.75 Smokers
have increased risk of a number of different cancers (seeChapter 7). Worldwide, around 80 per cent of lung cancer
cases in men and 50 per cent in women are caused
by tobacco smoking.103 104 In 2002, out of all new cases ofcancer in low-income countries, over 1 in 5 in men andalmost 4 per cent in women were attributable to tobacco.
In high-income countries, one third of all new cancer cases
in men and just over 1 in 8 in women were attributed totobacco smoking.
Cigarette smoke contains at least 80 known mutagenic
carcinogens, including arsenic, cadmium, ammonia,
formaldehyde, and benzopyrene. Each will have a separate
mechanism for causing cancer. For example, following metabolic activation, the activated derivative of benzopyrene,benzo(a)pyrenediol epoxide, can form DNA adducts in lungepithelial cells.105
Cigarette smoke is a powerful carcinogen and also a sourceof oxidative stress. Compared with non-smokers, active
smokers have lower circulating concentrations of several
antioxidant micronutrients including alpha-carotene, betacarotene, cryptoxanthin, and ascorbic acid.106
2.4.2.2 Infectious agents

Infectious agents, including viruses, bacteria, and parasites,
can induce DNA damage and promote cancer development.
Some infectious agents, including hepatitis viruses, the bacterium Helicobacter pylori (H pylori), and parasites, also promote cancer by causing chronic inflammation (see 2.4.1.3).
Both DNA and RNA viruses can cause cancer, although themechanisms differ.75 DNA viruses encode viral proteins thatblock tumour suppressor genes, whereas RNA viruses orretroviruses encode oncogenes (box 2.2). Human papilloma
virus is an established cause of cervical cancer, Epstein-Barrvirus of nasopharyngeal cancer and lymphoma, and hepatitis B and C infection of liver cancer.
As summarised in Chapter 7, H pylori is associated withstomach cancer, liver flukes (from eating raw or undercooked
freshwater fish) with liver cancer, and Schistosoma haematobium infection with bladder cancer.
In most cases, infection with these agents by itself does notlead to cancer but is a contributory or necessary factor in
the cancer process. Multiple factors are thought to beimportant in determining why cancer is the result in only
some cases.

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2.4.2.4 Industrial chemicals

Certain industrial chemicals and pesticides persist in
the environment and become concentrated in the foodchain. Some of these are within the scope of this Report andare summarised in Part 2. In 1982, industrial chemicals were
calculated to account for less than 1 per cent of cancer
deaths.74
Polychlorinated biphenyls (PCBs), organic compounds previously used in plasticisers, adhesives, paints, and various
oils, do not readily degrade. They are soluble in fat rather
than water and thus accumulate in carnivorous fish such as
salmon, and can be absorbed by people who eat these types

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of fish.109 They also accumulate in human milk, and can bepassed to the infant during breastfeeding. There is limited
experimental evidence suggesting that PCBs have sex
steroid activity and alter oestrogen levels, which may contribute to breast cancer risk.109
Arsenic is genotoxic, causes gene mutations, and is carcinogenic to humans; arsenic in drinking water is absorbed
from the gastrointestinal tract.75 The Panel’s judgements on
arsenic are summarised in chapter 4.7. Arsenic can modify
the urinary excretion of porphyrins in animals and humans.
It also interferes with the activities of several enzymes of thehaem biosynthetic pathway. There is clear evidence that selenium binds heavy metals such as arsenic and thus modifies
their absorption.75
2.4.2.5 Medication

A number of medical treatments modify the risk of some cancers. As indicated in 2.4.2.3, X-rays are carcinogenic, as isradiation used as cancer treatment.
The most notorious example has been diethylstilboestrol,
once prescribed in pregnancy and now withdrawn, whichcaused cancers of the vagina and cervix of female children
born to mothers who received this drug. Treatments that
affect hormonal status have been studied extensively and aredescribed in 2.4.1.4. Chemotherapy as cancer treatment during childhood is followed by an increased risk of lymphoma
in adulthood.110
2.4.2.6 Carcinogenic agents in food

Food may be contaminated with natural or man-madecarcinogenic toxicants. These are within the scope of thisReport, and are assessed and judged in Part 2.
Moulds and the toxins produced by some moulds cause
DNA adducts and are carcinogenic. Aflatoxin B, a product of
the Aspergillus fungus and a common contaminant of cereals (grains) and peanuts, is an established cause of livercancer (see chapter 4.1). Fumonisin B, a toxin produced by
the fungus Fusarium verticillioides, may be found on maize
and may be carcinogenic, although epidemiological studies
are lacking.
Some carcinogenic compounds are formed during foodpreparation (see chapter 4.3 and 4.9). Heterocyclic amines
are formed by cooking meat at high temperatures, and polycyclic aromatic hydrocarbons can be produced in meat andfish that has been grilled (broiled) or barbecued (charbroiled)over a direct flame. Also see box 4.3.4. High environmental
concentrations of polycyclic aromatic hydrocarbons, which
also come from pollution caused by traffic and industry,
can contaminate other foods such as cereals, vegetables,and fruits.
Some N-nitroso compounds are carcinogens, and areformed in foods containing added nitrates or nitrites; examples include fish and meat preserved with salting or preservatives, and smoking or drying. These carcinogens can also
be generated from ingested foods containing nitrate or
nitrite. N-nitroso compounds are also produced endogenously in the stomach and colon of people who eat large
amounts of red meat or take nitrite supplements. Also seebox 4.3.2.

2.5 Nutrition and cancer
The majority of cancers are not inherited. Cancer is, however, a disease of altered gene expression that originates inchanges to DNA, the carrier of genetic information. For a cellto be transformed from normal to cancerous, it has to acquiredifferent phenotypic characteristics that result from alterations to the genotype. Most cancers develop to the stage ofbeing clinically identifiable only years or decades after the
initial DNA damage.
Cancer development, or carcinogenesis, requires a series ofcellular changes. No single gene causes cancer. It is a multistep process caused by accumulated errors in the genes that
control cellular processes. One genetic mutation may allow
a single trait (such as increased survival) to be acquired bya lineage of cells, and descendants of these cells may thenacquire additional genetic mutations. However, cancer only
develops when several genes are altered that confer growthand survival advantages over neighbouring normal cells.
The capacity of a cell to achieve effective cancer prevention or repair is dependent on the extracellular microenvironment, including the availability of energy and thepresence of appropriate macro- and micronutrients. Tumours
are not simply masses of cancer cells. Rather, they are heterogeneous collections of cancer cells with many other cell
types — so-called stromal cells; cancer cells communicate
with stromal cells within the tumour. The tumour microenvironment comprises many cell types including infiltrating
immune cells such as lymphocytes and macrophages,
endothelial cells, nerve cells, and fibroblasts. All these cell
types can produce growth factors, inflammatory mediators,
and cytokines, which can support malignant transformationand tumour growth, and attenuate host responses. In addition, factors produced by the cancer cells themselves modulate the activity and behaviour of the tumour stroma.
Initiation is the exposure of a cell or tissue to an agent that
results in the first genetic mutation. This can be an inherited mutation or an exogenous or endogenous (produced
through oxidative metabolism) factor. Even without external oxidative stress, hundreds of sites within DNA are damaged each day but are normally repaired or eliminated.
Exposure to the carcinogen initiates DNA damage, usually
via the formation of DNA adducts. If left uncorrected, theseadducts can be transferred to daughter cells during divisionand confer the potential for neoplastic (new and abnormal)
growth.
Initiation alone is insufficient for cancer to develop. An initiated cell must go through a process of clonal expansion
during promotion to become neoplastic; the larger the number of initiated cells, the greater the risk of progressing tocancer. Promotion involves exposure of the initiated cell toa promoting agent. This may allow alterations in the rate ofproliferation or additional DNA damage to occur, leading tofurther mutations within the same cell, which alter gene
expression and cellular proliferation. Finally, these initiatedand promoted cells grow and expand to form a tumour mass.
DNA damage continues at this stage and cancer cells often
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may be less clear in sporadic cancers in humans.
At the end of the multistage process of carcinogenesis, thecell will bear some or all of the hallmarks of cancer111 (figure2.4). Several genes can contribute to each hallmark and one
gene (for example p53) can contribute to several of the hallmarks. These hallmarks or traits are shared by most, if notall, cancer cells. The six hallmarks of cancer cells are selfsufficiency in growth signals; insensitivity to antigrowthsignals; limitless replicative potential; evasion of apoptosis;
sustained angiogenesis; and tissue evasion and metastasis.111
Food, nutrition, and physical activity-related factors influence cellular processes and lead to cells accumulating these
traits (figure 2.5).
2.5.1 Cell proliferation
Three hallmarks of cancer, namely growth signal autonomy,
evasion of growth inhibitory signals, and unlimited replication,
promote enhanced cell proliferation. Over a normal human
lifetime, approximately 1016 (10000 000 000 000 000) cell
divisions will take place. The sequence of stages of a cell
dividing into two daughter cells is called the cell cycle (figure2.3). Normal cells require external signals from growth factors, which stimulate them to divide. Proliferation of normal
cells depends, in part, on the presence in the cellular environment of signals that both promote and inhibit growth, andthe balance between them.
Most cells in adults are not in the process of actively dividing, but are in an inactive or quiescent state termed G. To
re-enter the cell cycle, cells must be stimulated with growth
factors and have sufficient space and nutrients for division.
During the G1 phase, the cell increases in size, and synthesises RNA and proteins. At the end of the G1 phase, cells
must pass through the G1 checkpoint, which arrests the cycle
if damaged DNA is detected, ensuring that it is not replicated. During the S phase, DNA is replicated. The S phase ends
when the DNA content of the nucleus has doubled and thechromosomes have been replicated.
When DNA synthesis is complete, the cell enters the G2phase, during which the cell continues to increase in size andproduce new proteins. The G2 checkpoint leads to arrest of
the cell cycle in response to damaged or unreplicated DNA;otherwise the cell divides into two daughter cells during theM (mitosis) phase, and the M checkpoint ensures eachdaughter cell receives the correct DNA. The cell cycle is controlled by a set of proteins called cyclins and their specificcyclin-dependent kinases (CDKs). These join to form
cyclin–CDK complexes, which activate transcription factors.
This in turn activates transcription of the genes required forthe next stage of the cell cycle, including the cyclin genes.
In this section, examples are given to illustrate the known
interactions between nutritional factors and these physiological processes.
Among the modulators of cell-cycle progression are
specific nutrients, which can either function as energy
sources or regulate the production and/or function of proteins needed to advance cells through the replicative cycle.
Vitamin A, vitamin B12, folic acid, vitamin D, iron, zinc, andglucose all contribute to the control of cell cycle progression(figure 2.3).

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2.5.1.1 Growth signal autonomy

Unlike normal cells, cancer cells are not dependent on external growth factors to stimulate their division. Instead, they
can generate their own signals or respond to lower concentrations of external signals. This frees cancer cells from thegrowth constraints of normal cells.
2.5.1.2 Insensitivity to antigrowth signals

Normal cells also receive growth inhibitory signals. Indeed,most cells of the body are quiescent and not actively dividing. Cells respond to negative environmental signals such as
contact with other cells. Cancer cells have acquired mutations that interfere with these pathways and so do notrespond to growth inhibitory signals.
2.5.1.3 Limitless replicative potential

Normal cells can divide a finite number of times. Once they
have replicated 60 or 70 times they stop — a process termed
senescence, which is thought to constitute a protective mechanism against unlimited proliferation. This preordained number of cell doublings is controlled by telomeres. Telomeres
are segments of DNA on the ends of chromosomes, which
are shortened during each round of DNA replication.
Eventually when the telomeres are too short, the cell can nolonger divide and it undergoes apoptosis.
By contrast, cancer cells have acquired the ability to maintain the length of their telomeres, which means they canreplicate endlessly. Recent work has suggested that senescence can be induced prematurely, particularly in premalignant cells, by activation of the normal, non-mutated formsof genes such as p53 and Rb.111 This senescence is a normal
active process involving genetic and phenotypic changes thatmay protect against cancer development; for example, it may
be one mechanism preventing benign moles from progressing to malignant melanoma. However, in malignant
melanoma, cell markers of senescence are lost.112
In experimental conditions, many constituents of foodsuch as retinol, calcium, allyl sulphide, n-3 fatty acids, andgenistein are known to influence progression of cells
through the cell cycle. These studies, when conducted in cells
in culture, need to be assessed cautiously because they may
not always adequately reflect events in vivo. However, they
can and do provide evidence additional to that gained fromepidemiological studies. Also see chapter 3.1 and 3.2.
Specific dietary components have effects on cell cycle progression and proliferation in experimental settings. Someknown or hypothesised benefits of some dietary constituentsare summarised here.
Vitamin A (in the form of retinol) can lead to cell cycle
arrest.113 Retinoids and carotenoids inhibit proliferation bybinding retinoid receptors on the cell surface. Reduced
expression of retinoid receptors occurs during developmentof lung cancer114; retinoic acid receptor silencing is also common in other malignancies. Retinoic acid, a metabolite of vitamin A, has been used as a chemopreventive and therapeutic
agent in cervical cancer.115 Retinoids can inhibit proliferationof initiated cells by inducing apoptosis or inducing differentiation of abnormal cells back to normal.116 Retinoids may
also cause regression of precancerous lesions in the cervix.117

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responsive genes.122
Calcium has a growth
inhibiting action on normal
and tumour gastrointestinal
cells.123 However, certain
dietary compounds can also
stimulate proliferation inexperimental cell lines, forexample, colonic cells can be
induced to hyperproliferateby dietary haem iron.124
In a variety of animalstudies, certain dietary components have shown reductions in experimentallyinduced cancers. Allyl sulphides in garlic inhibit
experimentallyinducedcolon tumour formation.
Although this is not completely understood, experiments with diallyl disulphidesuggest a block in the G2/M
phase in the progression of
the cell cycle, and inductionof apoptosis.125
Fish oil supplements
decrease the number oftumours in experimental
models of colorectal cancer.126 Long-chain n-3 PUFAs
Nutrition may influence the regulation of the normal cell cycle, which ensures correct DNA
in fish oils can limit tumour
replication. G0 represents resting phase, G1 the growth and preparation of the chromosomes for
replication, S phase the synthesis of DNA, G2 the preparation of the cell for division, and M
cell proliferation30 31 byrepresents mitosis.
modifying signalling pathways,127 128 129 for example,
by decreasing signalling of
Butyrate and diallyl disulphide can act as histone deacety- activated oncogenes.130 Animals that receive a diet supplelase inhibitors16 (see 2.2.2), and arrest the cell cycle. Folate mented with n-3 fatty acids have fewer colonic tumours thanis a necessary cofactor for DNA synthesis, and deficiency can those fed a diet supplemented with corn oil,131 due to dietary
reduce cell proliferation due to decreased DNA synthesis.
fibre-altering, fatty acid-binding, protein expression in
Phenolic compounds, including genistein and EGCG, can colonocytes during tumour development.
inhibit some cyclins and cyclin-dependent kinases.118
Various growth factors and hormones involved in normal
Specifically, in people with oral leukoplakia, green tea (which cell processes can be used or produced by cancer cells tocontains EGCG) has been associated with significant decreas- maintain or augment uncontrolled cell proliferation. The
es in the size of cancers and of micronuclei formation in exfo- receptor for IGF-1 is overexpressed on many cancer cells.
liated oral cells.119
IGF-1 can enhance the growth of a variety of cancer cell
Phytoestrogens are found in high concentrations in soya lines132 by stimulating progression of the cell cycle from G1beans, and have been shown in vitro to exhibit a plethora of to S phase.13
Insulin itself can also act as a growth factor for tumour celldifferent anti-cancer effects, including inhibiting proliferation.120 121 Glucosinolates from cruciferous vegetables are con- proliferation, both by binding to the insulin receptor on canverted in the liver to ITCs, which can arrest cell cycle cer cells and by stimulating increased IGF-1 production by the
progression, as well as induce phase 2 enzymes, which can liver.13 133 Insulin resistance increases with body fatness, inpromote carcinogen excretion (see 2.3). Only about one third particular abdominal fatness, and the pancreas compensatesof people have the types of microbial flora in their gut that by increasing insulin production. This hyperinsulinaemia is
are capable of metabolising the dietary isoflavone daidzein associated with a risk of cancers of the colon and endometrito equol. Compared with Western populations, Asian popu- um, and possibly of the pancreas and kidney.13 Leptin, a horlations are more likely to produce equol, and this affects the mone produced by fat cells, can also stimulate proliferation
expression of genes involved in cell signalling and differen- of many premalignant and malignant cell types,134 as can atiation, and cell division. Equol can also modulate oestrogen- number of sex steroid hormones (see Chapter 6, and box 2.4).

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B A C K G R O U N Dage, disruption of the cell
cycle, hypoxia, reactive oxygen species, and physical orchemical insult. Two nonexclusive pathways, theintrinsic(mitochondrial)
pathway or the extrinsic(death-receptor) pathway,
can be activated. Bothinvolve activation of caspases, a family of protease
enzymes that cleave intracellular proteins.143 In apoptosis, p53 functions as atranscriptional activator ofgenes encoding apoptosis
effectors. p53 can also exert
a direct apoptotic effect bydamaging mitochondria.144
Cancer cells have acquired
mutations in genes regulating apoptosis and therefore
can evade apoptotic signals.
Defects in apoptosis are
Cancer cells have different characteristics from normal cells. The six ‘hallmarks’ shown here are theoften observed in establishedphenotypic changes that need to be accumulated over time as a result of genetic changes (mutations
and epigenetic factors) in order for a cell to become cancerous.
cancers. In cancer cells,
many signals that normallyinduce apoptosis, such as
Physical activity improves insulin sensitivity and decreasdamaged DNA or expression of activated oncogenes, are prees levels of insulin.135 However, exercise has little or no longsent but apoptosis is not induced. This avoidance of apopterm effects on circulating IGF-1 levels.136-138 IGF binding
tosis allows further opportunity for additional mutations toactivity may increase with physical activity, and thus overdevelop. In cancer cells with mutations in p53 or other
all IGF-1 bioavailability and activity may decrease. Physicalmembers of this family, apoptosis may not occur.
activity decreases serum oestrogen and androgens in postAdditionally, mutations in genes that would normally
activate p53 or regulate its activity, or in genes that shouldmenopausal women. In premenopausal women, it decreasbe switched on as a result of p53 activation, can have the
es circulating oestrogens, increases cycle length, andsame effect. Cancer cells with upregulated expression of
decreases ovulation, all of which provide a protective effect
IGF-1R and increased responses to IGF-1 have decreased
for breast and endometrial cancers. Also see Chapter 5.
apoptosis.133
In experimental animals, energy restriction leads to a
In experimental settings, energy restriction creates a proreduction in cell proliferation66 (box 2.5). At the molecularlevel, dietary energy restriction affects levels of cell cycle conapoptotic environment, adjacent to premalignant andtrol proteins (decreased cyclins, increased levels of cyclinmalignant breast pathologies.145 Long-chain n-3 PUFAs in
dependent kinase inhibitors, and decreased cyclin-dependent
fish oils limit tumour cell proliferation, increasing apoptotkinases), leading to reduced Rb phosphorylation and inhibic potential along the crypt axis, promoting differentiation
ited cell cycle progression.139 This, in turn, may directly
and limiting angiogenesis.30 31 126
inhibit tumour growth and/or indirectly reduce cancer develReactive oxygen species can induce apoptosis, but it isalso possible that scavenging of reactive oxygen species byopment by reducing the number of cell divisions, thus reducdietary antioxidants can delay or inhibit apoptosis, and thus
ing the chances for incorrect DNA replication or preventing
favour survival of premalignant cells. Indeed, this could
damaged DNA from being replicated.
explain why dietary antioxidant intervention trials have produced mixed results.146 147
2.5.2 Evasion of apoptosis
Apoptosis is the tightly regulated process of cell death that
Many dietary components have been shown to induce
controls cell numbers, removes damaged cells, and prevents
apoptosis in cultured cancer cells and in experimental moddamaged cells being replicated, thereby maintaining
tissue integrity and protecting against cancer. Ultimately,
Maintenance of healthy cells depends on regulated processes,
cells break into small membrane-surrounded fragments
which can be influenced by factors related to food, nutrition, and(apoptotic bodies) that are phagocytosed without inducing
physical activity, either to protect the cell from or to promoteinflammation.
cancer. The evidence for what is shown here comes from a variety
Triggers for apoptosis in normal cells include DNA damof experimental studies.

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Box 2.5•

B A C K G R O U N D

Energy restriction

Restriction of energy intake from food is
the most effective single intervention forpreventing cancer in experimental animals.
It increases the lifespan of rodents, andsuppresses tumour development in mice. In
addition, energy restriction can suppress
the pro-cancer effects of many carcinogens
in experimental animal models.66
Energy restriction leads to a reduction incell proliferation.66 This may directly inhibit tumour growth, and also indirectlyreduce cancer development by reducing
overall proliferation, thus reducing thechances for incorrect DNA replication, orby preventing damaged DNA from being
replicated. Reduced metabolism results in
reduced generation of reactive oxygen

species, and therefore less exposure of
DNA to damaging oxygen radicals.
Dietary energy restriction reduces levelsof circulating IGF-166 140 and insulin, which
are growth factors for many cells, including breast cancer.141 IGF-1 stimulates progression through the cell cycle from G1 to
S phase, and high levels of insulin increase
production of IGF-1.13 Energy restriction
also decreases expression of cyclins andcyclin-dependent kinases (CDKs), andincreases levels of CDK inhibitors, leading
to reduced Rb phosphorylation and inhibited cell cycle progression.139 Energy restriction also decreases other inflammatory
markers.66 Conversely, increased glucose
levels associated with increased energy

els of cancer.148 These include EGCG, curcumin, genistein,indole-3-carbinol, resveratrol, ITCs, lycopene, capsaicin,
and organosulphur compounds.149 In premalignant cells,
retinoids, polyphenols, and vanilloids stimulate apoptosis.150
Alpha-tocopherol (a form of vitamin E) has been shown bothto induce151 and to protect against apoptosis.152
2.5.3 Sustained angiogenesis
Angiogenesis, the formation of new blood vessels, is essential for the supply of nutrients and oxygen to any growing
tissue, including tumours. Most cells within tissues residewithin 100 mm of a capillary blood vessel. The generationof blood vessels in adults is fairly constant and tightly
controlled by a balance of angiogenesis inducers andinhibitors. For a cancer to progress to a larger size, it must
acquire the ability to induce angiogenesis. Currently about
35 proteins have been identified as angiogenesis activators
or inhibitors.153
In experimental settings, one of the first dietary components for which a beneficial anti-angiogenic effect was
clearly demonstrated was EGCG from green tea.154 Now
some 20 different compounds consisting mainly of flavonoids
and isoflavones (including genistein) are documented as
being able to modulate the angiogenic process. Diets highin n-6 fatty acids are associated with poor prognosis in breast
cancer patients, whereas those high in n-3 fatty acids appear
to suppress angiogenesis.155 Long-chain n-3 PUFAs in fishoils limit angiogenesis in other experimental cancers.30 31
Curcumin, quercetin, and resveratrol have all been shown to
inhibit the angiogenic factor, vascular endothelial growth
factor (VEGF), in cultured cancer cells. Garlic extract may
inhibit experimentally induced angiogenesis, as it can suppress endothelial cell motility, proliferation, and tube formation.156 Phytoestrogens found in high concentrations insoya beans have also been shown to inhibit angiogenesis.120
Energy restriction reduces blood vessel density in premalignant and malignant breast pathologies.145 Exercise
increases the levels of a circulating endogenous VEGF-

46

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intake are associated with increased DNA
synthesis and levels of some cyclins and
CDKs.113 Energy restriction may also createa pro-apoptotic environment and reduce
blood vessel density, as shown in premalignant and malignant breast pathologies.139 It may also activate otherprotective pathways, such as the activationof protein deacetylases.142
The data on energy restriction must be
interpreted with caution, as all studies
have been performed in experimental animals and there is an absence of epidemiological and mechanistic data in humans.
Therefore the relevance of these findings
in experimental animals to the humancondition is not yet clear.

inhibitor in healthy people, which could decrease plasma
levels of VEGF.157
2.5.4 Tissue invasion and metastasis
Normal cells in solid tissues maintain their position in the
body and generally do not migrate. As a cancer increases, it
eventually reaches the membrane encapsulating the organ.
Tumour cells secrete enzymes such as matrix metalloproteases (MMPs), which digest the membrane and allow thecancer to invade adjacent tissue. Once through the membrane, cancer cells can access other sites via the blood andlymphatic systems. This migration of cancer cells, or metastasis, is a common characteristic of most cancer deaths.
There is limited evidence for dietary components to influence these late stages of cancer, although in vitro, EGCG,
resveratrol, quercetin, curcumin, and genistein can inhibit
one or more MMPs. Vitamin C can inhibit MMP production
by a number of human cancer cell lines and prevent invasion of these lines in vitro.158 Vitamin E can inhibit metastasis of pre-established tumours in mouse models of breast
cancer.159

2.6 Conclusions
Great progress has been made since the mid-1990s in theunderstanding of the cancer process. Evidence is accumulating that shows or suggests that food and nutrition, andphysical activity and associated factors, are important inmodification of the cancer process. Moreover, there isincreased evidence that specific dietary patterns, foods anddrinks, and dietary constituents can and do protect against
cancer, not only before the process starts, but also afterwards.
Understanding the mechanisms that control cell structureand function, and so influence the cancer process, will aid
not only understanding of cancer as a whole, but also thedevelopment of preventive strategies.

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3Judging the evidence
The task of expert committees responsible forreports such as this is to collect, discuss, and judgescientific evidence, as a basis for recommendations
made in the public interest. The purpose of this third
introductory chapter is to summarise the process the
Panel has used in the five years of its work, in orderto ensure that its assessments, judgements, andrecommendations made in the chapters that follow
are reliable.
As shown in the previous chapters, while cancer isa disease of cells and tissues, the main determinantsof many cancers are environmental, which meansthat most cancers are, at least in theory,
preventable. Environmental factors that modify therisk of cancer include food and nutrition, physicalactivity, and body composition. One purpose ofscientific research in this field is to determine whichaspects of these factors protect against, and which
are causes of, cancers of various sites. Such researchis also concerned with which aspects are mostimportant — that is, which have the most powerfulor general effects.
Some of the methods used by the Panel
responsible for this Report are new. Others aredeveloped from those used elsewhere, including in
the previous report. The best evidence that aspectsof food, nutrition, physical activity, and body fatness
can modify the risk of cancer does not come fromany one type of scientific investigation. It comesfrom a combination of different types of
epidemiological and other studies, supported byevidence of plausible biological mechanisms. Suchcomprehensive evidence has been collected in theform of 20 systematic literature reviews speciallycommissioned as the basis for this Report, compiled
by nine independent centres of scientific excellence,covering 20 cancer sites, the determinants ofobesity, and recommendations made by otherauthoritative reports. These reviews amount to acomprehensive examination of the relevant types of
epidemiological and experimental evidence,organised using a common methodology. Theirfindings, as summarised for and then assessed andjudged by the Panel, are shown in Part 2 of thisReport. The full systematic literature reviews arecontained on the CD included with this Report.

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Judgements of the Panel are shown in the form of
matrices at the beginning of the chapters of Part 2 ofthis Report. Two key judgements in these matrices,
and in the text, are those of ‘convincing’ and‘probable’. These denote the Panel’s judgements thatthe evidence of causality — that a factor either
decreases or increases the risk of cancer — is strong
enough to justify population goals and personal
recommendations, which are made in Part 3. The
criteria agreed by the Panel for grading the evidence‘convincing’, ‘probable’, or ‘limited’, or else showingthat any substantial effect on the risk of cancer isunlikely, are also specified in this chapter.

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Since the mid-1990s, the discipline of epidemiology has
placed increasing emphasis on the use of meta-analyses andsystematic reviews, both of which have informed the Panel
responsible for this Report. Taken together with lines of evidence from other types of study, these provide a reliable basis
for judgements and recommendations designed to improve
public health.
The task of the Panel, with the supporting Secretariat, hasbeen to commission, summarise, and display a comprehensive
range of evidence; to assess and judge this evidence; and to
draw conclusions and make recommendations based on thissystematic and transparent process. Also see Appendix A.
This chapter details the nature of the science relevant to
the work of the Panel. It also summarises the processes developed from initial work done by a Methodology Task Force.
Its findings have been a foundation for the work of the Panel.
The two most important parts of this process are the systematic literature reviews (SLRs), explained in box 3.4, andthe criteria the Panel has agreed for grading the evidence,described in box 3.8. These and other methods have determined the Panel’s approach to gathering, summarising,assessing, and judging evidence, and agreeing on population
goals and personal recommendations as a basis for the prevention of cancer.

3.1 Epidemiological evidence
Epidemiological research describes and seeks to explain the
distribution of health and disease within human populations.
The methods used are based mainly on comparative observations made at the level of whole populations, specialgroups (such as migrants), or individuals within populations.
This type of investigation is known as observational. By relating differences in circumstances and behaviour to differencesin the incidence of disease, associations are identified that
may be causal. In epidemiological studies, an ‘exposure’ is afactor or condition that may increase or decrease the risk of
disease. In this Report, food, nutrition, physical activity, andbody composition are the ‘exposures’ investigated. The methods summarised here and applied to cancer are also used to
study and understand other diseases.
3.1.1 Descriptive studies
The most basic information about cancer comes from statistics on cancer incidence and mortality. See chapter 1.2.4,

the introductory passages of the sections of Chapter 7, andbox 7.1.1.
The International Agency for Research on Cancer (IARC),a branch of the World Health Organization, compiles international cancer statistics using data from national andregional cancer registries around the world.1 Cancer incidence rates are usually specified by gender and age. Cancer
mortality rates, generally derived from data collected routinely on causes of death, are more widely available thancancer incidence rates.
Descriptive epidemiology informs cancer surveillance
programmes, and is a basic tool for determining patternsof cancer, relative rates of cancer and other diseases, andchanges in patterns and trends over time. Remarkablechanges in the incidence of cancers (for example, thegeneral drop in rates of stomach cancer or the increasein rates of lung cancer in many middle- and low-income
countries) provide first lines of evidence pointing to causation due to corresponding changes in environmental
circumstances.
Like all types of study, descriptive epidemiology has limitations. Apparent trends in cancer incidence and mortality
may be due in part to changes and developments in screening, diagnosis, or treatment. For example, the rapid rise in
the recorded incidence of prostate cancer in the USA, the UK,
and other higher-income countries is largely due to widespread use of diagnostic techniques that identify early
evidence of this cancer.
3.1.2 Ecological studies
Ecological studies are designed to explore relationships
between environmental factors and disease amongst populations rather than individuals.
Within the scope of this Report, ecological studies compare
relationships between estimated levels of consumption offoods and drinks, levels of physical activity, and degrees ofbody fatness with rates of cancer for populations. For example, as already mentioned, early observations found impressive correlations between national per capita intake of total
dietary fat and rates of breast cancer mortality, mapped
across many countries,2 leading to the hypothesis that relatively high consumption of total fat was an important causeof breast cancer.
The findings of ecological studies, together with thosefrom migrant and laboratory studies (see 3.1.3 and 3.2),
were important factors leading to judgements and recom-49

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Box 3.1•

B A C K G R O U N D

Issues concerning interpretation of the evidenceInterpretation of epidemiological evidence
on any and all aspects of foods and drinks,
physical activity, body composition, andassociated factors, with the risk of cancer,
is never simple. General considerations
include the following, which need to betaken into account when evidence is assembled and assessed. This emphasises thatexpert judgement is essential.
Patterns and ranges of intakes. Most studies are carried out in high-income countries.
Their findings may have limited applicationin countries where dietary and physicalactivity patterns are different. They may
also be unrevealing in their own countries
if the ranges examined are relatively narrow. Some foods that are important dietary
constituents outside high-income countries
are often not examined.
Classification. Following from the above,
studies usually classify foods and drinks,
and physical activity in ways that correspond to the patterns of high-income countries. Their findings may over-emphasise
the significance (or insignificance) of foods
and drinks commonly consumed in highincome countries, and they may overlook
other foods and drinks consumed inother parts of the world. The same points
apply to types of physical activity. This
may impede understanding, not only in

middle- and low-income countries, but also
globally.
Measurement. Many study exposures are
difficult to determine and are thus measured imprecisely. It is easier to measure
food intakes than intakes of dietary constituents of foods. This can lead to an
undue degree of importance being given to
studies of aspects of food and nutrition
that happen to be more easily measured.
Terminology. For some foods and drinks,
and dietary constituents, there are no generally agreed definitions. Examples include‘dietary fibre’ and ‘processed meat’. Also,
some common definitions may disguise realdifferences: different types of ‘dietary fibre’
have different biological effects.
Study design. The relative merits of different types of epidemiological study design,and the relative value of epidemiologicalevidence compared with experimental evidence, are likely to remain to some extent
a matter of opinion. The special power ofrandomised controlled trials (see 3.1.6),
most often used to test the effects of
dietary constituents as opposed to wholediets, could lead to over-emphasis of theimportance of isolated constituents which,within the context of food and diets, may
have other effects.

mendations made in reports on diet and cancer published in
the 1980s.3-5
While ecological studies, like other observational studies,
may suggest a relationship between a specific environmental factor (such as an aspect of food and nutrition) anddisease, the actual causal relationship may be with a different ‘confounding’ factor, which may or may not be associated with the environmental factor being investigated.6 The
example of total fat consumption and breast cancer is a casein point: total fat consumption, disposable income, and consumption of alcoholic drinks might all correlate with one
another, and also with breast cancer. See box 3.1.
Ecological studies are often used to identify associations
or trends that warrant further investigation. They have special strengths, particularly when conducted between populations, either internationally, or cross-culturally among
different populations within a country. Thus, the contrast in
dietary intake between countries is often much larger thanthe contrast within countries. In addition, average national
diets are likely to be more stable over time than the diets ofcommunities, families, or individual people. For most countries, the changes in overall national dietary intakes over a
decade or two are relatively small.

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Confounding. A confounder is a factor
associated with both the outcome (in thiscase, cancer) and the exposure being studied, but is not an effect of the exposure. It
is never possible from observational studies
to eliminate completely the possibility thatan evident effect of a constituent, or aspectof a food or drink, is at least in part causedby another factor.
Reporting bias. Studies reliant on selfreporting of dietary intake are prone to systematic bias. People tend to over-reportconsumption of foods and drinks they
believe to be healthy, and under-reportfoods and drinks they believe to beunhealthy. Under-reporting of energy
intake has been shown to be associatedwith factors such as age, overweight andobesity, perceived body size, and other personal characteristics.7-14 Allowance for thisis an inexact science. Also see 3.3.
Production, preservation, processing,
preparation. Studies of foods and drinks,
and of food groups, may neglect theeffects of methods of production, preservation, processing, and preparation (including cooking). They are also inclined tounderestimate the significance of foods
and drinks combined in dishes or meals,
and as components of whole dietary
patterns.

3.1.3 Migrant studies
Migrant studies compare cancer rates for migrants, and fortheir offspring, in their current country of residence, with
rates in their country of origin.16 These studies show that
populations migrating between areas with different cancer
incidence rates acquire the rates characteristic of their new
location for some cancers, often after only one or two generations. This shows that environmental, rather than inherited, factors are primarily responsible for the large differences
in cancer rates in different regions and countries (see chapter 1.3).17 Those diseases for which incidence shifts with
migration, such as cancer, are diseases with evidently important environmental causes.
3.1.4 Case-control studies
In case-control studies, individuals diagnosed with a specific type of cancer (‘cases’) are compared with otherwise similar individuals who have not been diagnosed with cancer(‘controls’). The control group is a sample of the populationfrom which the cases arose, and provides an estimate of how
the exposures being studied are distributed in that population. Identifying and enrolling appropriate controls is a major
challenge in case-control studies.18-20

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Case-control studies are subject to recall bias, which canoccur when participants’ reporting of various exposures(dietary intake, medication, physical activity, and so on) isdifferentially affected by whether they are cases or controls
in the study. Selection bias is an increasing problem in highincome countries, where participation rates among both caseand control groups may be substantially less than 100 per
cent, and where participation may be related (in differentways) to various exposures. However, case-control studies
are usually less expensive than cohort studies, and can becompleted over shorter periods of time.
A ‘nested’ case-control study is carried out within an existing cohort study (see 3.1.5). In this type of study, all of thecases in the cohort are compared with a sample of the noncases. A nested case-control study has the strengths of acohort study — notably that diet is assessed among study
participants prior to the diagnosis of cancer, so avoiding
recall bias — but is less expensive to conduct, since only asample of the non-cases are included in the analysis.
3.1.5 Cohort studies
In prospective cohort studies (usually simply called cohort
studies), the diets, body compositions, and/or physical activity levels of a large group (cohort) of people who areassumed to be healthy are assessed, and the group is followed over a period of time. During the follow-up period,
some members of the cohort will develop and be diagnosed
with cancer, while others will not, and comparisons arethen made between these two groups. Because measurements are made before any cancer diagnosis, cohort studies
are not subject to recall bias. A single cohort study allows
examination of the effects of diet and physical activity on
multiple types of cancer and other diseases. Also, in cohort
studies, blood and tissue samples are often collected andstored for future analysis. Finally, cohort studies provide theopportunity to obtain repeated assessments of participants’
diets at regular intervals, which may improve the dietaryassessment.
Cohort studies may need to be very large (up to tens oreven hundreds of thousands of participants) to havesufficient statistical power to identify factors that may
increase cancer risk by as little as 20 or 30 per cent. Also,
meaningful comparisons between cases and non-cases canbe made only for factors that vary sufficiently within thecohort.
Cohort studies are expensive, so they have been conducted mostly in high-income countries. The European
Prospective Investigation into Cancer and Nutrition (EPIC),
started in 1992, is a cohort of more than 520 000 men andwomen in 10 European countries.21 22 In the US, large cohorts
include the Nurses’ Health Study, established in 1976, and the
Nurses’ Health Study II, established in 1989, each with acohort of more than 100 000 women.23-25 Increasing numbersof cohort studies are now being conducted in middle- andlow-income countries.
3.1.6 Randomised controlled trials
A randomised controlled trial (RCT) is an experiment inwhich participants are randomly assigned to groups, often

called intervention and control groups, to receive or notreceive an experimental intervention. The main use of RCTs
has generally been to test the efficacy of drugs and othermedical treatments.
In a ‘double blind’ RCT, neither the participants nor theinvestigators know to which group (intervention or control)
the participant has been assigned. Blinding is used because
the knowledge of group assignment might influence study
results, but it is usually impossible to achieve with trials
involving physical activity, or those investigating foods anddrinks in their usual form.
An effective use of RCTs is to test the effects of supplementation with specified doses of dietary micronutrients(as pills or by other means). However, pharmacological dosesof supplements are often studied — doses much higher
than can be derived from diets — and results may not bedirectly relevant to dietary intakes of that micronutrient.
Such trials may yield powerful evidence of the effect of a
specific dietary constituent. However, they are often conducted as a result of promising epidemiological studies
that have shown protective effects of a particular group offoods, and there is always a possibility that the actual active
agent or combination of agents in the foods has not beenused in the trial. Dietary constituents that are or may beprotective when contained within foods may have unexpected effects in isolation, especially at doses higher thanthose found in normal diets. For example, in the AlphaTocopherol, Beta-Carotene Cancer Prevention Trial (ATBC
Trial) of male smokers in Finland, high dose beta-carotene
supplementation was associated with increased incidence oflung cancer.26
RCTs are also used to test interventions designed to change
behaviour, including dietary intakes and physical activity.
Such trials require a high level of commitment by participants, and learning how to conduct them well is a topic ofactive investigation.
A unique and important strength of sufficiently large RCTs
is that confounding variables, both known and unknown,
will on average be distributed equally between the treatment
and control groups, and will therefore not bias the study
results.
3.1.7 Meta-analysis
Meta-analysis is a method used to combine the results of several studies addressing similar questions. Unless an epidemiological study is sufficiently large, modest but
potentially important associations can be missed, simply
because of the inadequate statistical power of the individual
study. Meta-analysis is used to provide summaries of selected collections of studies.
Study-level meta-analysis provides single estimates ofeffect using information from multiple studies of the same
design. These summary estimates can provide evidence
regarding the presence or absence of an association, as well
as examining possible dose-response relationships (box 3.2).
Meta-analysis, often displayed graphically on a forest plot(box 3.3), can also identify heterogeneity between studies.
This heterogeneity can be quantified using a measure called
I2, which ranges from 0 to 100 per cent, and indicates the51P A R T

Box 3.2•

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Dose response‘Dose response’ is a term derived frompharmacology, where it denotes a change
in the effect of a drug according to thedose used. This concept can be applied toany exposure, including food, nutrition,and physical activity. For example, different
amounts of food and drink consumed, orof physical activity taken, may lead to a different likelihood of any particular outcome, such as cancer. Such a graded
response, or biological gradient, may showthat higher exposure leads to increased
risk, or to reduced risk, and vice versa.
Dose responses take different forms. The
effect may be linear, shown in graphic form
as a straight line. There may be a ‘threshold’ below which there is no effect, but
above which there is an effect. This isshown as a horizontal line that inclines
once the threshold is reached. Or the effectmay be to influence risk one way at both

low and high levels of exposure, but theother way at intermediate levels of exposure, shown as ‘J’- or ‘U’-shaped curves.
In such cases, the exposure is evidently
beneficial or harmful only within certain
ranges.
Throughout Chapters 4–6, this Report
uses two forms of dose-response graph asa means of displaying graded responses.
These show the direction and shape of theassociation, and allow estimates to bemade of levels of exposure that may influence risk. In order to combine and quantify study results, the dose-response curves
are also presented with the exposure variable displayed per standard unit ofincrease. The demonstration of a biological gradient adds weight to evidence thatan exposure may be causal. Diet and physical activity exposures are continuous variables, but are often reported in discrete

percentage of total variation across studies that is not due
to chance. In general, an I2 of 25 per cent or less indicates
low heterogeneity; around 50 per cent indicates moderateheterogeneity; and 75 per cent or more indicates highheterogeneity.27
For this Report, RCTs and ecological, cohort, and case-control studies have been the subjects of systematic review, and,
when possible (and separately) of study-level meta-analysis.
Studies were included in a meta-analysis only when sufficient data were included in the publication. In addition toeffect measures and their standard errors (or confidence
intervals, see box 3.3), key elements of adequate reporting
included the number of people with and without disease
for each exposure category, and boundaries of exposure
categories.
The SLRs on which the conclusions of this Reportare based include original study-level meta-analyses
undertaken by the independent centres of scientific excellence. The Panel considered all studies identified in the SLR,
not just the results of the meta-analyses. Full details of
the methods used for the meta-analyses are contained in
the SLR specification manual. The full SLRs and the manual are contained on the CD included with this Report. Also
see box 3.4.
Pooled analysis is a type of meta-analysis where originalindividual-level data from various published epidemiological studies of the same type — usually prospective cohort
studies — are combined and reanalysed. The combinationof data from multiple studies creates a larger data set andincreased statistical power. Published studies from poolingprojects, in addition to the SLR study-level results generated specifically for this Report, were taken into account by the
Panel in making its assessments and judgements.

52

I

categories. Although this is done for statistical reasons and can make effects easier to detect, the number and location of
category boundaries may obscure the true
relationship between exposure and theoutcome, and non-linear effects of exposure may be missed if insufficient categories are used.
Evidence of dose response is importantwhen framing recommendations. For
example, if the evidence for cancer showedno threshold of effect for alcoholic drinks,
such that the risk of cancer increased fromhaving any amount of alcoholic drink,however modest, then a recommendation
based on the evidence for cancer would be
to avoid alcoholic drinks. However, if thereis clear evidence of no effect below a certain level of consumption, then the recommendation would differ accordingly.
Also see chapter 4.8.

3.2 Experimental evidence
Epidemiological studies all have strengths and limitations. So
do laboratory and mechanistic studies; their main strength iscontrol. The environment of these research studies is definedby chosen experimental conditions: precise manipulations canbe made and relatively exact measures taken. Occasionallythe test participant is a human volunteer, but usually thesestudies are conducted in animals (in vivo) or using humanor animal cells grown in the laboratory (in vitro).
Rodents (usually rats or mice) are the most commonly usedanimals in laboratory experiments. Their relatively short lifespan provides comparatively fast results in cancer studies, andthey offer a ‘whole body system’ suited to a wide variety oftests. Rodent studies can show how nutrients and other compounds might affect the cancer process. But it is known thatsome interventions that affect rodents do not affect humans,or do not affect them in the same ways or to the same degrees,and vice versa. Also, experiments on animals may be highly
artificial, using special breeds of rodents initially given massive doses of carcinogenic agents, and then fed nutrients orother substances at levels far higher than humans would normally consume, or could ethically be given.
Human or animal cells, sometimes derived from particular cancers, can be grown in vitro in the laboratory and usedin experiments to help researchers understand mechanismsthat may lead to the development of cancer. The Panel’s decision on what types of experimental studies were admissible
as evidence for this Report is summarised in box 3.5.
3.2.1 Human feeding studies
Human volunteers can be studied in a controlled environment, such as within a metabolic unit, where their diets andC H A P T E R

Box 3.3

3•

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Forest plots

The graphic device known as a ‘forest
plot’ is the usual method of presenting
the results of meta-analysis of a number of studies. In the forest plot below,
studies are presented that examine therelationship between alcoholic drinks
and oesophageal cancer. This plot isalso shown as figure 4.8.5.
This plot shows 1 cohort study and23 estimates from 20 case-control studies. The horizontal axis of the plotshows the relative risk (RR) and isbisected by the vertical axis, which represents ‘no difference in effect on risk’between the exposure categories thatare compared (the RR is 1.00). Alsosee 3.4.3.
The squares represent the results ofeach individual study. Each square iscentred on the point estimate of the
RR for that study. The point estimate is
the extent to which any exposure (inthis case, alcoholic drinks) is associatedwith the risk of cancer (in this case, ofthe oesophagus). The line running
through the squares represents the 95
per cent confidence interval (CI) of theestimate. Where no line is apparent,
the CI falls within the square. The CI is
an indication of how much random
error underlies the point estimate; itdoes not take into account confounding and other forms of systematic bias.15 A
confidence level of 95 per cent indicates a
95 per cent probability that the true population value falls within the CI.28
When the CI does not cross the verticalaxis representing ‘no difference’, the estimate is considered statistically significant.
Looking at the example above, the value

Figure 3.1

Alcoholic drinks and oesophageal cancer;
cohort and case-control studies
Relative risk (95% CI)

CohortKjaerheim 1998

1.26 (1.10–1.44)

Case control
Tuyns 1983 Men

1.12 (1.07–1.17)

Tuyns 1983 Women

1.04 (1.00–1.09)

Decarli 1987

1.04 (1.03–1.05)

La Vecchia 1989

1.01 (0.99–1.03)

Franceschi 1990

1.02 (1.01–1.04)

De Stefani 1990 Men

1.04 (1.03–1.06)

De Stefani 1990 Women

1.13 (0.99–1.29)

Sankaranarayanan 1991 Men

1.02 (1.01–1.03)

Cheng 1992

1.08 (1.07–1.09)

Tavani 1993

1.03 (1.00–1.06)

Tavani 1994

1.02 (1.00–1.04)

Hanaoka 1994

1.24 (1.14–1.33)

Brown 1994 Black men

1.04 (1.03–1.04)

Brown 1994 White men

1.03 (1.05–1.07)

Castelletto 1994

1.05 (1.03–1.07)

Gammon 1997

1.07 (1.05–1.08)

Bosetti 2000

1.03 (1.03–1.03)

Takezaki 2001

1.00 (0.96–1.04)

Sharp 2001

1.00 (0.95–1.05)

Boonyaphiphat 2002

1.05 (1.04–1.07)

Dal Maso 2002

1.03 (1.02–1.04)

Lee 2005

0.99 (0.97–1.00)

Yang 2005

1.05 (1.03–1.06)

Summary estimate

0.8

1.04 (1.03–1.05)

1

1.25

1.5

Relative risk, per drink/weekof meta-analysis is demonstrated: of the
20 case-control studies, 6 are non-significant or only marginally so, of which 1 suggests a protective effect (that is, it has an
RR of less than 1.00). But taken together,as shown by the summary diamond, an
overall significant effect, consistent with ajudgement that alcoholic drinks are acause of oesophageal cancer, is shown.

activity levels can be highly regulated and measured. In somestudies, subjects live at the metabolic unit for short periodsof time, eating only foods and meals provided as part of thestudy. Since the nutrient composition of such diets can becontrolled and manipulated, investigators can study theeffects of various changes in nutrient intakes on factors suchas hormone levels or cell proliferation assays, which may be
important predictors of cancer or other diseases. These areintermediate markers, however, and relating the results tocancer occurrence may be problematic.
3.2.2 Live animal models
Laboratory animals can be used to test the effects of food,nutrition, and physical activity on the development of cancer. Human genes can be added to animals’ DNA (creatingtransgenic animal models) or key genes can be removed (creating ‘knockout’ animal models) to address specific research

There is only one cohort study shownon the forest plot, and it has a wide CI,
but the estimate is statistically significant and consistent with results fromthe case-control studies.
The size of each square on the plot
represents each study’s calculated
weight (influence) on the combined(summary) estimate (the diamond). The
size of the square is calculated taking
a number of factors into account, suchas the number of people in the study,
and the event rate (here, the rate ofoesophageal cancer occurrence). The
diamond summarises the meta-analysis.
The width of the diamond represents
the 95 per cent CI of the overall
estimate. Unless indicated otherwise,
random effects models, which do notassume that the links between exposure
and outcome are the same in different
studies, were used to generate theforest plots presented in this Report.
The Panel’s judgement for this particular example is given in chapter 4.8.5.
The forest plots presented in this Report
do not contain all of the studies identified in the SLRs. Sometimes, more studies could be included in a comparison
between those at the highest levels
compared with the lowest levels of
exposure in different studies. This cangive an indication as to whether or notthere is an association between exposure
and outcome. However, because the actual levels of exposure vary between studies,
this cannot give a quantified summary
estimate of effect. The Panel discussed all
studies identified, not just those included
in a meta-analysis.

Fquestions. Often the animals have tumours produced by irradiation, viruses, chemicals, or other carcinogens, or they may
be genetically prone to develop cancer. The effect of dietaryor other interventions on the prevention or progression ofsuch tumours is then investigated.
As indicated in 3.2, the strength of these studies is the tightcontrol of experimental conditions. Their limitations are
their artificiality and the fact that no effect on rodents, however unequivocal, can be assumed to apply to humans.
Rather like the results of population ecological studies,
results from animal studies provide first lines of evidence
that may prompt more persuasive research; they can also corroborate such findings.
3.2.3 In vitro studies
In vitro studies are conducted using cells or other test systems. Human cells, animal cells, mechanistic test systems,

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Box 3.4•

B A C K G R O U N D

Systematic literature reviews

The main basis for the Panel’s work in coming to judgement on the causal relationships between food, nutrition, physicalactivity, and cancer is a series of 20 speciallycommissioned systematic literature reviews(SLRs). These have all been conductedaccording to a common, detailed specification, following recommendations madeby the Methodology Task Force, which
completed its work before the Panel’s firstmeeting. The SLRs form the main evidencebasis for the assessments and judgements
made by the Panel in Part 2 of this Report,
on which the Panel’s population goals andpersonal recommendations in Part 3 arebased.
This approach differs from that used toprepare most other expert reports.
Previously, expert reports concerned withthe prevention of disease, and other topics, have relied on less formal methods tocollect and assess relevant literature. Until
the 1980s, most such reports were assembled by members of panels of scientists
who, assisted by secretariats, wrote draftsof chapters themselves using their own
knowledge, either with or without additional research. The panel then reviewed
the draft report until consensus wasachieved. In some cases, report authors
took total responsibility for assembling andjudging the evidence. In the 1990s, more
ambitious reports placed greater emphasis
on secretariats, which tended to take more
responsibility for drafting the report, andfor some original research, as directed by
the panel. More recently, panels havesometimes been informed by ‘narrative
reviews’ commissioned from specialists andprepared independently from the panel
process. Such reviews are usually writtenfrom the specialists’ existing knowledge,
and form background ‘substrate’ for thereports. Narrative reviews may be published separately.29

Current practice, when resources allow,
is to separate the process of collecting anddisplaying evidence from that of discussing
and judging evidence. Evidence is collected systematically, after agreeing criteria forinclusion or exclusion for review. As well as
reducing possible bias, this is a more comprehensive and transparent approach. This
process was used by the previous report,
which at the time of its publication was themost comprehensive in its and allied fields.
This current Report has made a stepchange in this process, by commissioning
independent SLRs, and making full use ofelectronic resources.
The Panel, in commissioning the SLRs
and supplementary work, decided torequire evidence from all relevant epidemiological and experimental studies,
together with biological findings. The
alternative approach would have been toagree a hierarchy of epidemiological evidence, perhaps with one study type given
pre-eminent importance. Instead, whileallowing for some types of epidemiological study being more or less prone to bias
than others, the Panel has based its conclusions and judgements on evidence accumulated from different types of study. For
the Panel to be convinced that a relationship between an exposure and cancer iscausal, or that it is probably causal, consistent evidence from different types of study
was required, with the exception of randomised controlled trials.
The teams responsible for producing the
SLRs gathered relevant studies in a common, systematic fashion, using a protocol
designed to limit the potential for bias indeciding which evidence should be included or excluded from analysis.
The first stage of the SLRs was a comprehensive search of the scientific literatureand other sources catalogued on electronic databases, using all relevant keywords

and bacterial systems can be used.
Cell cultures can be primary, where tissue (such as atumour biopsy) is taken directly from humans or animals andthen cultured; or secondary, where the original cells are cultured a number of times. Such cell lines are commonly usedin laboratory research, and can become immortal — cultured
again and again. The cells or tissues are subjected to potential carcinogens, and then markers of damage are measured.
Conducting studies in vitro has two main advantages.
First, specific, well defined interventions can be tested; andsecond, intracellular mechanisms can be examined. However,these studies do not allow the study of integrated systems,
such as how organs or the whole body responds to the54

Iand terms. The papers identified wereassessed for relevance using reproducible
criteria. Study characteristics and results
were extracted and recorded. Data fromdifferent studies were combined andanalysed, using meta-analysis when appropriate. Key features of selected studies arepresented in graphic form in Chapters 4–6
and 8, to aid comparison and quality assessment. Existing SLRs were also identified toensure, as far as possible, that all relevant
papers were included.
An important aspect of an SLR is that allstages of searching, selection, assessment,
and analysis are prespecified, objective,
reproducible, openly documented, andsubject to peer review at critical stages. As
stated, full details of the approach taken
can be found in the SLR specification manual contained on the CD included with thisReport (together with the SLRs).
The SLRs included evidence published up
to the end of 2005, and the Panel’s conclusions are based on these SLRs. To ensurethat the Panel’s recommendations, which
are derived from their conclusions andjudgements, take into account developing
evidence, a further review of studies published during 2006 was conducted. This
review was more limited than the full SLRs:
it was confined to exposures that had
been judged ‘convincing’, ‘probable’, ‘substantial effect on risk unlikely’, and ‘limited–suggestive’, based on the SLRs. (See box
3.8 for an explanation of these terms.) At
this second review stage, no further metaanalyses were performed and a review ofstudy quality was not included. For thesereasons, the results of this 2006 review
have been noted but have not been used
to alter the Panel’s judgements based on
the full SLRs. A further process has been
established for a continuous review of
evidence published since 2006, after publication of this Report.

interventions. Therefore extrapolation of results to humans
is limited.
3.2.4 Biological pathways
Epidemiological and experimental evidence indicating a
causal association between an aspect of diet and cancer isstrengthened when there is evidence of a plausible biological pathway or mechanism by which the cancer process may
be modified. The Panel agreed that simply identifying such
plausible mechanisms is not sufficient evidence for a causal
relationship; but it also agreed that the case for a causal relationship is strengthened when there is evidence of biological plausibility.

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Narrative reviews of experimental studies and of evidenceof plausible biological mechanisms were included in the SLRs
that inform this Report. Summaries of these SLRs are presented in Part 2, Chapters 4–10. Also see box 3.4.

3.3 Methods of assessment
Some exposures are easier to measure than others. Thus, it
is relatively easy to assess the impact of tobacco smoking andexposure to tobacco on cancer risk. Although tobacco smoke
is a mixture of many chemicals, and its interactions withthe body are complex, tobacco can be considered a single
exposure.
By contrast, diets are multidimensional exposures and in
free-living populations cannot be measured with complete
accuracy. Moreover, the foods and drinks people consume
every day contain thousands of constituents, some wellknown, others unknown and unmeasured. The relationships
between food, nutrition, physical activity, and health and disease are complex and difficult to untangle. The presence orabsence of effect modification (box 3.6) can create additional
challenges.
3.3.1 Foods, drinks, and nutrients
People’s dietary intake varies from day to day and over thecourse of their lives. There are interrelationships between
food components, between foods in whole diets, andbetween diets and other behavioural characteristics such as
physical activity or smoking. There are several methods forassessing food and drink consumption, all with their own
weaknesses and strengths.
3.3.1.1 Dietary assessment methods

Food intakes can be measured for populations, groups, orindividuals. The most commonly used techniques for assessing food and drink consumption are diet histories, 24-hour

Box 3.5

dietary recalls, food frequency questionnaires, and food diaryor food record methods. Most of the studies included in thisReport used dietary assessment data from individuals,
recorded using food frequency questionnaires.
Diet histories take the form of unstructured enquiries,
more useful in clinical settings than in research studies.
Dietary recalls may use structured or unstructured methods,
and are often administered many times over the course of astudy. In a 24-hour dietary recall, a record is made of everything a person can recall eating or drinking over the previous 24 hours. Automated systems for collecting andanalysing dietary recalls have been developed, which facilitate the use of this method of assessment in large studies.32
Food frequency questionnaires collect information on foodconsumption patterns, typically over the past year. A record
is made of the frequency of consumption of perhaps 100 to
150 items, and often includes information on serving sizes.
Food frequency questionnaires may be designed to gain
detailed information about specific aspects of diets, such as
intakes of fats or dietary fibre, leaving other components lesswell characterised. A questionnaire for whole diets cannot
adequately capture the full variety and composition of individual diets without becoming unwieldy. Food frequency
questionnaires are inexpensive, however, and are practicalfor use in large-scale epidemiological studies.
Food diary or food record methods rely on the participantsin the study recording everything they eat and drink over thecourse of one or more days. Participants may be asked toestimate portion sizes, or weigh foods and drinks.
All dietary assessment methods that rely on self-reportingare subject to measurement error. Further errors are introduced by the conversion of food data to nutrient data, using
tables of the chemical composition of foods, which give average nutrient contents for defined foods. This implicitly
assumes that all participants eat foods that have the same
standard composition and portion size. But in reality, foodcomposition varies widely, depending on soil quality,

Experimental findings

The Panel agreed a ‘hierarchy of robustness’ recommended by the Methodology
Task Force, which completed its work
before the Panel’s first meeting. The ‘hierarchy of robustness’ was designed to determine which types of human and animal
experimental study are likely to be mostapplicable to human cancer. This was done
for practical and scientific reasons. The
body of experimental literature is verymuch larger than the body of epidemiological literature, and an exhaustive systematic review of this literature would
have been impractical. Also, most experimental work, such as that conducted as a
guide to toxicological regulations, either
has no evident relevance to the work of
the Panel, or else would be unlikely to sig-

nificantly influence judgements derived
from consideration of the collective weightof evidence from all other types of study.
For these reasons, eight types of experimental evidence were identified and split
into three classes:
Class 1
• In vivo data from studies in humanvolunteers (controlled human feedingstudies).
• In vivo data from studies using
genetically modified animal models
related to human cancer (such as geneknockout or transgenic mouse models).
• In vivo data from studies using rodent
cancer models designed to investigate
modifiers of the cancer process.

Class 2
• In vitro data from studies using humancells validated with an in vivo model;
for example, a transgenic model.
• In vitro data from studies using primary
human cells.
• In vitro data from studies using humancell lines.
Class 3
• In vitro data from studies on animal cells.
• Data from mechanistic test systems; forexample, isolated enzymes or genes.
For the systematic literature reviews in thisReport, only class 1 evidence was reviewed.
Illustrative evidence from in vitro studies is
included only in Chapter 2.

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Box 3.6

Effect modification

Effect modification (or effect-measure modification) occurs
when a measure of effect for an exposure changes over levelsof another variable (the modifier).30 Effect modifiers can sometimes even change the direction of an effect. For example, apooled analysis of seven cohort studies found an association
between body fatness and decreased risk of breast cancer in premenopausal women, but with increased risk in postmenopausal
women.31 In this case, menopausal status modifies the effect ofbody fatness on breast cancer risk.

harvesting conditions, animal feed, storage, and food processing, for example. Furthermore, food tables can be incomplete: for instance, they may not include information on
phytochemical or fatty acid levels in foods. In many countries, there may be no records of the composition of traditional and indigenous foods.
Multiple-day food records or 24-hour dietary recalls havebeen used as reference instruments to check the validity offood frequency questionnaires.33 34 However, studies using
biomarkers (see 3.3.1.2) have shown that food record andrecall methods are also liable to measurement error, and thatthese errors are correlated with errors from food frequency
data. This means that the use of food record or recall methods to validate food frequency data results in an overestimation of the validity of the food frequency data.35-38
Often, estimated intakes of macro- and micronutrients areadjusted for energy intake (box 3.7).
3.3.1.2 Biomarkers‘Recovery’ biomarkers, such as doubly labelled water or 24hour urinary nitrogen excretion, can be used to assess theaccuracy of various dietary assessment methods. The doubly labelled water test accurately measures a person’s totalenergy expenditure, which equals energy intake when a person is in energy balance.39 Urinary nitrogen excretion is used
as a biomarker of protein consumption.40 Studies using theserecovery biomarkers suggest that measurement errors fromall types of dietary assessment instruments are larger thanpreviously appreciated.35 38 41‘Concentration’ biomarkers, such as blood levels of fatty
acids or vitamins, can be used to indirectly estimate dietaryintake of these compounds. However, blood levels are determined not only by a person’s intake of the compound, butalso by factors such as the compound’s bioavailability andexcretion, intakes of other dietary components, personal
characteristics such as smoking, and individual variation inmetabolism. These determinants — and therefore the relations between true intakes and the biomarkers — vary
among people, and this can bias observed diet–cancer
associations.9
For some compounds, such as selenium, biomarkers are amore accurate indicator of dietary intakes than data fromfood frequency questionnaires.42 43 Many studies examine
concentration biomarkers as indirect proxies for intake, andthere is growing interest in combining these data with resultsfrom self-report dietary assessment instruments.

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3.3.2 Nutrition status
Nutrition status is not simply a function of dietary intake. It
includes energy and nutrient intakes, and also body nutrient stores and body composition, all of which can be studied at various levels of complexity. Nutrition status cannot
be completely measured by any one method, and judging
which methods are most useful is an important aspect of thescience in this field.
Some aspects of nutrition status can be assessed relatively
accurately. These include body fatness and measurements ofweight and height at birth, during growth, and in adulthood.
Nutrition status is affected by other biological andbehavioural factors, and also by social and environmental factors. Social factors include economic and political drivers offood supplies, availability of food, and tradition and culture.
3.3.3 Physical activity
Study of the effects of physical activity on health requires reliable and valid measurements of physical activity in whatever setting it occurs — occupational, household, transport,
and recreational — and also of frequency, duration, andintensity. Effects of physical activity are not just a functionof total overall energy expenditure. A person may expend
the same amount of energy during a short period of intense
exercise or in a longer period of moderate activity, but
the physiological effects may be different. Also see
Chapter 5.
Assessments of physical activity may use objective biochemical, physiological, or other methods, but these are
expensive and not commonly used in large studies.
Epidemiological studies usually rely on self-completed questionnaires. These vary in the duration and type of physicalactivity, the length and detail of the questionnaire, and how
the physical activity measures are calculated.
As with food questionnaires, physical activity questionnaires have limitations. Activities may be over-reported whenparticipants overestimate their recreational activity, forexample, or under-reported, such as when participants do
not take account of everyday activities, such as walking
around their home or office. Many questionnaires ask only
about occupational activity or recreational activity, and therefore do not provide a comprehensive account of people’s total
physical activity.
Results from questionnaires are commonly reported interms of energy expenditure. This is usually done by assigning an ‘energy cost’ (derived from published guides) to theenergy value of various activities, and multiplying this by the
duration and frequency of the activity. But there are large
variations in the energy values of different activities depending on age, gender, body mass, skill, and level of fitness;these can lead to significant errors in estimates.
3.3.4 Cancer outcomes
In studies of food, nutrition, physical activity, and cancer,
accurate identification of cancer occurrence is as importantas making accurate measures of food and drink consumption,and of physical activity. In most epidemiological studies,
data from cancer registries are used, or else participants
report whether they have been diagnosed as having cancer.

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Studies may also require participants to undergo clinicalexamination, or provide tissue biopsy samples.
The duration of a study can also affect whether the full
effects of exposures are identified. Relatively short-term
prospective studies may miss any late effects on cancers. Thisis one reason why results from studies with long-term follow-up periods are particularly valuable.
Population-based cancer registries collect cancer incidence
and mortality data for the areas they serve, and produce cancer registers.
In the US, the Surveillance, Epidemiology, and End Results(SEER) programme collects population-based data on newly
diagnosed cancers from registries that cover approximately
23 per cent of the US population.49 The European Networkof Cancer Registries represents population-based cancer registries in Europe.50 Population-based registries are becoming
increasingly available in middle- and low-income countries.
In total, 57 countries and 186 cancer registries are represented in Volume VIII of the Cancer Incidence in Five
Continents series published by IARC.1 Also see box 1.2.
Cancer incidence data are coded in a standardised way,using International Classification of Disease (ICD) codes thathave been established for oncology.51 These 10-digit codes
specify the site of origin of the tumour (topography), thetumour or cell type (morphology), the behaviour of thetumour (malignant, benign, or in situ), and the tumour
grade or degree of differentiation.
In addition to providing cancer incidence and mortality
statistics, cancer registries are used by researchers to identify people who are eligible to enrol in a case-control study,
or to collect information on cancer diagnosis relating to people who are enrolled in a cohort study.

Box 3.7

3.4 Causation and risk
One of the Panel’s tasks has been to devise a transparent andobjective method that enables evidence of relationships
between diet, physical activity, body fatness, and associatedfactors, and cancer of one or more sites, to be judged as
causal, with varying degrees of confidence.
3.4.1 Inferring causation
The Panel endorses the view of the panel responsible for theprevious report, that causal relationships between food andnutrition, and physical activity can be confidently inferred
when epidemiological evidence, and experimental and otherbiological findings, are consistent, unbiased, strong, graded,coherent, repeated, and plausible. Individually, none of thesefactors is likely to be sufficient to infer a causal relationshipwith confidence. Also, individual relationships may be deficient in various respects, but collectively can still be judged
as causal because of their cumulative weight.
Many types of evidence can contribute to causal inference.
However strong the evidence from any single study, it will
rarely justify a conclusion of causality. Increasing ‘survivability’ of an observed relationship, when supported by further studies, or which produces corroborative evidence inother categories, as listed above, strengthens the evidence
for a causal relationship.52 53
With regard to food and nutrition, and physical activity,
single exposures are unlikely to act alone to cause or prevent cancer. In general, many factors act together as contributory or component causes, forming a complete causal
process. Component causes can interact biologically, evenwhen exerting their effects at different times.30

Energy adjustment

One of the basic principles in controlledhuman and animal feeding experiments toevaluate the effect of a specific dietary factor is that the diets should be isocaloric(i.e., total energy intake is the same in bothgroups). This is because differences inenergy intake between two groups would
cause one group to gain or lose moreweight than the other. The effects of the
dietary factor being investigated could notthen be distinguished from the effects ofchanges in weight. This is important,because differences in weight themselves
may have different physiological effects.
In epidemiological studies, there are similar reasons to conduct isocaloric analyses.
These use statistical methods to ‘adjust’intakes of the dietary factor under study
for total energy intake. The rationale forenergy-adjusted intakes is that theabsolute intake of a nutrient is a functionof two factors: first, the total amount offood consumed, represented by total energy intake; and second, the composition ofdiets. The total amount of food consumed
is determined primarily by body size andphysical activity.
Body size and physical activity are ofinterest in their own right, but their effects
need to be disentangled from the effects
of a specific nutrient. This can be done byusing energy-adjusted nutrient intakes.
Expressed another way, studies designed tochange the intake of a specific nutrient
usually should do so by changing the composition of diets rather than total energy
intake. Epidemiological studies therefore
should adjust for energy and not rely on
absolute intakes, which reflect both dietarycomposition and variation in total energy
intake due to differences in body size andphysical activity.
The best method to adjust for totalenergy intake has been a matter of considerable discussion.44-48 The two basic
approaches are to use the nutrient density (for example, expressing intake per unitof energy or, for macronutrients, as a per-centage of total energy) or regression
analysis to calculate nutrient residuals. Inan epidemiological analysis, the nutrient
density does not adequately adjust for
total energy intake if energy intake itself
is associated with disease risk. In this case,total energy intake must be added as aseparate term to the model. Anothermethod, that of ‘energy partition’, hasbeen used in some studies, but this is notan ‘isocaloric’ analysis and thus does notcontrol for total energy intake.
An additional advantage of energyadjusted nutrient intakes is that they areoften measured with less error thanabsolute nutrient intakes. This is because
over- or under-reporting of specific nutrients tends to be strongly correlated withover- or under-reporting of total energy
intake, especially for macronutrients, being
calculated from the same foods. Theseerrors are highly correlated, so tend to cancel each other when calculating nutrient
densities or energy-adjusted intakes.

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3.4.2 The ‘portfolio’ approach
Many different types of study, all of which have strengths andweaknesses, investigate links between food, nutrition, physical activity, and cancer. Persuasive evidence comes from different types of epidemiological study, supported byexperimental findings that indicate a relevant biologicalmechanism.
The Panel’s judgements, presented in Part 2 of this Report,
are based on its assessment of the evidence available in thescientific literature, with due consideration given to theadvantages and disadvantages of each type of study design,and to the quality of individual studies. An inclusive or ‘portfolio’ approach has been taken, recognising the relative
strengths and weaknesses of different types of study, but inwhich no single type of study design is given pre-eminence.
In general, the strongest evidence comes from consistentfindings from different types of studies, preferably also indiverse populations.
3.4.3 Quantification of risk
Quantification of the risk of any disease is an essential basis
for public health policy planning. It also guides people inmaking their own decisions about how they lead their lives.
It is not enough to know that the risk of cancer is affectedby diet. It is also important to know by how much. For example, if consumption of alcohol increases the risk of breast cancer, and diets high in vegetables decrease the risk of various
cancers, to what extent may the incidence of cancer on a
population basis be affected by these factors? And on a personal level, how can people best judge how their current
diets and ways of life, and any changes they might want tomake, are likely to affect their own risk of cancer?
Quantifying risk helps to answer such questions.
The strength of a relationship between any risk factor andthe occurrence of disease is commonly expressed in terms of
relative risk (RR). In cohort studies, this is the ratio of risk
(or incidence) of a disease among people with a particularcharacteristic (say, high consumption of red meat) to thatamong people without that characteristic (in this example,
low or no consumption of red meat). In case-control studies, the odds ratio is used, which is the ratio of the odds of
exposure among cases to the odds of exposure among controls. Relative risks below 1.0 imply a protective effect: so a
relative risk of 0.5 for high compared with low vegetable consumption implies a halving of risk. Relative risks above 1.0
indicate an increased risk.
Absolute risk is also important. Small RR values, when
consistent, are important when the number of people affected is large. A large RR of a rare type of cancer amounts toonly a small absolute risk, which may reasonably be considered not significant, either by public health planners or
by individuals assessing their own choices. By contrast, asmall RR may amount to a large number of cases for a common type of cancer. For example, an increased risk of 10 per
cent implied by a RR of 1.10 amounts to many extra casesof colorectal and breast cancer in Europe and North
America, where these cancers are common. Assessmentof small RRs depends on the size and quality of thestudies in which such risks are identified. Small RRs may

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amount to strong evidence if consistently found in large, welldesigned studies.

3.5 Coming to judgement
A crucial part of the process that has informed this Reportis the methods used by the Panel in judging whether the evidence that a relationship between aspects of food, nutrition,
physical activity, and body fatness, and cancers of the sites
specified, is or may be causal. The need for evidence fromdifferent types of study and the characteristics looked for insuch studies have been outlined already. Here, the precise
methods used by the Panel are explained.
The previous report broke new ground in a number ofrespects. One was to display panel judgements in the formof matrices within which panel judgements on causal relationships, of different degrees of confidence, were shown,
and repeated in the text of the report. This method has been
adapted in other reports.29 Another was the specification of
criteria guiding these judgements. The previous report also
used explicit statements explaining why, on occasion, thepanel had made judgements that did not obviously derivefrom the evidence as presented. One general principle wasthat of transparency. Readers and users of the previous report
have been able to follow its reasoning, to challenge any
judgements that might seem questionable, and to modify
or reinforce judgements in the light of further and better
evidence.
The Panel responsible for this Report decided to adapt
those innovative approaches, and use them as the basis for
its work. Some of the judgements made in this Report are
different from those based on the evidence available adecade previously, while others confirm or strengthen previous judgements.
3.5.1 The matrix approach
An example of a matrix used in this Report is shown in figure 3.1. This particular matrix displays the Panel’s judgements on the likelihood that physical activity modifies therisk of cancers of specified sites. This matrix is used here as
an example, to explain the nature of the matrices displayedin all chapters in Part 2 of this Report. This matrix and its
judgements are discussed fully in Chapter 5.
The title of the matrix is self-explanatory. In this and othercases, the introductory words are important: here, thefootnote specifies that the physical activity referred to is of
all types.
The matrices display the Panel’s judgements on whether
particular aspects of food and nutrition, physical activity, andbody composition do or may modify (or not modify) the riskof cancers of specific sites. The matrices are of course shorthand, and the entries cannot convey all nuances. Necessary
clarifications and qualifications are stated in footnotes to thematrices.
Matrix entries themselves need to be explained. For example, an entry ‘fruits’ or ‘foods containing dietary fibre’ in amatrix column headed ‘decreases risk’ means that the Panelhas judged that these foods are or may be protective against

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T H E

E V I D E N C E

PHYSICAL ACTIVITY, AND THE RISK OF CANCER
In the judgement of the Panel, physical activity1 modifies the risk of thefollowing cancers. Judgements are graded according to the strength ofthe evidence.

DECREASES RISK
Convincing

Colon2

Probable

Breast(postmenopause)

INCREASES RISK

Endometrium
Limited —suggestive

Lung
Pancreas
Breast (premenopause)

Substantial
effect on risk
unlikely12None identified

Physical activity of all types: occupational, household, transport,
and recreational.
Much of the evidence reviewed grouped colon cancer and rectal cancer
together as ‘colorectal’ cancer. The Panel judges that the evidence isstronger for colon than for rectum.

For an explanation of the terms used in the matrix,
please see chapter 3.5.1, the text of this chapter,and the glossary.

Figure 3.1 Example of a matrix

the cancer specified. The judgements are derived fromanalysis of studies in which relatively high intakes of (in thisexample) fruits and foods containing dietary fibre are compared with relatively low intakes. The same point applies tomatrix entries ‘physical activity’ and ‘body fatness’ incolumns headed ‘decreases risk’ and ‘increases risk’, respectively, which are derived from analysis of studies of people
whose physical activity levels or degree of body fatness isrelatively high compared with people whose physical activity levels or degree of body fatness is relatively low.
In some cases, analysis may show that any effect begins
or ends, or is less apparent, below or above evident ‘thresholds’. For example, it has been thought that alcoholic drinks
increase the risk of some cancers only above certain levelsof consumption. Such amounts would be specified in a footnote to the relevant matrices, and could be reflected in Panelrecommendations. When matrices include no such footnotes, this is because no lower or upper threshold of effecthas been identified. In such cases, matrix entries showing
or suggesting a causal association should be taken to meanthat the effect is across the whole range of dietary intake,amounts of physical activity, or degrees of body fatness
found in the studies analysed. The implications of the natureof the dose-response relationships for recommendations arefurther discussed in Chapter 12, in Part 3 of this Report.
3.5.2 Levels and types of judgement
The top half of the matrix in figure 3.1 shows that theevidence of causality, either of decreased risk or increased

risk, is judged to be convincing, or else probably causal. A
judgement of ‘convincing’ in turn generally justifies a recommendation designed to inform policies and programmes
designed to prevent cancer. A judgement of ‘probable’ also
normally justifies a recommendation. So in the case of thematrix shown, it follows that the Panel would make a recommendation on physical activity designed to reduce the riskof cancer.
The top two rows of the matrix are separated from the row
below, which shows judgements that the evidence is too limited, for a variety of reasons (see 3.5.5), to conclude that a
relationship is causal, but that there are enough data tosuggest that such a relationship might exist. Normally, ajudgement of ‘limited — suggestive’ does not justify any recommendation. The matrices used in Chapter 7 also include
a row showing judgements where the evidence is so limited(again for a variety of reasons) that no judgement can bemade whether any association exists or not. For this reason,such judgements of ‘limited — no conclusion’ do not indicate whether the evidence is in the direction of decreasing
or increasing risk. The final, bottom row of the matrix, ‘substantial effect on risk unlikely’, shows judgements for which
the evidence, equivalent to a judgement of ‘convincing’ or‘probable’, shows that no causal relationship is likely to exist.
Terms used in the text and matrices to refer to foods anddrinks, physical activity, body fatness, and other factors arenecessarily shorthand. Thus, in chapter 4.2, the matrix displays judgements that ‘non-starchy vegetables’ probably protect against a number of cancers. The matrix in chapter 4.8
displays judgements that the evidence that ‘alcoholic drinks’cause a number of cancers is convincing. What is meant by‘non-starchy vegetables’ and by ‘alcoholic drinks’ is definedin the text of these sections.
Further, when ‘non-starchy vegetables’ is used as a matrix
entry and contained in Panel judgements, it means ‘relatively
high consumption of non-starchy vegetables and/or foods
containing them’. The same point applies to many othermatrix entries and also to the accompanying text.
Within all matrix cells, exposures are listed in the order ofthe contents of the Report. There are a number of cancer sites
where a substantial number of related exposures meet thecriteria for matrix entry. The Panel has judged that it is often
appropriate to aggregate such exposures. For example, if
both ‘alcoholic drinks’ and ‘wine’ are judged as exposuresthat probably increase the risk of a type of cancer, then
only ‘alcoholic drinks’ will appear in the matrix for thatcancer site.
The matrices used in this Report differ from those used in
the previous report in a number of respects. The previous
report used categories of ‘possible’ and ‘insufficient’ defineddifferently from the categories of ‘limited — suggestive’ and‘limited — no conclusion’ used here. Also, the previous report
allowed for different weights of evidence for no causal relationship, whereas this Report includes just the one judgement of ‘substantial effect on risk unlikely’. The judgementsof ‘convincing’ and ‘probable’, both agreed to be a sufficientbasis for recommendations, are common to both reports,
although the criteria allowing such judgements have beenrefined for this Report (see 3.5.5).

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Box 3.8•

B A C K G R O U N D

Criteria for grading evidenceThis box lists the criteria finally agreed by
the Panel that were necessary to support
the judgements shown in the matrices andtext of the Part 2 chapters. The grades
shown here are ‘convincing’, ‘probable’,‘limited — suggestive’, ‘limited — no conclusion’, and ‘substantial effect on risk
unlikely’. In effect, the criteria define theseterms.
Convincing
These criteria are for evidence strong
enough to support a judgement of a convincing causal relationship, which justifies
goals and recommendations designed toreduce the incidence of cancer.
A convincing relationship should berobust enough to be highly unlikely to bemodified in the foreseeable future as new
evidence accumulates. All of the following
were generally required:• Evidence from more than one study type.
• Evidence from at least two independentcohort studies.
• No substantial unexplained
heterogeneity within or between study
types or in different populations
relating to the presence or absence ofan association, or direction of effect.
• Good quality studies to exclude withconfidence the possibility that theobserved association results fromrandom or systematic error, including
confounding, measurement error, andselection bias.
• Presence of a plausible biologicalgradient (‘dose response’) in theassociation. Such a gradient need not
be linear or even in the same direction
across the different levels of exposure,

so long as this can be explained
plausibly.
• Strong and plausible experimental
evidence, either from human studies or
relevant animal models, that typicalhuman exposures can lead to relevantcancer outcomes.
Probable
These criteria are for evidence strong
enough to support a judgement of a probable causal relationship, which would generally justify goals and recommendations
designed to reduce the incidence of cancer.
All the following were generally
required:• Evidence from at least two independentcohort studies, or at least five casecontrol studies.
• No substantial unexplained
heterogeneity between or within study
types in the presence or absence of an
association, or direction of effect.
• Good quality studies to exclude withconfidence the possibility that theobserved association results fromrandom or systematic error, including
confounding, measurement error, andselection bias.
• Evidence for biological plausibility.
Limited — suggestive
These criteria are for evidence that is too
limited to permit a probable or convincing
causal judgement, but where there is evidence suggestive of a direction of effect.
The evidence may have methodologicalflaws, or be limited in amount, but showsa generally consistent direction of effect.
This almost always does not justify recom-

3.5.3 The food-based approachTerms used in the text of this Report and in the matrices
reflect the Panel’s decision that the Report, and its judgements and recommendations, should whenever possible bebased on foods and drinks rather than on nutrients. This
food- (and drink-) based approach is also apparent in theoverall structure of the Report. Chapter 4, the first chapter
in Part 2, on foods and drinks, is the longest chapter. This is
in part because dietary constituents associated with foods aregrouped with these foods. Thus, matrix entries in chapter 4.1
identify ‘foods containing dietary fibre’ (rather than dietary
fibre), and in 4.8 identify ‘alcoholic drinks’ (rather than alcohol or ethanol). Chapters 4, 5, and 6 also include materialpresented graphically, such as the forest plots described inbox 3.3.
The food-based approach is also justified because of theuncertainty that any food constituent is a true causal factor,

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mendations designed to reduce the incidence of cancer. Any exceptions to thisrequire special explicit justification.
All the following were generally
required:• Evidence from at least two independentcohort studies or at least five casecontrol studies.
• The direction of effect is generally
consistent though some unexplained
heterogeneity may be present.
• Evidence for biological plausibility.
Limited — no conclusion
Evidence is so limited that no firm conclusion can be made.
This category represents an entry level,
and is intended to allow any exposure forwhich there are sufficient data to warrant
Panel consideration, but where insufficientevidence exists to permit a more definitive
grading. This does not necessarily mean alimited quantity of evidence. A body of evidence for a particular exposure might begraded ‘limited — no conclusion’ for anumber of reasons. The evidence might belimited by the amount of evidence in termsof the number of studies available, byinconsistency of direction of effect, bypoor quality of studies (for example, lackof adjustment for known confounders), orby any combination of these factors.
Exposures that are graded ‘limited — noconclusion’ do not appear in the matrices
presented in Chapters 4–6, but do appear
in Chapters 7 and 8.
When an exposure is graded ‘limited —no conclusion’, this does not necessarily
indicate that the Panel has judged that
there is evidence of no relationship. Withrather than simply a marker for the particular foods in which
it is found; or for other dietary constituents found in thesame foods; or other associated health-related factors. In
chapter 4.10, some micronutrients appear in matrices graded as ‘convincing’ or ‘probable’. These judgements arederived from the findings of good quality, randomised, controlled trials, sometimes also supported by observational
studies, clearly showing that supplements of these micronutrients, rather than the foods containing them, affect the riskof cancer.
Sometimes the studies that are the basis for the Panel’s work
have used markers of exposure. Thus, many epidemiologicalstudies use body mass index as a marker of body fatness.
When there is clear evidence of an underlying mechanism forbody fatness, the Panel has agreed that the term ‘body fatness’
best represents the causal factor. Usually, anthropometricindices — other examples being waist to hip ratio and waist

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3•J U D G I N G

T H E

further good quality research, any exposure graded in this way might in the future
be shown to increase or decrease the riskof cancer. Where there is sufficient evidence to give confidence that an exposureis unlikely to have an effect on cancer risk,
this exposure will be judged ‘substantial
effect on risk unlikely’.
There are also many exposures for which
there is such limited evidence that nojudgement is possible. In these cases, evidence is recorded in the full SLR reports
contained on the CD included with thisReport. However, such evidence is usually
not included in the summaries and is notincluded in the matrices in this printed
Report.
Substantial effect on risk unlikely
Evidence is strong enough to support a
judgement that a particular food, nutrition, or physical activity exposure is unlikely to have a substantial causal relation to acancer outcome. The evidence should berobust enough to be unlikely to be modified in the foreseeable future as new evidence accumulates.
All of the following were generally
required:• Evidence from more than one study
type.
• Evidence from at least two independentcohort studies.
• Summary estimate of effect close to
1.0 for comparison of high versus low
exposure categories.
• No substantial unexplained
heterogeneity within or between study
types or in different populations.
• Good quality studies to exclude, withE V I D E N C E

confidence, the possibility that theabsence of an observed association
results from random or systematic
error, including inadequate power,
imprecision or error in exposure
measurement, inadequate range of
exposure, confounding, and selectionbias.
• Absence of a demonstrable biologicalgradient (‘dose response’).
• Absence of strong and plausible
experimental evidence, either fromhuman studies or relevant animalmodels, that typical human exposureslead to relevant cancer outcomes.
Factors that might misleadingly imply an
absence of effect include imprecision of
the exposure assessment, an insufficient
range of exposure in the study population,and inadequate statistical power. Defects
in these and other study design attributes
might lead to a false conclusion of noeffect.
The presence of a plausible, relevant
biological mechanism does not necessarily
rule out a judgement of ‘substantial effecton risk unlikely’. But the presence ofrobust evidence from appropriate animalmodels or in humans that a specific mechanism exists, or that typical exposures canlead to cancer outcomes, argues against
such a judgement.
Because of the uncertainty inherent inconcluding that an exposure has no effecton risk, the criteria used to judge an exposure ‘substantial effect on risk unlikely’ areroughly equivalent to the criteria usedwith at least a ‘probable’ level of confidence. Conclusions of ‘substantial effectcircumference — do not appear in the matrices.
As exceptions to this approach, the Panel has made judgements on ‘adult attained height’ and ‘greater birth weight’,as shown in the matrices. Many epidemiological studies havereported on height and birth weight. It is thought that associations between height, birth weight, and cancer risk reflect
some causal association with a combination of genetic, hormonal, nutritional, and other factors. Uncertainty as to themechanisms underlying the observations with ‘adult attainedheight’ and ‘birth weight’ mean that the Panel was not able
to determine the appropriate causal factors to be shown inthe matrices. Instead, the anthropometric markers have been
included, with appropriate footnotes.
3.5.4 The basis for robust judgements
The Panel has been particularly careful in deciding the criteria for judgement on causal relationships (or lack of suchon risk unlikely’ with a lower confidence
than this would not be helpful, and could
overlap with judgements of ‘limited — suggestive’ or ‘limited — no conclusion’.
Special upgrading factors
These are factors that form part of theassessment of the evidence that, when present, can upgrade the judgement reached.
So an exposure that might be deemed a‘limited — suggestive’ causal factor in theabsence, say, of a biological gradient,might be upgraded to ‘probable’ in its
presence. The application of these factors(listed below) requires judgement, and theway in which these judgements affect the
final conclusion in the matrix are stated.
• Presence of a plausible biologicalgradient (‘dose response’) in theassociation. Such a gradient need not
be linear or even in the same direction
across the different levels of exposure,
so long as this can be explained
plausibly.
• A particularly large summary effect size
(an odds ratio or relative risk of 2.0 or
more, depending on the unit of
exposure) after appropriate control for
confounders.
• Evidence from randomised trials inhumans.
• Evidence from appropriately controlled
experiments demonstrating one ormore plausible and specific mechanisms
actually operating in humans.
• Robust and reproducible evidence fromexperimental studies in appropriate
animal models showing that typicalhuman exposures can lead to relevantcancer outcomes.

relationships). Its decisions here have been enlightened by
the rapid development since the mid-1990s of the techniqueof systematic review, using search techniques enabled by theelectronic revolution.
Since the mid-1990s, about as many studies in the fieldof this Report have been published as were published in theprevious 35 years. This development has not just been oneof quantity but also of design and quality. In particular, many
cohort studies have been published in the period analysedby the SLRs, and some of these have also been pooled. The
Panel agreed that in general, cohort studies provide more
impressive evidence than case-control and other epidemiological study designs, and this decision affected the criteria
for judgement. For this reason, while the best evidence
comes from a number of different study designs, the Panelagreed that reasonably strong and consistent evidence wasneeded from studies where biases could reasonably be

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excluded. Usually this evidence came from cohort studies
with a prospective design or, where available and appropriate, from randomised controlled trials, to allow a judgementof ‘convincing’ or ‘probable’. This was not a requirement specified for the previous report. See box 3.8.
A consequence is that the same amount of evidence for any
particular association has sometimes led to a different judgement and level of matrix entry from the previous report.
Sometimes, in cases where there is a greater quantity of evidence, this might not lead to a ‘higher’ classification, andcould even possibly lead to a ‘lower’ one. These refinements
are intended to give as robust an assessment as possible,
given current understanding. In these respects, the criteria
used by the Panel are more stringent than those pioneeredby the previous panel.
The Panel agreed that the criteria for their judgements
should be detailed and precise. But such criteria do notlead to automatic judgements. However meticulous, theycannot replace expert judgement. If a reviewer or a Panelmember felt that important considerations had been overlooked by the overall agreed process, this was discussed,
and the Panel’s final judgement specified, with reasonsprovided.
3.5.5 The grading criteria
Specification of criteria for the grading of judgements
enables a common, transparent approach. But as indicated,
any such criteria cannot fully capture the sophistication andnuances of all the studies considered, or the nature and quality of different studies.
In using the criteria specified here, the Panel has taken into
account additional factors including, but not confined to, thetype, number, and size of studies; their design and execution; the nature of any intervention; the definition of cases
and non-cases; the selection of any comparison group; methods of characterising exposure and outcome; length andcompleteness of follow-up; and the methods used to ascertain cases.
Other factors might lead to one or another grading. Failure
to achieve a higher grade might result from several small
deficits against a number of standards, or from a major shortfall in one particular aspect of evidence. Panel expertise was
essential in judging whether criteria were met, or ‘upgrading factors’ (box 3.8) were applicable, as well as deciding
what constituted substantial heterogeneity, high-quality
study design, and so on. The criteria provide a consistentbasis for judgement, not a ‘set of boxes to be ticked’. As wellas these ‘upgrading factors’, particular reasons why any specific judgement was reached are presented under the relevant exposure and cancer site in Chapters 4–7.
The following grading criteria specify the quantity, quality, and nature of evidence that can lead to associations being
graded differently.
Convincing, probable

In considering the criteria allowing a judgement that the evidence of a causal relationship was convincing, or that theevidence showed a probable causal relationship, the Panelwas conscious that both judgements were liable to generate

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public health goals and personal recommendations.
Limited and ‘below’

For the two types of ‘limited’ judgement, the evidence falls
short of a ‘higher’ judgement for a variety of reasons. There
are also many exposures for which evidence was so limited
that it did not warrant detailed consideration. In these cases,
evidence is recorded in the full SLR reports contained on the
CD included with this Report. However, this evidence is notincluded in the summaries or matrices in this printed Report.
Absence of a causal relation

The strength of this judgement corresponds to that for ‘convincing’ or ‘probable’ (and replaces the previous report’s ‘norelationship’ category). This judgement does not reflect theabsence of evidence, which in itself is not evidence ofabsence of effect. As with judgements of ‘convincing’ or‘probable’, evidence from both observational studies and randomised trials contribute to such an inference.

3.6 Conclusions
Reports such as this address issues of public importance.
They are informed by a process of collection, display, discussion, and judgement of evidence as the basis for recommendations made in the public interest.
We, the members of the Panel responsible for this Report,
have had the responsibility to ensure that the judgements wehave made in Part 2, and the public health goals and personal recommendations we have specified in Part 3, areclearly and reliably based on current evidence.
In the five years of our work, we have built on the work of
the previous report, and have been supported by the findingsof a preliminary Methodology Task Force; by the evidence
gathered and presented by independent SLR centres; byobservers from United Nations and other international organisations; and by the Report’s Secretariat. As far as we know,
the whole process, which has also included eight face-to-facePanel meetings, each lasting up to four days, is the most comprehensive and rigorous of its kind yet undertaken.
As this chapter shows, no method used to ascertain causal
relationships between food, nutrition, physical activity, andcancer is perfect. But we believe that the integrated andsometimes innovative approaches we have taken, summarised here, have enabled us to make sound judgements
and reliable recommendations. We have also done our best
to make sure that the methods we have used are explainedand displayed transparently, so they can be readily accessedand challenged as science develops, or from different pointsof view. We believe this best serves science, and also thecause of cancer prevention.

Part 2

Û  ` i  Vi >  ` Õ` } i i  ÌÃ
Chapter 4
Foods and drinks
Chapter 5
Physical activity

66

198

Chapter 6
Growth, development, body composition

210

Chapter 7
Cancers

244

Chapter 8
Determinants of weight gain, overweight, obesity

322

Chapter 9
Cancer survivors

342

Chapter 10
Findings of other reports

348

Chapter 11
Research issues

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EVIDENCE AND JUDGEMENTSP A R T

2

Introduction to Part 2

The brief of the Panel, and of the systematic literature review teams thatprovided the basis for the Panel’s work, has included the task of presenting aclear, strong, and reliable foundation for the final recommendations. These inturn form the basis of sound policies and effective programmes to reduce therates of cancer in populations, and the risk of cancer in people, whether as
members of communities, or as families, or as individuals.
In this central part of the Report, seven chapters display the findings of the
independently assembled systematic literature reviews, and the judgements of
the Panel derived from these reviews and other evidence as needed. The Panel’s
judgements are displayed in the form of matrices that introduce five of thesechapters. Judgements of ‘convincing’ and ‘probable’ causal relationships,
shown in the top part of these matrices, are the basis for recommendations
made in Part 3 of the Report.
Chapter 4, the first and longest chapter that follows, is concerned with types offood and drink. The judgements of the Panel are generally food- and drinkbased, reflecting the evidence. Findings on dietary constituents andmicronutrients are identified as, for example, on ‘foods containing dietary
fibre’ or ‘foods containing folate’. For consistency, findings on methods of foodprocessing are, where possible, shown as part of the whole evidence on theassociated foods so that, for example, the processing and preparation of meatis integrated with the evidence on meat. Evidence specifically on dietary
supplements and on patterns of diet is included in the two final sections of thischapter.
Chapters 5 and 6 are concerned with physical activity, and with bodycomposition, growth, and development. Evidence in these areas is more
impressive than was the case up to the mid-1990s; the evidence on growth anddevelopment indicates the importance of a whole life-course approach to theprevention of cancer. As with the chapter on foods and drinks, these chapters
include detailed summaries of the evidence collected in the systematic
literature reviews together with graphic representations of the most significant
evidence.
Chapter 7 summarises and judges the evidence as applied to 17 cancer sites,with briefer summaries based on narrative reviews on cancers of five otherbody systems and sites. The judgements as shown in the matrices in thischapter correspond with the judgements shown in the matrices in the previous
chapters.
Chapter 8, in which judgements are also based on the evidence from thesystematic literature reviews amplified by knowledge of physiologicalprocesses, concerns the biological and associated determinants of weight gain,
overweight, and obesity. Before work on this chapter began, the Panel agreed
that a comprehensive review of the evidence would be likely to show that64

obesity is or may be a cause of a number of cancers. It was therefore important
to identify what aspects of food, nutrition, and physical activity themselvesaffect the risk of obesity and associated factors.
Improved screening, diagnosis, and medical services, including therapy andsurgery, are in many countries improving the rates of survival for people withcancer. The number of cancer survivors — people living after diagnosis of cancer— is therefore increasing. The relevance of food, nutrition, physical activity, andbody composition to people living with cancer, and to the prevention ofrecurrent cancer, is summarised in Chapter 9.
The Panel agreed that its final recommendations should be principally based on
the evidence concerning cancer, and also should take into account findings onfood, nutrition, physical activity, and the prevention of other chronic diseases,
and of nutritional deficiencies and nutrition-related infectious diseases,
especially of childhood. Chapter 10, which is also based on a systematic
literature review, is a summary of the findings of expert reports in these areas.
The proposals for further research contained in Chapter 11 are, in the view of
the Panel, the most promising avenues to explore in order to refine
understanding of the links between food, nutrition, physical activity, andcancer, and so improve the prevention of cancer, worldwide.
As expected, a comprehensive assessment of all relevant types of evidence
relating to food, nutrition, physical activity, body composition, and the risk ofcancer has proved to be a massive task. The Panel was impressed not only by
the quantity but also the quality of much of the evidence, and the degree towhich a great deal of the evidence was consistent. As a result,recommendations designed to prevent cancer in general can be made withconfidence. These are contained in Part 3.

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2•E V I D E N C E

A N D

J U D G E M E N T S

4Foods and drinks
This chapter, with the following chapters in Part
Two, forms the basis for the population goals andpersonal recommendations in Part Three.
The Panel decided that the evidence on food,nutrition, and cancer is generally most persuasive
for foods rather than for specific nutrients or otherfood constituents; and that the evidence fromepidemiological and experimental studies in thisfield, usually undertaken to address questions
about cancers of specific or related sites, is mostusefully synthesised in terms of foods and drinks.
The detailed evidence on foods and drinks ispresented in this chapter, and that on physicalactivity and on body composition in the following
two chapters. These three chapters include
summaries of the evidence, including meta-analyses
presented in graphic form, as well as the Panel’s
judgements. Chapter 7 presents the evidence on
cancer sites in more summarised form.
In this chapter, whenever possible andappropriate, the evidence on dietary constituents,and on food production, preservation, processing,and preparation (including cooking), is integrated
with the evidence on foods and drinks. So here, forexample, the evidence on carotenoids is considered
together with the evidence on vegetables andfruits; the evidence on methods of cooking meats is
considered with the evidence on red meat and on
processed meats; and the evidence on ethanol isconsidered with alcoholic drinks.
The result is not perfect. There is no single, ideal
way of categorising the evidence on food andnutrition. But an approach emphasising foods anddrinks is consistent with the generally acceptedview that food-based dietary guidelines andrecommendations are particularly valuable as afoundation for policies designed to improve publichealth.
The first two sections of this chapter summarise
and judge the evidence on plant foods; the next
two sections that on animal foods; and thefollowing two sections that on fats and oils, andsugars and salt. The next two sections concern
drinks, the second of which covers alcoholic drinks.
These are followed by sections concerned withthose aspects of dietary constituents, and with food66

production, preservation, processing, andpreparation (including cooking), that have not been
incorporated in previous sections. The final section
summarises evidence on dietary patterns, including
being breastfed.
The pattern that emerges, though different insome important respects, is largely similar to thatbased on the evidence gathered in the mid-1990s,
although the confidence with which various
exposures are judged to cause or protect fromcancer has sometimes changed.

C H A P T E R

4•F O O D S

A N D

D R I N K S

4.1 Cereals (grains), roots, tubers,
and plantains
CEREALS (GRAINS), STARCHY ROOTS AND TUBERS, PLANTAINS, AND THE RISK OF CANCER
In the judgement of the Panel, the factors listed below modify the risk of cancer. Judgements are graded according to the strength of the evidence.

DECREASES RISK
Exposure

INCREASES RISK

Cancer site

Convincing
Probable

Foods containing
dietary fibre2

Colorectum

Limited —suggestive

Foods containing
dietary fibre2

Oesophagus

Substantial
effect on risk
unlikely12

Exposure

Cancer site

Aflatoxins1

Liver

None identified

Foods that may be contaminated with aflatoxins include cereals (grains), and also pulses (legumes), seeds, nuts, and some vegetables and fruits (see chapter 4.2).
Includes both foods naturally containing the constituent and foods which have the constituent added (see chapter 3.5.3). Dietary fibre is contained in plant foods(see chapter 4.2 and box 4.1.2).

For an explanation of all the terms used in the matrix, please see chapter 3.5.1, the text of this section, and the glossary.

These starchy plant foods have been the staple sources of
dietary energy and bulk for humans since thedevelopment of settled communities and agriculture. They
have to be prepared in some way to make them edible. In
whole or relatively unprocessed forms, they are also
sources of dietary fibre and various micronutrients.
Cereals in whole form contain essential fats. When theouter layers of these foods are removed and they arerefined, most of what remains is starch and protein.
In general, with industrialisation and urbanisation,
consumption of these foods decreases, and more isconsumed in the form of cereal products, which are
typically more energy-dense and which may contain
substantial amounts of fat, sugar, or salt. Pure starch fromthese foods is also used as an ingredient in many
processed foods. Wheat, rice, maize (corn), and potatoes
and their products are now the main cereals androots/tubers produced and consumed globally.
Overall, the Panel judges that evidence indicating that
cereals (grains), roots, tubers, or plantains affect the riskof any cancer, remains insubstantial.

The Panel judges as follows:
Foods containing dietary fibre probably protect against
colorectal cancer; and there is limited evidence
suggesting that such foods protect against oesophageal
cancer. Dietary fibre is found in plant foods: vegetables,
fruits, and pulses (legumes) (see chapter 4.2), as well as
in cereals, roots, tubers, and plantains. All these foods arehighest in dietary fibre when in whole or minimallyprocessed form.
Foods high in dietary fibre may have a protective effectbecause of being bulky and relatively low in energy
density. See chapters 6.1, 7.3, 7.9, and Chapter 8 fordiscussion of the role of energy density in weight gain,
overweight, and obesity, and of weight gain, overweight,
and obesity in the risk of some cancers, including those of
the oesophagus and colorectum.
The Panel also judges that the evidence that foods
contaminated with aflatoxins are a cause of liver cancer isconvincing. Cereals (grains) and peanuts (see chapter
4.2) are the foods most commonly infested by these
fungal toxins. Contamination is most widespread in

67

P A R T

countries with hot, damp climates and poor storage
facilities.
Within the remit of this Report, the strongest evidence,corresponding to judgements of ‘convincing’ and‘probable’, shows that foods containing dietary fibre
probably protect against colorectal cancer; and that foods
contaminated with aflatoxins are a convincing cause ofliver cancer. Also see chapter 4.2 for judgements ofprobable protective effects of foods containing various
micronutrients also found in cereals, roots, and tubers,
particularly when relatively unprocessed.

Cereals (grains) are the staple foods in large parts of the world,
supplying most of the energy and bulk in diets. In some regions,roots, tubers, or plantains are staple foods as well as or insteadof cereals (grains). These generalisations apply to practicallyall settled rural and most urban populations. Monotonous‘poverty diets’ containing very high levels of these foods, particularly if refined, are low and sometimes inadequate in protein and other nutrients. Gatherer–hunter and pastoral
communities usually consume less of these starchy foods. Theirnutrient content is variable, largely depending on the degree
to which they are refined.
Consumption of cereals, roots, and tubers in general gradually drops with industrialisation and urbanisation, and anincreasing amount of wheat in particular is grown for animal
feed. These foods are increasingly used as a basis for or ingredients in processed products that are often energy-dense,
high in fats or sugars, and sometimes salt. In lower-income
countries, total population consumption of these foods
may amount to 60–80 per cent of total energy, and in highincome countries, usually to less than 30 per cent. Also see
Chapter 1.
Early reports concerned with nutritional deficiencies generally did not pay much attention to these foods and instead
gave priority to energy- and nutrient-dense foods of animal
origin, such as milk, eggs, and meat. Beginning in the 1970s,
interest in dietary fibre increased, following informal epidemiological findings that diets high in dietary fibre wereassociated with a lower risk of a number of chronic diseases.1
2
By the 1990s, it was generally agreed that diets relatively
high in cereals (grains) and other starchy staple foods, preferably relatively unrefined, protect against obesity, type 2 diabetes, coronary heart disease, and perhaps also digestive
disorders.3 4 Evidence that such diets protect against cancerof any site has been less impressive, but epidemiologicalstudies tend not to distinguish between degrees of refinement of cereals, roots, and tubers.
This section (4.1) includes cereal products and dietary
fibre. It also includes contamination by aflatoxins, though
this may also affect other plant foods (also see chapter 4.2).
Non-starchy root vegetables such as carrots are included inchapter 4.2. Micronutrients found in plant foods are included in chapter 4.2, though most of these are also found in
cereals (grains), roots, tubers, and plantains.

68

2

•

E V I D E N C E

A N D

J U D G E M E N T S

4.1.1 Definitions, sources
Cereals (grains)

Cereals (grains) are the seeds and energy stores of cultivated grasses. The main types are wheat, rice, maize (corn),millet, sorghum, barley, oats, and rye. In some countries,‘cereal’ is also a term for dry foods made from grains andother ingredients, often eaten with milk for breakfast.
Roots, tubers, plantains

Roots and tubers are energy stores of plants. Names and definitions can vary around the world — potatoes are tubers,
which are the tips of underground stems that swell withstarch (a polysaccharide) and water. While potatoes areoften classed as vegetables (in the USA, for instance), they
are grouped separately from non-starchy vegetables in thisReport. Sweet potatoes, sometimes called ‘yams’ in North
America, are a type of storage root rather than a tuber, buttrue yams are starchy tubers. Cassava (manioc) and yucca
are elongated roots, and sago is a starchy food made fromthe pith of some types of palm tree. Taro is cultivated for its
edible leaves, as well as its starchy corm, which is similar toa tuber. Plantains are one of several fruits used as vegetables: they grow on trees and look like bananas, but only asmall proportion of the starch is converted to sugar during
the ripening process, which makes them similar to potatoes
to cook with.
Box 4.1.1

Wholegrain and refinedcereals and their products

Many of the cereals (grains) that we consume are refined. Grains
are first broken into pieces and then refined, sifting away thebran, germ and, usually, the aleurone layer. This removes mostof the fibre, oil, and B vitamins, as well as approximately 25 percent of the protein. Polishing, as often performed on rice,
removes additional nutrients. Many high-income countries
therefore fortify refined cereals, including flour, with B vitamins
and iron. Wholegrain products generally contain the constituents of the grain but, given the absence of an internationally accepted definition, intact grains are present to a variable
extent. The extent to which the grain remains intact influences
physiological processes in the bowel and hence health.
Cereal foods may be eaten in wholegrain form, although consumption in refined forms, such as white rice, bread, or pasta,
is generally much more common, particularly in high-income
countries. Refined grains are considered easier than wholegrains
to cook and to chew; are light in colour — which is attractive
to many consumers; and also have a longer shelf-life thanwholegrain products, as the oil in bran goes rancid relatively
quickly.
Breakfast cereals, particularly in the United States and partsof Europe, also account for a significant proportion of grain
eaten. Many breakfast cereals, although based on grains(whole or refined), may contain substantial amounts of addedsugars. Grains are further processed to provide ingredients suchas corn syrup, starch, or alcohol. They also form the basis ofmany animal feeds.
Processed grains have a higher glycaemic index thanunprocessed grains and, generally, the greater the degree ofprocessing, the greater the glycaemic index (box 4.1.3).

C H A P T E R

4

Box 4.1.2•

F O O D S

A N D

D R I N K S

Foods containing dietary fibre

The concept of dietary fibre arose from observations of the low
prevalence of colon cancer, diabetes, and coronary heart diseasein parts of Africa amongst people whose diets were high in
unrefined carbohydrates and whose stools were typically bulky,
and often or sometimes semisolid. Considerable efforts havebeen dedicated to characterising the dietary components ofwhat has come to be called dietary fibre that might confer
health benefit. Naturally occurring dietary fibre is only derived
from plant foods. Pulses (legumes) and minimally processedcereals are particularly concentrated sources, but vegetables andfruits also contain significant amounts. Dietary fibre isolated
from plant cell walls and in synthetic forms are increasingly
entering the food supply.
High intakes of dietary fibre, variously defined, have been
associated with reduced risk of cardiovascular disease as well asof some cancers. Definitions of dietary fibre vary. Some arebased on chemical analyses of the components of plant cell
walls, such as non-starch polysaccharide, others on physiological effects — the carbohydrates that enter the large bowel having escaped digestion in the small intestine being defined as
dietary fibre. The latter definition includes oligosaccharides andresistant starch. The World Health Organization and Food andAgriculture Organization have recently proposed that only polysaccharides which form part of plant cell walls should be regarded as dietary fibre and that the health benefits of resistantstarch and oligosaccharides are more appropriately consideredseparately.

This section refers to starchy roots, tubers, and plantains.
Carrots, beets, parsnips, turnips, and swedes are non-starchy
roots, and are classified as non-starchy vegetables in thisReport. Also see chapter 4.2.

Box 4.1.3

Glycaemic index and load

The degree to which different foods and meals raise blood glucose depends not only on the nature of the carbohydrate, butalso on the characteristics of the foods consumed. Glycaemic
index (GI) is a measure of the degree to which a food raises
blood glucose compared with a standard food (usually glucose
or white bread) under standard conditions. The test food must
contain the same amount of available carbohydrate (usually 50
grams) as the standard. GI was originally used as an aid to foodchoice in diabetes and has more recently been applied to people without diabetes. The rise in blood glucose after consuming
a food depends not only on the GI but also on the amount offood eaten. A related measure, glycaemic load (GL), takes into
account both the GI of a food as well as the actual amount ofcarbohydrate consumed. The GL of a food may be measured
directly or calculated by multiplying the GI of a food by the number of carbohydrate grams in a serving of the food.
Factors that influence the GI of a food include the type of carbohydrate, how the food is processed or cooked, and the othercomponents present in the food (for example, fat, protein,fibre). There is some relationship (inverse) between GI and fibre
content, although some foods high in fibre have a high GI andvice versa. Factors can affect GI by influencing speed of absorption, for instance higher fat foods tend to have a low GI. The
calculated GI of a mixed meal or whole diet has been shown insome studies to correlate with the actual GI obtained by feeding a mixed meal. Although the concept of GI has been controversial, the GI and GL of diets have predicted risks of type 2
diabetes and coronary heart disease and related biomarkers,
independent of dietary fibre, in prospective epidemiologicalstudies, suggesting that GI and GL may be useful markers.
The relevance to cancer might lie in the fact that the rise inblood glucose after a meal is closely linked to that of insulin,which apart from its crucial role in carbohydrate and lipid
metabolism, is also one of a family of important growth factors(also see Chapter 2).

4.1.2 Composition
Cereals (grains)

The relative amounts of dietary constituents in cereals andcereal foods depend largely on the degree of refinement andother forms of processing (box 4.1.1). Starch makes up
about 70 per cent of the raw weight of the storage tissues(endosperm) of unprocessed cereal grains. The outer partsof the grain (the bran and the aleurone layer) contain nonstarch polysaccharide, a type of carbohydrate that characterises dietary fibre (box 4.1.2).
Cereals also contain variable amounts of protein, oils, B
vitamins, vitamin E and tocotrienols, iron, and various traceelements, as well as phytochemicals, some of which, suchas the antioxidants, are bioactive (box 4.1.2). The germ isthe embryonic part of cereal plants and contains oils, proteins, and fibre. Various cereals contain other specific components. Wheat contains gluten (a mixture of proteins). Rye
has high levels of pentosans and oats contain beta-glucans,
both of which are non-starch polysaccharides, a characterising feature of dietary fibre.
Cereals (grains) and pulses (legumes) may be contaminated with aflatoxins. See box 4.1.4.

Roots, tubers, and plantains

Roots and tubers are less concentrated stores of starch,
although this accounts for almost all of their raw weightapart from water. Starch content varies from around 15–20
per cent in sweet potatoes to 25–30 per cent in cassava andyams, which translates into around 80–95 per cent of the
dietary energy of these roots and tubers. Cooking sweet
potatoes makes them taste sweet because an enzyme converts as much as 75 per cent of the starch into maltose (adisaccharide). Roots and tubers eaten with the skin on arehigh in dietary fibre. These foods are generally poor sourcesof protein, so although protein deficiency is uncommon,
populations that subsist on these foods, and do not eat protein-rich pulses (legumes), are at risk of deficiency, especiallychildren weaned on thin gruels made with these low-protein
foods. They contain variable amounts of other nutrients.
Potatoes contain vitamin C, for example, and the orange
varieties of sweet potatoes contain carotenoids. Yams contain many bioactive compounds and taro corms are high invitamin B6, fibre, and manganese.

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Box 4.1.4•

E V I D E N C E

A N D

J U D G E M E N T S

Aflatoxins

Mycotoxins are toxins produced by certain
moulds or fungi. Although moulds that
contaminate foods are usually destroyedby cooking temperatures, the toxins they
produce may remain. Aflatoxins are one
type of mycotoxin. All naturally occurring
aflatoxins are classified as human carcinogens (group 1) by the International Agency
for Research on Cancer; other mycotoxins,
such as fumonisins, are suspected carcinogens.5 It is common to find co-contamination by more than one species of mycotoxin-producing fungus. In Europe, theJoint FAO/WHO Expert Committee on Food
Additives and Contaminants recommends
that aflatoxin concentrations in foods bekept as low as possible.6
The main foods that may be contaminated by aflatoxins are all types of cereal(grain), including wheat, rice, maize (corn),barley, and oats; and pulses (legumes) —notably peanuts. Nuts and seeds may also
be contaminated. Feedstuffs for farm animals may also be contaminated with aflatoxins, which can then be secreted in milkor accumulated in tissues.
Aflatoxins, which are produced byAspergillus flavus and A. parasiticus, aremost problematic in countries with hot,damp climates and poor storage facilities.
Under these conditions, foods may becomecontaminated with fungi and then accumulate such toxins. Such foods are marketed and consumed in the countries inwhich they are produced; they are also
exported to neighbouring countries andintercontinentally. Aflatoxin contamination is therefore a international issue.

4.1.3 Consumption patterns
Cereals and grains

As societies moved to more settled, agricultural ways of life
10–15 000 years ago, cereals became the main staple foods;
the types of cereal crops grown depended largely on climate
and terrain. Wheat, barley, oats, and rye are traditionally staple foods for people living in the Middle East and Europe;and with rice in Asia; maize (corn) in the Americas; andsorghum and millet in Africa. But the market for cereals andtheir products is now global, although some, such assorghum, remain largely regional.
The importance of starchy staples in food systems anddiets is broadly connected to economic and industrial development. Both in higher-income countries and across theworld, there has been a long-term decline in their consumption. With increasing urbanisation in lower-income
countries, wheat and maize are replacing traditional staple
foods. An important exception is Asia, where rice remains thestaple grain. Cereal cultivation and consumption tends to behighest in most of Asia and lowest in Oceania, parts ofEurope, and North America.
Globally, cereal foods provide more than 45 per cent of
dietary energy; diets based on these foods tend to be bulky
with a low energy density (see chapter 8.8.4). Cereals provide more than 50 per cent of dietary energy in low-income
countries, but only around 30 per cent in high-income countries. While grains contribute roughly 20 per cent of dietaryenergy in Australia, North America, and central Europe, they
can provide as much as 70 per cent in parts of Asia (mainly from rice). Although more wheat is grown than rice on a
global basis, much of it is used for animal feed. Rice is theprincipal food for half of the world’s population.
Cereals are very versatile once they have been processedfrom the raw grain. Wheat is mainly milled to make flour
for bread, pastries, cakes, and pasta. Maize (corn) is a staple food in Latin America and parts of Asia and Africa, where70

2Levels of aflatoxin contamination tend
to be highest in countries where rates ofliver cancer are high, such as some Africancountries and South-East Asia, including
China. In general, rates are low in Europe,
but relatively high rates of contamination
have on occasion been found in the USA.
Aflatoxin exposure levels are low inEurope and Australia, higher in the USA,and high in many low-income countries.
This is particularly the case in tropical andsubtropical regions where grains and nuts
are stored for long periods under non-ideal
conditions.
Rates are reduced by inspection, use offungicides, and screening of imported
foods. However, monitoring of levels ofaflatoxin contamination in low-income
countries is generally lacking.

it is used to make grits, cornmeal (used for polenta as wellas corn breads), corn flour, tortillas, tamales, and corn chips.
It is also the basis of corn starch (a thickener), corn syrup(a sweetner), and corn oils. Sweetcorn is also eaten as a vegetable, either on or off the cob. Rice is usually processed toremove the bran and aleurone layers, turning ‘brown rice’
into ‘white’. It is also used to make flour (the basis for glutenfree breads), rice powder, noodles, rice paper, rice milk,
Japanese mochi, and lao-chao (Chinese fermented rice).
Barley is used primarily in Asia (tsampa and miso soya paste)
and in North Africa (soups, porridges, and flat breads).
Whole rye grains are milled and used to make bread in somenorth and east European countries. Whole oats are madeinto porridges and used in muesli and baked goods, suchas biscuits. Fonio, millet, sorghum, teff, and triticale are
traditional crops and staples in parts of Africa and Asia.
Many grains are also fermented to make alcoholic drinks (seechapter 4.8.1).
Roots, tubers, and plantains

Roots, tubers, and plantains are staple foods in some partsof the world. For instance, populations in some regionsof sub-Saharan Africa, Latin America, and Oceania basetheir diets on these foods. Globally, starchy roots provide
around 5 per cent of dietary energy. Consumption is highest in the Pacific islands and parts of Africa, with cassava andyams providing more than 40 per cent of dietary energy in
Ghana. Potatoes can provide as much as 10 per cent of
dietary energy in North America and Europe. Globally, plantains provide less than 0.5 per cent of dietary energy, butthey are locally important in some African, Latin American,
and Caribbean countries, where they can provide more than
15 per cent of dietary energy. Some populations do not relyon any of these foods — for instance, pastoralist societies
such as the Maasai hunters in East Africa, and the Inuit andother Arctic populations, maintain their traditional ways oflife and diets.

C H A P T E R

4•F O O D S

A N D

D R I N K S

Dietary fibre

Production, preservation, processing, preparation. Few stud-

Dietary fibre intake, measured as non-starch polysaccharides,
varies from 10–13 grams (g)/day in Japan and the UK to
15–20 g/day or more in Africa and India. Intake among individuals in a population may vary between 7 and 25 g/day.7

ies distinguish between unrefined and refined cereals andtheir products. Many processed foods grouped as cereal
products, such as ready-to-eat breakfast cereals, are high in
added sugars and sometimes salt. The ways in which cereals are processed, prepared, and consumed varies greatly in
different cultures.

4.1.4 Interpretation of the evidenceInterpretation of the evidence on any and all foods anddrinks, their constituents, their methods of production,
preservation, processing and preparation, and other factors,
with the risk of cancer, is never simple, for general and specific reasons.
4.1.4.1 General
For general considerations that may affect interpretation of
the evidence, see chapters 3.3 and 3.5, and boxes 3.1, 3.2,
3.6, and 3.7.
‘Relative risk’ (RR) is used in this Report to denote ratio
measures of effect, including ‘risk ratios’, ‘rate ratios’, ‘hazard ratios’, and ‘odds ratios’.

4.1.5 Evidence and judgements
The full systematic literature review (SLR) is contained on
the CD included with this Report.
4.1.5.1 Cereals (grains)
The evidence was too limited in amount, consistency, or
quality to draw any conclusions.
4.1.5.2 Roots, tubers, and plantains
The evidence was too limited in amount, consistency, or
quality to draw any conclusions.
4.1.5.3 Foods containing dietary fibre

4.1.4.2 SpecificSome considerations specific to cereals (grains), roots,
tubers, and plantains are as follows.
Classification. ‘Cereals’ is a broad classification. Different
cereals have different nutritional composition and biologicaleffects, as do different types of dietary fibre. Any effectsof specific cereals or their constituents may not become
apparent.
Patterns and ranges of intake. Little evidence relates to roots,

or tubers other than potatoes, or plantains, some of which,such as cassava (manioc) or yams, are staple foods in someparts of the world.
Terminology. Potatoes are usually (as here) defined as tubers,
but are sometimes (in the USA especially) included with vegetables. Bananas, a significant item in many diets, may be(as here) defined as a fruit, or else with plantains as a starchy
food. There is no internationally agreed definition for dietary
fibre (box 4.1.1).
Measurement. Non-starch polysaccharides are measured pre-cisely by the Englyst method,8 but there are fewer epidemiological data on non-starch polysaccharides specifically thanfor dietary fibre. The various analytical techniques used toassess the fibre content of foods give widely different results.
Confounding. In high-income countries, high intakes ofwholegrain cereal products tend to go together with other
health-conscious dietary and other habits. Also there is possible confounding between dietary fibre and other dietary
constituents and in general with ‘healthier’ dietary patterns
and ways of life. Data on dietary fibre come predominantly
from dietary sources, that is, plant-based foods (also see box
4.1.1 and chapter 4.2); therefore, no effect can be attributed
to different types and sources of dietary fibre.

Colorectum

Sixteen cohort studies9-37 and 91 case-control studies investigated dietary fibre and colorectal cancer. The Harvard pooling project also analysed original data from 13 separate
cohort studies.38
An association was apparent from many, though not all,cohort studies. Ten studies showed decreased risk when comparing high with low intake groups,14 19 21 25-29 33 34 which wasstatistically significant in one (figure 4.1.1).28 Two reported
non-significant increased risk,36 39 one showed no effect onrisk,30 and one reported no association.18 One study reported non-significant decreased risk in women and nonsignificant increased risk in men23; one study reported
non-significant increased risk in women and non-significant
decreased risk in men.37 Meta-analysis was possible on eightstudies, giving a summary effect estimate of 0.90 (95% confidence interval (CI) 0.84–0.97) per 10 g/day increment,with moderate heterogeneity (figure 4.1.2). A dose-response
relationship was apparent from cohort data.
Because of the abundant prospective data from cohort
studies, case-control studies were not summarised.
The Harvard pooled analysis from 13 prospective cohort
studies (725 628 participants, followed up for 6 to 20 years,
8081 colorectal cancer cases) gave a significant inverse association in the age-adjusted model (0.84, 95% CI
0.77–0.92).38 However, the association was attenuatedand no longer statistically significant after adjusting forother risk factors (0.94, 95% CI 0.86–1.03). One comparison group was statistically significant when maximally
adjusted, others were not. Compared with dietary fibre
intake of 10 to < 15 g/day, the pooled effect estimate was
1.18 (95% CI 1.05–1.31) for less than 10 g/day (low compared with moderate intake). All other measures were notassociated with risk of colorectal cancer. The pooled analysis therefore found that, after accounting for other dietaryrisk factors, high dietary fibre intake was not associated71P A R T

Figure 4.1.1

Dietary fibre and colorectal cancer;
cohort studies

2

Figure 4.1.2•

E V I D E N C E

A N D

J U D G E M E N T S

Dietary fibre and colorectal cancer;
cohort studies
Relative risk (95% CI)

Relative risk (95% CI)
Wu 1987 Men

1.19 (0.60–2.11)

Heilbrun 1989 Men

0.77 (0.48–1.24)

Wu 1987 Women

0.64 (0.37–1.11)

Bostick 1993 Women

0.88 (0.77–1.01)

Heilbrun 1989 Men

0.71 (0.45–1.13)

Fuchs 1999 Women

0.99 (0.83–1.18)

Giovannucci 1994 Men

1.08 (0.68–1.71)

Terry 2001 Women

1.08 (0.84–1.39)

Steinmetz 1994 Women

0.80 (0.40–1.91)

Colbert 2001 Men

1.02 (0.88–1.18)

Gaard 1996 Men

0.82 (0.46–1.46)

Konings 2002 Men

0.95 (0.84–1.07)

Kato 1997 Women

0.95 (0.79–1.24)

Konings 2002 Women

0.85 (0.73–1.00)

Pietinen 1999 Men

1.00 (0.68–1.58)

Higginbotham 2004 Women

0.83 (0.61–1.13)

Soneham 2000 Women

0.96 (0.70–1.32)
Norat 2005 Men

0.77 (0.71–0.83)

Norat 2005 Women

0.89 (0.82–0.97)

Summary estimate

0.90 (0.84–0.97)

Bingham 2003

0.75 (0.50–0.95)

COL00535 Women

0.94 (0.70–1.26)

IARCIM 1977 Men

0.92 (0.64–1.32)

IARCIM 1977 Women

0.86 (0.52–1.42)

Baron 1997 Women

0.79 (0.45–1.38)

0.2

0.5

1

2

5

Relative risk, per 10 g/day
0.2

0.5

1

2

5

Relative risk, highest vs lowest exposure category

with a reduced risk of colorectal cancer.
Fibre exerts several effects in the gastrointestinal tract but
the precise mechanisms for its probable protective role are
not clearly understood. Fibre dilutes faecal contents, decreases transit time, and increases stool weight.40 Fermentation
products, especially short-chain fatty acids, are produced by
the gut flora from a wide range of dietary carbohydrates thatreach the colon. Short-chain fatty acids, particularly
butyrate, can induce apoptosis and cell cycle arrest, and promote differentiation. Fibre intake is also strongly correlatedwith intake of folate.
A clear dose-response relationship is apparent fromgenerally consistent cohort studies, supported byevidence for plausible mechanisms, but residual
confounding could not be excluded. Foods containing
dietary fibre probably protect against colorectal cancer.

The Panel is aware that since the conclusion of the SLR, sixcohort studies41-46 and one case-control study47 have been published. This new information does not change the Panel judgement (see box 3.8).
Oesophagus

One cohort study,48 nine case-control studies,49-58 and two
ecological studies59 60 investigated dietary fibre and cancerof the oesophagus.
There was some evidence of an association between dietary
fibre and reduced oesophageal cancer risk. The single cohort
study reported decreased risk when comparing high with low
intakes, with an effect estimate of 0.50, though no assessment of statistical significance was included.48

72

The nine case-control studies produced 13 independent
effect estimates. Of these, 11 estimates were of decreased
risk,50-53 55 56 58 61 which were statistically significant in eight.
One estimate indicated no effect on risk54 and one other gave
non-significant increased risk.62 The data were mostconsistent when stratified for adenocarcinomas; of six
studies, five reported significant decreased risk; results wereless consistent for squamous cell carcinoma. All studies
were adjusted for alcohol and smoking except one, which
was adjusted for alcohol but not smoking.50
The ecological studies were inconclusive. Neither was statistically significant, with one in the direction of increased
and the other of decreased risk.
There is no evidence of a plausible biological mechanism
through which dietary fibre reduces the risk of oesophageal
cancer. It is not possible to conclude whether an as yet
unknown mechanism is responsible for an apparent reduction in risk, or whether it is due to other components foundin the vegetables and fruits that contain dietary fibre.
There is limited evidence from sparse and inconsistentcase-control studies only, suggesting that foods
containing dietary fibre protect against oesophageal
cancer.

4.1.5.4 Aflatoxins(Also see box 4.1.4; chapter 4.9; and chapter 7.8). There are
two approaches to measuring aflatoxin intake. The first uses
local food tables to estimate exposure to aflatoxins from diet.
The second approach uses biomarkers of exposure. These arederived from knowledge of aflatoxin metabolism. In humans,
metabolised products of aflatoxins can be detected in blood,C H A P T E R

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urine, or breastmilk. Biomarkers of exposure are more accurate and precise.
Liver

Five cohort studies63-70 and seven case-control studies71-79
assessed associations between biomarkers of exposure toaflatoxin and hepatocellular carcinoma.
The cohort studies used a variety of different biomarkers
for exposure to aflatoxin, some in blood and some in urine.
Despite this variety, all five studies reported increased risk
for the highest levels when compared to the lowest, and allof these reported at least one measure that resulted in a statistically significant increased risk (figure 4.1.3). Studies that
adjusted for hepatitis virus infection tended to show thegreater effects.65 66 There is some evidence of an interaction
whereby the risk is increased by a multiplicative effect if aflatoxin exposure is combined with hepatitis infection. One
study showed that people with hepatitis virus antibodies andbiomarkers of aflatoxin exposure had a higher risk than thosewith hepatitis virus antibodies alone, with an effect estimateof 10.0 (95% CI 1.6–60.9).65
There is evidence from some of the cohort studies for interaction with glutathione-S-transferase (GST) genotype.63 64
GST is an enzyme involved in the metabolic pathway that
‘detoxifies’ aflatoxins. Different genotypes show varying efficiencies at this task. Two genes (GSTT1 and GSTM1) wereassessed separately. For each, it is possible to have a positive or negative genotype. In each case, a negative genotype
increases risk of hepatocellular carcinoma when exposed toaflatoxins. There is clear, consistent evidence that
GSTM1/GSTT1 positive genotypes protect against theincreased risk of liver cancer from hepatitis infection combined with aflatoxin exposure, which supports a causal role
for aflatoxins in hepatocellular carcinoma.
Four case-control studies showed statistically significant
increased risk for the highest levels of biomarkers when compared to the lowest.71 74 78 79 Two studies showed no effecton risk.73 77 One study showed a non-significant decreased
risk.72 Heterogeneity may be explained by the diversity inmethods of exposure assessment.
A dose-response relationship is apparent from most cohort

Figure 4.1.3

Aflatoxins and liver cancer;
cohort studies
Relative risk (95% CI)

Qian 1994 Menstudies and some of the case-control studies.
The areas in the world where there is considerable aflatoxin contamination of foods coincide with the areas where
primary liver cancer rates are high. The epoxide product ofaflatoxin AFB1 is known to be genotoxic and is formed in theliver.80 It damages DNA, causing G:C base pairs to become
T:A. GST enzymes can repair this damage with varying efficiency between genotypes. Recent studies have shown thataflatoxins can damage the p53 gene, which is an important
regulator of normal growth.67 Damage to p53 DNA can leadto increased proliferation of abnormal cells and formationof cancers.
The synergistic effect of hepatitis virus infection and aflatoxin exposure might be explained by hepatitis virus increasing the production of the enzyme (CYP1A2) that produces
the genotoxic metabolite of aflatoxin.81 It is also possible thatthe hepatitis virus increases the number of G:C to T:A transversions, or that it inhibits nucleotide repair, or that it acts
as a tumour promoter.
The evidence is ample and consistent and is supported
by strong evidence for mechanisms operating inhumans. A dose response is apparent from both cohortand case-control studies. The evidence that aflatoxins
and aflatoxin-contaminated foods are a cause of livercancer is convincing.

4.1.6 Comparison with previous report
The previous report concluded that dietary fibre/non-starchpolysaccharides possibly protect against cancers of the pancreas, colorectum, and breast. The previous report also concluded that wholegrain cereals possibly decrease the risk ofstomach cancer and that refined cereals possibly increase therisk of oesophageal cancer.
Since the mid-1990s, evidence for a protective effect of
dietary fibre against colorectal and oesophageal cancer riskhas become somewhat stronger. The finding of the previous
report, suggesting that the degree of refinement (other thanrelative amounts of dietary fibre) may be a factor in modification of the risk of some cancers, was not found.
The previous report classified bananas as plantains. Herethey are classified as fruits. The previous report considereddietary fibre separately from cereals (grains) and other plantfoods. Here, dietary fibre is considered in the context of cereals (grains) and other plant foods.

5.00 (2.11–11.85)

Wang 1996

3.80 (1.11–12.96)

Yu 1997 Men

6.00 (1.22–29.49)

Sun 1999 Men

4.52 (1.57–13.01)

1

2

5

6

Relative risk, highest vs lowest exposure category

4.1.7 Conclusions
The Panel concludes:
The direct evidence that cereals (grains), roots, tubers, orplantains affect the risk of any cancer remains unimpressive.
However, foods containing dietary fibre probably protect
against colorectal cancer; and there is limited evidence suggesting that such foods protect against oesophageal cancer.
Dietary fibre is mostly found in cereals, roots and tubers, andalso in vegetables, fruits, and pulses (legumes) (see chapter

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4.2). All of these are highest in dietary fibre when in wholeor minimally processed forms.
Foods high in dietary fibre may also have a protective
effect indirectly because they are relatively low in energy
density. See chapters 6.1, 7.3, 7.9, and 8 for discussion of
the role of energy density in weight gain, overweight, andobesity, and of weight gain, overweight, and obesity in therisk of some cancers, including those of the oesophagus andcolorectum.
The evidence that foods contaminated with aflatoxins area cause of liver cancer is convincing. Cereals (grains) andpeanuts (see chapter 4.2) are the foods most commonly
infested by these fungal toxins. Contamination is most widespread in countries with hot, damp climates and poor storage facilities.

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4.2 Vegetables, fruits, pulses (legumes),
nuts, seeds, herbs, spices
Vegetables and fruits are generally low in energy density(with a few exceptions) and, when consumed in variety,are sources of many vitamins, minerals, and otherbioactive compounds (phytochemicals). Many non-starchy
vegetables, including salad vegetables and fruits, may beeaten raw and may also be cooked. Pulses (legumes) arehigh in protein. Traditional diets all over the worldcombine cereals (grains) with pulses (legumes) and, in
this way, ensure sufficient protein of adequate quality,
usually with small amounts of animal foods. Nuts andseeds are concentrated sources of numerous
micronutrients and of essential fatty acids. All these foods
are sources of dietary fibre. Many herbs and spices havepotent pharmacological as well as culinary properties.
Consumption of vegetables and fruits is very variable:high around the Mediterranean littoral and some tropicalcountries; low in many low-income countries, including
some in which fruits are abundant. Consumption of pulses(legumes) is also very variable: beans and chickpeas andtheir products are basic foods in a number of Latin
American, Middle Eastern, and Asian countries, but pulses
are insignificant in typical North American and most
European diets. Consumption of nuts, seeds, herbs, andspices also varies. Traditional Middle Eastern and Indian
cuisines use a great variety of herbs and spices; garlic,usually classified as a herb, is consumed in remarkable
quantities in some countries.
In general, the Panel judges that findings from cohort
studies conducted since the mid-1990s have made theoverall evidence, that vegetables or fruits protect against
cancers, somewhat less impressive. In no case now is theevidence of protection judged to be convincing. However,in a substantial number of cases, a judgement of probableis justified. Evidence on legumes (pulses), nuts, seeds, and(with two exceptions) herbs and spices remains
insubstantial.
The Panel judges as follows:
Non-starchy vegetables probably protect against cancers ofthe mouth, pharynx, and larynx, and those of theoesophagus and stomach. There is limited evidence
suggesting that they also protect against cancers of thenasopharynx, lung, colorectum, ovary, and endometrium.
Allium vegetables probably protect against stomach
cancer. Garlic (an allium vegetable, commonly classed as aherb) probably protects against colorectal cancer. There islimited evidence suggesting that carrots protect against
cervical cancer; and that pulses (legumes), including soya
and soya products, protect against stomach and prostatecancers. Fruits in general probably protect against cancersof the mouth, pharynx, and larynx, and those of theoesophagus, lung, and stomach. There is limited evidence
suggesting that fruits also protect against cancers of thenasopharynx, pancreas, liver, and colorectum. There islimited evidence suggesting that chilli is a cause of
stomach cancer.
Fruits and non-starchy vegetables are generally low
energy-dense foods. For a discussion of the effect of such
foods and drinks on weight gain, overweight, and obesity,and the role of weight gain, overweight, and obesity in therisk of some cancers, see Chapters 6, 7, and 8.
Evidence that vegetables and fruits protect against somecancers is supported by evidence on foods containing
various micronutrients, found especially in vegetables,
fruits, and pulses (legumes), and nuts and seeds, as wellas in cereals, roots, tubers, and other plant foods. Foods
containing folate probably protect against pancreaticcancer, and there is limited evidence suggesting that thesefoods also protect against oesophageal and colorectal
cancers. Foods containing carotenoids probably protect
against cancers of the mouth, pharynx, and larynx, andalso lung cancer. Foods containing the carotenoid betacarotene probably protect against oesophageal cancer; andfoods containing lycopene probably protect against
prostate cancer. Foods containing vitamin C probably
protect against oesophageal cancer. There is limited
evidence suggesting that foods containing quercetin
protect against lung cancer.
Evidence also relevant to chapter 4.1 is grouped here.
Foods containing selenium (also found in animal foods)
probably protect against prostate cancer; and there islimited evidence suggesting that they protect against
stomach and colorectal cancers. There is limited evidence
suggesting that foods containing pyridoxine protect
against oesophageal and prostate cancers; and that foods
containing vitamin E protect against oesophageal andprostate cancers.
The strongest evidence, here corresponding tojudgements of ‘probable’, shows that non-starchy
vegetables and also fruits probably protect against cancersof the mouth, larynx, pharynx, oesophagus, and stomach,and that fruits also probably protect against lung cancer;
and that allium vegetables, and garlic specifically,
probably protect against stomach cancer. The case thatvegetables, fruits, and pulses (legumes) may be protective
against cancers of some sites is supported by evidence on
foods containing micronutrients found in these and otherplant foods. Thus, foods containing carotenoids probably
protect against cancers of the mouth, pharynx, larynx, andlung; foods containing beta-carotene and also vitamin C
probably protect against oesophageal cancer; foods
containing selenium and also lycopene probably protect75

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VEGETABLES, 1 FRUITS, 1 PULSES (LEGUMES), NUTS, SEEDS, HERBS, SPICES,AND THE RISK OF CANCER
In the judgement of the Panel, the factors listed below modify the risk of cancer. Judgements are graded according to the strength of the evidence.

DECREASES RISK
Exposure

Cancer site

Non-starchy vegetables1

Mouth, pharynx, larynx
Oesophagus
StomachAllium vegetables1

StomachGarlic1

Colorectum

Fruits1

Mouth, pharynx, larynx
Oesophagus
Lung
Stomach

INCREASES RISK
Exposure

Cancer site

Chilli1

StomachConvincing
Probable

Limited —suggestive

Substantial
effect on risk
unlikely

1
2
3
4
5
6
7
8
9

Foods containing folate2

Pancreas

Foods containing
carotenoids2

Mouth, pharynx, larynx
Lung

Foods containing
beta-carotene2

Oesophagus

Foods containing
lycopene2 3

Prostate

Foods containing
vitamin C2 4

Oesophagus

Foods containing
selenium2 5

Prostate

Non-starchy vegetables1

Nasopharynx
Lung
Colorectum
Ovary
Endometrium

Carrots1

Cervix

Fruits1

Nasopharynx
Pancreas
Liver
Colorectum

Pulses (legumes)7

StomachProstate

Foods containing folate2

Oesophagus
Colorectum

Foods containing
pyridoxine2 8

Oesophagus

Foods containing
vitamin E2 6

Oesophagus
Prostate

Foods containing
selenium2 5

Lung
StomachColorectum

Foods containing
quercetin2

Lung

Foods containing beta-carotene9: prostate; skin (non-melanoma)

Judgements on vegetables and fruits do not include those preserved by salting and/or pickling.
Includes both foods naturally containing the constituent and foods which have the constituent added (see chapter 3.5.3).
Mostly contained in tomatoes and tomato products. Also fruits such as grapefruit, watermelon, guava, and apricot.
Also found in some roots and tubers — notably potatoes. See chapter 4.1.
Also found in cereals (grains) and in some animal foods. See chapters 4.1 and 4.3.
Also found in plant seed oils. See chapter 4.5.
Including soya and soya products.
Vitamin B6. Also found in cereals. See chapter 4.1.
The evidence is derived from studies using supplements and foods containing beta-carotene: see chapter 4.10.

For an explanation of all the terms used in the matrix, please see chapter 3.5.1, the text of this section, and the glossary.

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against prostate cancer; and foods containing folate
probably protect against pancreatic cancer. Also see
chapter 4.1 for the evidence that foods containing dietary
fibre, found in plant foods (particularly when in whole orrelatively unprocessed forms), probably protect against
colorectal cancer.

Vegetables and fruits (including berries), nuts and seeds, andherbs and spices, where they grow and can be cultivated,have always been part of human diets. Gatherer–hunters andpastoral peoples probably consumed more than relatively
impoverished urban dwellers: for them, vegetables were themain sources of many vitamins, and fruits were a main
source of energy, from sugar (also found in wild honey).
They are consumed abundantly as part of many long-established traditional cuisines, around the Mediterranean littoral,
the Middle East, in many Asian countries, and the Pacificislands, where substantial amounts of meat, dairy products,
and other animal foods are traditionally consumed only occasionally. In contrast, monotonous ‘poverty’ diets include few
of these foods.
Globally, consumption of these foods is lower than now
generally recommended. Vegetables and fruits are sometimes
seen as relatively expensive. Well stocked supermarkets usually now display a variety of local and imported fresh vegetables and fruits, although supplies in smaller stores are
more variable. Consumption of fresh vegetables and fruits inmany tropical countries in Africa and Latin America is low:on average people in Brazil, for example, consume roughly
the same as people in Britain. The explanation may be thatin Africa, many rural communities are obliged to grow cash
crops that displace gardens, and that in Latin America knowledge of the value — and pleasure — of many indigenous
vegetables and fruits has been lost. Many programmes intropical countries are now dedicated to regaining this knowledge.1
Even before the discovery of vitamins as essential nutrients beginning in the early 20th century, vegetables andfruits have been recommended as ‘protective foods’. Earlyreports concerned with nutritional deficiencies paid lessattention to pulses (legumes), nuts, and seeds, even thoughthese plant foods contain protein, and nuts and seeds are
nutrient- and also energy-dense, perhaps because they are
not much consumed in the countries where most suchreports were compiled. Instead, as already mentioned, priority was given to energy- and nutrient-dense foods of animal origin. By the 1980s, most reports concerned withprevention of chronic diseases recommended relatively highintakes of vegetables and fruits and sometimes also pulses(legumes), either because these foods were seen as nourishing substitutes for energy-dense fatty or sugary foods, orelse because they were identified as positively protective
against cardiovascular disease.2 Evidence that vegetables
and fruits might be protective against some cancers emergedin the 1990s.3 A common recommendation has been for atleast five portions (or at least 400 g) of vegetables and fruits
a day.4
Non-starchy root vegetables such as carrots are included

here. Chapter 4.1 includes dietary fibre, only found naturally
in plant foods. Chapter 4.1 also includes aflatoxins, which
also contaminate pulses (legumes), notably peanuts, nuts
and seeds, and other plant foods. The micronutrients included here, as contained in vegetables, fruits, pulses (legumes),
nuts and seeds, are also found in other plant foods, and somealso in animal foods.

4.2.1 Definitions, sources
Vegetables and fruits are defined in this Report by their culinary use, and are grouped for discussion below as vegetables and fruits, pulses (legumes), nuts and seeds, and herbs,
spices, and condiments.
Vegetables and fruits

Vegetables are the edible parts of plants, usually including
fungi. Typical examples include cultivated or gathered
leaves, roots, stalks, bulbs, and flowers. Some foods are culinary vegetables but are classified botanically as fruits; theseinclude cucumbers, peppers, squash, and tomatoes. Nonstarchy vegetables are included here, while starchy root vegetables are considered in chapter 4.1. Non-starchy vegetables
can be further divided into green, leafy vegetables, such as
spinach and lettuce; cruciferous vegetables (the cabbage
family), for example, bok choy, broccoli, cabbage, and watercress; and allium vegetables, such as onions, garlic, andleeks.
A fruit is the seed-containing part of the plant; but only
those that are eaten as fruits are included in the culinary definition, for example, apples, bananas, berries, figs, grapes,
mangoes, and melons. This also includes citrus fruits suchas oranges, grapefruits, lemons, and limes; and also dried
fruits, such as apricots, figs, and raisins.
Pulses (legumes)

Leguminous plants produce their fruits as pods and are considered here separately. The dried, edible seeds of this family are often called pulses, although this term is usedinterchangeably with legumes. They include beans, lentils,
peas, and peanuts (groundnuts). The dried forms, whichhave matured and dried on the plant, are eaten most widely. But some varieties are eaten as a green vegetable, suchas peas; the pods are sometimes eaten like this too, for example, green beans and runner beans. Some legumes can also
be sprouted (germinated) and eaten, such as beanspouts.
Nuts and seeds

Nuts are edible seeds surrounded by a tough, dry shell. Thisdefinition includes true nuts (such as hazelnuts and chestnuts), as well as seeds that most people think of as nuts
(including Brazil nuts, macadamia nuts, and cashews). Other
seeds commonly eaten include sunflower, sesame, pumpkin,
and poppy seeds. Nuts and seeds are processed for their oil,ground into pastes, used as ingredients, or eaten raw orroasted as snack foods. Cereals (grains) are also the seedsof plants, but these are discussed separately in this Report(see chapter 4.1). Seeds, like nuts, have a relatively high oil

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Box 4.2.1•

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Micronutrients and other bioactive compounds and cancer risk

Vegetables, fruits, pulses (legumes), nuts,
and seeds are sources of a wide variety of
micronutrients and other bioactive compounds. Foods containing several of these
constituents have been identified in the systematic literature reviews, on which thischapter is based, as being associated withcancer risk. These are carotenoids (including beta-carotene and lycopene), folate,vitamin C, vitamin D, vitamin E, quercetin,
pyridoxine, and selenium. Mechanisms bywhich they might affect cancer risk are discussed in chapter 4.2.5. However, it is notpossible to ascribe the association between
these foods and lower cancer risk to a
causal effect of specific compounds withconfidence, as each food contains a complex mixture of different constituents, all ofwhich might also contribute to any effect.
Carotenoids are found in varying concentrations in all vegetables, particularly
those that are red or orange. They are afamily of more than 600 fat-soluble
red/orange pigments that comprise xanthophylls (such as lutein) and carotenes(such as alpha- and beta-carotene, andlycopene). Some carotenoids, most importantly beta-carotene, can be converted by
the body to retinol and are sometimes
called pro-vitamin A carotenoids. These
compounds tend to be the main dietary
source of vitamin A in low-income countries.
Only about half of the 50 or so
carotenoids in human diets can be absorbed. They have antioxidant and other bioactivities that are discussed in chapter 4.10.
Sources of carotenoids include spinach,kale, butternut squash, pumpkin, red (bell)
peppers, carrots, tomatoes, cantaloupe
melon, and sweet potatoes.
Beta-carotene is found in yellow, orange,and green fruits and green, leafy vegetables including carrots, spinach, lettuce,
tomatoes, sweet potatoes, broccoli, cantaloupe melon, oranges, and winter squash(pumpkin).

As a rule of thumb, the greater the intensity of the colour of the fruit or vegetable,
the more beta-carotene it contains.
The most concentrated source oflycopene is tomatoes, but it is also present
in watermelon, red (bell) peppers, pink or
red grapefruit, pink-fleshed guava, andpersimmons.
The B-vitamin folate is a family of compounds essential for human health. Folic
acid, the synthetic form, is used to fortify
manufactured cereal products, spreads,
and, in some countries, flour or grains.
Folates are involved in a number of metabolic pathways, especially in the synthesisof purines and pyrimidines, which areimportant for DNA synthesis and cell replication (also see chapter 4.2.5.4). Sources of
dietary folate include liver, beans, spinach,broccoli, romaine lettuce, chicory, oranges,
and papaya.
Vitamin C (ascorbic acid) is a water-soluble vitamin. Humans, like a small number ofother animals, cannot synthesise vitamin C,
so it is an essential part of diets. Vitamin C
is essential for collagen synthesis and also
has antioxidant activity. Severe deficiency
causes scurvy. It is added to many foods,
including bread and soft drinks, in small
amounts as an antioxidant preservative.
Natural dietary sources are vegetables,
tubers, and fruits, including red/yellow(bell) peppers, kiwi fruits, broccoli, papaya,
citrus fruits, strawberries, and potatoes, but
it is destroyed by heat or contact with theair (for instance, when vegetables arechopped), or lost into cooking water.
Vitamin E is a fat-soluble vitamin and apotent antioxidant that occurs as eight different forms: alpha- and gamma-tocopherol are the most common. The mostimportant dietary sources of vitamin E arevegetable oils such as palm, sunflower,
corn, soya bean, and olive oils. Nuts, sunflower seeds, and wheatgerm are also
sources. Wholegrains, fish, peanut butter,green, leafy vegetables, and fortified

content, and the oils produced from them are considered inchapter 4.4.
Herbs, spices, and condiments

Herbs and spices, which are generally used to flavour or preserve foods, are of plant origin, although a very small number of animal products are classed as spices (such as
ambergris). Definitions of herbs and spices vary, but herbs
are usually the fresh or dry leaves or whole plant, while
spices are produced from other parts of the plant, such as
the seeds, and are usually dried.5 Many different parts of78

2

breakfast cereals also contain this vitamin.
Pyridoxine is one of a group of watersoluble compounds collectively known as
vitamin B6. This vitamin is involved in neurotransmitter synthesis, red blood cell formation and function, niacin (vitamin B3)
formation, steroid hormone function, andnucleic acid synthesis (also see chapter
4.2.5.5).15 Food sources include bananas,
fish, poultry, liver, potatoes eaten with theskin, green, leafy vegetables, beans, pulses(legumes), nuts, wholegrains, and fortified
breakfast cereals.
Selenium is a mineral element that
occurs in different chemical forms. It is
toxic in large amounts, but is essential in
the diet at trace levels. It is present at varying concentrations in different soils; andsince plants take up selenium from the soil,
these levels determine the amount present
in vegetables. Thus selenium deficiency ismore prevalent in regions where the soil
selenium content is low. Selenium is a component of the amino acids selenocysteineand selenomethionine, which are integrated into proteins to form selenoproteins. Selenoproteins include antioxidant
enzymes such as glutathione peroxidases,thioredoxin reductase, which is importantfor DNA synthesis, and iodothyronine deiodinase, which is important for the synthesis of thyroid hormones.16 Dietary sourcesof selenium include brazil nuts, fish, wholegrains, wheatgerm, and sunflower seeds.
Quercetin is a flavonoid, which is a typeof polyphenol; it is not an essential dietarycomponent. Many studies in cultured cells
and animals suggest that quercetin has
antioxidant activity, which could give rise
to a range of biological activities, including
reducing inflammation (also see chapter
4.2.5.9). Quercetin is found in apples,
green and black tea, onions, raspberries,
red wine, red grapes, citrus fruits, leafy,
green vegetables, cherries, elderberries,
broccoli, blueberries, cranberries, andbilberries.

plants are used as herbs or spices, such as the leaves (sage,bay, or basil), stems (ginger, lemongrass), bark (cinnamon),rhizomes (ginger), roots (horseradish), flower buds (cloves),
stamens (saffron), seeds (mustard, cumin), kernels (nutmeg), and fruits (peppers).
A condiment is a substance that adds taste to other foods;
the term is often used for sauces added at the table, which
are usually of plant origin. Examples include vinegars,
ketchups, chutneys, harissa, mustard, and soy sauce. Salt isneither a herb nor a spice, although it is used as a condiment(see chapter 4.5).

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Box 4.2.2

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Phytochemicals

Plants contain a wide range of biologically active compounds,
some of which are known as phytochemicals. There may be as
many as 100 000 different compounds, which determine particular properties in plants, and in the fruits and vegetables they
produce, such as flavour and colour. Phytochemicals are classified according to their chemical structure and functional characteristics, and include salicylates, phytosterols, saponins,
glucosinolates, polyphenols, protease inhibitors, monoterpenes,
phytoestrogens, sulphides, terpenes, and lectins.
It is widely believed that the health benefits of diets high infruits and vegetables are likely to be due partly to the presenceof phytochemicals. For instance, several act as antioxidants, preventing oxidative damage to cells, proteins, and DNA. It is likely that other bioactive phytochemicals have yet to be identified,
and those that are known may have additional properties in the
body that are not yet understood. But it is thought that nutrients, phytochemicals, and other, as yet unknown, bioactive components act together to influence physiological responses.
Although many phytochemicals are bioactive, they are notessential in the diet and there is no daily requirement, so they
are not classed as nutrients. Humans have developed tastes forsome phytochemicals, such as the hot flavours of mustard oil,
bitter alkaloids, and irritating capsaicins. There is geneticallyinherited variation in sensitivity to some tastes, for example, thebitter taste of isothiocyanates in cruciferous vegetables such as
cabbage.

4.2.2 Composition
Vegetables and fruits

The composition of fruits and vegetables depends both on
species and on subtype, as well as on the environmental,
farming, production, and storage conditions. These include
factors such as sun exposure, soil quality, agricultural practices, harvesting time, ripeness, length of time between harvest and consumption, and preservation and preparation

Box 4.2.3

methods. For instance, the outer leaves of lettuces can havehigher levels of some micronutrients than the inner leaves;and harvested, unripe fruit that ripens in transit may havelower levels of nutrients than fruits ripened on the plant(box 4.2.1).6
Vegetables and fruits contain vitamins, minerals, dietary
fibre, and other bioactive compounds, such as phytochemicals (box 4.2.2). This is a collective term for a variety of plantcomponents that often perform important functions in theplant, such as providing colour, flavour, or protection, but
are not essential in the human diet. They include salicylates,
flavonoids, glucosinolates, terpenes, lignans, andisoflavones. All of these groups of compounds have beenshown either in humans or in laboratory experiments to havepotentially beneficial health effects when they are included
in diets. However, the bioavailability of these compounds
is variable (box 4.2.3) and their ultimate heath effects
uncertain.
Plant cell walls are the main source of dietary fibre, andall whole fruits and vegetables (but not their juices) containvarying amounts of fibre (box 4.2.4). Most vegetables andfruits are low energy-dense foods, although there are exceptions, for example, avocados, nuts, and seeds.
Some families of fruits and vegetables have characteristic
components that may confer a particular health benefit (orrisk) to the whole family. For instance, cruciferous vegetables are sources of glucosinolates and their products isothiocyanates and indoles. Allium vegetables and others, suchas chicory and Jerusalem artichokes, store energy as inulin(chains of fructose sugars) rather than starch (chains of glucose sugars). The body cannot digest inulin, which is calleda prebiotic — a substance that is claimed to have health benefits by promoting the growth of certain types of gut bacteria. Allyl sulphides and allicin in garlic are distinctive flavour
molecules that give vegetables of the onion family their‘sting’ (box 4.2.3). Green, leafy vegetables are sources offolate, and tomatoes have high levels of lycopene. All ofthese components, as well as other phytochemicals (boxPreparation of vegetables and nutrient bioavailability

While some vegetables, often termed‘salad vegetables’, are commonly eatenraw, many are cooked before they areeaten. In most cases, whether a vegetableis eaten raw depends on personal choice.
Most forms of cooking reduce the total
nutrient content of vegetables, although
the degree to which this happens varies
between nutrients and with cooking methods. However, cooking also increases thebioavailability of some nutrients.12
Therefore, although raw vegetables havehigher amounts of nutrients overall, thebody may absorb more of a nutrient fromthe cooked vegetable.
For instance, carotenoid absorption in
the small intestine is relatively inefficient(5–50 per cent); the bioavailability ofcarotenes is increased by cooking andpureeing vegetables, particularly byadding oil, because these compounds are
fat soluble.13 Similarly, processing tomatoes
increases the bioavailability of lycopene,
another carotenoid: it is four times morebioavailable from tomato paste than from
fresh tomatoes. Thus processed tomato
products such as pasteurised tomato juice,
soup, sauce, and ketchup provide the mostbioavailable lycopene. Cooking and crushing tomatoes (as in the canning process)and including them in oil-rich dishes (suchas pasta sauce or pizza) greatly increases
lycopene absorption from the digestive
tract.
The biological response to garlic can also
be influenced by the way that it isprocessed. Peeling and chopping garlicreleases an enzyme, alliinase, which is
known to promote the formation of somesulphur compounds that are not only odoriferous but may provide some health benefits. Heating garlic without peelinginactivates this enzyme and has beenfound to substantially reduce or eliminate
the active properties. If garlic is peeled or
chopped and allowed to stand for 15–20
minutes, the active agents that are formed
are not destroyed by normal cooking procedures.14
The ways in which vegetables and fruits
are produced and stored may affect nutrient levels as much as cooking, or more. For
example, nutrient levels tend to fall rapidly after harvest.

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Box 4.2.4

Foods containing dietary fibre

The concept of dietary fibre arose from observations of the low
prevalence of colon cancer, diabetes, and coronary heart diseasein parts of Africa amongst people whose diets were high in
unrefined carbohydrates and whose stools were typically bulky,
and often or sometimes semisolid. Considerable efforts havebeen dedicated to characterising the dietary components ofwhat has come to be called dietary fibre that might confer
health benefit. Naturally occurring dietary fibre is only derived
from plant foods. Pulses (legumes) and minimally processedcereals are particularly concentrated sources, but vegetables andfruits also contain significant amounts. Dietary fibre isolated
from plant cell walls and synthetic forms are increasingly entering the food supply.
High intakes of dietary fibre, variously defined, have been
associated with reduced risk of cardiovascular disease as well asof some cancers. Definitions of dietary fibre vary. Some arebased on chemical analyses of the components of plant cell
walls, such as non-starch polysaccharide, others on physiological effects — the carbohydrates that enter the large bowel having escaped digestion in the small intestine being defined as
dietary fibre. The latter definition includes oligosaccharides andresistant starch. The World Health Organization and Food andAgriculture Organization have recently proposed that only polysaccharides which form part of plant cell walls should be regarded as dietary fibre and that the health benefits of resistantstarch and oligosaccharides are more appropriately consideredseparately.
This box also appears as box 4.1.2 in the previous section

4.2.2), have been shown to have potentially beneficial effects
in laboratory experiments, as detailed in the evidence inchapter 4.2.5 (also see Chapter 2).7-9
Pulses (legumes)

Dry pulses are seeds and are higher in protein than mostother plant foods. Soya beans and peanuts contain 37 g per
100 g and 26 g per 100 g protein dry weight respectively,
although, on average, pulses contain around 20 g per 100 gprotein dry weight.10 These foods are typically high in carbohydrates and non-starch polysaccharides (dietary fibre),and are generally low in fat. Soya beans and peanuts are
exceptions, being relatively high in fat with 8 g per 100 g
and 47 g per 100 g fat, respectively (mostly mono- andpolyunsaturated fatty acids). They also contain oligosaccharides that are not digested in the gut but are fermented
by bacteria in the colon. Soya beans are distinct from otherlegumes in that they have a high content of bioactive
isoflavones, or phytoestrogens, which have hormone-like
effects in the body. They are also good sources of saponins
and phytosterols, which decrease cholesterol absorption.
Many legumes contain deguelin, which has been shown tohave anti-tumour effects in laboratory experiments.11 Most
pulses are virtually indigestible and inedible before cooking;immature legumes that are eaten green have higher levelsof sugar and lower levels of non-digestible polysaccharides
than dried pulses.

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Nuts and seeds

Other seeds and nuts are also relatively high in protein andfat; some contain as much as 60 g fat per 100 g. They are
therefore energy-dense foods (see Chapter 8), as well as
being nutrient-dense. Weight-for-weight, nuts provide morecalories than either meat or cereals (grains), although chestnuts are the exception as they are relatively low in fat. Most
nuts contain mainly monounsaturated fatty acids, although
the exceptions are coconuts, which contain a high proportion of saturated fatty acids, and walnuts and pecans, whichcontain mostly polyunsaturated fatty acids (see chapter
4.5.2). Nuts and seeds are high in dietary fibre (box 4.2.4),
especially when they are eaten with their skins or hulls; thefibre content is typically 5–11 g per 100 g. Nuts and seeds
are also high in vitamins and minerals, particularly the B vitamins, vitamin E, and folate; and the seed coats contain phenolic compounds.
Herbs and spices

Nearly all herbs and spices contain aromatic compounds,
which are volatile molecules that are usually fat- rather thanwater-soluble. The flavour compounds may make up as muchas 15 g per 100 g of a spice by weight, although herbs contain much lower levels — typically around 1 g per 100 g.
Many plants have evolved to contain these compounds
because they act as deterrents to herbivores. Some of thesearomatic compounds may be bioactive, although possibly notat the levels found in most diets. Isothiocyanates are responsible for the spicy/hot flavour of mustard and horseradish,produced from glucosinolates in cruciferous plants. Chives
and garlic (allium vegetables) contain the distinctive sulphides discussed above. Terpenoids are common components
in herbs and spices, providing distinctive flavours. Examples
include monoterpenes, such as geranial in lemon grass, andlinalool in bergamot; sesquiterpenes, such as bisabolene inginger; triterpenoids, such as the saponin glycrrhizic acid,found in liquorice root; and tetraterpenoids, such as the
carotenoid, lycopene.

4.2.3 Consumption patterns
Fruits and vegetables

The global average for vegetable consumption (based on
availability and not including vegetable oils) is 2.6 per centof total daily energy intake.17 It is generally highest in North
Africa, the Middle East, parts of Asia, the USA and Cuba, andin southern Europe. Although consumption levels are similar
in countries of high and low economic status, vegetables represent a greater proportion of daily energy intake in the lowincome countries. Intakes range from 5.3 per cent in parts ofAsia to as little as 0.2 per cent in sub-Saharan Africa. On average, the availability of vegetables is increasing globally.
The global average for fruit consumption (based on availability) is 2.7 per cent of total daily energy intake. Fruit consumption is generally higher than vegetable consumption,
but it shows a greater degree of variability. Fruit consumption is higher in high-income countries, although it represents a similar percentage of total available dietary energy

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D R I N K S

to that seen in low-income countries. Intakes are highest insome parts of Africa, the Middle East, southern Europe, andOceania, and lowest in other parts of Africa and Asia. Fruitconsumption also tends to be low in north-eastern Europe.
Intakes range from as much as 20 per cent of daily energy
in parts of Africa to as little as 0.5 per cent in parts of Asia.
The availability of fruit has increased globally in recent
decades, although there was a slight decrease in the 1990s.
Most countries have national recommendations for the
daily amount of vegetables and fruits that need to be eaten
to maintain optimal health (Chapter 10). These vary, butthey tend to recommend three or more servings per day ofvegetables and two or more servings per day of fruits; a serving is about 80 g (or half a US cup). In most high-income
countries for which data were available, daily consumptionof vegetables fell short of this target, although this is not due
to lack of availability; indeed, availability is high due to thewide use of refrigeration. Fruit consumption tended to becloser to national targets. Seasonal availability influences
overall availability, although less so in high-income countries
where vegetables and fruits are more likely to be imported.
Pulses (legumes)

Globally, pulses supply 2 per cent of total energy intake(based on availability) and 3.5 per cent of daily protein
intake.17 The highest availability is in parts of Africa, SouthAmerica, Asia, and the Middle East. In these areas, pulses
are a dietary staple, and can account for as much as 20 per
cent of daily energy intake and 50 per cent of protein intake.
In societies with high intakes of meat and other foods of animal origin, pulses are less important in diets, and are usually consumed infrequently or in small amounts. Peanuts andsoya beans account for most of the legume products eaten
around the world.
Soya bean availability per person represents 0.5 per centof daily energy intake globally, but it is notably high in partsof Asia, and higher than average in parts of Africa andCentral America. In parts of Asia, soya beans account for up
to 4.9 per cent of daily energy availability and 15 per centof protein.
Pulses are eaten in a variety of ways around the world; forinstance, Japanese and Chinese bean curd (tofu), Chinesemung bean sprouts, Mexican chilli and refried beans, Indiandahl, Middle Eastern falafel and hummus, Indonesian cultured soya bean cakes (tempeh), Cuban black beans and rice,
Boston baked beans, French cassoulet, Brazilian feijoada,
Swedish pea soup, and US peanut butter. Soya beans are particularly versatile and their products are a common feature
in manufactured foods, although they are not commonly
eaten whole. Soya foods include soya drinks and flour, tofu,
tempeh, textured vegetable protein, and the many productsthat can be prepared from these foods. Fermented soya beans
produce soy sauce and miso. Soya bean oil is also used widely (see chapter 4.5.3).
Nuts and seeds

Nuts and seeds were an important part of human diets before
the advent of agriculture and they remain locally importantin a few areas. Globally, tree nuts supply 0.4 per cent of dailyenergy availability. The highest availability is in the Middle
East and parts of Europe, and the lowest is in South America
and parts of Africa; intakes range from 3 per cent of totalenergy in parts of the Middle East to virtually zero in many
low-income countries.
Coconuts represent 0.5 per cent of daily energy availability globally, although coconuts can be locally important intropical islands, for instance in parts of Oceania, Asia (SriLanka and Indonesia), the Caribbean, and in the Africanislands. In parts of Oceania, for example, coconuts provide
as much as 20 per cent of energy in the diet.
Sunflower, rape, mustard, and sesame seeds together supply 0.2 per cent of daily energy intake globally. There arefewer data available for seeds than for many other foods,
although sesame seed intake is relatively high in parts ofAfrica and Asia, providing a maximum of 3.9 per cent ofenergy in parts of central Africa. Oils from seed crops arewidely used (see chapter 4.5.3).
Herbs, spices, and condiments

Although spices are consumed in small amounts to flavour
food, they are such a regular feature of some diets that theyaccount for a measurable quantity of daily energy intake.
Worldwide, spices provide 0.3 per cent of available dietaryenergy and in parts of Asia they constitute as much as 1.8
per cent. Herbs and spices tend to be part of the traditional diet in the areas from which they originate, and many traditional cuisines are characterised by the use of herbs, spices,and condiments. Most are now available worldwide,
although their use still varies greatly in different parts of theworld. Many herbs and spices are believed to have medicinal or tonic value and have been used in this way at least
since the times of the earliest medical records. Many modern pharmaceuticals are derived from herbs and other plants.
Many herbs and some spices are biologically very potent:
the modern pharmacopoeia lists drugs, many of which havebeen isolated from herbs, sometimes known as ‘plants withhealing powers’. There are some in vivo experimental datafor potentially beneficial effects in the cases of turmeric, saffron, ginger, pepper, garam masala (a herb and spice mix),
and also eugenol and myristin, constituents of a number ofherbs and spices.
Conversely, it is at least theoretically possible that somecondiments have adverse effects. Two examples are hot chilli
juices and harissa, a fiery condiment; both are consumed in
substantial quantities in Mexico and the Mahgreb countries
of North Africa, respectively, and both irritate the mouth andthroat.

4.2.4 Interpretation of the evidence
4.2.4.1 General
For general considerations that may affect interpretation of
the evidence, see chapter 3.3 and 3.5, and boxes 3.1, 3.2,
3.6 and 3.7.
‘Relative risk’ (RR) is used in this Report to denote ratio
measures of effect, including ‘risk ratios’, ‘rate ratios’, ‘hazard ratios’, and ‘odds ratios’.

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4.2.4.2 Specific
Considerations specific to vegetables, fruits, pulses(legumes), nuts, seeds, herbs, and spices include:2•

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4.2.5 Evidence and judgements
The full systematic literature review (SLR) is contained on
the CD included with this Report.

Patterns and ranges of intake. Most studies of consumptionof vegetables, fruits, and pulses (legumes) have been conducted in populations that have relatively homogeneous
diets. The limited data on nuts, seeds, herbs, spices, andcondiments come mainly from a few human case-control
studies and some experimental animal studies.
Classification. There is no general agreement on classification. Some studies have included cereals such as corn, andtubers such as potatoes, as vegetables, and plantains as fruit.
Broccoli and green peppers are included as ‘green vegetables’
in some studies, while only leafy greens are included in thiscategory in others; tomatoes are considered ‘yellow-orange
vegetables’ in some but not in others. Some studies reportresults only for broad categories (for example, ‘all vegetables’or ‘all fruits’), whereas others have reported results for morenarrowly defined categories (for example, ‘raw vegetables’,‘green vegetables’, ‘citrus fruits’) or for individual food items(for example, ‘spinach’, ‘carrots’, ‘tomatoes’). In some studies, vegetables and fruits have been categorised according tobotanical classification; in others, categorisation has been
according to culinary usage. In this report, the terms ‘vegetables’ and ‘fruits’ are used according to their culinary definition. Some studies have included pulses as vegetables
whereas others have classified these as a separate entity or
not at all. Many older studies have not differentiatedbetween retinol and carotenoids. Vitamin E intakes are difficult to quantify since much comes from the vegetable oils
used in food preparation, and intakes within populations areusually homogenous because of the widespread occurrenceof vitamin E in commonly consumed foods.
Measurement. Assessment of selenium intake is problemat-

ic because the content of selenium in foods depends to alarge extent on the soil selenium content of the area in which
the foods were grown. Blood and toenail levels of selenium
are thought to be fairly accurate indicators of intake andhave been used in several studies.

4.2.5.1 Non-starchy vegetables
Mouth, pharynx, and larynx

Thirty-one case-control studies21-50 and 3 ecological studies51investigated non-starchy vegetables and mouth, pharynx,
or larynx cancers; 1 cohort study54 and 6 case-control studies33 39 45 55-57 investigated non-starchy vegetables and fruits;
23 case-control studies investigated raw vegetables24 27 28 33
36-43 45 47 50 58-65; 1 cohort study,66 14 case-control studies,24
26-29 39 41 43 45-47 50 63 67
and 1 ecological study68 investigatedcruciferous vegetables; 1 cohort study66 and 10 case-control
studies24 26-29 39 47 61 67 69 investigated green, leafy vegetables;
3 cohort studies66 70 71 and 18 case-control studies23 24 26-29 39
41-43 46 49 50 63 65 72-75
investigated carrots; and 1 cohort study66
and 12 case-control studies26-29 39-43 46 50 58 62 65 investigatedtomatoes.

53

Non-starchy vegetables

Most studies showed decreased risk with increased intake ofnon-starchy vegetables. Twenty-two studies reported comparisons of high against low intake (figure 4.2.1).22 23 25 26 2931 33 35-46 49 50
Of these, 19 showed decreased risk for thehighest intake group,22 25 26 30 31 33 35-44 46 49 50 which was statistically significant in 13.22 25 30 31 35 37 38 40 42 43 46 49 50 The
other 3 studies showed non-significant increased risk.23 29 45

Figure 4.2.1

Non-starchy vegetables and mouth, pharynx,
and larynx cancer; case-control studies
Relative risk (95% CI)

Notari 1987

0.42 (0.25–0.71)

Franco 1989

1.70 (0.92–3.16)

Oreggia 1991

0.19 (0.05–0.68)

Franceschi 1991

0.80 (0.55–0.68)

Franceschi 1992

0.40 (0.20–0.80)

Zheng 1993

1.73 (0.79–3.78)

Kune 1993

0.30 (0.11–0.85)

De Stefani 1994

0.40 (0.19–0.85)

Takezaki 1996

0.80 (0.59–1.08)

Esteve 1996

0.61 (0.45–0.81)

Confounding. Smokers consume fewer vegetables and fruits

Levi 1998

0.14 (0.08–0.23)

than non-smokers.18 19 Fat intake inversely correlates withvegetable and, particularly, fruit intake in the USA.20 Recent
studies of the effects of fruits and vegetables in cancers
thought to be caused by smoking have controlled for theeffect of smoking. Folate intake is correlated with intake ofnon-starchy polysaccharide (dietary fibre).

De Stefani 1999

0.50 (0.29–0.87)

Reporting bias. Studies using self-reporting tend to over-report vegetable and fruit consumption. Where an effectexists, results from such studies are liable to underestimate
the extent to which vegetables and fruits modify the risk ofcancer.

82

Franceschi 1999

0.50 (0.33–0.76)

De Stefani 1999

0.57 (0.30–1.08)

Garrote 2001

0.78 (0.40–1.52)

Bosetti 2002

0.17 (0.11–0.27)

Marchioni 2003

0.86 (0.54–1.38)

Lissowska 2003

0.17 (0.07–0.27)

Rajkumar 2003

0.44 (0.28–0.69)

Sanchez 2003

0.54 (0.34–0.86)

Gaud 2004

1.40 (0.71–2.76)

De Stefani 2005

0.60 (0.33–1.10)

0.2

0.5

1

2

5

Relative risk, highest vs lowest exposure category

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4•

Figure 4.2.2

F O O D S

A N D

D R I N K S

Non-starchy vegetables and mouth, pharynx,
and larynx cancer; case-control studies
Relative risk (95% CI)

De Stefani 1994

0.53 (0.26–1.09)

Levi 1998

0.62 (0.53–0.74)

De Stefani 2000

0.82 (0.64–1.05)

Bosetti 2002

0.75 (0.70–0.81)

Summary estimate

0.72 (0.63–0.82)

0.5

0.75

1

1.5

Relative risk, per 50 g/day(international) found no significant association with cancer
mortality.52 53
Non-starchy vegetables and fruits

A cohort study that reported results for non-starchy vegetables and fruits in combination reported a statistically significant protective effect in the highest consumers (0.55, 95%
CI 0.32–0.95).54 All six case-control studies looking at thesame exposure group reported reduced risk estimates in similar comparisons,33 39 45 55-57 which were statistically significant in four.33 39 55 57 All of these studies adjusted for smoking
and alcohol consumption.
Raw vegetables

Figure 4.2.3

Non-starchy vegetables and mouth,
pharynx, and larynx cancer; case-control
studies: dose response

De Stefani 1994

Levi 1998

De Stefani 2000

Twenty-three case-control studies reported separate risk estimates for raw vegetable consumption.24 27 28 33 36-43 45 47 50 5865
All of these reported comparisons of risk between high andlow intake groups, which produced reduced risk estimatesin 2224 27 28 33 36-43 45 47 50 58 60-65; 16 of these were statistically significant.24 33 36-40 42 43 47 50 60-63 65 No studies reported statistically significant increased risk estimates. Meta-analysisof 7 case-control studies gave an effect estimate of 0.71 (95%
CI 0.59–0.86) per 50 g/day, with moderate heterogeneity.37
39 42 45 59 62 65
These studies also provided evidence of a doseresponse relationship. The heterogeneity could be partiallyexplained by variable exposure definitions. These results are
consistent with data for non-starchy vegetables.
Cruciferous vegetables

Bosetti 2002

0

100

200

300

400

Non-starchy vegetables (g/day)The remaining studies showed no consistent association,
probably due to varying exposure definitions and study
design.21 24 27 28 32 34 47 48 Meta-analysis was possible on 4 casecontrol studies, giving a summary effect estimate of 0.72
(95% confidence interval (CI) 0.63–0.82) per 50 g/day, withmoderate heterogeneity (figure 4.2.2). All studies adjusted
for sex, smoking, and alcohol consumption.
A dose-response relationship is apparent from the fourcase-control studies that could be meta-analysed (figure
4.2.3). There is some suggestion that the greatest effectappears to be with the first increment. That is, any increase
above the lowest levels of vegetable consumption confers aprotective effect. However, it is not clear that the effect continues in a linear fashion with increased dose.
Of the three ecological studies, one (Hong Kong) study
found a significant negative association between vegetableconsumption and cancer incidence51; the other two

One cohort study,66 14 case-control studies,24 26-29 39 41 43 4547 50 63 67
and 1 ecological study68 reported separate risk estimates for cruciferous vegetable consumption.
The single cohort study showed a non-significant increased
risk for increased intake of cauliflower and a non-significant
decreased risk for cabbage.66 Four case-control studies
showed statistically significant decreased risk with increased
intake, either overall or in specific subgroups.24 29 43 47 One
study showed statistically significant increased risk associated with eating kimchi or pickled cabbage.67 The other ninestudies showed inconsistent and non-significant associations.26-28 39 41 45 46 50 63 The ecological study showed a statistically significant decreased risk.68
Green, leafy vegetables

One cohort study66 and 10 case-control studies24 26-29 39 47 61
67 69
reported separate risk estimates for green, leafy vegetable consumption.
The single cohort study showed no effect for the highest
intake group of lettuce when compared to the lowest.66 Nine
case-control studies showed decreased risk with increased
intake,24 26 27 29 39 47 61 67 69 which was statistically significant
in four.24 39 61 69 One study showed non-significant increased
risk.28
Carrots

Three cohort studies66 70 71 and 18 case-control studies23 24
investigated non-starchy root vegetables and mouth, larynx, or pharynx cancers. There wasvariation in the exposure classification in studies. Most

26-29 39 41-43 46 50 63 65 72-75

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assessed carrots, but some looked at ‘tubers and carrots’ or‘non-starchy root vegetables’ or ‘yellow/orange vegetables’.
One cohort study, looking at ‘tubers and carrots’, reported a non-significant increased risk when comparing highagainst low intakes, with a wide confidence interval (1.9,
95% CI 0.6–6.0).66 Another that reported on ‘carotene-richfruits and vegetables’ found a non-significant reduced risk
when comparing the highest intake group against the lowest (0.50, p value for linear trend 0.10).70 The third, which
evaluated yellow/orange vegetables in postmenopausal US
women, reported a significant reduced risk for the same comparison (0.58, 95% CI 0.39–0.87).71
All of the 18 case-control studies reported comparisons ofrisk between high- and low-intake groups.23 24 26-29 39 41-43 46
49 50 63 65 72-75
Sixteen reported reduced risk estimates,23 26-29
39 41-43 50 63 65 72-75
6 of which were statistically significant.49
72 75
The other 2 were non-significant in the direction ofincreased risk.24 27 28 39 43 46 The majority of studies were
hospital-based and analysed carrots as a separate exposure.

2•

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vegetables and oesophageal cancer. Eight case-control studies investigated vegetable and fruit consumption (combined)95 104 107 114 120-123; 16 case-control studies investigated
raw vegetables40 60 85 95-97 103 109 113 114 124-129; 1 cohort study66
and 5 case-control studies86 93 107 124 125 investigated cruciferous vegetables; 1 cohort study82 and 8 case-control studies86 101 103 107 109 111 129 130 investigated allium vegetables; 1
cohort study66 and 11 case-control studies86 96 98 111 124 127 131135
investigated green, leafy vegetables; 1 cohort study66 and9 case-control studies58 62 109 111 113 129-132 136 investigatedtomatoes.
Non-starchy vegetables

Data suggest an association with reduced risk. Of the fivecohort studies, three reported decreased risk when comparing the highest intake group against the lowest, one of which
was statistically significant (0.66, 95% CI 0.44–0.99, nonstarchy vegetables82; 0.5, p value for linear trend 0.1, yel-Tomatoes

One cohort study66 and 12 case-control studies26-29 39-43 46 50
58 62 65
investigated tomatoes and mouth, larynx, or pharynx
cancers.
The cohort study reported a non-significant increased risk
when comparing the highest intake group against the lowest, with a wide confidence interval (1.7, 95% CI 0.8–3.7).66
Of the 12 case-control studies,26-29 39-43 46 50 58 62 65 10 reported reduced risk estimates,26 29 39-43 46 50 58 62 65 5 of which were
statistically significant.26 29 39 40 62 Only 2 reported anincreased risk, which was non-significant.27 28 These studies
were also the only studies not to adjust for both smoking andalcohol intake.
The general mechanisms through which vegetables could
plausibly protect against cancers of the mouth, larynx, andpharynx are outlined below.
Although all of the studies mentioned here adjust forsmoking behaviour and nearly all adjust for alcohol, the relative risk of smoking is large (particularly when combinedwith alcoholic drinks). It is therefore difficult to eliminate
confidently the possibility of residual confounding with waysof life associated with smoking: for instance, smokers consume fewer vegetables than non-smokers.
A substantial amount of consistent evidence on nonstarchy vegetables, including specific subtypes, mostly
from case-control studies, shows a dose-response
relationship. There is evidence for plausible
mechanisms. Non-starchy vegetables probably protect
against mouth, pharynx, and larynx cancers.

The Panel is aware that since the conclusion of the SLR, twocohort76 77 and two case-control studies78 79 have been published. This new information does not change the Panel judgement (see box 3.8).

Figure 4.2.4

Non-starchy vegetables and oesophageal
cancer; cohort and case-control studies
Relative risk (95% CI)

CohortHiryama 1990

1.06 (0.91–1.24)

Yu 19930.66 (0.44–0.99)

Guo 1999

0.80 (0.62–1.53)

Tran 2005

1.02 (0.85–1.18)

Case control
Cook-Mozalfari 1979 Men

0.85 (0.58–1.25)

Cook-Mozalfari 1979 Women

0.81 (0.49–1.33)

Notani 1967

1.06 (5.70–1.64)

Brown 1968

0.70 (0.39–1.20)

Jun-lao 1989

1.50 (0.19–1.89)

De Stefani 1990

0.56 (0.31–1.02)

Ren 1991

2.57 (1.25–5.27)

Negni 1991

0.20 (0.09–0.45)

Sammon 1992

1.44 (0.62–2.10)

Ho 1994

0.60 (0.30–1.35)

Sammon 1998

2.30 (1.06–4.89)

Lauroy 1998

0.24 (0.11–3.54)

De Stefani 1999

0.50 (0.29–0.87)

Takazaki 2000

0.60 (0.45–0.78)

De Stefani 2000

0.64 (0.34–1.20)

Levi 2000

0.19 (0.11–0.33)

Nayor 2000

0.53 (0.36–0.87)

Cheng 2000

0.56 (0.22–1.34)

Bosets 2000

0.79 (0.47–1.32)

Takezaki 2001

0.81 (0.40–1.43)

Terry 2001

0.60 (0.38–5.35)

Zhany 2001

1.94 (1.22–2.85)

Chen 2002

0.62 (0.26–1.35)

Cnuk 2002

10.10 (4.42–23.09)

Xibin 2003

0.44 (0.21–0.34)

Li 20030.76 (0.55–1.19)

Hung 2004

0.50 (0.31–0.82)

De Stefani 2005

0.53 (0.27–1.00)

Yang 2005

0.62 (0.32–1.18)

0.2

0.5

1

2

5

Relative risk, highest vs lowest exposure category

Oesophagus

Five cohort studies,70 80-83 37 case-control studies22 40 60 84-115
and 6 ecological studies51 52 116-119 investigated non-starchy84

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Figure 4.2.5

F O O D S

A N D

D R I N K S

Non-starchy vegetables and oesophageal
cancer; case-control studies
Relative risk (95% CI)

Jun-Lao Li 1989

1.08 (1.03–1.14)

De Stefani 2000

0.81 (0.66–0.99)

Levi 2000

0.66 (0.58–0.74)

Cheng 2000

0.90 (0.74–1.11)

De Stefani 2005

0.94 (0.86–1.02)

Summary estimate

0.87 (0.72–1.05)

0.5

0.75

1

1.5

2

Relative risk, per 50 g/day

Raw vegetables

Sixteen case-control studies investigated raw vegetables andoesophageal cancer.40 60 85 95-97 103 109 113 114 124-129
All of these studies reported associations with decreased
risk, which were statistically significant in 10.40 60 85 95 97 109
113 126 127 129
Dose-response meta-analysis was possible on fivestudies, giving a summary effect estimate of 0.69 (95% CI
0.58–0.83) per 50 g/day increment (figures 4.2.6 and 4.2.7).
This exposure category could be less disparate than othervegetable groupings, as it is clear that preserved vegetables
are not included and variation in cooking methods isremoved. This may account for the lack of heterogeneity indirection of effect in this subcategory of vegetables.

Figure 4.2.6

low/orange vegetables70; and 0.8, 95% CI 0.60–1.0 and pvalue for trend 0.08, stated as not statistically significant,non-starchy vegetables80). The other two reported a nonsignificant increased risk (1.06, 95% CI 0.91–1.24, nonstarchy vegetables81; and 1.02, 95% CI 0.88–1.19, fresh
non-starchy vegetables83) (figure 4.2.4).
Most (29) of the case-control studies published decreased
risk estimates when comparing the highest intake groupagainst the lowest,40 60 85-90 94-99 101-105 107-109 111-115 which were
statistically significant in 14 (figure 4.2.4).40 88 89 94 97-99 101
102 104 105 109
Five studies reported statistically significant
increased risk.84 91 93 100 106 110 Meta-analysis was possible on
5 of the case-control studies, giving a summary effectestimate of 0.87 (95% CI 0. 72–1.05) per 50 g/day increment, with high heterogeneity (figure 4.2.5). A potential
cause of heterogeneity is the disparate nature of the exposure definition in different studies, some of which included
pickled and cured vegetables, cooked or uncooked
vegetables.
Two of the ecological studies reported a statistically significant, positive association between vegetable consumption
and cancer incidence116 117; one reported a statistically significant, negative association between vegetable consumption and cancer incidence51; and the other three reported nosignificant association between vegetable consumption andcancer mortality.52 118 119
The Panel is aware that data from the European
Prospective Investigation into Cancer and Nutrition (EPIC;
521 457 participants from 10 European countries; 65 casesof adenocarcinomas of the oesophagus), published after theconclusion of the SLR,140 showed a non-significant reduced
risk (0.72, 95% CI 0.32–1.64) per 100 g/day increase in vegetable consumption (adjusted for several variables including
smoking and alcohol, red meat, and processed meat).

Raw vegetables and oesophageal cancer;
case-control studies
Relative risk (95% CI)

De Stefani 2000

0.38 (0.21–0.69)

Levi 2000

0.64 (0.57–0.72)

Cheng 2000

0.83 (0.68–1.02)

Sharp 2001

0.84 (0.75–0.95)

De Stefani 2003

0.60 (0.48–0.76)

Summary estimate

0.69 (0.58–0.83)

0.25

0.5

0.75

1

1.5

Relative risk, per 50 g/day

Figure 4.2.7

Raw vegetables and oesophageal cancer;
case-control studies: dose response

Castelletto 1994

Cheng 2000

De Stefani 2000

Levi 2000

Sharp 2001

De Stefani 2003

0

100

200

300

Non-starchy vegetables (g/day)

Non-starchy vegetables and fruits

Eight case-control studies investigated vegetable and fruit
consumption (combined) and oesophageal cancer. All
reported a decreased risk with increased consumption.95 104
107 114 120-123
Six of these were statistically significant.95 104 107
114 120 121

85

P A R T

Non-starchy root vegetables and tubers

One cohort study66 and six case-control studies114 122 128 132
136 141 142
reported separate risk estimates for consumption of
non-starchy root vegetables and tubers.
The single cohort study showed a non-significant increased
risk for the highest intake group when compared to the lowest, after adjustment.66 All six case-control studies showednon-significant decreased risk with increased intake.114 122 128
132 136 141 142

Cruciferous vegetables

One cohort study66 and five case-control studies86 93 107 124 125
reported separate risk estimates for consumption of cruciferous vegetables.
The single cohort study showed a non-significant
decreased risk for increased intake of cauliflower or swede
and a non-significant increased risk for cabbage, after adjustment.66 Three case-control studies showed decreased risk
with increased intake,93 107 124 which was statistically significant in two.93 124 One study showed a non-significant
increased risk125; and one study showed a non-significant
increased risk in women and a non-significant decreased risk
in men.86
Allium vegetables

One cohort study82 and eight case-control studies86 101 103 107
reported separate risk estimates for allium
vegetable consumption.
The single cohort study showed that garlic intake had noeffect on risk.82 Four case-control studies showed non-significant decreased risk with increased intake.101 103 107 130 Two
studies showed non-significant increased risk.86 111 One study
showed a statistically significant decreased risk for garlic andthat onions/leeks had no effect on risk109; and one study
showed a statistically significant reduced risk for onions anda non-significant increased risk for garlic.129
109 111 129 130

2•

E V I D E N C E

A N D

J U D G E M E N T S

The general mechanisms through which vegetables could
plausibly protect against oesophageal cancer are outlined
below.
There is more evidence, including on vegetable
subtypes, from case-control studies than from cohort
studies, but both are moderately consistent and there
is some evidence for a dose-response relationship.
There is evidence for plausible mechanisms. Nonstarchy vegetables probably protect against
oesophageal cancer.

The Panel is aware that since the conclusion of the SLR, onecohort140 and two case-control studies78 143 have been published. This new information does not change the Panel judgement (see box 3.8).
StomachTen cohort studies,71 80 140 144-150 45 case-control studies,109
151-195
and 19 ecological studies51 52 116-119 196-209 investigatedtotal vegetables. Eleven cohort studies,71 144 150 210-218 21 casecontrol studies,89 165 169 178 179 188 191 219-232 and 8 ecologicalstudies233-240 investigated green-yellow vegetables; 6 cohort
studies70 140 144 146 150 241, 13 case-control studies,162 174 175 179
180 187 223 227 229 230 232 242 243
and 2 ecological studies202 240
investigated green, leafy vegetables; 3 cohort studies70 146 241
and 19 case-control studies58 109 129 152 156 164 171 172 174 232 243251
investigated tomatoes; 2 cohort studies150 214 and 6 casecontrol studies157 165 169 226 228 243 investigated white or palevegetables; 6 cohort studies,146 148 214 252-254 25 case-control
studies,109 129 161 162 167 172 174 183 184 191 219 225 226 243 247 248 250 255264
and 3 ecological studies202 208 238 investigated raw vegetables; 5 cohort studies144 146 148 253 265 and 6 case-control
studies158 161 162 164 257 266 267 investigated non-starchy vegetables and fruits.
Non-starchy vegetables

Green, leafy vegetables

One cohort study66 and 11 case-control studies86 96 98 111 124
127 131-135
reported separate risk estimates for green, leafy vegetable consumption.
The single cohort study showed no effect for the highest
intake group of lettuce when compared to the lowest.66 Tencase-control studies showed decreased risk with increased
intake,96 98 111 124 127 131-135 which was statistically significant
in five.96 127 132-134 One study showed a non-significant
increased risk in women and a non-significant decreased risk
in men.86
Tomatoes

One cohort study66 and nine case-control studies58 62 109 111
113 129-132 136
reported separate risk estimates for consumptionof tomatoes.
The single cohort study showed a non-significant increased
risk for the highest intake group of lettuce, when comparedto the lowest, after adjustment.66 Eight case-control studies
showed decreased risk with increased intake,58 62 109 111 113 129
131 132 136
which was statistically significant in two.62 129 One
study showed no effect on risk.130

86

Of 12 independent estimates from the 10 cohort studies thatinvestigated non-starchy vegetable consumption, none wasstatistically significant.71 80 140 144-150 Seven studies showednon-significant reduced risk71 140 144-147 150 and 2 reported
non-significant increased risk.80 149 One study showed nonsignificant increased risk in women and non-significant
decreased risk in men.148 Most effect estimates were close to
1. Meta-analysis was possible on 9 independent estimatesfrom 7 cohort studies, giving a summary effect estimate of
0.98 (95% CI 0.91–1.06) per 100 g/day, with moderate heterogeneity (figure 4.2.8).
Of 45 case-control studies that reported on non-starchy
vegetable consumption, 28 reported statistically significant
decreased risk.109 151-153 156-160 163 164 168 169 171 173 176-179 181 182
184 185 187 190 192
The majority of the 17 remaining studies thatreported no significant effect on risk were in the direction of
decreased risk.155 162 165-167 170 172 174 183 191 194 195 Four studies
showed non-significant increased risk,180 188 189 193 1 study
showed no effect on risk,154 and 1 study stated that there wasno significant association.175 One study showed non-significant decreased risk in women and non-significant increased
risk in men186; and 1 study showed statistically significant

C H A P T E R

4•

Figure 4.2.8

F O O D S

A N D

D R I N K S

Non-starchy vegetables and stomach cancer;
cohort and case-control studies

Figure 4.2.9

Green-yellow vegetables and stomach
cancer; cohort and case-control studies

Relative risk (95% CI)
CohortRelative risk (95% CI)
CohortChyou 1990 Men

0.76 (0.53–1.10)

Chyou 1990 Men

0.74 (0.52–1.05)

Guo 1994

1.05 (0.93–1.18)

Kasum 2002 Women

0.57 (0.19–1.75)

Botterweck 1998

0.92 (0.78–1.09)

Kobayashi 2002

0.56 (0.33–0.94)

McCullough 2001 Men

0.98 (0.84–1.02)

Ngoan 2002

0.41 (0.18–0.94)

McCullough 2001 Women

1.16 (1.00–1.34)

Khan 2004 Men

0.66 (0.11–3.89)

Fujino 2002 Men

1.12 (0.93–1.34)

Fujino 2002 Women

1.03 (0.77–1.36)

Kobayashi 2002

0.86 (0.72–1.02)

Khan 2004 Women

0.18 (0.02–2.13)

Summary estimate

0.63 (0.48–0.82)

Gonzalez 2006

0.91 (0.66–1.28)

Case control

Summary estimate

0.98 (0.91–1.06)

Lee 1990

0.94 (0.68–1.29)

Cai 1991

0.44 (0.38–0.50)

Negri 1991

0.24 (0.13–0.44)

Case control
Risch 1985

0.84 (0.73–0.97)

You 1988

0.81 (0.75–0.86)

De Stefani 1990

0.40 (0.27–0.60)

Menik 1992

0.36 (0.16–0.80)

Hansson 1993

0.60 (0.46–0.79)

Cornee 1995

0.85 (0.57–1.28)

De Stefani 1998

0.39 (0.32–0.48)

Ji 1998 Men

0.86 (0.82–0.90)

Ji 1998 Women

0.94 (0.86–1.01)

Ward 1999

0.22 (0.11–0.43)

Mathew 2000

0.52 (0.18–1.46)

De Stefani 2001

0.89 (0.60–1.32)

Takezaki 2001

0.47 (0.26–0.81)

Sriamporn 2002

0.86 (0.56–1.33)

Hara 2003

1.06 (0.84–1.33)

Sipetic 2003

0.07 (0.03–0.15)

Suh 2003

1.04 (0.89–1.22)

Lagiou 2004

0.51 (0.39–0.68)

Lissowska 2004

0.90 (0.74–1.09)

Boccia 2005

1.09 (0.56–2.12)

Nan 2005

Hoshiyama and Sasaba 1992

0.49 (0.32–0.74)

Ji 1998 Men

0.77 (0.69–0.86)

Ji 1998 Women

0.89 (0.77–1.04)

Ward 1999

0.33 (0.24–0.46)

Hamada 2002

1.09 (0.41–2.93)

Nishimoto 2002

0.62 (0.33–3.43)

Hara 2003

1.59 (0.73–3.43)

Ito 2003 Women

0.55 (0.38–0.81)

Lissowska 2004

0.28 (0.12–0.66)

Summary estimate

0.59 (0.46–0.75)

0.5

1

2

Relative risk, per 100 g/day

0.90 (0.66–1.25)

Summary estimate

0.70 (0.62–0.79)

0.5 0.75 1

1.5 2

Relative risk, per 100 g/day

decreased risk in men and non-significant increased risk in
women.161 No studies reported statistically significant
increased risk. Meta-analysis was possible on 20 studies, giving a summary effect estimate of 0.70 (95% CI 0.62–0.79)
per 100 g/day, with high heterogeneity (figure 4.2.8). This
heterogeneity tended to reflect differences in size, rather
than direction, of effect.
A dose-response relationship was apparent from casecontrol but not cohort data.
Results from ecological studies reporting on non-starchy
vegetable consumption were mixed, with almost as manystudies reporting increased risk as reported decreased
risk.51 52 116-119 196-209
Green-yellow vegetables

Eight of the 11 cohort studies that reported on green-yellow
vegetable consumption showed decreased risk,71 144 150 210 211
214-217
statistically significant in 4.150 210 215 216 Two other studies showed non-significant increased risk212 213 and 1 otherstudy reported no statistically significant association.218

Meta-analysis was possible on 6 independent estimates from5 studies, giving a summary effect estimate of 0.63 (95% CI
0.48–0.82) per 100 g/day, with no heterogeneity (figure
4.2.9).
Of the 21 case-control studies that reported on greenyellow vegetable consumption, 16 showed decreased risk,89
165 169 178 179 191 219 220 222-228 230-232
statistically significant in
12.89 165 169 178 179 191 220 222 223 226 231 232 The remaining 5 studies reported increased risk,111 188 221 229 1 of which was statistically significant.221 Meta-analysis was possible on 12
independent estimates from 11 studies, giving a summary
effect estimate of 0.59 (95% CI 0.46–0.75) per 100 g/day,with high heterogeneity (figure 4.2.9).
All of the studies adjusted for age and sex; none wasadjusted for infection with Helicobacter pylori. Nine studies
were maximally adjusted, seven of which reported asignificant negative association with higher consumption ofgreen-yellow vegetables, and the other two reported nosignificant association.
A dose-response relationship was apparent from both87

P A R T

Figure 4.2.10

Green-yellow vegetables and stomach
cancer; cohort and case-control studies:dose response

2

Figure 4.2.11•

E V I D E N C E

A N D

J U D G E M E N T S

White or pale vegetables and stomach
cancer: cohort and case-control studies
Relative risk (95% CI)

CohortCohortChyou 1990 Men

Kobayashi 2002

0.52 (0.23–1.18)

Khan 2004 Men

0.63 (0.09–4.12)

Khan 2004 Women

0.15 (0.01–2.34)

Summary estimate

Kasum 2002 Women

0.49 (0.24–1.01)

Case control

Kobayashi 2002
Ngoan 2002

Risch 1985

0.29 (0.07–1.15)

Cai 1991

0.45 (0.34–0.60)

Hoshiyama and Sasaba 1992
Khan 2004 Men

0.86 (0.32–1.09)

Summary estimate

0.57 (0.32–1.02)

Khan 2004 Women

0.5

1

2

Relative risk, per 100 g/day

Case control
Lee 1990
Cai 1991
Negri 1991
Hoshiyama and Sasaba 1992
Ji 1998 Mencohort and case-control data on green-yellow vegetableconsumption (figure 4.2.10).
Five out of the eight ecological studies that reported on
green-yellow vegetable consumption showed decreased risk
with increased consumption,236-240 two showed no association,233 234 and one study showed increased risk.235
This exposure included green-yellow vegetables, green
vegetables, yellow vegetables, yellow-orange vegetables, carrots and pumpkins, and high-carotenoid vegetables.

Nine case-control studies showed decreased risk withincreased intake,179 187 223 227 229 230 232 242 243 which was statistically significant in three,223 232 243 and in men, but not
women, in a fourth study.227 Two further studies showednon-significant increased risk174 180; one study showed noeffect on risk162; and one study stated that there was no significant association.175 Meta-analysis was possible on six
case-control studies, giving a summary effect estimate of
0.90 (95% CI 0.70–1.16) per 100 g/day, with no heterogeneity.162 179 180 187 229 230
One ecological study showed statistically significant
decreased risk240 with high intake, the other showed nonsignificant increased risk.202
One cohort study146 and 15 case-control studies152 156 164
167 172 231 243-246 261 268-271
also reported separately on lettuce
and salad leaves. The single cohort study showed a nonsignificant decreased risk with increased intake. The effectestimate was 0.88 (95% CI 0.38–2.60) per 50 g/day.146
Twelve case-control studies showed decreased risk withincreased intake of lettuce or salad leaves,152 156 164 167 231 243
246 261 268-271
which was statistically significant in 7.156 243 246
261 268-270
Two studies showed non-significant increased
risk.172 245 One study showed no effect on risk.244 Metaanalysis was possible on 5 case-control studies that investigated lettuce or salad leaves, giving a summary effectestimate of 0.43 (95% CI 0.24–0.77) per 50 g/day, with highheterogeneity.152 231 268-270 Heterogeneity was related
primarily to the size, and not the direction, of the effect.

Green, leafy vegetables

Tomatoes

Four cohort studies showed non-significant decreased
risk with increased intake70 144 146 150; two studies showednon-significant increased risk.140 241 Meta-analysis was possible on four cohort studies, giving a summary effect estimateof 0.85 (95% CI 0.58–1.25) per 100 g/day, with no heterogeneity.140 144 146 150

Two cohort studies showed a non-significant increased
risk with increased intake.146 241 One study stated that there
was a non-significant decreased risk (unquantified).70
The effect estimates were 1.81 (95% CI 0.85–3.85) per 100
g/day,146 and 1.1 (95% CI 0.76–1.60) for women and1.19 (95% CI 0.88–1.61) for men (both for the highest

Ji 1998 Women
Ward 1999
Hamada 2002
Nishimoto 2002
Hara 2003
Ito 2003 Women
Lissowska 2004

0

100

200

300

400

Green-yellow vegetables (g/day)88

C H A P T E R

4

Figure 4.2.12•

F O O D S

A N D

D R I N K S

Raw vegetables and stomach cancer;
cohort and case-control studies

Figure 4.2.13

Raw vegetables and stomach cancer;
case-control studies: dose response

Relative risk (95% CI)
Jedrychowski 1981

CohortBotterweck 1998

0.51 (0.05–4.73)

Galanis 1998

0.81 (0.53–1.23)

Khan 2004 Men

0.63 (0.16–2.51)

Khan 2004 Women

2.03 (0.14–29.46)

Summary estimate

0.80 (0.54–1.18)

Jedrychowski 1986
Buiatti 1989
Coggon 1989
Kato 1990 Men

Case control
Jedrychowski 1981

0.10 (0.02–0.41)

Jedrychowski 1986

1.56 (0.12–20.74)

Buiatti 1989

0.56 (0.45–0.71)

Caggon 1989

0.13 (0.01–2.88)

Kato 1990 Men

0.59 (0.38–0.91)

Kato 1990 Women

0.86 (0.48–1.48)

Hoshiyama and Sasaba 1992

0.44 (0.29–0.68)

Ramon 1993

0.35 (0.16–0.78)

Cornee 1995

0.27 (0.10–0.72)

Huang 1999

0.77 (0.62–0.94)

De Stefani 2001

0.46 (0.16–1.34)

Sriamporn 2002

0.40 (0.01–15.73)

Lee 2003

0.11 (0.04–0.27)

Lissowska 2004

0.82 (0.52–1.28)

Summary estimate

0.50 (0.38–0.65)

0.5 1

Kato 1990 Women
Hoshiyama and Sasaba 1992
Ramon 1993
Cornee 1995
Huang 1999
De Stefani 2001
Sriamporn 2002
Lee 2003

20

intake group when compared to the lowest).241
Most case-control studies showed decreased risk withincreased intake, which was statistically significant in 10.58
109 152 156 164 171 232 246-248
No studies showed statistically significant increased risk. Meta-analysis was possible on 6 casecontrol studies, giving a summary effect estimate of 0.40
(95% CI 0.19–0.82) per 100 g/day, with high heterogeneity.109 152 171 232 244 250
White or pale vegetables

This incorporates a wide range of vegetables. For example,
in Japan white vegetables such as daikon (radish) are commonly consumed. Descriptions used for this exposure werewhite vegetables, pale green or light green vegetables, andraw chicory.
Both cohort studies showed non-significant decreased risk
with increased intake.150 214 Meta-analysis was possible on
both studies, giving a summary effect estimate of 0.49 (95%
CI 0.24–1.01) per 100 g/day, with no heterogeneity (figure
4.2.11).
All six case-control studies showed decreased risk withincreased intake,157 165 169 226 228 243 which was statistically significant in three.165 169 243 Meta-analysis was possible on threestudies, giving a summary effect estimate of 0.57 (95% CI
0.32–1.02) per 100 g/day, with high heterogeneity, which
was caused by varying size, not direction of the effect (figure
4.2.11).

50

100

150

Raw vegetables (g/day)

Relative risk, per 100 g/day

Raw vegetables

Of seven independent estimates from six cohort studies thatreported on raw vegetables, four reported non-significant
reduced risk,146 214 253 254 two reported non-significant
increased risk,214 252 and the other reported a significant
increased risk.148 Two of the increased risk estimates, including the one that reached statistical significance, were stratified for women only. Meta-analysis was possible on four
estimates from three studies (not including the one that was
statistically significant), giving a summary effect estimate of
0.80 (95% CI 0.54–1.18) per 100 g/day, with no heterogeneity (figure 4.2.12).
Of the 25 case-control studies that reported on raw vegetables, 21 reported decreased risk,109 129 161 162 167 172 174 183
184 191 219 225 226 243 247 248 250 255 256 258 260 261 264
which was statistically significant in 13.129 161 172 174 225 226 243 247 248 256 260 261
264
None of the remaining 4 studies that reported increased
risk reached statistical significance.257 259 262 263 Meta-analysis was possible on 14 independent estimates from 13 casecontrol studies, giving a summary effect estimate of 0.50
(95% CI 0.38–0.65) per 100 g/day, with moderate heterogeneity (figure 4.2.12).
A dose-response relationship was apparent from casecontrol but not cohort data (figure 4.2.13).
Of the three ecological studies, two reported statistically significant reduced risk208 238 and one reported a non-significant
increased risk with increased raw vegetable consumption.202

89

P A R T

Non-starchy vegetables and fruits

All five cohort studies showed decreased risk for the highest intake group when compared to the lowest,144 146 148 253
265
which was statistically significant in two,253 265 and inmen, but not women, in a third study.148 Meta-analysis was
possible on two cohort studies, giving a summary effect estimate of 0.81 (95% CI 0.58–1.14) per 100 g/day.146 253 All
six case-control studies showed decreased risk with increased
intake,158 161 162 164 257 266 267which was statistically significant
in four.158 162 164 257 Meta-analysis was possible on two casecontrol studies, giving a summary effect estimate of 0.79
(95% CI 0.63–0.99) per 100 g/day.162 267
The stomach is a particularly unusual chemical environment and it is possible that, in addition to the general mechanisms described below, specific mechanisms apply, forinstance, in relation to nitrosamine formation.
A substantial amount of evidence is available,
including on specific subtypes, particularly greenyellow vegetables, with a dose-response relationship incase-control, but not cohort data. There is evidence forplausible mechanisms. Vegetables probably protect
against stomach cancer.
Nasopharynx

Five case-control studies272-276 and two ecological studies51
investigated non-starchy vegetables and nasopharyngeal
cancer; a further four case-control studies investigated green
vegetables.278-281 Preserved vegetables were excluded fromall categories.
Eight of the case-control studies reported reduced risk
when comparing high against low intake groups,272 273 275 276
278-281
which was statistically significant in three of the nonstarchy vegetable studies272 275 276 and in two of the green
vegetable studies.279 280 One other study stated that there wasno significant association.274 All studies were based in China.
The ecological studies produced mixed results. One
showed significant correlations between the consumptionof fresh vegetables and reduced risk of nasopharyngeal carcinoma after adjusting for age (r2 = -0.77, p = 0.009 among
men and r2 = -0.75, p = 0.013 among women).51 The second
study showed an increasing risk with increases
in local consumption of non-starchy vegetables (r2 = 2.36).277
This study did not report any adjustments for potential
confounding variables or whether the finding was significant.
The general mechanisms through which vegetables could
plausibly protect against nasopharyngeal cancer are outlined
below.
277

The evidence for non-starchy vegetables is sparse but
generally consistent. There is limited evidence
suggesting that non-starchy vegetables protect against
nasopharyngeal cancer.
Lung

Seventeen cohort studies,282-300 27 case-control studies,301-331
and 6 ecological studies52 116 332-335 investigated total vegetables and lung cancer (some studies did not separate non-

90

2

•

E V I D E N C E

A N D

J U D G E M E N T S

starchy vegetables from this grouping); in addition, therewas 1 relevant pooling project publication.336 Three cohort
studies337-339 and 1 case-control study321 investigated nonstarchy vegetables specifically; 5 cohort studies285 292 299 340341
and 17 case-control studies65 301 307 312 320-322 326 330 342-350
investigated green, leafy vegetables (excluding cruciferous);
2 cohort studies investigated non-starchy root vegetables andtubers289 291; and 6 cohort studies,285 289 293 299 339 341 21 casecontrol studies,65 261 304 307 313 320-322 325-327 342 344 346-348 351-358
and 1 ecological study333 investigated carrots specifically.
Total vegetables

Out of 19 effect estimates from 17 cohort studies, 14 showed
reduced risk with higher levels of vegetable consumption,282
283 286-289 291-297 299 300
which was statistically significant in 3286
297 299 300
and in women only in another285; 1 reported noeffect on risk,298 2 showed increased risk,284 290 none of which
was statistically significant, and 2 showed non-significant
increased risk in men but not women.285 296 Meta-analysis
was possible on 10 studies, all of which adjusted for smoking, giving a summary effect estimate of 0.95 (95% CI
0.92–0.98) per 80 g serving/day, with no heterogeneity.282
283 285-287 292 296 297 300
Two studies did not adjust for smoking,1 of which showed a non-significant lower vegetable intake
in cases than in controls,295 and the other reported no effecton risk.298
Pooled analysis from 8 cohort studies (over 430 000 participants, followed up for 6 to 16 years, more than 3200 lungcancer cases) showed a non-significant reduced risk whencomparing high against low intake groups (0.88, 95% CI
0.78–1.00), with a p value for trend of 0.12.336
Out of 27 case-control studies, 17 showed reduced risk
with higher levels of vegetable consumption,301-304 306-312 314
316 317 319 322 325-331
which was statistically significant in 8303
304 306 308-310 314 316 319 325-328; 7 studies showed non-significant
increased risk305 313 315 318 320 323 324 and 1 study showed noeffect on risk.321 Meta-analysis was possible on 10 studies,
all of which adjusted for smoking, giving a summary effectestimate of 0.67 (95% CI 0.53–0.86) per serving/day, withhigh heterogeneity.303 308 309 313 316 317 323 325 326 328 329 Threestudies did not adjust for smoking, all of which showedstatistically significant decreased risk.306 316 319
A dose-response relationship was apparent from bothcohort and case-control data.
Most of the ecological studies are suggestive of an association between increased vegetable consumption anddecreased risk.
Non-starchy vegetables

All three cohort studies reported non-significant reduced risk
when comparing highest and lowest vegetable intakes, witheffect estimates of 0.9 (lung cancer mortality, 95% CI
0.61–1.33),337 0.75 (95% CI 0.41–1.37),338 and 0.54 (p value
for trend 0.2, squamous and small-cell carcinomas only)
when comparing the highest with the lowest intake
groups.339 The single case-control study reported a nonsignificant increased risk when comparing high and low
vegetable intakes.321

C H A P T E R

4•F O O D S

A N D

D R I N K S

Green, leafy vegetables

Colorectum

All five cohort studies reported reduced risk when comparing high to low intake groups,285 292 299 340 341 which was statistically significant in one.299 Dose-response meta-analysis
was possible on three cohort studies, giving a summary effectestimate of 0.91 (95% CI 0.89–0.93) per serving/day, withno heterogeneity.285 340 The two non-included studies reported high-versus-low effect estimates of 0.89 (95% CI
0.66–1.19)292 and 0.45 (95% CI 0.26–0.78).299 All fivecohort studies adjusted for smoking.
Of the 17 case-control studies, 12 reported decreased risk65
301 307 320 321 326 330 342 343 345-348(reaching statistical significancein 2343 345 348 and 5 reported non-significant increased risk.312
322 344 349 350
Dose-response meta-analysis was possible on 8
case-control studies, giving a summary effect estimate of
0.96 (95% CI 0.91–1.02) per serving/day, with moderateto-high heterogeneity.65 322 326 343 346-349 Some of this heterogeneity may be due to variation in exposure classification,with some studies listing ‘green vegetables’ being includedin this category.

Seventeen cohort studies81 359-379 and 71 case-control
studies investigated non-starchy vegetables and colorectal
cancer.
Of 20 effect estimates from 17 cohort studies that reported comparisons of the highest and lowest intake groups, 11were in the direction of reduced risk,81 362 364 366 371-374 376-378
3 of which were statistically significant.81 366 371 377 One study
showed non-significant decreased risk in women and nonsignificant increased risk in men.360 The other 8 reported
non-significant increased risk.359 361 363 365 367-370 375 One study
stated that there was no significant association.379 Metaanalysis was possible on 9 independent estimates from 6
studies, giving a summary effect estimate of 1.00 (95% CI
0.90–1.11) per 2 servings/day increment, with moderate tohigh heterogeneity.360 362-364 366 370
Because of the abundant prospective data from cohort
studies, case-control studies were not summarised.
The general mechanisms through which vegetables could
plausibly protect against colorectal cancer are outlined
below.

Total non-starchy root vegetables and tubers

Both cohort studies reported reduced risk with increased consumption,289 291 with effect estimates of 0.56 (95% CI
0.36–0.88)289 when comparing the highest with the lowest
intake groups, and 0.70 (95% CI 0.53–0.93) when comparing the third highest quartile with the lowest (the highest
intake group had a non-significant decreased risk).291 Bothstudies adjusted for smoking.
Carrots

All six cohort studies reported reduced risk,285 289 293 299 339 341
which was statistically significant in one (0.4, p value fortrend 0.003).341 The other, non-significant, risk estimates
ranged from 0.61 to 0.82.285 289 293 299 339
Twenty of the 21 case-control studies showed decreased
risk when comparing high against low intake groups,65 261 304
307 313 321 322 325-327 342 344 346-348 351-358
which was statisticallysignificant in 8.261 304 321 325 327 346 347 351 353 356-358 One study
reported no effect.320 Meta-analysis on studies that adjusted
for smoking was possible on 11 studies, giving a summary
effect estimate of 0.81 (95% CI 0.73–0.89), per serving/day
increment, with high heterogeneity.65 307 313 322 325-327 347 348 351
352 354-357

There was some evidence of publication bias for bothcohort and case-control studies.
The single ecological study reported lower mean intake ofcarrots in an area of high lung cancer risk.333
The general mechanisms through which vegetables could
plausibly protect against lung cancer are outlined below.
A substantial amount of evidence is available but somestudies were not adjusted for smoking. A doseresponse relationship is apparent from both cohort andcase-control studies. There is limited evidence
suggesting that non-starchy vegetables protect against
lung cancer.

A substantial amount of evidence is available but it isinconsistent. There is limited evidence suggesting that
non-starchy vegetables protect against colorectal
cancer.

The Panel is aware that since the conclusion of the SLR, threecase-control studies78 261 380 have been published. This new
information does not change the Panel judgement (see box
3.8).
Ovary

Five cohort studies,381-385 eight case-control studies,89 386-392
and two ecological studies393 394 investigated non-starchy
vegetables, and three cohort studies381-383 and two casecontrol studies395 396 investigated green, leafy vegetables.
Non-starchy vegetables

All of the cohort studies reported decreased risk withincreased vegetable consumption.381-385 Meta-analysis was
possible on four cohort studies, giving a summary effect estimate of 0.64 (95% CI 0.33–0.97) for an increase of one serving/day, with no heterogeneity.381 383-385 The study that could
not be included reported an effect estimate of 0.76 (95% CI
0.42–1.37) for the highest intake group when compared withthe lowest.382
Pooled analysis from 12 cohort studies (over 560 000 participants, followed up for 7 to 22 years, more than 2100 lungcancer cases) showed a non-significant reduced risk whencomparing high against low intake groups (0.90, 95% CI
0.78–1.04), with a p value for trend of 0.06.397
All of the case-control studies reported reduced risk,89386-392
which was statistically significant in five.89 386 387 391 392
One ecological study reported a non-significant positive
regression/correlation between continents393 and theother reported a negative regression/correlation between
countries.394

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Green, leafy vegetables

All three cohort studies reported decreased risk withincreased green, leafy vegetable consumption.381-383 Metaanalysis was possible on two cohort studies, giving a summary effect estimate of 0.96 (95% CI 0.88–1.03) per two
servings/day, with no heterogeneity.381 383 The third cohort
study reported a statistically significant reduced risk (0.44,
95% CI 0.25–0.79) when comparing the highest and lowest
intake groups.382
Both case-control studies reported reduced risk fromincreased consumption of green, leafy vegetables,395 396 oneof which was statistically significant.396
The general mechanisms through which vegetables could
plausibly protect against ovarian cancer are outlined below.
Evidence from cohort and case-control studies issparse. There is limited evidence suggesting that nonstarchy vegetables protect against ovarian cancer.

The Panel is aware that since the conclusion of the SLR one
case-control study78 has been published. This new information
does not change the Panel judgement (see box 3.8).
Endometrium

Ten case-control studies investigated non-starchy vegetableconsumption.398-407 Seven case-control studies investigatedcruciferous vegetables and endometrial cancer.398-400 405 407-410
Of the 10 studies that reported on non-starchy vegetables,
7 showed decreased risk when comparing the highest withthe lowest intake groups,400-405 407 which was statistically significant in 5.400 402-404 407 Two reported a non-significant
increased risk398 406 and the other showed no effect on risk.399
Meta-analysis was possible on 8 studies, giving a summary
estimate of 0.90 (95% CI 0.86–0.95) per 100 g of vegetableintake/day, with low heterogeneity.399 401-407 A dose-response
relationship was apparent from these data.
Five out of the seven case-control studies that investigated cruciferous vegetables reported reduced risk when comparing high to low intake groups,399 405 407-410 which wasstatistically significant in one.405 The other two studies
reported non-significant increased risk.398 400 Meta-analysis
was possible on five studies, giving a summary effect estimate of 0.79 (95% CI 0.69–0.90) per 100 g/day, with no heterogeneity.399 405 407 409 410 The two studies that could not be
included suggested increased risk, though not statisticallysignificant.398 400
A dose-response relationship is apparent from case-control
data.
The general mechanisms through which vegetables could
plausibly protect against endometrial cancer are outlined
below. Cruciferous vegetables contain glucosinolates. Certainhydrolysis products of glucosinolates, including indoles andisothiocyanates, have shown anti-carcinogenic properties inlaboratory experiments and in diets in live experiments inanimals.411 The human genotype of glutathione S-transferase
has been shown to have a significant role in the metabolismof these phytochemicals and may therefore influence potential anti-cancer properties.412

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Evidence comes from case-control studies only.
There is limited evidence suggesting that non-starchy
vegetables protect against endometrial cancer.
General mechanisms — non-starchy vegetables

Also see Chapter 2. Non-starchy vegetables provide a plethora of potentially cancer-preventive substances, including several antioxidant nutrients (such as carotenoids and vitaminC), dietary fibre, as well as phytochemicals (such as glucosinolates, dithiolthiones, indoles, chlorophyll, flavonoids,
allylsulphides, and phytoestrogens). Phytochemicals might
influence cancer risk through their antioxidant activities,
modulation of detoxification enzymes, stimulation of theimmune system, antiproliferative activities, and/or modulation of steroid hormone concentration and hormone metabolism, to name a few possible mechanisms. Non-starchy
vegetables are also a source of folate, which plays an important role in synthesis and methylation of DNA. Abnormal
DNA methylation has been linked to aberrant gene expression and also to cancers at several sites, and may be particularly important in rapidly dividing tissues. It is difficult tounravel the relative importance of each constituent and likely that a protective effect may result from a combination of
influences on several pathways involved in carcinogenesis.
Carrots are a source of carotenoids, particularly alphacarotene and beta-carotene, as well as other vitamins andphytochemicals with potentially protective effects. Tomatoes
are a source of vitamin C and carotenoids, particularly
lycopene. Potential mechanisms of inhibition include theantioxidant properties of carotenoids and ligand-dependent
signalling through retinoid receptors (see chapter 4.2.5.3).
There is a complex mixture of phytochemicals present inwhole vegetables and these may have additive and synergistic effects responsible for anti-cancer activities.
4.2.5.1.1 Allium vegetables
StomachTwo cohort studies,413 414 27 case-control studies,109 129 152 162
and
2 ecological studies202 208 investigated allium vegetables andstomach cancer; 1 cohort study,413 16 case-control studies,109
129 182 184 195 232 246 247 251 262 418 420-422
and 2 ecological studies203
208
investigated garlic and stomach cancer. There was also 1
relevant intervention study that combined allitridium andselenium supplements.423 424

164 171 178 182 185 187 191 194 195 232 243-245 247 248 251 266 270 415-419

Allium vegetables

Both cohort studies reported decreased risk,413 414 which wasstatistically significant in one.413 Meta-analysis was possible
on both, giving a summary effect estimate of 0.55 (95% CI
0.35–0.87) per 100 g/day, with no heterogeneity (figure
4.2.14).413 414
Twenty of the case-control studies showed reduced risk
when comparing high with low intake groups,129 152 162 164 171
178 182 185 187 191 194 195 232 243 247 248 270 416 418 419
which was statistically significant in 12.129 152 162 164 182 187 194 243 248 270 416 418
Four studies showed increased risk,109 245 266 415 which was statistically significant in 2,245 and the remaining 3 reported nosignificant effect on risk.244 251 417 Meta-analysis was possible

C H A P T E R

4

Figure 4.2.14•

F O O D S

A N D

D R I N K S

Allium vegetables and stomach cancer;
cohort and case-control studies
Relative risk (95% CI)

CohortDorant 1996

0.55 (0.35–0.88)

Gonzalez 2006

0.31 (0.01–11.69)

Summary estimate

0.55 (0.35–0.87)

Case control
Haenszel 1972

0.49 (0.33–0.72)

Trichopoulos 1985

0.23 (0.16–0.35)

You 1988

0.32 (0.17–0.59)

Buiatti 1989

0.85 (0.72–1.00)

Hansson 1993

0.79 (0.47–1.34)

Ji 1998 Men

0.66 (0.43–1.02)

Ji 1998 Women

0.69 (0.38–1.24)

Gao 1999

0.00 (0.00–0.02)

De Stefani 2001

0.29 (0.11–0.81)

Munoz 2001

0.70 (0.61–0.80)

Takezaki 2001

1.45 (0.74–2.82)

Sipetic 2003

0.40 (0.20–0.80)

Lissowka 2004

0.86 (0.67–1.10)

Nan 2005

0.49 (0.28–0.84)

Zickute 2005

0.91 (0.71–1.16)

Summary estimate

0.59 (0.47–0.74)

0.5 1 2
Relative risk, per 100 g/day

on 14 studies, giving a summary effect estimate of 0.59 (95%
CI 0.47–0.74) per 100 g/day, with high heterogeneity(figure 4.2.14).109 129 152 162 171 178 182 187 191 194 232 247 270 416
Both ecological studies reported statistically significant
decreased risk with increased consumption.202 208
A statistically significant dose-response relationship isapparent from cohort and case-control data.
GarlicThe single cohort study, which was specific to supplementary garlic, showed a non-significant increased risk whencomparing garlic supplement use versus no supplement use(1.29, 95% CI 0.62–2.67).413
Fifteen of the case-control studies showed decreased risk
when comparing highest to lowest intake groups,109 129 182 184
195 232 246 247 251 418 420-422
which was statistically significant inseven.129 182 232 246 247 418 420 422 One study showed a nonsignificant increased risk.262 Meta-analysis was possible onfive studies, giving a summary effect estimate of 0.41
(95% CI 0.23–0.73) per serving/day.109 129 182 232 421
One ecological study showed statistically significant
decreased risk with increased intake208; the other showed nosignificant association.203

was a combined selenium/allitridium supplement.423 424 The
5-year follow-up suggested that the intervention was
effective in reducing stomach cancer incidence in men (0.36,
95% CI 0.14–0.92) but not in women (1.14, 95% CI
0.22–5.76).423 The statistically significant protective effectfor men had dissipated at the 10-year follow-up.424 (Also see
chapter 4.2.5.8.)
Allium vegetables are high in flavonols and organosulphur
compounds. They also, particularly garlic, have antibiotic
properties. Although this may act directly against H pylori(a known cause of stomach cancers), a study in humans has
not shown this effect.425 It is also possible that antibacterial effects of garlic might inhibit the secondary colonisationof the stomach after H pylori-induced atrophy. At present,
there is no evidence to support or refute this mechanism. An
animal study provides evidence that dietary garlic can reduce
the severity of H pylori-associated gastritis.426
The evidence, though not copious and mostly fromcase-control studies, is consistent, with a doseresponse relationship. There is evidence for plausible
mechanisms. Allium vegetables probably protect
against stomach cancer.
Colorectum
GarlicTwo cohort studies361 362 and six case-control studies427-435
investigated garlic consumption.
Both cohort studies reported non-significant decreased risk
when comparing the highest with the lowest intake groups,
with effect estimates of 0.77 (95% CI 0.51–1.16)361 and 0.68
(95% CI 0.46–1.01) (figure 4.2.15).362
All six case-control studies showed decreased risk for thehighest consumers of garlic,427-435 which was statistically significant in three (figure 4.2.16).431 432
There is considerable preclinical evidence with model carcinogens and transplantable tumours that supports an anticancer effect of garlic and some of its allyl sulphur
components. Animal studies demonstrate that allyl sulphides
effectively inhibit colon tumour formation and also caninhibit cell growth in the laboratory.436-439

Figure 4.2.15

Garlic and colon cancer; cohort studies
Relative risk (95% CI)

Giovannucci 1994 Men

0.77 (0.51–1.16)

Steinmetz 1994 Women

0.68 (0.46–1.01)

0.2

Intervention study

The double-blind, randomised trial had an intervention duration of 3 years, and a 5- and 10-year follow-up, and morethan 5000 participants, all of whom had been identified as
being at increased risk of stomach cancer. The intervention

0.5

1

2

5

Relative risk, highest vs lowest exposure category93

P A R T

Figure 4.2.16

Garlic consumption and colorectal cancer;
case-control studies
Relative risk (95% CI)

Huetal 1991

0.21 (0.04–0.98)

Le Marchand 1997 Men

0.80 (0.54–1.19)

Le Marchand 1997 Women

0.90 (0.59–1.37)

Franceschi 1998

0.90 (0.80–1.01)

Levi 1999

0.39 (0.21–0.71)

Kamel 2002

0.83 (0.44–1.55)

0.2

0.5

1

2

5

Relative risk, highest vs lowest exposure category

The evidence, though not copious and mostly fromcase-control studies, is consistent, with a doseresponse relationship. There is evidence for plausible
mechanisms. Garlic probably protects against
colorectal cancer.

The Panel is aware that since the conclusion of the SLR, one
case-control study78 has been published. This new information
does not change the Panel judgement (see box 3.8).
In addition to this judgement, data on garlic havecontributed to the evidence base for allium vegetables andstomach cancer (also see chapter 7.5).
4.2.5.1.2 Carrots
CervixFive case-control studies440-444 and one ecological study445
investigated carrots and cervical cancer.
Case-control studies were consistent in showing reduced
risk for the highest levels of consumption, which was statistically significant in three.440-442 All studies used hospitalbased controls and none adjusted for human papilloma virus
status. The single ecological study showed non-significant
increased risk with high intake of carrots.445
Some carotenoids, including beta-carotene and alphacarotene, which are found at high levels in carrots, are precursors of vitamin A. They also have properties independentof their pro-vitamin A activity. Carotenoids are recognised
antioxidants and low blood levels of dietary antioxidants areassociated with human papilloma virus persistence.446
The evidence, from case-control studies only, is sparse
but consistent. There is limited evidence suggestingthat carrots protect against cervical cancer.

Data on carrots have contributed to the evidence base fornon-starchy vegetables and mouth, pharynx, and larynx cancers (chapter 7.1) and lung cancer (chapter 7.4). Also see
chapter 4.2.5.1.

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4.2.5.2 Fruits
Mouth, pharynx, and larynx

One cohort study,447 35 case-control studies21 22 24-26 28 30-33 35
and 2 ecological studies52 68
investigated fruits and mouth, pharynx, and larynx cancers;
and 1 cohort study,66 23 case-control studies23 26-29 31 33 34 3739 41-43 45-47 50 63 65 75 451 452
and 1 ecological study52 investigatedcitrus fruits. In addition, 1 cohort study54 and 6 case-control
studies33 39 45 55-57investigated non-starchy vegetables andfruits in combination (also see evidence on non-starchy
vegetables, chapter 4.2.5.1).
36 39-50 59-61 63 64 67 69 72 74 448-450

General fruits

The single cohort study, which adjusted for smoking,showed a non-significant decreased risk for the highest whencompared to the lowest intake groups, with an effect estimate of 0.82 (95% CI 0.64–1.04) (figure 4.2.17).447
Most (32) of the case-control studies reported decreased
risk associated with higher intake of fruits,24-26 28 30-33 35 36 3948 50 59-61 63 64 69 72 74 448 450
which was statistically significant
in 17.26 31 32 35 39-43 46-48 50 63 64 69 72 448 No study reported statistically significant increased risk. Meta-analysis was possible on 7 studies (all of which adjusted for smoking), giving
a summary effect estimate of 0.72 (95% CI 0.59–0.87) per
100 g/day, with high heterogeneity (figure 4.2.17).30 39 42 44
45 69 72
Heterogeneity came from the varying size, not direction, of effect.
One ecological study showed a weak inverse correlation
between fruits and oral cancer.68 The other observed inverse
correlations among women for fruit and both oral and laryngeal cancers and positive correlations among men for thesame two sites.52

Figure 4.2.17

Fruits and mouth, pharynx, and larynx
cancer; cohort and case-control studies
Relative risk (95% CI)

CohortChyou 1995

0.82 (0.64–1.04)

Summary estimate

0.82 (0.64–1.04)

Case control
La Vecchia 1991

0.59 (0.41–0.86)

De Stefani 1994

0.58 (0.30–1.12)

De Stefani 2000

0.66 (0.52–0.85)

Bosetti 2002

0.92 (0.88–0.97)

Marchioni 2003

0.96 (0.86–1.08)

Gaudet 2004

0.90 (0.74–1.10)

Kapil 2005

0.17 (0.10–0.31)

Summary estimate

0.1

0.72 (0.59–0.87)

0.5

0.75

1

Relative risk, per 100 g/day

1.5

C H A P T E R

4•

Figure 4.2.18

F O O D S

A N D

D R I N K S

Citrus fruits and mouth, pharynx, andlarynx cancer; case-control studies

Figure 4.2.20

Citrus fruits and mouth, pharynx, and larynx
cancer; case-control studies: dose response

Relative risk (95% CI)
Franco 1989

0.72 (0.56–0.93)

Zheng 1993

0.45 (0.31–0.66)

Levi 1998

0.88 (0.82–0.95)

De Stefani 2000

0.27 (0.14–0.52)

Bosetti 2002

0.91 (0.85–0.97)

Pisa 2002

0.71 (0.51–0.99)

Gaudet 2004

0.89 (0.73–1.10)

Summary estimate

0.76 (0.66–0.87)

Franco 1989
Zheng 1993
Levi 1998
De Stefani 2000
Bosetti 2002
Pisa 2002
Gaudet 2004

0.5

0.75

1

1.5

2

Relative risk, per 50 g/day

0

100

200

300

Citrus fruits (g/day)Figure 4.2.19

Fruits and mouth, pharynx, and larynx
cancer; case-control studies: dose response

LaVecchia 1991
De Stefani 1994
De Stefani 2000
Bosetti 2002
Marchioni 2003
Gaudet 2004
Kapil 2005

0

200

400

600

800

1000

Fruits (g/day)

Citrus fruits

The single cohort study, which was specific to oranges andwas adjusted for smoking, showed a non-significant
decreased risk for the highest when compared to the lowest
intake groups, with an effect estimate of 0.50 (95% CI
0.30–1.00), with a p value for trend of 0.03.66 This risk estimate was for cancers of the upper aerodigestive tract.
Twenty-two of the case-control studies showed decreased
risk associated with higher intake of fruits,23 27-29 31 33 34 37-39
41-43 45-47 50 63 65 75 451 452
which was statistically significant in
13.23 27-29 31 33 37 39 42 43 47 50 75 The 23rd study showed no effecton risk.26 Meta-analysis was possible on 7 studies (all ofwhich adjusted for smoking), giving a summary effect estimate of 0.76 (95% CI 0.66–0.87) per 50 g/day, with highheterogeneity (figure 4.2.18).23 29 37 39 42 45 65 Heterogeneity

came from the varying size, not direction, of effect.
A dose-response relationship was apparent from casecontrol but not cohort data for both general and citrus fruits(figures 4.2.19 and 4.2.20). There is some suggestion thatthe greatest effect appears to be with the first increment.
That is, some fruit consumption confers a protective effectcompared to none. However, it is not clear that the effectcontinues in a linear fashion with increased doses.
One ecological study found no significant association
between citrus fruit consumption and cancer mortality inmen or women.52
Studies that reported on combined intake of non-starchy
vegetables and fruits showed evidence of an association withdecreased risk (see chapter 4.2.5.1).
The general mechanisms through which fruits could plausibly protect against mouth, pharynx, and larynx cancer are
outlined below.
The evidence, including on fruit subtypes, thoughmostly from case-control studies, is consistent, with adose-response relationship. There is evidence forplausible mechanisms. Fruits probably protect against
mouth, pharynx, and larynx cancers.

The Panel is aware that since the conclusion of the SLR, twocohort studies76 77 and one case-control study79 have been published. This new information does not change the Panel judgement (see box 3.8).
Oesophagus

Four cohort studies,80 82 83 447 36 case-control studies22 40 60
84 86 87 89 94-96 98-100 102 104 108-110 112-115 125-129 134-136 138 453-456
and7 ecological studies52 68 116 118 119 234 457 458 investigated fruits
and oesophageal cancer; 1 cohort study,66 16 case-control

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Figure 4.2.21

Fruits and oesophageal cancer; cohortand case-control studies

2

Figure 4.2.22•

E V I D E N C E

A N D

J U D G E M E N T S

Fruits and oesophageal cancer;
case-control studies
Relative risk (95% CI)

Relative risk (95% CI)
Jun-lao 1989

CohortYu 19930.99 (0.85–1.15)

Chyou 1995

0.65 (0.39–1.08)

Guo 19990.90 (0.77–1.06)

Tran 2005

0.80 (0.70–0.91)

Case control

1.52 (0.47–4.91)

Hanaoke 1994

0.30 (0.13–0.67)

Castelletto 1994

0.33 (0.13–0.80)

Gao 1999

0.38 (0.01–20.03)

De Stefani 2000

0.53 (0.42–0.67)

Wolfgarten 2001

0.40 (0.27–0.59)

Notani 1987

0.99 (0.63–1.57)

Sharp 2001

0.84 (0.74–0.96)

Victoria 1987

0.66 (0.50–0.88)

De Stefani 2005

0.59 (0.49–0.71)

Nakachi 1988 Women

0.23 (0.12–0.45)

Summary estimate

0.56 (0.42–0.74)

Nakachi 1988 Men

0.31 (0.22–0.44)

Brown 1988

0.50 (0.29–0.87)

Jun-lao 1989

1.00 (0.82–1.22)

De Stefani 1990

0.33 (0.21–0.52)

Negri 1991

0.30 (0.21–0.42)

Tavani 1993

0.40 (0.19–0.85)

Tavani 1994

0.30 (0.11–0.85)

Castelletto 1994

0.70 (0.31–1.57)

Hanaoka 1994

0.50 (0.18–1.39)

Srivastava 1995

3.15 (1.29–7.72)

Gimeno 1995

0.55 (0.33–0.94)

Zhang 1997

0.40 (0.16–0.98)

De Stefani 1999

0.30 (0.17–0.52)

Wang 1999

0.51 (0.27–0.98)

Gao 1999

0.75 (0.36–1.56)

Cheng 2000

0.08 (0.01–0.56)

Nayar 2000

0.96 (0.45–2.05)

De Stefani 2000

0.18 (0.09–0.37)

Takezaki 2000

0.70 (0.52–0.94)

Phukan 2001

0.30 (0.04–2.17)

Terry 2001

0.60 (0.36–0.99)

Wolfgarten 2001

0.32 (0.12–0.89)

Takezaki 2001

0.91 (0.48–1.73)

Sharp 2001

0.64 (0.25–1.65)

Zhang 2001

0.64 (0.42–0.97)

Onuk 2002

7.10 (3.21–15.73)

Lik 2003

0.08 (0.06–0.11)

Hung 2004

0.60 (0.40–0.90)

Yang 2005

0.42 (0.19–0.91)

De Stefani

0.21 (0.10–0.44)

0.2

0.5

1

2

5

0.2

0.5

0.75

1

1.5

Relative risk, per 100 g/day

Figure 4.2.23

Citrus fruits and oesophageal cancer;
cohort and case-control studies
Relative risk (95% CI)

CohortKjaerheim 1998

0.50 (0.27–0.91)

Case control
Brown 1988

0.50 (0.29–0.87)

Cheng 1992

0.10 (0.04–0.26)

Castelletto 1994

1.60 (0.81–3.15)

Cheng 1995 Non-smokers

0.39 (0.16–0.97)

Cheng 1995 Never drinkers

0.59 (0.23–1.52)

Zhang 1997

0.70 (0.29–1.71)

Launoy 1998

0.54 (0.33–0.89)

Levi 2000

0.22 (0.09–0.54)

Bosetti 2000

0.42 (0.25–0.71)

Terry 2000

0.90 (0.50–1.61)

Chen 2002

0.48 (0.21–1.10)

De Stefani 2005

0.28 (0.15–0.54)

Relative risk, highest vs lowest exposure category
0.2

0.5

1

2

5

Relative risk, highest vs lowest exposure category

studies,33 85 86 88 90 97 105 111 113 124 125 128 130 132 133 136 459 and 1
ecological study52 investigated citrus fruits.
General fruits

All of the cohort studies reported reduced risk with higher
intakes of fruit,80 82 83 447 which was statistically significant
in two.83 447 One study reported a statistically significant
dose-response relationship, with a risk estimate of 0.68
(95% CI 0.53–0.88) per 100 g/day after adjustment forsmoking.447 The other three reported risks for the highest
intake groups relative to the lowest, with risk estimates of
0.8 (95% CI 0.7–0.9; not adjusted for smoking),83 0.9 (95%96

CI 0.8–1.1; adjusted for smoking),80 and 0.99 (95% CI
0.85–1.15; not adjusted for smoking).82
Thirty-two of the case-control studies reported reduced
risk for the highest intake groups when compared to the lowest (figure 4.2.21),22 40 60 84 86 87 89 95 96 98 99 102 104 108-110 113-115
125-129 134-136 138 453-456
which was statistically significant in
24.40 60 84 86 87 89 95 96 102 104 110 113-115 127 134-136 138 454-456 One
study reported statistically significant increased risk,100 one
reported no effect on risk,112 and one reported no statisticallysignificant association.94 Meta-analysis was possible on eightstudies, giving a summary effect estimate of 0.56 (95% CI
0.42–0.74) per 100 g/day, with high heterogeneity (figure

C H A P T E R

4

Figure 4.2.24•

F O O D S

A N D

D R I N K S

Citrus fruits and oesophageal cancer;
case-control studies
Relative risk (95% CI)

Cheng 1992

0.46 (0.39–0.55)

Castelletto 1994

1.22 (0.79–1.89)

Cheng 1995 Never drinkers

0.65 (0.48–0.89)

Cheng 1995 Non-smokers

0.57 (0.43–0.75)

Levi 2000

0.75 (0.67–0.84)

Terry 2000

0.97 (0.84–1.13)

De Stefani 2005

0.62 (0.49–0.78)

Summary estimate

0.70 (0.56–0.88)

0.2

0.5

0.75

1

1.5

2

Relative risk, per 50 g/day

4.2.22). Heterogeneity may be partially explained by differential adjustment for confounders between studies.
All seven ecological studies reported reduced risk withincreased intake,52 68 116 118 119 234 457 458 which was statisticallysignificant in one.68 458
Citrus fruits

The single cohort study, which was specific to oranges andwas adjusted for smoking, showed a non-significant
decreased risk for the highest when compared to the lowest
intake groups, with an effect estimate of 0.50 (95% CI
0.30–1.00), with a p value for trend of 0.03.66 This risk estimate was for cancers of the upper aerodigestive tract; 22 outof 71 cases were oesophageal cancers.
Fifteen of the case-control studies reported decreased risk
for the highest intake groups when compared to the lowest,33
85 86 88 90 97 105 111 113 124 125 130 132 133 136 459
which was statistically significant in 10 (figure 4.2.23).33 85 86 88 97 105 113 132 133
136 459
The other study reported a non-significant increased
risk.128 Meta-analysis was possible on six studies, giving asummary effect estimate of 0.70 (95% CI 0.56–0.88) per
50 g/day, with high heterogeneity (figure 4.2.24).33 97 128 130
132 133
Four of these studies adjusted for smoking.33 97 128 132
133
Heterogeneity may be partially explained by differential
adjustment for confounders between studies.
The single ecological study reported a non-significant
increased risk.52
The general mechanisms through which fruits could plausibly protect against cancer are outlined below.
The evidence, including on fruit subtypes, thoughmostly from case-control studies, is consistent, with adose-response relationship. There is evidence forplausible mechanisms. Fruits probably protect against
oesophageal cancer.

published. This new information does not change the Panel
judgement (see box 3.8).
Lung

Twenty-five cohort studies,214 216 282-300 337 339 360 461-467 32
case-control studies,261 303-306 308-318 320-322 324 326-328 330 331 343 346
349 350 352 355 357 358 468-472
and 7 ecological studies52 116 332-334
473 474
investigated fruits and lung cancer.
Twenty of the cohort studies showed decreased risk for thehighest intake groups when compared to the lowest,214 216 282289 291-294 296 297 299 300 337 461-467
which was statistically significant in four.216 289 292 300 461 464 Four studies showednon-significant increased risk290 295 339 360 and the other reported no statistically significant association.298 Meta-analysis was
possible on 14 cohort studies, giving a summary effect estimate of 0.94 (95% CI 0.90–0.97) per 80 g serving/day, withlow heterogeneity (figure 4.2.25). All but one of these studies adjusted for smoking.462
Pooled analysis from 8 cohort studies (over 430 000 participants, followed up for 6 to 16 years, more than 3200 lung

Figure 4.2.25

Fruits and lung cancer; cohort andcase-control studies
Relative risk (95% CI)

Cohort
Alavanja 2004 (pesticide applicators)

0.89 (0.59–1.35)

Alavanja 2004 (applicator spouses)

0.65 (0.28–1.51)

Breslow 2000

0.92 (0.71–1.18)

Feskanich 2000 (HPFS) Men

1.05 (0.94–1.17)

Feskanich 2000 (NHS) Women

0.94 (0.87–1.02)

Fraser 1991

0.47 (0.32–0.69)

Fu 1997

0.94 (0.67–1.32)

Holick 2002

0.94 (0.89–1.00)

Jansen 2004

0.84 (0.65–1.09)

Miller 2002

0.96 (0.86–1.07)

Olson 2002

0.91 (0.86–0.96)

Shibata 1992

0.99 (0.87–1.14)

Skuladottir 2004

0.95 (0.86–1.05)

Takezaki 2003

0.63 (0.24–1.63)

Vorrips 2000

0.92 (0.86–0.98)

Summary estimate

0.94 (0.90–0.97)

Case control
Axelsson 1996

0.77 (0.46–1.28)

Brennan 2000

1.08 (0.52–2.28)

De Stefani 2002

0.84 (0.66–1.06)

Gao 1993

0.45 (0.30–0.67)

Hu 2002

1.04 (0.85–1.27)

Ko 1997

1.00 (0.54–1.84)

Kreuzer 2002

0.79 (0.45–1.39)

Lagiou 2004

0.79 (0.60–1.04)

Pawlega 1997

0.01 (0.00–0.24)

Rachtan 2002

0.49 (0.32–0.75)

Raunoi-Ravina 2002

1.19 (0.74–1.91)

De Stefani 1999

0.67 (0.54–0.82)

Suzuki 1994

1.33 (0.56–3.18)

Swanson 1997

0.91 (0.76–1.09)

Summary estimate

0.80 (0.68–0.94)

0.05

1

2

Relative risk, per serving/day

The Panel is aware that since the conclusion of the SLR, onecohort study140 and two case-control studies143 460 have been97

P A R T

Figure 4.2.26

2•

E V I D E N C E

A N D

J U D G E M E N T S

Of the seven ecological studies, four reported nonsignificant decreased risk in areas of higher fruit consumption,52 332 473 474 one reported no consistent association,334 andtwo reported non-significant increased risk.116 333
The general mechanisms through which fruits could plausibly protect against cancer are outlined below. In addition,
flavonoids found in fruit directly inhibit expression of
CYP1A1 (a cytochrome P450 enzyme that helps tometabolise toxins), resulting in decreased DNA damage.475
Elevated CYP1A1 activity has been associated with increased
risk of lung cancer, primarily in smokers.476 The protective
association of flavonoids is associated with specific CYP1A1
genotypes, which supports the importance of flavonoids andpotentially explains heterogeneous results.476 477

Fruits and lung cancer; cohort andcase-control studies; dose response

CohortVoorrips 2000
Takezaki 2003
Skuladottir 2004
Oslon 2002
Miller 2002
Jansen 2004
Holick 2002
Fu 1997
Fraser 1991
Feskanich 2000 (NHS)
WomenFeskanich 2000 (HPFS)Men

The evidence is ample and consistent. A dose-response
relationship is apparent from both cohort and casecontrol studies and there is evidence for plausible
mechanisms operating in humans. The evidence thatfruits protect against lung cancer is convincing.

Breslow 2000
Alavanja 2004
(Pesticide applicators)
Alavanja 2004
(Applicator spouses)
Case control

The Panel is aware that since the conclusion of the SLR, one
case-control study478 has been published. This new information
does not change the Panel judgement (see box 3.8).

Swanson 1997
Suzuki 1994
Stefani 1999
Ruano-Ravina 2002
Rachtan 2002

StomachPawlega 1997
Lagiou 2004

Sixteen cohort studies,71 80 144-147 149 150 213-217 252-254 414 51
case-control studies,89 109 129 151 154 156 158-163 167-169 174-176 178-180

Kreuzer 2002

182 184-187 189-191 193 195 219 221 222 224-227 229 230 246 255-258 260 261 264

Ko 1997

270 479-482

cancer cases) showed a statistically significant reduced risk forthe highest intake group when compared to the lowest (0.77,
95% CI 0.67–0.87), with a p value for trend of < 0.001.336
Twenty-one case-control studies showed decreased risk forthe highest intake groups when compared to the lowest,261

and 23 ecological studies52 116 118 119 197 198 200-202 204investigated fruits.
Ten cohort studies reported decreased risk for the highest
intake groups when compared to the lowest,71 80 144 146 150 214217 253 254
which was statistically significant in one,253 and in
women only in a second study.216 Six studies showed
increased risk,145 147 149 213 214 252 414 which was statistically significant in one.213 Meta-analysis was possible on eight studies, giving a summary effect estimate of 0.95 (95% CI
0.89–1.02) per 100 g/day, with low heterogeneity (figure
4.2.27).
One of the cohort studies considered in the meta-analysis
above (EPIC, more than 521 000 participants in over 10
European countries) reported results stratified by H pylori
status. The effect estimate for the H pylori-negative group
was 0.72 (95% CI 0.39–1.33) and 0.98 (95% CI 0.81–1.2)
for the positive group.140
Forty case-control studies showed decreased risk for thehighest intake groups when compared to the lowest,89 109 151

303 305 306 308 309 311 312 315 317 318 320-322 324 327 328 331 343 346 349 350

156 158-160 162 163 167-169 174 176 178-180 184 186 187 189-191 195 219 221 222

Hu 2002209 234 236-240 483-485

Gao 1993
De Stefani 2002
Brennan 2000
Axelsson 1996

0

1

2

3

4

5

Fruits (servings/day)

355 357 358 468 469 472

261

which was statistically significant in 7.
Three studies reported no effecton risk310 316 330 352 and 8 showed increased risk,304 313 314 326
470 471
which was statistically significant in 3.304 326 470 Metaanalysis was possible on 14 case-control studies, giving asummary effect estimate of 0.80 (95% CI 0.68–0.94) per
serving/day, with moderate heterogeneity (figures 4.2.25
and 4.2.26). All but 2 of these studies adjusted for smoking,and exclusion of these 2 studies did not significantly alter
the meta-analysis.316 352
309 311 324 327 343 346 357 358 468 472

98

225 226 229 230 246 256-258 260 261 264 270 479-481

which was statistically significant in 25.89 109 151 158-160 162 163 167-169 174 176 178 186 187
190 191 221 222 226 229 246 256 261 264 479 481
Seven showed increased
risk,129 161 182 185 193 224 482 which was statistically significant
in two.182 193 One study showed non-significant increased risk
in men and non-significant decreased risk in women.227 Twostudies showed no effect on risk154 255 and the remaining one
reported that there was no significant association.175 Metaanalysis was possible on 26 studies, giving a summary effectestimate of 0.67 (95% CI 0.59–0.76) per 100 g/day, with

C H A P T E R

4•

Figure 4.2.27

F O O D S

A N D

D R I N K S

Fruits and stomach cancer; cohort andcase-control studies
Relative risk (95% CI)

CohortChyou 1990

0.95 (0.84–1.07)

Botterweck 1998

0.92 (0.83–1.02)

Galanis 1998

0.68 (0.51–0.92)

Fujino 2002 Men

1.01 (0.90–1.13)

Fujino 2002 Women

1.12 (0.85–1.49)

Kobayashi 2002

0.75 (0.55–1.00)

Ngoan 2002

0.94 (0.28–1.19)

Khan 2004 Men

1.14 (0.28–4.70)

Gonzalez 2006

1.04 (0.91–1.19)

Summary estimate

0.95 (0.89–1.02)

Case control
Jedrychowski 1981

0.71 (0.53–0.95)

Jedrychowski 1986

0.98 (0.66–1.47)

You 1988

0.61 (0.48–0.79)

Burr 1989 Men

0.53 (0.32–0.89)

Burr 1989 Women

0.39 (0.15–0.97)

Coggon 1989

0.48 (0.07–3.45)

De Stefani 1990

0.42 (0.30–0.61)

Kato 1990 Men

0.89 (0.65–1.22)

Kato 1990 Women

0.85 (0.49–1.50)

Lee 1990

1.05 (0.79–1.39)

Wu-Williams 1990 Men

0.64 (0.37–1.11)

Hoshiyama 1992

0.54 (0.41–0.70)

Memik 1992

0.57 (0.36–0.90)

Cornee 1995

0.75 (0.67–0.99)

De Stefani 1998

0.49 (0.42–0.58)

Ji 1998 Men

0.49 (0.37–0.80)

Ji 1998 Women

0.55 (0.37–0.80)

Gao 1999

5.46 (0.36–17.98)

Huang 1999

0.93 (0.80–1.08)

Ward 1999

0.90 (0.55–1.47)

Mathew 2000

0.90 (0.55–1.47)

De Stefani 2001

0.65 (0.53–0.79)

Takezaki 2001

0.60 (0.37–0.97)

Nishimoto 2002

0.74 (0.62–1.06)

Lee 2003

0.36 (0.18–0.73)

Sipetic 2003

0.17 (0.07–0.32)

Suh 2003

0.80 (0.69–0.92)

Lissowska 2004

0.65 (0.47–0.91)

Boccia 2995

2.06 (1.10–3.84)

Summary estimate

0.67 (0.59–0.76)

0.5 1

2

Relative risk, per 100 g/day

showed non-significant increased risk in white men andJapanese men and women, and non-significant decreased
risk in white women.483
The stomach is a particularly unusual chemical environment and it is possible that, in addition to the general mechanisms described below, specific mechanisms apply, forinstance, in relation to nitrosamine formation.486 It is also
plausible that bioactive constituents in fruit would protect
against H pylori-induced damage, particularly inflammation,
which is implicated in the development of stomach cancers.
The evidence is ample and more consistent with adose-response relationship for case-control studies
than for cohorts. There is evidence for plausible
mechanisms. Fruits probably protect against stomach
cancer.

The Panel is aware that since the conclusion of the SLR, threecase-control studies487-489have been published. This new information does not change the Panel judgement (see box 3.8).
Nasopharynx

Six case-control studies investigated general fruits andnasopharyngeal cancers274 275 281 490-492; a further five casecontrol studies investigated citrus fruits.273 278-281 Preserved
fruits were excluded from all categories.
Of the six case-control studies that investigated generalfruits, four reported decreased risk for the highest intake
groups when compared to the lowest,275 281 491 492 which wasstatistically significant in two.275 491 The other two studies
reported that there was no significant effect on risk, without further detail.274 490 All five of the case-control studies
that investigated citrus fruits reported decreased risk for thehighest intake groups when compared to the lowest,273 278281
four of which were statistically significant.273 278-280
Preserved fruits were excluded as they introduced substantial heterogeneity.
The general mechanisms through which fruits could plausibly protect against nasopharyngeal cancer are outlined
below. In addition, it is possible that active constituents infruit could act directly on Epstein-Barr virus infection.493
The evidence, from case-control studies only, is sparse.
There is limited evidence suggesting that fruits protect
against nasopharyngeal cancer.

high heterogeneity (figure 4.2.27).
A dose-response relationship is apparent from case-control
but not cohort data. There is statistically significant heterogeneity between study types.
Eighteen ecological studies showed decreased risk withincreased intake of fruits,116 118 197 200 201 204-208 234 237-239 484 485
which was statistically significant in eight.204-208 237 Four studies showed increased risk with increased intake,52 118 119 202
239 240
which was statistically significant in one.240 Two studies showed non-significant decreased risk in women andnon-significant increased risk in men209 236; one study
showed non-significant decreased risk in men and nonsignificant increased risk in women198; and one study

Pancreas

Six cohort studies,214 216 252 494-496 16 case-control studies,219
and 8 ecological studies52 197 485 512-515 investigatedfruits and pancreatic cancer.
All six cohort studies showed decreased risk for the highest intake groups when compared to the lowest,214 216 252 494496
which was statistically significant in one.496 Meta-analysis
was possible on three cohort studies, giving a summary effectestimate of 0.92 (95% CI 0.81–1.04) per 100 g/day, with noheterogeneity.216 494 495
Eleven case-control studies showed decreased risk for thehighest intake groups when compared to the lowest,219 497 498
500 501 503-509 511
which was statistically significant in four,503

497-51199

P A R T

504 508 511

and in men but not women in a fifth study,506 andin women but not men in a sixth.501 One study reported a statistically significant increased risk for men and a statisticallysignificant decreased risk for women.510 No other study
reported statistically significant increased risk. Meta-analysis
was possible on eight case-control studies, giving a summary effect estimate of 0.89 (95% CI 0.82–0.98) per 100 g/day,with high heterogeneity.497 498 502 503 505 506 508 510 Heterogeneity
could be partly explained by proxy reporting, poor study quality, and varying adjustment for known confounders.
A dose-response relationship is apparent from case-control,
but not cohort data.
Ecological studies show no consistent association.52 197 485
512-515

The general mechanisms through which fruits could plausibly protect against pancreatic cancer are outlined below.
The evidence is inconsistent. There is limited evidence
suggesting that fruits protect against pancreatic cancer.

The Panel is aware that since the conclusion of the SLR, onecohort study516 has been published. This new information does
not change the Panel judgement (see box 3.8).

2•

E V I D E N C E

A N D

J U D G E M E N T S

sex, a statistically significant decreased risk was apparent in
women (0.81, 95% CI 0.85–0.98 per serving/day based on
five studies), with low heterogeneity.
Because of the abundant prospective data from cohort
studies, case-control studies were not summarised.
The mechanism for this sex difference is unknown. Thereis speculation the mechanism could be related to the (partly understood) explanation for protective effects observed in
postmenopausal women provided with hormone replacement therapy. Another possibility is that the result could be
artifactual if men are poorer at reporting their diets than
women.
The general mechanisms through which fruits could plausibly protect against colorectal cancer are outlined below.
There is a substantial amount of evidence but it isinconsistent. There is limited evidence suggesting thatfruits protect against colorectal cancer.

The Panel is aware that since the conclusion of the SLR, onecohort530 and five case-control studies 261 380 531-533 have been
published. This new information does not change the Panel
judgement (see box 3.8).

Liver cancer

One cohort study216 517 and five case-control studies89 518-521
investigated fruits and liver cancer.
The single cohort study showed non-significant decreased
risk for the highest intake groups when compared to the lowest (0.98, 95% CI 0.75–1.21).216 517
Four case-control studies showed decreased risk for thehighest intake groups when compared to the lowest,89 518 520
521
which was statistically significant in two.89 518 One study
showed non-significant increased risk.519 Heterogeneity
could be partly explained by poor study quality and varying
adjustment for known confounders.
The general mechanisms through which fruits could plausibly protect against liver cancer are outlined below. In addition, grape extracts and auraptene (from citrus fruit) haveshown protective effects against the development of hepatocellular carcinoma in rats.522-525
The evidence is sparse and inconsistent. There islimited evidence suggesting that fruits protect against
liver cancer.

The Panel is aware that since the conclusion of the SLR, one
case-control study526 has been published. This new information
does not change the Panel judgement (see box 3.8).
Colorectum

Twenty cohort studies214 216 359-372 374-376 378 379 527-529 and 57
case-control studies investigated fruits and colorectal cancer.
Thirteen cohort studies showed decreased risk withincreased intake,214 216 360-364 366 371 374-376 378 which was statistically significant in two.360 364 No studies reported statistically significant increased risk. Meta-analysis was possible
on eight cohort studies, giving a summary effect estimate of
0.97 (95% CI 0.92–1.03) per serving/day, with high heterogeneity.360 362-364 366 370 529 When results were stratified by

100

General mechanisms — fruits

Fruits, in particular citrus fruits, are sources of vitamin C andother antioxidants, such as phenols and flavonoids, as wellas potentially bioactive phytochemicals. Vitamin C traps free
radicals and reactive oxygen molecules, protecting against
oxidation damage. It also regenerates other antioxidant
vitamins such as vitamin E.534 Vitamin C also inhibits
the formation of carcinogens and protects DNA frommutagenic attack.535
Beta-carotene and other carotenoid antioxidants are also
found in fruits. Some fruits contain high levels of flavonoids,
including apples (quercetin) and grapefruit (naringin).
Flavonoids have antioxidant effects and can also inhibit
carcinogen-activating enzymes. Flavonoids can also alter the
metabolism of other dietary agents. For instance, quercetin
directly inhibits expression of CYP1A1 (a cytochrome P450
enzyme that helps to metabolise toxins), resulting indecreased DNA damage.475 The phytochemical antioxidants
contained in fruit could reduce free-radical damage generated by inflammation. A single study reported that apples
given in physiological quantities inhibited carcinogeninduced mammary cancer in rodents in a dose-responsemanner.536
There is a complex mixture of phytochemicals present inwhole vegetables and these may have additive and synergistic effects responsible for anti-cancer activities.
4.2.5.3 Foods containing carotenoids
Mouth, pharynx, and larynx

Two cohort studies537 538 investigated total serum carotenoids
and two case-control studies539 540 investigated total dietary
carotenoids and mouth, pharynx, and larynx cancers.
Ten case-control studies investigated pro-vitamin A carotenoids.26-29 47 48 450 451 541-544 Three cohort studies investigated serum alpha-carotene537 538 545; one cohort study

C H A P T E R

4•F O O D S

A N D

D R I N K S

investigated dietary alpha-carotene71; three cohort studies537
and two case-control studies546 547 investigated serumbeta-carotene; one cohort study71 and seven case-control
studies34 35 67 74 540 548 549 investigated dietary beta-carotene.
One cohort study71 and four case-control studies62 450 540 543
548
investigated dietary lycopene; one cohort study538 andone case-control study547 investigated serum lycopene.
538 545

Total carotenoids

The two cohort studies both showed decreased risk,537 538
one was statistically significant for the highest serum levelsof total carotenoids when compared to the lowest (0.33,
p value for trend 0.05; not adjusted for smoking andalcohol); and 0.22 (95% CI 0.05–0.88; adjusted for smoking and alcohol).537
The two case-control studies showed decreased risk for thehighest intake group when compared to the lowest,539 540
which was statistically significant in men but not women in
one study539 and statistically significant for all in the other.540
Both case-control studies adjusted for smoking.
Pro-vitamin A carotenoids

Nine case-control studies reported decreased risk,26-29 47 48 450
541-544
which was statistically significant for five studies.29 48
541-543
One other study reported decreased risk for men andincreased risk for women but neither was statistically significant.451 All studies adjusted for smoking.
Alpha-carotene

All four cohort studies reported decreased risk for the highest
intake group or serum level compared to the lowest,71 537 538
545
which was statistically significant in three,71 537 545
although one of the latter reported a separate estimate
specific to oral cancers, which suggested a non-significant
increased risk.545 Only one study adjusted for smoking.537
The effect estimates were 0.62 (95% CI 0.41–0.94)
for dietary alpha-carotene,71 and 0.48 (laryngeal cancers,
p value for trend 0.18), 1.26 (oral cancers, p value fortrend 0.54),545 0.20 (95% CI 0.05–0.75; adjusted for smoking),537 and 0.37 (p value for trend 0.06) for serum levels.538
These tended to be based on a relatively small numberof cases.

Lycopene

One cohort study71 and four case-control studies62 450 540 543
investigated dietary lycopene and mouth, larynx, andpharynx cancers; one cohort study538 and one case-control
study547 investigated serum lycopene.
One cohort study reported a non-significant decreased risk
for the highest serum lycopene levels when compared to thelowest (0.61; p value for trend 0.37).538 The other stated that
there was no relationship between dietary lycopene andrisk.71
All four case-controls that investigated dietary lycopene
reported decreased risk for the highest intake groups whencompared to the lowest,62 450 540 543 548 which was statistically significant in two.62 548 The single case-control that investigated serum lycopene reported contrary results, showingthat levels were significantly higher in cases than controls.547
The general mechanisms through which foods containing
carotenoids could plausibly protect against mouth, pharynx,
and larynx cancer are outlined below.
548

There is a considerable amount of evidence, andthough it is for different carotenoid types, it isgenerally consistent, with a dose-response
relationship. There is evidence for plausible
mechanisms. Foods containing carotenoids probably
protect against mouth, pharynx, and larynx cancers.

The Panel is aware that since the conclusion of the SLR, onecohort study76 has been published. This new information does
not change the Panel judgement (see box 3.8).
Lung

Eleven cohort studies,284 286 288 289 298 299 341 550-555 16 case-control studies,306-308 310 311 321 322 327 330 342 344 350 352 556-561 and 1
ecological study333 investigated total dietary carotenoids andlung cancer; 4 cohort studies298 562-566 and 5 case-control
studies567-571 investigated total serum or plasma carotenoids;
7 cohort studies,286 289 293 341 552 566 572 573 8 case-control studies,306 308 320 321 327 350 560 574 and 1 ecological study333 investigated dietary beta-cryptoxanthin; 6 cohort studies563-566
575-577
and 1 case-control study578 investigated serum or
plasma beta-cryptoxanthin.

Beta-carotene

The single cohort study that investigated dietary betacarotene intake reported that there was no significant association, but provided no further details.71 All three cohort
studies that investigated serum levels showed decreased risk
for the highest group when compared to the lowest,537 538 545
which was statistically significant in one.537 The effect estimates were 0.10 (95% CI 0.02–0.46; adjusted for smoking),537 0.42 and 0.88 for oral/oropharyngeal and laryngeal
cancers, respectively (not adjusted for smoking),545 and 0.5(p value for trend 0.17), which was attenuated after adjustment for smoking (0.69).538
Five case-control studies reported decreased risk,34 35 74 540
549
which was significant in two.35 549 One study reported
non-significant increased risk548 and one study reported a significant increased risk.67

Figure 4.2.28

Carotenoids and lung cancer;
cohort studies
Relative risk (95% CI)

Shekelle 1981

0.97 (0.95–0.99)

Wright 2004

0.99 (0.97–1.01)

Summary estimate

0.98 (0.96–0.99)

0.75

1 1.05101

P A R T

Figure 4.2.29

Carotenoids and lung cancer; cohort andcase-control studies
Relative risk (95% CI)

CohortBandera 1997

0.75 (0.61–0.93)

Chow 1992

0.80 (0.52–1.24)

Holick 2002

0.84 (0.72–0.98)

Knekt 1999

0.92 (0.60–1.41)

Michaud 2000 (HPFS) Men

0.64 (0.37–1.12)

Michaud 2000 (NHS) Women

0.69 (0.46–1.03)

Neuhouser 2003

0.90 (0.62–1.32)

Yong 1997

0.74 (0.52–1.06)

Case control
Bond 1987

1.18 (0.73–1.91)

Brennan 2000

0.80 (0.62–1.03)

Candelora 1992

0.30 (0.12–0.73)

Darby 2001

0.74 (0.57–0.97)

Dorgon 1993

0.83 (0.66–3.11)

Fontham 1988

0.88 (0.70–1.11)

Garcia 1995

1.45 (0.68–3.11)

Mohr 1999

0.60 (0.36–1.00)

Nyberg 1998

0.43 (0.20–0.91)

Samet 1985

0.77 (0.54–1.09)

De Stefani 1999

0.43 (0.29–0.64)

Wright 2003

0.61 (0.41–0.91)

0.05

1

2

Relative risk, highest vs lowest exposure category

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0.1–0.7; adjusted for age, sex, smoking habits, alcohol drinking, and cholesterol),563 0.57 (95% CI 0.35–0.93; adjusted
for age, smoking habits, and the intake of other nutrients,
foods, and supplements),298 1.84 (low compared to high; pvalue for trend 0.033; adjusted for age and smoking),562 and0.84 (95% CI 0.48–1.47; adjusted for age and smoking).566
All five of the case-control studies showed decreased
risk of lung cancer for the highest serum or plasma levels
when compared to the lowest567-571; one was statisticallysignificant.568
Dietary beta-cryptoxanthin

All seven cohort studies showed decreased risk withincreased intake of beta-cryptoxanthin,286 289 293 341 552 566 572
573
which was statistically significant in one.293 566 Metaanalysis was possible on two studies, giving a summary effectestimate of 0.98 (95% CI 0.96–1.00) per 10 µg/day, with noheterogeneity.286 572
Pooled analysis from 7 cohort studies (almost 400 000 participants, followed up for 7 to 16 years, more than 3100 lungcancer cases) showed a statistically significant decreased risk
when comparing high against low intake groups (0.76, 95%
CI 0.67–0.89), p value for trend < 0.001.579
Six case-control studies showed increased risk for the highest intake groups when compared to the lowest,306 308 321 327
560 574
which was statistically significant in four.306 308 327 560
Two studies showed non-significant increased risk.320 350
The single ecological study showed an association between
increased intake and increased risk.333
Serum or plasma beta-cryptoxanthin

Dietary carotenoids

All 11 cohort studies showed decreased risk of lung cancer
for the highest intake group when compared to the lowest,284
286 288 289 298 299 341 550-555
which was statistically significant inthree.286 550 553 Meta-analysis was possible on two cohort
studies, giving a summary effect estimate of 0.98 (95% CI
0.96–0.99) per 1000 µg/day, with no heterogeneity (figure
4.2.28).553 554 All cohort studies adjusted for smoking.
Twelve of the case-control studies showed decreased riskof lung cancer for the highest intake group when comparedto the lowest,306-308 310 311 321 322 327 330 344 350 352 556 559-561 which
was statistically significant in seven (figure 4.2.29).306-308 321
322 327 344 556 560
Three studies reported increased risk,342 557 558
which was statistically significant in one,557 and one reported no effect on risk.350 Heterogeneity was high, which may
be partially explained by varying adjustment for known
confounders. Four case-control studies did not adjust forsmoking.306 352 556-558
The single ecological study showed an association between
increased carotenoid intake and decreased lung cancer
risk.333
Serum or plasma or carotenoids

All four of the cohort studies showed decreased risk of lungcancer for the highest serum or plasma levels when compared to the lowest,298 562-566 which was statistically significant in three.298 562 563 Effect estimates were 0.27 (95% CI

102Five cohort studies showed decreased risk with increased
intake,563-566 575 576 which was statistically significant inthree.563 566 575 One study showed statistically significant
increased risk.577 Meta-analysis was possible on two studies(including the latter described study), giving a summary
effect estimate of 0.95 (95% CI 0.69–1.29) per 0.05 µmol/l,with high heterogeneity.563 577
The single case-control study showed a non-significant
decreased risk with increased consumption.578
Data on beta-carotene supplements (see chapter
4.10.6.4.2) provide convincing evidence that high-dose
supplements have a contrasting effect, at least in smokers,
increasing the risk of lung cancer. Data on dietary betacarotene (15 cohort studies, a pooled analysis, 32 casecontrol studies, 2 ecological studies) and serum or plasmabeta-carotene (13 cohort studies, 16 case-control studies, 1
ecological study) showed no consistent evidence of an association. The full SLR is contained on the CD included withthis Report.
The general mechanisms through which foods containing
carotenoids could plausibly protect against lung cancer are
outlined below.
There is a substantial amount of evidence available
from both cohort and case-control studies. A clear
dose-response relationship is apparent from cohort
studies. Foods containing carotenoids probably protect
against lung cancer.

C H A P T E R

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D R I N K S

Oesophagus

Three cohort studies537 545 580 and one case-control study581
investigated serum beta-carotene; 10 case-control studies
investigated dietary beta-carotene and oesophageal cancer95
107 125 141 548 582-587; one cohort study70 and three case86 585 587
investigated dietary pro-vitamin A
control studies
carotenoids.
Serum beta-carotene

One of the cohort studies showed decreased risk for the highest levels when compared to the lowest, which was statistically significant after adjusting for smoking (0.11, 95% CI
0.04–0.34).537 Another cohort study showed no effect on risk
(RR 1.0) and was specific for squamous cell carcinoma.580
Another study reported a non-significant association but did
not provide further details.545
The single case-control study showed that serum betacarotene levels were non-significantly lower in cases thancontrols.581

All case-control studies showed decreased risk for the highest intake group when compared to the lowest,86 585 587 which
was statistically significant in one585 and in men, but not
women, in another (figure 4.2.30).86
The general mechanisms through which foods containing
carotenoids, including beta-carotene, could plausibly protect
against oesophageal cancer are outlined below.
There is a substantial amount of consistent evidence
available from both cohort and case-control studies.
Foods containing beta-carotene probably protect
against oesophageal cancer.
Prostate

Five cohort studies,588-594 9 case-control studies,595-608 and 3
ecological studies609-611 investigated tomatoes; 3 cohort studies590 591 612-615 and 14 case-control studies595 596 598 599 601 602
606 616-625
investigated dietary lycopene; 6 cohort studies576
594 626-630
and 2 case-control studies596 608 619 investigatedserum or plasma lycopene.

Dietary beta-carotene

Nine of the case-control studies showed decreased risk forthe highest intake group when compared to the lowest,95 107
125 141 582-587
which was statistically significant in six.95 141 582585
One study reported a non-significant increased risk (figure 4.2.30).548
Dietary pro-vitamin A carotenoids

The single cohort study showed a non-significant decreased
risk for the highest intake group when compared to thelowest, with an effect estimate of 0.70 (95% CI 0.29–1.71)(figure 4.2.30).70

Figure 4.2.30

Beta-carotene and oesophageal cancer;
cohort and case-control studies
Relative risk (95% CI)

CohortZheng 1995

0.70 (0.29–1.71)

Case control
Decarli 1987

0.23 (0.12–0.45)

Brown 1988

0.80 (0.45–1.43)

Graham 1990

0.66 (0.36–1.22)

Valsecchi 1992

2.50 (1.67–3.74)

Tavani 1993

0.50 (0.22–1.12)

Tavani 1994

0.40 (0.19–0.85)

Hu 19940.70 (0.37–1.31)

Launoy 1998

0.61 (0.31–1.20)

De Stefani 1999

0.60 (0.40–0.90)

Franceschi 2000

0.30 (0.17–0.52)

Mayne 2001

0.43 (0.29–0.63)

Chen 2002

0.60 (0.31–1.15)

Tomatoes

Three of the cohort studies showed decreased risk for thehighest intake groups when compared to the lowest,588 591
592
which was statistically significant in two.591 592 One study
showed a non-significant increased risk589 and one study
reported that there was no statistically significant association.594 Meta-analysis was possible on four of the cohort
studies, giving a summary effect estimate of 0.69 (95% CI
0.43–1.08) per serving/day, with moderate heterogeneity.588
589 591 592
One of these studies reported an effect estimate of
0.24 (95% CI 0.13–0.47) per 15 g/day for cumulative intake
of tomato sauce.591 Two of the cohort studies reported on
advanced or aggressive prostate cancer.590 591 594 One reported a risk estimate of 0.11 (95% CI 0.02–0.70) per increase
in serving/day for tomato sauce590 and the other found nostatistically significant association.594
Seven of the case-control studies showed decreased risk
for the highest intake groups when compared to the lowest,595 598-600 602 603 608 which was statistically significant in
one.602 One study reported non-significant increased risk597
and the other stated that there was no significant association without further details.606 Meta-analysis was possible onfive relatively high quality studies595 597-600 and two relatively
low quality ones.602 603 The former gave a summary effectestimate of 0.97 (95% CI 0.91–1.03) per serving/day, withno heterogeneity; the latter gave a summary effect estimateof 0.33 (95% CI 0.04–2.74) per serving/day, with highheterogeneity.
The three ecological studies showed no consistentassociation.609-611
Dietary lycopene

0.2

0.5 0.75 1

1.5 2

5

Relative risk, highest vs lowest exposure category

Two cohort studies showed non-significant decreased risk forthe highest intake groups when compared to the lowest,590
614
the other study showed non-significant increased risk.613
Meta-analysis was possible on all three cohort studies, giving a summary effect estimate of 0.97 (95% CI 0.64–1.45)
per 5 mg/day, with low heterogeneity (figures 4.2.31 and

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Figure 4.2.31

Lycopene and prostate cancer; cohort andcase-control studies
Relative risk (95% CI)

CohortSchuurman 2002

1.01 (0.46–2.22)

Parker 1999

0.01 (0.00–2.26)

Giovanucci 2002

0.99 (0.95–1.02)

Summary estimate

0.97 (0.64–1.45)

Case control
McCann 2005

0.99 (0.79–1.22)

Hodge 2004

0.93 (0.81–1.05)

Norrish 2000

0.70 (0.35–1.38)

Cohen 2000

0.96 (0.79–1.16)

Jain 1999

1.01 (0.96–1.06)

Key 1997

1.05 (0.13–8.85)

Summary estimate

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or aggressive cancer, giving estimates of 0.89 (95% CI
0.28–2.84) per 5 mg /day613 and 0.57 (95% CI 0.37–0.87)
for the highest intake groups when compared to the lowest.591
Nine case-control studies showed decreased risk for thehighest intake groups when compared to the lowest,595 598 602
606 616 617 619 621 624
which was statistically significant in one.602
Five studies reported non-significant increased risk.596 599 601
620 625
Meta-analysis was possible on six relatively high quality case-control studies595 598 599 601 616 617 and three relatively low quality ones.602 619 620 The former gave a summary
effect estimate of 0.995 (95% CI 0.95–1.04) per 5 mg/day,with no heterogeneity and the latter gave a summary estimate of 0.56 (95% CI 0.23–1.36) per 5 mg/day, with highheterogeneity (figures 4.2.31 and 4.2.32).

1.00 (0.95–1.04)

Serum or plasma lycopene
0.125

0.5

1

2

4

8

Relative risk, per 5 mg/day

Figure 4.2.32

Dietary lycopene and prostate cancer; cohortand case-control studies: dose response

CohortParker 1999
Giovanucci 2002
Schuurman 2002Case control
McCann 2005
Hodge 2004
Key 1997
Jain 1999
Cohen 2000
Norrish 2000

0

1

2

3

4

5

Five cohort studies showed a non-significant reduced risk forthe highest intake groups when compared to the lowest576
626-628; the other study showed a non-significant increased
risk.629 Meta-analysis was possible on four cohort studies,giving a summary estimate of 0.96 (95% CI 0.926–0.999)
per 10 µg/l, with no heterogeneity.576 626 627 All cohort studies were fully adjusted.
Both case-control studies of serum or plasma lycopene
showed a statistically significant reduced risk for the highest intake groups when compared to the lowest.596 619
Lycopene is most bioavailable from cooked and pureed
tomatoes. The best measures of systemic exposure are therefore studies on tomato sauce, particularly of cumulative consumption, or on serum or plasma lycopene. The Panel also
gave emphasis to studies on advanced or aggressive cancers,which may be better linked to prognosis than studies that
include early stage or latent disease, or screening-detecteddisease.
The general mechanisms through which foods containing
carotenoids, including lycopene, could plausibly protect
against prostate cancer are outlined below. In addition,
amongst the common carotenoids, lycopene is thought to be
the most efficient antioxidant in the body.631
There is a substantial amount of consistent evidence,in particular on tomato products, from both cohort andcase-control studies. There is evidence for plausible
mechanisms. Foods containing lycopene probably
protect against prostate cancer.

Dietary lycopene (mg/day)

The Panel is aware that since the conclusion of the SLR, twocohort studies632 633 and one case-control study634 have been
published. This new information does not change the Panel
judgement (see box 3.8).
Prostate

4.2.32). One of these studies also reported cumulative measures of lycopene consumption, which is a robust measureof long-term consumption.590 The effect estimate was 0.95
(95% CI 0.92–0.99) per 5 mg/day. All studies were fully
adjusted.
Two of the cohort studies reported separately on advanced

104

Also see chapter 4.10.6.4.2 for evidence on beta-carotene
supplements. Six cohort studies147 360 591 594 613 635 636 and 21
case-control studies595 598 599 602 616 617 619-621 624 625 637-648 investigated dietary beta-carotene and prostate cancer.
Ten cohort studies576 594 626 628-630 635 649-652 and five casecontrol studies584 596 608 619 653 investigated serum or plasmabeta-carotene.

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D R I N K S

Dietary beta-carotene

Three cohort studies showed non-significant increased risk
with increased intake.594 635 636 Three studies showed noeffect on risk.360 591 613 Meta-analysis was possible on all six
cohort studies, giving a summary effect estimate of 1.00
(95% CI 0.99–1.01) per 700 µg/day, with no heterogeneity.360 591 594 613 635 636
Two cohort studies reported results separately foradvanced/aggressive prostate cancer.594 613 Meta-analysis
was possible on both studies, giving a summary effect estimate of 0.97 (95% CI 0.88–1.06) per 700 µg/day, with noheterogeneity.
Fourteen case-control studies showed decreased risk withincreased intake,595 599 602 616 617 619-621 625 637 638 642 646 648 which
was statistically significant in two relatively low quality studies.602 646 648 Four studies showed no effect on risk624 639 644
645
and three studies showed non-significant increased
risk.598 640 641 Meta-analysis was possible on nine relatively
high quality595 598 599 616 617 637-640 and six relatively low quality case-control studies,602 619 620 624 641 642 giving summary
effect estimates of 0.99 (95% CI 0.98–1.00) and 0.98 (95%
CI 0.94–1.01) per 700 µg/day, with no and moderate heterogeneity, respectively.
Serum or plasma beta-carotene

Five cohort studies showed decreased risk with increased
intake,576 626 628 649 651 652 which was statistically significant in
one.649 Four studies showed non-significant increased risk.594
626 629 635
Meta-analysis was possible on seven cohort studies, giving a summary effect estimate of 1.00 (95% CI
0.91–1.09) per 10 µg beta-carotene/100 ml, with moderateheterogeneity.576 626 629 635 649
Four case-control studies showed decreased risk withincreased intake,584 608 619 653 which was statistically significant in one relatively low quality study.653 One study showednon-significant increased risk.596
It is unlikely that foods containing beta-carotene havea substantial effect on the risk of prostate cancer.

The Panel is aware that since the conclusion of the SLR, twocohort studies632 633 have been published. This new information
does not change the Panel judgement (see box 3.8).
Skin

Also see chapter 4.10.5.1 for evidence on beta-carotene supplements. Two cohort studies654 655 and seven case-control
studies656-663 investigated dietary beta-carotene and skin cancer. Three cohort studies655 664-666 and one case-control
study657 investigated beta-carotene from food and supplements combined; eight cohort studies545 630 651 655 667-672 andthree case-control studies584 673 674 investigated serum or plasma beta-carotene.

increased risk of squamous cell carcinoma.658 659 Threecase-control studies showed decreased risk of melanoma forthe highest intake group when compared to the lowest,657 661
663
which was statistically significant in two.657 663
Two studies showed non-significant increased risk of melanoma.656 660
Beta-carotene from foods and supplements

Two cohort studies showed increased risk of basal cell carcinoma for the highest intake group when compared to thelowest.655 665 One cohort study showed non-significant
increased risk of squamous cell carcinoma.666 One cohort
study showed a non-significant increased risk ofmelanoma.664 One case-control study showed a statisticallysignificant decreased risk of melanoma for the highest intake
group when compared to the lowest.657
Serum or plasma beta-carotene

Two studies showed decreased risk for skin cancer of unspecified type with increased serum or plasma beta-carotene,669
671
which was statistically significant in one.669 One cohort
study showed non-significant decreased risk of nonmelanoma skin cancer.667 One cohort study (fully adjusted)showed a non-significant decreased risk for basal cell carcinoma672; two showed a non-significant increased risk630 655;
and one a non-significant increased risk in women and anon-significant decreased risk in men.651 Two studies
showed non-significant decreased risk on squamous cell carcinoma.668 672 Two studies showed decreased risk ofmelanoma, which was statistically significant in one545 670;
and one study showed non-significant increased risk.630
Meta-analysis was possible on both cohort studies that investigated squamous cell carcinoma, giving a summary effectestimate of 0.99 (95% CI 0.98–1.00) per µg betacarotene/100 ml, with no heterogeneity.668 672 Meta-analysis was possible on two cohort studies that investigatedmelanoma, giving a summary effect estimate of 0.90 (95%
CI 0.78–1.03) per µg beta-carotene/100 ml, with moderateheterogeneity.545 670
One case-control study showed a statistically significant
decreased risk of non-melanoma skin cancer, which, at 0.999
per µg/100 ml (95% CI 0.999–0.999), was close to noeffect.673 One case-control study showed non-significant
increased risk of basal cell carcinoma for the highest intake
group when compared to the lowest.584 The same study
showed non-significant increased risk of squamous cell carcinoma and non-significant increased risk of melanoma.584
One additional study showed non-significant decreased riskof melanoma.674
It is unlikely that foods containing beta-carotene haveany substantial effect on the risk of non-melanoma
skin cancer.

Dietary beta-carotene

Both cohort studies showed non-significant increased risk
with increased intake, both for basal cell carcinoma.654 655 One
case-control study showed a non-significant decreased risk ofbasal cell carcinoma for the highest intake group when compared to the lowest662; one showed a non-significant

General mechanisms — foods containing carotenoids

Carotenoids are antioxidants, which can prevent lipid oxidation and related oxidative stress. Oxidative stress inducedby free radicals causes DNA damage. Base mutation, singleand double-strand breaks, DNA cross-linking, and chromo-

105

P A R T

somal breakage and rearrangement can all occur if this initial damage is left unrepaired. This damage could plausibly
be prevented or limited by dietary antioxidants found in
fruits and vegetables.675
Many of the carotenoids, including beta-carotene, are also
retinoid (vitamin A) precursors. The pro-vitamin A
carotenoids may be converted to retinol where they functionin cellular differentiation, immunoenhancement, and activation of carcinogen-metabolising enzymes.580 676
Lycopene is the most potent carotenoid antioxidant, has
an antiproliferative effect, reduces plasma low-density
lipoprotein cholesterol, improves immune function, andreduces inflammation.
4.2.5.4 Foods containing folate
Foods naturally containing folates are vegetables, fruits, andliver, but increasingly foods such as breakfast cereals are fortified with folic acid.
Pancreas

Three cohort studies,677 678 two case-control studies,509 679
and one ecological study515 investigated folate from foods
and/or supplements, and pancreatic cancer.
One cohort study reported a statistically significant
reduced risk for the highest intake groups (without specifying the source of folate) when compared to the lowest677; one
reported no effect on risk in men678 and the other reported
a non-significant increased risk in women.678 Meta-analysis
was possible on all three cohort studies, giving a summary
effect estimate of 0.94 (95% CI 0.80–1.11) per 100 µg/day,with high heterogeneity.677 678
When these results were stratified according to dietary or
supplemental folate, this heterogeneity was removed. Twocohort studies reported separately on dietary folate.678 Bothreported non-significant decreased risk; meta-analysis was
possible on both, giving a summary effect estimate of 0.86
(95% CI 0.73–1.00) per 100 µg/day, with no heterogeneity(figure 4.2.33). All three cohort studies reported separately
on supplemental folate, showing non-significant increased
risk, with no heterogeneity.677 678
In addition, one of the cohort studies included a nested
case-control study investigating blood folate levels. This
reported a statistically significant decreased risk for the high-Figure 4.2.33

Folate and pancreatic cancer;
cohort studies
Relative risk (95% CI)

Skinner 2004 Women

0.85 (0.63–1.15)

Skinner 2004 Men

0.86 (0.71–1.04)

Summary estimate

0.86 (0.73–1.00)

0.5

0.75

1

1.5

2

2

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J U D G E M E N T S

est levels when compared to the lowest, with an effect estimate of 0.45 (95% CI 0.24–0.82).680
The Panel is aware of an additional cohort study, publishedafter the conclusion of the literature review, which showeda statistically significant decreased risk for the highest intake
groups when compared to the lowest.681 The effect estimate
was 0.25 (95% CI 0.11–0.59) for dietary folate and 0.33
(95% CI 0.15–0.72) for total folate (combining dietary andsupplemental sources). No association was observed with
folate supplements only.
One of the case-control studies reported a statistically significant reduced risk for the highest intake groups when compared to the lowest.679 The other reported a non-significant
decreased risk in women and no effect on risk in men.509
The ecological study showed a statistically significant
decreased risk in areas of high folate intake.515
The possible differential effect between folate from foods
and from supplements could be explained by folate serving
as a marker for fruit and vegetable intake, by a different
metabolic effect of the folic acid in supplements, or by confounders associated with supplement use.
The general mechanisms through which foods containing
folate could plausibly protect against pancreatic cancer are
outlined below.
The evidence available is sparse but a dose-response
relationship was apparent from cohort studies. There islimited evidence suggesting that foods containing
folate protect against pancreatic cancer.

The Panel is aware that since the conclusion of the SLR, onecohort study681 has been published. This new information does
not change the Panel judgement (see box 3.8).
Oesophagus

Eight case-control studies investigated dietary folate113 124 125
and two case-control studies investigated red
cell and/or plasma folate.682-684
All eight case-control studies that investigated dietary
folate reported decreased risk for the highest intake groups
when compared to the lowest,113 124 125 136 548 583 585 587 which
was statistically significant in two.583 587 Most studies adjusted for smoking and alcohol.
Both case-control studies that investigated red cell and/or
plasma folate reported that levels were lower (statisticallysignificant) in cases than controls.682-684 One study was
adjusted for smoking and alcohol.684
The general mechanisms through which foods containing
folate could plausibly protect against oesophageal cancer are
outlined below. In addition, folate may reduce human papilloma virus proliferation in cells.685
136 548 583 585 587

The evidence, from case-control studies only, is sparse.
There is limited evidence suggesting that folate
protects against oesophageal cancer.

The Panel is aware that since the conclusion of the SLR, one
case-control study78 has been published. This new information
does not change the Panel judgement (see box 3.8).

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D R I N K S

Colorectum

Nine cohort studies investigated dietary folate and colorectal cancer.686-694 Two cohorts investigated serum folate.694 695
Seven cohort studies that investigated dietary folate
showed decreased risk for the highest intake groups whencompared to the lowest, 686-690 692 693 which was statisticallysignificant in one.689 Two cohort studies reported nonsignificant increased risk.691 694 Meta-analysis was possible onfour studies, giving a summary effect estimate of 0.84 (95%
CI 0.76–0.93) per 100 µg/day, with low heterogeneity(figure 4.2.34).686 689 692 696
One study of serum folate levels showed statistically significant decreased risk for the highest intake groups whencompared to the lowest, with an effect estimate of 0.52 (95%
CI 0.27–0.97).695 The other showed a non-significant
decreased risk for colon cancer (0.96, 95% CI 0.4–2.3) anda non-significant increased risk for rectal cancer incidence(2.94, 95% CI 0.84–10.33).694
Because of the abundant prospective data from cohort
studies, case-control studies were not summarised.
A published meta-analysis of seven cohort studies and ninecase-control studies reported a statistically significant
decreased risk of colorectal cancer for the highest dietary
folate intake when compared to the lowest (0.75, 95% CI
0.64–0.89).697
The general mechanisms through which foods containing
folate could plausibly protect against colorectal cancer are
outlined below. In addition, folate intake is also strongly correlated with intake of dietary fibre, which probably prevents
colorectal cancer (also see chapter 7.1).
The evidence from cohort studies is plentiful, with adose-response relationship, but there is unexplainedinconsistency. Residual confounding from dietary fibre ispossible. There is limited evidence suggesting that foods
containing folate protect against colorectal cancer.

The Panel is aware that since the conclusion of the SLR, fourcohort698-701 and two case-control studies380 702 have been

Figure 4.2.34

Dietary folate intake and colorectal cancer;
cohort studies
Relative risk (95% CI)

Giovannucci 1998 Women

0.91 (0.76–1.10)

Su 2001 Women

0.93 (0.72–1.19)

Su 2001 Men

0.69 (0.52–0.90)

Konings 2002 Men

0.81 (0.64–1.03)

Konings 2002 Women

0.90 (0.63–1.29)

Larsson 2005 Women

0.77 (0.60–0.98)

Summary estimate

0.84 (0.76–0.93)

0.5

0.75

1

1.5

2

published. This new information does not change the Panel
judgement (see box 3.8).
General mechanisms — foods containing folate

Also see Chapter 2. Folate plays an important role in the synthesis and methylation of DNA.703 Abnormal DNA methylation leading to aberrant gene expression has been
demonstrated in several types of cancer. Folate deficiency
may produce misincorporation of uracil instead of thymine
into DNA. The effects of folate deficiency and supplementation on DNA methylation are gene- and site-specific, andappear to depend on cell type, target organ, stage of transformation, and degree and duration of folate depletion.
Animal studies have shown that dose and timing of folate
intervention are critical in determining its effect: exceptionally high folate doses, and intervention after the formation of microscopic neoplastic foci, may promote rather than
suppress colorectal carcinogenesis, at least in the animalmodels studied.704
There is a known interaction between folate and alcoholand the risk of some cancers.
4.2.5.5 Foods containing pyridoxine (vitamin B6)
Oesophagus

Six case-control studies investigated foods containing pyridoxine and oesophageal cancer.88 125 548 583 585 587
All six studies showed decreased risk for the highest intake
groups when compared to the lowest,88 125 548 583 585 587 which
was statistically significant in four.88 125 583 585 All studies
adjusted for alcohol and five adjusted for smoking.
Together with folate and cobalamin (B12), vitamin B6 isinvolved in one-carbon metabolism and thus is important for
DNA synthesis, repair, and methylation.
The evidence, from case-control studies only, wassparse. There is limited evidence suggesting thatpyridoxine protects against oesophageal cancer.

The Panel is aware that since the conclusion of the SLR, one
case-control study78 has been published. This new information
does not change the Panel judgement (see box 3.8).
4.2.5.6 Foods containing vitamin C
Oesophagus

One cohort study,70 19 case-control studies,86 88 94 95 104 105 107
113 120 121 124 125 136 548 583 585-587 705-707
and 3 ecological studies118 203 708 investigated vitamin C and oesophageal cancer.
The single cohort study reported a non-significant reduced
risk for the highest intake groups when compared to the lowest after adjustment for smoking, with an effect estimate of
0.70 (95% CI 0.3–1.7).70
Eighteen of the case-control studies showed decreased risk
for the highest intake groups when compared to the lowest,86
88 94 95 104 105 107 113 120 121 124 136 548 583 585-587 705-707
which wasstatistically significant in 13 (figure 4.2.35).86 88 95 104 105 113
120 121 136 548 583 585 705 707
Three studies showed a non-significant increased risk, all specific to adenocarcinoma.124 125 706
None of the ecological studies reported a statistically significant association.118 203 708

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Figure 4.2.35

Vitamin C and oesophageal cancer;
case-control studies
Relative risk (95% CI)

Mettlin 1981

0.42 (023–0.77)

Tuyns 1983 Men

0.63 (0.50–0.79)

Tuyns 1983 Women

0.56 (0.20–0.91)

Brown 1988

0.50 (0.27–0.91)

Barone 1992

0.40 (0.10–1.55)

Kabat 1993

0.53 (0.22–1.25)

Hu 1994

0.60 (0.31–1.15)

Launoy 1998

0.40 (0.20–0.79)

De Stefani 1999

0.70 (0.52–0.94)

De Stefani 1999

0.50 (0.31–0.82)

Terry 2000

0.60 (0.38–0.95)

De Stefani 2000

0.14 (0.06–0.35)

Franceschi 2000

0.40 (0.24–0.65)

Mayne 2001

0.53 (0.36–0.79)

Zhang 1997

1.30 (0.48–3.49)

Chen 2002

0.60 (0.30–1.20)

0.2

0.5

1

2

5

Relative risk, highest vs lowest exposure category

It is biologically plausible that vitamin C should protect
against cancer. It traps free radicals and reactive oxygen molecules, protecting against lipid peroxidation, reducing
nitrates, and stimulating the immune system.586 709 Moreover,it can recycle other antioxidant vitamins such as vitamin E.534
Vitamin C has also been shown to inhibit formation of carcinogens and protect DNA from mutagenic attack.535
However, evidence supporting a specific mechanism in theoesophagus is limited.586
A substantial amount of consistent evidence isavailable, from both cohort and case-control studies.
Foods containing vitamin C probably protect against
oesophageal cancer.

The Panel is aware that since the conclusion of the SLR, one
case-control study710 has been published. This new information
does not change the Panel judgement (see box 3.8).
4.2.5.7 Foods containing vitamin E
Oesophagus

One cohort study,70 nine case-control studies,86 88 95 105 125 548
583 585 587
and one ecological study708 investigated dietary vitamin E and oesophageal cancer. Three cohort studies537 545
711
and four case-control studies581 682 683 712 investigatedserum vitamin E.
Dietary vitamin E

The single cohort study showed decreased risk for the highest intake groups when compared to the lowest, with an effectestimate of 0.8 (95% CI 0.3–2.0; adjusted for smoking).70

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Eight case-control studies reported decreased risk for thehighest intake groups when compared to the lowest,86 88 95
105 125 548 583 585
which was statistically significant in seven86
88 95 105 548 583 585; the other study reported no effect on risk.587
All studies adjusted for alcohol and all but one also adjusted for smoking.
The single ecological study reported no association.708
Serum vitamin E

All three cohort studies showed decreased risk for the highest intake groups when compared to the lowest,537 545 711
which was statistically significant in two. The effect estimates
were 0.63 (95% CI 0.44–0.91) for alpha-tocopherol(the same study showed no significant association withserum gamma-tocopherol),711 and 0.39 (95% CI 0.19–0.80)
for gamma-tocopherol.537 The third cohort study found lower
mean values in cases than controls (8.52 vs 10.21 mg/l),
which was not statistically significant.545 The two former
studies were maximally adjusted.537 711
Two case-control studies reported that cases had higher
plasma vitamin E than controls,682 683 statistically significant
in one.683 One study reported statistically significant lower
levels in cases than those in controls712; and another reported no significant difference.581 None of these studies was well
adjusted.
The general mechanisms through which foods containing
vitamin E could plausibly protect against oesophageal cancer
are outlined below.
Much of the evidence on vitamin E, mostly from casecontrol studies, was of poor quality. There is limited
evidence suggesting that foods containing vitamin E
protect against oesophageal cancer.
Prostate

Two cohort studies,147 613 650 713 13 case-control studies,595 599
and 1 ecological study708 investigated dietary vitamin E and prostate cancer; 4 cohort studies629 630 718-722 and 1 case-control study716 investigated serum
vitamin E; 8 cohort studies576 626 627 629 635 650 652 713 718 723-725
and 2 case-control studies619 653 investigated serum or plasma alpha-tocopherol; 6 cohort studies576 626 627 629 650 718 724
and 1 case-control study619 investigated serum gammatocopherol.
601 604 607 616 619-621 625 637 714-717

Dietary vitamin E

Most studies showed non-significant decreased risk, although
there is heterogeneity in the direction of effect reported andeffect estimates are usually very close to 1 (no effect). One
cohort study reported an effect size of 0.96 (0.75–1.2) per
10 mg/day for advanced/aggressive prostate cancer.613 Metaanalysis was possible on seven relatively good quality casecontrol studies, giving a summary effect estimate of 1.04
(95% CI 0.99–1.11) per 10 mg/day, with low heterogeneity.595 599 601 616 637 714 715 Dietary studies produce noconsistent effect.
Serum or plasma alpha-tocopherol

Seven cohort studies showed decreased risk for the highest

C H A P T E R

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D R I N K S

intake groups when compared to the lowest,576 626 629 635 650
which was statistically significant in one.576
One cohort study showed no effect on risk.627 Meta-analysis
was possible on seven cohort studies, giving a summary
effect estimate of 0.99 (95% CI 0.97–1.00) per mg/l, withno heterogeneity.576 626 713 723-725
Both case-control studies showed decreased risk for thehighest intake groups when compared to the lowest,619 653
which was statistically significant in one.653

652 713 718 723-725

Lung

Two cohort studies,288 464 two case-control studies,469 557 andtwo ecological studies728 729 investigated dietary selenium
and lung cancer.
Ten cohort studies,463 575 577 730-738 seven case-control studies,570 571 739-743 and four ecological studies729 744-746 investigated plasma or serum selenium; three cohort studies747-749
investigated selenium levels in nails.
Dietary selenium

Serum gamma-tocopherol

All six cohort studies showed decreased risk for the highest
intake groups when compared to the lowest,576 626 627 629 650
718 724
which was statistically significant in two.650 724 Metaanalysis was possible on all six cohort studies, giving a summary effect estimate of 0.90 (95% CI 0.81–0.996) per mg/l,
with moderate heterogeneity.
The single case-control study showed non-significant
decreased risk for the highest intake groups when comparedto the lowest.619
The general mechanisms through which foods containing
vitamin E could plausibly protect against prostate cancer
are outlined below. Vitamin E has also been shown to
inhibit the growth of human prostate tumours induced inmice.726
The evidence, mostly from case-control studies, wasinconsistent. There is limited evidence suggesting thatfoods containing vitamin E protect against prostatecancer.

The Panel is aware that since the conclusion of the SLR, twocohort studies632 633 have been published. This new information
does not change the Panel judgement (see box 3.8).
General mechanisms — foods containing vitamin E

Vitamin E is an antioxidant that has been reported to prevent DNA damage, enhance DNA repair, prevent lipid peroxidation, and prevent activation of carcinogens such as
nitrosamines. Vitamin E protects vitamin A and selenium inthe body. In addition to acting as a free-radical scavenger,
vitamin E enhances the body’s immune response, which may
play a role in cancer defences.727
4.2.5.8 Foods containing selenium
Data from selenium levels in serum or nails can be interpreted more robustly than dietary data because they are lessprone to certain sources of error; serum data are a short-term
reflection of intake; levels in nails are cumulative and reflect
long-term intake.
It is not possible to rule out residual confounding between
selenium levels and healthy lifestyles. Individuals with higher selenium levels may be more likely to be following several strategies to improve their health, including taking
supplements.
It is plausible that an effect attributed to selenium could
only be apparent in areas of selenium deficiency.

One cohort study showed non-significant decreased risk forthe highest intake group when compared to the lowest.464
One cohort study showed non-significant increased risk in
non-smokers and non-significant decreased risk in
smokers.288 Both case-control studies showed a non-significant increased risk for the highest intake group when compared to the lowest.469 557 One ecological study showedstatistically significant decreased risk in high-intake areas,728
the other showed no consistent association.729
Plasma or serum selenium

Seven cohort studies showed decreased risk for the highest
selenium levels when compared to the lowest,463 575 731-734
736-738
which was statistically significant in two.733 737 Fourstudies showed increased risk,577 730 735 738 which was statistically significant in two.735 738 Meta-analysis was possible onfour cohort studies, giving a summary effect estimate of
0.969 (95% CI 0.940–0.999) per 10 µg/l, with low heterogeneity.577 731 733 736
Six case-control studies showed decreased risk for thehighest levels when compared to the lowest,570 739-743 which
was statistically significant in four.739 740 742 743 One study
showed non-significant increased risk.571
One ecological study showed statistically significant
decreased risk in areas of high plasma selenium729; the others showed no consistent effect.729 744-746
Nails

Two cohort studies showed decreased risk for the highest
selenium levels when compared to the lowest,748 749 which
was statistically significant in one.749 One study showed nonsignificant increased risk.747
The general mechanisms through which selenium could
plausibly protect against lung cancer are outlined below.
The evidence available is sparse. There is limited
evidence to suggest that foods containing selenium
protect against lung cancer.
Prostate

One cohort,713 750 7 case-control studies,599 601 639 715 716 751 752
and 2 ecological studies729 753 754 investigated dietary selenium; 12 cohort studies652 730 732 755-765 and 4 case-control
studies716 741 752 754 766 767 investigated serum or plasma selenium; and 3 cohort studies,615 724 768 3 case-control studies,717
769 770
and 1 ecological study771 investigated levels in nails.
Further to this, 1 randomised controlled trial772 773 and 2cohorts612 628 713 investigated selenium supplements (seechapter 4.10.6.4.5).

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Dietary selenium

Nails

One cohort study showed a statistically significant decreased
risk. The effect estimate was 0.66 (95% CI 0.44–0.98) per
50 µg/day.713 This study did not adjust for confounders.
Two case-control studies showed non-significant decreased
risk for the highest intake groups when compared to the lowest751 752; five showed increased risk,599 601 639 715 716 one ofwhich was statistically significant.715 Meta-analysis was possible on three studies, giving a summary effect estimate of
1.07 (95% CI 0.92–1.25) per increase in 50 µg/day, with noheterogeneity.599 601 639
The two ecological studies reported that increasing
selenium intake was associated with decreasing prostatecancer levels.729 753 754

Two cohort studies investigated selenium levels in nails for
all prostate cancer. Both showed non-significant decreased
risk for the highest intake groups when compared to the lowest. Meta-analysis was possible on both studies, giving a summary effect estimate of 0.91 (95% 0.81–1.02) per 100 ng/g,with moderate heterogeneity.724 768
Two cohort studies investigated selenium levels in nails foradvanced or aggressive prostate cancer. Both showed statistically significant decreased risk for the highest intake groups
when compared to the lowest. Meta-analysis was possible on
both studies, giving a summary effect estimate of 0.80 (95%0.69–0.91) per 100 ng/g, with no heterogeneity.615 768
One case-control study showed non-significant decreased
risk for the highest intake groups when compared to the lowest,770 one showed no effect on risk717 and the other showeda non-significant increased risk.769
The single ecological study reported a non-significant association.771
These data are supported by data on supplements, whichhave been shown to decrease prostate cancer risk (see chapter 4.10.6.4.5).
There is no significant heterogeneity within the meta-

Serum or plasma selenium

Eight cohort studies that investigated serum or plasma selenium showed decreased risk for the highest intake groups
when compared to the lowest,652 732 755-759 761 763 764 which wasstatistically significant in two. Four reported non-significant
increased risk.730 760 762 765 Meta-analysis was possible on nineof these studies, giving a summary effect estimate of 0.95
(95% CI 0.89–1.00) per 10 µg/l, with moderate heterogeneity (figure 4.2.36).732 755 757 758 761 762 764 765
Two of these 12 cohort studies reported separately on
advanced/aggressive cancer.730 755 758 Both showed decreased
risk for the highest intake groups when compared to the lowest, which was statistically significant in one.758 Meta-analysis was possible on both, giving a summary effect estimateof 0.87 (95% CI 0.79–0.97) per 10 µg/l, with no heterogeneity (figure 4.2.37).755 758
A dose-response relationship is apparent from the studies
on advanced or aggressive disease (figure 4.2.38).
All four of the case-control studies showed decreased risk
for the highest intake groups when compared to the lowest,716 741 752 766 767 which was statistically significant inthree.741 752 767

Figure 4.2.36

Figure 4.2.37

Selenium (in serum or plasma) andadvanced or aggressive prostate cancer;
cohort studies
Relative risk (95% CI)

Nomura 2000

0.80 (0.64–1.00)

Li 2004

0.89 (0.80–1.00)

Summary estimate

0.87 (0.79–0.97)

0.5

1

2

Selenium (in plasma or serum) andprostate cancer; cohort studies
Relative risk (95% CI)

Figure 4.2.38
Nomura 2000

0.89 (0.40–0.99)

Li 2004

0.95 (0.89–1.01)

Knekt 1990

0.99 (0.78–1.24)

Goodman 2001

1.01 (0.93–1.11)

Brooks 2001

0.77 (0.65–0.89)

Ringstad 1988

0.99 (0.97–1.01)

Willett 1983

0.64 (0.37–1.12)

Virtamo 1987

1.16 (0.82–1.65)

Salonen 1984

1.03 (0.63–1.70)

Summary estimate

0.95 (0.89–1.00)

0.5

110

1

2

Selenium (in serum or plasma) and advanced
or aggressive prostate cancer;
cohort studies: dose response

Li 2004
Nomura 2000

8

10

12

14

16

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analyses of advanced/aggressive cancer. The low to moderate heterogeneity observed for other outcomes and different
study types may be explained by the variable inclusion oflatent cancers in the outcome and by variations in study
quality.
The general mechanisms through which foods containing
selenium could plausibly protect against prostate cancer are
outlined below. In addition, selenoproteins are involved in
testosterone production, which is an important regulator ofboth normal and abnormal prostate growth.774 775
The evidence from cohort and case-control studies is
consistent, with a dose-response relationship. There isevidence for plausible mechanisms. Foods containing
selenium probably protect against prostate cancer.

Nails and hair

The single cohort study that investigated selenium in nails
showed statistically significant decreased risk for the highest levels when compared to the lowest in men, but not
women. The effect estimates were 0.4 in men (95% CI
0.17–0.96; 72 cases) and 1.68 in women (95% CI 0.43–6.54;
20 cases).787
The single case-control study found that mean hairselenium levels were significantly lower in the 15 stomach
cancer cases than in controls.788
The general mechanisms through which foods containing
selenium could plausibly protect against stomach cancer are
outlined below. In addition, selenoproteins with powerfulantioxidant activity may provide protection against the
inflammatory effect of H pylori, which can lead to gastriccancer in infected individuals.791

StomachOne case-control study776 and five ecological studies238 729 777investigated dietary selenium and stomach cancer. Threecohort studies,731 732 736 nine case-control studies,738 741 754
780-785and three ecological studies236 729 786 investigated blood
selenium. One cohort study787 and one case-control study788
investigated selenium in toenails or hair. In addition, one
randomised controlled trial and one combined trial investigated selenium supplements.423 424

779

A substantial amount of evidence was available on
selenium, from dietary questionnaires, as well as
blood, nails, and hair, mostly from case-control
studies. There is limited evidence suggesting that foods
containing selenium protect against stomach cancer.
Colorectum

Fifteen case-control studies investigated dietary selenium
and colorectal cancer.738 785 792-795

Dietary selenium

The single case-control study showed that dietary selenium
was not significantly associated with risk of stomach
cancer.776
Most ecological studies showed that low selenium levels
were associated with increased stomach cancer risk,238 777-779
one of which was statistically significant.779
Blood selenium

All three cohort studies that investigated blood selenium levels showed decreased risk for the highest levels when compared to the lowest,731 732 736 which was statisticallysignificant in men in one study.732 Meta-analysis was possible on all three, giving a summary effect estimate of 0.89
(95% CI 0.78–1.00) per 0.1 µmol/l, with moderate heterogeneity.731 732 736
All nine case-control studies showed statistically significant
decreased risk for the highest levels when compared to the lowest.738 741 754 780-785 Meta-analysis was possible on six of these,
giving a summary effect estimate of 0.44 (95% CI 0.35–0.55)
per 0.1 µmol/l, with high heterogeneity.741 754 782-785
This heterogeneity was caused by varying size, not direction,of effect.
All three ecological studies reported inverse associations
between blood or plasma selenium and stomach cancer
mortality,236 729 786 which were statistically significant in
two.236 786
A dose-response relationship is apparent from case-control
but not cohort data.
Two additional cohort studies, both from China, stratified
results according to tumour location.789 790 The apparent protective effect was strengthened for cardia cancers, but disappeared for proximal.

Dietary, serum or plasma, toenail selenium

Meta-analysis was possible on six independent effect estimates from five case-control studies, giving a summary effectestimate of 0.86 (95% CI 0.78–0.95) per 10 µg/dl serum,with high heterogeneity.785 792-795 All of these studies reported decreased risk, which was statistically significant in fourof the five studies.792-795 The heterogeneity is therefore
derived from varying size, but not direction of effect. The
remaining 10 studies reported non-significant decreased
risk.738 These data are supported by limited evidence suggesting that there is also a protective effect from selenium
supplements (see chapter 4.10.6.4.5).
The general mechanisms through which foods containing
selenium could plausibly protect against colorectal cancer are
outlined below.
A substantial amount of data was available, from casecontrol studies only. There is limited evidence
suggesting that foods containing selenium protect
against colorectal cancer.
General mechanisms — foods containing selenium

Dietary selenium deficiency has been shown to cause a lackof selenoprotein expression. Twenty-five selenoproteins
have been identified in animals and a number of these haveimportant anti-inflammatory and antioxidant properties.796
Four are glutathione peroxidises, which protect against
oxidative damage to lipids, lipoproteins, and DNA. These
enzymes are rapidly degraded during selenium deprivation.
Three are thioredoxin reductases and, amongst other functions, these regenerate oxidised ascorbic acid to its active
antioxidant form.

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Selenoproteins appear to reach their maximal levels
relatively easily at normal dietary selenium intake andnot to increase with selenium supplementation. It is, however, plausible that supraphysiological amounts of selenium
might affect programmed cell death, DNA repair, carcinogenmetabolism, immune system, and anti-angiogenic effects.797
4.2.5.9 Foods containing quercetin
Lung

Two cohort studies147 798 and three case-control studies327 477
799
investigated foods containing quercetin and lung cancer.
Both cohort studies showed statistically significant
decreased risk for the highest intake groups when comparedto the lowest.147 798 The effect estimates were 0.63 (95% CI
0.52–0.78)147 and 0.42 (95% CI 0.25–0.72).798 Both studies
adjusted for smoking.
Two case-control studies showed decreased risk for thehighest intake groups when compared to the lowest,327 477
which was statistically significant in one.327 One study
reported non-significant increased risk.799 The effect estimates were 0.58 (95% CI 0.39–0.85),327 0.7 (95% CI
0.4–1.1),477 and 1.89 (95% CI 0.72–4.92).799 The latter study
may have been over-adjusted.
Quercetin is a flavonoid. It is an antioxidant and also
directly inhibits expression of CYP1A1 (a cytochrome P450
enzyme that helps to metabolise toxins), resulting indecreased formation of DNA adducts.475 Elevated CYP1A1
activity has been associated with increased risk of lung cancer, primarily in smokers.476 The evidence for CYP1A1/
flavonoid interactions is supported by the observation that
protective associations of flavonoids are associated withspecific CYP1A1 genotypes.476 477
The evidence available is sparse and inconsistent.
There is limited evidence suggesting that foods
containing quercetin protect against lung cancer.

4.2.5.10 Pulses (legumes)
Studies conducted in Western countries, as most cohorts
have been, are likely to have limited power to detect an association between pulses, and particularly soya intake, andcancer risk because consumption tends to be low.
StomachThree cohort studies,144 146 241 22 case-control studies,109 157
161 162 165 175 179 180 185-187 190 219 224 243 244 247 249-251 270 271 482

2 cross-sectional studies,196 800 and 16 ecological studies116119 197 198 200-203 208 209 236 238 239 801
investigated pulses(legumes) and stomach cancer. Two cohort studies,802 803
9 case-control studies,109 129 159 178 184 194 226 229 262 and 2 ecological studies208 804 investigated soya and soya products.

2•

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J U D G E M E N T S

highest intake groups when compared to the lowest,109 157 161
165 179 185-187 190 219 247 249 250 271
which was statistically significant in six.109 161 165 179 190 249 Six studies reported increased
risk,162 224 243 251 270 482 which was statistically significant in
two.224 243 270 The remaining four studies reported no effecton risk,180 244 or stated that there was no significant effecton risk.175 Meta-analysis was possible on eight studies, giving a summary effect estimate of 0.93 (95% CI 0.87–0.99)
per 20 g/day, with moderate to high heterogeneity.157 162 179
180 186 187 247 249

A dose-response relationship is apparent from case-control
but not cohort data.
One ecological study reported a statistically significant
association, so that higher soya consumption was associatedwith lower stomach cancer risk.208 The other 15 reported nosignificant association.116-119 197 198 200-203 209 236 238 239 801
Soya and soya products

Both cohort studies showed decreased risk for the highest
intake groups when compared to the lowest,802 803 which wasstatistically significant in one.803 The effect estimates were0.60 (44 cases, 95% CI 0.40–1.10)802 and 0.86 (121 cases,
95% CI 0.77–0.96) per 20 g/day.803 The smaller study was
not adjusted for any confounders.
All nine case-control studies showed decreased risk for thehighest intake groups when compared to the lowest,109 129 159
178 184 194 226 229 262
which was statistically significant in five.129
159 178 184 226
Meta-analysis was possible on seven studies, giving a summary effect estimate of 0.82 (95% CI 0.72–0.94)
per 20 g/day, with high heterogeneity.109 129 159 178 194 226 229
Heterogeneity is derived from the size, and not the direction,of the effect.
A dose-response relationship is apparent from case-control
data, as well as from one of the two cohort studies.
Both ecological studies reported statistically significant
inverse relationships, with stomach cancer risk decreasing inareas of increased soya consumption.208 804
The general mechanisms through which pulses (legumes),soya and soya products could plausibly protect against stomach cancer are outlined below. In addition, laboratory experiments have shown that genistein slows down thedevelopment of stomach cancers promoted by sodium chloride by increasing apoptosis, and lowering cell proliferation
and blood vessel growth.805 Additionally, in a rodent model,
a diet containing miso inhibited N-nitrosamine-induced
stomach tumours.806
The evidence, mostly from case-control studies, isinconsistent. There is limited evidence suggesting that
pulses (legumes), including soya and soya products,
protect against stomach cancer.

Pulses (legumes)

Prostate

All three cohort studies reported decreased risk with increased
intake of pulses (legumes),144 146 241 which was statisticallysignificant in one.146 Meta-analysis was possible on two
studies, giving a summary effect estimate of 0.93 (95% CI
0.82–1.05) per 20 g/day, with moderate heterogeneity.144 146
Twelve case-control studies showed decreased risk for theThree cohort studies,589 592-594 11 case-control studies,595 597
and 6 ecological studies116 118 609 807809
investigated pulses (legumes) and prostate cancer. Fourcohort studies,597 810-813 4 case-control studies,603 715 814-816
and 2 ecological studies804 808 investigated soya and soya
products.

112599-601 604 608 617 620 624 715

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Pulses (legumes)

General mechanisms — pulses (legumes)

Two cohort studies reported statistically significant decreased
risk with increased intake589 592; the third study reported that
there was no significant association.594 The reported effectestimates were 0.93 (95% CI 0.87–0.996)589 and 0.817 (95%
CI 0.714–0.934)592 per serving/week. The latter was specific to beans and lentils.
Eight of the case-control studies showed decreased risk
with increased intake,595 597 599 608 617 620 624 715 which was statistically significant in two.597 624 One study showed a nonsignificant increased risk604 and the other reported no effecton risk.600 One study showed a non-significant increased riskfor dried beans and lentils and a non-significant decreased
risk with fresh beans and lentils.601 Meta analysis was possible on four relatively good quality case-control studies, giving a summary effect estimate of 0.97 (95% CI 0.95–0.98)
per serving/week, with no heterogeneity.595 597 599 601
A dose-response relationship is apparent from two of thecohort studies, as well as case-control data.
The five ecological studies generally fail to show a clear
relationship between consumption of pulses and prostatecancer risk; correlations range from -0.15 to -0.63.116 118 609

Pulses (legumes), particularly soya foods, contain various
compounds that may have anti-cancer effects, including protease inhibitors, saponins, and phytoestrogens, such as genistein and daidzein, which are found in high concentrations
in soya.817 These compounds could plausibly influenceoestrogen metabolism. They have also been shown to haveantioxidant effects, inhibit the growth of blood vessels to atumour, and may influence apoptosis and cell growth.818

807-809

Soya and soya products

The cohort studies reported a wide range of results based on
different specific exposures.810-813 One study, which reported on soya and soya products, showed a non-significant
decreased risk for the highest intake groups when comparedto the lowest, with an effect estimate of 0.79 (95% CI
0.53–1.18).810 One study reported a statistically significant
decreased risk with increased intake of soya milk (0.93, 95%
CI 0.87–0.99) per serving/week and a non-significant
decreased risk with increased intake of vegetarian soya products (0.93, 95% CI 0.85–1.01) per serving/week.813 One
reported no association between soya bean paste soup intake
and prostate cancer.811 The final study reported non-significant harmful effects for miso soup and foods cooked in soy
sauce, with effect estimates of 1.05 (95% CI 0.94–1.18) and1.06 (0.474, 2.39) respectively per serving/day.812
All four case-control studies showed non-significant
decreased risk with increased intake.597 603 715 814-816 Meta
analysis was possible on two case-control studies, giving asummary effect estimate of 0.98 (95% CI 0.95–1.00).597 715
The two ecological studies reported no clear relationshipbetween soya consumption and prostate cancer.804 808
Heterogeneity is likely to be derived from the wide variety in specific foods being investigated.
The general mechanisms through which pulses (legumes),soya and soya products could plausibly protect against
prostate cancer are outlined below. In addition, phytoestrogens in pulses and soya can have an androgenic effect, potentially inhibiting testosterone-induced growth of the prostate.
The evidence, mostly from case-control studies, isinconsistent. There is limited evidence suggesting that
pulses (legumes), including soya and soya products,
protect against prostate cancer.

4.2.5.11 Nuts and seeds
The evidence was too limited in amount, consistency, or
quality to draw any conclusions
4.2.5.12 Herbs and spices
Garlic can be classified as a herb or as an allium vegetable.
Data on garlic have contributed to the evidence base for allium vegetables and stomach cancer (see chapter 4.2.5.1.1)
and garlic also probably protects against colorectal cancer(see chapter 4.2.5.1.1).
4.2.5.12.1 Chilli
StomachFourteen case-control studies investigated chilli use andstomach cancer.171 175 176 180 182 187 189 219 246 247 259 415 819-821
Nine studies showed increased risk for the highest intake
groups when compared to the lowest,175 176 180 187 189 219 259
415 820 821
which was statistically significant in four,175 180 259
821
statistically significant in men but not women in a fifth
study,219 and statistically significant in non-drinkers of alcohol, but not alcohol drinkers, in a sixth.176 Four studies
showed decreased risk,171 182 246 247 which was statistically significant in three.182 246 247 One study reported no significant
effect on risk.819
Chilli may be used to disguise ‘off’ flavours in foods, therefore these data may be confounded by socioeconomic status, the availability of refrigeration, and H pylori infection.
Some constituents of chilli are irritants which could therefore plausibly increase inflammation in the stomach.
The evidence, from case-control studies only, isinconsistent. There is limited evidence suggesting thatchilli is associated with an increased risk of stomach
cancer.

4.2.4 Comparison with previous report
The previous report concluded that the evidence that dietshigh in vegetables and fruits protect against cancers of themouth, pharynx, oesophagus, lung, and stomach was convincing; and that the evidence that diets high in vegetables
protect against colorectal cancer was also convincing. The
previous report also judged that diets high in vegetables andfruits probably protected against cancers of the larynx, pancreas, breast, and bladder. The panel also noted a patternwhereby diets high in vegetables and fruits possibly protected against cancers of the cervix, ovary, endometrium,
and thyroid; and that diets high in vegetables possibly pro-113

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tected against cancers of the liver, prostate, and kidney.
Since the mid-1990s, a number of cohort studies havesomewhat weakened the overall evidence for the protective
effects of vegetables and fruits. A number of judgements ofprobable protective effects are made for non-starchy vegetables and for fruits (mouth, pharynx, larynx, oesophagus,
stomach, and (fruits only) lung). In general, the reason forthis is that the more recent cohort studies failed to show theeffect seen in case-control studies.
The previous report also made judgements on types of vegetables and fruits in a footnote, while choosing not to enter
these into the matrix. The evidence that green vegetables
protected against lung and stomach cancer was judged convincing; and probable for mouth and oesophageal cancer.
The evidence that cruciferous vegetables protected against
colorectal and thyroid cancer was judged probable. The evidence that allium vegetables protected against stomach cancer was judged probable. The evidence that raw vegetables
and citrus fruits protected against stomach cancer was
judged convincing. These classifications are somewhat different from those made in this Report, but mostly also generated more confident judgements than are made here.
Vitamins, minerals, and other bioactive constituents offoods and drinks were assessed as such in the previous
report, whereas here they are assessed either as containedin foods and drinks or (see chapter 4.10) as supplements.
The previous report judged that carotenoids (in food) probably protected against lung cancer; that vitamin C (in food)probably protected against stomach cancer; and that thesevitamins and vitamin E possibly protected against cancers of
a number of sites.
The previous panel regretted the lack of evidence on pulses (legumes), nuts, seeds, herbs, and spices, and made no
significant judgements. Since then, evidence on soya and its
products, and on garlic (as well as allium vegetables in general) and chilli, has increased and allowed some judgements.
The previous report judged that aflatoxin contamination
was a probable cause of liver cancer. Since then, the overall
evidence, particularly on the underlying mechanisms, has
strengthened.
The previous report emphasised evidence on vegetables
and on fruits as a whole, while noting evidence on categories
of vegetables and fruits. This Report has not made any separate judgement on raw vegetables and fruits. The previous
report classified bananas as plantains. Here they are classified as fruits. The previous report considered micronutrientsand phytochemicals contained in foods of plant origin in separate chapters. Here, the evidence has been characterised interms of foods containing specified micronutrients, and they
are considered together with vegetables and fruits, pulses(legumes), nuts and seeds, and other plant foods. Similarly,
the previous report considered dietary fibre separately from
cereals (grains) and other plant foods. Here, dietary fibre isconsidered in the context of cereals (grains) and other plantfoods, including those assessed in this section.

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4.2.7 Conclusions
The Panel concludes:
Findings from cohort studies conducted since the mid-1990s
have made the overall evidence that vegetables, or fruits,
protect against cancers, somewhat less impressive. In no case
now is evidence of protection judged to be convincing.
However, there is evidence that some types of vegetables,and fruits in general, probably protect against a number ofcancers. The few judgements on legumes (pulses), nuts,
seeds, and (with two exceptions) herbs and spices, reflect thesmall amount of epidemiological evidence.
Non-starchy vegetables probably protect against cancers ofthe mouth, pharynx, and larynx, and those of the oesophagus and stomach. There is limited evidence suggesting thatthey also protect against cancers of the nasopharynx, lung,colorectum, ovary, and endometrium. Allium vegetables probably protect against stomach cancer. Garlic (an allium vegetable, commonly classed as a herb) probably protects against
colorectal cancer.
Fruits in general probably protect against cancers of themouth, pharynx, and larynx, and of the oesophagus, lung,and stomach. There is limited evidence suggesting that fruits
also protect against cancers of the nasopharynx, pancreas,
liver, and colorectum.
There is limited evidence suggesting that carrots protect
against cervical cancer; and that pulses (legumes), including
soya and soya products, protect against stomach and prostatecancers. There is limited evidence suggesting that chilli is a
cause of stomach cancer.
Fruits and non-starchy vegetables are low energy-dense
foods. For a discussion of the effect of such foods and drinks
on weight gain, overweight, and obesity, and the role ofweight gain, overweight, and obesity in the risk of some cancers, see Chapters 6, 7, and 8.
Evidence that vegetables, fruits, and pulses protect against
some cancers is supported by evidence on various micronutrients, which act as markers for consumption of vegetables,
fruits, and pulses (legumes), and other plant foods. Foods
containing folate probably protect against pancreatic cancer,
and there is limited evidence suggesting that these also protect against oesophageal and colorectal cancers. Foods containing carotenoids probably protect against cancers of themouth, pharynx, and larynx, and also lung cancer. Foods containing the carotenoid beta-carotene probably protect against
oesophageal cancer; and foods containing lycopene, found intomatoes and also fruits such as watermelon, guavas, andapricots, probably protect against prostate cancer. Foods containing vitamin C, found in some vegetables, citrus and otherfruits, and potatoes, probably protect against oesophageal
cancer. There is limited evidence suggesting that foods containing quercetin, such as apples, tea, and onions, protect
against lung cancer.
Evidence on foods containing other micronutrientsis grouped here, for ease of reference. Foods containing

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selenium probably protect against prostate cancer; there
is limited evidence suggesting that they protect against
stomach and colorectal cancers. There is limited evidence
suggesting that foods containing the B vitamin pyridoxine
protect against oesophageal and prostate cancers; and thatfoods containing vitamin E protect against oesophageal andprostate cancers.

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4.3 Meat, poultry, fish, and eggs
MEAT, POULTRY, FISH, EGGS, AND THE RISK OF CANCER
In the judgement of the Panel, the factors listed below modify the risk of cancer. Judgements are graded according to the strength of the evidence.

DECREASES RISK
Exposure

INCREASES RISK

Cancer site

Convincing

Probable

Limited —suggestive

Fish

Colorectum

Foods containing
vitamin D4 7Colorectum

Substantial
effect on risk
unlikely

1
2
3
4
5
6
7

Exposure

Cancer site1

Red meat

Colorectum

Processed meat2

Colorectum

Cantonese-stylesalted fish3

Nasopharynx

Red meat1

Oesophagus
Lung
Pancreas
Endometrium

Processed meat2

Oesophagus
Lung
StomachProstate

Foods containing iron4 5

Colorectum

Smoked foods6

StomachGrilled (broiled) orbarbecued (charbroiled)animal foods6

StomachNone identified

The term ‘red meat’ refers to beef, pork, lamb, and goat from domesticated animals.
The term ‘processed meat’ refers to meats preserved by smoking, curing, or salting, or addition of chemical preservatives.
This style of preparation is characterised by treatment with less salt than typically used, and fermentation during the drying process due to relatively high outdoor
temperature and moisture levels. This conclusion does not apply to fish prepared (or salted) by other means.
Includes both foods naturally containing the constituent and foods which have the constituent added (see chapter 3.5.3).
Although red and processed meats contain iron, the general category of ‘foods containing iron’ comprises many other foods, including those of plant origin.
The evidence is mostly from meats preserved or cooked in these ways.
Found mostly in fortified foods and animal foods.

For an explanation of all the terms used in the matrix, please see chapter 3.5.1, the text of this section, and the glossary.

These animal foods are sources of protein andmicronutrients. The amount and nature of the fat content
of meat, poultry, and fish depends on methods of rearing,processing, and preparation, as well as the type of animal.
Production and consumption of red meat and processedmeat generally rise with increases in available income.
Consumption of beef and products made with beef is still
increasing, notably in China and other middle- and lowincome countries. In many countries, poultry is now also
intensively reared and consumption has increased greatly.
Much fish is now farmed.
In general, the Panel judges that the evidence on red meatand processed meat is stronger than it was in the mid-1990s.
Epidemiological evidence on other methods of preserving
and preparing meats and other animal foods is sparse; theoverall evidence remains suggestive, at most. The evidence
on poultry, fish, and eggs is generally insubstantial.

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The Panel judges as follows:
The evidence that red meats and processed meats are acause of colorectal cancer is convincing. Cantonese-stylesalted fish is a probable cause of nasopharyngeal cancer.
This finding does not apply to any other type of fish
product. Cantonese-style salted fish is also subject tofermentation.
There is limited evidence suggesting that fish, and also
foods containing vitamin D, protect against colorectal
cancer. There is limited evidence suggesting that red meatis a cause of cancers of the oesophagus, lung, pancreas
and endometrium; that processed meat is a cause ofcancers of the oesophagus, lung, stomach and prostate;
and that foods containing iron are a cause of colorectal
cancer. There is also limited evidence that animal foods
that are grilled (broiled), barbecued (charbroiled), or
smoked, are a cause of stomach cancer.

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Red meat can be relatively high in animal fats. For a
discussion of the role of animal fats on cancer, see chapter
4.4 and Chapter 7. Meat can also be energy dense. For
discussion on the role of energy-dense foods on weight
gain, overweight, and obesity, and the role of weight gain,
overweight, and obesity in the risk of some cancers, see
Chapters 6 and 8.
The strongest evidence, corresponding to judgements of‘convincing’ and ‘probable’, shows that red meat andprocessed meat are causes of colorectal cancer, and that
Cantonese-style salted fish is probably a cause ofnasopharyngeal cancer. The Panel also notes limited
evidence suggesting that red meat and processed meat arecauses of other cancers.

It is generally, though not universally, agreed that humans
evolved as omnivores, and that healthy diets usually include
foods of plant and of animal origin — including meat, poultry, fish, and eggs, as well as milk and other dairy products.
Most people who do not eat meat, flesh, or any food of animal origin do so for religious or ethical reasons. Impoverishedcommunities eat little flesh and meat is reserved for feasts.
Partly because meat-eating is a sign of prosperity and partly
because many people enjoy eating meat, poultry, and fish,
production and consumption generally rise as available
income increases. Consumption of beef is, for example, now
increasing very rapidly in China, and consumption of ‘burgers’ made from beef is increasing worldwide.
Early reports concerned with nutritional deficiencies identified meat, poultry, and fish as good sources of protein, iron,and other nutrients, and eggs as a ‘complete food’, especiallyfor children. By contrast, in the second half of the 20th century, reports on meat, poultry, fish, and eggs tended to focus
on red meat as a source of fat and saturated fatty acids andon eggs as a source of dietary cholesterol in the causationof coronary heart disease. These reports promoted poultry
and fish as better choices than red meat, either because they
contain less fat and saturated fatty acids or, in the case ofoily fish, they contain unsaturated fats identified as protective. Little attention has been given to flesh from wild animals and birds, despite this being known to have a different
nutritional profile — lower in total fat and higher in unsaturated fatty acids. On the other hand, since the mid-1990s
more attention has been given in epidemiological studies toprocessed meat as a cause or possible cause of cancers ofsome sites.
For discussion of the role of red meat and processed meatin energy-dense foods and drinks, the effect of energy-dense
foods and drinks on weight gain, overweight, and obesity,and the role of weight gain, overweight, and obesity in therisk of some cancers, see Chapters 6 and 8.
In this Report, methods of production, preservation, processing, and preparation (including cooking), that are solely or mainly to do with meat and other animal foods, areincluded here. Processed meat as a category is included here.
The mineral iron is also covered here, although it is also
found in plant foods.

4.3.1 Definitions and sources
Meat and poultry

In this Report, meat includes all animal flesh apart from fishand seafood. Meat can be further classed as either red meat,
which generally refers to flesh from animals that have more
red than white muscle fibres (in this Report, beef, goat, lamb,and pork), or poultry, which usually has more white than red
muscle fibres (from birds such as chickens, guinea fowl, andturkeys). Meat can also be categorised by dividing it intomeats from skeletal muscles or the internal organs (offal,
such as the brain, liver, heart, intestines, and tongue). Meat
can also be divided according to whether the animal wasdomesticated or wild. Most meats consumed around theworld today are from domesticated animals. ‘Wild’ meats,that is from non-domesticated or free-ranging species, are asignificant source of protein and energy among some populations. Some non-domesticated animals, such as deer or buffalo, are also farmed. However, the evidence presented inthis chapter applies only to meat from domesticated animals.
Some meats are processed in various ways (box 4.3.1).
FishThis Report uses the culinary definition of fish, which
includes shellfish. There are more than 27 000 species of salt
and freshwater fish; many more crustaceans, bivalves, andcephalopods can also be eaten. Fish and shellfish are the only
foods that, globally, are still obtained in significant quantities from the wild. But many species are on the verge of commercial extinction and aquaculture is increasing worldwide.
For instance, more than a third of the salmon eaten worldwide is farmed. Like meat, fish is also processed, for instanceby drying, salting, and smoking.
Eggs

Eggs are the ova of animals and in this Report mean only

Box 4.3.1

Processed meat

What is ‘processed meat’? The question is important because, as
shown here, the evidence that processed meat is a cause ofcolorectal cancer is convincing.
In the broad sense of the word, most meat is processed — cooking is a process. But as commonly used, the term ‘processed meat’refers to meats (usually red meats) preserved by smoking, curing,or salting, or by the addition of preservatives. Meats preserved
only by refrigeration, however they are cooked, are usually notclassified as ‘processed meat’.
There is no generally agreed definition of ‘processed meat’. The
term is used inconsistently in epidemiological studies. Judgements
and recommendations are therefore less clear than they could be.
Ham, bacon, pastrami, and salami are processed meats. So aresausages, bratwursts, frankfurters, and ‘hot dogs’ to which nitrites
or nitrates or other preservatives are added (box 4.3.2). Mincedmeats sometimes fall inside this definition, often if they are preserved chemically, but not always. The same point applies to ‘hamburgers’. Given the importance of this issue, transnational
burger caterers should specify the methods they use to process
their products.

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those of birds; because they are generally eaten before they
have been fertilised, they do not contain an embryo. Eggs
are eaten both on their own and as an ingredient in a variety of baked goods, sauces, and other composite foods.
Chicken eggs are most commonly eaten, although people
also eat duck, ostrich, and quail eggs. Fish eggs (roe) andturtle eggs are not included here.

4.3.2 Composition
Meat and poultry

Meat contains around 20–35 per cent protein by weight. The
fat content by weight ranges from less than 4 per cent in leanpoultry to 30–40 per cent in fatty meat from domesticated,
farmed animals. About 50 per cent of the fatty acids in leanmeat are monounsaturated fatty acids, while saturated fatty
acids make up around 40–50 per cent (see chapter 4.4.2).
Poultry contains a lower proportion of saturated fatty acids(30–35 per cent) and a higher proportion of polyunsaturated fatty acids (15–30 per cent compared with 4–10 per cent).1
There are differences between meats from domesticated animals and wild meats. Wild animals are typically more mature,leaner, and contain a greater variety of aromatic compounds
than farmed animals. They will have received no medicationand their diets will have been uncontrolled. Wild animals are
not only lower in fat, but also have a higher proportion ofpolyunsaturated fatty acids than farmed varieties and a lower
proportion of saturated fatty acids.
Two iron-containing components of muscle tissue, myoglobin and cytochromes, give meat its red colour. It also contains relatively high levels of B vitamins, particularly B6(pyridoxine) and B12, as well as vitamin D, and provides

Box 4.3.2

Nitrates, nitrites, andN-nitroso compounds

Nitrate occurs naturally in plants; levels vary between species
and with different soil conditions and the amount of fertiliser
used. In high-income countries, vegetables account for 70–97
per cent of dietary nitrate intake.2 Between 5 and 20 per centof the nitrate in diets is converted by the body into nitrite, a substance that is also found in some vegetables (notably potatoes).
Nitrite is used to preserve processed meats (it is extremely toxic
to bacteria) and gives cured meats their recognisable colour andflavours. The addition of nitrite and nitrate to food is regulated and monitored in most countries.
Nitrite can react with the degradation products of aminoacids to form N-nitroso compounds (nitrosamines ornitrosamides). These may be formed in meat during the curing
process or in the body (particularly in the stomach) from dietarynitrite (or nitrate).
Several N-nitroso compounds are known human or animal
carcinogens.3 There is concern that nitrite, from processed meats
for example, nitrates in vegetables, and preformed nitrosamines
may be involved in carcinogenesis, particularly in the stomach(see Chapter 2). Dietary nitrates and nitrites are probable humancarcinogens because they are converted in the body to N-nitroso
compounds.3

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Box 4.3.3

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Foods containing iron

Iron deficiency is the most common and widespread nutritional
disorder in the world. It is most common among children andpremenopausal women, and results in iron deficiency anaemia.
Haem iron is found only in foods of animal origin, such asmeat and meat products, fish, and blood products. Non-haemiron is found in plant foods, such as lentils, beans, leafy vegetables, tofu, chickpeas, black-eyed peas, figs, and apricots. The
amount of dietary iron needed to meet the body’s requirements
depends on its bioavailability from the diet. This varies with thediet, as well as factors related to the consumer such as their ironstatus. Iron from animal sources is better absorbed than ironfrom plant sources, but non-haem iron absorption is enhanced
when the body’s iron status is low, or when iron-rich foods areeaten together with vitamin-C rich foods or with meat.
Iron has a central role in metabolism. It is involved in oxidative metabolism within cells and is a component of a numberof enzymes. Free iron can also catalyse the generation of free
radicals, which cause oxidative damage to specific cell components including DNA, protein, and membrane lipids. Iron metabolism and transport are strictly regulated to reduce thelikelihood of cells being exposed to free iron and so to oxidative damage; most iron in living tissues is bound to proteins, suchas transferrin and ferritin, which prevent its involvement in freeradical generation. Also see chapter 4.10.

readily absorbable iron, zinc, and selenium. Eating red meatincreases levels of N-nitroso compounds in the body (box4.3.2), which may be partially due to its high haem content(box 4.3.3). If meat is cooked over an open flame, at hightemperatures, and charred or ‘well done’, heterocyclic
amines or polycyclic aromatic hydrocarbons can be formed(box 4.3.4).
Vitamin D is a fat-soluble vitamin that plays a critical rolein calcium and bone metabolism and in controlling cell differentiation. Low levels may lead to osteomalacia or, in children, rickets and possibly osteoporosis, with increased
fracture risk. Most vitamin D is derived from the action ofsunlight on the skin. Foods such as milk or fat spreads (seechapter 4.9) may be fortified, and then become the major
dietary source of vitamin D; natural sources include sardines
and other oily fish, meat, and eggs.
Fish

Fish has similar levels of protein to meat. It has a fat byweight content of between 0.5 per cent in low-fat fish suchas cod or skate to as much as 20 per cent in oily fish suchas Atlantic salmon or eels. Fat from fish contains lower levels of saturated fatty acids (around 20–25 per cent) thanmeat.
Fish oils from saltwater fish contain long-chain n-3 fatty
acids (see chapter 4.4.2). Wild fish have a lower fat content
than farmed fish, with a higher proportion of n-3 fatty acids.
Only marine algae and phytoplankton produce these fatty
acids, so the fish that feed on them are the primary dietary
sources. These fatty acids are essential to the development
and function of the brain and retina; they also reduce inflammation, blood clotting, and cholesterol production. The bodyC H A P T E R

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Heterocyclic amines and polycyclic aromatic hydrocarbons

Heterocyclic amines are formed when muscle meats such as
beef, pork, fowl, and fish are cooked. High cooking temperatures cause amino acids and creatine (a chemical found in muscles) to react together to form these chemicals. So far, 17different heterocyclic amines have been identified as being
formed by cooking muscle meats and which may pose a cancer
risk (also see Chapter 2).
Temperature is the most important factor in the formation ofthese chemicals. Frying, grilling (broiling), and barbecuing (charbroiling) produce the largest amounts because these cooking
methods use very high temperatures. Oven roasting and baking involve lower temperatures, so meats cooked in this way are
lower in heterocyclic amines, but gravy made from meat drippings contains substantial amounts. Meats that are partiallycooked in a microwave oven before being cooked by otherhigher-temperature methods also have lower levels of thesechemicals.4
Polycyclic aromatic hydrocarbons (PAHs) are a group of over
100 different chemicals formed when organic substances like
tobacco or meat are burnt incompletely. Grilling (broiling) andbarbecuing (charbroiling) meat, fish, or other foods with intenseheat over a direct flame results in fat dropping on the hot fire;
this produces PAHs that stick to the surface of food. The more
intense the heat, the higher the level of contamination; usingwood creates more PAHs than charcoal. Cereals contaminatedwith PAHs are also a common source of these chemicals in thediet. Levels in cereals are considerably lower than in grilledmeats, but their overall contribution to diets is larger.5 Taken
together, cereals and meat and meat products account for morethan 50 per cent of dietary levels of these chemicals. Intakes arethought to be relatively high in Europe, particularly in northern Europe, although measures are only available from a few,
generally high-income, countries.6

can convert alpha-linolenic acid (found in plant foods andessential in the diet) to eicosapentaenoic acid and docosohexanoic acid, which are found in fish oils, but the rates of
conversion are low.
Fish contain lower levels of B vitamins, iron, and zinc thanmeat and poultry, but oily fish are a source of retinol and vitamin D. Fish are also a source of calcium if the bones areeaten with the flesh, for example, when canned.
Fish and shellfish have the potential to accumulate pollutants that are washed into rivers and oceans, and these tend
to accumulate in their fat. These pollutants can include
heavy metals and organic compounds, some of which are
known carcinogens. Farmed fish are exposed to veterinary
medicines, and some environmental toxins may reach highconcentrations in their food. But farmed fish are less likely
than wild fish to become contaminated with environmental
pollutants. The balance of risks and benefits of eating fish
at various stages of the life course needs to be determined.
Also see chapter 4.9.
Eggs

Eggs, like meat, poultry, and fish, contain all the essential

amino acids needed by humans. A typical large hen’s egg has
roughly equal weights of protein and fat, with 60 per centof the energy coming from fat. A typical large shelled egg
contains 6 g protein; 1 g carbohydrate; 4.5 g fat (2.0 gmonounsaturated, 0.5 g polyunsaturated, and 1.5 g saturated fatty acids); and about 200 mg cholesterol. It also contains retinol, folate, thiamin, riboflavin, vitamin B12,
vitamin D, and iron. The yolk’s colour comes fromcarotenoids, and contains all of the fat and cholesterol andmost of the iron, thiamin, and retinol. The white is 90 per
cent water and is virtually fat free, containing mainly protein, with some vitamins, and traces of glucose.
In Asia, eggs containing 2–3 week old chick fetuses may
occasionally be included in diets. There is no nutritional difference between these and unfertilised eggs, except that fertilised eggs contain additional calcium absorbed from theshell.

4.3.3 Consumption patterns
Meat and poultry

Globally, meat accounts for about 8 per cent of total energy
availability, 18 per cent of dietary protein, and 23 per centof dietary fat. Meat consumption is considerably higher inhigh-income countries (10 per cent of total energy intake
compared with 7 per cent in low-income countries), and isparticularly high in the USA, parts of South America, someparts of Asia, northern Europe, and most of Oceania.
Consumption is particularly low in most of Africa and otherparts of Asia where vegetarian ways of life are commonplace.
Bangladesh has the lowest level of intake (0.6 per cent) andMongolia the highest (28 per cent).7
As a general rule, meat consumption increases with economic development. Worldwide, between 1961 and 2002,
meat consumption per person doubled, with pork and poultry showing the greatest increases; in Japan it increased
nearly six-fold. Globally, overall energy availability increased in the same period by just 12 per cent. Consumption ofmeat and other animal foods from wild and undomesticated animals is low on a global basis, but these foods areimportant parts of diets within many middle- and lowincome countries, as well as being delicacies in high-income
countries.
Fish

Worldwide, fish (including shellfish) account for 1 per centof available dietary energy; these foods are particularly
important in island and coastal communities. For instance,in the Maldives, marine fish account for 15 per cent of
dietary energy, but in some landlocked, low-income countries, this figure is practically zero. In general, fish consumption is highest in Asia and Oceania. Freshwater fishprovide a relatively small proportion of dietary energy (0.3
per cent), but they are a more important source of dietaryenergy in low-income countries, and are particularly important in regions with large lakes and rivers. Salting is a traditional method of preserving raw fish throughout much of
the world (box 4.3.5).

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Box 4.3.5

Cantonese-style salted fish

Salting is a traditional method of preserving raw fish throughout much of the world. The freshness of the fish and the salting and drying conditions vary considerably between regions,although fish are usually dried outside, in direct sunlight. This
results in varying levels of fermentation and/or insect infestation. Salted fish is a component of diets typical of Asia, Africa,and parts of the Mediterranean.
Depending on the precise conditions, salt-preserved fish may
also undergo fermentation. The degree of fermentation that
occurs depends on the freshness of the raw fish, the amount ofsalt used, the outdoor temperature, and the duration of the drying process. In general, excluding the factor of freshness, salted fish is less likely to be fermented in the northern part ofChina compared with the southern part of China (where
nasopharyngeal cancer is more common). Cantonese-style salted fish is characterised by using less salt and a higher degree offermentation during the drying process, because of the relatively high outdoor temperature and moisture levels.
Cantonese-style salted fish are a traditional part of the dietin southern China, Taiwan, Malaysia, and Singapore.

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processed meat could possibly be due, at least in part, to low
intakes of these other foods.
Production, processing, patterns. Practically all the evidence
relates to these foods as preserved, processed, or prepared(cooked) in some way. Evidence on meat, poultry, andincreasingly on fish, is practically all from these foods as produced industrially. There is very little evidence on wild animals and birds, despite the quantity and nature of their bodyfat, and other aspects of their nutritional profile, being different. Epidemiological evidence on specific methods ofpreservation, processing, and preparation/cooking of meat,
poultry, and fish is mostly patchy, despite some of these being
known to generate carcinogens established as such in experimental studies. Also see chapter 4.9.

4.3.5 Evidence and judgements
The full systematic literature review (SLR) is contained on
the CD included with this Report.
4.3.5.1 Meat

Eggs

4.3.5.1.1 Red meat

Worldwide, eggs provide 1.2 per cent of available food energy. Egg consumption is highest in the Far East, North
America, and Europe, ranging from nearly 3 per cent in theseareas to virtually zero in many African countries; it is significantly higher in high-income countries. Preserved eggs
(pickled, salted, or cured) are traditional in some cultures.

Some studies may have included processed meats in theirclassification of red meat intake.

4.3.4 Interpretation of the evidence
4.3.4.1 General
For general considerations that may affect interpretation of
the evidence, see chapters 3.3 and 3.5, and boxes 3.1, 3.2,
3.6 and 3.7.
‘Relative risk’ (RR) is used in this Report to denote ratio
measures of effect, including ‘risk ratios’, ‘rate ratios’, ‘hazard ratios’, and ‘odds ratios’.
4.3.4.2 SpecificSome considerations specific to meat, poultry, fish, and eggs
include:Classification. ‘Fish’ is a broad classification. Different fish

have different nutritional profiles and biological effects, one
obvious example being white fish and oily fish. These areoften not distinguished in epidemiological studies.
Terminology.

As yet, there is no agreed definition for‘processed meat’. Some studies count minced meat, or ham,bacon, and sausages as processed meats; others do not. See
the footnote to the matrix and box 4.3.1.

Confounding. People who consume large amounts of meatand processed meats tend to consume less poultry, fish, andvegetables, and vice versa. So an apparent effect of meat and120

Colorectum

Sixteen cohort studies8-24 and 71 case-control studies investigated red meat and colorectal cancer.
All of the cohort studies that reported analyses of risk forthe highest intake group when compared to the lowest
showed increased risk (figure 4.3.1),8-24 which was statistically significant in four (one of these was specific to rapidacetylator genotypes).9 10 12 18 23 Meta-analysis was possible

Figure 4.3.1

Red meat and colorectal cancer;
cohort studies
Relative risk (95% CI)

Philips 1975

2.70 (1.60–4.55)

Slattery 2001 Women

1.04 (0.62–1.75)

Kato 1997 Women

1.23 (0.68–2.22)

Singh 1998

1.41 (0.90–2.21)

Pietinen 1999 Men

1.20 (0.80–1.80)

Jarvinen 2001

1.50 (0.77–2.93)

Tiemersma 2002 Men

2.70 (1.09–6.66)

Tiemersma 2002 Women

1.20 (0.51–2.84)

Wei 2003 Men

1.35 (0.80–2.27)

Wei 2003 Women

1.31 (0.73–2.36)

Chen 2003

1.48 (0.85–2.59)

English 2004

1.40 (1.02–1.93)

Norat 2004

1.17 (0.92–1.49)

0.2

0.5

1

2

5

Relative risk, highest vs lowest exposure category

C H A P T E R

4•

Figure 4.3.2

F O O D S

A N D

D R I N K S

Red meat and colorectal cancer;
cohort studies

Figure 4.3.3

Red meat and colorectal cancer;
cohort studies

Relative risk (95% CI)
Willet 1990 Women

1.81 (1.17–2.80)

Bostick 1994 Women

0.96 (0.80–1.14)

Giovannucci 1994 Men

2.20 (1.24–3.91)

Singh 1998

4.51 (0.38–53.27)

Chen 1998 Men, NAT rapid

2.57 (0.78–8.84)

Chen 1998 Men, NAT slow

0.88 (0.45–1.75)

Tiemersma 2002 Men

3.44 (0.83–14.18)

Tiemersma 2002 Women

1.42 (0.22–9.00)

English 2004

1.23 (0.88–1.73)

Summary estimate

1.43 (1.05–1.94)

0.2

0.5

1

2

5

Relative risk (95% CI)

Pietinen 1999

1.05 (0.74–1.48)

Norat 2005

1.49 (0.91–2.43)

Larsson 2005 Women

1.43 (1.05–0.95)

Summary estimate

1.29 (1.05–1.59)

0.2

0.5

1

2

5

Relative risk, per 100 g/day

9

Relative risk, per time/week

Figure 4.3.4

on seven studies that measured red meat intake in ‘times per
week’ and three studies that measured grams per day. The
summary effect estimates were 1.43 (95% confidence interval (CI) 1.05–1.94) per times/week and 1.29 (95% CI
1.04–1.60) per 100 g/day, respectively (figures 4.3.2 and4.3.3). There was moderate heterogeneity in the former
analysis and low heterogeneity in the latter.
A dose-response relationship is apparent from cohort data
(figure 4.3.4).
These data are supported by a recently published metaanalysis of 15 prospective studies, which reported a summary effect estimate of 1.28 (95% CI 1.18–1.39) per 120
g/day.25
Because of the abundant prospective data from cohort
studies, case-control studies were not summarised.
The general mechanisms through which red meat could
plausibly cause cancer are outlined below. In addition,
dietary haem iron induces colonic cytotoxicity and hyperproliferation.26
A substantial amount of data from cohort and casecontrol studies showed a dose-response relationship,
supported by evidence for plausible mechanisms
operating in humans. Red meat is a convincing causeof colorectal cancer.

The Panel is aware that since the conclusion of the SLR, sixcohort27-32 and four case control studies33-36 have been published. This new information does not change the Panel judgement (see box 3.8).
Oesophagus

Twelve case-control studies37-50 investigated red meat andoesophageal cancer.
Eight studies reported increased risk for the highest intake
group when compared to the lowest,37-39 41-45 49 50 which wasstatistically significant in five.37 41 42 45 Three studies reported

Red meat and colorectal cancer; cohort
studies: dose response

Kinlen 1983 Men

Kinlen 1983 Women

Giovannucci 1994 Men

Bostick 1994

English 2004

0

5

10

15

Red meat (times/week)

non-significant decreased risk38 40 46; one study reported
no significant effect on risk,47 48 but did not provide further
details. Most of these studies adjusted for smoking andalcohol.
The general mechanisms through which red meat could
plausibly cause cancer are outlined below.
There is limited evidence, from case-control studies,some of which were poor quality, suggesting that redmeat is a cause of oesophageal cancer.

The Panel is aware that since the conclusion of the SLR, onecohort study51 has been published. This new information does
not change the Panel judgement (see box 3.8).
Lung

One cohort study52 and nine case-control studies53-62 investigated red meat and lung cancer.

121

P A R T

The single cohort study showed increased risk for the highest intake group when compared to the lowest, with an effectestimate of 1.6 (95% CI 1.0–2.6; p value for trend < 0.014),
based on 158 cases.52
Seven case-control studies showed increased risk for thehighest intake group when compared to the lowest,53-58 60 61
which was statistically significant in four.54 55 60 61 One study
reported non-significant decreased risk59 and one study
showed no effect on risk.62 All except the latter study adjusted for smoking.
The general mechanisms through which red meat could
plausibly cause cancer are outlined below.
There is limited evidence, mostly from inconsistentcase-control studies, suggesting that red meat is a
cause of lung cancer.

2•

E V I D E N C E

A N D

J U D G E M E N T S

Five case-control studies showed increased risk for thehighest intake group when compared to the lowest,46 76-79
which was statistically significant in two.77 78 Two studies
showed non-significant reduced risk.80 81 Meta-analysis was
possible on six studies, giving a summary effect estimate of
1.20 (95% CI 1.03–1.39) per 50 g red meat/day, with moderate heterogeneity.46 76-80
The general mechanisms through which red meat could
plausibly cause cancer are outlined below.
The evidence, mostly from case-control studies, issparse. There is limited evidence suggesting that redmeat is a cause of endometrial cancer.

The Panel is aware that since the conclusion of the SLR, one
case-control study82 has been published. This new information
does not change the Panel judgement (see box 3.8).

Pancreas

Seven cohort studies63-69 and four case-control studies46 70-72
investigated red meat and pancreatic cancer.
Six cohort studies showed increased risk for the highest
intake group when compared to the lowest,63-65 67-69 which
was statistically significant in one,64 and two of the studies
also had statistically significant tests for trend.65 67 One study
reported a non-significant increased risk that was very close
to no effect.66 Meta-analysis was possible on two studies, giving a summary effect estimate of 1.00 (95% CI 0.95–1.05)
per 20 g/day, with no heterogeneity.63 66 However, the two
included studies were not typical. The effect estimates for thehighest intake group when compared to the lowest in theother five cohort studies were 1.45 (95% CI 1.19–1.76),64
1.73 (95% CI 0.99–2.98; with a statistically significant test
for trend),65 2.4 (95% CI 1–6.1; with a statistically significant test for trend),67 1.1 (95% CI 0.9–1.2),68 and 1.4 (95%
CI 0.4–4.8) for men and 2.7 (95% CI 0.8–8.9) for women.69
All of the case-control studies showed increased risk forthe highest intake group when compared to the lowest,46 7072
which was statistically significant in three.46 71 72 Metaanalysis was possible on three case-control studies, giving asummary effect estimate of 1.11 (95% CI 1.08–1.15) per 20
g/day, with no heterogeneity.46 71 72
The general mechanisms through which red meat could
plausibly cause cancer are outlined below. In addition, boththe secretory function of the pancreas and cell turnover within the pancreas are altered by the types of foods eaten.73
Amino acids and fatty acids stimulate more pancreatic secretions than do carbohydrates.74
Evidence from cohort studies is less consistent thanthat from case-control studies. There is limited
evidence suggesting that red meat is a cause ofpancreatic cancer.
Endometrium

One cohort study75 and seven case-control studies46 76-81
investigated red meat and endometrial cancer.
The single cohort study showed a non-significant increased
risk for the highest intake group when compared to the lowest, with an effect estimate of 1.10 (95% CI 0.70–1.73).75

122

General mechanisms

There are several potential underlying mechanisms for an
association between red meat consumption and cancer,
including the generation by stomach and gut bacteria ofpotentially carcinogenic N-nitroso compounds. Some redmeats are also cooked at high temperatures, resulting in the
production of heterocyclic amines and polycyclic aromatichydrocarbons (box 4.3.4). Haem promotes the formationof N-nitroso compounds and also contains iron. Free iron canlead to production of free radicals (box 4.3.3). Iron overload
also activates oxidative responsive transcription factors,
pro-inflammatory cytokines, and iron-induced hypoxia
signalling.83

Figure 4.3.5

Processed meat and colorectal cancer;
cohort studies
Relative risk (95% CI)

Philips 1975

2.05 (1.50–4.06)

Goldbohm 1994 Men

1.84 (0.85–3.97)

Goldbohm 1994 Women

1.66 (0.82–2.36)

Bostick 1994 Women

1.51 (0.72–3.17)

Gaard 1996 Women

3.50 (1.02–11.95)

Gaard 1996 Men

1.98 (0.70–5.59)

Kato 1997 Women

1.09 (0.59–2.02)

Pietinen 1999 Men

1.20 (0.75–1.92)

Tiemersma 2002 Men

1.00 (0.51–1.95)

Tiemersma 2002 Women

0.80 (0.43–1.50)

Flood 2003 Women

0.97 (0.73–1.28)

Wei 2003 Men

1.27 (0.87–1.85)

Wei 2003 Women

1.32 (0.95–1.83)

English 2004

1.50 (1.11–2.02)

Chao 2005 Men

1.11 (0.80–1.54)

Chao 2005 Women

1.16 (0.85–1.58)

Norat 2005

1.42 (1.09–1.85)

0.2

0.5

1

2

5

Relative risk, highest vs lowest exposure category

C H A P T E R

4•F O O D S

A N D

D R I N K S

4.3.5.1.2 Processed meat

The variation in definitions for processed meat used by different studies (see chapter 4.3.1) is likely to contribute tothe observed heterogeneity.

Figure 4.3.6

Processed meat and colorectal cancer;
cohort studies
Relative risk (95% CI)

Colorectum

Goldbohm 1994

1.69 (1.10–2.58)

Fourteen cohort studies8-10 14-19 21 27 69 84 85 and 44 case-control
studies investigated processed meat and colorectal cancer.
Twelve cohort studies showed increased risk for the highest intake group when compared to the lowest (figure
4.3.5),8-10 14-19 21 27 69 85 which was statistically significant inthree.9 14 15 85 One study reported non-significant decreased
risk and one study reported that there was no effect on risk.84
Meta-analysis was possible on five studies, giving a summary
effect estimate of 1.21 (95% CI 1.04–1.42) per 50 g/day,with low heterogeneity (figures 4.3.6 and 4.3.7). What heterogeneity there is could be explained by the disparity in category definitions between studies, as well as by improved
adjustment for confounders in recent studies. A doseresponse relationship was also apparent from cohort studies
that measured in times/day (figure 4.3.8).
The majority of case-control studies showed increased risk
with increasing intake of processed meat. Because of theabundant prospective data from cohort studies, case-control
studies were not summarised.
These data are supported by a recently published metaanalysis of 14 cohort studies, which reported a summary
effect estimate of 1.09 (95% CI 1.05–1.13) per 30 g/day.25
The general mechanisms through which processed meat
could plausibly cause cancer are outlined below.

Pietinen 1999

0.99 (0.79–1.24)

Chao 2005 Men

1.40 (1.04–1.88)

Chao 2005 Women

1.14 (0.64–2.05)

Norat 2005

1.30 (0.93–1.80)

Larsson 2005 Women

1.13 (0.85–1.51)

Summary estimate

1.21 (1.04–1.42)

0.2

0.5

Figure 4.3.7

2

5

Processed meat and colorectal cancer;
cohort studies: dose response

Choa 2005 Men

Choa 2005 Women

Goldbohm 1994 Men

Goldbohm 1994 Women

There is a substantial amount of evidence, with a doseresponse relationship apparent from cohort studies.
There is strong evidence for plausible mechanisms
operating in humans. Processed meat is a convincing
cause of colorectal cancer.

The Panel is aware that since the conclusion of the SLR, fivecohort28 30 32 86 87 and two case-control studies36 88 have been
published. This new information does not change the Panel
judgement (see box 3.8).

1

Relative risk, per 50 g/day

0

100

200

300

Processed meat (g/day)Figure 4.3.8

Processed meat and colorectal cancer;
cohort studies: dose response

Oesophagus

Two cohort studies89 90 and eight case-control studies40 41 43
investigated processed meat and oesophageal
cancer.
Both cohort studies showed non-significant increased risk
for the highest intake groups when compared to the lowest.89
90
The effect estimates were 1.24 (95% CI 0.73–2.1)90 and
1.6 (95% CI 0.4–6.9).89 Both analyses adjusted for age,smoking, and alcohol.
Six case-control studies showed increased risk for the highest intake groups when compared to the lowest,43 44 49 50 9193
which was statistically significant in one.93 Two studies
showed non-significant reduced risk.40 41 94
The general mechanisms through which processed meat
could plausibly cause cancer are outlined below.
44 49 50 91-94

Giovannucci 1994 Men

Bostick 1994 Women

English 2004

0

0.2

0.4

0.6

0.8

1

Processed meat (times/day)

123

P A R T

2•

E V I D E N C E

A N D

J U D G E M E N T S

There is limited evidence, mostly from case-control
studies, suggesting that processed meat is a cause ofoesophageal cancer.

The evidence is inconsistent. There is limited evidence
suggesting that processed meat is a cause of stomach
cancer.

The Panel is aware that since the conclusion of the SLR, onecohort study51 has been published. This new information does
not change the Panel judgement (see box 3.8).

The Panel is aware that since the conclusion of the SLR, onecohort135 and two case-control studies136 137 have been published. This new information does not change the Panel judgement (see box 3.8).

Lung

Four cohort studies52 69 95 96 and 10 case-control studies33 5557 59 97-104
investigated processed meat and lung cancer.
Three cohort studies reported non-significant increased
risk for the highest intake group when compared to the lowest.69 95 96 One study reported no effect on risk.52 95 Metaanalysis was possible on two of the studies, giving asummary effect estimate of 1.03 (95% CI 0.92–1.16) per
serving/week, with no heterogeneity.52 All four cohort studies adjusted for smoking.
Six case-control studies reported increased risk for thehighest intake group when compared to the lowest,33 56 57 59
99 100 102-104
which was statistically significant in two.100 102
Four studies reported non-significant decreased risk.55 97 98 101
All of the studies adjusted for smoking.
The general mechanisms through which processed meat
could plausibly cause cancer are outlined below.
There is limited, inconsistent evidence suggesting thatprocessed meat is a cause of lung cancer.
Stomach cancer

Eight cohort studies,51 69 105-110 21 case-control studies,49 111132
1 cross-sectional study,133 and 1 ecological study134 investigated processed meat and stomach cancer.
Five cohort studies showed increased risk for the highest
intake group when compared to the lowest,51 106-108 110 which
was statistically significant in one.51 Two studies reported
non-significant decreased risk105 109; and one showed noeffect on risk in men and non-significant decreased risk in
women.69 Meta-analysis was possible on all eight cohort
studies, giving a summary effect estimate of 1.02 (95% CI
1.00–1.05) per 20 g/day, with no heterogeneity.
Thirteen case-control studies showed increased risk for thehighest intake group when compared to the lowest,49 113 117
119-121 124-132
which was statistically significant in seven.120 125
128-132
Three studies showed decreased risk,118 122 123 which
was statistically significant in one118; and one showed noeffect on risk.116 Four other studies reported no significant
difference between mean intakes in cases and controls.111 112
114 115
Meta-analysis was possible on nine studies, giving asummary effect estimate of 1.13 (95% CI 1.01–1.25) per
20 g/day, with high heterogeneity.49 117-119 121 123 128-130
A dose-response relationship is apparent from case-control
but not cohort data.
The single ecological study reports a statistically significant
correlation between increased processed meat and stomach
cancer risk.134
The general mechanisms through which processed meat
could plausibly cause cancer are outlined below.

124

Prostate

Four cohort studies138-141 and six case-control studies142-147
investigated processed meat and prostate cancer.
All four cohort studies showed increased risk for the highest intake group when compared to the lowest,138-141 which
was statistically significant in two.139 141 Meta-analysis was
possible on all four cohort studies, giving a summary effectestimate of 1.11 (95% CI 0.995–1.25) per serving/week,with high heterogeneity. Heterogeneity was caused by varying size, not direction, of effect.
Two of these studies reported separately on advanced
or aggressive cancer. Both showed increased risk withincreasing intake of processed meat,138 141 which was statistically significant in one.141 Meta-analysis was possible on
both studies, giving a summary effect estimate of 1.09 (95%
CI 0.98–1.22) per serving/week, with moderate heterogeneity.
Four case-control studies showed non-significant
decreased risk with increasing intake of processed meat143145 147; two showed non-significant increased risk.142 146 Metaanalysis was possible on five case-control studies, giving asummary effect estimate of 1.01 (95% CI 0.98–1.04) per
serving/week, with low heterogeneity.143-147 The generalmechanisms through which processed meat could plausibly
cause cancer are outlined below.
There is limited evidence from sparse and inconsistentstudies suggesting that processed meat is a cause of
prostate cancer.

The Panel is aware that since the conclusion of the SLR, twocohort studies148 149 have been published. This new information
does not change the Panel judgement (see box 3.8).
General mechanisms

Nitrates are produced endogenously at the low pH in thestomach and are added as preservatives to processed meats,both of which may contribute to N-nitroso compound production and exposure. N-nitroso compounds are suspectedmutagens and carcinogens.150 Many processed meats also
contain high levels of salt and nitrite. Some processed meats
are also cooked at high temperatures, resulting in the production of heterocyclic amines and polycyclic aromatichydrocarbons. Red meat contains haem iron. Haem promotes
the formation of N-nitroso compounds and also contains
iron. Free iron can lead to production of free radicals (box4.3.3).

C H A P T E R

4•F O O D S

A N D

D R I N K S

4.3.5.2 Poultry
The evidence was too limited in amount, consistency, or
quality to draw any conclusions.
4.3.5.3 Fish, shellfish
Colorectum

Nineteen cohort studies8-10 14-18 21 23 69 85 151-161 and 55 casecontrol studies investigated fish and colorectal cancer.
Nine cohort studies showed decreased risk for the highest
intake group when compared to the lowest,8 15-17 21 69 85 154
157 158 160
which was statistically significant in two.15 16 Eightstudies showed non-significant increased risk.9 10 18 23 151-153
155 156 159
One study showed no effect on risk14 and one study
reported that there was no statistically significant association.161 Meta-analysis was possible on seven cohort studies,giving a summary effect estimate of 0.96 (95% CI 0.92–1.00)
per serving/week, with low heterogeneity.8 9 14 18 21 158 160
Because of the abundant prospective data from cohort
studies, case-control studies were not summarised.
Heterogeneity may be partially explained by varying definitions of fish in different studies that included fresh and/or
salted or dried fish. It is also possible that high fish intake
is associated with low meat intake, which is a potential confounder that has not been adjusted for.
It is biologically plausible that fish n-3 polyunsaturated
fatty acids (PUFAs) protect against cancer. Fish oils reducetumours in animal studies.162 Likely mechanisms are thought
to revolve around their role in reduction of n-6 PUFA-derived
eicosanoid biosynthesis (eicosanoids promote inflammation)and direct inhibition of COX-2 (cyclooxygenase-2, an enzyme
involved in the production of prostaglandins), which is also
implicated in the cancer process (see Chapter 2). This mechanism, though plausible, is not well supported.163 Alternative
suggestions include the relatively high selenium or vitamin
D content of fish.

assessed in the 1960s, 1970s, and 1980s. The p value fortrend for the association between each decade’s intake andincreased risk was < 0.001, 0.014, and 0.21, respectively.
Seventeen of the case-control studies showed increased
risk for the highest intake group when compared to the lowest,169-178 182-188 which was statistically significant in nine.170
172 173 176 178 182 185-188
One study showed a non-significant
decreased risk168; three studies reported that there was no
association.179-181 Meta-analysis was possible on nine studies, giving a summary effect estimate of 1.28 (95% CI
1.13–1.44) per serving/ week, with high heterogeneity (figure 4.3.9). Heterogeneity was related to size, and not direction, of effect.

Figure 4.3.9

Salted fish and nasopharyngeal cancer;
case control
Relative risk (95% CI)

Yuan 2000

1.73 (0.66–4.52)

Lee 1994

1.17 (0.85–1.61)

Zheng 1994

2.50 (1.63–3.85)

Sriamporn 1992

1.35 (1.06–1.72)

Yu 1989

1.10 (1.00–1.21)

Yu 1986

1.31 (1.13–1.51)

Weiming 1995

1.71 (1.08–2.70)

Cai 1996

1.06 (1.00–1.02)

Zou 1999

1.32 (1.13–1.54)

Summary estimate

1.28 (1.13–1.44)

0.1

Figure 4.3.10

A substantial amount of data is available but theresults are inconsistent, and residual confounding bymeat could not be excluded. There is limited evidence
suggesting that eating fish protects against colorectal
cancer.

The Panel is aware that since the conclusion of the SLR, sixcohort28 30 164 165 and two case-control studies33 166 have been
published. This new information does not change the Panel
judgement (see box 3.8).
4.3.5.3.1 Cantonese-style salted fish
Nasopharynx

One cohort study167 and 21 case-control studies161-188 investigated Cantonese-style salted fish (box 4.3.5) intake inadults and nasopharyngeal cancer. Sixteen case-control studies168 170-174 177-179 181 188-193 investigated intake in childhoodand 10 case-control studies168 171-174 177 188 189 194 195 investigated intake in infancy (less than 3 years).

1

5

Relative risk, per time/week

Salted fish and nasopharyngeal cancer;
case-control studies
Relative risk (95% CI)

Ward 2000

0.80 (0.52–1.24)

Yuan 2000

1.82 (0.86–3.86)

Armstrong 1998

4.22 (2.23–7.99)

Lee 1994

4.40 (0.72–26.76)

Zheng 1994

4.07 (0.36–45.80)

Zheng 1994b17.20 (2.28–104.79)

West 1993

1.30 (0.67–2.52)

Sriamporn 1992

2.50 (1.20–5.20)

Yu 1989

1.80 (0.90–3.60)

Yu 1986

7.50 (0.88–63.89)

Ning 1990

2.20 (1.30–3.71)

Ye 1995

5.00 (1.27–19.72)

Ye 1995b

2.00 (0.88–4.56)

Cai 1996

1.32 (0.98–1.77)

Chen 1994

5.51 (1.74–17.44)

Wang 1993

8.99 (1.60–50.44)

Zou 1999

3.04 (1.66–5.69)

0.01

1

100

Relative risk, highest vs lowest exposure category

Adult intake

The single cohort study showed increased risk for the highest intake group when compared to the lowest. Intake was125

P A R T

Figure 4.3.11

Salted fish and nasopharyngeal cancer;
case-control studies: dose response

Zou 1999
Cai 1996
Ye 1995

2•

E V I D E N C E

A N D

J U D G E M E N T S

pounds with a common carcinogenic mechanism.150 Salted
fish has been shown to contain N-nitrosamines, with thehighest levels in salted fish from areas with the highest mortality from nasopharyngeal cancer.196 197 The variation innitrosamine content of salted fish may contribute to heterogeneity in assigning risk to salted fish consumption in different geographic locations. There is also some evidence thatgenotype interacts with the risk associated with salted fish
intake, particularly the gene for the cytochrome P450
enzyme, CYP2E1.192 198

Yu 1986

Evidence from several case-control studies is
consistent and shows a dose-response effect. There isevidence for plausible mechanisms. Cantonese-stylesalted fish is probably associated with increased risk ofnasopharyngeal cancer.

Yu 1989
Sriamporn 1992
Zheng 1994b
Lee 1994
Yuan 2000

0

2

4

6

8

Salted fish, times/week

4.3.5.4 Eggs
The evidence was too limited in amount, consistency, or
quality to draw any conclusions.
4.3.5.5 Foods containing vitamin D
Colorectum

Eleven cohort studies17 24 154 199-210 and 17 case-control studies investigated total vitamin D and/or dietary vitamin D andcolorectal cancer. Four cohort studies investigated plasma or
serum vitamin D.22 210-212
Childhood intake

Dietary vitamin D

Fifteen case-control studies that investigated the intake ofsalted fish at 10 years of age showed increased risk for thehighest intake group when compared to the lowest,168 170 172174 177-179 181 188-193
which was statistically significant in 8170
172 173 177-179 188 190(figure 4.3.10). One study showed a nonsignificant decreased risk.171 Meta-analysis was possible on
9 studies,171 173 174 177 178 181 188-190 giving a summary effectestimate of 1.35 (95% CI 1.14–1.60) per serving/week, withhigh heterogeneity. Heterogeneity was related to size, andnot direction, of effect.
Nine case-control studies that investigated the intake ofsalted fish at 3 years of age showed increased risk for thehighest intake group when compared to the lowest,171-174 177
188 189 194 195
which was statistically significant in five.172 173
177 188 195
One study showed no effect on risk.168 Meta-analysis was possible on five studies,171 173 174 177 189 giving a summary effect estimate of 1.42 (95% CI 1.11–1.81) per
serving/week, with moderate heterogeneity. Heterogeneity
was related to size, and not direction, of effect.
A dose-response relationship is apparent from case-control
data (figure 4.3.11). Cohort and case-control data suggest adelayed and/or cumulative effect from eating Cantonesestyle salted fish.

Twelve estimates from 11 cohort studies reported analysesof the highest intake groups compared to the lowest.17 154 199206
Six of these showed non-significant decreased risk154 199202 205; 2 studies reported no effect on risk17 205; and 4 studies
show non-significant increased risk.203 204 206 Meta-analysis
was possible on 9 studies that investigated dietary vitaminD, giving a summary effect estimate of 0.99 (95% CI
0.97–1.00) per 100 IU/day, with moderate heterogeneity.17

General mechanisms

Evidence suggests that high intake of nitrate and nitrosaminefrom salted fish accounts for some of this increased risk ofnasopharyngeal cancer development. Nitrosamines are
known mutagens and animal carcinogens that induce genemutation. The N-nitrosamines are a large group of com-126

154 199 202 204-206 209 210

Serum or plasma vitamin D

All four cohort studies showed non-significant decreased risk
for the highest intake groups when compared to the lowest.22
210-212
Effect estimates were 0.73 (stated as non-significant)211; 0.4 (95% CI 1–1.4; serum 25-hydroxyvitamin D)
and 1.1 (95% CI 0.4–3.2; serum 1,25 hydroxyvitamin D)212;
0.6 (95% CI 0.3–1.1; serum 25-hydroxyvitamin D) and 0.9(95% CI 0.5–1.7; serum 1,25 hydroxyvitamin D)210; and 0.53
(95% CI 0.27–1.04).22
Because of the abundant prospective data from cohort
studies, case-control studies were not summarised.
The effects of vitamin D and calcium are strongly interrelated because both are growth restraining, both induce differentiation and apoptosis in intestinal cells, and calciummediated effects are strongly dependent on vitamin D levels. Data from observational studies are probably hamperedby the fact that total levels of the biologically active form are
not only dependent on diet but also on supplements and UV
exposure of the skin.

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The evidence on vitamin D was inconsistent. There islimited evidence suggesting that foods containing
vitamin D, or better vitamin D status, protect against
colorectal cancer.

The Panel is aware that since the conclusion of the SLR, twocase-control studies166 213 have been published. This new information does not change the Panel judgement (see box 3.8).
4.3.5.6 Foods containing iron
Colorectum

Four cohort studies214-217 and 23 case-control studies investigated iron intake and colorectal cancer. One cohort study
investigated haem iron intake.218
The four cohort studies showed increased risk for the highest intake group when compared to the lowest,214-216 218
which was statistically significant in two.214 218 Effect estimates were 1.17 (95% CI 0.6–2.3)216; 3.35 (95% CI
1.74–6.46; colon cancer)214; and 2.18 (95% CI 1.24–3.86;
proximal colon cancer).218 One study reported a non-significant higher intake in cancer cases (18.4 mg) than in controls (17.4 mg).215 The other reported that mean iron intakes
were similar between male colon cancer cases, rectal cancer
cases, and male sub-cohort cases (13.2, 13.3, and 13.2 mg
per day, respectively), and between female colon cancer
cases, rectal cancer cases, and female sub-cohort cases (11.4,
11.6, and 11.7 mg/day, respectively).217
Data suggest that the effect may be limited to proximal
cancer cases and attenuated in distal cancer. Two studies
reported results separately for proximal and distal colon cancer cases.214-218 The effect estimates for the former were 1.44
(95% CI 1.23–1.69)214 and 2.18 (95% CI 1.24–3.86),218 and1.03 (95% CI 0.8–1.32)214 and 0.90 (95% CI 0.45–1.81) forthe latter.218
Because of the abundant prospective data from cohort
studies, case-control studies were not summarised.
It is biologically plausible that iron increases colorectal
cancer risk due to its catalytic activity on the formation ofreactive oxygen species. Haem promotes the formation of Nnitroso compounds and also contains iron. Free iron can leadto production of free radicals (box 4.3.3). However, this role
has not been confirmed in animal studies. Another hypothesis is that dietary haem induces colonic cytotoxicity andhyperproliferation.26 Iron overload also activates oxidative
responsive transcription factors, proinflammatory cytokines,
and iron-induced hypoxia signalling.83
The evidence is sparse, of poor quality, andinconsistent. There is limited evidence suggesting thatfoods containing iron are in general a cause ofcolorectal cancer. (Also see chapter 4.3.5.1.1 forevidence on red and processed meat, which areclassified as convincing causes of colorectal cancer.)

The Panel is aware that since the conclusion of the SLR, twocohort studies87 219 have been published. This new information
does not change the Panel judgement (see box 3.8).

4.3.5.7 Smoked foods
StomachSeventeen case-control studies116 118 220-235 and two ecologicalstudies236 237 investigated smoked foods and stomach cancer.
Fourteen case-control studies showed increased risk for thehighest intake group when compared to the lowest,118 220 221
224-235
which was statistically significant in 11.118 224-234 One
study reported non-significant decreased risk222 and 2 studies reported no effect on risk.116 223 More than half of theeffect estimates were greater than 1.5. None of the studies
adjusted for infection with Helicobacter pylori.
One ecological study reported a statistically significant
increased risk with higher intake of smoked foods236; theother reported decreased risk, though one constituent ofsmoked food (3,4-benzopyrene) was associated withincreased risk.237
Heterogeneity may be partly explained by variation
between studies in the definition of smoked foods — somewere specific to smoked meats and most included meats.
Smoked foods, particularly meats, may contain polycyclicaromatic hydrocarbons, depending on the fuel burned to
produce the smoke.238 Smoked meats are also often salted
or cured, meaning that they are likely to raise endogenous
production of N-nitroso compounds in the stomach (box
4.3.4).
There is limited evidence from case-control andecological studies, some of which were of poor quality,that smoked foods are causes of stomach cancer.

The Panel is aware that since the conclusion of the SLR, threecase-control studies136 137 239 have been published. This new
information does not change the Panel judgement (see box
3.8).
4.3.5.8 Grilled (broiled) or barbecued(charbroiled) animal foods
StomachThree cohort studies240-242 and 12 case-control studies investigated grilled (broiled) and barbecued (charbroiled) foods
and stomach cancer.
Two cohort studies showed increased risk for the highest
intake group when compared to the lowest,240 242 which wasstatistically significant in one.242 One study reported a nonsignificant reduced risk.241 Effect estimates were 1.67 (pvalue for trend < 0.05)242; 1.77 (95% CI 0.59–5.33) for
grilled (broiled) fish and 2.08 (95% CI 0.97–4.46) for grilled(broiled) meat240; and 0.84 (95% CI 0.55–1.29).241 None of
the studies adjusted for H pylori infection.
Eight case-control studies showed increased risk for thehighest intake group when compared to the lowest,126 129 130
233 243 245-247
which was statistically significant in seven. One
study reported a statistically significant decreased risk121;
two studies reported non-significant decreased risk220 248;
and one study stated that there was no significant effect on
risk.244
Charring or cooking meats over open flame generates heterocyclic amines and polycyclic hydrocarbons, which may
cause cancer (box 4.3.4).

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There is limited, inconsistent evidence, mostly fromcase-control studies, that grilled (broiled) orbarbecued (charbroiled) animal foods are causes ofstomach cancer.

4.3.6 Comparison with previous report
The panel responsible for the previous report judged thatdiets relatively high in red meat were probable causes of colorectal cancer, and noted a pattern whereby red meat was a
possible cause of cancers of the pancreas, breast, prostate,
and kidney.
The previous report considered methods of production,
preservation, processing, and preparation (including cooking). Cured meats were judged to be a possible cause of colorectal cancer; and grilled, barbecued, and fried meats, andother foods to be a possible cause of colorectal cancer; andgrilling (broiling) and barbecuing (charbroiling) to be a possible cause of stomach cancer. Processed meat was not identified as such. The evidence on Cantonese-style salted fish
was judged to be convincing for nasopharyngeal cancer. The
panel noted that the risk was highest when this food is eaten
frequently in early childhood. This Report concluded the evidence to be probable, in view of the paucity of prospective
data
Since the mid-1990s, the results of cohort studies havestrengthened the evidence on red meat and processed meatas causes of colorectal cancer.

4.3.7 Conclusions
The Panel concludes:
The evidence on red meat and processed meat is stronger
than in the mid-1990s. Epidemiological evidence on othermethods of preserving and preparing meats and other animal foods is sparse, and the overall evidence remains suggestive, at most. The evidence on poultry, fish, and eggs is
generally insubstantial.
The evidence that red meats and processed meats area cause of colorectal cancer is convincing. Cantonese-stylesalted fish is a probable cause of nasopharyngeal cancer.
This finding does not apply to any other type of fish
product. Cantonese-style salted fish is also subject tofermentation.
There is limited evidence suggesting that fish, and also
foods containing vitamin D, protect against colorectal cancer. There is limited evidence suggesting that red meat is a
cause of cancers of the oesophagus, lung, pancreas andendometrium; that processed meat is a cause of cancers of
the oesophagus, lung, stomach and prostate; and that foods
containing iron are a cause of colorectal cancer. There is also
limited evidence that foods that are grilled (broiled), barbecued (charbroiled), and smoked are a cause of stomach
cancer. The evidence comes mostly from meat preserved or
prepared in these ways.
Meat, as mentioned above, is likely to be relatively highin animal fats. For discussion of the role of animal fats on

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cancer, see chapter 4.4. Meat may also be energy dense. For
discussion on the role of energy-dense foods on weight gain,
overweight, and obesity, and the role of weight gain, overweight, and obesity in the risk of some cancers, see Chapters
6 and 8.

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4.4 Milk and dairy products
MILK, DAIRY PRODUCTS, AND THE RISK OF CANCER
In the judgement of the Panel, the factors listed below modify the risk of cancer. Judgements are graded according to the strength of the evidence.

DECREASES RISKINCREASES RISK

Exposure

Cancer site

Exposure

Cancer site

Probable

Milk1 4

Colorectum

Diets high in calcium2 3

Prostate

Limited —suggestive

Milk1

Bladder

Milk and dairy products2

Prostate

Cheese4

Colorectum

Convincing

Substantial
effect on risk
unlikely1234None identified

Milk from cows. Most data are from high-income populations, where calcium can be taken to be a marker for milk/dairy consumption. The Panel judges that a higher
intake of dietary calcium is one way in which milk could have a protective effect.
Effect only apparent at high calcium intakes (around 1.5 g/day or more). Evidence for milk and dairy products (but not calcium) was derived only from data forcountries with populations that have high calcium and dairy consumption.
Includes diets that naturally contain calcium and that contain foods fortified with calcium. See box 4.10.1.
Although both milk and cheese are included in the general category of dairy products, their different nutritional composition andconsumption patterns may result in different findings.

For an explanation of all the terms used in the matrix, please see chapter 3.5.1, the text of this section, and the glossary.

Milk and products made from milk, such as cheese, butter,ghee, and yoghurt, have been consumed ever since suitableanimals were domesticated. Whole milk and cheese andyoghurt made from whole milk have a high proportion ofenergy from fat and from protein, although the absoluteconcentrations in liquid milk are lower than those in cheese
due to the higher water content. They also contain anumber of vitamins, including retinol and riboflavin, andminerals, particularly calcium. In countries where
consumption of milk and dairy products is high, these are
the main sources of calcium. Low-fat dairy products retain
all of the protein, the water-soluble vitamins, and themineral content. However, the fat-soluble vitamins are
significantly reduced. Low-fat milk or whole milk issometimes fortified with vitamins A and D.
Until the late 19th century, milk from animals was used asa substitute for human milk for feeding infants. Adults did
not usually consume such milks; if they did, it was in low
amounts. Populations that kept milk-giving animals
consumed other dairy products. From the early 20th
century, a number of factors were responsible for cow’s milk
becoming almost a staple food in the USA and some
European countries. These included the industrialisation of
cattle farming; the identification of milk as a basic food,especially for children; and the development of refrigeration
techniques and ultra-heat treated packaging. Dried milk is
now a common ingredient in many processed foods.

Overall, the Panel judges that the evidence on milk anddairy products, and on calcium, shows that their impact
on the risk of cancer varies in different tissues.
The Panel judges as follows:
Milk probably protects against colorectal cancer. There islimited evidence suggesting that milk protects against
bladder cancer. There is limited evidence suggesting thatcheese is a cause of colorectal cancer. Diets high incalcium are a probable cause of prostate cancer; and there
is limited evidence suggesting that high consumption ofmilk and dairy products is a cause of prostate cancer.
The strongest evidence, corresponding to judgements of‘convincing’ and ‘probable’, shows that milk probably
protects against colorectal cancer, and that diets high incalcium are a probable cause of prostate cancer.

Milk and dairy products are important components of diets
in some but not all parts of the world. Until recently in history, milk from several ruminant animals was used as a partial substitute for or in addition to human milk; but thesemilks were usually consumed infrequently and, if at all, laterin childhood or by adults. In countries where milk-giving
animals were raised, their products were consumed in theform of cheese, butter, ghee, and in fermented form as
yoghurts or in combination with alcoholic drinks.

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From the late 19th century, consumption of cow’s milk
greatly increased in the USA, the UK, and some other
European countries. This was a result of a massive increase
in dairy farming supported by new techniques such as condensation, drying, and cooling. In the 20th century,
consumption was further boosted by pasteurisation anddoorstep delivery, the decline of breastfeeding, and the common view that modified cow’s milk is a suitable food for
infants and an excellent food for young children. Dried milk
is a mainstay of programmes of food aid to impoverishedcountries. However, populations living outside North America
and northern Europe have until recently consumed little milk
as such, and dairy products consumed are in the form of
yoghurt or products derived from it. This may be due to thelimited capacity to digest lactose beyond infancy observed inthese populations. Yoghurt is fermented, which lowers lactose
concentration, and is therefore better tolerated.
Reports in the early part of the 20th century of different
forms of malnutrition in young children, which documented
a requirement for high amounts of animal protein to curethese conditions, supported the categorisation of milk, eggs,
and meat as protective foods. By contrast, reports publishedsince the 1960s have identified whole milk and dairy products, which have a high proportion of energy from fat and saturated fatty acids, as foods that contribute to the pathogenesisof coronary heart disease. More recently, some reports concerned with the prevention of osteoporosis in Western populations have recommended high intakes of calcium.
This chapter is concerned with milk and its products. The
evidence on milk is on milk from cows, and the evidence on
cheese is from all sources. It does not consider human milk
or infant formula. For human milk, see chapter 4.11. Nor doesit consider soya drinks or other plant-derived alternatives. For
soya drinks, see chapter 4.2. For butter, see chapter 4.5.
Calcium is included here because in countries where milk
and dairy products are important in diets, these are the main
sources of what is a generally high intake of calcium. Dietarycalcium also comes from bones when these are consumed(small or tinned fish, for example, and in stews), egg shells,
and from some plant foods. In many countries, plant foods
are the main source of calcium. See chapters 4.1, 4.2, and 4.4.

4.4.1 Definitions, sources
Milk is produced by all mammal species to suckle their
young. It has evolved to be the ideal nourishment for mammalian infants of each species and, in normal conditions,contains all the nutrients they need at that stage of theirlives. Although all mammal species produce milk, only a few
are employed widely as milk producers, and they are allruminants. Milk from other species must be modified before
feeding to infants to allow for their limited capacity tometabolise and excrete nitrogenous compounds and salts inearly life.
Ruminant animals have a large, multichambered stomachthat contains microbes, which allows them to ferment cellulose and extract nutrients from green and dried grasses.
Some species or breeds (notably European cows) have been

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bred to produce copious amounts of milk. Around the world,
other bovine animals used to supply milk include zebu cows
in Asia, water buffalo in Asia and some parts of Europe, andyaks, although usually only in the mountainous regions in
Asia. Goats and sheep are also important and widespreadmilk-producing animals, as well as camels, which live in arid
climates around the world. In some areas of the world, otheranimals such as horses, old- and new-world camels, and reindeer are locally important.
Fresh milk can be consumed raw (untreated) or, as is common in many high-income countries, pasteurised (see chapter 4.9.3). Milk is also commonly processed into a wide
variety of foods including cream, concentrated milks,
cheese, fats such as butter and ghee, and fermented foods
such as yoghurt.

4.4.2 Composition
Milk and dairy products in whole form have a high proportion of energy from fat and protein, and contain some vitamins and minerals.1 The precise composition varies between
species and breeds, and with the nature of their feed. Sheepand yak milks are particularly high in protein; buffalo, sheep,and yak milks are high in fat. Typical whole cow’s milk contains 3.4 g protein and 3.6 g fat per 100 g.1 Reduced fat(semi-skimmed) and low-fat (skimmed) milks are produced
from whole milk, and the foods made from these milks havea correspondingly lower fat and fat-soluble vitamin content
than those made from whole milk.
Around two thirds of the fatty acids in cow’s milk are saturated. Polyunsaturated fatty acids make up less than 4 percent of milk fat (see chapter 4.5.2). Fat accounts for half ofthe energy in whole milk. Milk contains all the essential
amino acids in the appropriate proportions for humans (seechapter 4.10.1).
The only significant carbohydrate found in milk is thedisaccharide lactose. Milk products such as cheese andyoghurt contain varying amounts of lactose. Hard cheeses
contain only traces, soft cheeses 2–3 per cent, yoghurts 4 percent, compared to 5 per cent found in whole milk; this isbecause cheese and yoghurt have been fermented by bacteria used in the production of these foods.
Milk, cheese, and yoghurt contain high levels of calcium(box 4.4.1). They are also sources of riboflavin and vitamin
B12, and full-fat dairy products are sources of retinol, andto a lesser extent, other fat-soluble vitamins. Milk also contains several growth factors and hormones, though these areprobably digested in the stomach. However, milk consumption has been shown to elevate circulating levels of insulinlike growth factor.

4.4.3 Consumption patterns
Consumption of milk and dairy products throughout theworld is highly variable. The overall global average of around
5 per cent of available dietary energy2 conceals wide variations. The range is from 10–15 per cent of dietary energy inC H A P T E R

Box 4.4.1

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Foods containing calcium

In countries with high intakes of milk and dairy products, these
are the main source of calcium. Most of the epidemiologicalstudies reviewed here are from those countries.
Calcium is found in plant as well as in animal foods, but it is lesseasily absorbed. Other animal sources include small fish (wheneaten with their bones) and meat (when rendered on the bone instews). Plant sources include green vegetables, nuts, and pulses(legumes).1 3
Calcium is the most abundant mineral in the body and is the
major mineral constituent of bones. It is central to a variety offunctions in the body, such as bone metabolism, nerve and muscle activity, and the control of cell differentiation and proliferation. Calcium metabolism is controlled by various factors,
including vitamin D and related hormonal compounds formedby the liver and kidney, necessary for the absorption of calcium
from foods, and its regulation in the body.

the USA and some European countries to less than 0.5 percent in some African and Asian countries.

4.4.4 Interpretation of the evidence
4.4.4.1 General
For general considerations that may affect interpretation of
the evidence, see chapters 3.3 and 3.5, and boxes 3.1, 3.2,
3.6 and 3.7‘Relative risk’ (RR) is used in this Report to denote ratio
measures of effect, including ‘risk ratios’, ‘rate ratios’, ‘hazard ratios’, and ‘odds ratios’.
4.4.4.2 SpecificPatterns and ranges of intake. Most studies are carried out

in high-income countries where consumption of cow’s milk
and its products is high, and where the main dairy productconsumed is milk.

Milk and dairy products

Seven cohort studies showed increased risk with increased
intake of milk and dairy products,4 6 8-11 13 15 which wasstatistically significant in two.6 10 Two studies showed nonsignificant decreased risk5 12 14; and one study showed noeffect on risk.7 Meta-analysis was possible on eight studies,giving a summary effect estimate of 1.06 (95% confidence
interval (CI) 1.01–1.11) per serving/day, with moderateheterogeneity.4-12
Five of these cohort studies reported separately on
advanced/aggressive prostate cancer.5 7 9 10 12 Two studies
showed increased risk with increased intake of milk anddairy products,9 10 which was statistically significant in one.9
Three studies showed non-significant decreased risk.5 7 12
Meta-analysis was possible on four studies, giving a summary effect estimate of 1.00 (95% CI 0.94–1.06) per serving/day, with low heterogeneity.5 7 10 12 The study that could
not be included in the meta-analysis was inconsistent withthis result, reporting an effect estimate of 2.35 (95% CI
1.29–4.26) per serving/day increase (dry weight).9
Eight case-control studies showed increased risk withincreased intake of milk and dairy products,16 19-21 23 24 26 28
which was statistically significant in one. 28 Four studies
showed non-significant decreased risk17 18 22 25 27; and one
study reported that there was no statistically significant
effect on risk.29 Meta-analysis was possible on five relatively high-quality studies, giving a summary effect estimate of
1.03 (95% CI 0.99–1.07) per serving/day, with low heterogeneity.16-20
One ecological study showed no significant association,with an age-adjusted correlation coefficient of -0.49.30 One
other ecological study reported no statistically significant
effect.31
There are many separate exposures being measured within this broad category, which may explain the observed heterogeneity.
A dose-response relationship is apparent from cohort dataon all prostate cancer, but not from cohort data on
advanced/aggressive prostate cancer or case-control data.
Milk

Classification. Studies usually do not make any distinction

between dairy products, such as cheeses from different
sources and with different compositions.

4.4.5 Evidence and judgements
The full systematic literature review (SLR) is contained on
the CD included with this Report.
4.4.5.1 Milk and dairy products
Prostate

Ten cohort studies,4-15 13 case-control studies,16-29 and 2 ecological studies30 31 investigated milk and dairy products andprostate cancer; 16 cohort studies,5-8 10 12 14 32-40 11 case-control studies,21 26 27 41-51 and 11 ecological studies30 31 52-61
investigated milk.

Six cohort studies showed increased risk with increased
intake of milk,6 8 33 36 37 39 which was statistically significant
in one.6 Three studies showed no effect on risk32 34 35 and one
study showed non-significant decreased risk.14 The remaining six studies did not report quantified results, but statedresults were not statistically significant.5 7 10 12 38 40 Metaanalysis was possible on eight studies, giving a summary
effect estimate of 1.05 (95% CI 0.98–1.14) per serving/day,with low heterogeneity.6 8 14 32-36
Six studies reported separately on advanced/aggressive
prostate cancer.7 12 33 36 39 40 Three studies showed increased
risk with increased intake of milk, with effect estimates of
1.30 (95% CI 1.04–1.61) per serving/day36; 2.8 (in men
aged 72.5 years or less, for the highest intake groups compared to the lowest, with no CI reported)33; and an increased
risk with a p value for trend of 0.005.39 Three studies did
not report quantified results but stated that there was no significant association.7 12 40

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Seven case-control studies showed increased risk withincreased intake of milk,27 41-44 47-51 which was statisticallysignificant in three (including the single relatively high quality study).41 43 44 47 Two studies showed non-significant
decreased risk21 45; one study reported no effect on risk46 andone study stated that there was no significant association but
did not present results.26 Meta-analysis was possible on six
relatively low quality studies, giving a summary effect estimate of 1.08 (95% CI 0.98–1.19) per serving/day, with moderate heterogeneity.21 27 42-45
Ten ecological studies reported correlations in the direction of increased risk.31 52 54-61 One study did not provide aquantified result, but stated there was no statistically significant association.53 One study showed a non-significant
decreased risk in areas of increased intake.30
Milk could plausibly cause prostate cancer through theactions of calcium (see chapter 4.4.5.1.1). Also, consumption of milk increases blood levels of insulin-like growth factor-1, which has been associated with increased prostatecancer risk in some studies.62 63
The evidence is inconsistent from both cohort andcase-control studies. There is limited evidence
suggesting that milk and dairy products are a cause of
prostate cancer.

The Panel is aware that since the conclusion of the SLR, twocohort studies64 65 and one case-control study66 have been published. This new information does not change the Panel judgement (see box 3.8).
4.4.5.1.1 Milk
Colorectum

Thirteen cohort studies67-82 and 36 case-control studies investigated milk and colorectal cancer. Fifteen cohort studies7277 79 80 82-101
and 58 case-control studies investigated dietarycalcium.
Milk

Nine cohort studies showed decreased risk with increased
intake of milk,67 69 70 72 74 75 77 80-82 which was statistically sig-

Figure 4.4.1

Milk and colorectal cancer; cohort studies
Relative risk (95% CI)

Keamey 1996 Men

0.80 (0.57–1.11)

Gaard 1996 Women

1.05 (0.74–1.49)

Gaard 1996 Men

0.98 (0.86–1.11)

Ma 2001 Men

0.64 (0.35–1.19)

McCullough 2003 Women

1.08 (0.86–1.36)

McCullough 2003 Men

0.86 (0.72–1.01)

Summary estimate

0.94 (0.85–1.03)

0.2

0.5

1

2

Relative risk, per serving/day

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Milk and colorectal cancer: cohort studies:dose response

Ma 2001 Men

McCullough 2003 Women

McCullough 2003 Men

Keamey 1996 Men

0

0.5

1

1.5

Milk (servings/day)nificant in two.67 80 Two studies showed non-significant
increased risk69 71 78 79 and two studies showed non-significant increased risk in women and non-significant decreased
risk in men.68 73 76 Meta-analysis was possible on four studies, giving a summary effect estimate of 0.94 (95% CI
0.85–1.03) per serving/day, with low heterogeneity (figures
4.4.1 and 4.4.2).72 73 76 81
In addition, there was a pooled analysis from 10 cohort
studies which included 534 536 participants with 4992 casesof colorectal cancer. Milk intake was related to a statistically significant reduced risk of colorectal cancer (relative risk
(RR) 0.78; 95% CI 0.69–0.88) for the highest intake groupwhen compared to the lowest.102
Dietary calcium

Eleven studies showed decreased risk with increased intake
of calcium,76 79 82 84 85 90-93 99 which was statistically significant
in three.84 85 90 One study showed non-significant increased
risk74; one study showed non-significant increased risk in
women and non-significant decreased risk in men73; and two
studies showed non-significant decreased risk of colon cancer and non-significant increased risk of rectal cancer.88 89
Meta-analysis was possible on 10 cohort studies giving a summary effect estimate of 0.98 (95% CI 0.95–1.00) per 200
mg/day, with low heterogeneity (figure 4.4.3).72 73 76 77 79 83
87 90 98 99
When meta-analysis was restricted to eight studies
that reported results separately for colon cancer, a summary
effect estimate of 0.95 (95% CI 0.92–0.98) per 200 mg/day
was produced, with no heterogeneity.72 73 76 77 83 87 89 90
Dose-response plot

Figure 4.4.4 shows the dose-response curve for dietary calcium intake and colorectal cancer incidence.
In addition, there was a pooled analysis from 10 cohort
studies which included 534 536 participants with 4992
cases of colorectal cancer. Dietary calcium intake wasrelated to a statistically significant reduced risk of colorectal cancer (RR 0.86; 95% CI 0.78–0.95) for the highest

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Figure 4.4.3

A N D

D R I N K S

Dietary calcium and colorectal cancer:
cohort studies
Relative risk (95% CI)

Stemmermann, 1990 Men

0.98 (0.91-1.06)

Bostick 1993 Women

0.95 (0.87-1.02)

Martinez 1996 Women

0.95 (0.89-1.01)

Kearney 1996 Men

0.95 (0.85-1.05)

Gaard 1996 Men

0.86 (0.68-1.09)

Gaard 1996

0.98 (0.71-1.36)

Tangrea 1997 Men

1.00 (0.92-1.08)

Terry 2002 Women >=55 years

0.85 (0.75-0.96)

Terry 2002 Women <55 years

0.97 (0.80-1.19)

McCullough 2003 Men

0.95 (0.88-1.02)

McCullough 2003 Women

1.02 (0.93-1.11)

Koh 2004

1.00 (1.00-1.00)

Lin 2005 Women

0.99 (0.90-1.10)

Summary estimate

0.98 (0.95-1.00)

0.5

1

2

Relative risk, per 200 mg/day

The evidence on milk from cohort studies is reasonably
consistent, supported by stronger evidence fromdietary calcium as a dietary marker. There is evidence
for plausible mechanisms. Milk probably protects
against colorectal cancer.

The Panel is aware that since the conclusion of the SLR, threecohort80 103 104 and three case-control studies66 105 106 have been
published. This new information does not change the Panel
judgement (see box 3.8).
Bladder cancer

Five cohort studies,34 107-111 14 case-control studies,48 112-124
and 1 ecological study56 investigated milk and bladdercancer.
All five cohort studies showed decreased risk withincreased intake of milk,34 107-111 which was statistically significant in one.108 Meta-analysis was possible on four studies, giving a summary effect estimate of 0.82 (95% CI
0.67–0.99) per serving/day, with moderate heterogeneity.34
108-110intake group when compared to the lowest.102
Because of the abundant prospective data from cohort
studies, case-control studies were not summarised.
Dietary calcium intake can be interpreted as a marker ofdairy intake only in those populations (usually European,
Australian, or from the Americas) that consume relatively
regular and large amounts of milk and dairy products. Other
dietary sources of calcium include vegetables, nuts, pulses,
and fish or meat cooked on the bone (box 4.4.1).
The general mechanisms through which milk could plausibly protect against cancer are outlined below.

Figure 4.4.4

Dietary calcium and colorectal cancer;
cohort studies: dose response

Seven case-control studies showed decreased risk withincreased intake of milk,48 112 115-117 121 122 which was statistically significant in four.115 117 121 122 Four studies showednon-significant increased risk,113 114 120 123 and three studies
stated that there was no significant association.118 119 124
Meta-analysis was possible on three relatively high-quality
case-control studies, giving a summary effect estimate of
1.00 (95% CI 0.87–1.14) per serving/day, with high heterogeneity.113-115
A dose-response relationship is apparent from cohort, but
not case-control data.
The single ecological study reported a correlation of 0.45
between milk consumption and death from bladder cancer.56
The general mechanisms through which milk could plausibly protect against cancer are outlined below.
The evidence is inconsistent and comes mainly fromevidence on dietary calcium. There is limited evidence
suggesting that milk protects against bladder cancer.
General mechanisms — milk

The probable effect of milk in reducing cancer risk is likely
to be mediated at least in part by calcium. Calcium from dietis an import micronutrient, and intracellular calcium directly influences cell growth and apoptosis. Calcium may alsobind to bile and fatty acids, preventing them from damaging the intestinal lining.125 Milk includes many bioactive constituents, however, which may also play a role.
4.4.5.1.2 Cheese
Colorectum
0

500

1000

1500

Dietary calcium (mg/day)2000

Eleven cohort studies67 68 70 72 74 78-80 82 126-128 and 25 casecontrol studies investigated cheese and colorectal cancer.
Eight cohort studies showed increased risk with increased
intake of cheese, none of which was statistically significant.67
68 70 72 74 79 80 126 127
Two studies reported non-significant
decreased risk78 82 and one study reported that there was no
significant association.128 Two meta-analyses were possible

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on three and two cohort studies, respectively, giving summary effect estimates of 1.14 (95% CI 0.82–1.58) per serving/day72 79 126 and 1.11 (95% CI 0.88–1.39) per 50 g/day,80
82
both with low heterogeneity.
Because of the abundant prospective data from cohort
studies, case-control studies were not summarised.
No specific mechanism has been identified but cheese
could plausibly cause colorectal cancer through the indirect
mechanisms connected to saturated fats. Saturated fats
intake increases insulin production and expression of insulin
receptors on colonic cells.129 Saturated fats can also induce
expression of certain inflammatory mediators associatedwith carcinogenesis.130
Epidemiological evidence for cheese intake is consistently in contrast to the probable protective effect from milk.
The evidence is inconsistent. There is limited evidence
suggesting that cheese is a cause of colorectal cancer.

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A dose-response relationship was apparent from cohort but
not case-control data.
One ecological study from Germany showed a significant
increased risk of prostate cancer with higher calcium
intakes.146 Another study from Taiwan reported a nonsignificant decreased risk with higher calcium intakes.145
High calcium intake downregulates the formation of 1,25
dihydroxy vitamin D(3) from vitamin D, thereby increasingcell proliferation in the prostate.7 Prostate cancer tumoursin rats treated with 1,25 dihydroxy vitamin D(3) were significantly smaller and presented smaller numbers of lungmetastases.147
The evidence, from both cohort and case-control
studies, is substantial and consistent with a doseresponse relationship. There is evidence for plausible
mechanisms. Diets high in calcium are a probablecause of prostate cancer.

The Panel is aware that since the conclusion of the SLR, twocohort studies66 103 104 and one case-control study66 have been
published. This new information does not change the Panel
judgement (see box 3.8).

The Panel is aware that since the conclusion of the SLR, twocohort studies64 65 have been published. This new information
does not change the Panel judgement (see box 3.8).

4.4.5.2 Diets high in calcium
For evidence on calcium supplements, see chapter
4.10.6.4.4.
Calcium is a good marker for dairy intake in Western diets.
In areas outside the USA, Europe, and Oceania, dairy products are not as widely consumed and the range of calcium
intake is smaller (see also box 4.4.1).

4.4.6 Comparison with previous report
The previous report judged that milk and dairy products possibly increase the risk of prostate and kidney cancer. Calcium
was judged possibly not to affect the risk of colorectal cancer. Since the mid-1990s, more evidence has emerged on
prostate cancer, and that for kidney cancer is now inconclusive.

Prostate

Nine cohort studies,4-8 10 11 131-133 12 case-control studies,18 19
and 2 ecological studies145 146 investigated dietarycalcium and prostate cancer.
Seven cohort studies showed increased risk with increased
intake of dietary calcium,4-7 10 11 131 133 which was statistically significant in three.6 10 133 Two studies showed non-significant decreased risk, including the only unadjusted study.8
132
Meta-analysis was possible on eight cohort studies, giving a summary effect estimate of 1.27 (95% CI 1.09–1.48)
per g/day, with moderate heterogeneity.5-8 10 11 131-133
Four of these cohort studies reported separately on
advanced/aggressive prostate cancer.5 7 10 133 Three studies
showed increased risk with increased intake of milk anddairy products,7 10 133 which was statistically significant in
one.133 One study showed non-significant decreased risk.5
Meta-analysis was possible on all four studies, giving a summary effect estimate of 1.32 (95% CI 1.05–1.64) per g/day,with moderate heterogeneity.5 7 10 133
Six case-control studies showed non-significant decreased
risk with increased intake of dietary calcium.18 134 136 138-140
143 144
Five studies showed increased risk,19 23 24 135 137 141
which was statistically significant in one19 138; and one otherstudy showed no effect on risk.142 Meta-analysis was possible on three relatively high-quality studies, giving a summary
effect estimate of 1.16 (95% CI 0.64–2.14) per gram ofcalcium/day, with high heterogeneity.18 19 134
23 24 134-144

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4.4.7 Conclusions
The Panel concludes:
The evidence on the relationship between milk and dairy
products, and also diets high in calcium, and the risk of cancer, points in different directions.
Milk probably protects against colorectal cancer; there islimited evidence suggesting that milk protects against bladder cancer. But there is limited evidence suggesting thatcheese is a cause of colorectal cancer.
Diets high in calcium are a probable cause of prostate cancer; there is limited evidence suggesting that high consumption of milk and dairy products is a cause of prostatecancer.

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4.5 Fats and oils
FATS, OILS, AND THE RISK OF CANCER
In the judgement of the Panel, the factors listed below modify the risk of cancer. Judgements are graded according to the strength of the evidence.

DECREASES RISK
Exposure

INCREASES RISK

Cancer site

Exposure

Cancer site

Total fat

Lung
Breast (postmenopause)

Convincing
Probable
Limited —suggestive

Foods containing animal fats1 Colorectum
ButterSubstantial
effect on risk
unlikely

1Lung

None identified

Includes both foods naturally containing the constituent and foods that have had the constituent added (see Chapter 3).

For an explanation of all the terms used in the matrix, please see chapter 3.5.1, the text of this section, and the glossary.

Fats and oils are the most energy-dense constituents offood supplies and diets. Their contribution to total dietaryenergy increases with industrialisation and urbanisation.
Meat from most industrially bred animals is higher in fat
than that from wild animals, and such meat fats, together
with fat from milk and dairy products, are a major sourceof fat in most high-income countries. Many processed
foods contain substantial amounts of oils from plantsources. Production and consumption of animal fats andoil from plant sources have greatly increased in recent
decades, most of all in China and elsewhere in Asia.
In general, the Panel judges that there is only limited
evidence suggesting that diets relatively high in fats andoils (in total, or any type) are in themselves a cause of any
cancer. This judgement contrasts with those of someearlier reports, which concluded from evidence thenavailable that diets high in fats and oils might be a
substantial cause of some cancers. Overall, the evidence
does not suggest that diets relatively high in fats and oils
might protect against the risk of any cancer.
The Panel judges as follows:
There is limited evidence suggesting that total fat is a
cause of lung cancer, and of postmenopausal breast
cancer; that animal fat is a cause of colorectal cancer;
and that consumption of butter is a cause of lung cancer.
The Panel stresses that the principal cause of lungcancer is tobacco smoking.
The evidence on fats and oils does not justify any
judgement of ‘convincing’ or ‘probable’. For discussion of

the role of fats and oils in energy-dense foods and drinks,
the effect of energy-dense foods and drinks on weight
gain, overweight, and obesity, and the role of weight gain,
overweight, and obesity in the risk of some cancers, see
Chapters 6 and 8.

Fats or oils may be an intrinsic part of the plant or animal,
as contained in the germ of cereals (grains) and the tissuesof animals, or extracted and added to food in manufacture,
cooking, or at the table.
Production and consumption of fats and oils in generalrises with industrialisation and urbanisation, and in particular with the extent to which animal production is intensified, milk and dairy products are consumed, and processed
foods include extracted oils. Availability and price are also
key factors. In lower-income countries, average population
consumption of fat may amount to less than 15 per cent,though usually to 20–30 per cent of total energy; in highincome countries, usually to 30–40 per cent. On a global
basis, and most notably in China and elsewhere in Asia, production and consumption of animal fats and plant oils are
increasing.
Early reports issued in the context of food insecurity inindustrialised countries, including Europe and North
America, recommended maintenance and even an increasein consumption of fats and oils. In the second half of the 20th
century, reports on fats, oils, and chronic diseases tended tofocus on the possible role of diets relatively high in fats andoils in the causation of obesity, type 2 diabetes, coronary

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heart disease, and cancers of some sites. In recent decades,
more attention has been given to issues of the nutritional
quality of fats and oils. Distinctions are made between relatively saturated (including hydrogenated) fats, such as frommeat, milk, and their products, or from hydrogenated oils in
baked goods and many other processed foods; relatively
monounsaturated oils, notably olive oil; and relatively
polyunsaturated oils, from seeds, nuts, fish, and othersources, some of which — like vitamins — are essential tohuman health and life. These distinctions are to some extent
reflected in the studies reviewed here.
For discussion of the role of fats and oils in energy-dense
foods and drinks, the effect of energy-dense foods and drinks
on weight gain, overweight, and obesity, and the role ofweight gain, overweight, and obesity in the risk of some cancers, see Chapters 6 and 8.
In this Report, fats and oils are classified as foods. This section also covers dietary cholesterol, as well as total fat andindividual fatty acids as dietary constituents. Food processes affecting the composition of fats and oils, such as hydrogenation, are also covered here.

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A small amount of dietary fat is essential to allow absorption of fat-soluble vitamins (A, D, E, and K) and to provide
the essential fatty acids that cannot be made by the body.
Fat also helps food to taste more interesting and be morepalatable, for instance in terms of its texture. Linoleic acidand alpha-linolenic acid are the two essential fatty acids, andare found in vegetables, nuts, and seed oils; lower levels arealso found in meat, eggs, and dairy products. Oily fish also
contain long-chain unsaturated fatty acids, which influence
inflammatory processes in the body.1 For instance, eicosapentaenoic and docosahexaenoic acids, and related fatty
acids, are precursors to prostaglandins, which are hormonelike compounds with diverse effects, including roles in bloodvessel dilation and constriction, blood clotting, and inflammation.
Cholesterol is found only in foods of animal origin, suchas cheese, butter, meat, seafood, and egg yolks. Most of thecholesterol in the body is manufactured in the liver, rather
than coming from these dietary sources.1 The proportion andtypes of saturated and unsaturated fatty acids eaten in thediet are more important influences on cholesterol metabolism than the amount of dietary cholesterol.

4.5.1 Definitions and sources
4.5.2 Composition
Dietary fat is mostly made up of triglycerides (three fatty acidmolecules attached to a glycerol backbone). Triglycerides are
lipids, a class of hydrocarbon-containing organic compounds,
which also includes cholesterol. Lipids are used by plants,
animals, and humans as a means of storing energy, as structural components of cell membranes, and as precursors ofimportant hormones.
Fatty acids are classified as either ‘saturated’ or ‘unsaturated’, depending on their chemical structure (see chapter
4.5.2), and these differences determine their shape and physical properties. Fats high in saturated fatty acids are generally solid at room temperature, whereas those rich inunsaturated fatty acids are liquid. Trans-fatty acids, formed
in a process called hydrogenation (box 4.5.1), are physically more like saturated fats (harder at lower temperatures),and have similar effects on the body.
The term ‘fats’ is often used for fats and for oils. Fats can
be classified according to their source, use, or chemical composition. Those that are solid or semisolid at ambient temperature are generally high in saturated fatty acids and areoften of animal origin; and oils, which are from plant andmarine sources, are liquid at ambient temperature in theirplaces of origin. Palm oil and coconut oil, which are relatively
high in saturated fatty acids, are semisolid in temperate climates but liquid in the tropics, where coconut and otherpalm trees grow (also see chapter 4.5.2).
Fats and oils are eaten as part of animal and plant foods,
are contained in manufactured foods, used for cooking, andmay be added at the table. Animal fats include tallow, lard,and suet, produced as part of the slaughtering process, andbutter. Margarine and other fat spreads are made from fishand plant oils. Plant oils are extracted from oily fruits (suchas olives), seeds (such as rape and sunflower), nuts (suchas walnuts), and other sources.

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The properties of fats and oils are determined by the lengthand structure of the fatty acids they contain. Liquid oils tend
to be higher in unsaturated fatty acids, whereas more solidfats have more saturated fatty acids.
Whether or not a fatty acid is saturated depends on thechemical bonds that join together the chain of carbon atoms
that forms the backbone of the molecule. Saturated fatty
acids have only single bonds, whereas unsaturated fatty acids
have at least one double bond between two adjacent carbon
atoms. Monounsaturated fatty acids have only one doublebond; polyunsaturated fatty acids have two or more double
bonds. The position of the first double bond along the carbon chain is denoted by an ‘n’. Thus linoleic acid is ‘n-6’ andalpha-linolenic acid is ‘n-3’. These were previously known as‘omega-6’ and ‘omega-3’ fatty acids.
Saturated fatty acids are long and straight, forming wellordered, relatively solid structures. But each of the double
bonds in an unsaturated fatty acid causes the carbon chain
to kink; and the more kinks, the less well they pack together, which means they form less solid structures. So, saturated fats are usually solid at room temperature andunsaturated fats are liquid (oils). Trans-fatty acids are unsaturated fatty acids formed by a process called hydrogenation,
which removes and reconfigures the double bonds, making
the carbon chain less kinked. Plant oils can be turned into
saturated fats by this process, which, when only partiallycomplete, also leads to production of trans-fatty acids (box4.5.1).
Fats from ruminants (cattle and sheep) contain moresaturated fatty acids than pork or poultry fats. Fatsfrom under the skin have a smaller proportion of saturated
fatty acids than fats stored around the organs. Beefsuet is the hardest culinary fat, while chicken, duck, andC H A P T E R

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Box 4.5.1•

F O O D S

A N D

D R I N K S

Hydrogenation and trans-fatty acids

The main single factor that has increased
production and consumption of total fat
and saturated fatty acids throughout theworld, and therefore the energy density offood supplies, is the industrial process ofhydrogenation, invented at the beginningof the 20th century.2 The hydrogenation
process was at first used mostly for the
manufacture of margarine, but it is now
used in the manufacture of many processed foods supplied and consumed
throughout the world.
Complete hydrogenation converts theunsaturated fatty acids in oils of plant andmarine origin into saturated fatty acids.
This process has two commercial benefits.

First, it greatly extends ‘shelf-life’: oils highin unsaturated fatty acids become rancid,
whereas fats high in saturated fatty acids‘keep’ for very much longer. Second, it
enables conversion of whatever plant andmarine oils are cheapest at the time into a
uniform, reliable ingredient and product.
Partial hydrogenation produces transfatty acids, which, although chemicallyunsaturated, physiologically behave more
like saturated fatty acids. For instance, highlevels in the diet increase the risk of coronary heart disease. Biscuits and other baked
goods may contain as much as 25 per centor more of their fats in trans form. Small
amounts of trans-fats are also naturally

goose fats are semiliquid at room temperature.
In general, the amount and type of body fat carried by animals and poultry depend on how they live, and this determines the fat content of their meat, unless some of it has
been removed during processing. Wild and free-living land
animals and birds are lean, and much of their fat is unsaturated; domesticated animals and birds carry more fat, which
is higher in saturated fatty acids. Indeed, they are often bred
to be more fatty, so that their meat is more succulent.

4.5.3 Consumption patterns
Consumption of total fats and oils varies greatly throughout
the world. Average intake of total fat is highest (30–40 per
cent of total energy) in most urbanised and industrialised
regions such as Europe, North America, Australia, and New
Zealand, where people consume relatively more meat andmilk and their products. By contrast, fat usually accounts for
only 20–30 per cent of total energy in lower-income parts of
the world, for instance in Africa, Asia, and Latin America;
this may be even lower in rural areas, where people consume
low levels of added fats or oils (for instance, from processed
foods). However, in general, consumption of fats — and inparticular plant oils — is increasing in middle- and lowincome countries. (Also see Chapter 1.)
Higher amounts of separated animal fats (as distinct fromthe fats that are naturally components of foods of animal origin) are consumed in high-income countries. Availability is
typically highest in North America, northern Europe,
Australia, and New Zealand — as much as 10 per cent inparts of northern Europe, compared with less than 0.5 percent in much of Africa and Asia.3
More plant oils are also consumed in high-income countries; availability is highest in North America, southern
Europe and some parts of the Middle East, and lowest inparts of Asia and Africa. Greece has the highest level of consumption — almost 20 per cent of dietary energy — compared with 1.4 per cent in Laos.

found in milk and butter.
Because of the evidence on coronary
heart disease, regulatory authorities inmany countries now require food manufacturers to list trans-fatty acid content on
nutrition labels of processed foods.
Hydrogenated fats found in foods, andlabelled as such, are hydrogenated to avariable extent and may therefore contain
unspecified amounts of trans-fatty acids.
This may not be clear on labels where a declaration of trans-fatty acid content is not
required.
The Panel notes that any effect of transfatty acids specifically on the risk of any
cancer is not known.

Soya bean oil is the most widely consumed oil in theworld, particularly in North America, as well as in some
Asian and African countries. Sunflower seed oil is the second most widely consumed vegetable oil (particularly inEurope, South Africa, Argentina, Chile, and New Zealand)and palm oil the third (particularly in some African, Asian,and Latin American countries, as well as in Australia). Oliveoil is the most widely consumed oil in southern Europe (particularly in Greece, Italy, and Spain). Rapeseed oils are mostcommon in northern Europe and Canada, while groundnut
oil is common in some African countries.
The industrial revolution brought significant changes tofood supplies, methods of food production, and hence people’s diets (see chapter 1.1.3). Before then, it is thought thatthe amounts of n-6 and n-3 oils in diets had been roughly
equal. But with the move to urban–industrial ways of life,
vegetable oils (which are predominantly n-6) became cheap
and widely available. The ratio of n-6 to n-3 fatty acids is
now thought to be between 10 and 20 to 1 in many highincome countries.4
The World Health Organization recommends limiting average fat intake for populations to between 15 and 30 per centof total daily energy intake, and saturated fatty acids to lessthan 10 per cent.5 In higher-income countries, fat consumption as a percentage of total energy has been decreasing for some time. However, this is no longer the case insome countries such as the USA, where the percentage ofenergy from fat has started to increase again.

4.5.4 Interpretation of the evidence
4.5.4.1 General
For general considerations that may affect interpretationof the evidence, see chapters 3.3 and 3.5, and boxes 3.1, 3.2,
3.6 and 3.7.
‘Relative risk’ (RR) is used in this Report to denote ratio
measures of effect, including ‘risk ratios’, ‘rate ratios’, ‘hazard ratios’, and ‘odds ratios’.

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4.5.4.2 SpecificSome considerations specific to fats and oils are as follows.
Patterns and ranges of intake. In high-income countries

where most studies are undertaken, average consumption offats and oils is relatively high and variation in consumption
is not great.
Classification. Studies tend to use classifications relevant tocoronary heart disease, some of which may not be relevant
to cancer. Thus, they examine not only animal and vegetablefats; meat, fish, and dairy fats; but also saturated and unsaturated fatty acids; monounsaturated and polyunsaturated
fatty acids; n-3 and trans-fatty acids; and oleic, linoleic, andother individual fatty acids. This makes aggregation andanalysis of intakes of fats and oils as a whole, problematic.
Study design. Practically all studies have analysed con-sumption of fats and oils as an issue of quantity (percentage
of total energy intake) rather than nutritional quality (effectof different types of fats and oils). But oils are complex mixtures of nutrients and other bioactive compounds, some ofwhich may have harmful effects on cancer risk and others
beneficial effects.
Reporting bias. The use of questionnaires to record con-sumption of fats and oils may change behaviour. As people
become more conscious of what they consume, they tend tounder-report true consumption of foods and drinks they
regard as unhealthy, including fats and oils. So studies using
questionnaires may disproportionately underestimate consumption of fats and oils.

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pants, followed up for 6 to 16 years, more than 3100 lung cancer cases) showed a non-significant increased risk of 1.01 (95%
CI 0.98–1.05) per 5 per cent daily energy intake from fat.37
Twelve of the case-control studies showed increased risk forthe highest intake group when compared to the lowest,16 17 1921 23 25 27-29 31 32
which was statistically significant infive.16 17 19-21 25 31 No studies reported statistically significant
reduced risk. Most (12) of these studies adjusted forsmoking.16 19-22 24 25 27 30-32
The ecological studies reported mixed results, most of whichwere not statistically significant.33-35 One study reported a statistically significant decreased risk with increased fat intake.36
Although no evidence for plausible mechanisms was found,based on the epidemiological evidence, there is limited evidence suggesting that total fat is a cause of lung cancer.
The mixed results from cohort studies contrast withthe more consistent results from other studies. Overall,there is limited evidence suggesting that consumptionof total fat is a cause of lung cancer. The Panelemphasises that the principal cause of lung cancer issmoking tobacco.
Breast (all ages)

Nineteen cohort studies,38-60 49 case-control studies,61-118 and
10 ecological studies119-128 investigated total fat intake andbreast cancer.
Breast (premenopause)

Total fat intake for all ages, and also for premenopausal
breast cancer, did not give any overall indication of effect.
Breast (postmenopause)

4.5.5 Evidence and judgements
The relationship between the risk of cancer and fat and oil
intake may be assessed as weight of fat consumed or adjusted for total energy intake, so that fat is assessed as a proportion of total dietary energy.6 Where this is the case, thishas been stated below.
The full systematic literature review (SLR) is contained on
the CD included with this Report.
4.5.5.1 Total fats
Lung

Nine cohort studies,7-15 17 case-control studies,16-32 and 4
ecological studies33-36 investigated total fat and lung cancer.
(Also see chapter 7.4.)
Six cohort studies showed non-significant increased risk forthe highest intake group when compared to the lowest.7 8 10
11 13 14
Three studies showed decreased risk,9 12 15 which wasstatistically significant in one.15 Meta-analysis was possible on
two cohort studies, with a summary effect estimate of 1.01
(95% confidence interval (CI) 0.94–1.09) per 10 g fat/day,with high heterogeneity.11 12 Six of the studies adjusted forsmoking, including the two studies in the meta-analysis andnot including the statistically significant reduced risk.7-12
Pooled analysis from 8 cohort studies (over 430 000 partici-

138

Nine cohort studies38 40 43 45 50-52 57-59 and 16 case-control studies62-65 75 79 85 86 96-98 101 102 109 110 112 116 reported results specifically for postmenopausal breast cancer.
Six cohort studies showed increased risk with increasing
fat intake,38 40 45 50-52 59 which was statistically significant inthree.38 51 52 Three studies reported non-significant reduced
risk.40 43 57 58 Meta-analysis was possible on five cohort studies, giving a summary estimate of 1.06 (95% CI 0.99–1.14)
per 20 g/day, with moderate heterogeneity.38 43 45 50 51
Pooling project data (7329 invasive postmenopausal
breast cancer cases among 351 821 women) showed areduced risk, with an estimate of 0.96 (95% CI 0.86–1.08)
per 25 g increase in energy-adjusted total fat. Menopausal
status was not an effect modifier on these data.129 130
Eleven case-control studies showed increased risk withincreasing fat intake,62 64 65 75 85 86 96-98 102 109 110 112 which wasstatistically significant in three.97 109 112 Five studies showeddecreased risk,63 64 79 101 116 which was statistically significant
in one.64 Meta-analysis was possible on seven control studies, giving a summary estimate of 1.11 (95% CI 1.06–1.16),
with no heterogeneity.62 63 65 75 97 102 109
There is also evidence on percentage energy from fat. There
are four cohort studies131-134; three reported decreased risk.131
133 134
The other study reported non-significant increased
risk.132 There were two case-control studies; both reported a
non-significant decreased risk.135 136

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There is interest in the varying role that different types ofindividual fatty acids might have on breast cancer risk but
there are insufficient data to draw any conclusions. There aremechanistic data connecting polyunsaturated fatty acids andperoxidation.
Higher endogenous oestrogen levels after menopause area known cause of breast cancer.137 138 Dietary fat is relatively well established as a cause of increased endogenous
oestrogen production.139 Low-fat diets are usually associated with high fibre consumption, which may reduce oestrogen concentration by decreasing intestinal reabsorption. In
premenopausal women, there is little evidence that serum
oestrogen levels are associated either with fat consumption
or with breast cancer risk.
An alternative mechanism by which dietary fat could influence steroid hormone levels is that increased serum-free fatty
acids could displace oestradiol from serum albumin, thusincreasing free oestradiol concentration.140 However, theserum concentration of sex hormone-binding globulin is amore important determinant of the proportion of oestradiolthat can enter the breast epithelial cells. Sex hormone-binding globulin decreases with increasing body mass index andinsulin resistance.
Energy-dense diets (among other factors) lower the ageof menarche. Early menarche is an established risk factor forbreast cancer.
Evidence from prospective epidemiological studies ofdifferent types shows inconsistent effects on the whole,while case-control studies show a significant positive
association. Mechanistic evidence is speculative.
Overall, there is limited evidence suggesting that
consumption of total fat is a cause of postmenopausal
breast cancer.
4.5.5.1.1 Butter
Lung

Two cohort studies8 141 and eight case-control studies142-149
investigated butter and lung cancer. (Also see chapter 7.4.)
One cohort study showed statistically significant increased
risk, with a summary estimate of 1.8 (95% CI 1.0–3.0) forthe highest intake group when compared to the lowest.8 The
other cohort study showed non-significant decreased risk inthree independent estimates: 0.92 (95% CI 0.65–1.30) formen; 0.90 (95% CI 0.46–1.77) for women; and 0.94 (95%
CI 0.62–1.42) for non-smokers.141 Both studies adjusted forsmoking.
Seven case-control studies showed increased risk for thehighest intake group when compared to the lowest,143-149
which was statistically significant in three.143 145 149 One study
showed a non-significant decreased risk.142 Most studies
adjusted for smoking.142 143 145-149
Although no evidence for plausible mechanisms was found,based on the epidemiological evidence, there is limited evidence suggesting that butter is a cause of lung cancer.
There is a limited amount of inconsistent evidence
suggesting that consumption of butter is a cause oflung cancer.

4.5.5.2 Foods containing animal fat
The evidence here refers to animal fats as foods, for instance,
lard, suet, or dripping, and not to estimated amounts contained within other foods (such as meat and milk and theirproducts, or baked goods).
Colorectum

Five cohort studies investigated animal fats and colorectal
cancer.150-154 (Also see chapter 7.9.)
Three studies showed increased risk with increasing intake
of animal fats,150 151 153 which was statistically significant in
one,150 and statistically significant when comparing the second highest intake to the lowest intake group, but not whencomparing the highest to lowest, in another study.151 One
study reported no effect on risk152 and another showed nonsignificant increased risk in men and non-significant
decreased risk in women.154 Meta-analysis was possible on
three studies, giving a summary effect estimate of 1.13 (95%
CI 0.92–1.38) per 20 g/day, with moderate heterogeneity.150
152 154

Because of the abundant prospective data from cohort
studies, case-control studies were not summarised.
There is a limited amount of fairly consistent evidence
suggesting that consumption of foods containing
animal fat is a cause of colorectal cancer.

The Panel is aware that since the conclusion of the SLR, onecohort study155 has been published. This new information does
not change the Panel judgement (see box 3.8).

4.5.6 Comparison with previous report
The panel responsible for the previous report judged it possible that diets relatively high in total fat, and/or in saturated/animal fat, were causes of cancers of the lung,colorectum, breast, endometrium, and prostate. That panel
noted a pattern whereby diets relatively high in fat could
increase the risk of some cancers, and pointed out that fats
and oils are energy-dense, and agreed that energy-dense
diets increase the risk of obesity, itself a risk factor for somecancers.
The previous report judged that diets high in dietary cholesterol were a possible cause of cancers of the lung and pancreas. The overall evidence now does not support anassociation.
Since the mid-1990s, the results of cohort studies haveoverall tended to weaken the evidence on fats and oils as
direct causes of cancer.

4.5.7 Conclusions
The Panel concludes:
Findings from cohort studies conducted since the mid-1990s
have made the overall evidence associating fats and oils withthe risk of any cancer somewhat less impressive.
There is limited evidence suggesting that total fat is a139

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cause of lung cancer or postmenopausal breast cancer; thatfoods containing animal fat are a cause of colorectal cancer;
and that butter is a cause of lung cancer. The Panel stresses
that the main cause of lung cancer is smoking tobacco.
Fats and oils are the most energy-dense constituents offoods. For discussion of the effect of energy-dense foods on
weight gain, overweight, and obesity, and the role of weight
gain, overweight, and obesity in the risk of some cancers, see
Chapters 6, 7, and 8.

140

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4•F O O D S

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D R I N K S

4.6 Sugars and salt
SUGARS AND SALT, AND THE RISK OF CANCER
In the judgement of the Panel, the factors listed below modify the risk of cancer. Judgements are graded according to the strength of the evidence.

DECREASES RISK
Exposure

INCREASES RISK

Cancer site

Exposure

Cancer site

Salt1

StomachSalted and salty foods

StomachFoods containing sugars2

Colorectum

Convincing
Probable

Limited —suggestive
Substantial
effect on risk
unlikely12None identified‘Salt’ here means total salt consumption, from processed foods, including salty and salted foods, and also salt added in cooking and at the table.
‘Sugars’ here means all ‘non-milk extrinsic’ sugars, including refined and other added sugars, honey, and as contained in fruit juices and syrups.
It does not include sugars naturally present in whole foods such as fruits. It also does not include lactose as contained in animal or human milk.

For an explanation of all the terms used in the matrix, please see chapter 3.5.1, the text of this section, and the glossary.

Sugars are sweeteners and, in some forms, also apreservative and a bulking agent. Free sugars in the solidstate or as syrups are ingredients in many processed foods
and drinks. Nutritionally, sugars supply energy andnothing else. Sugars added to food were a luxury until
sugar from cane became a major international cash crop,
beginning in the 16th century. Consumption of addedsugars, from beet as well as cane, and syrups increased
rapidly in industrialised countries in the 19th and 20th
centuries. High-fructose corn syrups are now also used
extensively. Overall consumption of sugars is increasing
worldwide, particularly in lower-income countries. In
recent decades, and in many countries, consumption ofadded sugars, notably in the form of sugary drinks,
accounts for a substantial proportion of energy intake.
Salt (sodium chloride) is also a preservative. The
sodium and chloride in salt are essential nutrients in small
amounts. In nature, foods are generally low or very low in
sodium. Like sugar, salt historically was scarce and a
precious commodity; the Romans paid their labourers in
salt, thus the word ‘salary’ (from ‘sal’ for salt).
Consumption of salt, in the form of many processed,
salted, and salty foods, or of salt added in cooking and at
table, remains variable. Consumption of salt, and salty andsalt-preserved foods, is high in some maritime nations
such as Japan, Portugal, and other Portuguese-speaking
countries. In inland regions, such as landlocked Africancountries, consumption has been very low.
Overall, the Panel judges that the evidence on salt

is confined to stomach cancer, and that on sugars islimited.
The Panel judges as follows:
Salt is a probable cause of stomach cancer. Salt-preserved
foods are also a probable cause of stomach cancer. Thereis limited evidence suggesting that sugars are a cause ofcolorectal cancer. Within the remit of this Report, thestrongest evidence, corresponding to judgements of‘convincing’ and ‘probable’, shows that salt, and also saltpreserved foods, are probably causes of stomach cancer.

‘Extrinsic’, mainly refined, sugars amount to a substantial
part of most industrialised food supplies. Sugars and syrups
manufactured from cane, beet, and corn are profitable cash
crops and are ingredients in many processed foods anddrinks.
There is reason to believe that humans have evolved witha built-in desire for sweet foods. It has also been proposedthat humans have a specific appetite for salt that might have
evolved because sodium is scarce in nature. In any case, assugars and salt become readily available and increasingly
cheap, consumption tends to rise. In industrialised settings,
sugars and salt are mostly consumed, not in food preparation or at the table, but as ingredients of processed foods.
Reports concerned with undernutrition have often, andstill do, recommend substantial consumption of sugars andfats; their energy density enables quick weight gain, and the141P A R T

taste preference promotes energy consumption. By contrast,
reports concerned with prevention of chronic diseases frequently recommend restraint in consumption of sugars. One
reason for this is that sugars are the dietary cause of dental
caries. Sugars in the amounts typically consumed in manyindustrialised countries have also been identified as a causeof obesity, and therefore also indirectly of obesity-related disease. Reports concerned with nutritional deficiencies often
recommend the iodisation of salt supplies, to prevent goitre.
Reports concerned with the prevention of chronic diseases
frequently highlight that salt intakes are usually greatly inexcess of requirements, and recommend substantial decreases in salt consumption to prevent hypertension and cardiovascular disease, especially stroke.
For sugared drinks, see chapter 4.7. For the contributionof sugar to weight gain, overweight, and obesity in drinks
or through energy density of foods, see Chapter 8. For salted animal products, including Cantonese-style salted fish, seechapter 4.3.
Non-caloric chemical sweeteners are included here.

4.6.1 Definitions, sources
4.6.1.1 Sugars
Sugars here means all sugars in the diet. These are mainly
but not only ‘extrinsic sugars’, which include sucrose (commonly called sugar), maltose, lactose, glucose, and fructose;in foods and drinks, including juices and milk, and in honeyand syrups, including high-fructose corn syrup; refined sugars added to food in processing, preparation (cooking), andat the table. ‘Intrinsic’ sugars are those naturally present inwhole foods such as fruits.
Sugars are now cheap and are used widely as sweeteners,
preservatives, and bulking agents. They also often have thefunction of making processed starches, fats, and other ingredients more palatable. Also see box 4.6.1
Sucrose is refined from sugar beet and sugar cane. Maltose
and glucose are refined predominantly from corn. High-fructose corn syrup comprises a mixture of glucose with fructose,commonly in close to equal amounts, and is now used ingreat quantity in food and drink manufacture, particularly in
the USA.
The amount of sugars in manufactured foods and drinks
varies. Sugared drinks are about 10 per cent by weight addedsugars, and up to 100 per cent of their energy comes fromsugars. Sugars are often added to fruit juices. Jams and otherpreserves are about 60 per cent sugars. Cakes, biscuits (cookies), and other baked goods contain starches, fats, and sugars in varying proportions. Most chocolate and muchconfectionery are high in sugars. It is often supposed that
almost all added sugars are contained in obviously sweet
foods: this is not so. Breakfast cereals may contain anythingfrom negligible amounts to 50 per cent sugars. Yoghurts may
contain anything between 0 to 20 per cent sugars; and readyto-eat desserts even more. Many canned products include
added sugars. Savoury processed foods, such as soups, pickles, bread, and buns, often contain significant amounts ofsugars.

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Box 4.6.1

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J U D G E M E N T S

Sugar, sugars, sugary foods,
and drinks

As indicated in chapter 4.6.4, it is particularly difficult to measure and assess the overall effect of sugars as possible modifiersof the risk of any disease, including cancer. This is partly because
of inconsistency in the classification of sugars. Sometimes ‘sugar’
is equated with sucrose, which has been the chief sugar inhuman diets, but now is less so. Some studies investigate only
‘packet’ sugar purchased for use in the home; this is in generala relatively small and diminishing proportion of total sugars consumed. Other studies include sugars as found naturally in fruits
and milk.

4.6.1.2 Salt
The term ‘salt’, in common usage, refers to sodium chloride.
It is now a cheap commodity. Like sugar, salt is a preservative and a flavour enhancer. Both salt and sugar trap freewater from foods, thus preventing microbial proliferationand spoilage. Salt is found in some rocks and dissolved inseawater, and can be extracted from seawater by evaporation. Both sodium and chloride are essential components ofthe diet in small amounts.
Usually most salt in diets is contained in processed foods,
with only a relatively small amount added in cooking or at
the table (box 4.6.2). Some traditional diets include substantial amounts of salt-preserved foods, including salted
meat, fish, vegetables, and sometimes also fruits; and also
salted foods such as bacon, sausages, and ham, which contain from 3 to 5 g of salt per 100 g. Industrialised diets include
many processed foods that are not salt-preserved but contribute substantial amounts of salt to the diet, even if they
do not seem salty, as well as more obviously salty foods suchas potato crisps (chips), salted nuts, and other salty snack
foods. Most of the sodium consumed in urban environments
comes from salt added to processed foods, and thus is beyond
the control of typical consumers. Many foods such as bread,soups, breakfast cereals, and biscuits may contain substantial
amounts of salt; anything from 1 to 4 g per 100 g.

4.6.2 Composition
4.6.2.1 Sugars
Sugars are simple carbohydrates, and provide 3.75 kilocalories per gram (see chapter 4.10.1). Sugars are single
molecules such as glucose, fructose, and galactose (monosaccharides), or two molecules bound together (disaccharides) such as sucrose (fructose and glucose), lactose(glucose and galactose), or maltose (two glucose molecules).
The body metabolises different sugars at different rates;
for instance, fructose is absorbed and metabolised more
slowly than either glucose or sucrose. It is also slightly sweeter than glucose or sucrose, and thus is able to replace themin lower total amounts. Non-caloric chemical sweeteners produce a sweet taste, but are not sugars (box 4.6.3).
There is no dietary requirement for sugars. The World

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Box 4.6.2

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F O O D S

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D R I N K S

Salt, and salty, salted, andsalt-preserved foods

As indicated in chapter 4.6.4.2, it is difficult to measure salt
intake, or the contribution from separate sources (salty, salted,
or salt-preserved foods). The most reliable estimates come frommeasuring the amount of sodium excreted in the urine.
Salt is itself readily identified, although it is sometimes combined in studies with other sodium compounds. Some studies
investigate only salt added in cooking or at the table, but thisis usually a small proportion of total salt consumption. Resultsfrom such studies are liable to produce different results, compared with those from studies that have examined total salt consumption.
It has been thought that any effect of salt on stomach cancer (see chapter 4.6.5.2) is principally the result of regularconsumption of salted and salt-preserved foods, rather than salt
as such. This is partly because such foods are a substantial partof traditional Japanese and other Asian diets, where incidenceof stomach cancer has been and still is high. However, the incidence of this cancer is also high in countries where traditional
diets contain substantial amounts of salty as distinct from saltpreserved foods; and the concentration of salt in many
processed foods consumed in Europe and North America
approaches that of salt-preserved foods.

Health Organization recommends that average consumptionof sugars by populations should be less than 10 per cent of
total energy.1
4.6.2.2 Salt
Pure salt, as sodium chloride, contains no metabolisableenergy. Formulated, granulated table salts often include
additives, such as anti-caking agents, which prevent salt crystals from sticking together; potassium iodide, included toprevent iodine deficiency; traces of other sodium compounds(carbonate or thiosulphate); and also sugar, to stabilise thepotassium iodide. Sea salt may be refined to almost puresodium chloride, or unrefined, in which case they may
include traces of other minerals, algae, and a few salt-tolerant bacteria. Salt may also be flavoured, for example withcelery or garlic.
Sodium is essential for the body to function normally. It
is a major electrolyte in extracellular fluid. The body’s sodium content and its concentration in body fluids are controlled homeostatically to very precise limits; excess sodium
is excreted in the urine. Sodium is also involved in regulation of osmolarity, acid-base balance, and the membranepotential of cells. The daily requirement for sodium has been
estimated at around 500 mg for adults. On a pragmatic basis,
WHO recommends restricting average salt consumption for
populations to less than 5 g per day.1

4.6.3 Consumption patterns
4.6.3.1 Sugars
Sugars supply on average around 8 per cent of dietary energy worldwide. This figure disguises a wide range of intakes

Box 4.6.3

Chemical sweeteners

Chemical sweeteners such as saccharin, cyclamates, and aspartame have been thought to be possible causes of cancer. This isbecause some animal studies have shown that very high dosesof saccharin, in particular, increase the incidence of bladder cancer in rats. In common with many chemical additives, some sweeteners can be shown to be carcinogenic in experimental settings
in massive amounts, far greater than humans could consume infoods and drinks.
The evidence from epidemiological studies does not suggestthat chemical sweeteners have a detectable effect on the risk ofany cancer.

in different parts of the world. Diets in high-income countries contain roughly twice the amount of sugars as those inlower-income countries. In North America and some
European countries, average consumption is around 15–17
per cent of dietary energy, with a fairly wide range aroundthis average. In the USA, in the last decades of the 20th century, many processed foods were reformulated to contain lessfat but more sugars. In some parts of Asia, consumption is
negligible, although globally sugar supplies are increasing
rapidly. Children in high-income countries usually obtain ahigher proportion of their daily energy from sugar thanadults.11
Consumption of sugars has generally increased over thelast century, particularly in high-income countries, and also
more recently in many countries undergoing economic transition in Asia, Africa, the Middle East, and Latin America.
4.6.3.2 Salt
The use of salt as a preservative has generally decreased asindustrial and domestic use of refrigeration has increased(box 4.6.4). But diets containing few salt-preserved foods
may nevertheless be high in salt.
The average adult daily intake of salt worldwide varies
from less than 6 g to 18 g. Very high levels of intake arefound in Japan, some parts of China, Korea, Portugal, Brazil,
and other Portuguese-speaking countries, where diets contain substantial amounts of salt-preserved, salt-pickled, salted, or salty foods. The average adult intake is around 9–12
g per day in high-income countries, including Europe andNorth America.

4.6.4 Interpretation of the evidence
4.6.4.1 General
For general considerations that may affect interpretation of
the evidence, see chapters 3.3 and 3.5, and boxes 3.1, 3.2,
3.6 and 3.7.
‘Relative risk’ (RR) is used in this Report to denote ratio
measures of effect, including ‘risk ratios’, ‘rate ratios’, ‘hazard ratios’, and ‘odds ratios’.
4.6.4.2 SpecificClassification. Studies of sugars may be of total sugars; of143

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Box 4.6.4•

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A N D

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Refrigeration

Freezing and cooling by use of natural ice
and snow is a method of food preservation
traditionally available only in cold climatesor in winter in temperate climates. Natural
ice refrigeration on an industrial scale firstdeveloped in the late 19th century, when
refrigerated containers used in trains,
ships, and then later trucks, greatly
increased the production and consumptionof red meat. Domestic freezing, chilling,
and refrigeration on a mass scale is a phenomenon mostly of the second half of the20th century.
Today, much perishable food is soldfrozen or chilled. Together with thegrowth of industrial refrigeration, domestic refrigerators began to be used in theUSA, Australia, and New Zealand on any
scale in the 1920s, and in Europe and Japan
mostly since the 1950s. In Japan, for example, households possessing refrigerators
increased from 9 per cent in 1960 to 91 percent in 1970, and 99 per cent in 2004.
Supermarkets with freezers, chill cabinets,
and domestic refrigerators are now com-monplace in the cities and towns of tropical countries; poorer rural communities still
rely on drying, fermenting, salting, bottling, tinning, and other methods of foodpreservation, as well as their own gardens
and farms. It is unlikely that refrigeration
itself has any direct effect on the risk ofcancer. Its effects are indirect.
Refrigeration:• Enables consumption of fresh perishable
foods including seasonal vegetables andfruits all year round, as well as of freshmeat.
• Reduces microbial and fungal
contamination of perishable foods,
notably cereals (grains) and pulses(legumes).
• Reduces the need for and use of salting,smoking, curing, and pickling as
methods of preserving vegetables,
fruits, and meat.
It can therefore be said that refrigeration(including freezing and chilling) indirectly

sugars added at the table; of sugary foods and/or drinks; of
sucrose; or of added sugars generally; and may or may notinclude those sugars naturally present in foods. Studies using
such varying classifications are difficult to compare.
Similarly, studies of salt may be of salt added in cooking
and/or at the table; of salty or salted foods; or of salt consumption as a whole. These studies are also difficult to compare. See box 4.6.1 and box 4.6.2.
Measurement. Measurement of salt intake is notoriously dif-ficult, and is best done by measuring the excretion of sodium in urine over a 24-hour period. But this method has only
rarely been used.
Study design. See Classification. Also studies may underestimate the amounts of sugars and of salt in foods anddrinks consumed outside the home.
Reporting bias. Added sugars are generally regarded as
unhealthy, and studies that depend on self-reporting may disproportionately underestimate the consumption of sugars.

4.6.5 Evidence and judgements
The full systematic literature review (SLR) is contained on
the CD included with this Report.
The relationship between the intake of sugars and the riskof cancer is often adjusted for total energy intake, meaningthat sugars are assessed as a proportion of total dietary energy.12 Where this is the case, this has been stated.

144

2

influences risk of those cancers, therisk of which is affected by the above
factors.
Evidence amounting to a judgement of‘convincing’ or ‘probable’ for such factors
is summarised in earlier sections of thischapter, and in Chapter 7, and relates tocancers of the mouth, pharynx, larynx,
nasopharynx, oesophagus, lung, stomach,pancreas, liver, and colorectum.
In particular, many studies have noted areciprocal relationship between use ofrefrigeration and consumption of salt andfoods preserved with salt. Meta-analysis ofeight case-control studies2-9 has shown asignificant association between the use ofrefrigeration (usually as gauged by possession of a domestic refrigerator) andreduced risk of stomach cancer.
The one cohort study10 identified measured effects in the Netherlands over a
25-year period, in which almost the entire
population had access to commercial anddomestic refrigeration, and did not findany association.

4.6.5.1 Sugars
Colorectum

One cohort study13 and 7 case-control studies14-20 investigated sugars as foods and colorectal cancer. Seven cohort
studies21-27 and 16 case-control studies investigated sugars
as nutrients, defined as sucrose or fructose.
Sugars as foods

The single cohort study stated that there was no association
between usually adding sugar to cereals and colorectal
cancer.13
All seven case-control studies showed increased risk withincreased sugar intake,14-20 which was statistically significant
in two.17 18 The classification of ‘sugars as foods’ varied considerably between studies.
Sugars as nutrients

Four cohort studies reported on total sugar intake.21 22 25 26 One
study reported a non-significant increased risk for the highest
intake group when compared to the lowest, with an effect estimate of 1.03 (95% confidence interval (CI) 0.73–1.44).22 One
study reported a non-significant lower sugar intake in cases
than controls.21 Two cohort studies stated that there was no
association between sugar intake and risk.25 26
Three cohort studies reported on sucrose intake.23 24 27 Twocohort studies showed non-significant increased risk whencomparing the highest intake group against the lowest.23 27
Effect estimates were 1.45 (95% CI 0.88–2.39)23 and 1.30
(95% CI 0.99–1.69) in men.27 One study reported a nonstatistically significant decreased risk (0.89 (95% CI
0.72–1.11) in women).27

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D R I N K S

Three cohort studies reported separate results for fructose23 24 27; one reported a significant increased risk in menof 1.37 (95% CI 1.05–1.78).27 Two other studies reported
non-significant decreased risk.23 27
Because of the abundant prospective data from cohort
studies, case-control studies were not summarised.
In most, though not all, animal experiments, sucrose andfructose are associated with increased colonic proliferation andaberrant crypt foci. These sugars may interfere with levels ofblood glucose and/or triglycerides, either directly or throughhormones like insulin and others (also see Chapter 2).28
The evidence is hard to interpret. There is limited
evidence suggesting that sugar is a cause of colorectal
cancer.

4.6.5.2 Salt
StomachThree cohort studies,10 29 30 21 case-control studies,2 4 31-48
and 12 ecological studies49-60 investigated total salt use andstomach cancer. Two cohort studies10 61 and 13 case-control
studies4 9 39 43 62-71 investigated salt added at the table; 1cohort study72 and 8 case-control studies4 39 73-78 investigated sodium intake.
Total salt use

Two cohort studies showed increased risk with increased salt
intake,10 30 which was statistically significant in one study inmen but not women.30 One study showed statistically significant decreased risk.29 Meta-analysis was possible on twocohort studies, giving a summary effect estimate of 1.08
(95% CI 1.00–1.17) per 1 g/day, with moderate heterogeneity (figure 4.6.1). The study that could not be included

Figure 4.6.1

Total salt use and stomach cancer; cohortand case-control studies
Relative risk (95% CI)

CohortVan de brandt 2003

1.07 (0.97–1.18)

Tsugane 2004 Men

1.14 (1.08–1.21)

Tsugane 2004 Women

1.01 (0.92–1.11)

Summary estimate

1.08 (1.00–1.17)

Case control
You 1988

1.00 (0.99–1.01)

Nazario 1993

1.17 (1.08–1.27)

Ramon 1993

1.36 (1.01–1.82)

Ye 1998

1.03 (0.99–1.07)

Setiawan 2000

1.02 (0.99–1.04)

Munoz 2001

0.96 (0.93–1.00)

Tsukino 2004

0.98 (0.88–1.10)

Setiawan 2005

1.00 (0.86–1.16)

Setiawan 2005

0.96 (0.99–1.04)

Summary estimate

1.01 (0.99–1.04)

0.5

0.75

1

1.5

Relative risk, per g/day2

was inconsistent with this summary, with an effect estimateof 0.53 (95% CI 0.31–0.91) for the highest intake groupwhen compared to the lowest; however, this study did not
adjust for other factors.29 The two cohort studies that reported increased risk used much more detailed questionnaires toassess salt intake (150 compared to 27 items). They also
adjusted for a greater number of confounders than the study
that reported decreased risk.
Twelve of the case-control studies showed increased risk
with increased salt intake,2 32 34 35 39 40 42-46 which was statistically significant in six.32 40 42-45 None of the studies showedstatistically significant decreased risk. Most other studies
reported either risk estimates close to 1.0 or reported that
there was no statistical association. Meta-analysis was possible on eight case-control studies, giving a summary effectestimate of 1.01 (95% CI 0.99–1.04) per 1 g/day, with highheterogeneity (figure 4.6.1).
A dose-response relationship was apparent from cohort but
not case-control data.
Seven ecological studies reported increased risk withincreased salt intake,49 52-55 57 58 which was statistically significant in four.53 54 57 58 The remaining five studies reported
either a decreased risk with increased salt intake50 56 59 60 orno association,51 none of which was statistically significant.
Stomach cancer rates are highest in those areas of the world,such as parts of Asia and Latin America, where diets are traditionally salty due to the regular consumption of meat, fish,
vegetables, and other foods preserved by salting, as well asof salty foods.
Salt added at the table

Both cohort studies reported that there was no significant
effect, and estimates were close to one (1.0) (95% CI
0.6–1.6)61 and 0.9 (95% CI 0.56–1.44).10
Twelve case-control studies showed increased risk for thehighest intake group when compared to the lowest,4 9 39 43 6264 66-71
which was statistically significant in eight.4 9 43 62-64 67
One other study reported similar intakes in cases andcontrol.65
SodiumThe single cohort study showed a non-significant decreased
risk.72
Six case-control studies showed increased risk for the highest intake group when compared to the lowest,39 73-77 which
was statistically significant in three.39 74 77 Two studies
showed decreased risk, which was statistically significant in
both.4 78 Meta-analysis was possible on five studies, giving
a summary effect estimate of 1.18 (95% CI 1.02–1.38) per
1 g/day, with high heterogeneity.39 74-76 78
Interaction with Helicobacter pylori infection

Two case-control studies that investigated total salt use also
investigated the potential for interaction with H pylori infection (also see box 7.5.1).79 80 One study was suggestive of amultiplicative effect on risk for high salt use and H pylori positive status79; the other stated that there was no association.80
Salt intake may be inversely related to the availability ofrefrigeration both within and between populations. Salt-

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preserved foods may be eaten more by those to whom
refrigeration is not available.
There is evidence from laboratory experiments that highsalt intake damages the lining of the stomach.81 It has also
been shown to increase endogenous N-nitroso compound
formation.82 In addition, a high salt diet has been shown tohave a synergistic interaction with gastric carcinogens.82 It
may only contribute to gastric cancer in subjects who have
H pylori infections and are also exposed to a chemical
carcinogen.
There is a substantial amount of evidence from studies
on total salt use, salt added at the table, and sodium
intake. For total salt use, a dose-response relationshipwas apparent from cohort but not case-control studies.
For sodium intake, a dose-response was also apparent
from case-control studies. The mechanistic evidence isstrong. Salt is a probable cause of stomach cancer.

The Panel is aware that since the conclusion of the SLR, onecohort83 and two case-control studies84 85 have been published.
This new information does not change the Panel judgement (seebox 3.8).
4.6.5.2.1 Salted and salty foods
StomachFour cohort studies86-89, 17 case-control studies4 6-8 33 41 45 90and 1 ecological study100 investigated salted or salty foods
and stomach cancer.
Three cohort studies showed non-significant increased
risk with increased salt intake.86 88 89 One study reported
that there was no association.87 Meta-analysis was possibleon three cohort studies, giving a summary effect estimateof 1.32 (95% CI 0.90–1.95) per one serving/day with
99

2

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no heterogeneity (figure 4.6.2).
Eleven case-control studies showed increased risk for thehighest intake groups when compared to the lowest,6-8 41 45
91 94-98
which was statistically significant in seven.6-8 45 94-96
Two studies showed non-significant decreased risk.4 99 Fourstudies reported either the same intakes in cases and controls or no statistical association.33 90 92 93 Meta-analysis was
possible on four case-control studies, giving a summary effectestimate of 5.2 (95% CI 2.49–10.83) per one serving/day,with high heterogeneity (figure 4.6.2).
A dose-response relationship is apparent from case-control,
but not cohort data (figure 4.6.3).
Heterogeneity may be partly explained by variation
between studies in the precise foods being assessed.
The single ecological study showed non-significant
decreased risk in areas of increased salt consumption.100
The mechanisms through which salt could plausibly cause
stomach cancer are given above.
The evidence from both case-control and cohort
studies is consistent. A dose-response relationship isapparent from case-control but not cohort studies.
There is robust evidence for mechanisms operating inhumans. Salted and salty foods are a probable cause of
stomach cancer.

Figure 4.6.3

Salted/salty foods and stomach cancer; cohortand case-control studies: dose response

CohortGalanis 1998
Ngoan 2002

Figure 4.6.2

Salty/salted foods and stomach cancer;
cohort and case-control studies

Khan 2004 Men
Khan 2994 Women

Relative risk (95% CI)
CohortGalaris 1998

1.14 (0.61–2.13)

Ngoan 2002

1.21 (0.68–2.16)

Khan 2004 Men

1.76 (0.58–5.32)

Khan 2004 Woman

6.01 (0.85–42.61)

Summary estimate

Case control
Demirer 1990

1.32 (0.90–1.95)

Hirayama 1992 Men
Case control
Demirer 1990

116.86 (13.16–1037.90)

Hirayama 1992 Men

2.85 (2.13–3.81)

Hirayama 1992 Women

3.53 (2.34–5.34)

Ward 1999

113.13 (3.76–3403.01)

Sriamporn 2002

3.98 (0.65–24.22)

Summary estimate

5.20 (2.49–10.83)

0.5 1 2

6

Relative risk, per serving/day

146

Hirayama 1992 Women
Ward 1999
Sriamporn 2002

0

0.2

0.4

0.6

0.8

1

1.2

Salted/salty foods (serving/day)

1.4

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4•F O O D S

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The Panel is aware that since the conclusion of the SLR, twocase-control studies84 85 have been published. This new information does not change the Panel judgement (see box 3.8).

4.6.6 Comparison with previous report
The judgement of the previous report on sugars and colorectal cancer was in effect similar to that in this Report.
The previous report judged that salt and also salting areprobable causes of stomach cancer. This judgement is alsomuch the same as that in this Report.

4.6.7 Conclusions
The Panel concludes:
Salt is a probable cause of stomach cancer. Salted and salty
foods are also a probable cause of stomach cancer. There islimited evidence suggesting that sugars are a cause of colorectal cancer.

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4.7 Water, fruit juices and other softdrinks, and hot drinks
WATER, FRUIT JUICES, SOFT DRINKS, HOT DRINKS, AND THE RISK OF CANCER
In the judgement of the Panel, the factors listed below modify the risk of cancer. Judgements are graded according to the strength of the evidence.

DECREASES RISK
Exposure

Cancer site

INCREASES RISK
Exposure

Cancer site

Convincing

Arsenic in drinking water1 Lung

ProbableArsenic in drinking water1 Skin

Limited —suggestive

Substantial
effect on risk
unlikely

1
2

Maté2

Oesophagus

Arsenic in drinking water1

KidneyBladder

Maté2

Mouth, pharynx, larynx

High-temperature drinks

Oesophagus

Coffee: pancreas; kidney

The International Agency for Research on Cancer has graded arsenic and arsenic compounds as class 1 carcinogens. The grading for this entry applies specifically toinorganic arsenic in drinking water.
As drunk traditionally in parts of South America, scalding hot through a metal straw. Any increased risk of cancer is judged to be caused by epithelial damage
resulting from the heat, and not by the herb itself.

For an explanation of all the terms used in the matrix, please see chapter 3.5.1, the text of this section, and the glossary.

Water is essential. Without water, people die in a matter ofdays. As well as adequate supplies of water, a major publichealth issue throughout the world is the safety of domestic
and other water. Water quality may be compromised bychemical or microbiological contamination.
Fruit juices made from fruits or fruit pulps are often
concentrated for storage and transport, then diluted withwater to produce the final product. Sugar and otheringredients are frequently added in this final
reconstitution process. Soft drinks are usually made fromwater, sugar, colourings, flavourings, and mixtures ofherbs and other ingredients, to give a distinctive taste andcharacter. Consumption of branded, carbonated softdrinks, and cola drinks in particular, has increased greatly
in the 20th century, and continues to increase throughout
the world. The rise is most marked in lower income
groups.
Tea and coffee are now the main hot drinks consumed
worldwide. Both contain stimulants and other bioactive
constituents, and many people add milk and sugar. A great
variety of herbal infusions are also drunk, including maté,
the traditional hot drink in parts of South America.
Overall, the Panel judges that the direct evidence relating
non-alcoholic drinks to cancer is contamination of watersupplies with inorganic arsenic and irritation of the oral

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cavity by maté, and possibly by other very hightemperature drinks. For evidence relating sugared softdrinks to body fatness, see Chapter 8.
The Panel judges as follows:
The evidence that inorganic arsenic in drinking water is a
cause of lung cancer is convincing. Water contaminated inthis way is probably a cause of skin cancer. Arsenic andarsenic compounds are recognised carcinogens. There islimited evidence suggesting that water contaminated inthis way is a cause of cancers of the kidney and bladder.
Maté, a herbal infusion, as drunk traditionally in partsof Latin America, is probably a cause of oesophageal
cancer. Damage caused by the very high temperature of
the drink, rather than by the herb itself, is judged to be
responsible. There is limited evidence suggesting thatmaté is a cause of cancers of the mouth, pharynx, andlarynx, for the same reason. There is also limited evidence
suggesting that high-temperature drinks are a cause ofoesophageal cancer.
It is unlikely that coffee has any substantial effect on therisk of cancer either of the pancreas or of the kidney.
Within the remit of this Report, the strongest evidence,corresponding to judgements of ‘convincing’ or ‘probable’,shows that inorganic arsenic in drinking water is a causeC H A P T E R

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of lung cancer and probably a cause of skin cancer. Maté isprobably a cause of oesophageal cancer. It is unlikely thatcoffee has any substantial effect on the risk of either
cancer of the pancreas or of the kidney.

Chapter 4.7 concerns all non-alcoholic drinks.
Water, including that contained in drinks and foods, is aninvariable part of all diets. Bottled spring and mineral waters
are consumed by people who can afford them. Juices madefrom fruits and water, often sweetened (at first with honeyand then sugar), have been drunk throughout history.
Cordials, squashes, and other drinks made mainly fromcolourings and flavourings, with some fruit juices, herbs, orother ingredients added, started to become popular from the
beginning of the 19th century. Carbonated sweet drinks(sometimes known as sodas) such as cola were first massmanufactured in the USA and are now commonly consumed
throughout the world.
Tea was cultivated and drunk in China for over a thousand
years. Then, from the 18th century, it became commonly
drunk in Britain, and was cultivated in India and other countries, and drunk in other parts of the world. The original teas
were green and drunk without adding milk or sugar.
Manufacture of black teas came later; from the 19th century, teas became the main hot stimulant drink in Britain,
almost always drunk with milk and often with sugar added.
Coffee was cultivated in and exported to many parts of theworld from the 19th century; it remains the main cash cropin a number of tropical countries such as Ethiopia and Brazil.
Coffee is the main hot stimulant drink in the Americas, many
European countries, and also in the Arab world. In someparts of the world, coffee is usually drunk black, with orwithout sugar; in other countries, milk or cream is often
added. Chocolate is also consumed as a beverage.
Reports concerned with infectious diseases, especially ofchildhood, usually emphasise the importance of safe watersupplies. Reports concerned with the prevention of chronic
diseases sometimes specify sugared soft drinks as contributors to overweight and obesity. They occasionally recommend substantial consumption of water as healthy in itself
and preferable to soft or alcoholic drinks.
Contaminants of water, and also of foods and other drinks,
are grouped here with water. High-temperature foods aregrouped here with high-temperature drinks.
For the relationship between sugared drinks and body fatness, see Chapter 8.

4.7.1 Definitions, sources
4.7.1.1 Water
Water comes from rain, underground aquifers accessed bywells, springs, and freshwater lakes and rivers.
People cannot live without water, which is vital for the normal functioning of the body. Even mild dehydration (water
loss of 1–2 per cent of the body weight) can produce symptoms such as dry mouth and headaches. Stopping all fluid
intake may cause death in days, the number depending on

the health of the individual and external conditions such astemperature and humidity.
Water can be used as a vehicle to provide fluoride and cancontribute to intakes of essential elements, calcium, iron,and copper, depending on its origin and the piping materials used.
The water content of the body is around 70 per cent: men’sbodies contain a higher proportion of water than those of
women because women have more body fat, which has minimal amounts of water. Adults produce an average of around
1.5 litres of urine each day and lose an additional litre ofwater through breathing, from the skin by evaporation or
sweating, and in the faeces. Approximately 80 per cent ofwater intake comes from drinks; food provides the other 20
per cent.
Tap water quality is regulated in most countries based on
World Health Organization guidelines for drinking waterthat includes tap water and bottled water.1
Around the world, ground, rain, and river waters are also
drunk, often without first being treated to secure safety. Morethan 1 billion people (around 15 per cent of the world’s population) lack access to safe, clean water2 and are at risk of
exposure to water-borne contaminants and infectious diseases. Arsenic, the bacterium Helicobacter pylori, and parasitic schistosomes are among the many contaminants that
may be found in water supplies. In many low-income countries, access to clean water is limited for the low-income
segments of the populations and those living in rural areas.
4.7.1.2 Fruit juices
Fruit juices include liquids extracted from whole or pulped
fruits. Commercially prepared fruit juices may be pasteurised
to extend shelf-life, and concentrated at source to be reconstituted before packaging, closer to the point of sale.
4.7.1.3 Soft drinks
The term ‘soft drinks’ is used for a wide range of coloured
and flavoured non-alcoholic drinks, usually sold in cans, cartons, or bottles. They may be carbonated (such as cola drinks
or lemonade) or still (such as fruit squashes). Some softdrinks are milk-based (milkshakes and yoghurt drinks).
Depending on the ingredients, some soft drinks may be marketed with health claims, and are sometimes known as ‘functional drinks’ (also see box 4.10.2).
4.7.1.4 Hot drinks
The most common hot drinks currently consumed are tea
and coffee. These are infusions (brewed using boiling water)
usually drunk hot, sometimes very hot (box 4.7.1). Coffee
is made from ground, roasted coffee beans — the dried seedsof coffee plant berries. The beans naturally contain caffeine.
Decaffeinated coffees are produced by various processes,
using water, organic solvents, steam, or by interfering withthe expression of the gene coding for caffeine. Instant coffee comprises the soluble solids derived from dried, doublebrewed coffee. Coffee is a large bush native to Ethiopia,
cultivated in many hot and humid climates. The main coffee-exporting countries are Brazil, Vietnam, and Colombia.
Although many herbal infusions are known as teas, tea is

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specifically the infusion of the dried leaves of the plant
Camellia sinensis. Green tea is made from leaves that havefirst been cooked, pressed, and dried. To produce black tea,
the fresh leaves are withered, rolled repeatedly, allowed toturn deep brown, and then air-dried until they are dark incolour. Tea leaves contain caffeine and theophylline.
Decaffeinated teas are produced using similar processes tothose used for coffee. Most tea is grown in Asia.
Maté is a type of herbal tea prepared from the dried leavesof the plant Ilex paraguariensis that has stimulant properties
similar to the other methylxanthine-containing drinks (coffee and tea).
Herbal and other teas are also consumed cold. Iced teas
are popular in the USA and some other countries: these aresugared and considered here as soft drinks.

4.7.2 Composition
4.7.2.1 Water
Water is a molecule comprising hydrogen and oxygen: chemically, H2O. Rainwater may contain traces of air pollutants;
water from underground aquifers may contain traces of minerals from surrounding rocks and other surfaces. Groundwater may also be contaminated with natural minerals aswell as with various industrial and agricultural chemicals,
some of which are carcinogenic in laboratory conditions (box4.7.2). Mineral water from springs and other sources con-Box 4.7.1

High-temperature, and irritantdrinks and foods

Constant mechanical irritation of epithelial surfaces causes
inflammation, which predisposes to the development of cancer(see Chapter 2). It has also been suggested that foods and drinks
with chemically irritant components may be a cause of cancersof those sites with which they come into direct contact. Again,
there is not much evidence for this theory, with the possible
exception of chilli and stomach cancer (see chapter 4.2).
There is, however, some evidence that some thermally hot(and therefore irritant) drinks are a cause of cancers of thosesites with which they come into direct contact. As shown in thissection, maté, the herbal infusion, is probably a cause of cancerof the oesophagus, and there is limited evidence suggesting that
it is also a cause of other cancers of the oral cavity. This is probably not because of any carcinogen in the herb itself, but
because of the way the infusion is traditionally drunk in the
pampas region within the southern cone of Latin America, in
northern Argentina, Paraguay, and southern Brazil. It is drunk
extremely hot from a gourd through a metal straw, which isoften kept rested in the mouth, rather like the stem of a tobacco pipe.3 There is no substantive evidence that maté preparedin the style of tea, loose or in sachets (bags), affects the risk ofcancer.
There is also limited evidence suggesting that various othervery hot drinks and foods are a cause of cancer of the oesophagus when they are consumed regularly. The implications of thisevidence, while so far not strong, suggest that more research
may be warranted (see chapter 4.7.5.6).

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tains higher trace amounts of various minerals and othersubstances, often detectable to taste. Some spring water isnaturally carbonated. Bottled water is either still or carbonated, sometimes artificially. The safety of water in termsof chemical and microbial contamination is well regulatedby the WHO programme on chemical safety, but unfortunately, monitoring and surveillance in most countries arelimited.
Arsenic residues can arise from agricultural, mining, andindustrial practices, or may occur naturally from volcanic
activity. WHO guidelines recommend that levels of arsenic
in drinking water should not exceed 10 µg/l.4 Levels ofarsenic in affected areas may range from tens to hundreds,
or even thousands, of micrograms per litre. In unaffectedareas, levels are typically less than 10 µg/l. Inorganic arsenic(arsenate or arsenite) is the form that predominantly contaminates drinking water.
Arsenic is classified as a human carcinogen by theInternational Agency for Research on Cancer. Drinking watercontaminated with arsenic is also classed separately as ahuman carcinogen.5
The bacterium H pylori is found in water supplies contaminated with faeces. It is an established necessary cause of
distal stomach cancer (see box 7.5.1).
Chronic schistosomiasis (infestation with schistosomes) isa known cause of bladder and liver cancer (see chapters
7.16 and 7.8).6 It is caused by contact with water contaminated by parasite eggs.

Box 4.7.2

Contamination of water, and offoods and other drinks

Water contaminants that are causes of cancer are inorganic
arsenic (reviewed here) and Helicobacter pylori and schistosomes(see Chapter 7).
Many other contaminants of water are identified as or havebeen thought to be carcinogenic, usually as a result of animaland other experiments, or else as a result of industrial accidents
or gross overuse. These include herbicides and pesticides, fertilisers that contain and release nitrates, and disinfectants that
also produce potentially toxic contaminants such as chlorinated and brominated organic compounds. They also include chemicals deliberately added to drinking water as public healthmeasures, notably chlorine and fluoride.
These and other industrial, agricultural, and other chemicals
are the subject of tests and regulations for toxicity and safety
in use. Nevertheless, they are often popularly believed to be significant causes of cancer. This subject is controversial and is likely to remain so.
Currently there is no substantial epidemiological evidence
that any of these substances, singly or in combination, as currently regulated and usually consumed in water, or in foods andother drinks, has any significant effect on the risk of any cancer. The Panel considers that the evidence is insufficient to conclude that usual intakes of industrial, agricultural, and otherchemicals have an effect on the risk of human cancer. Toxicity
and carcinogenicity of pollutants as a result of industrial accidents or overuse are outside the scope of this Report.

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4.7.2.2 Fruit juices
Bottled or canned or otherwise packaged fruit juices are
made from the fruits they contain or from fruit pulp. As wellas added water, they usually also contain some added sugars, preservatives, and other additives. They often containtrivial amounts of dietary fibre. Fruit and vegetable juices
have different nutritional properties from whole fruits andvegetables. For these reasons, the international ‘at least fivea day’ campaign to encourage people to eat more fruits andvegetables (at least five portions per day) recommends thatjuices only count as one portion per day, irrespective of theamount consumed.
4.7.2.3 Soft drinks
Soft drinks are made from water, colourings, flavourings, andherbal or other ingredients. They may or may not containfruit juice. They also contain either sugars or, in ‘diet’ form,chemical sweeteners (see chapter 4.6 and box 4.6.3). They
may or may not be carbonated. The original formulations ofcola drinks contained stimulants from the coca and cola
plants. Soft drinks may also include yoghurt and other milk
derivatives, as yoghurt drinks or fruit ‘smoothies’, and also
added vitamins and minerals. ‘Sports’ drinks contain sugars,
electrolytes, and other additives.
4.7.2.4 Hot drinks
The main hot drinks are tea (usually black tea but also green
tea, which is often preferred in China) and coffee. Both contain various antioxidants and phenolic compounds, some ofwhich have been shown to have anti-cancer properties in laboratory conditions.7 They both also contain caffeine (and therelated compound theophylline in tea). There is more caffeine
in tea leaves than in coffee beans, but brewed coffee contains
more caffeine than brewed tea. Caffeine and theophylline arebioactive, quickening reaction times, relieving fatigue, andstimulating the cardiovascular and central nervous systems.
Tea and coffee, when drunk without adding milk, cream,sugar, lemon, or honey, contain no energy and trivial
amounts of some micronutrients; the bioactive chemicals
they contain are mentioned above. When these drinks are
consumed frequently, both may be substantial dietary
sources of some of these bioactive constituents. Thus, coffee
is a major source of some antioxidants in the US diet.8

4.7.3 Consumption patterns
4.7.3.1 Water
Environmental conditions, health, activity levels, and otherfactors determine the amount of water needed, but there isno international recommendation for daily consumption.
The Institute of Medicine in the USA recommends 2.7 litres
per day total water for women and 3.7 litres for men. The
UK’s Food Standards Agency estimates that most people
need to drink at least 1.2 litres of fluids per day. Morethan half of the world’s population has access to drinking
water through taps in their homes or outside. Tap
water should be regulated to meet international quality
guidelines, such as those prepared by WHO.9

Most people who do not have access to clean drinking
water live in Asia, sub-Saharan Africa, and some parts of
Latin America. High concentrations of arsenic in drinking
water have been found in areas of Bangladesh, China, andWest Bengal (India), and also in more localised areas ofArgentina, Australia, Chile, Mexico, Taiwan, China, the USA,and Vietnam. In many of these regions, the drinking water
source is groundwater naturally contaminated by arsenicrich geological formations.10
4.7.3.2 Fruit juices
There is little information on the general or local consumption of fruit juices.
4.7.3.3 Soft drinks
In 2004, global consumption of soft drinks was estimated at
480 000 million litres (including bottled water),11 of whichcola and other carbonated drinks accounted for 40 per cent.
In terms of sales, carbonated drinks are the largest single category. World sales of cola drinks continue to rise, as do more
recently, sales of bottled waters, fruit juices, and ‘functional drinks’. The USA is the biggest per capita consumer of softdrinks, followed by Mexico and Chile. The USA alone
accounts for more than a 20 per cent share of the global
total. Asia is the fastest growing market for soft drinks: sales
are increasing at around 3.5 per cent each year.
Average consumption of soft drinks in the USA is arounda 12-ounce can (about 350 ml) per person/day. Older children consume about this amount, and sometimes more. Mostof these drinks are sugared. At this level, soft drinks contribute a substantial proportion of total sugars intake.
4.7.3.4 Hot drinks
After water, tea and coffee are the most commonly consumed drinks in the world. There are various different methods of preparing these hot drinks depending on culture andpersonal preference. Coffee consumption is high in northern
Europe and North America. Low-income countries export
most of the world’s coffee; high-income countries consume
approximately seven times as much (per capita) as lowincome countries.
Average worldwide consumption of tea is around 0.5 kg
per person/year; this is exceeded significantly in several
Asian countries (notably, China, India, and Japan), and in
the UK and Ireland. Worldwide, black tea is the most popular type, although green tea is more commonly drunk in Asia.
Maté, as traditionally prepared, is drunk almost exclusively
in parts of South America.

4.7.4 Interpretation of the evidence
4.7.4.1 General
For general considerations that may affect interpretation of
the evidence, see chapters 3.3 and 3.5, and boxes 3.1, 3.2,
3.6 and 3.7.
‘Relative risk’ (RR) is used in this Report to denote ratio
measures of effect, including ‘risk ratios’, ‘rate ratios’, ‘hazard
ratios’, and ‘odds ratios’.

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4.7.4.2 SpecificClassification. Different types of tea, coffee, and soft drinks
are consumed in different cultures. The ways in which tea
and coffee are prepared and drunk also vary. For coffee, thisincludes the degree of roasting, the methods of brewing(which determine the strength and composition), and thedifferent substances added. Similarly, tea may be consumed
with or without milk and in different strengths. Associations
seen in one population but not another may reflect some
aspect of the drink as consumed in that population rather
than the drinks themselves. In some studies, fruit juices andbottled waters are included in the definition of soft drinks.
Measurement. Fluid intake is best estimated from urine

collection, but this is rarely done. Instead, estimates areusually made from food frequency questionnaires.
Confounding. In interpreting the results of epidemiologicalstudies of all types of drink, confounding by other habits
should be considered. For example, heavy consumers of softdrinks, tea, or coffee may also be smokers and drinkers of
alcohol.
People who are physically active often consume more liquid than those who are not. Physical activity is therefore a confounder of the relationship between the volume of fluid drunkand cancer risk, but may not be adequately adjusted for.
Reporting bias. Soft and cola drinks are often identified as

unhealthy, and studies that depend on self-reporting may
disproportionately underestimate consumption.

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well water.13 The other study reported a quantified effectestimate, which was 3.66 (95% CI 1.81–7.03), but this study(based in Japan) did not adjust for smoking.17
Both case-control studies showed increased risk of lungcancer for the highest intake group compared to the lowest,18
19
which was statistically significant in one.19 The other study
did not report confidence intervals. Effect estimates were
3.0118 and 8.9 (95% CI 4.0–19.6).19
Ecological studies were made in populations from
Argentina,27 Belgium,21 Chile,29 China,23 Switzerland,20 and
Taiwan,22-26 30 as well as worldwide.28 Eight studies showed
increased risk of lung cancer with increasing levels of arsenic
in drinking water,21-25 27 29 30 which was statistically significant in four.24 27 29 30 Two studies showed decreased risk,20 26
which was statistically significant in one.26 One study reported different inconsistent results for men and women (correlation coefficients of -0.51 for men and 0.07 for women).28
One study showed that measures to lower arsenic levels in
drinking water by using tap water rather than well water
were associated with a fall in lung cancer rates in a regionof Taiwan with endemic black foot disease.25
The general mechanisms through which arsenic could
plausibly cause cancer are outlined below. In addition, soluble arsenic in drinking water induces lung cancers in animal models and causes chronic lung disease.5
The evidence is ample and consistent, both fromcohort and case-control as well as ecological studies.
There is a dose-response relationship and the effectsize is relatively large. There is robust evidence formechanisms. The evidence that arsenic is a cause oflung cancer is convincing.

4.7.5 Evidence and judgements
Skin

The full systematic literature review (SLR) is contained on
the CD included with this Report.
4.7.5.1 Water
The evidence was too sparse or inconsistent to draw any conclusion about the relationship between water quantity andcancer risk.
4.7.5.1.1 Water-borne contaminants: arsenic

Ecological studies based on known arsenic concentrations inwater may be interpreted more robustly than for many otherdietary exposures.
Lung

Two cohort studies,12-17 2 case-control studies18 19 and 12
ecological studies20-30 investigated arsenic in drinking waterand lung cancer.
Both cohort studies showed statistically significant
increased risk of lung cancer for the highest intake groupcompared to the lowest.12-17 Although meta-analysis was notpossible, both studies reported that a dose-response relationship was apparent. One study (in Taiwan) based in a
population with endemic black foot disease, a manifestationof arsenicosis, reported an effect estimate of 3.29 (95% confidence interval (CI) 1.60–6.78) for average arsenic level in152

Two cohort studies,31 32 5 case-control studies,33-37 1 crosssectional study,38 and 11 ecological studies20 22 24 27 29 30 39-43
investigated arsenic in drinking water and skin cancer.
Both cohort studies showed non-significant increased risk
with increasing levels of arsenic in the water31 32; however,for one study the increased risk was apparent in women but
not in men.32 Effect estimates were 1.82 (95% CI 0.5–4.66)
for women and 0.83 (95% CI 0.17–2.43) for men in Utah,32
and 1.21 (95% CI 1.00–1.47) per 100 µg/l.31
Two case-control studies measured arsenic levels in toeand fingernails.36 37 Such measures are less subject to error
and bias than some other methods to assess actual exposure
to a carcinogen. One study reported a significant increased
risk for melanoma with a risk estimate of 1.65 (95% CI
1.27–2.14) per 100 ng/g36; the other study reported non-significant increased risk 1.02 (95% CI 0.90–1.17) per 100 ng/g
for basal cell carcinoma and 1.12 (95% CI 0.95–1.32) forsquamous cell carcinoma.37
Two case-control studies that reported on dietary arsenic
showed increased risk with increased intake,33 35 which wasstatistically significant in one.33 One study reported a nonsignificant decreased risk.34
The cross-sectional study showed a statistically significant
increased risk, with a partially adjusted effect estimate of
5.04 (95% CI 1.07–23.8) for > 0.71 versus 0 parts per mil-

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D R I N K Slion average arsenic content in water.38
All 11 ecological studies reported increased risk for skincancer with increased arsenic exposure,20 22 24 27 29 30 39-43
which was statistically significant in 4,24 29 30 40 41 and statistically significant in women but not in men in 127; and significant in men but not women in another study.20 The effectincreased with age (cumulative exposure), where that wasmeasured, and the reported effect estimates were usuallylarge, more than half being greater than 2.5.
The general mechanisms through which arsenic could
plausibly cause cancer are outlined below.
The evidence is consistent, from cohort, case-control
and ecological studies. There is robust mechanistic
evidence. Arsenic is a probable cause of skin cancer.
KidneyThree cohort studies,32 44 45 one time-series study,46 and nine
ecological studies20 22 24 27 29 30 40 47 48 investigated arsenic indrinking water and kidney cancer.
All three cohort studies showed increased risk for the highest intake levels compared to the lowest,32 44 45 which wasstatistically significant in one.45 Effect estimates were 1.49
(95% CI 0.67–3.31; adjusted for smoking),44 2.82 (95% CI
1.29–5.36),45 and 1.13 (women; confidence intervals notreported) and 1.43 (men; confidence intervals not reported).32
The single time-series study reported a statistically significant decreased risk in kidney cancer following the installation of a tap water supply system in an arsenic-endemic areaof Taiwan.46
All nine ecological studies showed increased risk withhigher levels of arsenic in drinking water,20 22 24 27 29 30 40 47 48
which was statistically significant in six.24 27 30 40 48
The general mechanisms through which arsenic could
plausibly cause cancer are outlined below. In addition,arsenic in drinking water is well absorbed in the gastrointestinal tract, and both inorganic arsenic and its methylated metabolites are excreted in urine.49 Arsenic can modify
the urinary excretion of porphyrins in animals and humans.50
The evidence is sparse. There is limited evidence
suggesting that arsenic is a cause of kidney cancer.
Bladder

Six cohort studies,14 17 32 44 45 51 1 time-series study,52 7 casecontrol studies,18 53-60 and 11 ecological studies20 22 24 29 30 40
47 48 61-64
investigated arsenic in drinking water and bladdercancer.
Four cohort studies showed increased risk for the highest
intake levels compared to the lowest,14 17 44 45 which was statistically significant in two.17 45 One study showed non-significant decreased risk.32 The single cohort study thatmeasured arsenic levels in finger- or toenails reported aneffect estimate of 1.05 (95% CI 0.85–1.29) per 100 ng/g.51
Three case-control studies showed increased risk for thehighest intake levels compared to the lowest,18 56-59 which
was statistically significant in one.18 Two studies showednon-significant decreased risk,53 55 two studies showed noeffect on risk,54 60 including the single case-control study thatmeasured arsenic levels in finger- or toenails.60
Six ecological studies showed increased risk with higher
levels of arsenic in drinking water; all were statisticallysignificant.22 24 29 30 40 62 64 Two studies reported decreased
risk,47 61 which was statistically significant in one.47 One
study showed a non-significant decreased risk in men and anon-significant increased risk in women.20 Two studies did
not provide quantified results.48 63
The general mechanisms through which arsenic could
plausibly cause cancer are outlined below. In addition,arsenic in drinking water is well absorbed in the gastrointestinal tract, and both inorganic arsenic and its methylated metabolites are excreted in urine.49 Arsenic can modify
the urinary excretion of porphyrins in animals and humans.50
The evidence is inconsistent. There is limited evidence
suggesting that arsenic is a cause of bladder cancer.
General mechanisms — arsenic

Arsenic is carcinogenic to humans and causes chromosomal
abnormalities.10 It can result in changes in the methylationof oncogenes or tumour-suppressor genes. It also interfereswith the activities of several enzymes of the haem biosynthetic pathway. Exposure to arsenite or arsenate results ingeneration of reduced oxygen species (free radicals) in laboratory animals and human cells. Arsenic biotransformationis thought to deplete cells of reduced glutathione, leading
to a state of oxidative stress, characterised by decreased scavenging of free radicals, which can directly damage DNA andinduce cell proliferation.65
There are several compounds suspected to modulate thechronic environmental toxicity of arsenic –- variables that
may either enhance or suppress its genotoxicity and carcinogenicity. Among them are nutritional factors like selenium and zinc, as well as drinking water co-contaminants
like antimony.66
4.7.5.2 Soft drinks
The evidence was too limited in amount, consistency, or
quality to draw any conclusions
4.7.5.3 Fruit juices
The evidence was too limited in amount, consistency, or
quality to draw any conclusions.
4.7.5.4 Coffee
Pancreas

Eighteen cohort studies,67-83 37 case-control studies,77 84-119
and 11 ecological studies120-130 investigated coffee and pancreatic cancer.
Seven cohort studies showed increased risk for the highest intake groups when compared to the lowest,67 68 71 72 78
80
which was statistically significant in two.72 80 Seven studies showed non-significant decreased risk.69 70 73 75 79 81 83 Twostudies stated that there was no significant effect on risk.77
82
One study reported a non-significant increased risk in men
and decreased risk in women76; and one study reported a
non-significant increased risk in women and a non-signifi-

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cant decreased risk in men.74 Meta-analysis was possible oneight cohort studies, giving a summary effect estimate of
1.00 (95% CI 0.94–1.07) per cup/day, with low heterogeneity (figure 4.7.1).
Some, though not all, of the cohort studies suggest a Jshaped dose-response relationship. An effect at high levelsof coffee consumption cannot be excluded.
Case-control studies reported inconsistent results.77 84-119
Eighteen studies reported increased risk,84-87 89-91 94 97 99 102106 112 114 116 119
of which nine were statistically significant.85
87 94 102 112 114
Eleven studies reported decreased risk,77 92 93 95

Figure 4.7.1

Coffee and pancreatic cancer; cohort andcase-control studies
Relative risk (95% CI)

CohortSnowdon 1984

0.98 (0.69–1.40)

Zheng 1993 Men

0.93 (0.81–1.08)

Shibata 1994

1.13 (0.79–1.62)

Stensvold 1994 Men

0.97 (0.83–1.14)

Stensvold 1994 Women

1.08 (0.85–1.37)

Harnack 1997 Women

1.24 (1.02–1.49)

Michaud 2001 Men

0.86 (0.74–1.00)

Michaud 2001 Women

0.96 (0.87–1.07)

Lin 2002 Men

1.14 (0.92–1.41)

Lin 2002 Women

0.86 (0.58–1.26)

Stolzenberg-Solomon 2002 Men

1.05 (0.94–1.17)

Summary estimate

1.00 (0.94–1.07)

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96 101 107 109 111 113 118

which was statistically significant in
one.118 Three studies showed no effect on risk88 98 and one
study stated there was no significant effect on risk.110 Fourother studies reported different effects in men and women;
however none was statistically significant.100 108 115 117 Metaanalysis was possible on 26 studies, giving a summary effectestimate of 1.04 (95% CI 1.01–1.07) per cup/day, with moderate heterogeneity (figures 4.7.1 and 4.7.2). Studies that
did not adjust for smoking behaviour were more likely toreport increased risk. Confounding with smoking could not
be excluded.
The ecological studies overall showed an increased mortality between coffee consumption and pancreatic cancer.120130
Correlation coefficients ranged from +0.15122 to+0.59.124 125
There is ample evidence, including prospective data,
which is consistent and with low heterogeneity, andwhich fails to show an association. It is unlikely thatcoffee has any substantial effect on the risk ofpancreatic cancer.

Figure 4.7.2

Coffee and pancreatic cancer;
cohort studies: dose response

Case control
Elinder 1981

0.85 (0.66–1.09)

MacMahon 1981

1.13 (1.05–1.23)

Wynder 1983 Men

1.01 (0.93–1.10)

Wynder 1983 Women

1.00 (0.90–1.10)

Gold 1985

1.06 (0.89–1.26)

Mack 1986

1.20 (1.07–1.34)

La Vechhia 1987

1.06 (0.89–1.27)

Gorham 1988

1.15 (0.98–1.35)

Falk 1988 Men

1.09 (1.03–1.16)

Falk 1988 Women

1.06 (0.97–1.15)

Clavel 1989 Women

2.00 (1.22–3.28)

Olsen 1989 All respondents

0.97 (0.87–1.08)

Clavel 1989 Men

1.32 (0.91–1.92)

Cuzick 1989

0.93 (0.83–1.05)

Farrow 1990 Men

1.03 (0.94–1.13)

Jain 1991

1.00 (1.00–1.00)

Ghadirian 1991

0.99 (0.93–1.05)

Bueno de Mesquita 1992

0.78 (0.61–1.00)

Stefanati 1992

1.14 (0.80–1.62)

Lyon 1992

1.15 (1.02–1.30)

Zatonski 1993

0.53 (0.27–1.02)

Kalapothaki 1993

0.85 (0.68–1.06)

Sciallero 1993

1.02 (0.84–1.24)

Partanen 1995

0.97 (0.92–1.03)

Gullo 1995

1.25 (1.12–1.40)

Silverman 1998 Men

1.05 (0.98–1.13)

Silverman 1998 Women

1.03 (0.94–1.13)

Villeneuve 2000 Men

1.05 (0.94–1.17)

Villeneuve 2000 Women

0.99 (0.88–1.12)

Kreiger 2001 Women

1.00 (0.77–1.32)

Summary estimate

Snowdon 1984
Zheng 1993
Shibata 1994
Stensvold 1994 Men
Stensvold 1994 Women
Honack 1997 Women
Michaud 2001 Men
Michaud 2001 Women
Lin 2002 Men
Lin 2002 Women
Stolzenberg-Solomon
2002 Men

1.04 (1.01–1.07)

0.5

0.8 1 1.2

2

0

2

4

6

Coffee (cups/day)
Relative risk, per cup/day

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Kidney4.7.5.6 Herbal teas, infusions

Five cohort studies,73 74 131-134 18 case-control studies,135-152 and1 ecological study153 investigated coffee and kidney cancer.
Two cohort studies showed non-significant decreased risk
for the highest intake groups when compared to the lowest.73
131
One study showed non-significant increased risk133; one
study stated that there was no association132 134; and another study showed non-significant increased risk in women andnon-significant decreased risk in men.74 Effect estimates were0.15 (95% CI 0.02–1.16),73 0.87 (95% CI 0.66–1.16) per
cup/day,131 2.69 (95% CI 0.89–8.1),133 and 0.7 (no CI; men)and 1.2 (no CI; women) for highest versus lowest categories
of exposure.74
The case-control studies reported inconsistent results, only
one of which was statistically significant (in women but not
in men).146 Seven studies showed non-significant decreased
risk for the highest intake groups when compared to the lowest.135-138 140 142 143 145 Four studies showed non-significant
increased risk141 144 149 152; one study reported no effect on risk;
four studies stated that there was no association147 148 150 151;
and two studies showed increased risk in women, which wasstatistically significant in one,146 and non-significant decreased
risk in men.139 146 Only four of the best quality case-control
studies were able to be meta-analysed, giving a summary estimate of 0.99 (95% CI 0.96–1.01) (figure 4.7.3).
The ecological study reported correlation of incidence of0.62 for men and 0.4 for women.153

4.7.5.6.1 Maté
Oesophagus

There is substantial evidence both from cohort andcase-control studies, which is consistent and of low
heterogeneity, and which fails to show an association.
It is unlikely that coffee has a substantial effect on therisk of kidney cancer.

Eight case-control studies155-163 and one ecological study164
investigated maté and oesophageal cancer.
Seven case-control studies showed increased risk for thehighest intake groups when compared to the lowest (figure
4.7.4)155-159 161-163 which was statistically significant infour.155 157 159 161 One study showed non-significant decreased
risk.160 Meta-analysis was possible on five studies, all adjusting for smoking, giving a summary effect estimate of 1.16
(95% CI 1.07–1.25) per cup/day, with moderate heterogeneity relating to size but not direction of effect (figure
4.7.5). The two studies not included in the meta-analysis did
not adjust for smoking; both reported non-significant
increased risk.156 159
The single ecological study showed a non-significant
relationship between increased maté consumption andoesophageal cancer mortality.164
The general mechanisms through which maté could plausibly cause cancer are outlined below.
The evidence, from case-control studies, is consistentand a dose-response relationship is apparent. There isrobust evidence for plausible mechanisms. Regularconsumption of maté, as drunk in the traditional stylein South America, is a probable cause of oesophageal
cancer.
Mouth, pharynx, and larynx

The Panel is aware that since the conclusion of the SLR, onecohort study154 has been published. This new information does
not change the Panel judgement (see box 3.8).

Six case-control studies investigated maté and mouth,
pharynx, and larynx cancers.165-170
All six case-control studies showed increased risk for thehighest intake groups when compared to the lowest,165-170
which was statistically significant in four.165 167-169
The general mechanisms through which maté could plausibly cause cancer are outlined below.

4.7.5.5 Tea
The evidence was too limited in amount, consistency, or
quality to draw any conclusions.

The evidence is sparse. There is limited evidence
suggesting that maté is a cause of mouth, pharynx, andlarynx cancers.
General mechanisms — maté

Figure 4.7.3

Coffee and kidney cancer;
case-control studies
Relative risk (95% CI)

Maté is typically drunk scalding hot through a metal straw.
This produces heat damage in the mouth, pharynx, larynx,
and oesophagus. Repeated damage of this nature can leadto cancer (also see Chapter 2). Chemical carcinogenesis fromconstituents of maté has also been postulated.171 172

Mattioli 2002

0.89 (0.63–1.26)

Yuan 1998

0.98 (0.95–1.01)

4.7.5.7 High-temperature foods and drinks

McLaughlin 1984

1.00 (0.95–1.04)

Oesophagus

Kreiger 1993

0.99 (0.94–1.04)

Summary estimate

0.99 (0.96–1.01)

0.5

1Coffee (cups/day)2

Three cohort studies173-176 and 15 case-control studies162 177196
investigated hot foods or drinks and oesophageal cancer.
Two cohort studies showed increased risk for consuming
high-temperature foods or drinks,173 174 which was statistically significant in one.174 The other study stated that there
was no association for hot drinks.175 176 Effect estimates were1.44 (95% CI 0.91–2.26; hot food),173 and 1.5 (95% CI
1.1–2.0; men; hot tea) and 1.8 (95% CI 1.1–2.9; women;

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Figure 4.7.4

Maté and oesophageal cancer;
case-control studies
Relative risk (95% CI)

Victora 1987

1.47 (0.67–3.25)

Sewram 2003

1.62 (1.01–2.61)

Castelletto 1994

1.70 (1.00–2.89)

De Stefani 2003

3.50 (1.39–8.82)

De Stefani 1990

12.21 (3.78–39.42)

Dietz 1998

5.48 (0.96–31.44)

Rolon 1995

0.90 (0.44–1.86)

Vassallo 1985 Men

4.80 (1.90–12.11)

Vassallo 1985 Women

34.60 (4.88–245.40)

0.2 0.5

2

1

5

10

35

Relative risk, highest vs lowest exposure category

Figure 4.7.5

Maté and oesophageal cancer;
case-control studies
Relative risk (95% CI)

Vassallo 1995 Men

1.26 (1.18–1.35)

Vassallo 1995 Women

1.43 (1.20–1.69)

De Stefani 1990

1.17 (1.12–1.22)

Rolon 1995

1.04 (0.95–1.13)

Sewram 2003

1.17 (1.09–1.25)

De Stefani 2003

1.04 (1.00–1.08)

Summary estimate

1.16 (1.07–1.25)

0.95 1

1.4

1.75

Relative risk, per cup/day

hot tea).174 Both these studies adjusted for smoking.
Seven case-control studies investigated food temperature162 178-183 189-191; seven investigated hot drinks177 182 184-186
188 192 193; and four investigated high-temperature hot drinks
and soups combined.191 194-196 For high-temperature food, six
studies showed increased risk,162 178-183 187 189 191 which wasstatistically significant in three162 179 180 187 189; one study
showed non-significant decreased risk.190 For hot drinks, fivestudies showed increased risk,177 182 185 186 188 which was statistically significant in four177 185 186; two studies showed nosignificant association192 193; one study showed non-significant decreased risk.184 For hot drinks and soups combined,
all four studies showed increased risk,191 194-196 which wasstatistically significant in two.194 195 Several studies did not
adjust for smoking or alcohol.177 180 182 186 194 195
High-temperature foods and/or drinks produce heat damage in the mouth, pharynx, larynx, and oesophagus.

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Repeated damage of this nature can lead to cancer (also see
chapter 2.4.1.3).
The evidence is inconsistent. There is limited evidence
suggesting that high-temperature drinks are a cause ofoesophageal cancer.

4.7.6 Comparison with previous report
Water was not reviewed in the previous report, which had
little to say about contaminants in water and did not review
arsenic contamination. The previous report did not review
soft drinks as such.
The previous report judged that green tea possibly protects
against stomach cancer, but this was not supported by thecurrent review. The previous report judged that black tea
probably has no relationship with cancers of the stomach,pancreas, and kidney. This time the evidence was judged too
limited to draw a clear conclusion. The judgements of theprevious report on coffee were practically the same as in thisReport, except that the previous report judged that drinking
more than five cups per day was a possible cause of bladdercancer. The evidence now indicates that coffee is unlikely tohave a substantial effect on risk of this cancer. The previous
report judged it possible that maté and other very hot drinks
increase the risk of oesophageal cancer. Since the mid-1990s,
a greater body of consistent data has been published on
maté.
Skin cancer was not reviewed in the previous report.

4.7.7 Conclusions
The Panel concludes:
The evidence that inorganic arsenic in drinking water is a
cause of lung cancer is convincing. Water contaminated inthis way is probably a cause of skin cancer. There is limited
evidence suggesting that water contaminated in this way is
a cause of cancers of the kidney and bladder.
Maté is probably a cause of oesophageal cancer when
drunk scalding hot through a metal straw, as traditional inparts of South America. The temperature is judged to be
responsible for any increased risk of cancer. There is limited
evidence suggesting that maté as drunk traditionally is a
cause of cancers of the mouth, pharynx, and larynx. Thereis limited evidence suggesting that high-temperature drinks
are a cause of oesophageal cancer.
It is unlikely that coffee has a substantial effect on the riskof cancer either of the pancreas or of the kidney.

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4.8 Alcoholic drinks
ALCOHOLIC DRINKS, AND THE RISK OF CANCER
In the judgement of the Panel, the factors listed below modify the risk of cancer. Judgements are graded according to the strength of the evidence.

DECREASES RISKINCREASES RISK
Exposure

Cancer site

Convincing

Alcoholic drinks

Mouth, pharynx andlarynxOesophagus
Colorectum (men)1
Breast (pre- andpostmenopause)

Probable

Alcoholic drinks

Liver2
Colorectum (women)1

Exposure

Cancer site

Limited —suggestive
Substantial
effect on risk
unlikely12
3

Alcoholic drinks (adverse effect): kidney3

The judgements for men and women are different because there are fewer data for women. Increased risk is only apparent above a threshold of 30 g/day of ethanol
for both sexes.
Cirrhosis is an essential precursor of liver cancer caused by alcohol. The International Agency for Research on Cancer has graded alcohol as a class 1 carcinogen forliver cancer. Alcohol alone only causes cirrhosis in the presence of other factors.
The evidence was sufficient to judge that alcoholic drinks were unlikely to have an adverse effect on the risk of kidney cancer; it was inadequate to draw aconclusion regarding a protective effect.

For an explanation of all the terms used in the matrix, please see chapter 3.5.1, the text of this section, and the glossary.

Many plant and some animal foods can be fermented to
produce alcoholic drinks; alcohol has been made this way
for thousands of years.
The main alcoholic drinks consumed, in ascending orderof alcohol (ethanol) content, are beers and ciders; wines;
wines ‘fortified’ with spirits; and spirits (liquors) andliqueurs. The alcohol content of the many different drinks
within each of these categories varies.
Alcoholic drinks induce changes in mood; they also
produce physical effects such as loss of coordination. In
most countries they are the legal ‘intoxicant’ of choice,used as a social and professional lubricant; however,certain cultures forbid the drinking of alcohol.
With industrialisation and urbanisation, and the readyavailability of alcoholic drinks (which may or may not be
taxed), consumption tends to rise.
Alcohol relaxes people’s social inhibitions, but it isaddictive; dependency on alcohol can seriously affectpeople’s personal and professional lives.
It has been known for a long time that prolonged highconsumption of alcohol is a cause of cirrhosis of the liver,though not all people are equally susceptible. Knowledgeof its other ill-effects is more recent.
Overall, the Panel judges that alcoholic drinks are acause of cancers of a number of sites and that, in general,
the evidence is stronger than it was in the mid-1990s. The
evidence does not show any ‘safe limit’ of intake. The
effect is from ethanol, irrespective of the type of drink.
Ethanol is classified by the International Agency forCancer Research as a human carcinogen.
The Panel judges as follows:
The evidence that alcoholic drinks are a cause of cancersof the mouth, pharynx, and larynx, oesophagus,
colorectum (men), and breast is convincing. They areprobably a cause of liver cancer, and of colorectal cancer
in women. It is unlikely that alcoholic drinks have asubstantial adverse effect on the risk of kidney cancer.
In final summary, the evidence is that alcoholic drinks
are a cause of cancers of the mouth, pharynx, and larynx;
the oesophagus; the colorectum in men, and the breast;and probably of liver cancer and colorectal cancer inwomen. It is unlikely that alcoholic drinks have asubstantial adverse effect on the risk of kidney cancer.

Chapter 4.8 concerns all alcoholic drinks.
Alcoholic drinks have been popular in most societies ever157

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since the effects on mood of the fermented products of plantfoods and some animal foods were discovered, probably in
Palaeolithic or even earlier times.
Ethanol is the active ingredient in alcoholic drinks; the concentration varies, depending on the type of drink. In the past,
beers were made from grains, ciders from fruits, mead fromhoney, and brews from milk; these were followed by wines,
generally made from grapes and with higher concentrationsof ethanol. The process of distillation was a later invention,
which produced more highly concentrated alcoholic drinks
made from grains, fruits, sugar, and other substrates.
Alcohol is liable to be addictive. Its specific effects are toinduce a mood of euphoria and disinhibition, which may be
dangerous. Much domestic and other violence, and many
reckless and violent incidents, and crimes such as arson,
wounding, homicide, and car crashes, are alcohol-related.
Reports concerned with food, nutrition, and the prevention of disease have often excluded alcohol. This is because
alcohol is also a drug, the impact of which is behavioural andsocial, as well as biological. More recently, alcoholic drinks
have been included in such reports because of the evidence
that low to moderate consumption protects against coronary
heart disease (but not cerebrovascular disease), and also
because of the evidence on cancer, given that ethanol is ahuman carcinogen.

4.8.1 Definitions and sources
Alcohol is the common term for ethanol, one of a family of
alcohols, produced in nature when sugar molecules are broken down to release energy by yeasts. This process of fermentation is used to produce alcoholic drinks. Alcohol is asource of dietary energy (see chapter 4.10.1). It also acts asa drug, affecting both mental and physical responses (alcohol intoxication). Alcoholic drinks include beers, wines, andspirits. Other alcoholic drinks that may be locally important
include fermented milks, fermented honey-water (mead),and fermented apples (cider).
Most alcoholic drinks are manufactured industrially. Someare made domestically or illegally, as ‘moonshine’ or ‘hooch’.
4.8.1.1 Beers
Beer, ale, and lager are traditionally produced from barley;
today other cereal grains are used. Beer contains between 3
and 7 per cent alcohol. The grain starches are converted tosugars and then fermented by yeasts. The term ‘beer’ in thisReport includes ales and lagers.
4.8.1.2 Wines
Wines are usually produced from grapes and containbetween around 9 to 15 per cent alcohol; they are crushed
to produce juice and must, which is then fermented. The
colour of the grapes and the length of fermentation determine the colour and strength of the final product. Grape
vines grow best in temperate regions. Wines can also be produced from other fruits and from rice (sake). Here, wine istaken to mean grape wines. Wines may be fortified with spirits (see chapter 4.8.2.2) to produce drinks of alcohol con-

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tent between about 16 and 20 per cent.
4.8.1.3 Spirits/liquors
Spirits are usually produced from cereal grains and sometimes from other plant foods. They are distilled, to give adrink with a higher concentration of ethanol than either
beers or wines — around 35–50 per cent or higher. Some of
the most globally familiar spirits are brandy (distilled wine),
whisky and gin (distilled from grains), rum (from molasses),aguardente also known as cachaça (from sugar), vodka(sometimes from grain, sometimes potatoes), and tequila
and mescal (from agave and cactus plants). Spirits andliqueurs are also made from fruits.

4.8.2 Composition
Alcohol has an energy content of 7 kilocalories per gram, andis metabolised in the liver. On average, blood alcohol levels
reach a maximum between 30 and 60 minutes after
drinking an alcoholic drink, and the body can metabolise
10–15 g alcohol per hour.
Alcohol alters the way the central nervous system functions. Very high alcohol consumption (where blood alcohol
reaches 0.4 per cent) can be fatal, as can long-term, regular, high intakes.
4.8.2.1 Beers
There are many varieties of beer, with different compositions.
Their alcohol content ranges from around 3 to 7 per cent by
volume; beers generally contain a variety of bioavailable
phenolic and polyphenolic compounds, which contribute to
the taste and colour, many of which have antioxidant properties. Beer is also a source of magnesium, potassium,
riboflavin, folate, and other B vitamins.
4.8.2.2 Wines
The composition of wine depends on the grape varieties
used, as well as the growing conditions and the wine-making
methods, which may vary between vineyards. The alcohol
content ranges from around 9 to 15 per cent by volume. Redwines contain high levels of phenolic and polyphenolic compounds (up to a total of around 800–4000 mg/l), particularly resveratrol, derived from the grape skins. Like those inbeer, these phenolic compounds add taste and colour. White
wines contain fewer phenolics. Red wine has been shown tohave antioxidant activity in laboratory experiments. Winealso contains sugars (mainly glucose and fructose), volatile
acids (mainly acetic acid), carboxylic acids, and varying levels of calcium, copper, iron, magnesium, potassium, and vitamins B1, B2, B6, and C. Wines may be flavoured with herbs
and fortified with spirits (see chapter 4.8.2.3) to produce
drinks of alcohol content between about 16 and 20 per cent.
4.8.2.3 Spirits/liquors
The alcohol content of spirits/liquors and liqueurs is usually between 35 and 50 per cent by volume, but can be evenhigher. Distilled drinks may have herbs and other ingredients added to give them their distinctive character.

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4.8.3 Consumption patterns
Much of the information on average consumption of alcoholic drinks, internationally and nationally, is not informative. Within almost all populations, consumption varies
widely, usually as a function of availability, price, culture or
religion, and dependency. In general, men consume substantially more alcoholic drinks than women. In countries
where considerable amounts of alcoholic drinks are produced
domestically and by artisanal methods, overall consumption
will (if only for this reason) be underestimated. In many
countries, alcohol is a public health problem. This is not somuch because of the average level of intake, but because aminority of the population, which in high-income countries
includes an increasing number of young people, drink alcohol excessively (‘binge’ drinking).
Worldwide, alcoholic drinks supply an average of 2.3 percent of total dietary energy. This ranges from around 10 per
cent in some northern European countries, to (as recorded)practically zero in Islamic countries. Average consumption
is nearly four times higher in high-income compared with
low-income countries, and tends to be highest in Europe,
North America, and Oceania. Consumption varies withincountries: many people do not consume alcoholic drinks,
some drink occasionally and others consume 15–25 per centor more of their dietary energy as alcohol.
Alcoholic drinks are illegal in Islamic countries. In countries where these drinks are legal, there are often restrictions
on price and availability to adults, and in particular to young
people.
Many countries recommend restriction of alcohol intake
for health reasons. In the USA, men are advised not to exceed
two drinks per day and women one drink per day. In the UK,
the government advises men not to exceed 3–4 units per day
and women 2–3 units per day. One US ‘drink’ is equivalent
to about 15 g ethanol, almost two UK units; a unit is 10 ml
or 8 g of pure ethanol.

4.8.3.1 Beers
Beers are the most widely consumed alcoholic drinks worldwide. They provide an average of 1 per cent of dietary energy, with a peak of more than 6 per cent in parts of northern
Europe. People living in Europe, North America, andOceania tend to drink the most beer.
4.8.3.2 Wines
Wines provide an average of 0.2 per cent of dietary energy
worldwide. They are drunk mainly in Europe, Australasia,
and the Americas, with highest levels of consumption inwestern and southern Europe.
4.8.3.3 Spirits/liquors
There are few data on average consumption of spirits/liquors.

4.8.4 Interpretation of the evidence
4.8.4.1 General
For general considerations that may affect interpretation of
the evidence, see chapters 3.3 and 3.5, and boxes 3.1, 3.2,
3.6 and 3.7.
‘Relative risk’ (RR) is used in this Report to denote ratio
measures of effect, including ‘risk ratios’, ‘rate ratios’, ‘hazard ratios’, and ‘odds ratios’.
4.8.4.2 SpecificConfounding. At high levels of consumption, the effects ofalcohol are heavily confounded by other behaviours, such as
smoking tobacco.
Reporting bias. Self-reporting of consumption of alcoholic

drinks is liable to underestimate consumption, sometimes
grossly, because alcohol is known to be unhealthy and undesirable, and is sometimes drunk secretly. Heavy drinkers
usually underestimate their consumption, as do drinkers ofillegal or unregulated alcoholic drinks.
Measurement. In recent years, the strength and serving sizeBox 4.8.1

Types of alcoholic drink

The Panel judges that alcoholic drinks are or may be a cause ofvarious cancers, irrespective of the type of alcoholic drink. The
causal factor is evidently alcohol (ethanol) itself. There is no significant evidence that alcohol protects against any cancer. The
extent to which alcoholic drinks are a cause of various cancers
depends on the amount of alcohol drunk.
Epidemiological studies commonly identify the type of alcoholic drink consumed. Some of the evidence reviewed in chapter 4.8.5 does appear to show that some types of drink seem tohave different effects. For example, for cancers of the mouth,
pharynx, and larynx, the evidence is stronger for consumptionof beer and spirits than for wine. Here is the possibility of residual confounding: wine drinkers in many countries tend to have
healthier ways of life than beer or spirit drinkers.
Apparent discrepancies in the strength of evidence may also
be due partly to variation in the amounts of different types ofalcoholic drinks consumed. In general, the evidence suggests
similar effects for different types of alcoholic drink.

of some alcoholic drinks have increased. For example, in theUK, wine is commonly served in 250 ml glasses as opposedto the standard 125 or 175 ml glass. In addition, alcohol content of drinks varies widely. Studies that measure consumption in terms of number of drinks may be referring to very
different amounts of alcohol (also see box 4.8.1).

4.8.5 Evidence and judgements
The full systematic literature review (SLR) is contained on
the CD included with this Report.
4.8.5.1 Alcoholic drinks
There are two different measures of exposure: the numberof alcoholic drinks per time period and/or ethanol intake ingrams or millilitres per time period. The former measure is
likely to be less precise because the size and strength of eachdrink are unknown.

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Figure 4.8.1

Alcoholic drinks and mouth, pharynx, andlarynx cancer; cohort and case-control studies

2

Figure 4.8.2•

E V I D E N C E

Relative risk (95% CI)
CohortGronbaek 1998

11.70 (4.91–27.87)

Kjaerheim 1998

3.20 (1.64–6.25)

Boeing 2002

9.22 (2.75–30.25)

Case control
Maier 1992

9.00 (5.21–15.54)

Wynder 1976

22.10 (7.83–62.36)

Herity 1982

5.60 (2.99–12.48)

Elwood 1984

7.70 (3.16–18.76)

Zagraniski 1986

4.00 (1.80–8.89)

De Stefani 1987

9.30 (3.49–24.81)

Brownson 1987

Kjaerheim 1998

1.26 (1.10–1.44)

Boeing 2002

1.24 (1.18–1.30)

Summary estimate

1.24 (1.18–1.30)

Case control
Martinez 1969

1.02 (1.01–1.04)

Martinez 1969 Men

1.03 (1.01–1.05)

Elwood 1984

1.05 (1.04–1.06)

Brownson 1987

1.02 (1.02–1.03)

Blot 1988

1.05 (1.04–1.06)

4.55 (2.81–8.37)

Blot 1988 Women

1.04 (1.02–1.06)

Blot 1988 Men

8.50 (5.41–14.32)

Falk R 1989

1.02 (1.00–1.04)

Blot 1988 Women

9.10 (3.92–21.12)

Merletti 1989 Men

1.01 (0.99–1.04)

Tuyns 1988

2.56 (1.81–3.62)

Merletti 1989 Women

1.10 (0.99–1.22)

Franco 1989

8.50 (2.48–29.15

La Vecchia 1991

1.03 (1.01–1.02)

Falk 1989

2.12 (0.89–5.04)

Choi1991 Men

1.17 (1.08–1.04)

Sankaranarayanan 1989 a6.25 (0.76–51.16)

Choi 1991 Women

1.03 (0.89–1.18)

Sankaranarayanan 1989 b

3.15 (0.74–13.12)

Franceschi 1992

1.02 (1.01–1.03)

Merletti 1989 Men

2.10 (0.62–7.07)

Mashberg 1993

1.01 (1.00–1.01)

Merletti 1989 Women

3.40 (0.90–12.87)

Negri 1993

1.02 (1.02–1.03)

Zheng 1990

1.59 (1.05–2.41)

Day 1993 White

1.05 (1.04–1.06)

Sankaranarayanan 1990 a

7.69 (3.56–16.62)

Day 1993 Black1.05 (1.03–1.06)

Sankaranarayanan 1990 b

8.18 (2.79–23.97)

Ng 1993 Men

1.02 (1.01–1.04)

La Vecchia 1991

3.50 (2.03–7.11)

Ng 1993 Women

1.07 (0.99–1.02)

Choi 1991 Men

3.42 (1.77–6.60)

Su 1998 Men

1.18 (1.03–1.36)

Choi 1991 Women

1.48 (0.12–18.14)

Franceschi 1999

1.03 (1.02–1.03)

Zheng 1990 Men

0.80 (0.52–1.22)

Franceschi 1992

3.00 (1.38–6.51)

Zheng 1992 Men

1.56 (0.97–2.50)

Gonzalo 1992

4.64 (0.41–52.39)

Mashberg 1993

7.10 (4.12–12.25)

Day 1993 White

5.50 (5.72–13.54)

Day 1993 Black

16.60 (6.28–44.95)

Ng 1993 Men

4.36 (1.39–13.68)

Ng 1993 Women

2.62 (0.51–13.40)

Hedberg 1994

3.10 (1.21–7.95)

Rao 1994

1.51 (1.12–2.04)

Guo 1995

2.25 (1.23–4.13)

Takezaki 1996 Men

3.40 (1.18–9.77)

Takezaki 1996 Women

2.30 (1.58–3.58)

Zheng 1997

1.17 (0.58–2.35)

Sandersson 1997

20.80 (11.42–37.87)

Dosemeci 1997

1.60 (0.72–3.58)

Pintos 1998

4.10 (2.80–6.00)

Rao 1998

Hayes 199 Men

1.03 (1.03–1.04)

Zavras 2001

1.02 (1.00–1.04)

Garrote 2001

1.02 (1.01–1.03)

Dal Maso 2002

1.02 (1.01–1.03)

Pisa 2002

1.04 (1.01–1.06)

Lissowska 2002

1.04 (1.01–1.08)

Pelucchi 2003

1.03 (1.02–1.03)

Castellsague 2004

1.01 (1.01–1.02)

Altieri 2004

1.03 (1.02–1.03)

Peters 2005

1.04 (1.03–1.05)

Summary estimate

1.03 (1.02–1.04)

0.5

0.75

1

1.5

2

Relative risk, per drink/week

1.38 (1.00–1.91)

Wasnik 1998

1.84 (1.02–3.32)

Su 1998 Men

5.14 (0.95–27.81)

Smith 1998

2.57 (1.22–5.42)

Franceschi 1999

11.90 (6.22–22.77)

Rao 1999

1.53 (1.10–2.14)

Hayes 1999 Men

7.70 (3.31–17.93)

Zavras 2001

4.90 (1.20–19.95)

Brown 2001

60.40 (20.98–173.86)

Schlecht 2001

2.70 (0.90–8.11)

Garrote 2001

5.73 (1.77–18.53)

Zang 2001

4.80 (3.47–6.64)

Dal Maso 2002

4.30 (1.92–9.61)

Pisa 2002

4.00 (0.87–18.33)

Petridou 2002

2.02 (1.11–3.68)

Uzcudun 2002

3.50 (2.36–6.11)

Lissowska 2003

4.25 (1.07–16.90)

Pelucchi 2003

5.80 (3.79–8.88)

Sanchez 2003

3.28 (1.80–5.99)

Llewellyn 2004 Men

1.60 (0.81–3.15)

Llewellyn 2004 Women

1.60 (0.60–4.23)

Castellsague 2004

10.29 (4.57–23.17)

0.2 0.5 1 2

5Relative risk, highest vs lowest exposure category160

J U D G E M E N T S

Alcoholic drinks and mouth, pharynx, andlarynx cancer; cohort and case-control studies

Relative risk (95% CI)
CohortA N D

Mouth, pharynx, and larynx

Five cohort studies,1-6 89 case-control studies,7-93 and 4 ecological studies94-97 investigated alcoholic drinks and mouth,
pharynx, and larynx cancers.
Total alcoholic drinks

All five cohort studies showed increased risk for the highest
intake group when compared to the lowest (figure 4.8.1),1-6
which was statistically significant in four.1 2 4 6 Meta-analysis was possible on two studies, giving a summary effect estimate of 1.24 (95% confidence interval (CI) 1.18–1.30) per
drink/week, with no heterogeneity (figures 4.8.2 and4.8.3).1 2 All cohort studies adjusted for smoking.
Almost all of the case-control studies showed increased risk
for the highest intake group when compared to the lowest(figure 4.8.1),7-19 21-32 34-70 72-93 which was statistically significant in more than half (as can be seen from the high to low

C H A P T E R

4

Figure 4.8.3•

F O O D S

A N D

D R I N K S

Alcoholic drinks and mouth, pharynx, andlarynx cancer; cohort studies: dose response

Figure 4.8.4

Alcoholic drinks and mouth, pharynx,
and larynx cancer; case-control studies:dose response

Martinez 1969 Men

Kjaerheim 1998

Martinez 1969 Women
Elwood 1984

Boeing 2002

Brownson 1987
Blot 1988 Men
Blot 1988 Women
0

5

10

15

Falk 1989

Alcoholic drinks (drinks/week)

Merletti 1989 Men
Merletti 1989 Women
Choi 1991 Men
Choi 1991 Women
La Vecchia 1991
Franceschi 1992
Day 1993 Black

comparison plot).8-19 21 23-25 28-32 34-36 40-48 52 54-57 59-67 70 72-75 7786 89-91 93
No studies reported statistically significant contradictory results. Meta-analysis was possible on 25 studies,giving a summary effect estimate of 1.03 (95% CI 1.02–1.04)
per drink/week, with high heterogeneity (figures 4.8.2 and4.8.4).17 21 26 27 32 34 35 40-42 52 57 60 62 65 67 69 75 78-80 83-85 89
Heterogeneity related to the size, and not the direction, ofeffect, and is largely explained by varying design and quality of studies.
A continuous curvilinear dose-response relationship wasapparent from cohort and case-control data with no obvious
threshold (figures 4.8.3 and 4.8.4).
There was some evidence of publication bias as a result ofsmall studies that did not report a significant association
being unpublished. However, such small studies may sufferfrom issues of quality.
Ecological studies tended to show increased risk withincreased consumption.94-97

Day 1993 White
Mashberg 1993
Negri 1993
Ng 1993 Men
Ng 1993 WomenSu 1998 Men
Francechi 1999
Hayes 1999 Men
Garrote 2001
Zavras 2001
Dal Maso 2002
Pisa 2002
Lissowska 2003
Pelucchi 2003
Altieri 2004
Castellsague 2004
Peters 2005

0

50

100

150

200

250

Alcoholic drinks (drinks/week)

Beers

Two cohort studies,1 6 27 case-control studies,25 26 32 33 36 42 47
and 4 ecological studies94-96 106 reported separately on beer drinking.
Both cohort studies showed statistically significant
increased risk with increased intake; both studies adjusted
for smoking.1 6 Almost all case-control studies also showed
increased risk,25 26 32 33 36 42 47 58 62 64 65 68 83-85 98-104 which wasstatistically significant in many.36 42 47 62 68 83-85 98-102 Metaanalysis was possible on six case-control studies, giving asummary effect estimate of 1.06 (95% CI 1.03–1.08), withhigh heterogeneity. Most studies adjusted for smoking. The
ecological studies did not show any consistent or statisticallysignificant effect.94-96 106

was statistically significant in less than half.32 33 58 62 68 79 85
108 109
Five studies showed decreased risk,26 65 83 98 99 which
was statistically significant in one.98 99 Meta-analysis was
possible on 11 case-control studies, giving a summary effectestimate of 1.02 (95% CI 1.01–1.03), with high heterogeneity.32 33 62 68 79 83-85 102 105 109 All studies adjusted for smoking. All four ecological studies showed statistically significant
increased risk.94-96 110

Wines

Spirits

Twenty-six case-control studies25 26 32 33 42 58 62 64 65 68 79 83-85 98
99 101 102 104 105 107-109
and four ecological studies94-96 110 reported separately on wine drinking.
Most of the case-control studies showed increased risk withincreased intake,25 32 33 58 62 64 68 79 84 85 101 102 105 107-109 which

One cohort study,1 35 case-control studies,19 25 26 28 31-33 36 38
42 47 49 50 58 62 64 65 68 79 83-85 98 100-102 104 105 108 109 111-113
and 5 ecological studies94-96 106 114 reported separately on spirits.
The single cohort study showed a non-significant increased
risk with increased intake.1 Almost all case-control studies

58 62 64 65 68 79 83-85 98-105

161

P A R T

showed increased risk, which was statistically significant
in many. Meta-analysis was possible on nine case-control
studies, giving a summary effect estimate of 1.03 (95%
CI 1.04–1.05), with high heterogeneity. Most studies
adjusted for smoking. One ecological study reported a significant increased risk; the others tended to show nonsignificant increased risk in men and non-significant
decreased risk in women.
The general mechanisms through which alcohol could
plausibly cause cancer are outlined below. In addition, alcohol acts as a synergistic carcinogen with tobacco. Tobacco
may induce specific mutations in DNA that are less efficiently
repaired in the presence of alcohol. Alcohol may also function as a solvent, enhancing penetration of other carcinogenic molecules into mucosal cells.
There is ample and consistent evidence, both fromcase-control and cohort studies, with a dose-response
relationship. There is robust evidence for mechanisms
operating in humans. The evidence that alcoholic
drinks are a cause of mouth, pharynx, and larynx
cancers is convincing. Alcohol and tobacco together
increase the risk of these cancers more than either
acting independently. No threshold was identified.

The Panel is aware that since the conclusion of the SLR, onecohort115 and four case-control studies116-119 have been published. This new information does not change the Panel judgement (see box 3.8).
Oesophagus

Eight cohort studies,1 3 120-125 56 case-control studies,33 61 67
80 126-182
and 10 ecological studies2 94 95 114 183-189 investigated alcoholic drinks and oesophageal cancers.
Total alcoholic drinks

Eight cohort studies,1 3 120-125 56 case-control studies,33 61 67
80 126-137 139-182
and 10 ecological studies2 94 95 114 183-189 reported on total alcoholic drinks.
Six cohort studies showed increased risk for the highest
intake group when compared to the lowest (figure 4.8.5),1
3 120-122 124
which was statistically significant in four,1 120 122
124
and in men, but not in women in a fifth study.121 Twostudies showed non-significant decreased risk.123 125 Effectestimates for all studies are shown in the high to low forest
plot (figure 4.8.5). Four studies did not adjust for smoking.122-125
Most case-control studies showed increased risk for thehighest intake group when compared to the lowest (figure
4.8.5),33 61 67 80 126 128-137 139 141-148 150-166 169 170 172 174 175 177-182
which was statistically significant in 25.33 61 67 80 128 129 132 133
135 137 139 141 145 147 148 150 152 153 155-166 170 172 174 175 178-180 182

A few studies showed decreased risk, but none was statistically significant.140 149 167 168 171 173 176 Meta-analysis was possible on 20 case-control studies, giving a summary effectestimate of 1.04 (95% CI 1.03–1.05) per drink/week, withhigh heterogeneity (figures 4.8.6 and 4.8.7).33 61 67 131 133 137
144 149 150 156 157 160 161 170 178-182
Heterogeneity is related predominantly to size, rather than direction, of effect and may

162

2

•

Figure 4.8.5

E V I D E N C E

A N D

J U D G E M E N T S

Alcoholic drinks and oesophageal cancer;
cohort and case-control studies
Relative risk (95% CI)

CohortKono 1987

14.46 (3.00–69.70)

Hirayama 1990

2.28 (1.96–2.65)

Yu 19930.50 (0.21–1.20)

Zheng 1995

1.40 (0.62–3.18)

Kinjo 1998 Men

2.40 (1.77–3.25)

Kjaerheim 1998 Women

3.20 (1.64–6.25)

Khjo 1998 Women

2.00 (0.62–6.43)

Sakata 2005

2.40 (1.20–4.80)

Tran 2005

0.92 (0.82–1.03)

Case control
Jozala 1983

26.70 (6.87–10.374)

Tuyns 1982

2.72 (1.03–7.16)

Rossi 1982

13.08 (4.55–37.61)

Tuyns 1983 Men

101.03 (109.9–928.52)

Tuyns 1983 Women

11.04 (1.08–112.57)

Adelhardt 1985

2.95 (1.12–7.76)

Decarli 1987

10.43 (4.37–24.90)

La Vecchia 1989

3.60 (0.93–13.99)

Franceschi 1990

0.90 (0.57–1.42)

De Stefani 1990 Men

5.27 (2.71–10.24)

De Stefani 1990 Women

1.89 (0.71–5.00)

Sankaranarayaran 1991 Men

2.33 (1.52–3.56)

Choi 1991 Men

9.14 (3.79–22.06)

Valsecchi 1992

9.30 (5.11–16.93)

Wang 1992 Men

2.10 (1.06–4.15)

Cheng 1992

11.45 (6.66–19.69)

Tavani 1993

2.30 (0.99–5.34)

Kabat 1993 Men

10.90 (4.88–24.32)

Kabat 1993 Women

13.20 (6.08–28.68)

Parkin 1994

0.80 (0.59–1.08)

Castelletto 1994

8.00 (3.01–21.27)

Hanaoka 1994

6.59 (2.51–17.33)

Tavani 1994

5.40 (1.39–20.91)

Gao 1994 Men

1.40 (1.07–1.84)

Gao 1994 Women

0.60 (0.24–1.53)

Brown 1994 White Men

16.10 (6.68–38.79)

Brown 1994 Black Men

26.90 (11.89–60.85)

Vaughan 1995

9.50 (4.02–22.43)

Cheng 1995

1.50 (0.99–2.27)

Srivastava 1995

3.70 (1.50–9.11)

Gimeno 1995

4.40 (1.86–10.40)

Cheng 1995 Non-smokers

14.43 (3.60–57.82)

Vizcaino 1995

0.90 (0.69–1.18)

Nandakumar 1996 Men

1.80 (1.20–2.70)

Garidou 1996

1.26 (1.09–1.45)

Gammon 1997

7.40 (4.00–13.69)

Dietz 1998

8.60 (3.82–19.38)

Tao 1999

1.54 (0.86–2.76)

Gao 1999

0.78 (0.38–1.62)

Bosetti 2000

12.35 (8.37–18.22)

Levi 2000

15.65 (6.81–35.96)

Nayar 2000

7.81 (3.28–5.61)

Takezaki 2000

8.50 (5.56–13.00)

Takezaki 2001

0.75 (0.46–1.22)

Wu 20010.70 (0.47–1.04)

Sharp 2001

0.86 (0.25–2.95)

Dal Maso 2002

13.80 (4.00–47.60)

Gao 2002

1.48 (0.78–2.81)

Boonyaphiphat 2002

5.84 (3.15–10.83)

Engel 2003

9.40 (4.60–19.20)

Chita 2004 men

3.50 (1.72–7.10)

Wang 2004

3.45 (1.73–6.88)

Lee 2005

7.60 (5.20–11.10)

Yang 2005

6.71 (1.92–23.42)

Trivers 2005

1.08 (0.81–1.44)

0.2 0.5 1 2

5 10

Relative risk, highest vs lowest exposure category

C H A P T E R

4•

Figure 4.8.6

F O O D S

A N D

D R I N K S

Alcoholic drinks and oesophageal cancer;
cohort and case-control studies

Figure 4.8.7

Alcoholic drinks and oesophageal cancer;
case-control studies: dose response

Relative risk (95% CI)
CohortKjaerheim 1998

1.26 (1.10–1.44)

Case control

Tuyns 1983 Men

Tuyns 1983 Men

1.12 (1.07–1.17)

Tuyns 1983 Women

1.04 (1.00–1.09)

Decarli 1987

1.04 (1.03–1.05)

Decarli 1987

La Vecchia 1989

1.01 (0.99–1.03)

De Stefani 1990 Men

Franceschi 1990

1.02 (1.01–1.04)

De Stefani 1990 Men

1.04 (1.03–1.06)

De Stefani 1990 Women

1.13 (0.99–1.29)

Sankaranarayanan 1991 Men

1.02 (1.01–1.03)

Tavani 1993

Cheng 1992

1.08 (1.07–1.09)

Brown 1994 Black Men

Tavani 1993

1.03 (1.00–1.06)

Brown 1994 White Men

Tavani 1994

1.02 (1.00–1.04)

Hanaoka 1994

1.24 (1.14–1.33)

Brown 1994 Black men

1.04 (1.03–1.04)

Brown 1994 White men

1.03 (1.05–1.07)

Tavani 1994

Castelletto 1994

1.05 (1.03–1.07)

Gammon 1997

Gammon 1997

1.07 (1.05–1.08)

Bosetti 2000

Bosetti 2000

1.03 (1.03–1.03)

Takezaki 2001

1.00 (0.96–1.04)

Sharp 2001

1.00 (0.95–1.05)

Tuyns 1983 Women

De Stefani 1990 Women
Cheng 1992

Castelletto 1994
Hanaoka 1994

Cheng 2000
Sharp 2001

Boonyaphiphat 2002

1.05 (1.04–1.07)

Boonyaphiphat 2002

Dal Maso 2002

1.03 (1.02–1.04)

Dal Maso 2002

Lee 2005

0.99 (0.97–1.00)

Yang 2005

1.05 (1.03–1.06)

Summary estimate

0.8

01.04 (1.03–1.05)

1

1.25

20

40

60

80

100

Alcoholic drinks (drinks/week)

1.5

Relative risk, per drink/week

be partially explained by the variation in measurement of
alcohol intake, variation in the outcome measured(oesophageal or upper aerodigestive tract), or by inadequate
adjustment for smoking in some studies. There is a trend forsmaller effect estimates from more recent publications, which
could be due to improved methods of adjustment for confounders. Not all studies adjusted for smoking.
There is some evidence of publication bias; with smaller
studies tending to report larger effects.
The ecological studies were not consistent.2 94 95 114 183-189
Two reported statistically significant results, both in the
direction of increased risk.94 186
Beers

One cohort study,4 15 case-control studies,103 129 143 144 159 170
and seven ecological studies94 95 106 184 187 198 199
reported separately on beer drinking.
The single cohort study showed statistically significant
increased risk with increased intake after adjustment for
173 176 190-197

smoking.4 All case-control studies with the exception of
two173 176 also showed increased risk, which was statistically significant in seven.103 129 144 159 170 191 193 195-197 Meta-analysis was possible on five case-control studies, giving asummary effect estimate of 1.05 (95% CI 1.03–1.07), withhigh heterogeneity.144 159 170 193 197 About half of the studies
did not adjust for smoking. The ecological studies wereinconsistent and one reported a statistically significant result,which was in the direction of increased risk.94
Wines

Ten case-control studies,143 144 159 161 170 173 190 194 195 one crosssectional study,200 and five ecological studies94 95 106 184 198
reported separately on wine drinking.
All but one of the case-control studies showed increased
risk with increased intake,144 which was statisticallysignificant in seven.159 161 170 190 195 About half of the studies
adjusted for smoking. The single cross-sectional study
showed non-significant increased risk.200 Most ecological163

P A R T

studies were in the direction of increased risk.94 106 184 198

2•

Figure 4.8.8

There is ample and consistent evidence, both fromcohort and case-control studies, with a dose-response
relationship. There is robust evidence for mechanisms
operating in humans. The evidence that alcoholic
drinks are a cause of oesophageal cancer is convincing.
No threshold was identified.

The Panel is aware that since the conclusion of the SLR, onecohort203 and four case-control studies204-207 have been published. This new information does not change the Panel judgement (see box 3.8).
Colorectum

Twenty-four cohort studies investigated alcoholic drinks andcolorectal cancer.124 208-235 Thirteen cohort studies214 216 219 227
230 232 236-251
and 41 case-control studies investigated ethanol
intake and colorectal cancer.
Total alcoholic drinks

Eighteen cohort studies showed increased risk for the highest intake group when compared to the lowest,124 209 210 212217 220-223 225-228 233-235
which was statistically significant infour.209 210 216 227 One study showed non-significant increased
risk in men and non-significant decreased risk in women.211
219
Two studies reported no effect on risk218 231 and threestudies reported decreased risk; none was statistically significant.208 224 229 230 232 Meta-analysis was possible on six
cohort studies, giving a summary effect estimate of 1.01
(95% CI 0.95–1.08) per drink/day, with no heterogeneity(figure 4.8.8).

A N D

J U D G E M E N T S

Alcoholic drinks and colorectal cancer;
cohort studies

Spirits

One cohort study,4 15 case-control studies,139 143-145 159 170 173
181 190 191 194-196 201 202
one cross-sectional study,200 and five eco94 95 106 184 198
reported separately on spirits.
logical studies
The single cohort study showed statistically significant
increased risk with increased intake after adjustment forsmoking.4 All of the case-control studies also showed
increased risk, which was statistically significant in eight.139
144 145 191 194 195 201 202
Most studies adjusted for smoking. The
single cross-sectional study showed non-significant increased
risk.200 The ecological studies were inconsistent and tworeported statistically significant results; both were in the
direction of increased risk.94 106
The general mechanisms through which alcohol could
plausibly cause cancer are outlined below. In addition, alcohol acts as a synergistic carcinogen with tobacco. Tobacco
may induce specific mutations in DNA that are less efficiently
repaired in the presence of alcohol. Alcohol may also function as a solvent, enhancing penetration of other carcinogenic molecules into mucosal cells.

E V I D E N C E

Relative risk (95% CI)
Kato 1999 Women

1.00 (0.82–1.22)

Ford 1997

0.97 (0.82–1.15)

Schoen 1999

1.24 (0.91–1.69)

Chen 2001 Men

1.26 (0.79–2.01)

Flood 2002 Women

1.02 (0.85–1.21)

Pedersen 2003

1.00 (0.91–1.09)

Summary estimate

1.01 (0.95–1.08)

0.2

1

0.5

2

5

Relative risk, per drink/day

effect on risk for men and non-significant decreased risk for
women,238 and one study reported no statistically significant
association.236 Meta-analysis was possible on nine cohort
studies, of which one reported on colorectal cancer and eightreported on colon cancer, giving a summary effect estimateof 1.09 (95% CI 1.03–1.14) per 10 g/day, with moderate heterogeneity(figures 4.8.10 and 4.8.11).
In a separate meta-analysis of nine studies for rectal cancer, the summary effect estimate was 1.06 (95% CI
1.01–1.12) per 10 g/day, with low heterogeneity (figure
4.8.12). It is apparent from the meta-analysis that the reported effect for men was larger and more often statistically significant than for women. Stratified meta-analyses forcolorectal cancer gave summary effect estimates of 1.09
(95% CI 1.02–1.15) for seven studies for men, and 1.00
(95% CI 0.89–1.40) for three studies for women. There wasno statistically significant difference with cancer site. Therewas, however, apparent sexual dimorphism, with a larger
effect in men than in women, which explains the bulk of theobserved heterogeneity.

Figure 4.8.9

Ethanol and colorectal cancer; cohort studies
Relative risk (95% CI)

Slattery 1990 Men

2.21 (0.81–6.05)

Slattery 1990 Women

1.66 (0.78–3.52)

Goldbohm 1994

1.10 (0.32–3.81)

Glynn 1996 Men

3.60 (1.27–10.18)

Chyou 1996 Men

1.39 (1.05–1.84)

Murata 1996 Men

3.20 (1.53–6.70)

Harnack 2002 Women

1.08 (0.72–1.62)

Wei 2003 Men

1.55 (1.05–2.28)

Wei 2003 Women

1.14 (0.86–1.52)

0.2

Eleven of the cohort studies showed increased risk for thehighest intake group when compared to the lowest (figure
4.8.9),214 216 219 227 230 232 237 239-251 which was statistically significant in six.219 227 230 240 244 245 251 One study reported no

Relative risk, highest vs lowest exposure category

164

0.5

1

Alcohol (as ethanol)

2

5

C H A P T E R

4•

Figure 4.8.10

F O O D S

A N D

D R I N K S

Ethanol and colon cancer; cohort studies

Figure 4.8.12

Ethanol and colorectal cancer; cohort studies

Relative risk (95% CI)

Relative risk (95% CI)

Wu 1987

1.18 (1.06–1.31)

Kreger 1992 Men

0.98 (0.83–1.15)

Kreger 1992 Men

1.00 (0.92–1.09)

Kreger 1992 Women

0.81 (0.48–1.37)

Kreger 1992 Women

0.88 (0.71–1.10)

Goldbohm 1994 Men

1.08 (0.92–1.27)

Goldbohm 1994 Men

1.08 (0.95–1.23)

Goldbohm 1994 Women

1.05 (0.78–1.39)

Goldbohm 1994 Women

1.07 (0.90–1.29)

Chyou 1996 Men

1.11 (1.07–1.16)

Giovanucci 1995 Men, >646 µg/day folate intake

1.02 (0.64–1.61)

Murata 1996

1.14 (0.93–1.39)

Chyou 1996 Men

1.17 (1.06–1.28)

Colbert 2001 Women

0.99 (0.90–1.07)

Murata 1994 Men

1.12 (0.94–1.28)

Hamack 2002

0.94 (0.54–1.65)

Colbert 2001 Men

1.03 (0.96–1.12)

Nakaya 2005

1.15 (0.92–1.44)

Harnack 2002 Women

1.05 (0.80–1.38)

Summary estimate

1.06 (1.01–1.12)

Nakaya 2005 Men

1.25 (1.06–1.47)

Summary estimate

1.09 (1.03–1.14)

0.2

0.5

1

2

5

Relative risk, per 10 g/day
0.2

0.5

1

2

5

Relative risk, per 10 g/day

Figure 4.8.11

Ethanol and colon cancer incidence;cohort studies: dose response

Goldbohm 1994 Men
Goldbohm 1994 Women
Chyou 1996 Men

0

10

20

30

40

Ethanol (g/day)

When data were analysed separately for drink type (beers,
wines, or spirits), they became insufficient to draw any firm
conclusions.
Pooled analysis from 8 cohort studies (over 475 000 participants, followed up for 6 to 16 years, more than 4600 colorectal cancer cases) showed a significant increased risk forthe highest intake group when compared to the lowest, with
an effect estimate of 1.41 (95% CI 1.16–1.72) for those who
consumed 45 g/day or greater.252 No increased risk was
observed below intakes of 30 g/day. No significant heterogeneity was observed by sex or cancer site.
In addition, a published meta-analysis of 27 studies reported a statistically significant increased risk, with a summary
effect estimate of 1.10 (95% CI 1.05–1.14) per two
drinks/day.
Because of the abundant prospective data from cohort
studies, case-control studies were not summarized.
The general mechanisms through which alcohol could

plausibly cause cancer are outlined below. In addition, theassociation between alcohol intake and colorectal cancer risk
is modified by acetaldehyde dehydrogenase and alcohol
dehydrogenase genetic status.253 254 Alcohol may induce
folate deficiency in the colon and rectum, possibly by reducing absorption of folate or by inhibition of critical enzymes.
Also, alcohol may disrupt one-carbon metabolism (seeChapter 2). Intestinal bacteria, because of their high alcohol dehydrogenase activity, can oxidise ethanol in colorectal tissue to produce levels of acetaldehyde up to 1000-foldhigher than that in blood.
The more elevated risk related to alcohol intake among
men compared with women may be because of the generally lower consumption of alcohol among women. That is,
it is possible that men exhibit a greater range in the amountof alcohol drunk, which makes effects easier to detect. Also,
preferred beverages may differ between the sexes, or there
may be hormone-related differences in alcohol metabolism
or susceptibility to alcohol.
There is ample and generally consistent evidence fromcohort studies. A dose-response is apparent. There isevidence for plausible mechanisms. The evidence that
consumption of more than 30 g/day of ethanol fromalcoholic drinks is a cause of colorectal cancer in men
is convincing, and probably also in women.

The Panel is aware that since the conclusion of the SLR, fourcohort255-258 and four case-control studies259-262 have been published. This new information does not change the Panel judgement (see box 3.8).
BreastEleven cohort studies,183 263-271 31 case-control studies272-310
and 2 ecological studies311 312 investigated total alcoholic
drinks and breast cancer at all ages. Four cohort studies313316
and 19 case-control studies289 302 317-333 investigated alcoholic drinks. Twenty-five cohort studies,315 334-364 29 case-165

P A R T

control studies,280 282 317 318 332 333 365-391 and 4 ecologicalstudies392-395 investigated ethanol intake.

2

Figure 4.8.13•

E V I D E N C E

A N D

Alcoholic drinks and breast cancer; cohortand case-control studies

Total alcoholic drinks

Six cohort studies showed increased risk for the highest
intake group of total alcoholic drinks when compared to thelowest,263 264 267-271 which was statistically significant inthree.267 269 270 Three studies showed non-significant
decreased risk265 266; one study showed no effect on risk.183
Meta-analysis was possible on three cohort studies, giving asummary effect estimate of 1.07 (95% CI 0.89–1.29) per fivetimes/week, with no heterogeneity (figures 4.8.13 and4.8.14).263 271
Two cohort studies reported separately on premenopausal
breast cancer.264 268 Both showed increased risk for the highest intake group when compared to the lowest, which wasstatistically significant in one.268 Three cohort studies
reported separately on postmenopausal breast cancer.264 268
269
Two showed increased risk for the highest intake groupwhen compared to the lowest,264 269 which was statisticallysignificant in one.269 The other study showed non-significant
decreased risk.268
Four additional cohort studies investigated alcoholic
drinks.313-316 All four showed non-significant increased risk
for breast cancer at unspecified ages. One study also reported statistically significant increased risk for postmenopausal
breast cancer and non-significant decreased risk for premenopausal breast cancer.315
Most of the 22 case-control studies that reported on allage breast cancer and total alcoholic drinks showed
increased risk for the highest intake group when comparedto the lowest,273 274 280 282-285 287 288 290 295 297 301-303 305-309 318
which was statistically significant in seven.273 284 285 306 318
A few studies showed decreased risk, none was statisticallysignificant.276 291 295 298 302 304 Meta-analysis was possible on
10 case-control studies reporting on breast cancer at all ages,
giving a summary estimate of 1.05 (95% CI 1.03–1.07) for
an increment of five times/week, with high heterogeneity(figures 4.8.13 and 4.8.14).274 276 284 286 287 296 306 307 No heterogeneity was apparent with menopausal status. Twelve
case-control studies reported separately on premenopausal
breast cancer.272 275 277-279 281 282 292-294 297 299 300 306 310 318 Ten
showed increased risk,272 275 277 279 281 292-294 299 300 306 318 which
was statistically significant in two.272 281 294 299 300 306 One
study showed no effect on risk297 and the other study showednon-significant decreased risk.278 282 310 Six studies reported
separately on postmenopausal breast cancer.277 278 281 282 289
297 306 310
Five of these showed increased risk,278 281 282 289 306
310
which was statistically significant in one.306 The otherstudy reported non-significant decreased risk.297
In addition, 19 case-control studies investigated alcoholic
drinks.289 302 318-323 325-331 333 Most showed increased risk forthe highest intake group when compared to the lowest,
which was statistically significant in six.302 318 321 323 327 329
Two studies showed non-significant decreased risk317 324; one
study showed no effect on risk.332 Four studies reported separate results for premenopausal breast cancer.318 320 322 333 Of
these, two studies showed non-significant increased risk,318
333
one showed statistically significant increased risk in

166

J U D G E M E N T S

Relative risk (95% CI)
CohortWu 1999

1.38 (0.84–2.26)

Wu 1999

1.08 (0.78–1.50)

Byrne 1996

0.99 (0.77–1.28)

Summary estimate

1.07 (0.89–1.29)

Case control
La Vecchia 1989

1.10 (1.07–1.13)

Baumgartner 2002

1.07 (0.82–1.38)

Katsoyannis 1994

1.05 (0.97–1.12)

Kinney 2000

1.03 (0.92–1.15)

Lash 2000

1.01 (0.86–1.19)

Rosenberg 1990

0.97 (0.86–1.10)

Viladiu 1996

0.97 (0.93–1.11)

Freudenheim 1995

0.94 (0.79–1.13)

Sneyd 1991

0.94 (0.81–1.09)

Baughmater 2002

0.90 (0.79–1.03)

Summary estimate

1.05 (1.03–1.07)

0.2

1

0.5

1.5

2

4

6

Relative risk, per 5 times/week

Figure 4.8.14

Alcoholic drinks and breast cancer; cohortand case-control studies: dose response

CohortWu 1999
Byrne 1996

Case control
Baughmater 2002
La Vecchia 1989
Rosenberg 1990
Freudenheim 1995
Lash 2000
Baughmater 2002
Vlladiu 1996
Sneyd 1991
Kinney 2000
Katsouyanni 1994

0

4

8

12

16

20

24

Alcoholic drinks (times/week)28

C H A P T E R

4•F O O D S

A N D

D R I N K S

parous women,322 and one showed non-significant decreased
risk.320 Seven studies reported separately on postmenopausal
breast cancer.289 318 320-322 326 333 All seven studies showed
increased risk for the highest intake group when comparedto the lowest, which was statistically significant in three,318
321 333
and in oestrogen-sensitive cancers in a fourth study.326
Both ecological studies showed statistically significant,positive associations.311 312
When data were analysed separately for drink type (beers,
wines, or spirits), they became insufficient to draw any firm
conclusions.

Figure 4.8.15

Ethanol and breast cancer; cohort studies
Relative risk (95% CI)

Holmberg 1995

4.32 (1.34–13.89)

Rissanen 2003

2.33 (1.28–4.24)

Dumeaux 2004

1.41 (1.21–1.64)

Willett 1987

1.19 (1.11–1.29)

Lin 2005

1.15 (1.03–1.28)

Hines 2000

1.08 (0.88–1.33)

Rohan 2000

1.03 (0.98–1.09)

Oodman 1997

0.86 (0.67–1.11)

Schatzkin 1989

0.64 (0.43–0.94)

Summary estimate

1.10 (1.06–1.14)

Alcohol (as ethanol)

Twelve cohort studies investigated ethanol intake and all-age
breast cancer.315 336 338-341 343-350 352-354 361-364 Eight cohort studies showed increased risk for the highest intake group whencompared to the lowest,315 336 338-341 343 344 346-348 350 352-354 361
362
which was statistically significant in six.338 341 344 350 352 354
361
Four studies showed decreased risk,345 349 363 364 which wasstatistically significant in one.364 Meta-analysis was possible
on nine cohort studies, giving a summary effect estimate of
1.10 (95% CI 1.06–1.14) per 10 g/day, with high heterogeneity (figure 4.8.15). Heterogeneity could be partly
explained by differential adjustment for age and reproductive history.
Seven cohort studies reported separately on premenopausal breast cancer.315 340 343 347 348 352-354 361 Six studies showed increased risk,340 343 347 348 352-354 361 which wasstatistically significant in three.340 348 352 One study showeda non-significant decreased risk.315 Meta-analysis was possible on five studies, giving a summary estimate of 1.09 (95%
CI 1.01–1.17) per 10 g/day, with moderate heterogeneity.315
340 343 347 352
Eighteen cohort studies reported separately on
postmenopausal breast cancer.315 334 335 337 339 340 342 347 348 351361
Fifteen studies showed increased risk,315 335 337 339 342 347
348 351 353-361
which was statistically significant in seven.315 335
337 339 342 347 357-359
Three studies showed non-significant
decreased risk.334 340 352 Meta-analysis was possible on 11
studies, giving a summary effect estimate of 1.08 (95% CI
1.05–1.10) per 10g/day, with moderate heterogeneity.315 334

0.2

1

5

10

15

Relative risk, per 10 g/day

showed decreased risk,317 366 370 371 378 390 which was statistically significant in one378; and one study showed no effecton risk.282 Meta-analysis was possible on seven case-control
studies, giving a summary effect estimate of 1.06 (95% CI
1.04–1.09) per 10 g/day, with moderate heterogeneity(figure 4.8.16).
When case-control data were analysed separately bymenopausal status, the meta-analysis for premenopausal
breast cancer was consistent with that for all ages (1.08(95% CI 1.04–1.13) per 10 g/day; nine studies),317 318 369
373 376 377 380 383 389
but the meta-analysis for postmenopausal breast cancer was not (1.00 (95% CI 0.98–1.01)
per 10 g/day; 10 studies).318 369 372 373 375 380 382 383 385 388
All four ecological studies showed statistically significant
positive associations.392-395
The general mechanisms through which alcohol could
plausibly cause cancer are outlined below. In addition, mostexperimental studies in animals have shown that alcohol
intake is associated with increased breast cancer risk. Alcoholinterferes with oestrogen pathways in multiple ways,

335 339 340 347 352 355 358-360

Pooled analysis from 6 cohort studies (over 320 000 participants, followed up for up to 11 years, more than 4300
breast cancer cases) showed a significant increased risk withincreasing intake, with an effect estimate of 1.09 (95% CI
1.04–1.03) per 10 g/day.396 No significant heterogeneity wasobserved by menopausal status.
A separate pooled analysis of 53 case-control studies (morethan 58 000 cases and more than 95 000 controls) showeda significant increased risk with increasing intake, with aneffect estimate of 7.1 per cent increased risk (95% CI
5.5–8.7%; p < 0.00001) per 10 g/day.397 No significant heterogeneity was observed by menopausal status.
Eighteen case-control studies investigated ethanol intake
and all-age breast cancer.280 282 317 318 332 365-371 374 378 379 381 383
384 386 387 390 391
Twelve case-control studies showed increased
risk for the highest intake group when compared to the lowest,280 318 332 365 367-369 374 379 381 383 384 386 387 391 which was statistically significant in five.280 318 368 369 374 381 384 Five studies

Figure 4.8.16

Ethanol and breast cancer;
case-control studies
Relative risk (95% CI)

Bowlin 1997

1.44 (1.11–1.86)

Rohan 1988

1.21 (0.99–1.48)

Harvey 1987

1.10 (1.02–1.18)

Brandt 2004

1.08 (0.94–1.23)

Ferraroni 1998

1.06 (1.03–1.09)

Trentham-Dietz 2000

1.05 (1.00–1.11)

Webster 1983

1.01 (0.95–1.08)

Summary estimate

1.06 (1.04–1.09)

0.2

0.5

1

1.5

2

Relative risk, per 10 g/day

167

P A R T

influencing hormone levels and oestrogen receptors.398
There is an interaction between folate and alcohol affecting breast cancer risk: increased folate status partiallymitigates the risk from increased alcohol consumption.399
There is ample, generally consistent evidence fromcase-control and cohort studies. A dose-response
relationship is apparent. There is robust evidence formechanisms operating in humans. The evidence that
alcoholic drinks are a cause of premenopausal andpostmenopausal breast cancer is convincing. No
threshold was identified.

The Panel is aware that since the conclusion of the SLR, one
case-control study400 has been published. This new information
does not change the Panel judgement (see box 3.8).
Liver
120 208 220 227 401-422

Fifteen cohort studies
and 33 case-control
studies158 423-460 investigated alcoholic drinks and liver cancer. Fourteen cohort studies6 120 227 244 403 404 409 410 412 416 422
461-468
and 21 case-control studies158 427 431 434 436 440 446 452 456
459 469-485
investigated ethanol intake.

2

Figure 4.8.17•

E V I D E N C E

A N D

J U D G E M E N T S

Alcoholic drinks and liver cancer:
cohort and case-control studies
Relative risk (95% CI)

CohortKono 1987

2.36 (1.04–5.35)

Hirayama 1989

1.89 (1.40–2.55)

Ross 1992

1.10 (0.46–2.60)

Goodman 1995 Men

1.11 (0.72–1.71)

Goodman 1995 Women

1.25 (0.78–1.99)

Mutu 1989

1.50 (0.42–5.31)

Yu 1999

1.39 (0.68–2.14)

Evans 2002 Men

0.90 (0.90–1.01)

Evans 2002 Women

0.57 (0.29–1.18)

Wang 2003 HBsAg positive

1.29 (0.78–2.10)

Wang 2003 HBsAg negative

2.00 (0.89–4.51)

Case control
Stemhagen 1983 Men

1.30 (0.64–2.63)

Stemhagen 1983 Women

1.63 (0.92–2.89)

Inaba 1984

3.62 (1.68–7.79)

Austin 1986

2.60 (1.26–5.35)

Harris 1988 Men

1.28 (0.69–2.39)

La Vecchia 1988

1.43 (0.83–2.46)

Harris 1988 Women

1.93 (0.66–5.63)

Tsukuma 1990 Men

2.60 (1.70–3.99)

Olubuyide 1990 Men

1.70 (0.90–3.21)

Olubuyide 1990 Women

1.40 (0.04–50.00)

Hiyama 1990

8.00 (1.30–49.36)

Qureshi 1990

3.04 (0.31–29.54)

Total alcoholic drinks

Yu 1991 Anti-HCV negative

2.10 (1.20–3.69)

Data are available from 15 cohort studies.120 208 220 227 401-422
Eleven cohort studies showed increased risk for the highest
intake group when compared to the lowest,120 220 227 401-404 407410 413 414 416 417 420 422
which was statistically significant in
two.120 401 Two studies showed non-significant decreased
risk.405 406 412 418 419 Two studies stated that there was no significant difference but did not provide further data.411 415 421
Heterogeneity is partially explained by differences inwhether and how studies have adjusted for hepatitis virus
status. The effect estimates of eight studies are given in thehigh to low comparison forest plot (figure 4.8.17).
Data are available from 33 case-control studies.158 423-460
Twenty-eight case-control studies showed increased risk forthe highest intake group when compared to the lowest,158 423432 434-448 451-456 460
which was statistically significant in 12 (oneof these studies reported a non-significant decreased risk in
women, but a statistically significant increased risk inmen440).158 423 427 429-432 434 439 440 442 444 446 447 454-456 Two studies
showed non-significant decreased risk.449 Three studies stated that there was no significant effect on risk.433 450 457-459 Metaanalysis was possible on five studies, giving a summary effectestimate of 1.18 (95% CI 1.11–1.26) per drink/week, withhigh heterogeneity (figure 4.8.18).158 425 434 449 460
A dose-response relationship is apparent from case-control
but not cohort data.

Choi 1991 Men

2.46 (1.16–5.22)

Yamaguchi 1993 HBsAg negative

2.70 (1.81–4.02)

Newton 1996

1.20 (0.50–2.89)

Alcohol (as ethanol)

Ten cohort studies showed increased risk for the highest
intake group when compared to the lowest,6 120 244 403 404 409
410 416 422 461 465-468
which was statistically significant in five(one of these studies reported a non-significant increased risk
in women, but a statistically significant increased risk inmen461).6 120 244 416 461 465 468 Three studies in men with cirrhosis showed non-significant decreased risk.227 412 462 463 One

168

Wang 1996

1.28 (0.98–1.67)

Braga 2000 Men

1.68 (1.14–2.48)

Braga 2000 Women

1.30 (0.42–4.01)

Mukaiya 1998

2.31 (1.20–4.42)

Mandishona 1998

2.00 (0.49–8.10)

Kuper 2000

1.90 (0.91–3.96)

Yu 20021.38 (0.68–2.81)

Donato 2002 Men

2.70 (1.09–6.71)

Donato 2002 Women

0.90 (0.33–2.49)

Munaka 2003

1.45 (0.81–2.60)

Tsai 2004

2.55 (1.50–4.33)

0.2 0.5 1

2

5

Relative risk, highest vs lowest exposure category

study stated that there was no significant effect on risk.464
Meta-analysis was possible on six cohort studies, giving asummary effect estimate of 1.10 (95% CI 1.02–1.17) per 10
g/day or 10 ml/day, with no heterogeneity (figure 4.8.19).
Twenty case-control studies showed increased risk for thehighest intake group when compared to the lowest,158 427 431
434 436 440 446 452 456 469 470 472-475 477-479 481-485
which was statistically significant in 12.158 427 431 434 440 446 456 474 475 477-479 481 483485
One study showed non-significant decreased risk.476
Meta-analysis was possible on 14 case-control studies, giving a summary effect estimate of 1.17 (95% CI 1.09–1.25)
per 10 g/day or 10 ml/day, with high heterogeneity (figure

C H A P T E R

4•

Figure 4.8.18

F O O D S

A N D

D R I N K S

Alcoholic drinks and liver cancer;
case-control studies

Figure 4.8.20

Ethanol and liver cancer; case-control studies
Relative risk (95% CI)

Relative risk (95% CI)
Austin 1986 HBsAg

1.07 (0.86–1.33)

Lu 1988

0.89 (0.77–1.02)

Choi 1991

1.30 (1.19–1.41)

Yu 1991

1.39 (1.08–1.79)

Mukaiya 1998

1.21 (1.01–1.44)

Summary estimate

1.18 (1.11–1.26)

0.7

1

0.8

1.2

1.5

Relative risk, per drink/week

Figure 4.8.19

Ethanol and liver cancer; cohort studies

Infante 1980 Cirrhotic

5.01 (2.42–10.37)

Infante 1980 Non-cirrhotic

6.10 (2.20–16.93)

Yu 1983

1.12 (1.00–1.26)

Inaba 1984

1.81 (1.27–2.59)

Tsukuma 1990

1.17 (1.09–1.29)

Mayans 1990

1.19 (1.09–1.29)

Yamaguchi 1993 Men

1.11 (1.06–1.15)

Arico 1994

0.93 (0.87–1.00)

Pyong 1994 Men

1.40 (1.16–1.69)

Shin 1996

1.05 (0.97–1.15)

Zhang 1998

1.05 (0.95–1.17)

Mukaiya 1998

1.28 (1.05–1.57)

Kuper 2000

1.04 (0.96–1.13)

Hassan 2002

1.16 (1.03–1.30)

Gelatti 2005

1.28 (1.19–1.38)

Summary estimate

1.17 (1.09–1.25)

0.2

0.5

1

2

5

Relative risk, per 10 g/day
Relative risk (95% CI)
Oshima 1984

1.24 (1.03–1.50)

Ross 1992

1.20 (0.88–1.63)

Murata 1996

0.99 (0.85–1.16)

Miyakawa 1996 HBV-carrier

0.96 (0.62–1.48)

Khan 2000

1.09 (1.00–1.20)

Sharp 2005

1.26 (0.82–1.93)

Summary estimate

1.10 (1.02–1.17)

0.2

0.5

1

2

Figure 4.8.21

Ethanol and liver cancer; cohort studies:dose response

5

Relative risk, per 10 g/day

Sharp 2005

Ross 1992

Oshima 1984

4.8.20). Heterogeneity may be due to the inclusion of studies that reported alcoholic behaviour.
A dose-response relationship is apparent from cohort andcase-control data (figure 4.8.21).

Murata 1996

Miyakawa 1996 HBV-carrier

Beers

Two cohort studies6 486 and five case-control studies425 435 444
452 473 479
reported separately on beer drinking.
Both cohort studies showed statistically significant
increased risk with increased intake.6 486 Four case-control
studies also showed increased risk,425 435 444 452 479 which wasstatistically significant in three.435 444 452 479 One study reported no effect on risk.473

Khan 2000

0

20

40

60

80

100

Ethanol (g/day)Wines

Three cohort studies6 410 486 and one case-control study425
reported separately on wine drinking.
One cohort study showed non-significant increased risk
with increased intake.410 Two studies stated that there wasno significant effect on risk.6 486 The single case-control study
showed non-significant increased risk.425

169

P A R T

Spirits
6 486

425 444 469

Two cohort studies
and five case-control studies
472 479 487
reported separately on spirits.
Both cohort studies showed no significant effect on risk.6
486
All case-control studies showed increased risk,425 444 469 472
479 487
which was statistically significant in one444 479; and one
case-control study showed statistically significant increased
risk for consumption of illicit liquor.487
Several studies used participants judged to be at high riskof developing liver cancer, that is, people who already had
liver cirrhosis. These results are particularly hard to interpretas cirrhosis status affects drinking behaviour. Also the cancer disease path may be different in people with cirrhosis.
Assessment of some studies was hampered by poor exposure assessment, and not all studies adjusted for known confounders such as hepatitis B or C virus.
The general mechanisms through which alcohol could
plausibly cause cancer are outlined below. In addition, regular, high levels of alcohol consumption are known to causeliver damage. Tumour promotion has been linked to inflammation in the liver through alcohol-associated fibrosis andhepatitis.488 489 Alcohol consumption, even at moderate levels, is associated with increases in levels of circulating hepatitis C virus RNA in carriers. Hepatitis C virus infection ishighly prevalent among alcoholics with chronic liver disease
and appears to accelerate the course of alcoholic liver disease(see chapter 7.8).
There is ample, generally consistent evidence fromboth cohort and case-control studies. A dose-response
relationship is apparent. Alcohol is a cause of cirrhosisthat predisposes to liver cancer, but the factors that
determine why some people are susceptible tocirrhosis are not known. Alcoholic drinks are aprobable cause of liver cancer. No threshold was
identified.

2•

E V I D E N C E

A N D

J U D G E M E N T S

Three studies showed no effect on risk495 497 509; three studies stated that there was no significant association505-507; twostudies showed non-significant increased risk498 500; one
study showed a non-significant decreased risk in men and anon-significant increased risk in women.508 Meta-analysis
was possible on two studies that adjusted for smoking, giving a summary effect estimate of 0.92 (95% CI 0.71–1.20)
per serving/day, with moderate heterogeneity (figure
4.8.22).496 498
Alcohol (as ethanol)

All four cohort studies showed decreased risk with increased
ethanol intake,6 492 510-513 which was statistically significant
in one.510 512 Meta-analysis was possible on two unadjusted
studies, giving a summary effect estimate of 0.48 (95% CI
0.26–0.90) per serving/day, with no heterogeneity.492 511
Three case-control studies showed non-significant
decreased risk with increased ethanol intake.504 514 516 One
study showed no effect on risk,515 and one study stated nosignificant association.503 Meta-analysis was possible on two
unadjusted studies, giving a summary effect estimate of 0.90
(95% CI 0.77–1.05) per serving/day, with no heterogeneity(figure 4.8.23).514 515
There is no known mechanism through which alcohol
could decrease kidney cancer risk.
It is unlikely that alcohol increases the risk of kidneycancer, though a protective effect cannot be excluded.

Figure 4.8.22

Ethanol and kidney cancer;
case-control studies
Relative risk (95% CI)

Yuan 1998

1.01 (0.97–1.05)

Parker 2002

0.76 (0.53–1.07)

Summary estimate

0.92 (0.71–1.20)

The Panel is aware that since the conclusion of the SLR, one
case-control study490 has been published. This new information
does not change the Panel judgement (see box 3.8).

1

0.5

2

Relative risk, per unit/day

KidneyThree cohort studies491-493 and 16 case-control studies308 494509
investigated alcoholic drinks and kidney cancer. Fourcohort studies6 492 510-513 and five case-control studies503 504
514-516
investigated ethanol intake.

Figure 4.8.23

Alcoholic drinks and kidney cancer;
case-control studies

Total alcoholic drinks

Two cohort studies showed non-significant increased risk forthe highest intake group when compared to the lowest.491 493
One study showed a statistically significant decreased
risk.492 None of the studies was adjusted for smoking; effectestimates were 1.42 (95% CI 0.69–2.9),493 1.7 (95% CI
0.8–3.5) for women491 and 1.2 (95% CI 0.5–2.6) for men,491
and 0.62 (95% CI 0.41–0.94).492
Seven case-control studies showed decreased risk for thehighest intake group when compared to the lowest,308 494 496
499 501-504
of which one was statistically significant494and one
was statistically significant in women but not in men.504

170

Relative risk (95% CI)
Mattioli 2002

0.90 (0.76–1.04)

Lindblad 1997

1.00 (0.39–2.59)

Summary estimate

0.90 (0.77–1.05)

0.25

0.5

1

2

4

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The Panel is aware that since the conclusion of the SLR, onecohort study517 has been published. This new information does
not change the Panel judgement (see box 3.8).
General mechanisms

Evidence suggests that reactive metabolites of alcohol, suchas acetaldehyde, may be carcinogenic. Additionally, theeffects of alcohol may be mediated through the productionof prostaglandins, lipid peroxidation, and the generation of
free-radical oxygen species. Alcohol also acts as a solvent,enhancing penetration of carcinogens into cells. Alcohol has
been demonstrated to alter retinoid status in rodent studies
and, as a result, cellular growth, cellular differentiation, andapoptosis are adversely altered. For all these pathways,
genetic polymorphisms might also influence risk.398
Lastly, heavy consumers of alcohol may have diets
deficient in essential nutrients, making tissue susceptible tocarcinogenesis.

4.8.6 Comparison with previous report
In general, the evidence that alcohol is a cause of a numberof cancers has become stronger since the mid-1990s.
The previous report did not find any distinctions between
different types of alcoholic drink. This finding is upheld.
The previous report identified a threshold of modest
consumption of alcoholic drinks, below which no effect on
cancer risk was observed, with the exception of breast cancer. Current evidence does not identify a generally ‘safe’
threshold.
Current evidence strengthens the previous judgements oncolorectal and breast cancers.

4.8.7 Conclusions
The Panel concludes:
Evidence that alcoholic drinks of any type are a cause ofvarious cancers has, on the whole, strengthened.
The evidence that alcoholic drinks are a cause of cancersof the mouth, pharynx, and larynx, oesophagus, colorectum(men), and breast is convincing. They are probably a causeof colorectal cancer in women, and of liver cancer. It is
unlikely that alcoholic drinks have a substantial adverse
effect on the risk of kidney cancer.

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4.9 Food production, preservation,
processing, and preparation
Practically all food and drink is changed before it isconsumed, for instance by peeling or cooking. The
majority of foods and drinks consumed by most people
around the world are now modified in many more ways.
Products on sale in supermarkets, small shops, and otherretail outlets are chilled, pasteurised, canned, bottled,
vacuum packed, or otherwise packaged. Most contain anumber of ingredients, some of which are also processed.
The use of ingredients such as modified starches, addedsugars, hydrogenated fats, and also additives used as
bulking aids, preservatives, colours, flavours, sweeteners,
and for other purposes, is common. In general, rises in
consumption of fats, oils, and added sugars occur becauseof their increased use in processed foods and drinks.
Animal and plant products both contain traces ofagricultural chemicals. Methods of industrial and domestic
food preparation and cooking change the nature of food aseaten.
It is possible that processing and/or preserving methods
may alter the nature of food. Different methods of foodpreservation and processing may be protective, causative,
or neutral in their effects on the risk of cancer.
It is for this reason that the Panel decided that, as far aspractically possible, the evidence on methods of foodproduction, preservation, processing, and preparation(including cooking) should be summarised and judged in
the context of the relevant foods and drinks. Most of thisevidence is to be found in the previous sections of
Chapter 4.
This section summarises other information and findings
concerning the ways in which foods and drinks arechanged before consumption. These include where datafrom animal and other experimental studies are notsupported by evidence from epidemiological studies. Suchstudies are often carried out for the purposes of
establishing regulations for the safety in use of chemicals
known to be toxic, but may use levels of exposure far
higher than occur in foods and drinks.
In line with its general criteria for judgement, the Paneldecided to make no judgements on experimental findings
alone that are not supported by epidemiological or otherevidence. Nevertheless, the Panel concurs that, in general,
it seems reasonable to conclude that the changes made tofoods and drinks within well regulated, modern foodsystems, and made to foods and drinks as usually
prepared and cooked, are of themselves unlikely to modify
the risk of cancer significantly. For this reason, no matrix
showing Panel judgements is included in this section.
In line with its general criteria for judgement, the Panelhas decided to make no judgements on experimental
findings from studies using doses of substances at levels

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far above those found in foods and drinks, many if not
most of which are conducted to guide toxicologicalregulations. The Panel also concurs that changes made toprocessed foods and drinks within well regulated, modern
food systems are of themselves unlikely to modify the riskof cancer significantly. For this reason, no matrix showing
Panel judgements is included in this section. Those aspectsof food production, preservation, processing, andpreparation that have been examined in epidemiologicalas well as experimental settings are discussed and judged
in earlier sections of Chapter 4.

This section summarises some of the general methods bywhich foods and drinks may be changed during their production, preservation, processing, and preparation (including cooking) that may be relevant to the risk of cancer.
Almost all foods and drinks are altered — processed, in a
general sense of the word — before being consumed.
Reports concerned with the prevention of chronic diseases
often mention the added nutritional value of lightly
processed cereals (grains), and of vegetables and fruits. But
they may not make much distinction between foods anddrinks as such, and as modified in production, preservation,
processing, and preparation. Previous reports concerned withcancer have concluded that some methods of food and drink
modification can produce carcinogens in experimental settings, and that this might reasonably influence cancer risk.
Storage conditions that allow contamination of cereals(grains) and other plant foods by aflatoxins, and the preparation of fish Cantonese-style by salting and fermentation,
have previously been identified as causes of cancer.
This section covers aspects of food production, preservation, processing, and preparation that are sometimes thought
to be relevant to the risk of cancer, but where experimental
information (when this exists) is not supported by epidemiological evidence or where there is no such evidence. Wherethe evidence for foods or drinks is sufficient to judge thatthey may cause or protect against any cancer, this is summarised and judged in earlier sections of this chapter. For
example, see chapter 4.1 for the Panel’s findings on aflatoxin
contamination; for processed meat and also cooking methods, see chapter 4.3; for salting, see chapter 4.6.

4.9.1 Production
Modern food systems (box 4.9.1) involve various aspects offood production that have some potential to modify the riskof cancer. A clear benefit of these systems of production, distribution, and retail sale, with chilling used at all stages, isC H A P T E R

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the all-year round supply of fresh vegetables and fruits (seechapter 4.2).
The industrialised farming methods that are part of mostmodern food systems in most countries use various technologies to maximise production. These include the use offertilisers, pesticides, and herbicides on food crops; and ofveterinary drugs in rearing livestock and in aquaculture.
Fertilisers play a part in determining nutrient levels in plants,
as well as potentially modifying concentrations of otherbioactive microconstituents. Residues of these and otherchemicals applied to crops are washed from soils by therain and can contaminate water supplies. See boxes 4.9.2
and 4.9.3.
Methods or consequences of food production, where epidemiological evidence shows or suggests an effect on the riskof cancer, are summarised and judged earlier in this chapter.
These are fungal contamination (chapter 4.1), hot drinks
and foods (chapter 4.7), and arsenic contamination(chapter 4.7).

Box 4.9.1

Food systems

Food systems involve the production, preservation, processing,and preparation (including cooking) of food. Gatherer–hunterstake food as it is found in nature and modify it by the use of fire.
Pastoralists modify the animals that are a source of their food
through breeding. Agriculture improves plants for human fooduse, by selective breeding and planting, and animals too are subject to selective breeding. In Egypt, selectively bred wheat was
ground into flour, kneaded with water and other ingredients,
and baked into bread as early as 4000 years ago.
Thousands of years before industrialisation, most food anddrink consumed by the majority of people was modified in someway in its production. This included preservation by drying, andlater other methods such as salting, fermenting, pickling, curing,
spicing, and freezing in cold climates; and various methods ofpreparation and cooking, including boiling and roasting.
Food systems were transformed as part of the industrial andlater, the technological revolution. But this was not the point at
which foods and drinks became modified for the first time.
Rather, many new processes were developed such as sterile bottling and canning. Then, beginning in the late 19th century, steel
roller mills were devised for the mass-manufacture of white flour
and thus white bread; refrigerated transport using railways andships made possible the industrial production and international
export of meat and dairy products. In the 20th century, commercialisation of the hydrogenation process to turn liquid oils
into solid fats made margarine manufacture a big business, andthe mass manufacture of soft drinks developed.
What is now known as ‘conventional’ farming, making extensive use of chemical fertilisers, herbicides, and pesticides, andfeed concentrates for animals, developed mainly in the second
half of the 20th century. More recent developments in food systems include the use of containers to transport foods and drinks
nationally and internationally; the development of supermarkets, of which the biggest are now transnational; and the increasing concentration of food producers, manufacturers, retailers,and caterers.

4.9.1.1 Pesticides and herbicides
The use of synthetic pesticides and herbicides has increased
vastly since the middle of the 20th century. Nearly 2500
tonnes of these chemicals were used worldwide in 2001.1
The chlorinated pesticide dichloro-diphenyl-trichloroethane (DDT) has been banned from use in many countries.
Other organochlorine pesticides are now largely being
replaced with organophosphorus and carbamate pesticides.
These newer types are less persistent in the environment,
and have not been found to be carcinogenic in experimental settings.
In many countries, the use of pesticides and herbicides isregulated to minimise residues in foods and drinks, and there
are internationally recommended maximum residue limits(box 4.9.3). The use of persistent organic pollutants(organochlorine pesticides, furans, dioxins, and polychlorinated biphenyls) will be banned by 2025 under the United
Nations Environment Programme’s Stockholm Convention,
which entered into force in May 2004.
Many of these contaminants have the potential to accumulate within food systems, and residues of pesticides andherbicides that have been banned from use, or are being
phased out, may still be present in foods eaten today. Some
contaminants, such as heavy metals and persistent organic
compounds, tend to be deposited in fatty tissues and are noteasily metabolised or excreted. They accumulate in living
creatures, in amounts higher than background levels (forinstance, in the soil). Dietary exposure increases with eachstep up the food chain, as predators consume prey contaminated with these residues.
There are theoretical grounds for concern, which are constantly reviewed by international and national regulatory
bodies. However, there is no epidemiological evidence thatcurrent exposures are causes of cancers in humans, and so
the Panel has made no judgements. Nevertheless, a precautionary approach is wise for women of reproductive age,since vulnerability during embryonic phases of development
is increased, and early exposure may result in increased risk
at later stages in life.
4.9.1.2 Veterinary drugs
Industrial animal production, as distinct from ‘organic’ farming (box 4.9.2), requires constant use of antimicrobial drugs
to treat and prevent infectious diseases, and promote growth.
Residues of these antimicrobials can be found in foods anddrinks, normally at levels lower than internationally recommended maximum residue limits (box 4.9.3). When antimicrobials have been found to be carcinogenic in animals,
their licence for that use has been withdrawn.
Hormonal anabolic agents are used in animal husbandry
in some countries, including the USA, to prevent and terminate pregnancy in cows and to promote growth. Their use
has been banned in other countries as well as in theEuropean Union. Hormones designed to stimulate milk production include bovine somatotropin and porcine somatotropin. Many hormones have been found to be multisite
carcinogens in experimental settings.2 These include oestrogens, classed as group 1, human carcinogens, by theInternational Agency for Research on Cancer (IARC), prog-

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Box 4.9.2‘Organic’ farming

So-called ‘organic’ farming is essentially a reversion to, or revivalof, methods of agriculture that were the standard until the introduction of farming systems dependent on chemical fertilisers,
pesticides, and biocides, in the second half of the 20th century.
Organic farming avoids or largely excludes the use of synthetic
fertilisers and pesticides, plant growth regulators, and livestock
feed additives. Farmers tend to rely on crop rotation, crop
residues, animal manures, and mechanical cultivation to maintain soil productivity, and to supply plant nutrients and control
weeds, insects, and other pests. Organic farming is intended to
be indefinitely sustainable.
This type of farming has become well established within
Europe and is expanding at a steady rate. More than 10 per centof farms in Austria, Switzerland, and several other countries useorganic methods.
The retail market for organic farming in high-income countries
has grown about 20 per cent each year since the early 1990s due
to increasing consumer demand. Production and distribution
have become correspondingly large scale. The variety and availability of processed organic food has increased dramatically, andthe cost — which was initially high — is continuing to fall.
Claims that foods produced by organic methods are biologically or nutritionally superior to food produced by intensive
methods are not supported by clinical or epidemiological evidence, but some food compositional data indicates higher concentrations of some constituents like vitamin C and dietary fibre.
There is evidence that organic products contain fewer residues
from chemicals employed in conventional agriculture. However,the subject remains a matter of controversy.

estins (IARC group 2B, possible human carcinogens), andalso testosterone (IARC group 1, human carcinogens).
The toxicity of antimicrobial drugs is constantly reviewed
by international and national regulatory bodies. The Panelnotes the findings on hormonal anabolic agents and also thelack of epidemiological evidence. Because there is no supporting epidemiological or other evidence, the Panel madeno judgements.
4.9.1.3 Genetic modification
Plant breeding is a process of genetic exchange which is often
undertaken with the purpose of acquiring traits that areeither beneficial to humans or increase yield. More recently,
the use of new technologies of genetic modification, intrinsic to agriculture and animal husbandry from their beginnings, has raised great public interest and controversy. Many
crops are now genetically modified by means of gene transfer within and between species. Potential uses of modern
genetic modification technology in food production include
changing nutritional composition (for example, betacarotene in ‘golden rice’); increasing the hardiness of crops;
improving pest or disease resistance; and increasing herbicide tolerance in crop plants (to allow the use of genericherbicides).
Not all genetic modifications include transgenes, in whicha gene from one species is transferred across species, or even

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kingdoms — that is to say, from plants to animals. Somegenetic modifications involve only inactivating existing
genes. For example, tomatoes have been genetically modified to render inactive the enzyme that softens the tomato
once ripe; thus, the tomato remains hard despite being ripe.
This is beneficial for transport and storage purposes.
The production and use of transgenic and genetically modified foods for humans or animal consumption are regulated in most but not all countries. The regulations require thatall genetically modified foods be of equivalent safety as
the food they are replacing, both nutritionally andtoxicologically.
Any effect of genetically modified foods on risk of humandisease might be a result of changes in the types of chemical pesticides or herbicides used, rather than of genetic modification itself. Genetically modified crops may require lessuse of pesticides and herbicides.
Any effect of modern methods of genetic modification offoods on the risk of cancer is unknown. Because there is no
supporting epidemiological or other evidence, the Panelmade no judgements.
There is too little evidence to draw any conclusion about
the association between methods of production and risk ofcancer.

4.9.2 Preservation
Methods of preserving foods have probably been in use since
before recorded history began. Gatherer–hunter and peasant–agricultural food systems (see chapter 1.1) include
various techniques to preserve foods, which remain in use,such as drying, underground storage, fermenting, smoking,and salting. A range of other methods of preservation accompanies, and is part of, industrialisation and urbanisation.
These include canning, bottling, refrigeration, heat treatment, and irradiation.
Methods of food preservation, where epidemiological evidence shows or suggests an effect on the risk of cancer, aresummarised and judged earlier in this chapter. These arerefrigeration (box 4.6.4); processing meat (‘processed meat’refers to red meats preserved by smoking, curing, or salting,or by the addition of chemicals, see box 4.3.1 in chapter 4.3);
preserving fish Cantonese-style (see box 4.3.5 in chapter4.3); and salting (chapter 4.6).
4.9.2.1 Drying
Drying is an ancient method used to preserve cereals(grains), pulses (legumes), fruits, and other plant foods. It
is also used to preserve meat and fish, often as part of another preservation process such as salting (see box 4.3.5 in chapter 4.3). Freeze-drying, where the food is frozen and thewater extracted, has been in commercial use since the mid20th century, and is used to preserve fruits, herbs, meat, fish,
milk, eggs, coffee, and other foods.
4.9.2.2 Fermenting
Fermentation is an ancient method used to preserve many
foods and drinks. It may originally have been discovered by

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accident, because foods ferment as a result of the action ofbacteria or moulds (yeasts). Fermentation has special features. It characteristically changes the sensory and nutritional qualities of foods and drinks: for example, bacterial
fermentation turns milk into yoghurt and cabbage into kimchi (a staple food in Korea) and sauerkraut. Fermentationby yeasts turns sugar into alcohol, and so is an essential partof the process by which cereals (grains), vegetables, fruits,
and other plant foods are the basis for beers, wine, andspirits.
4.9.2.3 Canning, bottling
Bottling and canning were first developed around 1800. The
process involves heating or cooking fruits, vegetables, meats,
and other foods in containers, then sealing them while still
hot. Glass bottles were first used, and then cans.
4.9.2.4 Pasteurisation
Heat can be used to preserve milk and fruit juices by pasteurisation, which kills many micro-organisms. This involves
various methods of rapid heating to a specific temperature,
maintaining that temperature for a set period of time, followed by rapid cooling.
4.9.2.5 Chemical preservation
Chemical preservative additives are added to perishable
processed foods. Antimicrobials inhibit the growth of bacteria and fungi. Antioxidants reduce the rate at which lipids
are oxidised through exposure to air, which leads to rancidity. A third type blocks the natural ripening processes that
continue to occur in plant foods following harvest. The mostcommonly used antimicrobial preservatives are benzoates,
nitrites (see box 4.3.2 in chapter 4.3), and sulphites. There
are internationally specified limits for levels of chemicalpreservatives in foods and drinks.
4.9.2.6 Irradiation
Irradiation was first patented at the beginning of the 20th
century as a means of preserving food using ionising radiation. The process has been tested extensively, but there isconsiderable public suspicion over the safety of irradiatedfoods. For example, 2-alkylcyclobutanones, which interact
with DNA in laboratory settings, are found exclusively in
irradiated foods.
Methods of preservation tend to improve food security andenable more reliable availability of food, but may haveadverse effects too. Some methods of food preservation suchas drying are almost certainly benign, and others like fermentation may have some beneficial effects. The toxicity ofpreservatives and preservation methods is constantly
reviewed by international and national regulatory bodies.
Because experimental data are not supported by epidemiological or other evidence, the Panel made no judgements.
There is too little evidence to draw any conclusion about
the association between methods of preservation and risk ofcancer.

4.9.3 Processing
Food processing transforms basic ingredients into manufactured foods and drinks. In the broad sense of the word, foodproduction, processing, preservation, and preparation aremethods of processing. The term ‘processing’ here is used torefer to techniques and technologies other than methods ofpreservation that are used by manufacturers of industrialised
processed foods. The processes that take place in kitchens(commercial or domestic) are considered in chapter 4.9.4.
Methods of food processing, where there is evidence thatthey may affect the risk of cancer, are summarised andjudged earlier in this chapter. These are hydrogenation(chapter 4.5); refining (chapters 4.1 and 4.6); and the production of alcohol by fermentation (chapter 4.8).
4.9.3.1 Additives
Many if not most processed foods contain additives. Thesemay be synthetic, ‘nature-identical’, or natural. As well as
preservatives, these include bulking aids, colours, flavours,
solvents, and many other categories. For general issues of
toxicity in use, see box 4.9.3. Additives mentioned here aresome of those where issues of carcinogenicity have arisen(also see box 4.9.4).
Flavours

Alkenylbenzenes are a group of naturally occurring flavours,some of which have been found to cause liver cancer in
Box 4.9.3

Regulation of additives andcontaminants

Any chemicals that have a useful function in the production,
processing, or preservation of foods or drinks may nevertheless
be toxic, and possibly mutagenic or carcinogenic. For this reason, food additives and contaminants, such as traces of chemicals used in industrial agricultural production, are subject tointernational and national surveillance and regulations.
They are a cause for concern and vigilance because some, andin particular agricultural chemicals, are known to be toxic inexperimental settings, though at levels well above those foundin foods and drinks.
There is little epidemiological evidence on the possible effectsof contaminants and additives as present in foods and drinks.
Because contaminants and additives are subject to international and national regulation, there is a vast amount of toxicological information from experiments on laboratory animals
and other settings. Failing any other method, it seems reasonable to observe the effects of food additives and contaminantson laboratory animals at levels greatly in excess of any likely tobe present in foods and drinks; and based on several assumptions and judgements, to set limits for safety in use. When such
limits are used as regulatory limits, they are also subject to surveillance and special investigation when any chemical present
in foods and drinks seems to be a cause for special concern.
This area remains controversial. Theoretically, it would be
ideal if food supplies contained no trace of any toxic substance,
including those that are or may be mutagenic or carcinogenic.
However, some foods in nature contain carcinogens and theissue is not confined to methods of industrial food processing.

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Box 4.9.4

Water fluoridation

In the early 1940s, people who lived where drinking water supplies had higher naturally occurring fluoride levels were foundto have less dental caries than people who lived in areas withlower naturally occurring fluoride levels. This finding is supported
by more recent studies.5
Where natural fluoride levels are low, fluoride compounds are
sometimes added to water supplies in order to reduce dental
caries in the general population.
Most cities in the USA now fluoridate their water supplies;
most of Europe does not. The advisability of fluoridation is disputed: fluoride can have adverse effects at doses not much abovethat recommended for prevention of dental caries, and excess
can cause dental fluorosis and bone fragility.
Studies in experimental animals have identified an increased
risk of osteosarcomas (bone cancers) when exposed to water containing high concentrations of fluoride. A report published in the
USA in 2006 considered all the available evidence on fluoride andosteosarcoma and found the overall evidence to be tentative andmixed, and made no recommendations for revising current available fluoride levels in drinking water.6 A study published later in2006 suggested an association between drinking fluoridated
water and osteosarcoma in adolescent men.7 However, preliminary analysis of a second set of cases from the same study does
not replicate the findings.8 The US Centers for Disease Control
and Prevention continues to support community water fluoridation as a safe and effective public health measure to preventand control tooth decay.
These findings are not the basis for any judgement.9

rodents at levels vastly higher than normal human dietaryintakes.3
Colours

About 50 colour compounds are permitted for use in foods.4
The number varies in different countries. Various azo dyes
and other colours found to be carcinogenic in experimental
settings have been withdrawn from use.
Those dyes now regulated for use in food are judged by
UN and other expert committees not to be carcinogenic in
the amounts found in foods and drinks. The xanthene colour
erythrosine and ammonia caramel (a class 3 carcinogen,according to IARC) cause cancers in rats given high doses,
but are judged to be safe as now used.10
Solvents

Around 20 solvents are permitted for food use.4 Two —dichloromethane and trichloroethylene — once used widely for decaffeinating coffee and tea, have been classified by
IARC as possibly and probably carcinogenic to humans,
respectively. The Joint FAO/WHO Expert Committee on Food
Additives has recommended that use of these solvents should
be restricted, and that levels in food should be as low as technologically possible.10 These solvents are now generally not
used for decaffeination.
4.9.3.2 Packaging
Foods and drinks can become contaminated with traces of

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chemicals that migrate from packaging materials such as
plastic wrappings and bottles, and metal cans. Migrationfrom food-contact materials can occur during the processing,storage, and preparation of food. The polymers used in plastic packaging are biologically inert, but their monomers suchas vinyl chloride, acrylonitrile, and acrylamide can and do
migrate into foods. Plasticisers such as phthalates, used in
the manufacture of these polymers, can also migrate into
foods and drinks. These are mutagenic or carcinogenic inexperimental animals. Nonylphenol and bisphenol-A, usedin packaging, mimic the action of oestrogens in the body.
Synthetic oestrogens in the diet are not readily excreted andmay therefore accumulate in the body.
The potential effects of industrial food-processing methods and of additives and contaminants in foods and drinks
on carcinogenicity are constantly reviewed by internationaland national regulatory bodies. In view of the lack of supporting epidemiological or other evidence, the Panel madeno judgements. There is too little evidence to draw any conclusion about the association between methods of preservation and risk of cancer.

4.9.4 Preparation‘Preparation’ here means domestic cooking or the cooking
done in industrial kitchens, by caterers for indirect or directsale.
Methods of food preparation, where epidemiological evidence shows or suggests an effect on the risk of cancer, aresummarised and judged earlier in this chapter. These aregrilling (broiling) and barbecuing (charbroiling) animal
foods (chapter 4.3), and carcinogenic compounds generated by cooking these foods in a flame or at very high temperatures (see box 4.3.4 in chapter 4.3), and ‘fast foods’(Chapter 8).
4.9.4.1 Industrial cooking
Ready-to-heat and ready-to-eat dishes sold in supermarkets
and other retail outlets are a massively increasing market.
Like ‘fast foods’ sold for immediate consumption, these areusually energy dense (see Chapter 8). Intense and prolonged
industrial cooking of starch-based foods such as crisps(chips), French fries (chips), and other snack foods, generates acrylamides, classified by IARC as ‘probably carcinogenic
to humans’. At the time when this Report was completed,acrylamides were the subject of special surveillance andstudy.
4.9.4.2 Steaming, boiling, stewing
These are methods of cooking at up to 100°C. Some labile
water-soluble vitamins are destroyed or lost in this process.
4.9.4.3 Baking, roasting
These are methods of cooking at up to 200°C, but not on a
direct flame. During baking, the high temperatures are usually reached only on the surface of the food, while the innerparts often remain below 100°C. Traditional forms of roasting usually involve basting foods with oils or fats.

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4.9.4.4 Microwaving
Microwaving exposes food to temperatures up to 200°C.
Microwaves are a form of electromagnetic radiation. They
cause vibration of water molecules, which produces heat.
There is no evidence that microwaves have any specific effecton food composition beyond that of heat.
4.9.4.5 Frying, grilling (broiling), barbecuing(charbroiling)
Also see box 4.3.4 in chapter 4.3. Frying, grilling (broiling),
and barbecuing (charbroiling) generate temperatures of up
to 400°C, and sometimes use a direct flame to cook food.
These methods create high levels of carcinogenic compounds. For any cooking involving wood fires, the type ofwood used can also be an important factor in determining
which chemicals contaminate the food. Hardwoods such as
oak and hickory burn cleanly; others such as mesquite generate copious quantities of polycyclic aromatic hydrocarbons.
Because of the experimental evidence of carcinogen production, it is prudent not to consume burned or charredfoods frequently or in large amounts. Industrial food preparation methods are regulated. Because there is no supporting epidemiological or other evidence, the Panel made no
judgements.
There is too little evidence to draw any conclusion about
the association between methods of preparation and risk ofcancer.

in use, as a basis for food safety regulations. The relevanceof such work to the actual levels consumed of substances
identified in this section is obscure. Also, it is commonly
agreed, as in this Report, that information from animal andother experimental settings, which is unsupported by evidence from epidemiological studies, is not a sound basis forfirm judgements.
Confounding. Studies commonly report the difficulty in sep-arating out specific methods of processing or cooking, whenfoods are characteristically processed and prepared in a number of different ways.

4.9.6 Evidence and judgements
The Panel decided to make no judgements on experimental
findings of toxicity that are not supported by epidemiological or other evidence.
The evidence considered by the Panel is in the systematic literature review (SLR). Because the Panel made no judgement on the isolated experimental data, this evidence is not
summarised separately here.
The full SLR is contained on the CD included with thisReport.

4.9.7 Comparison with previous report
4.9.5 Interpretation of the evidence
4.9.5.1 General
For general considerations that may affect interpretation of
the evidence, see chapters 3.3 and 3.5, and boxes 3.1, 3.2,
3.6 and 3.7.
Aspects of food production, preservation, processing, andpreparation (including cooking), where epidemiological evidence enables judgements to be made, are summarised, with
Panel judgements, in previous sections of this chapter.
4.9.5.2 SpecificMeasurement. It is practically impossible to measure small
amounts of additives and trace amounts of contaminants infoods and drinks except by analysis. Epidemiological studies using usual methods of dietary assessment are therefore
generally uninformative.
Terminology. The terms used for different types of cooking
vary around the world. ‘Broiling’ in the USA is called ‘grilling’in other countries. ‘Barbecuing’ may mean grilling in flameor slow cooking near smoking embers. Results of studies inthese areas need to be interpreted with care, given that carcinogenic compounds are particularly generated when meatand other animal and plant foods are cooked in a flame, andeven more so when they are burned or charred.
Study design. Practically all studies of the topics covered inthis section are laboratory experiments on animals. They arecommonly carried out to assess toxicity to determine safety

In general, the previous report found that information fromanimal and other experimental settings unsupported by epidemiological evidence, was not a basis for judgement. In thisrespect, the view of the Panel responsible for this Report issimilar. The findings of the previous report on food additives,
microbial contaminants, salt and salted foods, salted fish
(Cantonese-style), cured meats, and the grilling and barbecuing of meat, fish, and other foods, were all contained ina chapter on food processing. The previous panel’s judgements were mostly similar to those made here, with theimportant exception of processed meat, which was not considered separately from smoked and cured meats by the previous report. The judgements of this Report on these subjects
are made in previous sections of this chapter.

4.9.8 Conclusions
The Panel concludes:
The Panel decided to make no judgements on isolated experimental findings that were not supported by epidemiological or other evidence.
It is not possible to make any definitive judgement in theabsence of epidemiological evidence. Nevertheless, the Panelconcurs that, in general, it seems reasonable to conclude thatthe changes made to foods and drinks within well regulated, modern food systems, and those made to foods anddrinks as usually prepared and cooked, are of themselves
unlikely to modify the risk of cancer significantly.
There are important exceptions to this tentative conclusion

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and in these cases, the Panel’s judgements and conclusions
are found in the relevant earlier sections of this chapter.
These judgements and conclusions are made in those sections wherever epidemiological and other evidence justifies
a judgement of a protective or causative effect, using theagreed criteria, for aspects of food production (including
contamination), processing, preservation, and preparation(including cooking).

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4.10 Dietary constituentsand supplements
DIETARY CONSTITUENTS AND SUPPLEMENTS, AND THE RISK OF CANCER
In the judgement of the Panel, the factors listed below modify the risk of cancer. Judgements are graded according to the strength of the evidence.

DECREASES RISK
Exposure

INCREASES RISK

Cancer site

Convincing

Probable

Limited —suggestive

Exposure

Cancer site

Beta-carotene
supplements1

Lung

Calcium2

Colorectum

Selenium3

Prostate

Retinol4

Skin5

Retinol supplements1

Lung

Alpha-tocopherol2

Prostate

Selenium supplements2

Skin

Selenium3

Lung3
Colorectum6

Substantial
effect on risk
unlikely

1
2
3
4
5
6
7

Beta-carotene7: prostate; skin (non-melanoma)

The evidence is derived from studies using high-dose supplements (20 mg/day for beta-carotene; 25 000 international units/day for retinol) in smokers.
The evidence is derived from studies using supplements at a dose of 200 µg/day.
The evidence is derived from studies using supplements at 200 µg/day. Selenium is toxic at high doses.
The evidence is derived from studies using supplements at a dose of 25 000 international units/day.
Applies only to squamous cell carcinoma.
The evidence is derived from studies using supplements at a dose of 200 µg/day. Selenium is toxic at high doses.
The evidence is derived from studies using supplements (at doses of 20, 30, 50 mg for prostate, and doses of 30, 50 mg/day for skin), and foods containing
beta-carotene: see chapter 4.2.

For an explanation of all the terms used in the matrix, please see chapter 3.5.1, the text of this section, and the glossary.

Nutritional science conventionally divides foods anddrinks into their chemical constituent parts, such as water,
carbohydrates, fats, proteins, vitamins, and minerals.
Their biological functions are then explored, singly or in
combination. It is now increasingly agreed by the nutrition
science community that research and also public healthcan additionally benefit from a more integrated approach,in which the emphasis is placed on foods and drinks. In
this Report, the evidence, its summaries, and the Panel’s
judgements are food-based, wherever possible.
Here, the evidence on macronutrients, micronutrients(isolated in the form of supplements), and bioactive
constituents of plant foods (also known as
phytochemicals) is summarised and judged.
Overall, the Panel judges that the evidence that dietary
macronutrients specifically affect the risk of cancer isunimpressive. The evidence, based on observational data
and randomised controlled trials of supplements, thatcertain vitamins and minerals affect the risk of specificcancers is, in some cases, impressive.

The Panel judges as follows:
The evidence that high-dose beta-carotene supplements
are a cause of lung cancer in tobacco smokers isconvincing. There is limited evidence suggesting that highdose retinol supplements are a cause of lung cancer intobacco smokers.
Calcium probably protects against colorectal cancer. At
specific doses, selenium probably protects against prostatecancer.
It is unlikely that beta-carotene has a substantial effecton the risk of either prostate cancer or non-melanoma
skin cancer.
There is limited evidence suggesting that retinol at
specific doses protects against squamous cell carcinoma of
the skin. There is also limited evidence suggesting thatalpha-tocopherol protects against prostate cancer, and thatselenium at specific doses protects against colorectal andlung cancer. There is limited evidence suggesting thatselenium supplements are a cause of skin cancer.
Within the remit of this Report, the strongest evidence,

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corresponding to judgements of ‘convincing’ or ‘probable’,shows that high-dose beta-carotene supplements in
tobacco smokers are a cause of lung cancer; that calcium
probably protects against colorectal cancer; and thatselenium probably protects against prostate cancer. It is
unlikely that beta-carotene, or foods containing it, have asubstantial effect on the risk of either prostate or skin(non-melanoma) cancer. The Panel emphasises that thisevidence and these judgements relate to thesemicronutrients only at the specified doses.

Nutrition science in its conventional form as a biological discipline was created in the early 19th century following theidentification of carbohydrates, fats, and proteins. As nutrients, these all supply energy and are essential for tissue structure and function, and physical and mental growth anddevelopment. Later research has divided these macronutrients into many constituent parts such as monosaccharides
and polysaccharides (including non-starch polysaccharidesor ‘dietary fibre’); saturated and unsaturated fatty acids(which themselves have many fractions); and amino acids.
Many of these constituents of the main nutrients are known
to have different metabolic, physiological, biochemical, andother effects, in isolation or combination.
Beginning in the early 20th century, a series of substancesthat do not supply energy were identified also as being vitalto life, typically in very small amounts: these are vitamins,
minerals, and trace elements. More recently a large numberof other substances that are not nutrients, in the sense ofbeing essential components of metabolic processes or cellstructure, have been identified as bioactive. Because these
are contained in plants, they are commonly known as
phytochemicals.
Reports concerned with specifying recommended dietary(or daily) amounts or reference values for nutrients, by theirnature, are structured accordingly. Compilations of the chemical composition of foods, used as standard references in epidemiological studies of food, nutrition, and the risk of
diseases including cancer, also specify macro- and microconstituents of foods and drinks, to varied degrees of completeness and accuracy.
Reports concerned with nutritional deficiencies characteristically make recommendations for the relevant microconstituents. Increasingly though, they often now makerecommendations for dietary patterns, diets, and foods anddrinks that are high in the microconstituents with which they
are concerned. So a report on vitamin A deficiency may specify foods high in carotenoids and retinol, and may also recommend methods of agriculture that emphasise such foods.
Reports concerned with prevention of chronic diseases were
initially structured in terms of dietary constituents, with only
secondary reference to foods. But following a general international agreement that food-based dietary guidelines are
more useful, and often better reflect the science, such reports
now give more emphasis to foods and drinks, both in theiranalysis of evidence and in their recommendations.
The policy of this Report is to always emphasise foods anddrinks. Thus, earlier sections of this chapter include sum-

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maries and judgements of the evidence on dietary fibre, vitamins, minerals, and trace elements as contained in foods,
and also on fats, oils, sugars, salt, and alcohol as foods. Also
see chapters 4.1 to 4.8. This section is concerned with macronutrients and micronutrients as such, and with non-nutrient
bioactive constituents of food (phytochemicals).

4.10.1 Macronutrients
Chemically, macronutrients are classified as carbohydrates,
fats, and proteins, and these categories have many subclassifications. Diets need to include adequate amountsof macronutrients for physical and mental growth and development, and for maintenance of normal tissue structure andfunction. All macronutrients supply energy. Alcohol also
supplies energy, but there is no requirement for it. Also see
chapter 4.8.
4.10.1.1 Carbohydrates
Carbohydrates consist of monosaccharide sugars, or larger
molecules of these units joined together: disaccharides (twounits), oligosaccharides (a few), or polymers (many). For
instance, glucose is a monosaccharide and starch is a polymer of glucose units. Polysaccharides are sometimes called‘complex’ carbohydrates and sugars ‘simple’ carbohydrates.
Carbohydrates are generally the largest single source ofenergy in diets. They supply around 4 kilocalories per gram.
They form part of important structural components in the
body and, in the form of glucose, are the principal and preferred energy source for metabolism. They also play majorroles in several essential cellular and physiological processes. Non-starch polysaccharides are the characterising featureof dietary fibre.
Glycaemic index and glycaemic load are terms used tocharacterise foods and diets based on their effects on blood
glucose levels. Also see box 4.1.3 in chapter 4.1.
Cereals (grains) and products made from them (such asbreads, pastas, and breakfast cereals), as well as starchy roots
and tubers, are all high in carbohydrates. These foods contain a mixture of complex and simple carbohydrates andother nutrients. Until recently, starches have been the main
source of carbohydrate in human diets. With industrialisation and urbanisation, sugars have been added in increasing quantities in food preparation and as an ingredient inprocessed foods. Diets consumed in some high-income
countries now may contain roughly as much carbohydrate
in the form of sugars as they do starches. Diets high in complex carbohydrates are usually associated with lower prevalence of obesity, heart disease, and type 2 diabetes.
For summaries and judgements on dietary fibre, see chapter 4.1. For summaries and judgements on sugars, seechapter 4.6. For food processing, see chapter 4.9.
4.10.1.2 Fat
Fats in diets are mostly made up from triglycerides — threefatty acid molecules attached to a glycerol backbone.
Triglycerides are lipids, a class of organic compounds characterised by their solubility in organic solvents (such as ether

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and chloroform); they are usually insoluble in water. The
body stores excess energy as lipids in the form of body fat(also known as adipose tissue). Lipids also form part of thestructural components of cellular membranes as well as
being precursors of important hormones.
Dietary fats include solid fats and liquid oils. Their physical form at a particular temperature is determined by thechemical structure of their constituent fatty acids. Fats witha high proportion of ‘saturated’ fatty acids are solid or semisolid at ambient temperatures; those with a higher amountof ‘unsaturated’ fatty acids are more likely to be oils. The different degrees of saturation produce various effects in the
body. Diets high in saturated fatty acids (and also trans-fatty
acids) (see chapter 4.5 and box 4.5.1) increase circulating
blood concentrations of cholesterol and the risk of cardiovascular disease. The World Health Organization recommends limiting total fat to between 15 and 30 per cent of
total daily energy intake and saturated fatty acids to less than
10 per cent.1
Fats are the most concentrated energy source, supplying
around 9 kcal per gram. They also carry the fat-soluble vitamins (see chapter 4.10.2.1). The body can make all but twoof the fatty acids it needs — linoleic acid and alpha-linolenicacid, known as the ‘essential’ fatty acids. Both are found invegetables, nuts, and seeds and their oils, in varying quantities. They are also found in meat, eggs, and dairy products,
but at lower levels. The long-chain fatty acids found in oily
fish (eicosapentaenoic and docosahexaenoic acids) can bemade to a limited extent in the body, where they play a rolein inflammation.2 These and related fatty acids are precursors to prostaglandins; these hormone-like compounds haveother diverse effects, including roles in blood vessel dilationand constriction, blood clotting, and transmission of nerve
impulses.
Nuts, seeds, meat, oily fish, whole milk and dairy products, cooking oils and fats, spreadable fats, and a wide rangeof manufactured foods all contain varying amounts and types
of fats. Those from animal sources usually have a higher proportion of saturated fatty acids, and these are common inprocessed foods.
For summaries and judgements on fats and oils as foods,
see chapter 4.5. For summaries and judgements on foods
that are or may be high in fats, see chapters 4.3 and 4.4.
4.10.1.3 ProteinsProteins are large organic molecules made up of amino acids
arranged in a chain. Short chains are called peptides, forinstance di- and tripeptides (made up of two and threeamino acids respectively). Longer chains are known as
oligopeptides, and long chains as polypeptides. Proteins arefundamental structural and functional elements within every
cell in the body.
Many proteins are enzymes that catalyse biochemical reactions and are vital to metabolism. Others have structural ormechanical functions, such as the proteins in the cytoskeleton, which give cells their shape and strength. They are also
important in cell signalling, immune responses, cell adhesion, and the cell cycle.
Proteins supply around 4 kcal per gram. They are digest-

ed into their constituent amino acids, which are thenabsorbed into the blood. The body has the ability to makesome amino acids, but others, so called essential aminoacids, must be obtained from foods and drinks.
Dietary sources of protein include meats, milk andcheese, pulses (legumes), nuts, and cereals (grains) andproducts made from them, such as breads. Animal proteinsfrom eggs, milk, and meat contain all the essential aminoacids in the proportions needed by humans; soya protein is
the only plant food to do so. Other plant protein sources havediffering proportions of various essential amino acids, so
diets without animal foods or soya need to include a variety of plant protein sources to provide enough of the essential amino acids.
For summaries and judgements on foods that containproteins, see chapters 4.1, 4.2, 4.3, and 4.4.

4.10.2 Micronutrients
Micronutrients are essential constituents of diets needed insmall quantities compared with macronutrients, and are notsources of energy. These are vitamins, minerals, and traceelements. Deficiency of any dietary constituents classified asa micronutrient causes debility, disease, and eventuallydeath.
Many processed foods are ‘fortified’ with synthetic vitamins and minerals (box 4.10.1). Others contain various
microconstituents such as phytochemicals, and sometimes
other ingredients such as bacteria and ‘prebiotic’ polysaccharides; these products are sometimes termed ‘functional
foods’ (box 4.10.2). Both types of product are often marketedwith health claims relating to these added constituents or to
the whole food.
4.10.2.1 Vitamins
Vitamins are organic molecules, classed as fat- or watersoluble, that are needed for metabolism but cannot be madein the body and so must be supplied in the diet. They havedifferent specific functions in the body. For example, vitamin
K is needed for blood clotting and vitamin C for the production of collagen in connective tissue.
Vitamins A (retinol), D, E, and K are fat-soluble and can
only be digested, absorbed, and transported in conjunction
with dietary fats. So they are found mainly in fatty foods
such as liver and oily fish, milk and dairy products, animalfats (such as butter), and vegetable oils. The main sourcesof vitamin A are plant foods containing the retinol precursors known as carotenoids, which are converted by the bodyto retinol (see box 4.2.1 in chapter 4.2). Preformed retinol,
which is absorbed better than carotenes in plant foods, isfound only in animal products, of which liver is a particularly rich source. Fat-soluble vitamins are stored in the liverand in body fat stores. For this reason, they do not need tobe consumed every day. For the same reason, some are toxic
in high doses.
Vitamin C and the B vitamins are water-soluble. The B
group includes thiamin (vitamin B1), riboflavin (B2), niacin(B3), pyridoxine (vitamin B6), biotin, pantothenic acid,181

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Box 4.10.1

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Food fortification

Food ‘fortification’ refers to the addition ofnutrients, often in synthetic form, to foods,
so that the food contains more of the nutrients added. The term ‘enrichment’ is sometimes also used.
The United Nations and other international organisations are responsible formajor food fortification programmes,
designed in particular to reduce rates of
deficiency of vitamin A, iodine, iron, andother nutrients, mostly within low-income
countries. But common foods have been
fortified in many countries since the early
20th century. For example, in some countries margarine and other fat spreads, ormilk, have been fortified with vitamins A
and D. White flour, and therefore whitebread and other products made from it, iscommonly fortified with some B vitamins,
and also sometimes with calcium and iron.
The term ‘fortification’ in these andother examples may refer to the partial
replacement of nutrients otherwise absent
or depleted by food-processing methods.
Or it may refer to the addition of nutrientsto levels not found in the food in wholeform; for example, the addition of calcium
to white bread in the UK is to levels higher than those found in wholegrain breads;
and salt may not contain iodine.
Many common processed foods anddrinks, including some that would otherwise be low in nutrients, are now fortified
with various combinations of synthetic
nutrients. These include breakfast cereals,
biscuits (cookies) and other baked goods,

folate, and cobalamin (vitamin B12). Excess amounts ofwater-soluble vitamins are generally not toxic because they
are excreted in the urine rather than stored in the body. This
also means that they generally have to be consumed more
frequently than fat-soluble vitamins. Plant foods are important sources of water-soluble vitamins: for example, cereals(grains), vegetables, fruits, some roots and tubers, and pulses (legumes). They can be destroyed by heat or exposure to
the air, or lost by leaching during cooking, for instance whenvegetables are boiled (see chapter 4.9.4).
4.10.2.2 Minerals, trace elements
Minerals are inorganic substances. Most foods contain significant amounts of one or more minerals, and these compounds have many specific functions in the body. Some are
essential components of enzymes and other proteins (as‘cofactors’, such as iron). They are also involved in maintaining normal cell function (sodium, potassium, calcium),and for structure (calcium in bones and teeth). Others
include magnesium, phosphorus, and sulphur.
Trace elements are minerals needed by the body in verysmall amounts. Whether a mineral is defined as a trace element is somewhat arbitrary: iron, zinc, and copper are minerals that may or may not be identified as trace elements.
Others include iodine, selenium, chromium, fluoride, boron,
cobalt, manganese, molybdenum, and silicon.

Box 4.10.2

dried milk, milk-based products, and softdrinks, and even confectionery. Many suchproducts are designed to be consumed bychildren.
In an increasing number of countries,
the nutrients consumed in fortified foods
and drinks amount to a substantial andgrowing proportion of total consumptionof these nutrients. For example, since 1998
in the USA, grain has been fortified with
folic acid, the synthetic equivalent offolate, as a public health measure designed
to reduce the incidence of neural tube
defects in the fetus. As a result, it is estimated that over one third of all intake of
this nutrient in the USA comes from thissource, as well as from fortified breakfast
cereals.3

Functional foods

Functional foods are so-called because they are believed or
claimed to have special qualities, such as promoting well-being
or protecting against disease. What marks them out from ‘normal’ foods is that they are specifically formulated, manufactured,and marketed as being ‘functional’ in specified ways, for whichclaims are made. Some fortified products, such as breakfast cereals and yoghurts, are positioned as functional foods.
The ingredients in functional foods claimed to have special
qualities may be added fractions of macronutrients, such asamino acids or fatty acids, or vitamins, minerals, or trace elements. Very often the ‘functional’ ingredients will be known orclaimed to be bioactive in other ways: these include phytochemicals, herbal extracts, and commensal bacteria.

Various phytochemicals have been shown to have antioxidant, anti-carcinogenic, anti-inflammatory, immunomodulatory, and antimicrobial effects in laboratory experiments.
But it is not yet clear whether consuming these compounds
produces these or other effects in the body.
Phytochemicals have various chemical structures and aregrouped into families on this basis. They include flavonoids,
isoflavones (phytoestrogens), glucosinolates, terpenes,
organosulphur compounds, saponins, capsaicinoids, andphytosterols. Many vegetables, fruits, pulses (legumes),
herbs, and teas are high in phytochemicals.

4.10.3 Phytochemicals
Phytochemicals are bioactive constituents of plant foods not
identified as nutrients because they are not essential in thesense of being vital to life itself. Unlike vitamins and minerals, people do not suffer diseases when their diets are low
in phytochemicals. However, consuming them may have beneficial effects on health or active roles in the prevention of
diseases. Also see box 4.2.2 in chapter 4.2.

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4.10.4 Supplements
Vitamins, minerals, trace elements, and other bioactive substances are available as supplements, usually in pill or powder form. These began to be manufactured and marketed
after their functions were identified, and claims made for
their general benefits in prevention of disease and promotion of well-being.
Many dietary supplements are classed as foods, althoughC H A P T E R

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Levels of supplementation

The effects of bioactive substances vary with the quantities consumed. The amounts of nutrients and other substances in diets
depend on the nature and quantity of the foods and drinks thattaken together make up diets.
The amounts of nutrients and other substances contained indietary supplements, in this context usually referred to as doses,
may or may not be at levels that can be found in diets. Lower
amounts, at levels about the same as those that can be foundin diets, are known as ‘physiological doses’. Higher amounts, atlevels above any that can be found in diets, are known as ‘pharmacological doses’, or sometimes as ‘mega-doses’.
Evidence from trials and studies using supplements are often
difficult to compare. One reason for this is that both human andanimal studies use supplements in different combinations andconcentrations. A nutrient that has one effect at a relatively low
or physiological dose may have a different effect at a higher or
pharmacological dose. For instance, a nutrient that may evidently be protective at a lower or physiological dose may be
toxic or pathogenic at a higher dose.
Randomised controlled trials using various doses of micronutrients have produced evidence of the effects of these
supplements in modification of the risk of cancers of some sites.
This evidence is summarised and judged in chapter 4.10.6.

‘Relative risk’ (RR) is used in this Report to denote ratio
measures of effect, including ‘risk ratios’, ‘rate ratios’, ‘hazard ratios’, and ‘odds ratios’.
4.10.5.2 Specific
These specific points apply only to trials using micronutrient supplements.
Measurement.

The results of supplement trials can beassumed only to apply to levels and forms of the micronutrient present in the supplement.

Study design. Randomised controlled trials (RCTs) using

nutrient supplements provide strong evidence. But the evidence can only be taken to apply to supplements at the doses
and in the form given, under the specific experimental conditions. The doses used in trials are often pharmacological,
in which case they cannot be taken as directly relevant to
the nutrients as contained in foods and diets. Supplements
in synthetic forms are sometimes but not always chemically identical to the nutrient as found in food, and so may havedifferent biochemical effects. This may also be because of thelevel of the dose, because the nutrient is given in isolationor separated from the nutritional matrix as found in foods,
or for other reasons.
Confounding. In trials using supplements given in combi-

some may be regulated medicinal products. Manufacturersof food supplements may market their products using healthclaims, although in some countries such as the UK, medicinal claims that the product can prevent, cure, or treat a disease may not be made. Herbal products may be permitted
to make certain claims based on their history of being used
for a particular condition. The regulatory status of dietary
supplements varies from country to country.
Some nutrients such as water-soluble vitamins have beenthought to be harmless at pharmacological doses; but there is
now evidence, including some summarised and judged in thisReport, that this is not always the case. Other nutrients, including fat-soluble vitamins and all minerals and trace elements,
are known to be toxic at pharmacological doses; some of these,
selenium being one example, are known to be toxic at relatively low pharmacological levels (also see box 4.10.3).
Expert reports issued by United Nations agencies andnational governments specify levels of nutrients agreed toprotect against deficiency diseases, and also (sometimes)
agreed to be safe in use.
Many people take dietary supplements. Their use is higher in high-income countries. In the UK, 35 per cent of respondents reported taking dietary supplements. Around 50 per
cent of people in the USA take supplements in some form.

4.10.5 Interpretation of the evidence
4.10.5.1 General
For general considerations that may affect interpretation of
the evidence, see chapters 3.3 and 3.5, and boxes 3.1, 3.2,
3.6 and 3.7.

nations, it is not possible to attribute any effect to an individual nutrient.

4.10.6 Evidence and judgements
The full systematic literature review (SLR) is contained on
the CD included with this Report.
4.10.6.1 Carbohydrates
For the evidence on foods containing carbohydrate, including dietary fibre, see chapter 4.1. For the evidence on sugars
as a food, see chapter 4.6.
4.10.6.2 Fats
For the evidence on foods containing substantial amounts offats and oils, see chapters 4.3 and 4.4. For the evidence
on fats and oils as foods, see chapter 4.5.
4.10.6.3 Proteins
The evidence from the SLRs did not suggest that proteinsspecifically modify the risk of cancers of any sites. For theevidence on foods containing protein, see chapters 4.1, 4.3,
and 4.4.
4.10.6.4 Vitamin supplements
The evidence presented here is derived from studies of vitamins and beta-carotene (a vitamin A precursor) in supplement form only. Microconstituents in supplement form may
have very different effects according to form, dosage, combination with other nutrients, interaction with diets as awhole, and other factors.

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4.10.6.4.1 Retinol
Skin

Two RCTs investigated retinol supplements and skin cancer(table 4.10.1).4 5
Both trials included only participants at risk of developing non-melanoma skin cancer. The retinoid skin cancer prevention (actinic keratoses) trial (SKICAP-AK) included
people with a history of precancerous lesions (actinin keratoses); the retinoid skin cancer prevention (squamous cell
carcinoma/basal cell carcinoma) trial (SKICAP-S/B) included people with a history of non-melanoma skin cancer. SKICAP-AK showed non-significant increased risk for basal cell
carcinoma, with an effect estimate of 1.14 (95% confidence
interval (CI) 0.91–1.43), but it did show a statistically significant decreased risk for squamous cell carcinoma 0.68
(95% CI 0.51–0.92), comparing intervention to placebo.5
SKICAP-S/B produced no evidence of effect for either basal
cell carcinoma (106 cases intervention group: 110 cases
placebo group) or squamous cell carcinoma (41 cases eachin intervention and placebo group).4
Meta-analysis was possible on both trials, giving summary
effect estimates of 1.10 (95% CI 0.90–1.34) for basal cell carcinoma and 0.93 (95% CI 0.70–1.23) for squamous cell
carcinoma.
The mechanism of anti-tumour action of the retinoids is
not completely known but retinol is known to bind to cell
receptors with promotion of differentiation, alteration of
membranes, and immunological adjuvant effects.6
The evidence is sparse and studies were conducted ona narrowly defined population group (people at risk ofdeveloping skin cancer). There is limited evidence
suggesting that retinol supplements protect againstsquamous cell skin cancer.

The Panel is aware that since the conclusion of the SLR, one
case-control study7 has been published. This new information
does not change the Panel judgement (see box 3.8).

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The single RCT was the Beta-Carotene and Retinol
Efficacy Trial (CARET) trial (table 4.10.2) among current
and former smokers (some of whom were asbestos workers)
who were given retinyl palmitate and beta-carotene, orplacebo. It showed statistically significant increased risk of
all lung cancers in the treated subjects, with an effect estimate of 1.28 (95% CI 1.04–1.57). The risk of death fromlung cancers was 1.46 (95% CI 1.07–2.00).9 The risk was
especially elevated in those who had the intervention as well
as exposure to either asbestos or heavy smoking, althoughneither subgroup analysis was statistically significant. At
follow-up (5 years after trial termination), the effect was
reduced and no longer statistically significant, with an effectestimate of 1.12 (95% CI 0.97–1.31).8
The other trial, which was not randomised, gave retinol
or beta-carotene to asbestos-exposed people and used amatched comparison group, giving an adjusted effect estimate of 0.67 (95% CI 0.33–1.37).11
One cohort study was stratified according to smoking status (current, former, and never).12 In current smokers, highdose vitamin A supplements (synthetic beta-carotene or
retinol) were associated with an increased risk, with an effectestimate of 3.42 (with no CI or value for trend reported),when compared to no supplements. Men who never smokedshowed a non-significant decreased risk.12 The other cohort
study showed no effect on risk for men and non-significant
decreased risk in women. Effect estimates were 1.0 (95% CI
0.66–1.51) for men and 0.65 (95% CI 0.39–1.06) for
women, when comparing supplement use to non-use.13 One
case-control study showed a non-significant increased risk
with supplement use,14 the other showed no effect on risk.15
It is possible that the potential protective associations present at dietary intake amounts of vitamins are lost or
reversed by pharmacological supplementation and the higher levels that this may supply.
The evidence is sparse and inconsistent. There islimited evidence suggesting that high-dose retinol

Lung

Two trials (one an RCT, the other a non-randomised trial),8-11
two cohort studies,12 13 and two case-control studies14 15
investigated retinol or vitamin A supplements and lungcancer (table 4.10.2).

Table 4.10.1

Retinol supplements andskin cancer; trials

Trial
name

Number of Intervention
participants

Length ofLength ofintervention follow-up

SKICAP-AK
Moon 1997

2297 withmoderaterisk of skincancer25000 IU
retinol orplacebo daily

5 years

SKICAP-S/B
Levine 1997

525 withhigh risk ofskin cancer

25000 IU
3 years
retinol, 5–10 mg
isotretinoin orplacebo daily

184

3.8 years

3 years

Table 4.10.2
Trial
name

Vitamin A supplements andlung cancer; trials

Number of Intervention
participants

Length ofLength ofintervention follow-up

18 314 at
Betahigh risk of
Caroteneand Retinol developing
lung cancer
Efficacy
Trial(CARET)
Goodman2004
Omenn 1996

4 years
30 mg beta(trial ended
carotene andearly)
25 000 IU
retinyl palmitate

5 years

WesternPerthasbestos
workers
Musk 1998

Annual supplies Maximumof vitamin A
of 4 years(either synthetic
beta-carotene or
retinol), help inquitting smoking,and dietary advice–

1203
participants,
996
comparison
subjects

C H A P T E R

4•F O O D S

A N D

D R I N K S

supplements are a cause of lung cancer in current
smokers.

Figure 4.10.1

Beta-carotene supplements and lungcancer; trials

4.10.6.4.2 Beta-carotene
Lung

Relative risk (95% CI)

Five RCTs8-10 16-20 and one cohort study21 investigated betacarotene supplements and lung cancer (table 4.10.3).
Four studies showed increased risk with a beta-carotene
intervention,16 17 19 20 which was statistically significant in
two (during the trial, not at follow-up; smokers).8-10 16 17 One
study showed a non-significant decreased risk.18 Metaanalysis was possible on three trials, giving a summary effectestimate of 1.10 (95% CI 0.89–1.36) for beta-carotene supplementation versus none, with moderate heterogeneity (figure 4.10.1). Two trials could not be included in themeta-analysis. One trial reported an effect estimate of 1.50
(95% CI 0.43–5.28) for those taking beta-carotene comparedto those taking retinol from a total of 10 lung cancers in allparticipants.20 The other RCT was the CARET trial (table
4.10.3) among current and former smokers (some of whomwere asbestos workers) who were given retinyl palmitate andbeta-carotene, or placebo. It showed statistically significant
increased risk of all lung cancers in the treated subjects, with
an effect estimate of 1.28 (95% CI 1.04–1.57). The risk ofdeath from lung cancers was 1.46 (95% CI 1.07–2.00).9 The
risk was especially elevated in those who had the intervention as well as exposure to either asbestos or heavy smoking, although neither subgroup analysis was statistically

Table 4.10.3
Trial
name

Beta-carotene supplements andlung cancer; trials

Number of Intervention
participants

Length ofLength ofintervention follow-up

Physicians’
22 071
Health Study(PHS)
Cook 2000

50 mg beta13 years
carotene taken
on alternate days–

Women’s
39 876
Health Study(WHS)
Lee 1999

50 mg of beta- 2 years
carotene taken
on alternate days

4 years

ATBC study 29 133(male
smokers)
Virtamo 2003
Albanes 1996

20 mg of beta- 5–8 years
carotene onlyor with 50 mg ofalpha-tocopherol

6–8 years

1024
WesternPerthasbestos
workersde Klerk 1998

Up to 5 years –30 mg/daybeta-carotene or
25 000 IU/day
retinol

Beta18 314 at
Carotenehigh risk ofand Retinol developing
Efficacylung cancer
Trial(CARET)
Goodman2004
Omenn 1996

30 mg beta4 years
carotene and(trial ended
25 000 IU
early)
retinyl palmitate

5 years

Virtamo 2003 (ATBC) Men

1.17 (1.02–1.34)

Cook 2000 (PHS) Men

0.90 (0.68–1.18)

Lee 1999 (Women’s Health Study)

1.43 (0.83–2.48)

Summary estimate

1.10 (0.89–1.36)

0

1

2

Relative risk, intervention group vs control group

significant. At follow-up (five years after trial termination),
the effect was reduced and no longer statistically significant,with an effect estimate of 1.12 (95% CI 0.97–1.31).8
One cohort study showed non-significant increased risk forbeta-carotene supplementation compared to none in women.
The other study showed non-significant decreased risk inmen. Effect estimates were 1.23 (95% CI 0.55–2.76;
women) and 0.82 (95% CI 0.36–1.85; men).21
There is a marked interaction between beta-carotene,
heavy smoking and genotype.22 23 When beta-carotene supplementation among those without the glutathione-S-transferase variant GSTM1 who smoked more than 42 cigarettes
per day was compared to beta-carotene supplementation
among those without GSTM1 who smoked less than 37 cigarettes per day, a RR of 6.01 (95% CI 1.90–19.08) was
observed.22 After adjusting for age and smoking habits, an
RR of 3 (95% CI 1.3–7.1) was observed for the Arg/Arg
genotype when 545 µg/l of serum beta-carotene was compared to 45 µg g/l.23 Glutathione-S transferase 1 and 2 are
carcinogen-detoxifying enzymes. People without or with lessactive forms of these enzymes, due to genetic variation, areless able to metabolise toxins than others and have higher
risk of cancer, particularly if they are smokers or exposed toregular doses of toxins through another source.
It is possible that the protective association present at
dietary intake amounts of carotenoids is lost or reversed bypharmacological supplementation and the higher levels that
this may supply. In one animal study, low-dose beta-carotene
was protective against smoking-induced changes in p53,
while high doses promoted these changes.24 A second explanation could be the complex nature of naturally occurring
carotenoids and the possibility that the protective associations are not due to the specific agent used in supplement
studies, but rather to other carotenoids present in dietary
exposure25 or other associated dietary or health related
behaviours.
There is strong evidence from good quality trials,
consistent with cohort studies. An interaction between
smoking, genetics, and beta-carotene is apparent. The
evidence that beta-carotene supplements cause lungcancer in current smokers is convincing.

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Table 4.10.4
Trial
name

Beta-carotene supplements andprostate cancer; trials

Number of Intervention
participants

Beta18 314 at
Carotenehigh risk ofand Retinol developing
Efficacylung cancer
Trial(CARET)
Omenn 1996

Length ofLength ofintervention follow-up

30 mg beta4 years
carotene and(trial ended
25 000 IU
early)
retinyl palmitate

5 years

50 mg beta13 years
carotene taken
on alternate days–

20 mg of beta- 5–8 years
carotene only orwith 50 mg ofalpha-tocopherol

6–8 years

2•

E V I D E N C E

Table 4.10.5
Trial
name

Number of Intervention
participantsNambourSkin Cancer
Prevention
Trial
Green 1999

1621

BetaCarotene
Trial
Greenberg
1990

1805 (with50 mg daily
history of
non-melanoma
skin cancer)

ATBC Study 29 133(male
smokers)
Virtamo 2003
Heinonen 1998

Prostate

See also chapter 4.2.5.3 for evidence on foods containing
beta-carotene. Three RCTs9 10 16 18 26 and two cohort studies27
28
investigated beta-carotene supplements (table 4.10.4).
Two trials showed a non-significant increased risk for betacarotene supplementation compared to none9 10 16; the othershowed no effect on risk.18 Effect estimates were 1.26 (95%
CI 0.98–1.62) for the 1985 to 1993 follow-up period,16 1.01
(95% CI 0.80–1.27),9 10 and 1.0 (95% CI 0.9–1.1).18
One cohort study showed a non-significant increased risk
for beta-carotene supplementation compared to none27;
the other stated that there was no significant association.28
The single reported effect estimate was 1.17 (95% CI
0.85–1.61).27
There is no evidence for any mechanism of action.

–

5 years

1–5 years

Physicians’
22 071
Health Study(PHS)
Frieling 2000
Hennekens
1999

50 mg beta12 years
carotene taken
on alternate days

Women’s
39 876
Health Study(WHS)
Lee 1999

50 mg of beta- 2 years
carotene taken
on alternate days

4 yearssummary effect estimate of 1.00 (95% CI 0.94–1.07) for
basal cell carcinoma and 1.01 (95% CI 0.95–1.06) for squamous cell carcinoma.
The single cohort study showed a non-significant
decreased risk for beta-carotene supplementation compared
to none. The effect estimate was 0.42 (95% CI 0.12–1.47).33

Figure 4.10.2

There is strong evidence from good quality trials, andfrom cohort studies, which consistently fails todemonstrate a protective effect. Beta-carotene
supplements are unlikely to have a substantial
protective effect against prostate cancer. The evidence
is too limited to draw a conclusion on a harmful effect.

Length ofLength ofintervention follow-up

Four treatment 4.5 years
groups: daily
application ofsunscreen andbeta-carotene
supplementation(30 mg per day);sunscreen plus
placebo tablets;beta-carotene only;or placebo only

2004
22 071J U D G E M E N T S

Beta-carotene supplements andskin cancer; trials

GoodmanPhysicians’
HealthStudy (PHS)
Cook 2000

A N D

Beta-carotene supplements and nonmelanoma skin cancer; trials
Relative risk (95% CI)

Basal cell carcinoma
Greenberg 1990

1.04 (0.89–1.21)

Green 1999

1.04 (0.79–1.37)

Frieling 2000

0.99 (0.92–1.06)

Skin

Summary estimate

1.00 (0.94–1.07)

See also chapter 4.2.5.3 for evidence on foods containing
beta-carotene. Four RCTs19 29-32 and one cohort study33 investigated beta-carotene supplements (table 4.10.5).

Squamous cell carcinoma

Non-melanoma skin cancer

Three RCTs investigated non-melanoma skin cancer as an
outcome.29 31 32 Two trials showed non-significant increased
risk for beta-carotene supplementation compared tonone31 32; one trial showed a non-significant decreased risk.29
The results are shown in the forest plot, separated for basal
cell carcinoma and squamous cell carcinoma (figure 4.10.2).
Meta-analysis was possible on all three trials, giving a

186

Greenberg 1990

1.22 (0.87–1.72)

Green 1999

1.35 (0.84–2.18)

Frieling 2000

0.97 (0.84–1.13)

Summary estimate

1.01 (0.95–1.06)

0.5

1

2

Relative risk, intervention group vs control group

C H A P T E R

4•F O O D S

A N D

D R I N K S

Melanoma skin cancer

The Women’s Health Study19 and Physicians’ Health Study30
investigated melanoma skin cancer as an outcome. Bothtrials stated that there was no significant effect from betacarotene supplementation compared to none.19 30
There is no evidence for any mechanism of action.
There is strong evidence from good quality trials thatconsistently fail to show an effect. It is unlikely thatbeta-carotene has a substantial effect on the risk ofnon-melanoma skin cancer.

Figure 4.10.3

Calcium supplements and colorectal
cancer; cohort studies
Relative risk (95% CI)

Bostick 1993 Women

0.66 (0.43–1.02)

Kampman 1994

0.95 (0.50–1.79)

Wu 2002 Men

0.70 (0.43–1.14)

McCullough 2003 Men

0.60 (0.33–1.10)

McCullough 2003 Women

0.73 (0.30–1.76)

Feskanich 2004 Women

0.87 (0.69–1.11)

Lin 2005 Women

1.30 (0.90–1.87)

4.10.6.4.3 Alpha-tocopherol
Prostate
0.2

One RCT investigated alpha-tocopherol supplements andprostate cancer (table 4.10.6).16 26
The ATBC (Alpha-Tocopherol Beta-Carotene) trial was alarge RCT of male smokers given 50 mg of alpha-tocopherol
and 20 mg of beta-carotene (see table 4.10.6 for details). It
showed a statistically significant decreased risk for alpha-tocopherol supplements, with an effect estimate of 0.66 (95% CI
0.52–0.86) for use compared to non-use. Prostate cancer was
not a prior-stated outcome for this trial.16 26
Data on dietary, serum, or supplemental vitamin E oralpha-tocopherol levels were suggestive of decreased risk,
though generally not statistically significant. Data on
gamma-tocopherol provided evidence of an association withdecreased risk.
Vitamin E exists in eight different forms or isomers: four
tocopherols and four tocotrienols. There is an alpha, beta,
gamma, and delta form of each. Each form has slightly different biological properties but all are antioxidants. Alphatocopherol is thought to be the most biologically active
isomer of vitamin E. It inhibits proliferation, can directly activate certain enzymes, and exerts transcriptional control onseveral genes.34 Vitamin E has also been shown to inhibit thegrowth of human prostate tumours induced in mice.35
The evidence is sparse. There is limited evidence thatalpha-tocopherol supplements protect against prostatecancer in smokers.

0.5

1

2

5

Relative risk, highest vs lowest exposure category

4.10.6.4.4 Calcium
Colorectum

Seven cohort studies investigated calcium supplements
and colorectal cancer.36-43 Three trials44-49 and four cohort
studies50-53 investigated calcium supplements and colorectal
adenomas.
Six cohort studies showed decreased risk for calcium supplements when compared to none,36-41 43 which was statistically significant in one.40 One study showed non-significant
increased risk.42 The effect estimates can be seen in the forest plot, apart from one study which reported an effect estimate of 0.76 (95% CI 0.56–0.98) for the highest intake
group compared to the lowest (figure 4.10.3).43
Pooled analysis from 10 cohort studies (with over 534 000
participants followed up for 6 to 16 years, 4992 cases of colorectal cancer) presented results for calcium from foodsources and total calcium which includes supplements. A
larger effect was seen for total calcium (0.78, 95% CI
0.69–0.88) than for calcium from food sources (0.86, 95%
CI 0.78–0.95).54
Because of the abundant prospective data from cohort
studies, case-control studies were not summarised.
Adenomas

Table 4.10.6
Trial
name

Alpha-tocopherol supplements andprostate cancer; trials

Number of Intervention
participants

ATBC Study 29 133(male
smokers)
Virtamo 2003
Heinonen 1998

Length ofLength ofintervention follow-up

20 mg of beta- 5–8 years
carotene only orwith 50 mg ofalpha-tocopherol

6–8 years

Two RCTs showed decreased risk of adenomas with calcium
supplementation,44-48 which was statistically significant in
one.44-47 Effect estimates were 0.81 (95% CI 0.67–0.99; 1200
mg calcium; adenoma incidence)44 and 0.66 (95% CI
0.38–1.17; 4 g calcium; adenoma recurrence).48
One additional trial showed a reduced risk of new adenoma growth during a 3-year intervention of a daily mixture of beta-carotene 15 mg, vitamin C 150 mg, vitamin E
75 mg, selenium 101 µg, and calcium (1.6 g daily) as carbonate (p value 0.035), though with no statistically significant effect on the growth of pre-existing adenomas.49
Three cohort studies showed decreased risk with calcium
supplementation,50-52 which was statistically significant for
one.50 One study reported no significant association.53 Meta-

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analysis was possible on two of these studies, giving a summary effect estimate of 0.91 (95% CI 0.85–0.98) per 200
mg/day.50 52 The other study that gave quantified results
reported an effect of 0.76 (95% CI 0.42–1.38).51
Calcium is an import micronutrient and intracellular
calcium is a pervasive second messenger acting on manycellular functions, including cell growth. It has been widely
demonstrated that calcium has direct growth-restraining, anddifferentiation- and apoptosis-inducing action, on normal
and tumour colorectal cells.55
There is generally consistent evidence from several
cohort studies, and evidence from trials for colorectal
adenomas. There is evidence for plausible
mechanisms. Calcium probably protects against
colorectal cancer.
4.10.6.4.5 Selenium
Prostate

One RCT56 57 and two cohort studies27 58 investigated selenium supplements and prostate cancer (table 4.10.7).
The RCT was conducted in men with a history of skin cancers. Prostate cancer was not a prior stated outcome and wasassessed as a secondary endpoint. Out of 974 participants,
approximately half were randomised to receive 200 µg ofselenium daily. There were 13 cases of prostate cancer inthe selenium group and 35 cases in the control group, giving an effect estimate of 0.37 (95% CI 0.20–0.70) for supplement use compared to non-use, after a mean of 4.5 yearsof the intervention and a mean of 6.5 years follow-up.56 The
effect was strongest in those with the lowest levels of selenium at the start of the trial.57
Both cohort studies showed non-significant decreased risk
with selenium supplementation.27 58 Effect estimates were0.94 (95% CI 0.57–1.55)27 and 0.91 (95% CI 0.57–1.48)58
for use versus non-use.
Dietary selenium data are supportive of an effect (seechapter 4.2.5.8).
The general mechanisms through which selenium could
plausibly protect against cancer are outlined below. In addition, selenoproteins are involved in testosterone production,
which is an important regulator of both normal and abnormal prostate growth.
There is strong evidence from trials and cohort studies.
Selenium probably protects against prostate cancer.

Table 4.10.7

2

Table 4.10.8

E V I D E N C E

A N D

J U D G E M E N T S

Selenium supplements and lungcancer; trials

Trial
name

Number of Intervention
participants

Length ofLength ofintervention follow-up

NPC Trial
Reid 2002

1312
200 µgpeople with selenium
a history ofdaily (primary
non-melanoma endpoint wasskin cancers skin cancer)

Mean
4.5 years

Mean
7.9 yearsLung

One RCT investigated selenium supplements and lung cancer (table 4.10.8).59
The Nutritional Prevention of Cancer (NPC) Trial consisted of more than 1300 participants enrolled from several dermatology practices who were treated with 200 µg ofselenium. The trial showed a non-significant decreased risk
with supplementation, with an effect estimate of 0.74 (95%
CI 0.44–1.24) after a mean of 4.5 years of the intervention
and a mean of 7.9 years follow-up, adjusted for age andsmoking. Subgroup analysis indicated that this risk differedaccording to baseline plasma selenium level, with an effectestimate of 0.42 (95% CI 0.18–0.96) for those in the lowest
tertile compared to no apparent effectiveness for individuals in the higher tertiles of plasma selenium.59 This suggeststhat selenium supplementation may decrease cancer risk inthose who are deficient in dietary selenium, but that thiseffect may not extend to those whose intake of selenium is
within the recommended levels.
The general mechanisms through which selenium could
plausibly protect against cancer are outlined below.
The evidence is sparse. There is limited evidence
suggesting that selenium protects against lung cancer.
Skin

One RCT60-62 and one cohort study33 investigated selenium
supplements and skin cancer (table 4.10.9).
The Nutritional Prevention of Cancer Trial (see above)
showed a non-statistically significant increased risk of total
non-melanoma skin cancer with supplementation, with aneffect estimate of 1.18 (95% CI 0.49–2.85). Subgroup analysis showed an effect estimate of 1.14 (95% CI 0.93–1.39) for

Table 4.10.9

Selenium supplements andprostate cancer; trials•

Selenium supplements andskin cancer; trials

Trial
name

Number of Intervention
participants

Length ofLength ofintervention follow-up

Trial
name

Number of Intervention
participants

Length ofLength ofintervention follow-up

NPC Trial
Clark 1998
DuffieldLillico 2003

974 men
200 µgwith aselenium
history ofdaily (primary
non-melanoma endpoint wasskin cancers skin cancer)

Mean
4.5 years

NPC Trial
Combs 1997
Clark 1996
DuffieldLillico 2002

1312
200 µgpeople with selenium
a history ofdaily (primary
non-melanoma endpoint wasskin cancers skin cancer)

Mean
4.5 years

188

Mean
6.5 years

Mean
6.4 years

C H A P T E R

4•F O O D S

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squamous cell carcinoma and 1.10 (95% CI 0.95–1.28) for
basal cell carcinoma.61
The single cohort study stated that there was no statistically significant association.33
The evidence is sparse and no plausible mechanisms
have been identified. There is limited evidence
suggesting that selenium supplements are a cause ofskin cancer.
Colorectum

One RCT60 62 and one cohort study63 investigated selenium
supplements and colorectal cancer (table 4.10.10).
The single trial included 1312 participants who were randomised to receive 200 µg selenium or a placebo. There were
8 colorectal cancer cases in the intervention group and 19
in the control group, giving an effect estimate of 0.36 (pvalue for trend 0.025) for use versus non-use.60 A hazard
ratio of 0.46 (95% CI 0.21–1.02) is given after a further 2.5
years follow-up.62
The single cohort study showed non-significant decreased
risk, with an effect estimate of 0.60 (95% CI 0.27–1.32) for
use versus non-use.63
Dietary selenium data are supportive of an effect (seechapter 4.2.5.8).
The general mechanisms through which selenium could
plausibly protect against cancer are outlined below.
The evidence is sparse. There is limited evidence tosuggest that selenium protects against colorectal
cancer.
General mechanisms

Dietary selenium deficiency has been shown to cause a lackof selenoprotein expression. Twenty-five selenoproteins
have been identified in animals, and a number of these haveimportant anti-inflammatory and antioxidant properties.64
Four are glutathione peroxidises, which protect against
oxidative damage to lipids, lipoproteins, and DNA. These
enzymes are rapidly degraded during selenium deprivation.
Three are thioredoxin reductases and, amongst other functions, these regenerate oxidised ascorbic acid to its active
antioxidant form.
Selenoproteins appear to reach their maximal levels
relatively easily at normal dietary selenium intake andnot to increase with selenium supplementation. It is,Table 4.10.10 Selenium supplements andcolorectal cancer; trials
Trial
name

Number of Intervention
participants

Length ofLength ofintervention follow-up

NPC Trial
Combs 1997
DuffieldLillico 2002

1312
200 µgpeople with selenium
a history ofdaily (primary
non-melanoma endpoint wasskin cancers skin cancer)

Mean
4.5 years

Mean
6.4 years

however, plausible that supraphysiological amounts ofselenium might affect programmed cell death, DNA repair,carcinogen metabolism, immune system, and anti-angiogenic effects.65

4.10.7 Comparison with previous report
This Report associates nutrients and dietary constituentswith foods and drinks wherever possible; and findings andjudgements on these as contained in foods and drinks arefound in previous sections of this chapter. The previous
report included a whole chapter on dietary constituents. It
found that starch (probably when it is the staple of poverty
diets) possibly protected against colorectal cancer but waspossibly a cause of stomach cancer. The evidence from the
SLRs undertaken for this Report did not reproduce thesefindings.
The previous report noted that trials using supplements ofvarious micronutrients such as beta-carotene, vitamin E, andmultiple vitamins and minerals had produced mixed results.
But it did not make formal judgements as a result of thesetrials, although one of the report’s recommendations wasthat dietary supplements are probably unnecessary, and possibly unhelpful, for reducing cancer risk. RCTs publishedsince the mid-1990s have strengthened the evidence on therelationship of some dietary supplements and the risk of cancers of some sites.
For comparisons with the previous report concerning
dietary constituents here identified as foods (such as sugars,
fats and oils, and alcohol) or foods which contain certain
constituents (such as dietary fibre, vitamins, minerals, andtrace elements), see chapters 4.1 to 4.8.

4.10.8 Conclusions
The Panel concludes:
The evidence that the use of high-dose beta-carotene
supplements in tobacco smokers is a cause of lung cancer isconvincing. There is limited evidence suggesting that highdose retinol supplements are a cause of lung cancer inthis group. The principal cause of lung cancer is smoking
tobacco.
Calcium probably protects against colorectal cancer. At
specific doses, selenium probably protects against prostatecancer.
There is limited evidence suggesting that retinol at specificdoses protects against squamous cell carcinoma of the skin.
There is also limited evidence suggesting that alpha-tocopherol protects against prostate cancer; and also that selenium at specific doses protects against colorectal cancer (ata level of 200 µg/day, the dose used in the studies on which
this judgement is based).
There is limited evidence suggesting that selenium supplements are a cause of skin cancer. It is unlikely that betacarotene supplements, or foods containing it, have asubstantial effect on the risk of either prostate cancer or skin(non-melanoma) cancer.

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2•

E V I D E N C E

A N D

J U D G E M E N T S

4.11 Dietary patterns
The nature, quality, quantities, and proportions ofdifferent foods and drinks in diets, and the frequency withwhich they are habitually consumed, constitute dietary
patterns. Populations, communities, and families may
share similar dietary patterns, which are determined byvarious factors such as the ecological niche they inhabit,
physical environments in which they live, or by tradition,
culture, religion, or choice. Dietary patterns, as well as
patterns of physical activity, have co-evolved with humans
over millennia and are intimately related to long-term
survival of the species within a given environment. Thechanges in environment including diets and activity
patterns over the past century are likely to have affected
the risk of chronic diseases, including cancer. Indeed, theimpact of food and nutrition on health is not generally
determined by individual foods and drinks, specific dietary
constituents, or the ways in which foods are modified, forexample by processing or cooking. No food or drink is anelixir and few are poisons, unless they are contaminatedwith pathogenic micro-organisms. It is dietary patterns,
with physical activity levels and other factors that
influence nutritional requirements, that determine
nutritional status and other health outcomes that are ofinterest to this Report.
Dietary patterns are difficult to characterise and are an
infrequent subject for epidemiological and experimental
investigations which, by their reductionist approach,typically address specific foods and dietary components.
This precisely focused approach may overlook thesignificance of diets as a whole. There is now increasing
interest in the examination of the impact of dietary
patterns on well-being and disease outcomes, including
the risk of cancer.
The Panel notes that existing studies of specific dietary
patterns use different definitions and that the evidence
they have produced is unclear. Currently, given the agreed
criteria for grading evidence in this Report, no judgements
can be made on any possible relationship between dietary
patterns, as defined in the literature, and the risk ofcancer. For this reason, no matrix showing Panel
judgements is included in this section. However, anarrative summary provides an analysis of existing
evidence relating dietary patterns and cancer-related
outcomes.

190

For most populations at most times, food systems determine
dietary patterns; traditionally, these systems have themselves
been largely determined by climate and terrain. Until recently in history, diets have been mostly made up from locallyavailable plant and animal sources, as gathered, hunted,
reared, cultivated, preserved, processed, prepared, and consumed. The current dietary patterns of subsistence farmers
around the world, in East Africa, Mexico, India, and China
for instance, differ mostly not as a matter of communal orfamily choice, but because different staple crops flourish indifferent parts of the world. The same applies to communities that live near rivers, lakes, and seas: their dietary patterns are different from those of inland populations largely
because fish and seafood are available. Traditional diets inthe territories on or close to the Mediterranean littoral are
typically high in vegetables, fruits, fish, and seafood. The
dietary patterns of pastoralist populations, especially thoseliving in Arctic climates, are high in meat and animal foods.
The extreme example of imposed dietary patterns are‘poverty’ or ‘deficiency’ diets, consumed by impoverishedcommunities.
One characteristic of human civilisation is food culture: thedevelopment of dietary patterns throughout or within societies as part of general culture. It is thought that dietary patterns have acquired a cultural dimension based on the factthat they have evolved with human populations providing
advantages for survival within a given ecological setting.
Thus food cultures sometimes have become an expression ofsome system of belief.
Dietetics, in its original form as a general philosophy of
the well-led life, was developed in Greece and then later inwestern Europe (for example, by the School of Salerno, fromthe 12th century). Scholars and teachers of dietetics recommended various dietary regimes, which involved dietary
patterns selected as a matter of choice. These were often simple or frugal, and not just for personal well-being and freedom from disease, but also as an expression of virtue.1 Morerecently, people began to adopt certain dietary patterns in
the belief that these could protect against disease.
The urban–industrial food systems that generate the foods
and drinks now purchased and consumed by most people in
the world are characterised by the increased use of technology in production, manufacture, processing, distribution,and sale. Another key feature is globalisation. Spices havebeen transported from Asia to Europe for thousands of years;
sugar has been shipped around the world for half a millennium; similarly, the export of tropical fruits, meat, and tea
became subject to major intercontinental trade in the 19th
century. Very many if not most foods, or their ingredients,
now travel long distances before reaching their point of sale.
Globalised food systems are now shaping dietary patterns in
all continents.2 3This chapter summarises some of the dietary patterns thatmight modify the risk of cancer. Breastfeeding is also men-C H A P T E R

4•F O O D S

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D R I N K S

tioned here in this context. For evidence and judgement onlactation, see Chapter 6; on being breastfed in relation toweight gain, overweight, and obesity, see Chapter 8.

4.11.1 Traditional and industrial dietary
patterns
Dietary patterns are determined by many factors. This firstgroup includes some traditional and industrial dietary patterns, determined mainly by climate and terrain, material
resources, technology, and culture.
4.11.1.1 Mediterranean
The traditional food systems of the territories on or near theMediterranean littoral, in southern-most Europe, the Middle
East, and northern-most Africa, are the fount of a numberof great cuisines. These were developed by peoples, often
from the East, who settled in successive waves within what
is now Spain, southern France and Italy, former Yugoslavia,
Greece, Turkey, Cyprus, Crete, Lebanon, Israel, Palestine,
Egypt, Libya, Algeria, Tunisia, and Morocco. The Mediterranean dietary patterns that have since evolved generally have some common aspects.
Traditional Mediterranean diets are broadly characterisedby high consumption of breads and other cereal foods usually made from wheat, and of vegetables and fruits, fish,cheese, olive oil, tree nuts (almonds and walnuts), and (innon-Islamic countries) wine. Extensive use is made of many
herbs and spices. Meat is also consumed, but often only on
relatively special occasions or in small amounts in combination with other foods in everyday dishes. Coffee, drunkwith added sugar (in modern times), is the traditional hot
drink. Desserts may also be sweet but overall consumptionof sugar is low.
Since the second half of the 20th century, much attention
has been given to the ‘Mediterranean’ diet. This interest is
because of evidence associating the dietary patterns of the
populations living in this region with low incidence of coronary heart disease.4 It is usually thought that this association is causal, and that the reasons include high consumptionof fresh foods, dietary fibre, vegetables, fruits, and fish; modest consumption of alcoholic drinks; and low intakes of saturated fatty acids. In addition, historically, habitual levels ofphysical activity have been high.
Recommendations published since the early 1980s on
food, nutrition, and the prevention of cancer have similarities with those for the prevention of coronary heart disease.
Mediterranean dietary patterns might therefore also be protective against cancer, either generally or of specific sites.
Traditional Mediterranean dietary patterns are gradually
becoming less common as the food supplies of the countriesof the Mediterranean littoral become increasingly ‘western’or ‘globalised’.
4.11.1.2 Asian
Traditional Asian cuisines are very diverse. But traditional
Asian dietary patterns do have some qualities in common,
certainly those of southern and eastern Asian countries

including India, Sri Lanka, Thailand, Cambodia, Vietnam,
China, and Korea.
Such traditional Asian dietary patterns are of low energy
density. The staple cereal (grain) is usually rice, which is also
usually the main source of energy. Traditionally, rice paddy
is often also used to breed fish. The amounts of vegetables,
fruits, and fish in diets vary; consumption is relatively low
in impoverished communities, and often high in those thatare more prosperous. In the more affluent centres of civilisation, traditional Indian and Chinese cuisines have been
and often remain extremely diverse. But they are almost
always made up mainly from foods of plant origin, again
with very extensive use of herbs and spices. As in the
Mediterranean region, large amounts of meat are usuallyreserved for special occasions. Japan is a maritime nation,and so the traditional dietary pattern is high in fish andseafood and in salt and salt-preserved foods. The maritime
regions of other Asian countries have the same dietary patterns. Traditionally, most alcoholic drinks consumed in Asia
are made from grains. Most foods are cooked at low temperatures (steaming, boiling), although some high-temperature methods are also used (stir-frying, deep-frying,roasting). Tea is the traditional hot drink in China, India, Sri
Lanka, and Japan. Consumption of fat and sugars is traditionally low.
As with Mediterranean dietary patterns, and probably forbroadly the same nutritional reasons, traditional southernand eastern Asian dietary patterns are associated with relatively low rates of obesity, type 2 diabetes, coronary heartdisease, and some cancers. However, those that are high insalt are associated with elevated rates of hypertension andstroke. Traditional Asian dietary patterns remain the normin rural and impoverished regions of southern and eastern
Asia, but are now gradually becoming increasingly ‘western’or ‘globalised’ in the urban and more prosperous parts ofthese countries.
These generalisations do not apply to the countries ofnorthern Asia, including those of the former USSR.
4.11.1.3 Plant-based
Plant-based diets are mainly but not necessarily solely madeup from foods of plant origin. Characteristically, cereals(whole or minimally processed grains) and other starchy
foods, vegetables and fruits, pulses (legumes), herbs andspices, plant oils, and other foods and ingredients of plantorigin are the basis of almost all everyday foods and meals.
Meat, poultry, fish, milk and dairy products, animal fats, andother foods and ingredients of animal origin are consumed,
usually in small amounts on normal days, but often abundantly on special and feast days. Consumption of alcoholic
drinks is also usually reserved for special social occasions.
It is estimated that the dietary patterns of most of theworld’s population — perhaps around 4 billion people — areplant-based. Traditional Mediterranean and southern andeastern Asian dietary patterns (summarised above) are plantbased, as are the dietary patterns of most rural communities in middle- and low-income countries. Most populations
that consume plant-based diets do not do so from choice, but
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relatively costly. In some traditions (see chapters 4.11.1.1
and 4.11.1.2), plant-based or vegetarian diets are consumed
as an expression of philosophy of life or of religion. These
cultures, teachings, or faiths often also include periodic periods of fasting.
The nutritional profiles of plant-based dietary patterns arevery variable, depending largely on the degree of variety of
the foods consumed, though their energy density is generally low. Traditional plant-based cuisines from all over theworld combine cereals (grains) and other starchy foods withbeans and other pulses (legumes) as the staple foods. Whenfood supplies are secure they are generally adequate in energy, and also in protein, unless reliant on very low-protein
starchy staples such as cassava (manioc). Plant-based diets
may be of relatively low energy density, but not necessarily
so. Most of the fatty acids in plant-based diets are unsaturated. Levels of vitamins, minerals, trace elements, and phytochemicals vary, again depending on the degree of variety
in diets.
Obesity, type 2 diabetes, coronary heart disease, cancers
of some sites, and other chronic diseases have been rare or
uncommon in those parts of the world where traditional
dietary patterns are plant-based. Such diets are now commonly advocated and consumed by health-conscious people
in high-income countries, partly on this basis. These diets arealso increasingly popular because of the epidemiological andother evidence that components of plant-based dietary patterns are potentially protective against various chronic diseases including some cancers.
4.11.1.4 ‘Western’The dietary patterns sometimes classified as ‘western’ havebeen generated by industrialised food systems, at first in
western Europe, then in the USA. These patterns have also
evolved in countries settled mostly by British and western
European peoples, including those of the white populationsof South Africa, Australia, New Zealand, and enclaves elsewhere in the world. This broad generalisation does not apply
to some countries of Latin America, but in general represents
the emerging dominant pattern observed in urban centres of
the region.
‘Western’ dietary patterns are energy dense, and areincreasingly made up from processed foods.5 They are highin meat, milk and other dairy products, fatty or sugary foods
such as processed meats, pastries, baked goods, confectionery, sugared and often also alcoholic drinks, with variable amounts of vegetables and fruits. The starchy staple
foods are usually breads, cereal products, or potatoes. A feature of the global ‘nutrition transition’ (see chapter 1.2.1) isthat ‘western’ dietary patterns are becoming ‘exported’ globally with accelerating speed.
‘Western’ diets defined in this way are associated withoverweight and obesity, type 2 diabetes, cardiovascular disease, stroke, some cancers, and other chronic diseases.
However, the term ‘western diet’ is potentially confusing:variations of such diets consumed within ‘western’ countries
can and do have very different nutritional profiles.

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4.11.2 Cultural dietary patterns
These dietary patterns are strongly influenced by cultural
factors. These include ethical and religious beliefs, andbeliefs about health. The distinction is somewhat arbitrary:these patterns are also influenced by climate and terrain,material resources, and technology.
4.11.2.1 Vegetarian and vegan diets
Plant-based dietary patterns need not be vegetarian, except
in a loose sense; but vegetarian diets are generally plantbased. The distinction is more one of attitude than nutritional profile. Typically, vegetarians are at least as concerned
about the ethics and environmental effects of consuming(and producing) animal foods as they are with their own
well-being and protection against disease.
There are many types of vegetarian dietary patterns, andall exclude red meat and processed meat made from redmeat. However, people whose intention is to be vegetarian
may occasionally eat these meats; and many if not most willconsume some foods containing ingredients derived fromanimals that supply red meat, perhaps inadvertently.
Lacto-ovo vegetarians consume milk and dairy products
and also eggs. Vegans consume no foods of animal origin,
although some are stricter than others about what they eat.
People who avoid red meats may consume poultry and fish,
and are sometimes termed ‘semi-vegetarian’. The dietary
practices of a number of religions are plant-based or vegetarian. Hindus are often vegetarian. Jains are vegan.
Rastafarians are semi-vegetarian. Zen macrobiotic food ismostly vegetarian, although the main emphasis is on wholefoods. For Seventh-day Adventists, see chapter 4.11.5.5.
Taken together, vegetarian dietary patterns are heterogeneous, as is the nutritional profile of most types of vegetarian diets. Studies of some vegetarians have identified lower
rates of obesity and cardiovascular disease, and all-cause
mortality. But people who are the subjects of such studies inhigh-income countries, who are vegetarian as a matter ofbelief or choice, are frequently of higher socioeconomic status compared with the general population. They are also lesslikely to smoke and more likely to be physically active (alsosee chapter 4.11.5.4).
4.11.2.2 Religious
Seventh-day Adventists are a Christian denomination of
about 14 million people who, among other ways of life aspart of their faith, are sparing in their consumption of meatand meat products; about half are lacto-ovo vegetarians.
Most avoid hot condiments and spices, tea and coffee, andalcoholic drinks. Smoking is proscribed. The effect ofSeventh-day Adventist ways of life on well-being and healthhas been the subject of a large number of studies. Rates ofchronic diseases are generally lower among Adventists, andthis is usually attributed to be their generally healthy waysof life.
Several other religions enjoin their adherents to refrainfrom consumption of certain foods or beverages — for
instance, Islam forbids consumption of pork and alcohol,
Judaism pork and other foods, and Hinduism beef.

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4.11.2.3 ‘Healthy’People who are conscious of the effects of food and nutrition on well-being, and on the risk of disease, may choose
to consume ‘healthy’ diets. Such diets are featured in very
many popular television programmes, newspapers, magazines, and books. However, there are as many ‘healthy’
dietary patterns as there are concepts of what constitutes ahealthy diet; and for many people a ‘healthy’ diet is seen asa diet regime designed to reduce excess body fat. In the USA,the ‘Healthy Diet Indicator’6 and also the ‘Healthy Eating
Index’ are used to assess how well people adhere to theDietary Guidelines for Americans.

4.11.3 Other dietary patterns
4.11.3.1 Meal frequency
One hypothesis about food, nutrition, and cancer is that risk
may be modified by meal patterns. The times of day at whichfood is eaten vary greatly in different populations.
Gatherer–hunters and pastoralists often consume most of
their food once a day only, or may not eat large amounts offood every day. Settled agriculturalists may consume two
meals at different times of the day, depending on their work.
In urban settings, having three meals a day has been acommon pattern. Some may be light meals and some more
substantial, but the time of day at which each type is eaten
varies in different parts of the world, and also within countries. Some people choose to eat lighter meals or snacks more
frequently throughout the day, rather than having threemeals. A feature of globalised food supplies and other aspectsof modern cultures is the decline of the family meal; instead,an increasing amount of food is eaten alone in the form ofquick meals or snacks, in fast-food outlets, in the street, or
at home.
4.11.3.2 Breastfeeding
Being breastfed is a type of dietary pattern for infants. In fact
it is the only pattern for healthy individuals based on a single food which provides all known essential nutrients for agiven period of life. For a general summary of lactation andbreastfeeding, see chapter 6.3. For being breastfed, see
Chapter 8.

4.11.4 Interpretation of the evidence
4.11.4.1 General
For general considerations that may affect interpretation of
the evidence, see chapters 3.3 and 3.5, and boxes 3.1, 3.2,
3.6 and 3.7.
‘Relative risk’ (RR) is used in this Report to denote ratio
measures of effect, including ‘risk ratios’, ‘rate ratios’, ‘hazard ratios’, and ‘odds ratios’.
4.11.4.2 SpecificClassification. A major limitation with most studies of dietary
patterns is that there is no general agreement on just what
constitutes any dietary pattern. For example, ‘healthy’ diets

vary substantially; different types of diets are termed ‘vegetarian’; and there are various types of ‘Mediterranean’ diet.
In general, there is considerable scope for variation within
any dietary pattern.
Confounding. Patterns of diet are interrelated with otherhabitual behaviour that may affect the risk of cancer, suchas smoking or physical activity; people who habitually consume any type of diet for the sake of their health or for reasons of belief, may also modify other aspects of their way oflife. This is likely to confound results that appear to show
associations with the risk of cancer.
Study design. The analysis of conventional epidemiologicalstudies tends to focus on specific foods and drinks and specific aspects of diets, rather than the overall pattern.
Reporting bias. People who habitually consume or who try

to follow types of diets in the belief that these are healthy
may, in studies relying on self-reporting, provide inaccurate
records. They may overestimate their consumption of foods
like vegetables, fruits, and other foods they believe to behealthy, and underestimate or fail to report consumption offoods and drinks they believe to be unhealthy. This type ofreporting bias is a general issue with studies relying on selfreporting, but may be a special issue here. Studies of
specific dietary patterns undertaken by scientists who themselves follow these patterns may be seen as biased for thisreason.

4.11.5 Evidence and judgements
Epidemiological research concerned with food, nutrition, andthe risk of cancer, characteristically examines individual
foods and dietary constituents.
There is a growing body of epidemiological work on
dietary patterns; these were within the terms of reference ofthe systematic literature reviews (SLRs) whose findings are
the primary basis for the Panel judgements in this Report.
However, the evidence on dietary patterns examined in thisway, relative to cancers of individual sites, does not permit
conclusions to be drawn and the Panel decided not to makeany judgements. Also see chapter 4.11.4.2.
In the case of dietary patterns, evidence from the SLRs has
been supplemented by an informal narrative literature
review, and the results are summarised here.
The full SLR is contained on the CD included with thisReport.
4.11.5.1 Mediterranean dietary patterns
In a Swedish cohort study, a 2-point increase in a‘Mediterranean’ diet score was associated with a 16% (95%
confidence interval (CI) 1%–29%) reduced risk of cancer
mortality in women aged 40–49, but not among younger
women.7
An intervention trial investigated the recurrence of colorectal adenomas. This showed that the ‘Mediterranean’ diet(characterised by high consumption of vegetables, fruit, lean

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meat, fish, and olive oil) was associated with a reduced riskof recurrence of colorectal adenomas in women (RR 0.30
(95% CI 0.09–0.98), but not in men. 8
4.11.5.2 Asian dietary patterns
A Japanese cohort study9 showed significant associations
between certain dietary patterns and the risk of stomach cancer. These were for a ‘traditional’ Japanese dietary pattern
in men (RR 2.88, 95% CI 1.76–4.72) and in women (RR
2.40, 95% CI 1.76–4.72); and for a ‘healthy’ dietary pattern
in women (RR 0.56, 95% CI 0.32–0.96) but not in men.
There was no association found with the ‘western’ dietary
pattern. In the same Japanese cohort,10 ‘traditional’ and‘western’ dietary patterns were both positively associatedwith colon cancer risk in women, but not in men: ‘traditional’
RR 2.06 (95% CI 1.10–3.84) and ‘western’ RR 2.06 (95% CI
1.10–4.45).
The narrative review did not identify any other studies on
Asian dietary patterns and the risk of cancer.
For evidence and judgements on salt, salting, and salted
food, and the risk of stomach cancer, see chapter 4.6 andchapter 7.5.
4.11.5.3 ‘Western’ dietary patterns
The narrative review identified several studies that have useddata from large cohorts, mostly undertaken in the USA, toderive various types of ‘western’ dietary patterns fromdietary intake information. This is done by combining key
components of diets into what is then identified as types of
dietary pattern that may be related to the risk of cancer risk.
Some case-control and ecological studies have also been carried out.
Analysis of data from the Health Professionals Follow-Up
Study found no association between a ‘western’ dietary pattern and prostate cancer risk. In the study, this pattern wascharacterised as being high in refined cereals (grains), redand processed meats, fat, and sweets.11 Similarly, for breast
cancer, another large cohort study reported no association
between a ‘western’ dietary pattern and breast cancer risk.12
A ‘drinker’ dietary pattern, characterised as being high inbeer, wine, and spirits, was identified as being associatedwith a moderately increased risk of breast cancer (RR 1.27,
95% CI 1.06–1.52).
A case-control study from Uruguay reported an association
with increased breast cancer risk and a ‘western’ diet; associations with decreased risk were found for ‘traditional’,‘stew’, and ‘healthy’ dietary patterns.13 Another case-control
study from Uruguay reported an association with increased
stomach cancer risk and a ‘starchy’ pattern; associations withdecreased risk were found for ‘healthy’ and ‘mixed’ patterns.14
A Swedish case-control study found that a diet high inmeat, red meat, high-fat dairy products, high-fat gravy, andsweets was significantly associated with increased risk of gastric cardia adenocarcinoma and oesophageal adenocarcinoma. It also found that a ‘drinker’ pattern (high intakes ofbeer, spirits/liquor, and French fries) was significantly associated with the risk of squamous cell carcinoma of theoesophagus.15
One of the first studies to investigate diet and cancer using

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factor analysis was a Japanese study looking at gallbladder/biliary tract cancer mortality using data collected
between 1958 and 1975.16 Western-style diets high in foods
with high levels of fats and proteins were associated withdecreased risk. For breast cancer mortality in Japan, another ecological study found that westernised diets high in bothanimal and saturated fats were associated with increased
risk.17
Another Japanese cohort study showed no association
between a western dietary pattern and stomach cancer risk.9
For colon cancer risk in the same Japanese cohort, ‘western’as well as ‘traditional’ dietary patterns were associated withincreased colon cancer risk in women, RR 2.06 (95% CI
1.10–3.84) and RR 2.06 (95% CI 1.10–4.45) respectively,
but not in men.10
Three dietary patterns were identified from analysis of a
Swedish cohort: ‘healthy’, including wholegrains, vegetables,
fruits, tomatoes, poultry, and fish; ‘western’, including
refined grains, fried potato, meat, processed meat, high-fat
dairy products, margarine/butter, sweets and soft drinks;and ‘drinker’, including beer, wine, spirits, and snacks. The
only pattern significantly associated with increased risk ofrenal cell carcinoma was the ‘drinker’ pattern (RR 0.56, 95%
CI 0.34–0.95).18
An analysis of the Nurses’ Health Study cohort also
showed no evidence of an association between breast cancer risk and either a ‘prudent’ or a ‘western’ dietary pattern.19
Similarly, no associations were reported between these
dietary patterns and pancreatic cancer in a US cohort study.20
Two ‘western’ dietary patterns were identified from a US
cohort. These were a ‘prudent’ type, characterised as being
high in wholegrains, vegetables, fruits, low-fat dairy products, poultry, and fish; and a ‘typical’ type, characterised as
being high in refined cereals (grains), red and processedmeats, high-fat dairy products, sweets, and desserts. Neither
was associated with overall breast cancer risk. However,
the typical western pattern was associated with higher riskof breast cancer among smokers (RR 1.44, 95%
CI 1.02–2.03).21
A Canadian case-control study identified an association
between prostate cancer risk and a ‘processed’ dietary pattern, characterised as being high in refined cereals (grains),
white bread, onions and tomatoes, red meat, processed meat,organ meats, vegetable oil and juice, soft drinks, and bottled
water. No significant associations were found with ‘healthyliving’, ‘traditional western’, or ‘beverages’ patterns.22
A case-control study conducted in central Italy identified
a ‘vitamin-rich’ as well as a ‘traditional’ dietary pattern; bothwere strongly associated with decreased risk of stomach
cancer.23
For colon cancer, a case-control study reported a protective effect of a ‘prudent’ western dietary pattern andincreased risk with a ‘typical’ western pattern.24 Anotherreported a protective effect of a western ‘physical activity’
pattern.25
Analysis of data from the French European Prospective
Investigation into Cancer and Nutrition (EPIC) cohort
showed a significant association between two ‘western’dietary patterns and increased risk of colorectal cancer. The

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first, RR 1.39 (95% CI 1.00–1.94), included cereal products,
potatoes, processed meat, eggs, cheese, butter, sweets, cakes,
pizzas and pies, and sandwiches. The second was a ‘drinker’
pattern, RR 1.42 (95% CI 1.10–1.83), including processed
meat, alcoholic beverages, sandwiches, and snacks. A ‘meateater’ pattern, including meat, poultry, and margarine, wasnon-significantly associated with increased risk of colorectal
cancer, RR 1.58 (95% CI 0.98–2.53).26
In an Italian cohort study, four dietary patterns were identified: ‘western’, ‘canteen’, ‘prudent’, and ‘salad vegetables’.
The ‘salad vegetables’ pattern was associated with lower riskof breast cancer, (RR 0.66, 95% CI 0.47–0.95).27 Another US
cohort study reported no association between either a‘vegetable–fish/poultry–fruit’ or a ‘beef/pork–starch’ pattern
and postmenopausal breast cancer. But it found a significant
association with decreased risk of invasive breast cancer anda ‘traditional southern’ pattern, including legumes, salad,and a low intake of mayonnaise salad dressing (RR 0.78,
95% CI 0.65–0.95).28
In the Netherlands Cohort Study on Diet and Cancer, factor analysis identified five types of western dietary patterns.
Both the ‘salad vegetables’ and the ‘sweet foods’ patterns
were associated with decreased risk of lung cancer: RR 0.75
(95% CI 0.55–1.01) and RR 0.62 (95% CI 0.43–0.89),
respectively. The other three patterns were not significantly
associated with lung cancer risk. These were ‘pork, processedmeats, and potatoes’, ‘brown for white bread substitution’,and ‘cooked vegetables’.29
One study found that associations between dietary patterns and colorectal cancer were not consistent acrossEuropean countries. As part of the Dietary Patterns andCancer (DIETSCAN) project, factor analysis of three
European cohorts identified five dietary patterns. Two ofthese, ‘vegetables’ and ‘pork, processed meats, and potatoes’,
were common across all three cohorts. The second dietary
pattern was associated with increased risk of colon cancer
in one cohort of women (RR 1.62, 95% CI 1.12–2.34), andwith increased risk of rectal cancer in one cohort of men (RR
2.21, 95% CI 1.07–4.57). Neither pattern was associatedwith the risk of colorectal cancer in the third cohort.30
For thyroid cancer, a case-control study showed that various western dietary patterns of ‘fruits’, ‘raw vegetables’, and‘mixed raw vegetables and fruits’ were associated with
reduced risk of thyroid cancer (RR 0.68, 0.71, and 0.73,
respectively). However, a pattern of ‘fish and cooked vegetables’ was associated with an increased risk (RR 2.79).31
Another case-control study showed that a ‘dessert’ pattern
and a ‘beef’ pattern were associated with increased risk ofkidney cancer. A ‘juices’ factor was associated with increased
risk of this cancer in men and an ‘unhealthy’ pattern withincreased risk in women.32
One case-control study from Uruguay reported an association with increased risk of oral and pharyngeal cancers anda ‘stew’ pattern, characterised by cooked vegetables, potatoand sweet potato, and boiled meat. It also found a decreased
risk of these cancers associated with a ‘vegetables and fruits’
pattern, characterised by raw vegetables, citrus fruits, otherfruits, liver, fish, and desserts.33
A case-control study of pancreatic cancer risk showed noassociation with ‘western’ and western ‘drinker’ patterns, but
an association with decreased risk and a ‘fruits and vegetables’ pattern.34
A Canadian case-control study found that four dietary patterns were associated with increased risk of kidney cancer:a ‘dessert’ pattern in both men and women; a ‘beef’ pattern
and a ‘juices’ pattern in men; and an ‘unhealthy’ pattern
among women.
4.11.5.4 Vegetarian dietary patterns
The narrative review identified several studies that haveinvestigated the relationship between vegetarian diets andthe risk of cancer. These often did not adjust for potentiallyconfounding factors. One study found that when adjusted forage only, women who said they consumed vegetarian diets
seemed to increase the risk of breast cancer (1.65, 95% CI
1.01–2.7) (vegetarian versus non-vegetarian).35
Plausible biological mechanisms have been identified bywhich vegetarian diets might specifically reduce the risk ofcancers of the colon, breast, and prostate (also see chapter
4.2). Any effect of vegetarian diets is likely to be due not only
to the exclusion of meat, but also to the inclusion of a larger number and wider range of plant foods, containing an
extensive variety of potential cancer-preventive substances.
4.11.5.5 Seventh-day Adventist diets
The SLRs identified a number of cohort studies on the relationship between Seventh-day Adventist diets — and also
general ways of life — and the risk of cancer. Two investigated oesophageal cancer,36 37 seven stomach cancer,37-43 two
kidney cancer,37 42 one breast cancer44 and three prostate cancer.37 41 45 For oesophageal, kidney, breast and prostatecancer, results were mixed and usually not statistically significant, although they were slightly suggestive of reducedrisk.
For stomach cancer, meta-analysis of five cohort studies37-40
42
gave a summary effect estimate of 0.60 (95% CI
0.44–0.80), with low heterogeneity, with non-included studies also reporting reduced risks. None of the studies thatreported reduced risk was adjusted for known confounding
factors such as smoking.
As not smoking is a feature of Seventh-day Adventism, thePanel concluded that data on the dietary patterns associatedwith this faith are limited and no conclusion can be reached
for any cancer site.
No conclusions can be based on this evidence, because thedata are too limited and not comparable across studies.
4.11.5.6 Meal frequency
The SLRs identified 20 case-control studies46-65 that investigated irregular eating and stomach cancer. All but 1 reported increased risk estimates and 15 were statisticallysignificant. Meta-analysis of 16 case-control studies50-65 gavea summary effect estimate of 2.76 (95% CI 2.10–3.64) for
irregular as opposed to regular eating (p < 0.001), but withhigh heterogeneity.
However, the reference period was generally some years
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meals. But none of these studies defined ‘irregular eating’ orquantified the frequency with which meals might beskipped.
Eight case-control studies investigated meal frequency andcolorectal cancer.66-80 Most showed increased risks withincreased frequency of meals. Meta-analysis of 11 estimatesfrom 7 of these studies67-69 76 78-80 gave a summary effect estimate of 1.10 (95% CI 1.02–1.19), with high heterogeneity.
This evidence is also unclear. No cohort studies have been
identified as examining meal frequency. People who havestomach or colorectal problems are likely to eat irregularly.
There is also high probability of confounding, as regular eating patterns are associated with generally healthy behaviour.
The significance of these findings on meal frequency andstomach and colorectal cancer is unclear, in part because of
the high probability of confounding. For this reason, no
judgement is made.
4.11.5.7 Being breastfed
The SLRs produced no evidence on any relationship between
having been breastfed and the risk of cancer in adult life.
However, the reviews did produce evidence on the relationship between lactation and cancer in women, and also
between having been breastfed and the risk of overweight
and obesity in childhood and thereafter. See chapters 6.3.3
and 8.8.3.

4.11.6 Comparison with previous report
The previous report reviewed evidence on vegetarian andmostly-vegetarian dietary patterns of various types, including Seventh-day Adventist and macrobiotic diets. The reportconcluded that various types of vegetarian dietary patternseem to decrease the incidence of cancer in general, as well
as of some specific sites. It also concluded that semi-vegetarian diets that include small amounts of meat and foodsof animal origin may also be beneficial. This conclusion was
not made as a formal judgement.
The previous report identified ‘poverty’ or ‘deficiency’ patterns of diet. These are monotonous, very high in refinedcereal foods (such as rice), with only small amounts of otherfoods. This was partly in response to its finding that refinedcereals (grains) were a possible cause of oesophageal cancer and that starch was a possible cause of stomach cancer.
In explanation, the panel responsible for that report concluded that any increase in the risk of cancer here was likely to be caused by poverty/deficiency dietary patterns, notby the specific food or dietary constituent.
The first recommendation of the previous report was ineffect for: ‘nutritionally adequate and varied diets, based primarily on foods of plant origin’. This was based partly on theevidently protective effects of vegetables and fruits, and also
on the general balance of evidence. The panel emphasisedthat ‘plant-based diets’ do and may include relatively modest amounts of foods of animal origin.

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4.11.7 Conclusions
The Panel concludes:
Currently, no firm judgements can be made on any possible
relationship between dietary patterns and the risk of cancer.

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5Physical activity
Physical activity is any form of movement using skeletal
muscles. Until very recently in history, people necessarily
engaged in regular, moderate, and at least occasional
vigorous, physical activity. However, with urbanisation andindustrialisation, general levels of physical activity havedeclined. Machines now do most of the work previously
done by hand; driving and using public transport havelargely replaced walking and cycling. While people inhigher income countries and in urban settings in mostcountries may engage in some active forms of recreation,
they remain largely inactive, and many spend much timein sedentary recreations, such as watching television andusing home computers.
In general, the Panel judges that the evidence on
physical activity and the risk of cancer, which has
continued to accumulate since the early 1990s, shows orsuggests that regular, sustained physical activity protects
against cancers of some sites. These include colon cancer
and female hormone-related cancers, independently ofother factors such as body fatness.
The Panel judges as follows. The evidence that physicalactivity protects against colon cancer is convincing.
Physical activity probably protects against postmenopausal
breast cancer; the evidence suggesting that it protects
against premenopausal breast cancer is limited. Physicalactivity probably protects against cancer of theendometrium. The evidence suggesting that physicalactivity protects against cancers of the lung and pancreas
is limited.
The Panel is impressed by the overall consistency of theevidence and concludes that relatively high levels ofphysical activity protect, or may protect, against cancers of
the colon, breast (postmenopause), and endometrium. To
prevent these cancers, the overall evidence supports themessage that the more physically active people are thebetter; however, this excludes extreme levels of activity.
The Panel also agrees that since physical activity protects
against overweight, weight gain, and obesity, it also
protects against cancers for which the risk is increased bythese factors (see Chapter 8).
The evidence assembled for this Report gives an accountof the beneficial effects of higher compared to lower levelsof physical activity. However, the Panel further agrees thatthe evidence can equally be interpreted as showing thatsedentary ways of life increase or may increase the risk ofthese cancers. Most people in urbanised, industrialised,198

and mechanised settings throughout the world now leadthese sedentary ways of life.
Finally, the Panel agrees that the evidence assembled andjudged in this chapter supports the general hypothesis thatpeople have evolved and adapted to be physically active
throughout life. The Panel also agrees, therefore, thatsedentary ways of life are unhealthy. It is aware of current
trends and also projections (summarised in Chapter 1)
showing that average physical activity levels arecontinuing to decrease throughout the world.
Within the remit of this Report, the strongest evidence,corresponding to judgements of ‘convincing’ and‘probable’, shows that physical activity of all types protects
against cancers of the colon, and also of the breast(postmenopause) and endometrium.
This chapter does not address the social orenvironmental (or underlying and basic) determinants ofphysical activity and its general decline; this is the subjectof an associated report to be published in late 2008.

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5•

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A C T I V I T Y

PHYSICAL ACTIVITY, AND THE RISK OF CANCER
In the judgement of the Panel, physical activity1 modifies the risk of thefollowing cancers. Judgements are graded according to the strength ofthe evidence.

DECREASES RISKINCREASES RISK

2Convincing

Colon

Probable

Breast(postmenopause)
Endometrium

Limited —suggestive

Lung
Pancreas
Breast (premenopause)

Substantial
effect on risk
unlikely12None identified

Physical activity of all types: occupational, household, transport,
and recreational.
Much of the evidence reviewed grouped colon cancer and rectal cancer
together as ‘colorectal’ cancer. The Panel judges that the evidence isstronger for colon than for rectum.

For an explanation of the terms used in the matrix,
please see chapter 3.5.1, the text of this chapter,and the glossary.

Since the emergence of Homo sapiens around 250 000 years
ago, and until very recently in history, people have usually
been regularly physically active from early childhood
throughout life unless prevented by disability or infirmity.
Gatherer–hunter (and pastoral) and peasant–agriculturalcommunities have to be physically active to sustain theirways of life. This includes building and maintaining
dwellings; raising families; seeking food security and feeding infants, dependants, the disabled, and elders; and travelling to find water, game, precious items, and better land.
Walking, as well as activities undertaken with hand tools
such as gathering, hunting, growing, harvesting, grinding,cooking, cleaning, building, and fighting, all require a regular and substantial amount of energy from food.
Throughout history, manual workers in and around cities
have also been physically active, by the nature of their occupations. These range from those who built pyramids in
Egypt, Mexico, and elsewhere, and fortifications in Asia,
Latin America, and Europe, to the working-class labourersof industrialised countries. Such labourers built houses,
sewers, bridges, canals, railways, roads, served in armies andnavies, and worked in mines and factories, ‘by the sweat of
their brow’, and still do so, throughout the world.
In modern times, the story of urbanisation and of industrialisation is one in which machines are increasingly used

to do the work previously done by hand. Early factory andfarm machinery still involved sustained, moderate or vigorous physical activity, as did housework; and most people
walked or (later) cycled to work. In the first half of the 20th
century, most occupations in high-income countries required
physical activity and only a minority of households ownedcars or televisions. In middle- and low-income countries atthat time, almost all occupations were physically active.
In the second half of the 20th century this all began tochange, at first gradually and then more rapidly. Now, at the
beginning of the 21st century, most occupations in urban
areas throughout the world are sedentary. Household tasks
are mostly mechanised; much food is purchased already prepared; most journeys (even short ones) are made by car or
public transport; and for young people, television viewing
and the use of computers have often largely replaced active
recreation.
In public health terms, given the known benefits of regular, sustained physical activity, this shift in whole populations
from being active to sedentary is one of the most ominous
phenomena of recent decades. This is not confined to highincome countries or urban areas. The ways of life of mostpeople in most countries are now sedentary, with the major
exception of peasant farmers and manual labourers, mostly
in Asia and Africa but also elsewhere.
General levels of physical activity in high-income countries, and more recently in most other countries, have
dropped and continue to drop. It is in this special context
that the Panel commissioned systematic literature reviews(SLRs) of the primary evidence on physical activity andcancer.

5.1 Definitions
Physical activity is any movement using skeletal muscles. For
people with sedentary ways of life, light physical activity
includes standing, walking around an office or home, andshopping and food preparation. Recreation time may involve
light, moderate, or vigorous physical activity depending on
the nature and intensity of activities, hobbies, and pursuits.
Most people with active ways of life are moderately or vigorously physically active at work (manual labour) or at home
(household work by hand), and are moderately physically
active in transport (walking, riding, and cycling). People
with sedentary occupations can be as physically active as
people engaged in manual labour, but usually only if they
engage in regular moderate and occasional vigorous physical activity away from work.1
Sitting, standing, and other light physical activity intrinsic to normal waking life, such as stretching, fidgeting, andmaintaining posture, are all forms of physical activity.
Exercise and other forms of physical training are types ofrecreational physical activity. These may be aerobic, such as

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running, cycling, dancing, and other activities that increase
oxygen uptake and improve cardiovascular function, among
other things; or anaerobic, such as resistance training using
weights, which increases muscle strength and mass.1
Physical activity increases energy expenditure and so is afactor in energy balance (see chapter 8.3.3). The intensityof physical activity can be categorised according to thedegree to which it increases energy expenditure above basal
metabolism. A table showing the intensity of physical activity involved in different forms of movement is included in
Chapter 12.

5.2 Types and levels of physical activity
5.2.1 Types of physical activity
Conventionally, and for the purposes of this Report, overall
physical activity is classified into four types. These are:• Occupational (at work)• Household (in the home)• Transport (such as travelling to and from work)• Recreational (leisure).

2•

E V I D E N C E

A N D

J U D G E M E N T S

ical activity as they do in 30 minutes of moderate activity
or 20 minutes of vigorous activity.
5.2.2 Levels of physical activity
For many years, planners responsible for keeping specified
population groups (such as builders, soldiers, schoolchildren, or office workers) healthy and productive have compiled
estimates of the food or energy needed by these groups. Suchestimates consistently show that some people need almost
as much energy from food for physical activity as they dofor the basic functions of vital organs and the assimilationof food. These are people who are moderately physically
active for roughly half of their waking day, are engaged inlight work or sitting or resting for most of the rest of theirwaking hours, and are occasionally vigorously physically
active.4
In physically active populations where energy from foodis not freely available, people tend to be lean, and also small.
Below critical levels, as has been observed in Asia and inEurope, food scarcity makes regular, sustained physical work
difficult and even impossible.5 6
5.2.2.1 Energy costs of ways of life

Much of the evidence summarised and judged below uses
these classifications. They also highlight differences between
various ways of life. Populations and communities where
physical activity at work and at home depends on hand tools
and walking (or riding or cycling) are overall physically
active or very active, even without recreational activity.
Conversely, people whose ways of life at work and at homeare sedentary, and who use mechanised transport, will beoverall sedentary, unless they engage in substantial amountsof moderate and perhaps some vigorous physical recreational
activity away from work. In general, in high-income countries recreational activity accounts for a greater proportionof an overall lower level of physical activity.2
Physical activity can also be classified by intensity: vigorous, moderate, light, or sedentary (see boxes 5.1 and 5.2).
It is the combination of frequency, intensity, and durationthat determines total physical activity levels. A person may
use the same total amount of energy in 1 hour of light phys-Box 5.1

Energy cost and intensity of activity

The total amount of energy a person uses
during a particular activity is determinedby a combination of the duration andintensity of the activity. Metabolic equivalents (METs) describe intensity relative to aperson’s resting metabolic rate. The energy costs of any particular activity vary,depending on a person’s basal energy
expenditure and their age, sex, size, skill,and level of fitness. MET values take thesefactors into account.
High total energy expenditure can beproduced by performing low-intensity
activity for a long duration or high-inten-

200

The energy requirements of healthy adults are determinedlargely by their habitual physical activity levels (PALs). PALs
are the ratio of a person’s daily total energy expenditure(TEE) to their basal energy expenditure, and thus take into
account the greater energy required for performing the sametask with a higher body mass.2 7
A sustained PAL of 1.2 corresponds roughly to a bedridden state. People whose occupations are exceptionally active,
such as miners, woodcutters, soldiers, and athletes, may
need more energy for physical activity than for their basic
functions. This translates into habitual PALs above 2.0. Suchunusual people are mostly young adults, and these levels ofphysical activity are not sustained throughout life. PALs
above 2.4 can only be sustained over a long period of timeby unusually physically fit people. Also see Chapter 12.
In general, in high-income countries in the first decade of
the 21st century, average levels of physical activity usuallyaccount for about 20 to 30 per cent of TEE, but for extreme-sity activity for a shorter duration.
However, these two different types ofactivity may have different physiologicaleffects. The intensity of physical activity istherefore sometimes stratified into levels,
such as vigorous (≥ 6 METs), moderate(3–5.9 METs), or light (<3 METs). METs canbe used to describe the intensity of single
activities, equivalent to the physical activity ratio (PAR), or the overall level of activity over a day, equivalent to the physicalactivity level (PAL).
Vigorous physical activity can also be
defined as that which increases heart andbreathing rates up to 80 per cent or moreof their maximum (the point at whichanaerobic metabolism is needed to provide
energy). Moderate physical activity increases heart rate to around 60–75 per cent of
its maximum (and the energy requirement
can usually be met by aerobic metabolism
using the body’s stores of glycogen andthen fats). Light physical activity has only
minor effects on heart and breathing
rates. Sedentary activity (or inactivity)
involves no noticeable effort: heart andbreathing rates are not raised perceptibly
above ‘resting’ levels.3 Also see 5.2.2.1.

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Box 5.2

5•

P H Y S I C A L

A C T I V I T Y

Sedentary ways of life

The evidence judged in this chapter showsthat higher rather than lower levels ofphysical activity protect, or may protect,against a number of cancers. Most studiesof physical activity are carried out in highincome countries with low average levelsof occupational, household, and transportphysical activity (characterised as sedentary
ways of life).
What are now regarded as high levels ofphysical activity in urbanised and industrialised settings correspond roughly to what
were average levels of physical activity inmost (including high-income) countries
until well into the second half of the 20th

century.4 Since then, occupations havegenerally become more sedentary:
machines do more household work; more
people drive or ride in cars or buses thancycle or walk; and for children as well as
adults, active recreation has been largely
replaced by watching television or othersedentary pursuits.
This Report has a global perspective, and
the Panel agrees that the evidence assessedin this chapter can, with equal validity, be
judged inversely. This means that relatively low levels of physical activity — as now
typical in high-income countries and in
urban–industrial settings in all continents

ly sedentary people this may be as little as 15 per cent.2 8 9
See box 5.2.
The combined contribution of multiple types of physicalactivity can also be characterised in terms of metabolic equivalent (MET)-hours. METs are usually converted to MET-hours
per day or per week, which are calculated as the sum of the
MET level for each activity multiplied by the duration theactivity was performed.

5.3 Interpretation of the evidence
5.3.1 General
For general considerations, see chapters 3.3 and 3.5 andboxes 3.1, 3.2, 3.6, and 3.7. Relative risk (RR) is used in thisReport to denote ratio measures of effect, including risk
ratios, rate ratios, hazard ratios, and odds ratios.
5.3.2 SpecificSome considerations specific to physical activity are as
follows.
Patterns and ranges. Large studies of physical activity aremainly undertaken in high-income countries. Such studies
tend to pay most attention to voluntary recreational activity
and may therefore have limited relevance to populations inlower-income countries. In these countries, overall activity
levels may be higher and physical activity is mostly of thetype classed as occupational, household, or transport.
The evidence summarised in section 5.4 of this chapter
generally suggests that the more physically active people are,the better, but with one cautionary note. At levels well above
what people at any level of fitness are accustomed to, andwell above the ranges reviewed in this Report, vigorous physical activity has a suppressive effect on immune function. Thisnot only increases vulnerability to infectious agents but also
to DNA damage. Also see chapter 2.4.1.3.
Classification. There is currently no generally agreed clas-

and most countries throughout the world— are or may be a cause of cancers of thecolon, breast (postmenopause), andendometrium. Also, these low levels are, or
may be, a cause of weight gain, overweight, or obesity, which themselves arecauses of some cancers. The evidence
judged in this chapter supports the general theory that the human species has
evolved and adapted to be physically
active throughout life, and therefore thatsedentary ways of life are unhealthy.
Evidence that sedentary ways of life
increase the risk of diseases other than cancer is summarised in Chapters 8 and 10.

sification of different levels of overall physical activity, withquantified degrees of activity corresponding to terms such as‘active’ and ‘sedentary’.
Measurement. Physical activity is rarely measured precisely. Ideally, studies would record the frequency, intensity, andduration of people’s physical activity over an extended period— day and night. But studies are generally not designed toobtain this information. Objective measures such as pedometers and microcomputer sensors are not often used in large
studies. Instead, questionnaires are most frequently used.
Terminology. Analysis of studies shows that what is meantby and included as ‘physical activity’ varies.
Study design. Different methods of measuring physicalactivity are reported in the literature, making comparison
between studies difficult.
Confounding. In high-income countries, people who arephysically active also tend to be health conscious and so, forexample, are more likely to be non-smokers and to choose
diets they believe to be healthy. This may confound findingsthat show associations with the risk of cancer.
Reporting bias. Questionnaires measure some forms of phys-

ical activity more accurately than others. Thus, people tend
to recall vigorous and recreational, and other voluntary activities, with relative accuracy. However, these activities are generally performed for relatively short periods of time and may
amount to a smaller than perceived proportion of a person’s
total physical activity.

5.4 Evidence and judgements
Studies examining physical activity and cancer were included in the SLRs. There is evidence, both epidemiological andmechanistic, that physical activity may protect against cancer

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Figure 5.4.1

Total physical activity and colorectal cancer;
cohort studies
Relative risk (95% CI)

Wu 1987 Men

0.89 (0.50–1.59)

Wu 1987 Women

0.40 (0.20–0.80)

Lee 1991 Men

1.02 (0.65–1.60)

Thune 1996 Men <45 yrs

2.23 (0.88–5.66)

Thune 1996 Women <45 yrs

0.62 (0.31–1.24)

Thune 1996 Men ≥45 yrs

0.66 (0.40–1.09)

Thune 1996 Women ≥45 yrs

0.66 (0.33–1.33)

Pietinen 1999 Men

0.47 (0.31–0.71)

Schoen 1999

0.80 (0.43–1.50)

Nilsen 2001 Men

0.54 (0.37–0.79)

Nilsen 2001 Women

0.81 (0.54–1.22)

0.2

0.5

1

2

5

Relative risk, highest vs lowest exposure category

in general. Large studies carried out in the USA have shownthat physical inactivity is associated with higher overall cancer incidence and mortality.10-12 These studies are supported by studies on animals.13 Mechanistic reasons why
physical activity may protect against cancer (or why sedentary living may promote cancer) include healthier levels of
circulating hormones and the ability of the more active bodyto consume more food and nutrients without gaining weight(see Chapter 2). Mechanisms by which physical activity may
protect against colorectal cancer and female hormone-related cancers are summarised in the following sections.
Evidence from the literature on physical activity and cancer in general indicates that the relationship between physical activity and health is continuous: that is, there does notappear to be a threshold below or above which no effect isfound.14 15 This implies that, in general, the more physically active people are, the better, within the range examined.
The Panel agrees that this general judgment is supported by
the evidence on physical activity and cancer, which is summarised, assessed, and judged below.
The full SLRs are contained on the CD included with thisReport.
5.4.1 Colorectal
Eleven cohort studies investigated total physical activity andcolon or colorectal cancer.16-26 Twelve cohort studies investigated occupational physical activity21 25 27-36 and 24 investigated recreational activity.10 17 21 25-27 29 30 34 37-51 Five cohort
studies investigated frequency of physical activity,10 16 26 50 52
and seven investigated intensity of physical activity.22 26 34 37
46 51 53
Case-control studies that investigated physical activity can be found in the full SLRs. Also see chapter 7.9.
Total physical activity

Of the 11 cohort studies considered, 816-22 26 reported

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2

•

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decreased risk for the highest physical activity groups whencompared to the lowest. This was significant overall in threestudies17-19 and in two additional studies in men but not in
women.16 26 One cohort study reported non-significant
increased risk for the lowest physical activity groups whencompared to the highest.25 Meta-analysis was not possible onthese studies due to the heterogeneity with which physicalactivity was measured. Six studies were included in a highest
versus lowest analysis, shown in figure 5.4.1. Three studies
investigated cancer of the rectum, with mixed results.17 18 21
Occupational

Of the 12 cohort studies considered, 6 compared highest to
lowest occupational activity groups.21 25 27-30 All reported
decreased risk, which was significant in two27 30 and borderline significant in one.25 Six cohort studies comparedsedentary occupational activity to high occupational activity31-36 and all reported increased risk for sedentary activity.
This was significant in three studies.32 33 35 Five studies thatinvestigated colorectal cancer are included in a highest versus lowest plot, shown in figure 5.4.2. Five studies that investigated rectal cancer are examined in a separate highest
versus lowest plot, shown in figure 5.4.3.
Recreational

Of the 24 cohort studies considered, 22 compared highest
to lowest physical activity groups. All but two of these studies reported decreased risk, which was significant in sevenstudies.21 25 26 30 38 41 46 The Health Professionals Follow-Up
Study reported an RR of 0.53 (95% confidence interval (CI)
0.32–0.88) comparing men in the highest quintile of physical activity to men in the lowest quintile, with evidence ofa dose-response relationship (p for trend = 0.03). In thehighest quintile, men reported a median of 47 MET-hours ofactivity a week; in the lowest quintile, the median was 0.9
MET-hours.41
Five studies examined rectal cancer separately, comparing
highest with lowest physical activity groups: two reported nonsignificant decreased risk,25 27 one reported significant
increased risk,30 and two reported non-significant increased
risk.30 41 Fourteen studies that examined colorectal cancer are
included in a highest versus lowest plot, shown in figure 5.4.4.
A published meta-analysis of 19 cohort studies reported
significant decreased risk of colon cancer for men with highlevels of occupational activity, and also for men and womenwith high levels of recreational activity. Nine of these studies examined dose response; a significant inverse trend wasreported in six studies. Physical activity was not associatedwith decreased risk of cancer of the rectum.54
Walking

Two cohort studies examined measures of walking. A significant increased risk was found in men who reported a‘slower walking pace than others’ compared to those who
said they had a ‘faster walking pace than others’.39 In a study
that examined time spent walking, decreased risk was reported in men who walked for more than 60 minutes a day compared to men who walked for less than 20 minutes a day,but this was not significant.51

C H A P T E R

5Figure 5.4.2•

P H Y S I C A L

A C T I V I T Y

Occupational physical activity and colorectal
cancer; cohort studies

Figure 5.4.4

Recreational physical activity and colorectal
cancer; cohort studies
Relative risk (95% CI)

Relative risk (95% CI)
Severson 1989 Men

0.72 (0.52–1.00)

Severson 1989 Men

0.66 (0.49–0.88)

Suadicani 1993 Men

0.69 (0.39–1.23)

Lee 1991 Men

0.95 (0.64–1.12)

Thune 1996 Men

0.82 (0.59–1.14)

Suadicani 1993 Men

0.77 (0.38–1.57)

Thune 1996 Women

0.69 (0.34–1.41)

Bostick 1994 Women

0.95 (0.66–1.36)

0.71 (0.52–0.96)

Giovannucci 1995 Men

0.53 (0.32–0.88)

0.43 (0.33–0.55)

Thune 1996 Men, high BMI

1.05 (0.69–1.59)

0.51 (0.38–0.69)

Thune 1996 Women, high BMI

0.93 (0.49–1.75)

Thune 1996 Men, low BMI

1.36 (0.74–2.51)

Thune 1996 Women, low BMI

0.45 (0.25–0.82)

Lee 1994 Men

1.10 (0.73–1.66)

Ford 1999

0.90 (0.62–1.29)

Wei 2004
Norat 2005 Men
Norat 2005 Women

0.2

0.5

1

2

5

Relative risk, highest vs lowest exposure category

Figure 5.4.3

Occupational physical activity and rectal
cancer; cohort studies

Wannamethee 2001

0.90 (0.80–1.35)

Nilsen 2001 Men

0.69 (0.50–0.95)

Nilsen 2001 Women

1.12 (0.93–1.52)

Malila 2002 Men

0.92 (0.60–1.24)

Tiemersma 2002

0.67 (0.46–0.96)

Wei 2003 Women

0.73 (0.53–1.01)

Sanjoaquin 2004

0.82 (0.49–1.37)

Relative risk (95% CI)
0.2
Severson 1989

1.23 (0.71–2.14)

Suadicani 1993 Men

0.77 (0.44–1.47)

Thune 1996 Men

1.00 (0.69–1.45)

Thune 1996 Women

0.80 (0.30–2.14)

Colbert 2001 Men

0.50 (0.26–0.97)

Wei 2003 Men

0.95 (0.56–1.61)

0.2

0.5

1

2

5

Relative risk, highest vs lowest exposure category

0.5

1

2

5

Relative risk, highest vs lowest exposure category

intensity of physical activity,34 and another study reported
no association.53
Mechanisms

There are a number of mechanisms by which physical activity may protect against colorectal cancer. These include a
reduction in insulin resistance, the beneficial effect of physical activity on body fatness (see Chapter 6), the effects on
endogenous steroid hormone metabolism, and reduced gut
transit time.55 56
Frequency

Of the five cohort studies assessed, three reported decreased
risk for the highest frequency of physical activity when compared to the lowest.16 26 50 In two of these studies, this finding was significant in men but not in women.16 26 One study
reported non-significant increased risk comparing highestwith lowest frequency of activity.44 Another study, comparing
lowest with highest frequency of activity, reported non-significant increased risk in women but no association in men.10
Intensity

Six cohort studies investigated intensity of physical activity,of which five reported an association between increased
intensity and decreased risk. Four reported decreased risk
comparing high with low intensity of physical activity,26 37 46
51
which was significant in all but one study.51 One study
reported a significant increased risk comparing low with highThere is abundant epidemiological evidence fromprospective studies showing lower risk of colorectal
cancer with higher overall levels of physical activity, as
well as with greater frequency and intensity, and thereis evidence of a dose-response effect. There is little
heterogeneity, except that the effect is not as clear forrectal cancer as it is for colon cancer. There is plausible
evidence for mechanisms operating in humans. The
evidence that higher levels of physical activity, within
the range studied, protects against colon cancer, isconvincing.

The Panel is aware that since the conclusion of the SLR, fourcohort56A–56D and four case control studies56E-56H have been published. This new information does not change the Panel judgement (see box 3.8).

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5.4.2 Breast
Six cohort57-62 studies and eight case-control studies63-70
investigated total physical activity and breast cancer. Fivecohort studies10 71-74 and seven case-control studies75-81 investigated occupational activity. Fourteen cohort studies10 58 72
74 82-91
and 11 case-control studies67 76 77 81 92-98 investigatedrecreational activity. Also see chapter 7.10.
5.4.2.1 Menopause status unspecified
Total physical activity

Two cohort studies59 60 and four case-control studies64-66 70
did not specify menopausal status.
One cohort study reported non-significant increased risk
for the highest activity group when compared to the lowest.59
The other reported non-significant decreased risk.60
All four case-control studies reported decreased risk for thehighest activity group when compared to the lowest. Thiswas significant in one study66 and in a second study in
Hispanic (but not in non-Hispanic) women.70
Occupational

Five cohort studies10 71-74 and two case-control studies76 81 did
not specify menopausal status.
Two cohort studies reported decreased risk comparing highwith low physical activity72 74; this was significant in one
study.72 Another cohort study reported a borderline increased
risk comparing sedentary activity with high activity,73 andtwo analyses of the NHANES Epidemiologic Follow-up Study
reported no significant associations.10 71
Both case-control studies reported non-significant
decreased risk for the highest activity group when comparedto the lowest.76 81
Recreational

Six cohort studies72 74 82 86 87 89 and six case-control studies76
81 92-94 98
did not specify menopausal status.
Three cohort studies reported decreased risk for the highest activity group when compared to the lowest72 82 87; thiswas significant in one study.72 Two studies reported no asso-

Figure 5.4.5

Recreational physical activity and breast
cancer; case-control studies
Relative risk (95% CI)

Bernstien 2005

0.94 (0.90–0.97)

Verloop 2000

0.92 (0.85–0.99)•

E V I D E N C E

A N D

J U D G E M E N T S

ciation74 86 and one study reported non-significant increased
risk.89 The effect estimates were RR 0.63 (95% CI
0.42–0.95),72 RR 0.80 (95% CI 0.58–1.12),87 RR 0.73 (95%
CI 0.46–1.14),82 RR 1.0 (95% CI 0.64–1.54),74 and RR 1.24
(95% CI 0.83–1.82).89
All six case-control studies reported decreased risk withincreased physical activity, which was significant in five studies.76 81 92 93 98 Meta-analysis was possible on these five studies, giving a summary effect estimate of RR 0.90 (95% CI
0.88–0.93) per 7 MET-hours per week (figure 5.4.5), withhigh heterogeneity. The heterogeneity was related to the size
but not the direction of effect.
Mechanisms

There are a number of mechanisms by which physical activity may protect against breast cancer in general. These
include the beneficial effect of physical activity on body fatness (see Chapter 6), effects on endogenous steroid hormone
metabolism, and a possible strengthening of the immune system. Physical activity may reduce levels of circulating oestrogens and androgens.
The Panel’s judgment is given not on breast cancer in general, but separately for premenopausal and postmenopausal
breast cancer. See 5.4.2.2 and 5.4.2.3.
5.4.2.2 Premenopause
Total physical activity

Two cohort studies58 61 and six case-control studies64-69
reported results for premenopausal breast cancer.
One cohort study reported non-significant but slightly
increased risk for the highest activity group when comparedto the lowest (RR 1.04; 95% CI 0.82–1.33).58 The otherstudy reported no association.61
Five case-control studies reported decreased risk for thehighest activity group when compared to the lowest64 66 67 69
77; this was significant in two.66 69 One study reported nonsignificant increased risk.68
Occupational

Three cohort studies10 72 73 and six case-control studies75-80
reported results for premenopausal breast cancer.
Two cohort studies reported decreased risk for the highest activity group compared to the lowest10 72; this was significant in one study (RR 0.48; 95% CI 0.24–0.95).72 One
study reported that there was no association.73
Two case-control studies reported non-significant
decreased risk for the highest activity group when comparedto the lowest.75 76 No associations were reported in the otherfour studies.77-80

Matthews 2001

0.86 (0.82–0.91)

Ueji 1998

0.85 (0.76–0.95)

Recreational

Yang 2003

0.69 (0.57–0.83)

Summary estimate

0.90 (0.88–0.93)

Four cohort studies58 72 82 84 and six case-control studies67 76
77 81 95 96
reported results for premenopausal breast cancer.
Two cohort studies reported non-significant decreased risk
for the highest activity group when compared to the lowest.58
72
Two studies reported non-significant increased risk.82 84
The effect estimates were RR 0.71 (95% CI 0.45–1.12),58 RR
0.53 (95% CI 0.25–1.14),72 RR 1.19 (95% CI 0.43–3.3),84
and RR 1.83 (95% CI 0.77–4.31).82

0.6

0.8

1

Relative risk per 7 MET-hours per week

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Four case-control studies76 81 95 96 reported decreased risk
with increased physical activity; this was significant in two
studies,81 95 neither of which could be included in the metaanalysis. One study reported no association with risk,67 andanother reported non-significant increased risk.77 Metaanalysis was possible on four case-control studies,67 76 77 96
giving a summary effect estimate of 1.00 (95% CI 0.97–1.04)
per 7 MET-hour per week, with low heterogeneity.
There is ample evidence from prospective studies, but
it is inconsistent. There is limited evidence suggestingthat physical activity protects against premenopausal
breast cancer.

Occupational

Five cohort studies10 72-74 85 and four case-control studies75
77-79
reported results for postmenopausal breast cancer.
All five cohort studies reported decreased risk for the highest activity group when compared to the lowest; this was significant in one study.73 The effect estimates were RR 0.85
(95% CI 0.57–1.28)74 and RR 0.78 (95% CI 0.52–1.18)72
for high compared to low occupational activity. The effectestimates were RR 1.5 (95% CI 0.70–2.80)10 and RR 1.3(95% CI 1.1–1.7),73 comparing sedentary to non-sedentary
occupations.
Three case-control studies reported decreased risk for thehighest activity group when compared to the lowest75 77 79;

Recreational physical activity andpostmenopausal breast cancer;
cohort studies
Relative risk (95% CI)

McTiernan 2003

0.97 (0.95–1.00)

Patel 2003

0.97 (0.94–1.00)

Dirx 2001

0.97 (0.94–1.00)

Summary estimate

0.97 (0.95–0.99)

0.8

Relative risk (95% CI)
1.04 (0.97–1.11)

Friedenreich 2001

1.02 (0.94–1.11)

Carpenter 2003

0.97 (0.95–1.00)

Moradi 2000

0.92 (0.86–0.97)

Ueji 1997

0.90 (0.76–1.07)

Summary estimate

0.97 (0.95–1.00)

0.8

1

1.2

Relative risk per 7 MET-hours per week

Two cohort studies57 62 and six case-control studies64 66 67 69
70 77
reported results for postmenopausal breast cancer.
Both cohort studies reported decreased risk for the highest
activity group when compared to the lowest.57 62 Effect estimates were RR 0.43 (95% CI 0.19–0.96)62 and RR 0.20 (95%
CI 0.5–1.0),57 comparing highly active with inactive women.
Five case-control studies reported decreased risk for thehighest activity group when compared to the lowest64 66 67 70
77; this was significant in three studies.66 70 77 One study
reported non-significant increased risk.69

0.6

Recreational physical activity andpostmenopausal breast cancer; case-control
studies

John 2003

0.6

5.4.2.3 Postmenopause
Total physical activity

Figure 5.4.6

Figure 5.4.7

1

Relative risk per 7 MET-hours per week

1.2

this was significant in one study.79 One study reported significant increased risk.78
Recreational

Eleven cohort studies10 72 74 82-85 87 88 90 91 and six case-control
studies67 76 77 81 94 97 reported results for postmenopausal
breast cancer.
Nine cohort studies reported decreased risk for the highest activity group when compared to the lowest10 72 82-85 87 88
90; this was significant in two.82 84 Two of the studies reported non-significant increased risk.74 91 Meta-analysis was possible on three studies, giving a summary effect estimate of
RR 0.97 (95% CI 0.95–0.99) per 7 MET-hours per week, withno heterogeneity. This is shown in figure 5.4.6.
Meta-analysis was possible on five of the case-control studies, giving a summary effect estimate of RR 0.97 (95% CI
0.95–1.00) per 7 MET-hours per week, with moderate heterogeneity. This is shown in figure 5.4.7.
There is ample evidence from prospective studies
showing lower risk of postmenopausal breast cancer
with higher levels of physical activity, with a doseresponse relationship, although there is someheterogeneity. There is little evidence on frequency,
duration, or intensity of activity. There is robust evidence
for mechanisms operating in humans. Physical activity
probably protects against postmenopausal breast cancer.

The Panel is aware that since the conclusion of the SLR, one
case-control study98A has been published. This new information
does not change the Panel judgement (see box 3.8).
5.4.3 Endometrium
Two cohort studies99 100 and four case-control studies101-104
investigated total physical activity and cancer of theendometrium. Three cohort studies105-107 and 10 case-control studies102-104 108-114 investigated occupational activity.
Four cohort studies107 115-117 and 10 case-control studies

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investigated recreational activity.102-104 108-111 118-120 Also see
chapter 7.12.

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Recreational physical activity andendometrial cancer; cohort andcase-control studies

Total physical activity

One cohort study reported non-significant decreased risk forthe highest activity group when compared to the lowest (RR
0.8; 95% CI 0.5–1.1).99 The other study reported no association when comparing any vigorous activity to none (RR
0.99; 95% CI 0.8–1.2).121
All four case-control studies reported decreased risk for thehighest activity group when compared to the lowest; this was
significant in one.101

Relative risk (95% CI)
CohortTerry 1999

0.10 (0.03–0.39)

Folsom 2003

1.05 (0.83–1.32)

Furberg 2003

0.71 (0.34–1.49)

Schouten 2004

0.54 (0.34–0.85)

Case control
Levi 1993

0.53 (0.25–1.11)

Occupational

Sturgeon 1993

0.83 (0.49–1.41)

All three cohort studies reported significant decreased risk forthe highest activity group when compared to the lowest. Effectestimates are shown in figure 5.4.8.
Seven case-control studies reported decreased risk for thehighest activity group when compared to the lowest,102 104 109111 113 114
statistically significant in three.102 104 113 Three studies reported non-significant increased risk.103 108 112 All threecohort studies and eight of the case-control studies were
included in a highest versus lowest analysis, most of whichshowed reduced risk with highwe activity (figure 5.4.8).

Hirose 1996

0.60 (0.38–0.94)

Olsen 1997

0.67 (0.42–1.08)

Jain 2000

0.64 (0.45–0.91)

Moradi 2000

0.77 (0.59–1.00)

Littman 2001

0.83 (0.59–1.16)

Matthews 2005

0.76 (0.51–1.14)

Trentham-Dietz 2006

0.65 (0.49–0.86)

0.1

0.5

1

2

3

Relative risk, highest vs lowest exposure category

Recreational

Three cohort studies reported decreased risk for the highest
activity group when compared to the lowest107 115 116; thiswas significant in two studies.115 116 One study reported nonsignificant increased risk.117 See figure 5.4.9.
Nine case-control studies reported decreased risk for

Figure 5.4.8

Occupational physical activity andendometrial cancer; cohort andcase-control studies
Relative risk (95% CI)

CohortMoradi 1998

0.76 (0.67–0.86)

Weiderpass 2001

0.77 (0.66–0.90)

Furberg 2003

0.49 (0.22–0.91)

the highest activity group when compared to the lowest,102
104 108-111 118-120
statistically significant in three.109 119 120 Thesestudies are included in figure 5.4.9. Another study (notincluded in this figure) reported no significant association.103
Mechanisms

As with breast cancer, there are a number of mechanisms bywhich physical activity may protect against cancer of theendometrium. These include the beneficial effect of physical activity on body fatness (see Chapter 6); effects on
endogenous steroid hormone metabolism; and a possible
strengthening of the immune system. Also, high levels ofphysical activity are associated with lower levels of circulating oestrogens and androgens in postmenopausal women.14

Case control
Levi 1993

0.67 (0.45–0.99)

Shu 1993

1.11 (0.68–1.81)

Sturgeon 1993

0.50 (0.31–0.80)

Kalandidi 1996

0.41 (0.18–0.91)

Goodman 1997

0.70 (0.47–1.03)

Olson 1997

1.19 (0.76–1.87)

Moradi 2000

0.77 (0.46–1.28)

Matthews 2005

0.86 (0.63–1.18)

0.5

1

2

3

Relative risk, highest vs lowest exposure category

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There is generally consistent evidence, mostly fromcase-control studies, showing lower risk of cancer ofthe endometrium with higher levels of physical activity.
There is evidence for mechanisms operating inhumans. Physical activity probably protects against
cancer of the endometrium.

5.4.4 Lung
Five cohort studies investigated total physical activity25 51 122124
and two investigated non-recreational activity.10 125 Fourcohort studies25 126-128 and two case-control studies112 129
investigated occupational activity. Eleven cohort studies10 25
51 126-128 130-134
and four case-control studies135-138 investigated recreational activity. Another two cohort studies
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these categories.31 126 Also see chapter 7.4.
Total physical activity

Four of the five cohort studies reported decreased risk for thehighest activity group compared to the lowest25 51 123 124; thiswas significant in two.123 124 The other study reported nonsignificant decreased risk in people under the age of 63, RR
0.84 (95% CI 0.69–1.03) per 20 hours a week; and non-significant increased risk in people aged 63 and over, RR 1.11
(95% CI 0.95–1.29) per 20 hours a week.122 The effect estimates were RR 0.61 (95% CI 0.41–0.89),123 RR 0.74 (95%
CI 0.59–0.93),124 RR 0.70 (95% CI 0.48–1.01),25 and RR 0.76
(95% CI 0.40–1.43),51 comparing highest to lowest activity
groups. All cohort studies were adjusted for smoking.
Non-recreational activity

Two cohort studies reported increased risk with inactivity(sedentary living)10 125; this was significant in one.10 In one
study of men, the effect estimate was RR 2.0 (95% CI
1.2–3.5)10; in the other study, the estimates were RR 1.26
(95% CI 0.71–2.24) for men and RR 1.41 (95% CI 0.59–3.35)
for women.125 Both studies were adjusted for smoking.
Other physical activity

Two cohort studies reported on other measures of physicalactivity.31 126 The Whitehall Study in England reported nonsignificant increased risk of lung cancer mortality comparing low to high transport-related physical activity.31 The
other study reported decreased risk in both men and women,
which was significant in men, comparing high to low occupational and recreational activity combined.126 Both studies
were adjusted for smoking.

0.6–1.06).25 One study reported that mean hours per weekof sports activity were lower in cases (0.70) than in controls(1.10).133 The exposure examined varied, with some studies
analysing leisure-time activities, sports, or exercise, and one
examining endurance skiers. All but the two studies specified
above were adjusted for smoking.
All four case-control studies reported a significant
decreased risk comparing high to low levels of activity.135-138
Mechanisms

No mechanisms were identified by which physical activity
might have a specific effect on the risk of lung cancer. The
possibility could not be dismissed that people with pulmonary
disease, who are at increased risk of lung cancer, might
reduce their level of physical activity.
The association between physical activity and lung cancer
is complex. Unlike many other cancers, lung cancer is not
positively associated with body mass index (BMI). The Panelis aware that the observed association between physical activity and lung cancer may be a reflection of reverse causation
due to chronic lung disease.
There is evidence from prospective and case-control
studies showing lower risk of lung cancer with higher
levels of physical activity, but there is no evidence ofplausible mechanisms. The relationship between activity,
BMI, and lung cancer makes the evidence difficult tointerpret. There is limited evidence suggesting thatphysical activity protects against lung cancer.

Occupational

The Panel is aware that since the conclusion of the SLR, onecohort study138A has been published. This new information does
not change the Panel judgement (see box 3.8).

Two cohort studies reported non-significant increased risk forthe highest activity group to the lowest.127 128 The effect estimates were RR 1.23 (95% CI 0.95–1.59) in a cohort of malenon-smokers in Finland,127 and RR 1.13 (95% CI 0.63–2.05)
for men and 1.80 (95% CI 0.75–4.31) for women in the second cohort.128 Another two cohort studies reported non-significant decreased risk comparing high to low activity.25 126
The effect estimates were RR 0.88 (95% CI 0.62–1.22) in acohort of men and women,25 and in another cohort were RR
0.79 (95% CI 0.30–2.12) for women and RR 0.99 (95% CI
0.70–1.41) for men.126 All studies were adjusted for smoking.
One case-control study reported non-significant increased
risk for the highest activity group when compared to the lowest112; the other reported non-significant decreased risk.129

5.4.5 Pancreas
Three cohort studies44 139 140 and one case-control study141
investigated total physical activity and pancreatic cancer.
Three cohort studies139 142 143 and two case-control studies129
144
investigated occupational activity. Nine cohort studies31 139
140 142 145-149
and three case-control studies150-152 investigatedrecreational activity. Four cohort studies (in three publications) investigated walking,140 145 146 while two investigatedtransportation activity.140 145 Five cohort studies (in four publications) 140 146 149 153 and one case-control study141 investigated vigorous activity. Four cohort studies (in threepublications)140 145 146 and one case-control study141 investigated moderate activity. Also see chapter 7.6.

Recreational

Total physical activity

Ten cohort studies reported decreased risk comparing thehighest activity group compared to the lowest25 51 126-128 130134; this was significant in five studies. One study reported
non-significant increased risk.10 Effect estimates were RR
1.11 (95% CI 0.71–1.74),10 RR 0.90 (95% CI 0.83–0.97),128
RR 0.97 (95% CI 0.88–1.07),127 RR 0.27 (95% CI 0.15–0.49,
unadjusted for smoking),130 RR 0.45 (95% CI 0.17–1.18),131
RR 0.80 (95% CI 0.71–0.90),132 RR 0.50 (95% CI 0.29–0.87,
unadjusted for smoking),134 RR 0.73 (95% CI 0.54–0.98),126
RR 0.81 (95% CI 0.58–1.13),51 and RR 0.8 (95% CI

Two cohort studies reported non-significant decreased risk forthe highest activity group compared to the lowest.44 139
Another cohort study reported non-significant increased
risk.140 The single case-control study reported decreased risk,
significant in men but not women.141
Occupational

One cohort study reported significant increased risk for people who reported that they felt ‘worn out’ after work.139 One
study stated they found no significant association143; and one207

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Five cohort studies reported non-significant decreased risk
for the highest activity group when compared to the lowest.139 142 145-147 Four cohort studies reported non-significant
increased risk.31 140 148 149 Meta-analysis was possible on threecohort studies, giving a summary effect estimate of RR 0.98
(95% CI 0.91–1.05) per 10 MET-hours per week, with noheterogeneity. All three case-control studies reported
decreased risk for the highest activity group compared to thelowest150-152; this was significant in one.150

5.4.6 Prostate
Two studies showed that higher levels of physical activity
were associated with lower risk specifically of advanced or
aggressive prostate cancer.155 156 Also see chapter 7.14.
In the Health Professionals Follow-Up Study, a strong inverse
association between vigorous physical activity and advanced
prostate cancer was seen in men 65 years or older: RR 0.33
(95% CI 0.17–0.62) for more than 29 MET-hours compared
to none. No association was seen in younger men.155
In the American Cancer Society Cancer Prevention Study
II Nutrition Cohort, high levels of recreational physical activity were associated with decreased risk of aggressive
prostate cancer: RR 0.69 (95% CI 0.52–0.92) for more than
35 MET-hours per week compared to no physical activity. No
association was found between recreational physical activity and overall prostate cancer.156

Walking

Mechanisms

Three cohort studies reported decreased risk for the highest
activity group compared to the lowest140 146; this was significant in two.146 The effect estimates were RR 0.48 (95% CI
0.24–0.97) for women in the Nurses’ Health Study146; RR
0.45 (95% CI 0.26–0.80) for men in the Health Professionals
Follow-up Study146; and RR 0.99 (95% CI 0.64–1.51) in astudy of pancreatic cancer mortality.140 The Whitehall Study
reported increased risk of pancreatic cancer mortality forslow compared to fast walkers (RR 1.1; 95% CI
0.20–5.10).145

Several mechanisms have been proposed for how physicalactivity may decrease the risk of prostate cancer. Exercise
may reduce prostate cancer risk by reducing levels of testosterone and insulin. Acute exercise may promote the formation of free radicals. In people who exercise consistently, thismay induce the production of enzymes, such as superoxide
dismutase, that protect against oxidative stress. These
enzymes may also protect against cancer, since dietary
antioxidants have been linked to reduced cancer risk.

study reported non-significant decreased risk for moderateor heavy work compared to sedentary jobs.142 Both case-control studies reported decreased risk for the highest activity
group when compared to the lowest129 144; this was significant in one study.144
Recreational

Vigorous

Three cohort studies reported non-significant decreased risk
for the highest activity group compared to the lowest.140 146
149
Two studies reported non-significant increased risk.146 153
The single case-control study reported non-significant
decreased risk.141
Moderate

Two cohort studies reported increased risk for the highest
activity group compared to the lowest140 149; this was significant in one.149 Two cohort studies reported decreased risk,146
which was significant in one.146 The single case-control study
reported non-significant increased risk in men and no association in women.141
Mechanisms

Mechanisms by which physical activity may protect against
cancer of the pancreas include reduced insulin resistance andreduced gut transit time, which has beneficial effects on bilecontent and secretion and general pancreatic activity.154
There is evidence from prospective studies showing
lower risk of pancreatic cancer with higher levels of
various types of physical activity, but it is rather
inconsistent. There is limited evidence suggesting thatphysical activity protects against pancreatic cancer.

The Panel is aware that since the conclusion of the SLR, onecohort study154A has been published. This new information does
not change the Panel judgement (see box 3.8).

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The Panel has noted the evidence presented here thatphysical activity is associated with reduced risk ofadvanced or aggressive cancer of the prostate, but has
not made a formal judgement.

5.5 Comparison with previous report
The panel responsible for the previous report judged that theevidence that physical activity protects against cancer of thecolon was convincing. Evidence for cancer of the rectum wasjudged to be unimpressive. Physical activity was judged to
be possibly protective against cancers of the lung and of thebreast. The previous report mentioned epidemiological,
experimental, and mechanistic evidence suggesting thatphysical activity is generally protective against cancer, andin particular against colon cancer and female hormone-related cancers. The panel responsible for that report also concluded that all types of physical activity were probably
beneficial and that people should remain physically active
throughout life.

5.6 Conclusions
The Panel concludes:
The evidence that physical activity protects against coloncancer is convincing. Physical activity probably protects
against postmenopausal breast cancer, whereas the evidence
suggesting that it protects against premenopausal breast cancer is limited. Physical activity probably protects against can-C H A P T E R

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cer of the endometrium. The evidence suggesting that physical activity protects against cancers of the lung and pancreas
is limited.
The Panel notes the overall consistency of the evidence. The
Panel emphasises that, taken together, the evidence suggeststhat all types and degrees of physical activity are or may beprotective, excluding extreme levels of activity: the evidence
for any specific type or degree of physical activity is limited.
The evidence is consistent with the message that the more
physically active people are, the better.
The Panel also agrees that physical activity, which promotes
healthy weight, would be expected to protect against cancers
whose risk is increased by overweight, weight gain, and obesity, and conversely that sedentary living increases or may
increase the risk of the specified cancers (see Chapters 6 and
8). Most people in urbanised and industrialised settings, notonly in high-income countries but throughout the world,
now lead sedentary ways of life.

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6Body composition, growth,and development
The size and shape of the human body, the rates atwhich humans grow from conception to adult life,and human physical and mental development are
all determined by interrelated genetic andenvironmental, including nutritional, factors.
Specifically, human nutrition, the degree to which
the body’s needs are met by the nature, quality, andquantity of the foods consumed, has a fundamental
effect on health and well-being, and also on the
body’s ability to resist diseases. These include not
only infectious diseases but also chronic diseases,
one of which is cancer.
The Panel decided that the evidence apparent in
the literature concerned with body composition,
growth, and development, including breastfeeding(lactation), was likely to prove of special interest.
For this reason, the independent systematic
literature reviews, on which the evidence andjudgements in this chapter are based, have covered
these areas more thoroughly than has previously
been attempted.
The three related sections of this chapter pay
special attention to degree of body fatness, rates ofgrowth and their outcomes, and also to lactation in
relation to the risk of cancer throughout the life
course. The first of these sections, which focuses onbody composition, is complemented by Chapter 8
on determinants of weight gain, overweight, andobesity.
The findings of the systematic literature reviews
are summarised and judged within each section. The
matrices that are part of the introduction of eachsection display the Panel’s judgements, which aredeveloped or qualified when necessary infootnotes. Introductory passages also summarise
relevant context. Other passages review issues ofinterpretation of the literature and compare thefindings of this with the previous report. For
convenience, and also throughout this Report, thePanel’s summary judgements are repeated at theend of each section.
The picture that emerges is impressive: much
more so than that based on the evidence gatheredin the mid-1990s using the then agreed
methodology. Its implications are also impressive.
Some of the most persuasive evidence in the whole

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field of food, nutrition, and physical activity
indicates that the basis for prevention of cancer
should be a whole life course approach, starting at
the beginning of life, or even in maternal
preparation for pregnancy.

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6.1 Body fatness
BODY FATNESS, AND THE RISK OF CANCER
In the judgement of the Panel, the factors listed below modify the risk of cancer. Judgements are graded according to the strength of the evidence.

DECREASES RISK
Exposure

INCREASES RISK

Cancer site

Convincing

Probable

Body fatness

Breast (premenopause)

Limited —suggestive
Substantial
effect on risk
unlikely12

Exposure

Cancer site

Body fatness

Oesophagus1
Pancreas
Colorectum
Breast (postmenopause)
Endometrium
KidneyAbdominal fatness

Colorectum

Body fatness

Gallbladder2

Abdominal fatness

Pancreas
Breast (postmenopause)
Endometrium

Adult weight gain

Breast (postmenopause)

Body fatness

Liver

Low body fatness

Lung

None identified

For oesophageal adenocarcinomas only.
Directly and indirectly, through the formation of gallstones.

For an explanation of all the terms used in the matrix, please see chapter 3.5.1, the text of this section, and the glossary.

A key reason for the success of Homo sapiens is ouradaptability. Humans have evolved to survive and flourish
in almost all environments and circumstances which,during the 250 000 years of our species’ existence, haveusually included occasional or regular food scarcity andinsecurity. We have built-in defences against starvation: ourown stores of fat that are used in times of need.
Food insecurity remains endemic, particularly in Africa
and Asia. But many people in the world now have access tomore than enough to eat and drink and are also relatively
physically inactive (see Chapter 5). As a result, stores ofbody fat tend to increase. What is now a pandemic ofoverweight and obesity can be seen as a response tocircumstances of plenty. One consequence, in the context of
reduction in rates of nutritional deficiencies and infectionsof childhood and early life, and the ageing of humanpopulations, is an increase in the rates of chronic diseases.
These include cancer.
Overall, the Panel judges that evidence on the degree ofbody fatness and the risk of cancers of a number of sites isstrong and generally consistent. The Panel emphasises thatthe risk of cancer is modified, not only by obesity, as
usually defined, but by overweight as well, and even bydegrees of body fatness generally regarded as healthy.
The Panel judges as follows:
The evidence that greater body fatness is a cause of
adenocarcinoma of the oesophagus, and cancers of thepancreas, colorectum, breast (postmenopause),
endometrium, and kidney, is convincing. Greater bodyfatness is probably a cause of cancer of the gallbladder.
There is limited evidence suggesting that greater bodyfatness is a cause of liver cancer. The evidence that greater
abdominal (central) fatness is a cause of colorectal cancer
is convincing; and greater abdominal fatness is probably acause of cancers of the pancreas, breast (postmenopause),and endometrium. By contrast, greater body fatness
probably protects against premenopausal breast cancer.

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The Panel notes that there is limited evidence suggestingthat low body fatness (underweight) is a cause of lungcancer, but residual confounding with smoking and lungdisease cannot be ruled out.
See Chapter 8 for judgements on physical activity andsedentary ways of life, the energy density of foods anddrinks, breastfeeding, other factors, and the risk of weight
gain, overweight, and obesity.
Within the remit of this Report, the strongest evidence,corresponding to judgements of ‘convincing’ and‘probable’, shows that greater body fatness and greater
abdominal fatness are causes of cancer of the colorectum;that greater body fatness is additionally a cause of cancersof the oesophagus (adenocarcinoma), pancreas, breast(postmenopause), endometrium, and kidney; and(probably) gallbladder. It also shows that greater
abdominal fatness is probably a cause of cancers of thepancreas, breast (postmenopause), and endometrium; butthat greater body fatness probably protects against
premenopausal breast cancer.

Body fatness and organ mass and composition, commonly
assessed by body size measurements, are key factors influencing health and well-being throughout the life course.
The main concern of nutrition science, since its beginnings
and until the mid-20th century, has been to protect populations against the consequences of malnutrition in the ‘classic’ sense of the word. That is undernutrition, which
increases vulnerability to infectious diseases, especially ininfancy and childhood, and results in people who are small
and weak, unable to be productive, and with low life
expectancy.1 This remains a central public health priority for
middle- and low-income countries.2
In the final two decades of the 20th century and into thiscentury, a different and imperative public health nutrition
concern has emerged: weight gain, overweight, and obesity. At first, it was generally assumed that societies whosebabies are big, whose children grow fast, and whose adults
are heavy and tall, were healthy. Compared to societies withinadequate nutrition and poor public health provision, such
populations are indeed physically stronger, more productive,
have longer lives, and are generally healthier.
This said, since the 1980s, a series of reports based on a
rapidly increasing evidence base have concluded that populations of high-income countries, and now also populationsof many middle- and low-income countries, are becoming
overweight to an extent that is bad for health. These countries are almost exclusively those experiencing social, economic, and nutritional transition. The nutritional transition
is characterised by a shift from ‘traditional’ diets that are low
in fat and high in fibre to high-energy ‘Western’ diets that arehigh in fat and low in fibre. It is now generally accepted thatobesity, but also overweight short of obesity, increases the riskof a number of major chronic diseases including insulin resistance, hyperlipidaemia, hypertension and stroke, type 2 diabetes, and coronary heart disease, as well as cancers of somesites.3 In this chapter, the evidence on body fatness and cancer is summarised and judged. Also see Chapter 8.

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In this Report, the term ‘body fatness’ refers to the degreeof body fatness across the whole range, not only the conventional categories of overweight and obesity.

6.1.1 Definitions and patterns
6.1.1.1 Body fatness
Excess energy from food is stored as fat in the body in adipose tissue. The amount of this body tissue varies more fromperson to person than any other type (such as muscle, bone,or blood). The size and location of these fat stores also varyconsiderably between populations, people, and over thecourse of a person’s life. Excess body fat is a cause of a number of chronic diseases and reduces life expectancy (also see
Chapter 8).
Since the 1980s, typical body compositions have changed,with a worldwide increase in average body fatness and in
overweight and obesity. This change is most notable in highincome countries, and in industrial and urban environments
in many if not most countries (see chapters 1.1.3 and 1.2.2).
In several low-income countries, high levels of body fatness
exist alongside undernutrition in the same communities andeven in the same families.3
Body fatness is difficult to measure directly or accurately.
However, because body fatness is the most variable determinant of weight, several weight-based measures are usedas markers of body fatness. The most common is the bodymass index (BMI), a measure of weight adjusted for height.
BMI is calculated as weight in kilograms divided by heightin metres squared (kg/m2). In most circumstances, BMI has
been shown to be reliably linked to body fatness.4 But thismethod does not always provide an accurate measure:unusually muscular and lean people (such as manual workers and power athletes) have a relatively high BMI, even if
they have relatively little body fat. See table 6.1.1 and also
Chapter 8.
A BMI of between 18.5 and 24.9 is generally regarded as‘healthy’ or ‘normal’ (healthy or normal body fatness). Thisis roughly equivalent to 15–20 per cent body fat in adultmen and 25–30 per cent in adult women.5 The ‘underweight’or ‘thin’ range is a BMI below 18.5 (low body fatness). Above
25 (high body fatness), there are common gradings for overweight, obesity, and extreme (‘morbid’) obesity. The risk oftype 2 diabetes and high blood pressure increases with BMI
with no clear threshold, but with a marked increase in risk
as BMI approaches 25.3 The ideal average BMI for populations has been estimated to be 21–22.6
The principal cut-off points shown in table 6.1.1 havebeen agreed by the World Health Organization and are basedon the risks associated with being underweight, overweight,
or obese (see Chapter 8). However, the healthy ranges of
BMI vary between populations. The additional cut-off points
take this into account and are recommended for reporting
purposes, with a view to facilitating international comparisons.
The principal BMI cut-offs are based on data primarily
derived from populations of European origin living in highincome countries, so they may not apply globally. Different

C H A P T E R

6Table 6.1.1•

B O D YC O M P O S I T I O N ,G R O W T H ,The international classification of adultunderweight, overweight, and obesity

A body mass index (BMI) of between 18.5 and 24.9 is generally regarded
as ‘acceptable’ or ‘normal’. The ‘underweight’ or ‘thin’ range is a BMI of
below 18.5. Above 25, the common gradings for overweight and obesity
are as shown below:

Underweight
Severe thinness
Moderate thinness
Mild thinness

BMI (kg/m2)
Principal
Additional
cut-off points
cut-off points<18.50<18.50<16.00<16.0016.00–16.99
16.00–16.99
17.00–18.49
17.00–18.49

Normal range

18.50–24.99

18.50–22.99
23.00–24.99

Overweight≥ 25.00≥ 25.00
25.00–27.49
27.50–29.99

Obese
Obese class I≥ 30.00
30.00–34-99

Obese class II

35.00–39.99

Obese class III≥ 40.00≥ 30.00
30.00–32.49
32.50–34.99
35.00–37.49
37.50–39.99≥ 40.00

Classification

Adapted with permission from WHO.3

BMI cut-off points have been proposed to classify overweight
and obesity in different populations, due to different bodycomposition and the relation of BMI to risk in these populations. However, these have not become universally accepted.7 8 A WHO expert consultation on BMI in Asian
populations recommended that the principal BMI cut-off
points (table 6.1.1) should be retained as the internationalclassification.9 However, it also recommended that additional cut-off points of 23, 27.5, 32.5, and 37.5 kg/m2
should be added to the international classification and, forreporting purposes, countries should use all categories (thatis, 18.5, 23, 25, 27.5, 30, and 32.5 kg/m2; and in many populations, 35, 37.5, and 40 kg/m2) with a view to facilitating international comparisons. The principal and additional
cut-off points are shown in table 6.1.1.
At equivalent BMIs, many Asian populations have a higher body fat content, whereas Maori people and PacificIslanders have more lean tissue and less fat.4 10 11 Many Asianexpert groups and health ministries now define the upper
limit of ‘acceptable’ as a BMI of below 23, whereas the equivalent cut-off point for China is 24. It is unlikely that theexcess risk in these populations at relatively low BMIs
reflects only differences in body fat — there are probably
other related metabolic changes, for instance, those inducedby fetal and early childhood nutritional differences. WHO
has recognised that Asian populations may choose a BMI
cut-off of 23 because of the greater susceptibility of thesegroups of people to type 2 diabetes and perhaps other complications of excess weight gain.9 Mexican people have also
been shown to be at greater risk, so Latin American popu-

A N D

D E V E L O P M E N T

lations may also be considered as more sensitive to theeffects of weight gain than white people of European
origin.12
6.1.1.2 Body fat distribution
Fat is not distributed equally around the body. It accumulates subcutaneously (beneath the skin) around the musclesof the upper arm, buttocks, belly, hips, and thighs. It also
accumulates intra-abdominally or viscerally (around theorgans). Fat stores can be categorised as ‘peripheral’ (notaround the trunk) or ‘abdominal’ (also called ‘central’). The
pattern of fat stores is determined largely by genetic factors,
with a typically different pattern in men and women, whichtends to change with age. Women tend to store more subcutaneous fat around their hips, buttocks, and thighs thanmen, producing a body profile known as a ‘pear shape’ (or‘gynoid’ pattern of fat distribution). Men are more likely tostore fat around their abdomen, producing an ‘apple shape’(or ‘android’ pattern).
The size of peripheral fat stores can be used as a measureof total body fatness, although the proportion of total toabdominal fat varies between people. Waist circumferenceis a measure that includes both subcutaneous and the moremetabolically active intra-abdominal fat stores. The sizeof intra-abdominal fat stores predicts the risk of chronic diseases, such as metabolic disorders and cardiovasculardisease, better than overall indicators of body fatness, suchas subcutaneous fat measures or BMI.13 The size of these fat
stores also influences several hormone systems, such as
insulin, as well as those involved in the body’s response toinflammation, both of which may play a role in cancer
processes (box 2.4).14 15
Crude estimates of excess abdominal fat can be made bymeasuring either waist circumference or by calculating theratio of this measurement to hip circumference (the ‘waist
to hip’ ratio), although this ratio is no longer recommended
as a useful indicator of abdominal obesity. Waist circumference is a better single indicator. As is the case for BMI, thecut-off points for excess waist measurements for Asian and
Mexican populations are usually lower than those suggested by WHO as suitable for people of European origin. Thisis because these non-white populations have a greater riskof disease with only modest increases in intra-abdominal fat.
The WHO reference values for waist circumferences of 94 cm(37 inches) in men and 80 cm (31.5 inches) in women (ona population basis) are based on their rough equivalence toa BMI of around 25, whereas waist circumferences of 102 cm(40.2 inches) in men and 88 cm (34.6 inches) in women areequivalent to a BMI of around 30.16 17 For Asian populations,
cut-offs for waist circumferences of 90 cm for men and 80
cm for women have been proposed.18
6.1.1.3 Adult weight gain
Increases in body weight during adulthood depend mostly
on accumulation of fat rather than lean tissue, and therefore any change may better reflect fatness than adultattained weight itself, which is more dependent on leanmass. For this reason, evidence of associations specificallybetween weight gain in adulthood and cancers was sought

213

P A R T

in the systematic literature reviews that informed the Panel’s
judgements.

6.1.2 Interpretation of the evidence
6.1.2.1 General
For general considerations that may affect interpretation of
the evidence, see chapters 3.3 and 3.5, and boxes 3.1, 3.2,
3.6 and 3.7.
6.1.2.2 SpecificSome considerations specific to body fatness are as follows.

2•

E V I D E N C E

A N D

J U D G E M E N T S

6.1.3 Evidence and judgements
The full systematic literature review (SLR) is contained on
the CD included with this Report.
There are several general mechanisms through which bodyfatness and abdominal fatness could plausibly influence cancer risk. For example, increasing body fatness raises the
inflammatory response, increases circulating oestrogens, anddecreases insulin sensitivity. The physiological effects of obesity are described in more detail in Chapter 8. The effects ofbody fatness-related hormonal changes and inflammation on
cancer processes are detailed in box 2.4. Additional sitespecific mechanisms are described with the evidence foreach cancer site in the following sections.

Classification. The system of classifying underweight, ‘nor-mal’ weight, overweight, and degrees of obesity as discrete
ranges of BMI, is in general use. However, as shown in thischapter and also Chapter 8, the relationship between bodyfatness and cancer is continuous across the range of BMI. For
this reason, the Panel has chosen to use the term ‘body fatness’ rather than ‘overweight’ or ‘obesity’.
Measurement. BMI is not a perfect marker of body fatness.

More precise techniques such as underwater weighing, magnetic resonance imaging, computerised tomography, or dualenergy X-ray absorptiometry are rare in large-scale
epidemiological studies due to their difficulty and expense.
Abdominal fatness is usually measured either using the waist
to hip ratio or the waist circumference alone. There is a lackof consensus on how abdominal fatness is best measured,and measurement error is more likely than for some otheranthropometric measures such as height and weight. The
currently proposed maximum ‘cut-off’ points for ‘healthy’
waist circumferences (94 cm or 37 inches for men; 80 cm or
31.5 inches for women) and for ‘healthy’ waist to hip ratios(1.0 for men; 0.8 for women) are based almost exclusively
on studies of cardiovascular or type 2 diabetes risk in white
populations in high-income countries. It is not known
whether they can be applied to other ethnic groups or outcomes. The relationship between waist circumference andthe size of intra-abdominal fat stores (as opposed to subcutaneous abdominal fat stores) may vary between different
ethnic groups.18 As body fatness tends to increase with age
in most populations, and is characteristically higher inwomen than in men, it is important that studies take into
account both age and sex. Measurement of change in weighttends to be more precise than static measures such as weightor BMI.

6.1.3.1 Body fatness
Oesophagus

Three cohort studies19-21 and eight case-control studies22-29
investigated body fatness (as measured by BMI) andoesophageal adenocarcinomas.
All three cohort studies showed increased risk for the highest body fatness, as measured by BMI, when compared to thelowest (figure 6.1.1); this was statistically significant in both
sexes in one study21 and in men but not women in two others.19 20 Effect estimates were 2.58 in men (95% confidence
interval (CI) 1.81–3.68; p < 0.001) and 2.06 in women (95%
CI 1.25–3.39; p = 0.002)21; 2.40 in men (95% CI 1.30–4.42)
and 1.57 in women (95% CI 0.51–4.84)20; and 1.76 in men(95% CI 1.03–3.02) and 2.13 in women (95% CI
0.97–4.71).19 The latter study was adjusted for smoking andalcohol but the other two were not.
Seven case-control studies22-25 27-29 showed increased risk
for the highest body fatness group, as measured by BMI, when

Figure 6.1.1

BMI and oesophageal adenocarcinoma;cohort and case-control studies
Relative risk (95% CI)

CohortTretli 1999 Men

2.40 (1.30–4.43)

Tretli 1999 Men

1.57 (0.51–4.84)

Case control
2.70 (1.68–4.34)

Engel 2003
Brown 1995

3.10 (1.81–5.32)

Chow 1998 Men

3.00 (1.75–5.14)

Reporting bias. Objective measures of height and weight, andChow 1998 Women

2.60 (0.80–8.47)

therefore BMI, are reliable. However, many studies rely on
self-reporting, which is liable to introduce bias. Although
reported and actual weights are correlated, weight tends tobe under-reported, especially by overweight and obese people. BMIs calculated from self-reported data will therefore
tend to be lower than from more objective measures.

Kabal 1993

1.20 (0.60–2.40)

Wu 2001

1.91 (1.28–2.85)

214

0.2

0.5 0.75 1

1.5 2

5

Relative risk, highest vs lowest exposure category

C H A P T E R

6•

B O D YC O M P O S I T I O N ,G R O W T H ,compared to the lowest (figure 6.1.1). This was statisticallysignificant in five studies,22-24 28 29 and in men but not womenin a sixth.25 One study showed non-significant decreased
risk.26 Meta-analysis was possible on four case-control
studies (all of which showed increased risk), giving an effectestimate of 1.11 (95% CI 1.07–1.15) per kg/m2, with moderate heterogeneity (figure 6.1.2). This would produce anincreased risk of 55 per cent for each 5 kg/m2, assuming alinear relationship, although a curvilinear dose-response
relationship cannot be ruled out.

Figure 6.1.2

BMI and oesophageal cancer;
case-control studies

A N D

D E V E L O P M E N T

A dose-response relationship is apparent from case-control
data (figure 6.1.3). Cohort data show a statistically significant trend in men and are suggestive of a similar trend in
women.
Studies that investigated body fatness, as measured by BMI,
and all types of oesophageal cancer or squamous cell carcinomas showed inconsistent results. Only when results werestratified by cancer type did a consistent pattern emerge, andthen only for adenocarcinomas.
An association between body fatness and increased risk ofoesophageal adenocarcinoma is consistent, with known geographical and time trends for both BMI and adenocarcinomas.
The general mechanisms through which body fatness
could plausibly influence cancer risk are outlined in 6.1.3(also see box 2.4).

Relative risk (95% CI)
Case control
Brown 1995

1.20 (1.12–1.29)

Chow 1998 Men

1.11 (1.05–1.17)

Chow 1998 Women

1.08 (0.99–1.17)

Chen 2002

1.08 (1.03–1.13)

Engel 2003

1.11 (1.05–1.16)

Summary estimate

1.11 (1.07–1.15)

0.5

0.75

1

1.5

2

Relative risk, per 1 kg/m2

Figure 6.1.3

BMI and oesophageal cancer; case-control
studies: dose response

Brown 1995

Chow 1998 Men

Chow 1998 Women

Chen 2002

Engel 2003

10

15

20

25

BMI (kg/m2 )30

35

The epidemiology is consistent, with evidence of adose-response relationship. There is evidence forplausible mechanisms that operate in humans. The
evidence that greater body fatness is a cause ofoesophageal adenocarcinoma is convincing.

The Panel is aware that since the conclusion of the SLR, twocohort30 31 and five case-control studies32-36 have been published. This new information does not change the Panel judgement (see box 3.8).
Pancreas

Twenty-three cohort studies37-58 and 15 case-control studies59-73 investigated body fatness (as measured by BMI) andpancreatic cancer.
Thirteen cohort studies showed increased risk withincreased body fatness,37 38 40 43 44 46 47 49 51 54 55 57 which wasstatistically significant in four.47 49 54 55 Two studies showed
increased risk in both sexes42 50; this was statistically significant in women but not in men in one study,42 and in men
but not women in the other.50 One study showed increased
risk in both black and white men, which was significant for
white men only.56 Two studies showed non-significant
increased risk in women and non-significant decreased risk
in men.45 52 One study showed statistically significant
increased risk in men and non-significant decreased risk in
women.39 Three studies showed non-significant decreased
risk41 48 53 and one study stated that there was no significant
association.58 Meta-analysis was possible on 17 cohort studies, giving a summary effect estimate of 1.14 (95% CI
1.07–1.22) per 5 kg/m2, with moderate heterogeneity (figure 6.1.4). Most studies adjusted for smoking, with no apparent difference between people who smoked and those that
did not.
Five case-control studies showed increased risk withincreased body fatness,62-66 which was statistically significant
in one,66 and in men but not women in another study.64 Fivestudies showed decreased risk,61 68-71 which was statistically significant in one.69 Two studies showed non-significant
decreased risk in men and a non-significant increased risk
in women.59 72 One study showed a statistically significant
increased risk in men and a non-significant decreased risk
in women.67 One study showed non-significant decreased215

P A R T

Figure 6.1.4

BMI and pancreatic cancer; cohort andcase-control studies

Figure 6.1.5

2•

E V I D E N C E

A N D

J U D G E M E N T S

BMI and pancreatic cancer; cohort andcase-control studies: dose response

Relative risk (95% CI)
CohortFriedman 1993
Shibata 1994
Gapstur 2000 Men
Michaud 2001 Men
Michaud 2001 Women
Stolzenberg 2002 Men
Calle 2003 Men
Calle 2003 Women
Lee 2003
Batty 2005 Men
Kuriyama 2005 Men
Kuriyama 2005 Women
Larsson 2005
Navarro Silvera 2005 Women
Navarro Silvera 2005
Patel
Rapp 2005 Men
Rapp 2005 Women
Sinner 2005 Women
Lukanova 2006 Men
Lukanova 2006 Women
Summary estimate

1.10 (1.00–1.22)
1.19 (0.68–2.06)
1.90 (1.27–2.84)
1.28 (0.98–1.66)
1.16 (0.98–1.37)
0.85 (0.65–1.10)
1.13 (1.00–1.29)
1.28 (1.14–1.43)
1.02 (0.78–1.34)
1.08 (0.76–1.53)
0.96 (0.42–2.19)
1.10 (0.60–1.99)
1.22 (0.89–1.62)
1.22 (1.05–1.41)
0.96 (0.88–1.05)
1.42 (1.18–1.70)
1.61 (1.08–2.41)
1.10 (0.86–1.40)
1.04 (0.90–1.21)
0.70 (0.31–1.58)
1.09 (0.68–1.74)
1.14 (1.07–1.22)

Case control
Bueno de Mesquita 1990 Men
Bueno de Mesquita 1990 Women
Howe 1990 Men – Direct interview
Howe 1990 Women – Direct interview
Howe 1990 Men – Indirect interview
Howe 1990 Women – Direct interview
Ghadirian 1991
Zatonski 1991
Ji 1996 Men
Ji 1996 Women
Silverman 1998 Men
Silverman 1998 Women
Kreiger 2007 WomenPan 2004
Eberle 2005 Men
Eberle 2005 Women
Fryzek 2005
Lin 2005
Pezzilli 2005
Rousseau 2005
Summary estimate

0.89 (0.56–1.42)
1.02 (0.71–1.47)
1.38 (0.76–2.50)
0.79 (0.49–1.27)
0.89 (0.63–1.26)
0.83 (0.61–1.14)
0.87 (0.56–1.36)
1.22 (0.92–1.61)
1.40 (0.99–1.97)
1.26 (0.87–1.84)
1.37 (1.05–1.80)
1.21 (0.94–1.55)
1.09 (0.82–1.47)
1.17 (1.06–1.29)
1.57 (1.21–2.05)
0.96 (0.75–1.24)
0.98 (0.82–1.18)
0.23 (0.16–0.33)
0.99 (0.80–1.21)
0.88 (0.66–1.17)
1.00 (0.87–1.15)

0.5 0.75 1

CohortFriedman 1993
Shibata 1994
Gapstur 2000
Michaud 2001
Michaud 2001
Stolzenberg-Soloman 2002
Calle 2003 Men
Calle 2003 Women
Lee 2003
Batty 2005 Men
Kuriyuma 2005 Men
Kuriyuma 2005 Women
Larsson 2005 Men
Larsson 2005 Women
Navarro Silvera 2005 Women
Nothings 2005
Patel 2005
Rapp 2005 Men
Rapp 2005 Women
Sinner 2005 Women
Lukanova 2006 Women
Case control
Bueno de Mesquita 1990 Men
Bueno de Mesquita 1990 Women
Howe 1990 Indirect interview Men
Howe 1990 Indirect interview Women
Ghadirian 1991
Zatonski 1991
Ji 1996 Men
Ji 1996 Women
Silverman 1998 Men
Silverman 1998 Women
Kreiger 2001 WomenPan 2004
Eberle 2005 Men
Eberle 2005 Women
Fryzek 2005
Lin 2005
Pezzili 2005
Rousseau 2005 Men

1.5 2

10

Relative risk, per 5 kg/m2

risk in both sexes when interviewed indirectly, a non-significant decreased risk in women when interviewed directly,
and a non-significant increased risk in men.60 One study stated that there was no significant association.73 Meta-analysis
was possible on 13 case-control studies, giving a summary
effect estimate of 1.00 (95% CI 0.87–1.15) per 5 kg/m2, withhigh heterogeneity (figure 6.1.4).
A dose-response relationship was apparent from cohort but
not case-control data (figure 6.1.5). Although meta-analysis
assumes a linear relationship, some cohort studies are suggestive of a curvilinear relationship, though not conclusively so.
The general mechanisms through which body fatness
could plausibly influence cancer risk are outlined in 6.1.3(also see box 2.4).
There is ample epidemiological evidence, which is
generally consistent, and there is a dose-response
relationship. There is evidence for plausible mechanismsthat operate in humans. The evidence that greater bodyfatness is a cause of pancreatic cancer is convincing.

216

15

20

25

30

35

40

BMI (kg/m2)

The Panel is aware that since the conclusion of the SLR, twocohort studies30 74 have been published. This new information does
not change the Panel judgement (also see box 3.8).
Colorectum

Sixty cohort studies42 45 50 54-58 75-142 and 86 case-control studies investigated body fatness (as measured by BMI) and cancers of the colon and rectum.
Most of the cohort studies showed increased risk withincreased body fatness,42 45 50 54 56-58 75 77 80-82 84-88 91-100 102-104
106 108-115 118-120 122 124-127 132 137 139 142
which was statisticallysignificant in approximately half of these studies.42 50 54 56-58
75 77 84-88 92-95 99 103 104 109 111 114 115 118-120 124 126 127 132 137 139 142

Relatively few studies showed lower risk with increased bodyfatness76 83 90 107 116; this was statistically significant in only
one.83 One study showed no effect on risk78 and three stated that there was no association.79 89 101 Meta-analysis was
possible on 28 cohort studies, giving a summary effect estimate of 1.03 (95% CI 1.02–1.04) per kg/m2, with moderateheterogeneity (figure 6.1.6). This would produce anincreased risk of 15 per cent for each 5 kg/m2, assuming a

C H A P T E R

Figure 6.1.6

6•

B O D YC O M P O S I T I O N ,G R O W T H ,BMI and colorectal cancer; cohort studies

A N D

D E V E L O P M E N T

Figure 6.1.7

BMI and colon cancer, cohort studies

Relative risk (95% CI)
Wu 1987 Men
Wu 1987 Women
Klatsky 1988
Kreiger 1992 Men
Kreiger 1992 Women
Suadcani 1993 Women
Giovannucci 1995 Women
Chyou 1996 Men
Thune 1996 Men
Thune 1996 Women
Martinez 1997 Women
Tulinius1997 Men
Singh 1998 Men
Singh 1998 WomenFord 1999
Schoen 1999
Kalo 1999 Women
Nilsen 2001 Men
Nilsen 2001 Women
Terry 2001 Women age 55–76
Terry 2001 Women age 40–54
Colbeit 2001 Women
Nielsen 2002 MenNielsen 2002 Women
Kmet 2003 Women
Sadah 2003
Shimizu 2003 Men
Shimizu 2003 WomenKoh 2004
Moore 2004 Men age 55–79
Moore 2004 Women age 55–79
Moore 2004 Men age 30–54
Moore 2004 Women age 30–54
Madnnis 2004 Men
Lin 2004 Men
Kuriyama 2005 Men
Kuriyama 2005 Women
Oh 2005 Men
Rapp 2005 Men
Rapp 2005 Women
Pischon 2006 Men
Pischon 2006 Women
Summary estimate

0.5

1.23 (0.98–1.54)
1.04 (0.92–1.18)
1.48 (1.22–1.79)
1.09 (1.00–1.18)
1.03 (0.99–1.08)
0.90 (0.84–0.98)
1.05 (1.01–1.10)
1.06 (1.03–1.10)
1.02 (1.00–1.04)
0.99 (0.95–1.04)
1.02 (1.00–1.05)
1.04 (1.00–1.08)
1.09 (0.98–1.21)
1.00 (0.95–1.07)
1.10 (0.92–1.32)
1.02 (0.98–1.07)
1.01 (0.98–1.05)
1.00 (0.98–1.03)
1.01 (0.97–1.04)
1.09 (1.02–1.16)
1.04 (0.99–1.08)
1.00 (0.97–1.03)
1.06 (1.01–1.11)
1.01 (0.98–1.05)
1.04 (0.99–1.10)
1.06 (0.90–1.24)
1.05 (1.00–1.10)
1.27 (1.08–1.50)
1.06 (0.98–1.14)
1.02 (0.95–1.09)
1.14 (1.01–1.28)
1.05 (1.01–1.10)
1.01 (0.92–1.11)
1.04 (1.01–1.08)
1.04 (0.99–1.10)
1.05 (1.00–1.10)
1.05 (1.02–1.07)
1.05 (1.01–1.08)
1.01 (0.99–1.03)
1.01 (0.99–1.03)
1.03 (1.02–1.04)
1.04 (1.01–1.08)
1.03 (1.02–1.04)

0.75

1

1.5

2

Relative risk (95% CI)
Wu 1987 Men
Wu 1987 Women
Gerhardsson 1988
Chute 1991 Women
Lee 1992 Men
Le Marchand 1992 Men
Moller 1994 Men
Moller 1994 Women
Chyou 2006 Men
Gaard 1997 Men
Gaard 1997 Women
Singh 1998 Men
Singh 1998 Women
Robsahm 1999 Men
Robsahm 1999 WomenFord 1999 Men
Ford 1999 Women
Folsom 2000 Women
Terry 2001 Women
Nilsen 2001 Men
Nilsen 2001 Women
Terry 2002 Women
Kmet 2003 Women
Saydah 2003
Shimizu 2003 Men
Shimizu 2003 Women
Wei 2003 Men
Samanic 2004 Men
Mclnnis 2004 Men
More 2004

25

2.23 (0.70–7.10)
1.33 (0.60–2.92)
1.00 (0.54–1.84)
1.50 (0.82–2.76)
1.52 (1.06–2.17)
1.40 (1.09–1.79)
1.30 (1.00–1.69)
1.20 (1.01–1.42)
1.38 (1.01–1.89)
1.64 (0.92–2.92)
1.02 (0.53–1.97)
2.63 (1.12–6.15)
1.05 (0.63–1.75)
1.39 (1.34–1.44)
1.07 (0.99–1.15)
2.95 (0.99–8.76)
2.74 (1.04–7.23)
1.70 (1.20–2.40)
1.21 (0.86–1.70)
1.11 (0.73–1.68)
1.11 (0.71–1.74)
0.95 (0.67–1.34)
2.20 (1.22–3.97)
1.79 (1.02–3.14)
2.11 (1.26–3.53)
1.22 (0.69–2.15)
1.85 (1.26–2.72)
1.47 (1.39–1.55)
1.70 (1.07–2.71)
1.60 (1.01–2.53)

1

2

5

Relative risk, highest vs lowest exposure category

Figure 6.1.8

BMI and rectal cancer, cohort studies

Relative risk, per 1 kg/m2
Relative risk (95% CI)

linear relationship, although a curvilinear dose-response
relationship cannot be ruled out.
When stratified according to cancer site, data suggest alarger increased risk and are more consistent for colon cancer (figure 6.1.7) than for rectal cancer (figure 6.1.8), or forcolorectal cancer as a whole (figure 6.1.6). A clear doseresponse relationship was apparent from cohort data forcolorectal cancer (figure 6.1.9).
Because of the abundant prospective data from cohort
studies, case-control studies were not summarised.
The general mechanisms through which body fatness
could plausibly influence cancer risk are outlined in 6.1.3(also see box 2.4).
There is abundant and consistent epidemiologicalevidence with a clear dose response, and evidence forplausible mechanisms that operate in humans. The
evidence that greater body fatness is a cause ofcolorectal cancer is convincing.

Le Marchand 1992 Men
Moller 1994 Men
Moller 1994 Women
Chyou 1996 Men
Gaard 1997 Men
Gaard 1997 Women
Robsahm 1999 Men
Robsahm 1999 Women
Terry 2001 Women
Schloss 1997 Women
Saydah 2003
Wei 2003 Men
Wei 2003 Women
Shimizu 2003 Men
Shimizu 2003 Women
Samanic 2004 Men

0.80 (0.52–1.24)
1.00 (0.71–1.41)
1.20 (0.93–1.04)
0.63 (0.38–1.04)
1.61 (0.76–3.43)
0.64 (0.31–1.33)
1.16 (1.06–1.26)
1.03 (0.93–1.14)
1.32 (0.83–2.09)
1.35 (0.88–2.08)
1.64 (0.68–3.95)
1.03 (0.49–2.15)
1.56 (1.01–2.41)
0.83 (0.42–1.64)
0.83 (0.35–1.98)
1.23 (1.14–1.33)

0.2
0.5
1
2
5
Relative risk, highest vs lowest exposure category

The Panel is aware that since the conclusion of the SLR, sevencohort30 31 52 143-146 and two case-control studies147 148 have been
published. This new information does not change the Panel
judgement (also see box 3.8).

217

P A R T

BMI and colorectal cancer; cohort studies:dose response

Figure 6.1.9

2

Figure 6.1.10•

E V I D E N C E

A N D

J U D G E M E N T S

BMI and breast cancer (age unspecified);cohort and case-control studies
Relative risk (95% CI)

Lee 1975 Men
Saydah 2003
Blondon 2000 Men
Kritchevsky 1984 WomenFord 1999 Women
Chyou 1996 Men

CohortGalanis 1998
Mills 1989
Key 1999
Wolk 1998
Silvera 2005
Byrne 1996
Overvad 1991
Tornberg 1994
Rapp 2005
Zhang 2003
Vatten 1992
Wu 1999
Wu 1999
Kilkkinen 2004
Rissanen 2003
Knekt 1996
Summary estimate

1.11 (1.05–1.18)
1.11 (1.01–1.22)
1.07 (1.00–1.08)
1.04 (1.00–1.08)
1.03 (0.99–1.07)
1.02 (0.90–1.16)
1.01 (0.85–1.21)
1.01 (0.97–1.05)
1.00 (0.98–1.03)
1.00 (0.96–1.05)
0.96 (0.93–0.99)
0.96 (0.82–1.11)
0.94 (0.80–1.12)
0.92 (0.85–1.00)
0.90 (0.81–1.01)
0.88 (0.79–0.99)
1.01 (1.00–1.02)

Case control
Henquin 1994
Henquin 1994
Hietanen 1994
Young 1989
Kato 1992
Zhu 2005
Talamini 1984
Wenten 2001
Hirose 1999
Malin 2005
Tung 1999
Eid 1998
Thomas 1996
Potischman 1990
Yoo 2001
Bonilla-Fernandez 2003
Dai 2002
Shu 2001
Do 2003
Richardson 1991
Pietinen 2001
Joensuu 1992
Viladiu 1996
Sarin 1985
Shrubsole 2001
Lopez-Carillo 1997
Hsieh 1990
Toti 1986
Zheng 2000
Holmberg 1994
Challier 1998
Trentham-Dietz 2000
Silva 2004
Newcomb 1994
Okobia 2005
Swanson 1989
Ingram 1991
Fioretti 1999
Adebamowo 2003
Gerber 1988Friedenreich 2001
Sonnichsen 1990
Adami 1977
Zheng 2000
Hislop 1986
McCredie 1998
Moorman 2001
Furberg 1999
Ferranoni 1991
Coates 1999
Kuru 2002
Chie 1998
Bagga 2002
Wenten 2001
Drewnowski 2000
Petrek 1993
Zheng 2000
Bouchardy 1990
Mendonca 1999
Ueji 1997
Agurs-Collins 1998
Ibarluzea 2004
Summary estimate

1.34 (1.05–1.71)
1.34 (0.91–1.96)
1.29 (0.92–1.82)
1.15 (1.06–1.24)
1.14 (1.06–1.24)
1.14 (1.05–1.24)
1.12 (1.03–1.21)
1.11 (1.03–1.20)
1.10 (1.06–1.15)
1.10 (1.05–1.16)
1.10 (1.01–1.20)
1.10 (0.89–1.36)
1.09 (1.02–1.17)
1.08 (0.96–1.22)
1.08 (1.04–1.12)
1.08 (0.98–1.19)
1.07 (1.03–1.12)
1.07 (1.03–1.12)
1.07 (1.04–1.11)
1.07 (0.98–1.17)
1.07 (0.98–1.16)
1.07 (0.97–1.17)
1.06 (0.98–1.16)
1.06 (0.90–1.24)
1.05 (1.01–1.10)
1.05 (0.95–1.17)
1.05 (1.03–1.07)
1.05 (1.00–1.10)
1.04 (0.93–1.17)
1.04 (0.94–1.15)
1.04 (0.95–1.15)
1.04 (1.02–1.06)
1.04 (0.97–1.11)
1.03 (1.01–1.05)
1.03 (0.93–1.14)
1.03 (1.00–1.06)
1.02 (0.94–1.12)
1.02 (0.96–1.08)
1.00 (0.92–1.09)
1.00 (0.90–1.10)
0.99 (0.97–1.02)
0.99 (0.86–1.13)
0.99 (0.89–1.09)
0.98 (0.87–1.12)
0.97 (0.91–1.04)
0.97 (0.92–1.03)
0.97 (0.92–1.03)
0.97 (0.94–1.01)
0.97 (0.88–1.06)
0.96 (0.94–0.98)
0.96 (0.90–1.01)
0.95 (0.80–1.14)
0.95 (0.85–1.07)
0.95 (0.89–1.02)
0.94 (0.86–1.01)
0.92 (0.81–1.04)
0.91 (0.83–1.01)
0.90 (0.86–0.94)
0.90 (0.81–1.00)
0.90 (0.78–1.03)
0.89 (0.82–0.98)
0.84 (0.77–0.90)
1.02 (1.02–1.03)

Bostick 1994 Women
Bostick 1994 WomenKoh 2004

10

20

30

40

BMI (kg/m2)

BreastForty-three cohort studies,42 45 50 122 149-204156 case-control
studies,66 205-359 and 2 ecological studies360 361 investigatedbody fatness (as measured by BMI) and breast cancer.
Age unspecified

Twenty-six cohort studies45 50 152-154 161 162 164 166 168 171 172 179 181
and 73 case-control studies investigated body fatness,66 205 207-209 211-215 219 221 222 224 225 228-230 232 234188 191 192 194-197 201-204

236 238-240 243-245 251 252 254 255 257 259-261 263-267 269 270 273 276-278 281 282
285 289-292 294-296 298-301 304-306 309 310 313 314 316-319 321-326 329 332 334337 341-344 347-356 359(as measured by BMI) and breast cancer at
all ages, or where menopausal status was unspecified.
Sixteen cohort studies showed increased risk withincreased body fatness,45 50 152-154 162 164 166 168 171 173 179 181 184
186 188 191 192 201 203 204
which was statistically significant inthree.162 171 179 201 Eight studies showed decreased risk,161 172
173 184 186 194-197 202
which was statistically significant in two.173
196 197
Two studies showed no effect on risk.50 204 Meta-analysis was possible on 16 cohort studies, giving a summary
effect estimate of 1.01 (95% CI 1.00–1.02) per 2 kg/m2, withmoderate heterogeneity (figure 6.1.10).
Forty-seven case-control studies showed increased risk
with increased body fatness66 208 211 213 215 221 222 224 230 232 235
236 239 240 251 252 254 255 257 260 261 265-267 269 276 277 281 282 285 294-296
298-301 305 306 309 310 313 314 316-319 323-326 329 332 334-337 341 343 344 347-

; this was statistically significant in 2266 208 211 222

350 352-356 359

230 232 235 254 255 269 277 285 295 296 298 316-318 329 332 334 336 337 341 349; 4 studies showed no effect on risk207 245 278 351; andthe remaining 22 showed decreased risk,205 209 212 214 219 225
228 229 234 238 243 244 259 263 264 270 273 289-292 304 321 322 342 349
which
was statistically significant in 4 studies.214 263 264 291 One of352 353 359

218

0.5

1

1.5

Relative risk, per 2 kg/m2

2

C H A P T E R

6•

B O D YC O M P O S I T I O N ,G R O W T H ,these studies showed significant increased risk withincreased body fatness in Hispanic-American people but nonsignificant decreased risks among white-American people.349
Meta-analysis was possible on 62 case-control studies, giving a summary effect estimate of 1.02 (95% CI 1.02–1.03)
per 2 kg/m2, with high heterogeneity (figure 6.1.10).
The two ecological studies showed no consistentassociation.360 361
Postmenopause

Twenty-four cohort studies42 45 50 122 149-151 155-159 162 163 165 167
and 56 case-control studies investigated body fatness,66 205-208 214 220 224-227 231 233 237 239
169 170 174 175 178 180 182-185 187-195 199 200

241 242 244 246-250 253-259 261-263 268 271 274 275 279-283 286-288 293 295-297
302 304 308 311 315 321 322 327 329 331 333 336-341 345 349 352 357-359(as measured by BMI) and postmenopausal breast cancer.
Nineteen cohort studies showed increased risk withincreased body fatness,42 45 50 122 149 151 155-159 162 163 165 167 174
175 180 183-185 187-194 199 200
which was statistically significant inseven.42 45 149 158 162 163 174 175 180 183 189 192 Five studies showeddecreased risk,150 169 170 178 182 195 which was statistically significant in one.150 Meta-analysis was possible on 17 studies,giving a summary effect estimate of 1.03 (95% CI 1.01–1.04)
per 2 kg/m2, with high heterogeneity (figure 6.1.11). This
would produce an increased risk of 8 per cent for each
5 kg/m2, assuming a linear relationship, although a curvilinear dose-response relationship cannot be ruled out.
Heterogeneity may be explained partially by failure to adjust
for hormone replacement therapy (HRT) use. Three major
studies that reported results stratified for HRT status all
found statistically significant increased risk with increasing
body fatness only in women not taking HRT.
Pooled analysis from seven cohort studies (more than
337 000 participants, followed up for up to 11 years, withmore than 4300 breast cancer cases) showed a significant

Figure 6.1.11

BMI and postmenopausal breast cancer;
cohort studies

A N D

D E V E L O P M E N T

Figure 6.1.12

BMI and postmenopausal breast cancer;
case-control studies
Relative risk (95% CI)

Chie 1996
Hu 1997
Zhu 1996
Hirose 2003
Park 2000
Hansen 1997
Rattanamongkolg 2002
Zhu 2005
Yoo 2001
Talamini 1984
Tung 1999
Lopez-Carrillo 1997
Graham 1991
Chow 2005
Magnusson 1998
Rosenburg 1990
Trentham-Dietz 2000
Toti 1986
Harris 1992
Taioli 1995
Kohlmeier 1997
Li 2000
Newcomb 1999
Shoff 2000
Swanson 1989
Trentham-Dietz 1997
Dorn 2003
Carpenter 2003
Li 2003
Hsieh 1990
Fioretti 1999
Franceschi 1996
Terry 2002
Ng 1997
Hall 2000
Adebamowo 2003
Van’t Veer 1989
Marubini 1988
Helmrich 1983
McCann 2004
Adami 1977
Hislop 1986
Hall 2000
Sonnichsen 1990
Friedenreich 2002
Petrek 1993
De Vasconcelos 2001
Adams-Campbell 1996
Summary estimate

0.8

1.31 (0.80–2.13)
1.25 (0.95–1.63)
1.21 (0.89–1.64)
1.18 (1.13–1.24)
1.18 (1.13–1.24)
1.17 (0.95–1.43)
1.15 (1.05–1.25)
1.15 (1.01–1.30)
1.14 (1.08–1.21)
1.13 (1.02–1.25)
1.13 (1.01–1.25)
1.13 (0.97–1.32)
1.11 (1.04–1.19)
1.10 (1.01–1.19)
1.09 (1.06–1.12)
1.08 (0.99–1.18)
1.08 (1.06–1.10)
1.08 (1.02–1.14)
1.08 (1.00–1.16)
1.07 (1.00–1.16)
1.07 (1.01–1.13)
1.06 (1.00–1.13)
1.06 (1.04–1.09)
1.06 (1.04–1.09)
1.06 (1.01–1.11)
1.06 (1.04–1.08)
1.06 (1.01–1.11)
1.06 (1.02–1.10)
1.06 (1.01–1.10)
1.05 (1.03–1.07)
1.05 (0.97–1.13)
1.05 (1.02–1.07)
1.05 (1.02–1.07)
1.04 (0.94–1.16)
1.04 (0.96–1.13)
1.04 (0.94–1.15)
1.04 (0.88–1.22)
1.03 (0.91–1.17)
1.03 (0.99–1.06)
1.02 (0.99–1.05)
1.01 (0.91–1.13)
1.01 (0.92–1.10)
1.00 (0.96–1.04)
1.00 (0.98–1.02)
1.00 (0.96–1.04)
0.97 (0.85–1.11)
0.94 (0.85–1.03)
0.90 (0.83–0.98)
1.05 (1.05–1.06)

1

1.5

2

Relative risk, per 2 kg/m2

Relative risk (95% CI)

Sonnenschein 1999
Toniolo 1994
Galanis 1998
Gapstur 1992
Wirfalt 2004
Saadatian-Elahi 2002
Barrett-Connor 1993
Tornberg 1994
Tulinius 1997
Tehard 2004
Van den Brandt
Huang 1997
Rissanen 2003
Manjer 2001
Kaaks 1998
Jumaan 1999
Summary estimate

0.5

1.20 (1.08–1.34)
1.20 (1.05–1.39)
1.09 (1.01–1.16)
1.08 (1.04–1.13)
1.07 (1.00–1.15)
1.07 (0.95–1.19)
1.06 (0.80–1.41)
1.05 (1.01–1.09)
1.04 (0.98–1.10)
1.03 (1.00–1.07)
1.03 (0.97–1.09)
1.02 (0.99–1.05)
1.01 (0.85–1.21)
0.97 (0.88–1.07)
0.97 (0.86–1.09)
0.95 (0.87–1.03)
1.03 (1.01–1.04)

1

1.5

Relative risk, per 2 kg/m2

2

increased risk of postmenopausal breast cancer withincreased body fatness. The effect estimate was 1.07
(95% CI 1.02–1.11) per 4 kg/m2.362
Most case-control studies showed increased risk withincreased body fatness,66 205 207 208 220 224-227 233 237 239 241 246-250
253-258 261 262 271 274 275 279-283 286-288 293 295-297 302 308 311 315 327 329
331 333 336-341 345 349 352 357-359
which was statistically significant
in approximately half of these studies.66 220 227 233 237 241 246 253258 261 275 280 283 293 295 296 302 308 315 329 333 336 338-341 352 359
Metaanalysis was possible on 48 studies, giving a summary effectestimate of 1.05 (95% CI 1.05–1.06) per 2 kg/m2, with moderate heterogeneity (figure 6.1.12). This would produce anincreased risk of 13 per cent for each 5 kg/m2, assuming alinear relationship, although a curvilinear dose-response

219

P A R T

Figure 6.1.13

BMI and postmenopausal breast cancer;
cohort studies: dose response

2

Figure 6.1.14•

E V I D E N C E

A N D

J U D G E M E N T S

BMI and premenopausal breast cancer;
case-control studies: dose response

Zhu 2005

Manjer 2001

Chow 2005
Toniolo 1994

Shoff 2000
Rosenberg 1990

Tehard 2004

Rattanamongkolg 2002
Newcomb 1999

Sonnenschein 1999

Park 2000
Ng 1997

Kaaks 1998

Marubini 1988
Magnusson 1998

Jumaan 1999

Lopez-Carillo 1997
Huang 1997

Li 2000

Gapstur 1992

Tung 1999

Li 2003
Toti 1986
Galanis 1998

Talamini 1984
Taioli 1995
Swanson 1989

16

18

20

22

24

26

28

30

32

34

Hu 1997

BMI (kg/m2)

Hislop 1986
Hirose 2003
Helmrich 1983
Harris 2003
Graham 1991
Friedenreich 2002
Fioretti 1999
De Vasconcelos 2001

relationship cannot be ruled out. Heterogeneity may be partially explained by differential adjustment between studies.
A dose-response relationship is apparent from cohort andcase-control data (figure 6.1.13, figure 6.1.14).
The general mechanisms through which body fatness
could plausibly influence cancer risk are outlined in 6.1.3(also see box 2.4).
There is abundant and consistent epidemiologicalevidence and a clear dose response, with robust
evidence for mechanisms operating in humans. The
evidence that greater body fatness is a cause of
postmenopausal breast cancer is convincing.

The Panel is aware that since the conclusion of the SLR, onecohort363 and one case-control study364 have been published.
This new information does not change the Panel judgement(also see box 3.8).
Premenopause

Twenty cohort studies45 122 149 150 155 162 167 170 174-178 184 185 188192 195-198
and 59 case-control studies66 205-208 210 214 216-218 223227 231 233 237 239 241 242 247-250 253-259 261-263 268 269 272 281 282 284 286-290
293 297 302-304 306-308 311 312 320-322 324-330 336-341 343-346 349 352 357-359

investigated body fatness (as measured by BMI) and premenopausal breast cancer.
Thirteen cohort studies showed decreased risk withincreased body fatness,45 149 150 167 170 174-176 184 185 189 191 192 195198
which was statistically significant in seven.149 150 167 176 184
192 195-198
Four studies showed non-significant increased
risk.155 162 188 190 Three studies showed no effect on risk.122

220

Chie 1996
Carpenter 2003

12

16

20

24

28

32

36

40

44

BMI (kg/m2)

177 178

Meta-analysis was possible on 14 studies, giving asummary effect estimate of 0.94 (95% CI 0.92–0.95) per
2 kg/m2, with moderate heterogeneity (figure 6.1.15). This
would produce a decreased risk of 15 per cent for each
5 kg/m2, assuming a linear relationship, although a curvilinear dose response cannot be ruled out.
Egger’s test for publication bias suggested some overrepresentation of studies showing a protective effect onpremenopausal breast cancer of increasing BMI.
Pooled analysis from 7 cohort studies (more than 337 000
participants, followed up for up to 11 years, with more than
4300 breast cancer cases) showed a significant decreased riskof premenopausal breast cancer with increased body fatness.
The effect estimate was 0.89 (95% CI 0.81–0.97) per 4
kg/m2.365
Most case-control studies showed decreased risk withincreased body fatness,205 206 214 216-218 223-225 231 233 237 239 241 242
247-250 259 262 263 268 281 282 284 286-290 293 297 302-304 311 324-328 330 338341 349

which was statistically significant in approximately one
third of these studies.214 218 223 231 237 250 262 268 303 304 326 327 330

C H A P T E R

6

Figure 6.1.15•

B O D YC O M P O S I T I O N ,G R O W T H ,BMI and premenopausal breast cancer;
cohort studies

A N D

D E V E L O P M E N T

Figure 6.1.16

BMI and premenopausal breast cancer;
cohort studies: dose response

Relative risk (95% CI)
Galanis 1998

1.09 (0.96–1.25)

Toniolo 1994

1.09 (0.96–1.23)

Manjer 2001

1.00 (0.89–1.13)

Tulinius 1997

1.00 (0.92–1.09)

Karaks 1998

0.99 (0.89–1.10)

Sonnenschein 1999

0.95 (0.84–1.07)

Huang 1997

0.95 (0.91–0.98)

Saadatien-Elahi 2002

0.94 (0.83–1.07)

Vatten 1992

0.94 (0.90–0.98)

Tehard 2004

0.93 (0.87–0.99)

Weiderpass 2004

0.92 (0.88–0.96)

Ahlgren 2004

0.92 (0.88–0.96)

Tornberg 1994

0.86 (0.80–0.92)

Rissanen 2003

0.75 (0.62–0.90)

Summary estimate

0.94 (0.92–0.95)

Manjer 2001

Vatten 1992

Toniolo 1994

Tehard 2004

Sonnenschein 1999

Kaaks 1998

Huang 1997
0.5

1
Relative risk, per 2 kg/m2

1.5
Galanis 1998

16

18

20

22

24

26

28

30

32

BMI (kg/m2)

Meta-analysis was possible on 51 case-control studies,205-208
216 218 223 226 231 233 239 241 242 247-250 256 258 259 261 262 272 281 282 284

outweighed by an increased risk of postmenopausal
breast cancer (also see chapter 7.10).

286-290 297 302-304 306-308 311 312 320-322 324-329 336 338-341 343-346 352 357
359
giving a summary effect estimate of 0.97 (95% CI
0.96–0.97) per 2 kg/m2, with moderate heterogeneity.
A dose-response relationship was apparent from cohort(figure 6.1.16) and case-control data.
There is no single, well-established mechanism throughwhich body fatness could prevent premenopausal breast cancer. According to the oestrogen plus progesterone theory,
overweight premenopausal women would be protected
because they would be more frequently anovulatory andtherefore less exposed to endogenous progesterone.
However, this theory is not well supported by recent studies,
which suggest that natural progesterone could be protective.365 Normal levels of natural progesterone are likely
to be protective and women who are well nourished, or
perhaps overnourished, who may become slightly overweight in adulthood, may be protected by their natural
fertile condition. Another possible mechanism is that theincreased adipose tissue-derived oestrogen levels in overweight children could induce early breast differentiation andeliminate some targets for malignant transformation.366
Anovulation and abnormal hormone profiles are commonly
associated with obesity.367 The age-specific pattern of association of breast cancer with BMI, therefore, is largely
explained by its relationship with endogenous sex hormone
levels.
Breast cancer diagnosed postmenopause is much morecommon. Therefore, throughout life, a decreased risk of
premenopausal breast cancer would be expected to be

There is a substantial amount of consistentepidemiological evidence, with a dose response, but
the mechanistic evidence is speculative. Greater bodyfatness probably protects against premenopausal
breast cancer.

The Panel is aware that since the conclusion of the SLR, onecohort363 and one case-control study364 have been published.
This new information does not change the Panel judgement(also see box 3.8).
Endometrium

Twenty-three cohort studies,45 50 52 55 122 137 168 192 368-385 41
case-control studies,254 386-455 and 2 cross-sectional studies456458
investigated body fatness (as measured by BMI) andendometrial cancer. Three cohort studies168 376 382 and 6 casecontrol studies254 409 416 422 424 425 441 investigated BMI measured as a young adult.
Twenty-two cohort studies showed increased risk withincreased body fatness,50 52 55 122 137 168 192 368-370 373-377 380-383
which was statistically significant in 16.384 One small study
showed non-significant decreased risk.376 382 Meta-analysis
was possible on 15 cohort studies, giving a summary effectestimate of 1.52 (95% CI 1.35–1.72) per 5 kg/m2, with highheterogeneity (figure 6.1.17).
Nearly all of the case-control studies showed increased risk
with increased body fatness, most of which were statistically significant.254 387-390 392 394-409 411-438 440-443 446 453 454 One

221

P A R T

Figure 6.1.17

BMI and endometrial cancer; cohort andcase-control studies

Figure 6.1.18

2•

E V I D E N C E

A N D

J U D G E M E N T S

BMI and endometrial cancer; cohort studies:dose response

Relative risk (95% CI)
Baanders-van Halewijn 1985

CohortEwertz 1984
Baanders-van Halewn 1985
Tornberg 1994
Tulinius 1997
Bernstein 1999
Calle 2003
Folsom 2003
Furberg 2003
Jonsson 2003
Schouten 2004
Kuriyama 2005
Lacey 2005
Rapp 2005
Silvera 2005
Lukanova 2006
Summary estimate

1.26 (0.93–1.70)
1.71 (0.83–3.50)
1.54 (1.33–1.78)
1.31 (1.07–1.61)
1.39 (1.15–1.69)
1.40 (1.29–1.51)
1.76 (1.58–1.96)
1.59 (1.21–2.09)
1.86 (1.49–2.33)
1.84 (1.48–2.30)
1.63 (0.94–2.82)
1.07 (1.00–1.14)
1.48 (1.29–1.71)
1.75 (1.56–1.96)
1.85 (1.33–2.57)
1.52 (1.35–1.72)

Case control
Elwood 1977
La Vecchia 1982
Evertz 1988
Cusimano 1989
Zhang 1989
Austin 1991
Levi 1993
Shu 1993
Swanson 1993
Olson 1995
Parazzini 1995
Gruber 1996
Kalandidi 1996
Goodman 1997
Geraci 1998
Hachisuga 1998
Hose 1999
Beard 2000
Salazar-Martinez 2000
Weiderpass 2000
Newcomer 2001
Petitlou 2002
Augustin 2003
Hom-Ross 2003
Augustin 2003
Trentham-Dietz 2005
Xu 2005
Okamura 2006
Summary estimate

Ewertz 1984
Calle 2003
Bernstein 1999
Jonsson 2003
Folsom 2003
Silvera 2005
Rapp 2005
Lukanova 2006
Lacey 2005
Kuriyama 2005

1.34 (1.10–1.63)
1.99 (1.62–2.46)
1.57 (1.19–2.08)
1.36 (0.98–1.88)
1.63 (1.29–2.05)
1.36 (1.15–1.60)
1.38 (1.12–1.71)
1.43 (1.07–1.91)
1.25 (1.07–1.47)
1.76 (1.41–2.20)
1.59 (1.44–1.76)
1.73 (1.57–1.91)
1.93 (1.48–2.51)
1.99 (1.62–2.44)
1.47 (0.96–2.24)
1.46 (1.17–1.81)
1.65 (1.18–2.29)
1.34 (1.06–1.69)
1.44 (1.09–1.90)
1.69 (1.50–1.89)
1.58 (1.44–1.74)
2.12 (1.37–3.27)
1.29 (1.08–1.54)
1.16 (1.08–1.25)
2.10 (1.27–3.48)
1.69 (1.54–1.84)
1.78 (1.54–2.06)
1.74 (1.02–2.97)
1.56 (1.45–1.66)

Furberg 2003

10

20

30

40

50

BMI (kg/m2)

evidence of effect modification by menopause, smoking, oroestrogen-use status.
Both cross-sectional studies reported an association
between higher BMI and increased risk of endometrial
cancer.456-458
The general mechanisms through which body fatness
could plausibly influence cancer risk are outlined in 6.1.3(also see box 2.4).
BMI as a young adult

0.5

1

2

3

Relative risk, per 5 kg/m2

study showed no effect on risk after adjustment for waist circumference, but the unadjusted result showed a statistically significant increased risk.455 No studies showed decreased
risk with increased body fatness. Meta-analysis was possibleon 28 case-control studies, giving a summary effect estimateof 1.56 (95% CI 1.45–1.66) per 5 kg/m2, with high heterogeneity (figure 6.1.17). Heterogeneity was predominantly
the result of variation in the size of effect, rather than direction of effect.
A dose-response relationship is apparent from cohort andcase-control data (figures 6.1.17 and 6.1.18). There was no222

All three cohort studies showed increased risk with increased
body fatness, which was statistically significant in two.376 382
Meta-analysis was possible on all three cohort studies, giving a summary effect estimate of 1.31 (95% CI 1.12–1.54)
per 5 kg/m2, with no heterogeneity.168 376 382
Four case-control studies showed non-significant increased
risk with increased body fatness,409 416 424 425 441 and two
showed non-significant decreased risk.254 422 Meta-analysis
was possible on all six case-control studies, giving a summary
effect estimate of 1.10 (95% CI 0.95–1.27) per 5 kg/m2, withlow heterogeneity.254 409 416 422 424 425 441
A dose-response relationship was apparent from cohort but
not case-control data.
There is abundant consistent epidemiological evidencewith a clear dose response, and robust evidence formechanisms operating in humans. The evidence that
greater body fatness is a cause of endometrial cancer isconvincing.

C H A P T E R

6•

B O D YC O M P O S I T I O N ,G R O W T H ,The Panel is aware that since the conclusion of the SLR, onecohort study146 and one case control study459 have been published. This new information does not change the Panel judgement (also see box 3.8).

D E V E L O P M E N T

Figure 6.1.20

BMI and kidney cancer; cohort andcase-control studies: dose response

CohortKidney42 45 57 122 279 460-473

Seventeen cohort studies
and 20 casecontrol studies66 474-502 investigated body fatness (as measured by BMI) and kidney cancer.
Fifteen cohort studies showed increased risk withincreased body fatness42 45 57 122 279 460-468 470-472; this was statistically significant in seven studies,57 122 460 461 465 466 468 472
and in women but not men in another.42 Two studies statedthat there was no statistically significant association.469 473 No
cohort studies showed decreased risk. Meta-analysis was possible on seven cohort studies that adjusted for smoking, giving a summary effect estimate of 1.31 (95% CI 1.24–1.39)
per 5 kg/m2, with low heterogeneity (figure 6.1.19)
Eighteen case-control studies66 474-493 495-497 499-502 showed
increased risk with increased body fatness; this was statistically significant in 14 studies,66 474 476-478 480-483 485 487 488 490493 495-497 500
and in men but not women in another.501 One
study showed no effect on risk498 and another (where thecontrols were not drawn from the same population as thecases, making it a relatively low-quality study) showed anon-significant decreased risk.494 Meta-analysis was possibleon two case-control studies that adjusted for smoking andeight unadjusted case-control studies. This gave summary
effect estimates of 2.05 (95% CI 1.43–2.92) per 5 kg/m2,
with low heterogeneity, and 1.42 (95% CI 1.17–1.72) per 5kg/m2, with high heterogeneity, respectively (figure 6.1.19).
A dose-response relationship is apparent from cohort andcase-control data (figure 6.1.20).
The general mechanisms through which body fatness
could plausibly influence cancer risk are outlined in 6.1.3

Figure 6.1.19

A N D

BMI and kidney cancer; cohort andcase-control studies

Flaherty 2005
Oh 2005
Hiatt 1994
Gamble 1996
Chow 2000

Case control
Boeing 1997
Mattioli 2002

17.5

20

22.5

25

27.5

30

BMI (kg/m2 )and box 2.4; in addition, laboratory studies point to a potential role for insulin and leptin in renal cell carcinoma.503 504
There is abundant and consistent epidemiologicalevidence with a dose-response relationship andevidence of plausible mechanisms. The evidence that
greater body fatness is a cause of kidney cancer isconvincing.

The Panel is aware that since the conclusion of the SLR, threecohort studies30 52 142 and one case-control study505 have been
published. This new information does not change the Panel
judgement (also see box 3.8).

Relative risk (95% CI)

Gallbladder

CohortChow 2000

1.37 (1.18–1.59)

Flaherty 2005

1.52 (1.00–2.31)

Oh 2005

1.43 (1.22–1.67)

Hiatt 1994

1.18 (0.82–1.70)

Van Dijk 2004

1.27 (1.23–1.31)

Bjorge 2004

1.28 (1.24–1.33)

Gamble 1996

2.53 (1.12–5.68)

Summary estimate

1.31 (1.24–1.39)

Case control
Mattioli 2002

2.74 (1.40–5.32)

Boeing 1997

1.83 (1.21–2.76)

Summary estimate

2.05 (1.43–2.92)

0.25

0.5

1

2

4

Relative risk, per 5 kg/m2

Five cohort studies,42 45 56 58 141 201 seven case-control studies,506-514 and two cross-sectional studies515-517 investigatedbody fatness (as measured by BMI) and gallbladder cancer.
Most cohort studies showed increased risk with increased
body fatness. For two studies, results for the whole cohort
showed statistically significant increased risk.42 201 One study
reported significant increased risk for women and nonsignificant increased risk for men,141 while another reported statistically significant increased risk for women andnon-significant decreased risk for men.45 One study reported a significant increased risk for white men and a nonsignificant decreased risk for black men.56 Meta-analysis was
possible on four cohort studies, giving a summary effectestimate of 1.23 (95% CI 1.15–1.32) per 5 kg/m2, withmoderate heterogeneity (figure 6.1.21).
Most case-control studies showed increased risk withincreased body fatness,506 507 509 510 513 514 which was223

P A R T

Figure 6.1.21

BMI and gallbladder cancer; cohort studies
Relative risk (95% CI)

Calle 2003 Men

1.38 (1.05–1.82)

Calle 2003 Women

1.28 (1.14–1.43)

Samanic 2004 Black Men

0.97 (0.58–1.64)

Samanic 2004 White Women

1.22 (1.05–1.42)

Kuriyama 2005 Men

0.42 (0.04–4.77)

Kuriyama 2005 Women

1.91 (1.16–3.13)

Engeland 2005 Men age 45–74

1.10 (0.99–1.23)

Engeland 2005 Men age 20–44

1.15 (0.92–1.44)

Engeland 2005 Women age 20–44

1.37 (1.24–1.50)

Engeland 2005 Women age 45–74

1.19 (1.13–1.25)

Summary estimate

1.23 (1.15–1.32)

2•

E V I D E N C E

A N D

J U D G E M E N T S

a protective effect.521 Gallstone formation is strongly associated with dieting, especially where it involves rapid weightloss — such as seen with very low-energy diets and bariatricsurgery.522 523 Rapid weight loss is also a common feature ofweight cycling. Weight cycling is associated with obesity andindependently associated with gallstones; people who are
more severe weight cyclers have a higher risk of gallstones.524
There is a substantial amount of generally consistentepidemiological evidence with some evidence of a dose
response. There is evidence for several plausible
mechanisms. Greater body fatness is a probable causeof gallbladder cancer, directly and also indirectly
through the formation of gallstones.
Liver

0.25

0.5

1

2

5

Relative risk, per 5 kg/m2

statistically significant in three.506 510 513 Two studies showeddecreased risk,511 512 which was statistically significant in
one.512 One study showed no effect on risk in men, but a statistically significant increased risk in women.508 Meta-analysis was possible on all seven case-control studies,506-514 giving
a summary effect estimate of 1.19 (95% CI 0.81–1.75) per
5 kg/m2, with high heterogeneity. Heterogeneity could be atleast partly attributed to differences in the study participants’ethnicity or sex, or to the number of adjustments made in
the study. In addition, there was variation according towhether BMI was derived from direct measurements or selfreports of weight and height, as well as in the outcome measured. For example, one cohort and one case-control study
reported biliary tract cancer as opposed to gallbladder cancer specifically, and some studies reported incidence whileothers reported mortality.
The general mechanisms through which body fatness
could plausibly influence cancer risk are outlined in 6.1.3(also see box 2.5). In addition, obesity is a known cause ofgallstone formation and having gallstones increases the riskof gallbladder cancer (see chapter 7.7), possibly through bilecholesterol supersaturation leading to cholesterol-based gallstones. High cholesterol in the bile is not necessarily related to dietary cholesterol — it can also be caused by insulin
resistance, which can be caused by obesity. Insulin resistancecan independently increase cholesterol synthesis in the liverand decrease cholesterol absorption.518 Bile cholesterol levels are also gender-linked: women excrete more cholesterolin bile than men.
Owing to the link between gallstones and gallbladder cancer, the Panel reviewed the dietary causes of having gallstones, especially in relation to body fatness. BMI increased
the risk of having gallstones in a linear fashion.519 Waist circumference was associated with gallstone risk in men, independently of BMI,520 and insoluble fibre in the diet showed224

Six cohort studies42 44 54-57 525 and two case-control studies
investigated body fatness526 527 (as measured by BMI), or
obesity, and liver cancer.
Five cohort studies showed increased risk for the highest
body fatness group compared to the lowest.42 44 54 55 57 Thiswas statistically significant in two studies,54 57 and in men
but not women in another two.42 55 One cohort study showeda statistically significant increased risk in white men and asignificant decreased risk in black men.56 Effect estimates
were 1.68 in women (95% CI 0.93–3.04) and 4.52 in men(95% CI 2.94–6.94)42; 1.44 in white men (95% CI
1.28–1.61) and 0.68 in black men (95% CI 0.49–0.94)56;
1.56 in men (95% CI 1.15–2.12)57; 3.88 in men (95% CI
0.96–15.69)44; 1.9 in both sexes (95% CI 1.5–2.5)54; and1.70 in women (95% CI 0.95–3.05) and 3.60 in men (95%
CI 2.08–6.24).55
Neither case-control study showed any statistically significant association.526 527
The general mechanisms through which body fatness
could plausibly influence cancer risk are outlined in 6.1.3(also see box 2.4).
The epidemiological evidence shows someinconsistencies, and the mechanistic evidence is
speculative. There is limited evidence suggesting that
greater body fatness is a cause of liver cancer.

The Panel is aware that since the conclusion of the SLR, twocohort studies30 528 have been published. This new information
does not change the Panel judgement (see box 3.8).
Lung

Twenty-one cohort studies,42 57 76 88 122 144 529-545 24 case-control studies,546-573 and 1 ecological study574 investigated bodyfatness (as measured by BMI) and lung cancer.
Twenty cohort studies showed decreased risk withincreased body fatness42 57 76 88 122 529-545; this was statistically significant in 12 studies,42 76 122 531 533-535 540 542 543 545 and in
women but not men in another study.536 One study showedno effect on risk.144 Meta-analysis was possible on 14 cohort
studies,57 88 122 144 530 532 534 535 537 538 540 543-545 giving a summary
effect estimate of 0.98 (95% CI 0.98–0.99) per kg/m2, withhigh heterogeneity. This would produce a decreased risk of

C H A P T E R

6•

B O D YC O M P O S I T I O N ,G R O W T H ,5 per cent for each 5 kg/m2, assuming a linear relationship,
although a curvilinear dose-response relationship cannot be
ruled out. When meta-analysis was restricted to the 10 studies that adjusted for smoking, the effect estimate and CIs
remained the same, but with low heterogeneity.57 88 144 530 534
537 538 540 544
Heterogeneity was caused by variation in the size
but not the direction of the effect.
Begg’s and Egger’s tests suggested publication bias; thatis, the smaller the study, the stronger the protective association observed. Smaller studies, with results of weak or no
association, appear to have been less likely to be published.
Twenty-two case-control studies showed decreased risk
with increased body fatness,546-560 562-570 572 573 which was statistically significant in nine.548 550 551 553 557 563 564 566 567 570 572
Two studies showed increased risk,561 571 which was statistically significant in one.561 Meta-analysis was possible on 10
case-control studies,546 550 554 555 557 566-568 570 572 giving a summary effect estimate of 0.98 (95% CI 0.98–0.99) per kg/m2,
with low heterogeneity. The effect estimate was unchanged
when three studies that did not adjust for smoking were
excluded from the analysis.546 568 572
The single ecological study showed a non-significant association between increased body fatness and decreased risk.574
Smoking is the principal cause of lung cancer and may also
be associated with lower BMI. There is a high potential for
confounding due to cigarette smoking, and residual confounding is therefore possible. In addition, it is possible thatpeople with undiagnosed lung cancer may lose weight, so
giving a spurious association (reverse causation).
There is no known mechanism through which greater bodyfatness could plausibly protect against lung cancer, or
through which low body fatness could increase risk.
Although the epidemiological evidence suggests aninverse relationship, this could be caused by
confounding by cigarette smoking or reverse causation
due to weight loss from undiagnosed cancer. There islimited evidence suggesting that low body fatness is a
cause of lung cancer.

6.1.3.2 Abdominal fatness
Colorectum

Seven cohort studies87 92 97 115 118 137 142 and two case-control
studies investigated waist circumference and colorectal
cancer. Six cohort studies82 87 92 97 115 137 142 and four casecontrol studies investigated waist to hip ratio.
Waist circumference

All seven cohort studies showed increased risk with increased
waist circumference, which was statistically significant insix.87 97 115 118 137 142 Meta-analysis was possible on four cohort
studies, giving a summary effect estimate of 1.05 (95% CI
1.03–1.07) per 2.5 cm (1 inch), with moderate heterogeneity(figure 6.1.22). Both case-control studies reported increased
risk with increased waist circumference.
Waist to hip ratio

All six cohort studies showed increased risk with increased
waist to hip ratio, which was statistically significant in

A N D

D E V E L O P M E N T

Figure 6.1.22

Waist circumference and colorectal cancer;
cohort studies
Relative risk (95% CI)

Giovanucci 1995 Men

1.10 (1.04–1.15)

Folsom 2000

1.03 (1.01–1.05)

Maclnnis 2004

1.08 (1.04–1.13)

Pischon 2006 Men

1.04 (1.04–1.13)

Pischon 2006 Women

1.03 (1.01–1.06)

Summary estimate

1.05 (1.03–1.07)

0.8

0.9

1

1.1

1.2

Relative risk, per inch

Figure 6.1.23

Waist to hip ratio and colorectal cancer;
cohort studies
Relative risk (95% CI)

Giovanucci 1995 Men

1.72 (1.10–2.68)

Martinez 1997 Women

1.27 (0.97–1.66)

Folsom 2000 Women

1.16 (1.03–1.29)

Maclnnis 2004

1.68 (1.27–2.22)

Pischon 2006 Women

1.27 (1.11–1.46)

Pischon 2006 Men

1.30 (1.08–1.55)

Summary estimate

1.30 (1.17–1.44)

0.2

0.5

1

2

5

Relative risk, per 0.1 increment

five.87 97 115 137 142 Meta-analysis was possible on five cohort
studies, giving a summary effect estimate of 1.30 (95% CI
1.17–1.44) per ratio increment of 0.1, with moderate heterogeneity (figure 6.1.23). Most case-control studies reported increased risk with increased waist circumference.
Because of the abundant prospective data from cohort
studies, case-control studies were not summarised.
The general mechanisms through which body fatness andabdominal fatness could plausibly influence cancer risk areoutlined in 6.1.3 (also see box 2.4). Many of these, such asincreased circulating oestrogens and decreased insulin sensitivity, are particularly associated with abdominal rather
than overall body fatness.
There is ample, consistent epidemiological evidencewith a clear dose response and robust evidence formechanisms that operate in humans. The evidence
that abdominal fatness is a cause of colorectal cancer
is convincing.

225

P A R T

The Panel is aware that since the conclusion of the SLR, threecohort studies31 142 143 have been published. This new information does not change the Panel judgement (see box 3.8).
Pancreas

Three cohort studies investigated waist circumference andpancreatic cancer.46 74 Two cohort studies investigated waist
to hip ratio51 74 and one investigated patterns of weight gain.49
Waist circumference

All three cohort studies showed increased risk with increased
waist circumference, which was statistically significant in one.
Effect estimates were 1.32 (95% CI 0.73–2.37) per 20 cm (7.9
inches) in women,46 1.74 (95% CI 1.00–3.01) per 20 cm (7.9
inches) in men,46 and 1.13 (95% CI 1.01–1.26) per 10 cm(3.9 inches).74 The latter study was published after the cutoff date for inclusion in the SLR. However, the Panel wasaware of the study and agreed to include it in its consideration of this exposure.
Waist to hip ratio

Both cohort studies showed increased risk with increased waist
circumference, which was statistically significant in one. Effectestimates were 1.12 (95% CI 0.81–1.55; high versus low)51
and 1.24 (95% CI 1.04–1.48) per ratio increment of 0.1.74 The
latter study was published after the cut-off date for inclusionin the SLR. However, the Panel was aware of the study andagreed to include it in its consideration of this exposure.

2•

E V I D E N C E

A N D

J U D G E M E N T S

Waist to hip ratio

Six cohort studies showed increased risk with increased waist
to hip ratio,157 159 163 170 174 180 187 199 575 which was statistically significant in four.163 170 187 199 575 Two studies showed nonsignificant decreased risk.189 576 Meta-analysis was possible
on five cohort studies, giving a summary effect estimate of
1.19 (95% CI 1.10–1.28) per ratio increment of 0.1, withmoderate heterogeneity (figure 6.1.24).
Five case-control studies showed increased risk withincreased waist to hip ratio,242 247 297 308 321 which was statistically significant in three.242 297 308 Three studies showednon-significant decreased risk.241 248 304 Meta-analysis was
possible on seven case-control studies, giving a summary
effect estimate of 1.07 (95% CI 1.00–1.14) per ratio increment of 0.1, with moderate heterogeneity (figure 6.1.24).
The general mechanisms through which abdominal fatness
could plausibly influence cancer risk are outlined in 6.1.3(also see box 2.4). Many of these, such as increased circulating oestrogens and decreased insulin sensitivity, are particularly associated with abdominal rather than overall
body fatness.
There is a substantial amount of epidemiologicalevidence but some inconsistency. There is robust
evidence for mechanisms that operate in humans.
Abdominal fatness is a probable cause of
postmenopausal breast cancer.

Patterns of weight gain

The single cohort study showed a statistically significant
increased risk with a self-reported tendency to abdominal(central) weight gain, when compared to peripheral weightgain. The effect estimate was 1.45 (95% CI 1.02–2.07).49
The general mechanisms through which abdominal fatness
could plausibly influence cancer risk are outlined in 6.1.3(also see box 2.4).
There is a substantial amount of epidemiologicalevidence, generally consistent, and there is evidence forplausible mechanisms. Abdominal fatness is a probablecause of pancreatic cancer.
Breast (postmenopause)
157 159 170 174 180 187 199 575-577

Eight cohort studies
and three casecontrol studies207 242 304 investigated waist circumference andpostmenopausal breast cancer. Eight cohort studies157 159 163
170 174 180 187 189 199 575 576
and eight case-control studies241 242
247 248 297 304 308 321
investigated waist to hip ratio.
Waist circumference

All eight cohort studies showed increased risk with increased
waist circumference, which was statistically significant in
two.157 180 199 Meta-analysis was possible on four cohort studies,159 170 575 577 giving a summary effect estimate of 1.05 (95%
CI 1.00–1.10) per 8 cm (3.1 inches), with no heterogeneity.
All three case-control studies showed increased risk withincreased waist circumference, which was statistically significant in two.207 242

226

Figure 6.1.24

Waist to hip ratio and postmenopausal breast
cancer; cohort and case-control studies
Relative risk (95% CI)

CohortKaaks 1998

2.04 (1.17–3.53)

Wirfalt 2004

1.49 (1.11–2.01)

Gapstur 1992

1.18 (1.05–1.31)

Huang 1999

1.15 (1.02–1.30)

Sonnenschein 1999

0.99 (0.69–1.40)

Summary estimate

1.19 (1.10–1.28)

Case control
Attanamongkolg 2002

1.68 (1.13–2.49)

Hall 2000 White women

1.34 (1.00–1.81)

Hall 2000 Black women

1.34 (0.90–2.00)

Friedenreich 2002

1.32 (1.10–1.58)

Sonnichsen 1990

1.0 (0.92–1.12)

Franceschi 1996

0.97 (0.86–1.10)

Hansen 1997

0.81 (0.44–1.51)

Petrek 1993

0.76 (0.41–1.42)

Summary estimate

1.07 (1.00–1.14)

0.25

1

2

3

Relative risk, per 0.1 increment

4C H A P T E R

6•

Figure 6.1.25

B O D YC O M P O S I T I O N ,G R O W T H ,Waist to hip ratio and endometrial cancer;
cohort and case-control studies
Relative risk (95% CI)

CohortFolsom 2003

1.33 (1.18–1.51)

Case control
Elliott 1990

2.13 (0.94–4.83)

Austin 1991

1.01 (0.74–1.38)

Goodman 1997

1.22 (1.00–1.49)

Xu 2005

2.03 (1.63–2.53)

Summary estimate

1.45 (1.00–2.09)

0.5

1

2

3

Relative risk, per 0.1 increment

Endometrium

One cohort study137 and four case-control studies419 455 578 579
investigated waist circumference and endometrial cancer.
One cohort study137 368 373 374 376 and six case-control studies388 404 423 424 446 455 578-580 investigated waist to hip ratios.
Waist circumference

The single cohort study showed a statistically significant
increased risk for the highest waist circumference groupwhen compared to the lowest. The effect estimate was 4.2(95% CI 2.8–6.2).137
All four case-control studies showed statistically significant
increased risk for the highest waist circumference groupwhen compared to the lowest.419 455 578 579 Three studies
adjusted for BMI.419 455 579

A N D

D E V E L O P M E N T

particularly associated with abdominal rather than overall
body fatness.
There is a substantial amount of generally consistentepidemiological evidence, but limited prospective
data. There is evidence for plausible mechanisms.
Greater abdominal fatness is a probable cause ofcancer of the endometrium.

6.1.3.3 Adult weight gain
Breast (postmenopause)

Seven cohort studies158 159 167 193 576 581-586 and 17 case-control studies217 220 225 231 241 242 255 274 280 283 315 318 327 338 339 349 359
587-591
investigated adult weight gain and postmenopausal
breast cancer.
All seven cohort studies showed increased risk withincreasing amounts of weight gained in adulthood, which
was statistically significant in two.159 167 581 583 586 Two cohort
studies stratified results according to whether or not participants were using HRT.158 576 584 Both studies showed astatistically significant increased risk in women not using
HRT. Studies of weight gain and premenopausal breast cancer showed no overall effect on risk.
The full SLR is contained on the CD included with thisReport.
Thirteen case-control studies showed increased risk withincreasing amounts of weight gained in adulthood,217 220 225
231 241 242 255 280 283 315 318 327 338 339 349 587 589-591
which was statistically significant in 11.217 220 242 255 280 283 315 318 338 339 349 587
589-591
No studies reported significant decreased risk. Metaanalysis was possible on six case-control studies, giving asummary effect estimate of 1.05 (95% CI 1.04–1.07) per
5 kg (11 lbs) gained, with high heterogeneity (figure 6.1.26).

Figure 6.1.26

Weight gain and postmenopausal breast
cancer; cohort and case-control studies

Waist to hip ratio

The single cohort study showed a statistically significant
increased risk for the highest waist circumference groupwhen compared to the lowest.137 368 373 374 376 The effect estimate was 1.96 (95% CI 1.43–2.71) or 1.33 (95% CI
1.18–1.51) per ratio increment of 0.1 (figure 6.1.25).373 An
earlier report from the same study adjusted for BMI, which
reduced the effect estimate and made it non-significant: 1.2(95% CI 0.8–1.9; high versus low).137
Five case-control studies showed increased risk withincreased waist to hip ratio,388 404 423 424 455 578 579 which wasstatistically significant in two.404 423 424 455 578 580 One study
showed non-significant decreased risk.446 Meta-analysis was
possible on four case-control studies, giving a summary effectestimate of 1.45 (95% CI 1.00–2.09) per ratio increment of
0.1, with high heterogeneity (figure 6.1.25). All four of thesecase-control studies were adjusted for BMI.
The general mechanisms through which abdominal fatness
could plausibly influence cancer risk are outlined in 6.1.3(also see box 2.4). Many of these, such as increased
circulating oestrogens and decreased insulin sensitivity, are

Relative risk (95% CI)
CohortBrestom 2001

1.11 (0.99–1.24)

Folsom 1990

1.11 (1.03–1.20)

Huang 1997

1.05 (1.02–1.08)

Barnes-Josiah 1995

1.03 (1.02–1.03)

Summary estimate

1.03 (1.02–1.04)

Case control
Jemstrom 1999

1.28 (1.05–1.55)

Chie 1998

1.09 (0.84–1.40)

Trentham-Dietz

1.07 (1.05–1.09)

Friedenreich 2002

1.06 (1.01–1.11)

Franceschi 1996

1.04 (1.00–1.07)

Trentham-Dietz 2000

0.97 (0.93–1.01)

Summary estimate

0.5

1.05 (1.04–1.07)

1

1.5

Relative risk, per 5 kg gained227

P A R T

Heterogeneity may be explained by failure to separate
postmenopausal participants using HRT.
There is ample, consistent epidemiological evidence
from both cohort and case-control studies. A dose
response was apparent from case-control and cohort
studies. Adult weight gain is a probable cause of
postmenopausal breast cancer.

6.1.4 Comparison with previous report
The previous report used different terminology. It concluded that the evidence that ‘high body mass’ was a cause ofcancer of the endometrium was convincing, and that highbody mass was probably a cause of cancers both of the breast(postmenopause) and the kidney. In the previous report, theevidence that high body mass was a cause of cancers of thecolon and gallbladder was judged to be possible. Since thattime, several cohort studies and other epidemiological andother evidence have greatly strengthened the evidence on
body fatness, and specifically on overweight and obesity.
Also, the distinction between adenocarcinomas and squamous cell carcinomas has identified a clear relationshipbetween body fatness and adenocarcinomas of the oesophagus. The previous report did not make any judgements
specifically on abdominal fatness.
The previous report did not include judgements on bodyfatness and pancreatic cancer, although it did conclude thathigh energy intake was a possible cause of this cancer.592 It
also noted data from correlation and animal studies suggesting that high energy intake might increase the risk ofcancer in general, without making any judgement.

6.1.5 Conclusions
The Panel concludes:
The evidence that greater body fatness is a cause of cancers
of various sites is more impressive now than it was in the
mid-1990s.
The evidence that greater body fatness is a cause of cancers of the oesophagus (adenocarcinoma), pancreas, colorectum, breast (postmenopause), endometrium, and kidney
is convincing. Greater body fatness is probably a cause of
gallbladder cancer , both directly, and indirectly through theformation of gallstones. There is also limited evidence suggesting that greater body fatness is a cause of liver cancer.
The evidence that abdominal fatness is a cause of colorectal
cancer is convincing; and abdominal fatness is probably acause of cancers of the pancreas, breast (postmenopause),and endometrium. By contrast, greater body fatness probably protects against cancer of the breast diagnosed before themenopause. The Panel notes that there is limited evidence
suggesting that low body fatness (underweight) is a causeof cancer of the lung, but residual confounding with smoking and lung disease cannot be ruled out. See chapters 7.4
and 7.10, and Chapter 8 for discussion of the role of energy density in weight gain, overweight, and obesity.

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6.2 Growth and development
GROWTH AND DEVELOPMENT, AND THE RISK OF CANCER
In the judgement of the Panel, the factors listed below modify the risk of cancer. Judgements are graded according to the strength of the evidence.

DECREASES RISK
Exposure

INCREASES RISK

Cancer site

Exposure

Cancer site
1

Convincing

Adult attained height

Colorectum
Breast (postmenopause)

Probable

Adult attained height1

Pancreas
Breast (premenopause)
Ovary

Greater birth weight

Breast (premenopause)

Adult attained height1

Endometrium

Limited —suggestive
Substantial
effect on risk
unlikely1None identified

Adult attained height is unlikely to directly modify the risk of cancer. It is a marker for genetic, environmental, hormonal, and also nutritional factors affecting
growth during the period from preconception to completion of linear growth (see 6.2.1.3).

For an explanation of all the terms used in the matrix, please see chapter 3.5.1, the text of this section, and the glossary.

Growth in childhood is a predictor of age at sexual
maturity and eventual adult attained height. Food quantityand quality, and the extent of infections and infestations
during crucial periods of growth, are critical in determining
speed of growth. Rate of growth has metabolic andhormonal effects, which can trigger lifelong consequences.
Since the recognition of the vital importance of nutrition
to human health and welfare, public health nutrition policy
has emphasised the need for birth weights and rates ofgrowth within ranges defined as those most likely to ensure
physical and mental development in childhood, and good
health in adult life. Such policies are essential. New
standards based on the ‘ideal’ pattern of growth of healthy,
breastfed infants have now been agreed by the World
Health Organization.
Overall, the Panel judges that evidence on the factors thatlead to greater adult attained height, or its consequences,and the risk of cancers of a number of sites, is strong,
consistent, and impressive. The Panel emphasises that
greater adult attained height, meaning how tall people are
as adults, is unlikely directly to modify the risk of cancer. It
is a marker for genetic, environmental, hormonal, andnutritional factors affecting growth during the period frompreconception to completion of linear growth.
The Panel concludes:
The evidence that the factors that lead to greater adultattained height, or its consequences, increase the risk ofcancers of the colorectum and breast (postmenopause) isconvincing; and they probably also increase the risk ofcancers of the pancreas, breast (premenopause), and ovary.
There is limited evidence suggesting that the factors thatlead to greater adult attained height, or its consequences,increase the risk of endometrial cancer.
In addition, the factors that lead to greater birth weight,
or its consequences, are probably a cause of
premenopausal breast cancer.
A major question for future research is: what are
the factors that determine height in adult life? And, given
the theme of this Report, what is the relative importanceof genetic and environmental factors, what is the roleof nutrition, and when in the life course are nutritional
factors most relevant? Weighing such evidence, giventhat adequate birth weight and growth are essential forgood health in infancy and childhood, and throughout
life, is a major challenge for the biological and nutritional
sciences.
Within the remit of this Report, the strongest evidence,corresponding to judgements of ‘convincing’ and‘probable’, shows that the factors that lead to greater adultattained height, or its consequences, are a cause of cancersof the colorectum and breast (postmenopause), andprobably also of cancers of the pancreas, breast(premenopause), and ovary. In addition, the factors thatlead to greater birth weight, or its consequences, probably
increase the risk of premenopausal breast cancer.

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Linear growth, from preconception to adulthood, influences
health and well-being throughout life, as do body composition and shape.
Standards for birth weight and growth developed byexpert panels for relevant United Nations agencies, andapproved by UN member states, form the basis for national, municipal, and local paediatric health policies and programmes throughout the world. The WHO/UNU Multicentre
Growth Reference Study (MGRS) of healthy, breastfedchildren is the basis for the WHO 2006 growth standards forchildren aged 0–5 years.593
However, no growth standard has been validated in termsof lifelong risk for chronic diseases, including cancer. As withbody weight (see chapter 6.1), policies and programmes concerned with the physical and mental development of infants
and children, and growth until adulthood, have focused on
the need to protect populations against the consequences of
inadequate nutrition and retarded growth. This remains acentral public health priority for middle- and low-income
countries.
In the 1990s, increasing concern, based on emerging evidence, was expressed by the scientific community in thisfield.594 The concern has been that the agreed standards had‘overshot the mark’ for optimum growth and health. For several reasons, the agreed growth standards for the first period of life seemed to have been set unnecessarily andunhelpfully high. This perception was heightened by evidence of rapidly increasing rates of childhood overweight
and obesity, which tend to track into adult life (see box 8.3).
As a result, new standards based on breastfed children wereagreed and ratified, and issued in 2005, as guides to optimum growth.593
This is the general context in which the Panel has examined the evidence on growth and development, and the riskof cancer.

6.2.1 Definitions and patterns
Growth increases metabolic capacity and also the ability tocope with environmental challenge. From a single cell at conception, human growth progresses through embryogenesis
and fetal development, involving cellular multiplication anddifferentiation in both structure and function. At birth, thebody’s tissues and organs are highly organised and regulated. The timing and order of these processes are determinedby the selective expression of genes, which is both innate andmodifiable by the wider environment, including the availability of oxygen, energy, and nutrients. Nutrients also act
by regulating hormones, growth factors, binding proteins,and receptors, and their activity.
For every tissue or organ, adverse environmental influences during critical periods of development, such as limited energy or nutrients, can restrict development and future
capacity for function. The timing, severity, and duration of
any adverse exposure will determine the extent and patternof any restriction in capacity.
Growth can be divided into three phases: fetal–infant,childhood, and puberty.595 During the first period, growth is

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most sensitive to the availability of energy and nutrients.
Brain growth is protected more effectively than growth instature, which is protected more effectively than weight. So
the timing of an adverse influence on growth tends to bereflected in a person’s body shape, both as a child and as anadult. For instance, for lean tissue to be deposited efficiently and effectively, the appropriate pattern of nutrients must
be available in a timely way.
If any nutrients are limited but energy intake is adequate— or more than adequate — a person will be predisposed
to excess body fatness. This is because their energy intake
will exceed the nutrients available in the body for laying
down lean tissue, so the excess energy is stored as fat. People
who were of low birth weight have a greater tendency tostore fat, in particular abdominally.
6.2.1.1 Birth weight
A baby’s size and shape at birth indicates the extent andquality of intra-uterine growth and development. Birthweight can be measured simply and reliably, whereas headcircumference, which marks growth of the brain, and length,
which marks linear growth, are more difficult to measure reliably. Within the usual range, heavier (and longer) babies
tend to become taller children and adults.
Birth weight predicts the risk of death and of various diseases in infancy and later in life. Very low birth weight —less than 2.5 kg (5.5 lbs) for boys and 2.4 kg (5.3 lbs) forgirls — increases the risk of perinatal death and disease, ordeath in infancy and young childhood, usually because ofincreased vulnerability to infection and infestation. It is wellestablished, at least in high-income countries, that smaller
size at birth, and at 1 year of age, predicts increased risk ofchronic disease such as cardiovascular disease and type 2
diabetes during adult life.596 This is due to a reduced capacity to cope with the stress of environmental challenges, suchas a poor diet (including excess energy) and physical inactivity. Very high birth weight may also be associated withincreased risk — for instance, maternal diabetes or poor glucose homeostasis can cause higher birth weight as well as
increased risk of diabetes in the infant.597 These findings
have been shown to be independent of smoking or socioeconomic status, although they may be accentuated in
the presence of these additional stress factors.598
The extent to which body fatness is a factor in any relationship between low birth weight and disease in later life
remains unclear. The associations described above arestrongest when low birth weight, or restricted fetal growth,
is followed by rapid growth during early childhood.599-602
Such effects can be experimentally induced in animals, lending weight to the observed associations in humans being
causal.
6.2.1.2 Infant and prepubertal growth
The fetal–infant growth phase slows during the second halfof the first year of life. The childhood phase of growth
becomes established at 6–18 months. Any delay in the onsetof this growth phase tends to lead to shorter stature duringchildhood. Over an extended period of time, growth inheight and weight is a smooth process, although there may

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be growth spurts or times of little change over shorter periods. Growth, through the formation of new tissue, requiresa dietary supply of energy (about 5 kilocalories per gram of
new tissue) and macronutrients such as amino acids andfatty acids, as well as vitamins, minerals, and trace elements.
Each individual factor is vital; if any are limited they will constrain normal growth and development.
At any age, therefore, normal development requires
appropriate genetic, hormonal, and nutritional factors to
support growth. These in turn require adequate quantity andquality of food, and minimal exposure to food and environmental toxicants, infection, and psychosocial stress. As an
infant gets older, the body is increasingly able to cope withenvironmental challenge.
The pattern and timing of any nutrient shortfall determines the pattern of constrained growth. Patterns of growth
failure are highly variable, comprising the differential effects
on linear growth (stunting), weight (underweight and wasting), or on specific tissues. Thus stunting may be due to aperiod of slow growth or a delay to the onset of the childhood phase of growth. If growth has been constrained as theresult of an adverse circumstance, which is then removed,
there is a drive towards returning to the growth patternestablished previously or to the genetically determined
growth pattern. This ‘catch-up’ growth may be in height orweight, or some combination of the two; the term is often
used without defining what type of growth is involved.
However, ‘catch-up’ in linear growth after malnutrition israre beyond the first 2–3 years of life.
In the first 6 months of life, infants who are breastfed andthen weaned appropriately to mixed diets grow differently
from those fed on formula. This is partly related to theincreased risk of infection for formula-fed infants and partly due to the different compositions of human milk and formula feed. Normal child growth (under optimal
environmental conditions) from birth to 5 years is specified
in the WHO Child Growth Standards.593
Throughout the world, particularly in high- and middleincome countries, and in urban areas generally, childhood
obesity and type 2 diabetes are becoming more common.
Childhood overweight and obesity often persists into adultlife. This exposes people to the hormonal and physiologicalconsequences of being overweight or obese earlier in adultlife, increasing their risk of related health problems at a relatively young age (also see box 8.3).

supplies become more secure; it continues to increase whenfood is abundant (also see chapter 1.1). This trend has now
slowed or even stopped in most high-income countries.
Increases in height between generations are generally due
to increased leg, rather than spine, length. Leg length islinked to prepubertal growth, particularly to infancy (below
the age of 5); after this age, trunk growth becomes more
prominent.604 605
Growth hormones, insulin-like growth factors, and sex
hormone binding proteins all define the biological activityof the respective hormones. These in turn impact on height,
growth, sexual maturation (boxes 6.2.1 and 6.2.2), fat storage, and many processes relevant to cancer (box 2.4). It istherefore plausible that nutritional factors that impinge onheight could also influence cancer risk, with adult height acting as a marker of that early life experience, in the same waythat taller people have a decreased risk of cardiovascular diseases, at least in high-income countries.606-608
Therefore, both birth weight and adult attained height aremarkers of an aggregated fetal and childhood experience;
they are clearly also surrogates for important nutritional
exposures, which impact on several hormonal and metabolic axes, and which influence cancer risk (also see Chapter 2).

6.2.1.3 Adult attained height
Genetic and early life environmental factors, even before
birth, are important in determining adult height. The environmental determinants of height attained in adulthood arehighlighted by the variation between generations in adoption and migrant studies, where children are moved from apoor or limited nutritional background to an area of high oreven overnutrition.603 Adult height is also linked to birthweight, rate of growth, and age of puberty. Periods of peakgrowth (such as in infancy and adolescence) are particularly important in determining adult height.
Adult height increases as populations become less vulnerable to undernutrition, infestation, and infection, and as food

The full systematic literature review (SLR) is contained on
the CD included with this Report.
As indicated in 6.2.1.3, there are several general mechanisms through which the factors that lead to greater adultattained height, or its consequences, could plausibly influence cancer risk. However, adult attained height is unlikely
to directly modify the risk of cancer. It is a marker for genetic, environmental, hormonal, and also nutritional factors
affecting growth during the period from preconception tocompletion of linear growth. For example, adult height is theresult of several stages of growth from fetal life throughchildhood. These are all influenced by nutrition, particularly in infancy, which in turn affects hormone levels, and there-

6.2.2. Interpretation of the evidence
6.2.2.1 General

For general considerations that may affect interpretation of
the evidence, see chapters 3.3 and 3.5, and boxes 3.1, 3.2,
3.6 and 3.7.
6.2.2.2 SpecificSome considerations specific to growth and development are
as follows.
Measurement. Weight at birth is usually recalled accurately

by parents. As well as full height, proxy measures may be
used in some studies, including leg length, sitting height, ora ratio of these two. The ratio between overall height andlimb length varies with genetic background and nutritional
experience over the life course.

6.2.3 Evidence and judgements

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Box 6.2.1

halted.609 In low-income countries, andparticularly among the most disadvantaged populations, the average age ofmenarche may be as high as 16.610 These
trends show the impact of environmental
influences on age at menarche.
Adrenal sex hormone production normally rises at around 6 years of age(adrenarchy) and coincides with a rise in
BMI (adiposity rebound). Growth hormone, insulin-like growth factors, and sex
hormone binding proteins all define thebiological activity of the respective hormones.
Children with an early adiposity
rebound have earlier sexual maturationand higher risk of later obesity.

fore many processes relevant to cancer (box 2.4). Site-specific mechanisms are described with the evidence for eachcancer site.
6.2.3.1 Adult attained height
Colorectum

Twenty-one cohort studies58 80 82-84 87 88 91 93 108 109 115 117 119 120
and 16 case-control studies investigated adult attained height and cancer of the colon and rectum.
Eighteen cohort studies showed increased risk withincreased adult attained height58 80 82-84 87 88 109 115 117 120 124
126 142 622-625; this was statistically significant in six,58 80 87 124
623 624and in another study in men, but not in women.108 119
621
One study showed non-significant increased risk in
men and no effect on risk in women.140 Two studies showedno effect on risk.91 93 133 Meta-analysis was possible on 12
cohort studies, giving a summary effect estimate of 1.09
124 126 133 140 142 621-625

E V I D E N C E

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Nutrition, birth weight, rates of growth,
body fatness, and age of sexual maturity
are all connected. The effects of thesefactors may be different in either sex,
with increased body fatness lowering
the age at menarche but slowing malesexual maturation.611 Conversely, early
menarche increases the risk of adultobesity.
Undernutrition delays the onset ofpuberty in both boys and girls.612 Regular,
intense physical activity can delay menarche or cause menstruation to stop in later
life. The combination of low birth weightand rapid growth in early childhood also
accelerates the development of sexual
maturity.

(95% CI 1.06–1.12) per 5 cm (2 inches), with no heterogeneity (figure 6.2.1).
A dose-response relationship was apparent from cohort
data.
Because of the abundant prospective data from cohort
studies, case-control studies were not summarised.
The general mechanisms through which the factors thatlead to greater adult attained height, or its consequences,
could plausibly influence cancer risk are outlined in 6.2.1.3(also see box 2.4). Many of these, such as early-life nutrition, altered hormone profiles, and the rate of sexual maturation, could plausibly increase cancer risk
There is ample prospective epidemiological evidence,
which is consistent, and there is a clear dose response,with evidence for plausible mechanisms operating inhumans. The evidence that factors that lead to greater

Age at menarche and risk of breast cancer

Early menarche is an established risk factor
for breast cancer. From pooling project
data, based on information from 322 647
women, 4827 breast cancer cases occurred
during follow-up, and the fully adjusted
risk due to late menarche (at 15 years orabove compared with under 12 years ofage) was 0.72 (95% confidence interval (CI)
0.62–0.82).613
A meta-analysis of 21 epidemiologicalstudies (including both case-control andcohort) reported a risk reduction of about
9 per cent (95% CI 7–11) for each additional year of age at menarche. There was alsoa statistically significant gradient of risk
when breast cancer was diagnosed early or
before menopause, and a risk of about 4
per cent (95% CI 2–5) for later diagnoses.614
A large cohort study (100 000 partici-

232•

Sexual maturity

Sexual maturity is the biological capability
to have children. In girls, this is characterised by ovulatory cycles and/or menarche, the onset of menstruation. In boys,
pubertal stages are less easy to characterise, and indirect markers (secondary sex
characteristics) are used, such as the age ofappearance of pubic hair. As a consequence, there are more data for sexual
maturation in girls than boys.
There is considerable variation in theage of sexual maturity, both between andamong populations. In high-income countries, the average age of menarche ranges
from 12–13 years; this has dropped byaround 3 years over the last 150 years,
although the change has now generally

Box 6.2.2

2

pants) reported a 7 per cent per year
decrease in breast cancer risk with increasing age of menarche for premenopause
cases (p < 0.05). Compared to those who
had their first period at 11 or younger,
women experiencing menarche at 15 years
or older had a risk of 0.66 (95% CI
0.45–0.97). There was no statistically significant effect for postmenopause cases.615
Menarche marks the start of the cyclic
production of oestrogen by the ovaries.
Therefore early menarche means that awoman is exposed to more oestrogen overthe course of her lifetime.616 This is likely tobe the mechanism by which age at menarche influences breast cancer risk. As well as
a longer lifetime exposure to oestrogen,early menarche may be associated withincreased oestrogen levels during thewhole period of adolescence and early
adulthood.617
The first onset of breast development ingirls occurs about two years before menarche. The years preceding menarche arecharacterised by a sharp increase in adrenal androgens and the associated appearance of the first pubic and axillary hairs,
and the first enlargement of the breasts.
At this age, adrenal androgens play animportant role in inducing hypothalamicchanges leading to menarche.618 In adulthood, both before and after menopause,high serum androgen levels are associatedwith increased breast cancer risk.619 620
Consequently, nutritional exposures in earlylife that influence sexual maturation in
women are also likely to have an indirect
impact on later breast cancer risk.

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Figure 6.2.1

B O D YC O M P O S I T I O N ,G R O W T H ,A N D

D E V E L O P M E N T

Figure 6.2.2

Height and colorectal cancer;
cohort studies

Height and breast cancer (age unspecified);cohort and case-control studies

Relative risk (95% CI)

Relative risk (95% CI)

Albanes 1988 Men

1.19 (0.98–1.45)

Albanes 1988 Women

1.17 (0.96–1.43)

Nilsen 2001

Suadini 1993 Men

1.07 (0.86–1.34)

Hoyer 1998

1.17 (1.00–1.36)

Bostick 1994 Women

1.11 (0.97–1.26)

Palmer 2001

1.15 (1.03–1.29)

Thune 1996 Men

1.06 (0.97–1.16)

Galanis 1998

1.13 (1.02–1.24)

Thune 1996 Women

1.04 (0.89–1.21)

Vatten 1992

1.13 (1.06,–1.20)

Tangrea 1997 Men

1.03 (0.88–1.20)

Tulinius 1997

1.10 (1.05–1.15)

Hebert 1997 Men

1.05 (0.97–1.15)

Tornberg 1988

1.10 (1.05–1.15)

Kato 1997 Women

0.99 (0.84–1.18)

Palmer 2001

1.10 (1.04–1.16)

Shimizu 2003 Men

1.30 (1.08–1.56)

Tryggvadottir 2002

1.09 (1.03–1.15)

Shimizu 2003 Women

1.18 (0.92–1.51)

Nilsen 2001

1.09 (0.79–1.50)

Maclnnis 2004 Men

1.10 (0.94–1.27)

Goodman 1997

1.03 (0.88–1.21)

Giovannucci 2004 Men

1.12 (1.04–1.21)

Key 1999

1.01 (0.90–1.13)

Otani 2005 Men

1.04 (0.95–1.13)

Overvad 1991

1.00 (0.77–1.31)

Otani 2005 Women

1.00 (0.88–1.14)

Kilkinnen 2004

1.00 (0.85–1.17)

Pischon 2006 Men

1.08 (1.01–1.17)

Drake 2001

1.00 (0.87–1.14)

Pischon 2006 Women

1.14 (1.06–1.23)

Nilsen 2001

0.99 (0.72–1.38)

Summary estimate

1.09 (1.06–1.12)

Wu 2005

0.98 (0.83–1.15)

Nilsen 2001

0.95 (0.68–1.32)

0.5

0.75

1

1.5

Cohort2

1.44 (1.10–1.88)

Nilsen 2001

0.80 (0.58–1.10)

Summary estimate

1.09 (1.07–1.12)

Relative risk, per 5 cm
Case control
Bruning 1992

adult attained height, or its consequences, are a causeof colorectal cancer is convincing. The causal factor isunlikely to be tallness itself, but factors that promote
linear growth in childhood.

The Panel is aware that since the conclusion of the SLR, threecohort studies31 141 145 have been published. This new information does not change the Panel judgement (see box 3.8).
Breast122 150 151 155-157 161 162 164 166 168 170-

Thirty-three cohort studies,

172 174-176 178 180 181 183 185-187 189-191 193 196 198-200 203 577 626-637

56

1.22 (1.06–1.42)

Ziegler 1996

1.18 (1.06–1.31)

Ueji 1997

1.15 (0.93–1.41)

Lebamowo 2003

1.15 (1.03–1.28)

Hu 19971.12 (0.95–1.31)

Challier 1998

1.11 (0.98–1.25)

Wenten 2001

1.08 (0.94–1.25)

Swanson 1989

1.08 (1.03–1.14)

Shu 2001

1.08 (1.00–1.15)

Hirose 1999

1.06 (1.00–1.11)

Adami 1977

1.05 (0.89–1.25)

Hsieh 1990

1.04 (0.91–1.07)

Wenten 2001

1.03 (0.91–1.17)

Silva 2004

1.03 (0.90–1.17)

Yoo 2001

1.02 (0.93–1.11)

McCredie 1998

1.02 (0.95–1.09)

Hislop 1986

1.02 (0.93–1.11)

Tung 1999

1.02 (0.88–1.17)

Drewnowski 2000

1.01 (0.85–1.20)

Zhang 1996

0.99 (0.96–1.02)

case-control studies,205 206 208 214 217 218 220 221 224 225 231 234 241 242

Chie 1998

0.97 (0.79–1.18)

247 248 253 254 256 257 259 261 262 269 272 274 279 280 283 290 297 303 304 306 308

Potischman 1990

0.96 (0.80–1.16)

312-314 318 319 323-327 331 333 336 338 339 341 342 346 349 352 588 638-647

Kato 1992

0.95 (0.86–1.05)

361 625 648

3 ecological studies
and breast cancer.

andinvestigated adult attained height

Bouchardy 1990

0.94 (0.88–1.01)

Toti 1986

0.89 (0.82–0.97)

Sarlin 1985

0.88 (0.58–1.34)

Summary estimate

1.03 (1.01–1.04)

Age unspecified

Twenty cohort studies122 150 161 162 164 166 168 171 172 181 186 191 196
and 29 case-control studies205 208 214 218 221

203 627-630 632 634-637

224 225 234 248 254 259 261 262 269 290 297 306 313 314 318 319 323 324 336 341

0.1

1

2

3

4

Relative risk, per 5 cm

342 349 352 638 641 646 647

investigated adult attained height andbreast cancer at all ages, or unspecified menopausal status.
Thirteen cohort studies showed increased risk with greater
adult attained height,122 161 162 164 168 171 191 196 628 629 632 634-637
which was statistically significant in nine.122 161 162 168 191 196
632 634-637
Four studies showed no effect on risk,172 181 186 630
and two showed decreased risk,150 166 203 627 which was statistically significant in one study.150 Another study showedvarying effects in different age groups.633 Meta-analysis was
possible on 14 cohort studies, giving a summary effect esti-

mate of 1.09 (95% CI 1.07–1.12) per 5 cm (2 inches), withlow heterogeneity (figure 6.2.2).
Twenty-two case-control studies showed increased risk
with greater adult attained height,205 208 218 221 224 234 248 254 259
261 262 290 297 318 319 323 324 341 342 349 352 638 641 647
which was sta-233

P A R T

tistically significant in seven.208 218 224 261 297 324 647 Seven studies showed decreased risk,214 225 269 306 313 314 336 646 which wasstatistically significant in one.336 Meta-analysis was possible
on 25 case-control studies, giving a summary effect estimateof 1.03 (95% CI 1.01–1.04) per 5 cm (2 inches), with moderate heterogeneity (figure 6.2.2).
A dose-response relationship was apparent from cohortand case-control data.
All three ecological studies showed increased risk withgreater adult attained height.361 625 648

2Figure 6.2.3•

E V I D E N C E

A N D

J U D G E M E N T S

Height and postmenopausal breast cancer;
cohort and case-control studies
Relative risk (95% CI)

CohortManjer 2001

1.21 (1.05–1.40)

Toniolo 1994

1.20 (1.00–1.44)

Mattisson 2004

1.19 (1.08–1.30)

Vatten 1990

1.18 (0.99–1.41)

Barrett-Connor 1993

1.17 (0.76–1.81)

Van den Brandt 1997

1.17 (1.08–1.27)

Galanis 1998

1.16 (1.03–1.31)

Postmenopause

Tryggvaddottir 2002

1.21 (1.03–1.22)

Twenty-two cohort studies122 151 155-157 162 168 170-172 174 175 178
180 183 185 187 189-191 193 199 200 577 626 631 634 636 637
and 34 case-control studies205 206 208 214 217 220 224 225 231 241 242 247 253 256 257 259 261

Tulinius 1997

1.10 (1.00–1.22)

Tornberg 1998

1.10 (1.07–1.13)

Saadatien-Elahi 2002

1.10 (0.88–1.37)

Sonnenschein 1999

1.09 (0.95–1.25)

274 280 283 297 304 308 318 327 331 333 338 339 341 352 588 638-640 642 643 646

Kaaks 1998

1.08 (0.85–1.38)

647

Palmer 2001

1.04 (0.94–1.14)

investigated adult attained height and postmenopausal
breast cancer.
Twenty-one cohort studies showed increased risk withgreater adult attained height,122 151 155-157 162 168 170-172 174 175
178 180 183 185 187 189-191 193 577 626 631 634 636 637
which was statistically significant in 12.122 155 162 168 171 172 175 178 183 191 193 577 626
631 636
One study showed no effect on risk.200 Meta-analysis
was possible on 15 cohort studies, giving a summary effectestimate of 1.11 (95% CI 1.09–1.13) per 5 cm (2 inches),with no heterogeneity (figure 6.2.3).
Pooled analysis from 7 cohort studies (more than 337 000
participants, followed up for up to 11 years, with more than
4300 breast cancer cases) showed a statistically significant
increased risk of postmenopausal breast cancer with greater
adult attained height. The effect estimate was 1.07 (95% CI
1.03–1.12) per 5 cm (2 inches).362
Twenty-two case-control studies showed increased risk
with greater adult attained height,205 208 214 217 224 231 242 253 256
257 259 261 279 280 283 297 318 331 338 339 352 588 638-640 642 643 647
which
was statistically significant in 11.208 217 224 253 256 261 297 318 338
339 639
Nine studies showed non-significant decreased risk.206
220 225 241 274 304 327 333 341 646
Two studies showed no effect on
risk.308 Another study showed non-significant increased risk
in white women and no effect on risk in black women.247
Meta-analysis was possible on 27 case-control studies, giving a summary effect estimate of 1.02 (95% CI 1.01–1.03)
per 5 cm (2 inches), with high heterogeneity (figure 6.2.3).
A dose-response relationship was apparent from cohortand from case-control data.
The general mechanisms through which the factors thatlead to greater adult attained height, and its consequences,
could plausibly influence cancer risk are outlined in 6.2.1.3(also see box 2.5). Many of these, such as early-life nutrition, altered hormone profiles, and the rate of sexual maturation, could plausibly increase cancer risk.
There is abundant prospective epidemiologicalevidence, which is generally consistent, with a clear
dose response, and evidence for plausible mechanisms
operating in humans. The evidence that factors thatlead to greater adult attained height, or its
consequences, are a cause of postmenopausal breast
cancer is convincing. The causal factor is unlikely to be234

Wirfalt 2004

1.00 (0.88–1.13)

Summary estimate

1.11 (1.09–1.13)

Case control
Chie 1996

2.35 (1.26–4.37)

Lebamowo 2003

1.40 (1.10–1.78)

Ng 1997

1.27 (1.05–1.53)

Shu 2001

1.24 (1.08–1.42)

Ziegler 1996

1.18 (0.94–1.49)

Hansen 1997

1.17 (0.80–1.72)

Hall 2000

1.16 (1.00–1.34)

Radimer 1993

1.13 (0.98–1.31)

Terry 2002

1.13 (1.08–1.18)

De Vasconcelos 2001

1.12 (0.90–1.40)

Li 2003

1.11 (1.03–1.21)

Hislop 1986

1.09 (0.98–1.22)

Magnusson 1998

1.08 (1.03–1.14)

Hirose 1995

1.08 (0.99–1.17)

Trentham-Dietz 1997

1.07 (1.041.11)

Adami 1977

1.07 (0.96–1.19)

Yoo 2001

1.06 (1.01–1.10)

Hsieh 1990

1.05 (0.93–1.18)

Li 2000

1.02 (0.94–1.10)

Friedenreich 2002

1.00 (0.86–1.16)

Hall 2000

1.00 (0.84–1.16)

Rattanamongkolg 2002

0.98 (0.96–1.01)

Carpenter 2003

0.98 (0.95–1.00)

Tung 1999

0.97 (0.76–1.25)

Petrek 1993

0.97 (0.76–1.25)

Franceschi 1996

0.97 (0.91–1.03)

Jams-Campbell 1996

0.90 (0.76–1.08)

Taioli 1995

0.88 (0.75–1.03)

Summary estimate

1.02 (1.01–1.03)

0.1

1
2
Relative risk, per 5 cm

4tallness itself, but factors that promote linear growthin childhood.

The Panel is aware that since the conclusion of the SLR, onecohort study649 has been published. This new information does
not change the Panel judgement (see box 3.8).

C H A P T E R

6•

B O D YC O M P O S I T I O N ,G R O W T H ,Premenopause
122 155 162 170 175 176 178 185 189-191 196 198

Seventeen cohort studies
626 631 634 636 637
and 38 case-control studies205 206 208 214 217 224

225 231 241 242 247 248 253 256 257 259 261 272 290 297 303 304 308 312 318 324327 339 341 346 352 588 638 640 644-647

investigated adult attainedheight and premenopausal breast cancer.
Eleven cohort studies showed increased risk with greater

Figure 6.2.4

Height and premenopausal breast cancer;
cohort and case-control studies
Relative risk (95% CI)

CohortPalmer 2001

1.17 (1.08–1.26)

Tulinius 1997

1.16 (0.95–1.41)

Vatten 1992

1.16 (1.06–1.27)

Tornberg 1988

1.11 (0.98–1.26)

Kaaks 1998

1.09 (0.93–1.29)

Galanis 1998

1.04 (0.86–1.25)

Manjer 2001

0.99 (0.87–1.14)

Tryggvadottir 2002

0.99 (0.79–1.24)

Sonnenschein 1999

0.99 (0.84–1.16)

Saadatian-Elahi 2002

0.98 (0.80–1.21)

Toniolo 1994

0.92 (0.78–1.09)

Summary estimate

1.09 (1.05–1.14)

Case control
Hall 2000

1.28 (1.00–1.63)

Tung 1999

1.25 (0.97–1.60)

Petrek 1993

1.24 (0.99–1.54)

Ng 1997

1.19 (0.91–1.55)

Adebamowo 2003

1.16 (1.00–1.34)

Ziegler 1996

1.15 (1.02–1.31)

McCredie 1996

1.15 (1.02–1.30)

Adams-Campbell 1996

1.12 (0.89–1.42)

Swanson 1996

1.12 (1.06–1.18)

De Vasconcelos 2001

1.11 (0.77–1.61)

Swanson 1997

1.10 (1.02–1.18)

Friedenreich 2002

1.09 (0.96–1.22)

Verla-Tebit 2005

1.08 (0.99–1.18)

Trentham-Dietz 1997

1.08 (1.02–1.14)

Shu 2001

1.05 (0.95–1.16)

McCredie 1998

1.03 (0.95–1.11)

Sanderson 2002

1.02 (0.88–1.18)

Franceschi 1996

1.00 (0.92–1.10)

Yoo 2001

1.00 (0.91–1.10)

Hsieh 1990

0.99 (0.94–1.05)

Radimer 1993

0.98 (0.83–1.17)

Peacock 1999

0.97 (0.90–1.04)

Hirose 1995

0.96 (0.89–1.03)

Hall 2000

0.95 (0.77–1.17)

Adami 1977

0.95 (0.59–1.42)

Taioli 1995

0.94 (0.77–1.15)

Rattanamonkolg 2002

0.93 (0.80–1.09)

Hislop 1986

0.92 (0.80–1.05)

Kumar 2005

0.91 (0.75–1.12)

Hansen 1997

0.82 (0.45–1.49)

Ursin 1994

0.62 (0.11–3.63)

Summary estimate

1.04 (1.02–1.06)

0.1

1

2

Relative risk, per 5 cm

3

4

A N D

D E V E L O P M E N T

adult attained height,122 155 162 170 175 176 191 196 626 631 634 637
which was statistically significant in two.196 634 637 Six studies showed non-significant decreased risk.178 185 189 190 198 636
Meta-analysis was possible on 11 cohort studies, giving asummary effect estimate of 1.09 (95% CI 1.05–1.14) per 5
cm (2 inches), with low heterogeneity (figure 6.2.4).
Pooled analysis from 7 cohort studies (more than 337 000
participants, followed up for up to 11 years, with more than
4300 breast cancer cases) showed a non-significant increased
risk of premenopausal breast cancer with greater adultattained height. The effect estimate was 1.02 (95% CI
0.96–1.10) per 5 cm (2 inches).362
Twenty-three case-control studies showed increased risk
with greater adult attained height,206 208 214 217 224 231 242 247 256
257 290 297 304 312 318 324-326 339 341 346 638 644 646 647
which was statistically significant in five.217 290 325 326 339 Thirteen studies
showed non-significant decreased risk.205 225 248 253 259 261 272
303 308 327 640 645
Two studies showed no effect on risk.241 352
588
Meta-analysis was possible on 31 case-control studies,giving a summary effect estimate of 1.04 (95% CI 1.02–1.06)
per 5 cm (2 inches), with moderate heterogeneity (figure
6.2.4).
A dose-response relationship was apparent from cohortand from case-control data.
The general mechanisms through which factors associated with adult attained height could plausibly cause cancer
are outlined in 6.2.1.3 (also see box 2.5). Many of these,such as early-life nutrition, altered hormone profiles, and therate of sexual maturation, could plausibly increase cancer
risk.
There are fewer data for premenopausal than forpostmenopausal breast cancer. The epidemiologicalevidence is generally consistent with a dose response
and evidence for plausible mechanisms. Greater adultattained height or factors that lead to it are probably acause of premenopausal breast cancer. The causal
factor is unlikely to be tallness itself, but factors that
promote linear growth in childhood.

The Panel is aware that since the conclusion of the SLR, onecohort study649 has been published. This new information does
not change the Panel judgement (see box 3.8).
Pancreas

Eight cohort studies,40 41 53 58 122 650-652 12 case-control studies,60-63 67 70 73 653-657 and 1 ecological study625 investigatedadult attained height and pancreatic cancer.
Six cohort studies showed increased risk with greater adultattained height,40 41 53 122 650 652 which was statistically significant in one.40 One study showed no effect on risk.651
Another stated that there was no significant association.58
Meta-analysis was possible on six cohort studies, giving asummary effect estimate of 1.11 (95% CI 1.05–1.17) per 5
cm (2 inches), with low heterogeneity (figure 6.2.5).
The Panel is aware of a further study, published after theconclusion of the SLR, from the European Prospective
Investigation into Cancer and Nutrition. This reported a statistically significant increased risk for the highest adult235

P A R T

Figure 6.2.5

Height and pancreatic cancer; cohort andcase-control studies

Figure 6.2.62•

E V I D E N C E

A N D

J U D G E M E N T S

Height and pancreatic cancer;
cohort studies: dose response

Relative risk (95% CI)
CohortOgren 1996

Ogren 1996

1.00 (0.81–1.24)

Tulinius 1997 Men

Tulinius 1997 Men

1.19 (0.97–1.45)

Tulinius 1997 Women

1.31 (0.97–1.77)

Michaud 2001 Women

1.21 (1.02–1.34)

Stolzenberg-Solomon 2002 Men

1.04 (0.92–1.17)

Song 2003 Men

1.07 (0.95–1.20)

Giovanucci 2004 Men

1.07 (0.94–1.22)

Summary estimate

Tulinius 1997 Women
Michaud 2001 Women
Stolzenberg-Solomon 2002 Men

1.11 (1.05–1.17)

Song 2003 Men
Giovannucci 2004 Men

Case control
Sarles 1979 Men

1.00 (0.74–1.35)

Howe 1990 Men – Direct interview

1.26 (0.95–1.68)

Howe 1990 Women –Direct interview

1.04 (0.71–1.51)

Howe 1990 Men –Indirect interview

1.04 (0.88–1.24)

Howe 1990 Women –Indirect interview

1.05 (0.84–1.32)

Ghadirien 1991

1.05 (0.83–1.32)

La Vecchia 1991 Men

1.05 (0.93–1.19)

La Vecchia 1991 Women

1.13 (0.97–1.33)

Zatorski 1991

0.89 (0.77–1.03)

Bueno de Mesquita 1992 Men

0.99 (0.83–1.19)

Bueno de Mesquita 1992 Women

1.46 (1.17–1.82)

Kalapothaki 1993

0.99 (0.83–1.18)

Ji 1996 Men

0.80 (0.68–0.94)

Ji 1996 Women

1.00 (0.79–1.27)

Eberle 2005 Men

0.96 (0.86–1.06)

Eberle 2005 Women

1.00 (0.89–1.12)

Pezzi 2005

1.01 (0.92–1.10)

Summary estimate

1.02 (0.96–1.07)

0.5

0.75

1

1.5

2

Relative risk, per 5 cm

attained height group when compared to the lowest, with aneffect estimate of 1.74 (95% CI 1.20–2.52).74
Five case-control studies showed increased risk withgreater adult attained height,60 61 70 654 657 which was statistically significant in women, but not men, in one.654 Fourstudies showed decreased risk,62 63 67 655 which was statistically significant in men, but not women, in one.63 Two studies showed no effect on risk653 656 and another stated that
there was no significant association.73 Meta-analysis was possible on 10 case-control studies, giving a summary effect estimate of 1.02 (95% CI 0.96–1.07) per 5 cm (2 inches), withmoderate heterogeneity (figure 6.2.5).
A dose-response relationship was apparent from cohort
data (figure 6.2.6), but not from case-control data.
The single ecological study showed an association between
greater adult attained height and increased pancreatic cancer incidence, which was statistically significant in men.625
The general mechanisms through which the factors thatlead to greater adult attained height, and its consequences,
could plausibly influence cancer risk are outlined in 6.2.1.3(also see box 2.4). Many of these, such as early-life nutrition,

236

155

160

165

170

175

180

Height (cm)altered hormone profiles, and the rate of sexual maturation,
could plausibly increase cancer risk.
There is ample prospective epidemiological evidence,
though there is some inconsistency. There is evidence
for a dose-response relationship and evidence forplausible mechanisms. Greater adult attained height orfactors that lead to it are probably a cause ofpancreatic cancer. The causal factor is unlikely to betallness itself, but factors that promote linear growthin childhood.
Ovary

Seven cohort studies,168 658-663 nine case-control studies,254 657
664-670
and two ecological studies625 671 investigated adultattained height and ovarian cancer.
All seven cohort studies showed increased risk with greater
adult attained height, which was statistically significant infour.168 659 661 663 Meta-analysis was possible on three cohort
studies, giving a summary effect estimate of 1.15 (95% CI
1.08–1.21) per 10 cm (3.9 inches), with low heterogeneity(figure 6.2.7).
Seven case-control studies showed non-significant
increased risk with greater adult attained height.254 664 666-670
Two studies showed decreased risk,657 665 which was statistically significant in one.665 Meta-analysis was possible onseven case-control studies, giving a summary effect estimateof 0.96 (95% CI 0.87–1.05) per 10 cm (3.9 inches), withmoderate heterogeneity (figure 6.2.7). Heterogeneity originated from one relatively large hospital-based study. The
confidence intervals of all other studies were large and overlapped the null effect.
A dose-response relationship was apparent from cohort

C H A P T E R

6

Figure 6.2.7•

B O D YC O M P O S I T I O N ,G R O W T H ,Height and ovarian cancer; cohort andcase-control studies
Relative risk (95% CI)

CohortSchouten 2003

1.42 (1.08–1.87)

Engeland 2003

1.14 (1.08–1.22)

Andersaon 2004

1.07 (0.89–1.28)

Summary estimate

1.15 (1.08–1.21)

Case control
Zhang 2005

1.26 (0.88–1.80)

Hirose 1999

1.12 (0.67–1.88)

Mori 1998

1.11 (0.67–1.88)

Polychronopoulou 1993

1.09 (0.75–1.59)

Kuper 2002

1.06 (0.75–1.59)

Cramer 1984

1.05 (0.79–1.39)

Del Maso 2002

0.81 (0.70–0.93)

Summary estimate

0.96 (0.87–1.05)

0.5

1

1.5

2

Relative risk, per 10 cm

data, but not from case-control data.
Both ecological studies showed an association between
greater adult attained height and increased cancer incidence.625 671
The general mechanisms through which the factors thatlead to greater adult attained height, and its consequences,
could plausibly influence cancer risk, are outlined in 6.2.1.3(also see box 2.4). Many of these, such as early-life nutrition, altered hormone profiles, and the rate of sexual maturation, could plausibly increase cancer risk.

A N D

D E V E L O P M E N T

increased risk for postmenopausal women and non-significant decreased risk for premenopausal women.371 One study
showed non-significant increased risk for metastatic
endometrial cancer and non-significant decreased risk fornon-metastatic endometrial cancer.675 One study reported nosignificant difference but gave no further information.385
Meta-analysis was possible on four cohort studies,372 375 382
674
giving a summary effect estimate of 1.17 (95% CI
0.96–1.42) per 10 cm (3.9 inches), with no heterogeneity.
Eight of the case-control studies showed increased risk
with greater adult attained height,254 389 396 404 416 420 422 435437 446 453 579 676 677
which was statistically significant in one.435
Two studies that showed decreased risk, which was not statistically significant in either case.402 434 578 Five other studies reported non-significant associations.409 419 423 424 657
Meta-analysis was possible on 11 case-control studies,254 402
416 419 420 422 435 436 455 579 676
giving a summary effect estimateof 1.10 (95% CI 1.00–1.21) per 10 cm (3.9 inches), withmoderate heterogeneity.
The general mechanisms through which the factors thatlead to greater adult attained height, or its consequences,
could plausibly influence cancer risk are outlined in 6.2.1.3(also see box 2.4). Many of these, such as early-life nutrition, altered hormone profiles, and the rate of sexual maturation, could plausibly increase cancer risk.
Although there is generally consistent evidence forprospective epidemiological data, there is someinconsistency in the evidence between cohort andcase-control studies, and the mechanistic evidence is
speculative. There is limited evidence that greater
adult attained height or factors that lead to it are acause of endometrial cancer. The causal factor isunlikely to be tallness itself, but factors that promote
linear growth in childhood.

6.2.3.2 Greater birth weight
There is some inconsistency, but the better quality
epidemiological data show a clearer effect, with adose-response relationship. There is evidence forplausible mechanisms operating in humans. Adult
attained height or factors that lead to it are probably acause of ovarian cancer. The causal factor is unlikely to
be tallness itself, but factors that promote linear
growth in childhood.

The Panel is aware that since the conclusion of the SLR, onecohort study672 and one case-control study673 have been published. This new information does not change the Panel judgement (see box 3.8).
Endometrium

Ten cohort studies,168 369 371 372 375 379 382 385 674 675 16 casecontrol studies,254 389 396 402 404 409 416 419 420 422-424 434-437 446 453
578 579 657 676 677
and one ecological study625 investigatedadult attained height and endometrial cancer.
Seven cohort studies showed increased risk with greater
adult attained height,168 369 372 375 379 382 674 which was statistically significant in one.379 One study showed significant

Breast (premenopause)

Six cohort studies150 319 678-681 and four case-control studies312
644 682 683
investigated birth weight and premenopausal breast
cancer.
All six cohort studies showed increased risk with greaterbirth weight, which was statistically significant in three.150
679 680
Meta-analysis was possible on four cohort studies, giving a summary effect estimate of 1.08 (95% CI 1.04–1.13)
per kg (2.2 lbs), with high heterogeneity (figure 6.2.8).
Three case-control studies showed increased risk withgreater birth weight,644 682 683 which was statistically significant in one.682 Another study showed non-significant
decreased risk.312
The general mechanisms through which the factors thatlead to greater birth weight, or its consequences, could plausibly influence cancer risk are outlined in 6.2.1.1. Many ofthese, such as long-term programming of hormonal systems,
could plausibly increase cancer risk.
There is general consistency amongst the relatively few
epidemiological studies, with some evidence for a dose
response. The mechanistic evidence is speculative.

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Figure 6.2.8

Birth weight and premenopausal breast
cancer; cohort studies
Relative risk (95% CI)

De Stavola 2000

1.79 (1.04–3.09)

McCormack 2005

1.52 (1.13–2.05)

Silva 2004

1.39 (0.86–2.26)

Ahlgren 2004

1.07 (1.02–1.12)

Summary estimate

1.08 (1.04–1.13)

1

2

3

Relative risk, per kg

Greater birth weight or factors that lead to greaterbirth weight are probably a cause of premenopausal
breast cancer.

The Panel is aware that since the conclusion of the SLR, onecohort363 and one case-control study684 have been published.
This new information does not change the Panel judgement (seebox 3.8).

6.2.4 Comparison with previous report
The previous report used different terminology from thisReport. It concluded that the evidence that rapid growthleads to earlier menarche (itself an established risk factor forbreast cancer), and that greater adult attained height increases the risk of breast cancer, was convincing. It also concluded
that greater adult height was a possible cause of colorectal
cancer.
In general, evidence that the factors that lead to greater
adult attained height, or its consequences, increase the riskof cancers of some sites, including colorectal and breast, has
become stronger since the mid-1990s.

6.2.5 Conclusions
The Panel concludes:
The evidence that the factors that lead to greater adultattained height (meaning relative tallness), or its consequences, are a cause of cancers of various sites, is more
impressive now than it was in the mid-1990s.
The evidence that the factors that lead to greater adultattained height, or its consequences, increase the risk ofcolorectal cancer and postmenopausal breast cancer isconvincing; and they probably increase the risk of cancersof the pancreas, breast (premenopause), and ovary. There islimited evidence suggesting that the factors that lead to adultattained height, or its consequences, increase the risk ofendometrial cancer. Greater adult attained height is unlike-

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E V I D E N C E

A N D

J U D G E M E N T S

ly to directly modify the risk of cancer. It is a marker for
genetic, environmental, hormonal, and also nutritional factors affecting growth during the period from preconception
to completion of linear growth.
The factors that lead to greater birth weight, or its consequences, are probably a cause of premenopausal breast
cancer.

C H A P T E R

6•

B O D YC O M P O S I T I O N ,G R O W T H ,A N D

D E V E L O P M E N T

6.3 Lactation
LACTATION, AND THE RISK OF CANCER
In the judgement of the Panel, the factors listed below modify the risk of cancer. Judgements are graded according to the strength of the evidence.

DECREASES RISK

Convincing

INCREASES RISK

Exposure

Cancer site

Exposure

Lactation

Breast (pre- and postmenopause)

Lactation

Ovary

Cancer site

Probable
Limited —suggestive
Substantial
effect on risk
unlikely

None identified

For an explanation of all the terms used in the matrix, please see chapter 3.5.1, the text of this section, and the glossary.

Human milk is the natural, complete food for infants
until around 6 months of age. There is no completely
adequate substitute. Breastfeeding is natural both forthe mother and her child, although some women findthat they are unable to or do not want to breastfeed.
Lactation is the process by which the mother produces
her milk.
The Panel judges as follows:
Evidence on lactation, breastfeeding by the mother, andher risk of breast cancer at all ages thereafter, is strong
and consistent. It is supported by strong evidence forplausible biological mechanisms.
The Panel concludes that lactation protects against bothpremenopausal and postmenopausal breast cancer. An
implication of this finding, together with those in theearlier sections of this chapter, and also as summarised
and judged in Chapter 8, is that more emphasis should begiven to factors acting throughout the life course thatmodify the risk of cancer. There is limited evidence
suggesting that lactation protects against cancer of theovary.
Within the remit of this Report, the strongest evidence,corresponding to the judgement of ‘convincing’, showsthat lactation — breastfeeding by the mother — protects
her against breast cancer at all ages thereafter.

Human milk gives infants the best start in life. The view
sometimes expressed in the past, that infant formula may innormal circumstances be a complete substitute for human
milk, is no longer held.685-687
The main focus of attention on breastfeeding and human
milk, throughout almost all of the last century, has been on

its benefits for the infant and young child during the period of breastfeeding, and then into the stage of weaning, andperhaps up to 5 years of age. This remains a central part ofpublic health nutrition science, policy, and practice.687
It is only recently that researchers and those concernedwith public health policies have paid substantial attention
to the effects of being breastfed on the health of the childin later life, and on the effects of lactation on the health ofthe mother.687 688 Thus, the previous report did not investigate what was then the small evidence base on breastfeeding and cancer risk (see 6.3.4).
As shown in the previous two sections of this chapter, it
is becoming increasingly evident that early-life environment,
including food and nutrition, is of fundamental importanceto health and well-being throughout the life course. This has
important implications for overall judgements and recommendations designed to promote health and prevent disease,and for public policy. These aspects are discussed in Part 3of this Report, and in an accompanying report on policy
implications, to be published in late 2008.689

6.3.1 Definition and patterns
In this Report, the term ‘lactation’ refers to the process bywhich the mother produces milk to breastfeed. While lactating women may express their milk for their own or another child, or for storage in human milk banks, lactation isusually synonymous with breastfeeding.
Breastfeeding provides a complete source of nourishment
for newborns and young infants, and human milk also contains immunologically active components. The UN global
strategy for infant and young child feeding recommends

239

P A R T

exclusive breastfeeding up to 6 months for the health of bothmother and child.687
A mother’s breasts change during pregnancy to prepare forlactation, although milk is not produced until after the baby
is born. Pituitary hormones promote milk production after
birth, with suckling acting as the stimulus to let down milk
and to continue its production. During breastfeeding, menstruation reduces and often stops (amenorrhea). In almost
all mammals, including humans, lactation induces a period
of infertility, which increases birth spacing. Babies tend tobe weaned earlier in high-income countries. It is recommended that solid foods are not introduced until the infant
is around 6 months old. With decreased suckling, lactation
slows and then stops, and this is usually accompanied by areturn to normal menstruation.
Breastfeeding was almost universal at the beginning of the20th century. It declined in the mid-1900s, but has been
increasing since the 1970s.690 However, disparity remains
with socioeconomic status of mothers.691 In some lowincome countries, high socioeconomic class or educationlevel of mothers is associated with reduced breastfeeding,whereas the opposite is true in many high-income countries.692 Older mothers and those educated to a higher level
are more likely to breastfeed in high-income countries.693 694
In Africa, more than 95 per cent of infants are breastfed,
often for a long duration, although exclusivity is low and therising prevalence of HIV may reduce breastfeeding.695 Also
see chapter 4.11.

6.3.2 Interpretation of the evidence
6.3.2.1 General
For general considerations that may affect interpretation of
the evidence, see chapters 3.3 and 3.5, and boxes 3.1, 3.2,
3.6 and 3.7.
6.3.2.2 SpecificSome considerations specific to breastfeeding and lactation
are as follows.
Patterns and ranges of duration. Most studies have been carried out in high-income countries where, since the second halfof the 20th century and until recently, duration of breastfeeding — exclusive or not — has usually been brief. Therefore
the findings of these studies may be of limited relevance toareas of the world where breastfeeding practices differ.
Classification. Reports (as distinct from studies) concernedwith chronic diseases have not usually considered breastfeeding or other factors specific to infancy and childhood,despite what is now the general agreement that the outcomes of early life experience tend to track into adult life.
Also, there is no agreed classification for duration and exclusivity of breastfeeding.
Measurement. Studies reporting on breastfeeding use theterm with different meanings. Some studies have simply distinguished between ‘ever’ and ‘never’, which means that

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results from minimal amounts of breastfeeding — exclusive
or not — are combined with results from extended and exclusive breastfeeding.

6.3.3 Evidence and judgements
The full systematic literature review (SLR) is contained on
the CD included with this Report.
The principal mechanism through which lactation or breastfeeding could plausibly influence cancer risk is the hormonal
influence of the associated period of amenorrhea and infertility. This decreases lifetime exposure to menstrual cycles
and therefore alters hormone levels, particularly androgens,which can influence cancer risk (box 2.4). Site-specific mechanisms are described with the evidence for each cancer site
discussed below.
BreastOne cohort study636 696 and 37 case-control studies207 208 219
investigated ever having
breastfed, as compared to never having breastfed, and breast
cancer. Five cohort studies164 177 721-724 and 55 case-control
studies213 215 216 229 232 244 246 254 262 273 279 281 290-292 295 296 299-302
306 312 318 335 337 340 349 355 356 697 699 701-705 707 712-714 717 725-748
investigated the total duration of lactation.

244 249 254 264 294-297 302 354 355 591 697-720

Ever compared to neverThe single cohort study showed a statistically significant
decreased risk for ever having breastfed when compared tonever. The effect estimate, which was adjusted for reproductive factors, was 0.95 (95% CI 0.91–0.99) per month ofbreastfeeding, based on 1120 cases (age unspecified). A statistically significant decreased risk was observed for premenopausal breast cancer, 0.76 (95% CI 0.59–0.99) per
month of breastfeeding, but not for postmenopausal breast
cancer, 0.96 (95% CI 0.91–1.01) per month of breastfeeding.636 696
Twenty-eight case-control studies investigated breast cancer (age unspecified).207 208 219 244 254 264 294 295 354 355 591 697 700
703-708 710-713 715-720
Twenty-four of these showed decreased
risk for ever having breastfed when compared to never,207 208
219 244 254 264 294 295 302 354 355 591 700 703-707 710-713 715-720
which wasstatistically significant in 10 studies.244 264 294 707 713 716 717 719
720
Four studies showed non-significant increased risk.219 302
697 708

Sixteen case-control studies investigated premenopausal
breast cancer.207 208 244 249 295 297 355 698 699 701 702 705 707 709 712 714
716 718
Fourteen of these showed decreased risk for ever having breastfed when compared to never,244 249 295 297 355 698 701
702 705 707 709 712 714 716 718
which was statistically significant infour.295 297 698 714 716 Two studies showed non-significant
increased risk.207 208 699
Fourteen case-control studies investigated postmenopausal
breast cancer.244 296 355 698 699 701 702 707 709 712-714 716 718 Ten ofthese showed decreased risk for ever having breastfed whencompared to never,244 249 295 296 355 698 701 702 705 707 709 712-714 716
718
which was statistically significant in six.296 698 701 707 716 Fourstudies showed non-significant increased risk.249 295 699 705

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Figure 6.3.1

B O D YC O M P O S I T I O N ,G R O W T H ,Total duration of lactation and breast
cancer (age unspecified); cohort andcase-control studies
Relative risk (95% CI)

CohortMichels 1996

1.00 (0.97–1.02)

Kvale 1987

0.97 (0.94–0.99)

Goodman 1997

0.96 (0.85–1.09)

Li 2005

0.96 (0.82–1.13)

Summary estimate

0.98 (0.97–1.00)

A N D

D E V E L O P M E N T(figure 6.3.1). There was no clear difference when results
were stratified according to menopause status.
Pooled analysis from 47 epidemiological studies in 30
countries (more than 50 000 controls and nearly 97 000
breast cancer cases) showed a statistically significant
decreased risk breast cancer with duration of lactation. There
was an estimated reduction in risk of 4.3 per cent (95% CI
2.9–5.8; p < 0.0001). Menopausal status was not an effectmodifier.749
Forty-four case-control studies investigated breast cancer(age unspecified).215 229 232 244 254 262 273 281 290-292 295 299-302 306
318 335 337 340 349 355 356 697 703-705 707 712 713 717 725-727 730 734-738 740-

Case control
Schecter 1997

1.12 (0.9–1.36)

Chie WeiChu 1997

1.02 (0.97–1.07)

Siskind 1989

1.02 (0.96–1.08)

Thirty-five of these showed decreased risk withincreased total duration of lactation,215 229 244 254 262 273 281 290

Abramson 1966

1.02 (0.90–1.15)

295 299-302 306 318 335 337 349 355 356 703-705 707 713 717 725-727 729 734 736

Mendoca 1999

1.02 (0.94–1.10)

Wrensch 2003

1.00 (0.87–1.15)

Trentham-Dietz 2000

1.00 (0.95–1.05)

Do 2003

1.00 (0.96–1.04)

745 747 748

0.93 (0.86–1.01)

737 742-745 747 748
which was statistically significant in 18 studies.215 244 254 273 281 300 337 349 705 707 713 717 726 727 736 737 743 747 748
Six studies showed non-significant increased risk291 292 697 730
735 738 740 741
and three studies showed no effect of risk.232 340
712
Meta-analysis was possible on 37 case-control studies,giving a summary effect estimate of 0.98 (95% CI 0.97–0.98)
per 5 months of total breastfeeding, with moderate heterogeneity (figure 6.3.1).
Twenty-six case-control studies investigated premenopausal breast cancer.216 244 254 281 290 295 312 337 355 699 701
702 705 707 712-714 728-732 739 741 743 745 746 748
Twenty-four studies
showed decreased risk with increased total duration of lactation,216 244 254 281 290 295 312 337 355 699 701 702 705 707 712-714 728 729
731 732 739 743 745 746 748
which was statistically significant ineight.254 295 707 713 714 732 739 745 746 One study showed no effecton risk741 and one study reported non-significant increased
risk.730 Meta-analysis was possible on 19 case-control studies, giving a summary effect estimate of 0.98 (95% CI
0.97–0.98) per 5 months of total breastfeeding, with moderate heterogeneity.216 244 254 281 295 312 355 701 702 712-714 729-732 741

Zheng 2000

0.93 (0.87–1.00)

743 745 746 748

Potischman 1990

0.93 (0.80–1.07)

Yuan 1988

0.93 (0.88–0.98)

Wenten 2001

0.92 (0.84–1.00)

Haring 1992

0.91 (0.78–1.06)

Brandt 2004

0.90 (0.82–0.99)

Becher 2003

0.90 (0.82–0.98)

Twenty-three case-control studies investigated postmenopausal breast cancer.213 216 244 246 254 279 281 295 296 337 355
699 701 702 705 707 712-714 728 730 731 739 741 743 748
Fourteen showeddecreased risk with increased total duration of lactation,213
216 244 246 279 281 296 337 355 699 701 705 707 713 714 728 745 746 748
which
was statistically significant in three.213 337 701 707 Two studies
showed no effect on risk739 743 and seven reported non-significant increased risk.254 295 702 712 730 741 745 746 Meta-analysis
was possible on 18 case-control studies, giving a summary
effect estimate of 0.99 (95% CI 0.98–1.00) per 5 months oftotal breastfeeding, with low heterogeneity.244 246 254 279 281 296

Tessaro 2003

0.99 (0.93–1.06)

Newcomb 1994

0.99 (0.97–1.01)

Thomas 1993

0.99 (0.98–1.00)

Coogan 1999

0.99 (0.96–1.01)

Gao Yu Tang 2000

0.99 (0.95–1.03)

Shu 2001

0.98 (0.95–1.00)

Lai FuMing 1996

0.98 (0.93–1.03)

Yavari 2005

0.97 (0.94–0.99)

McCredie 1998

0.96 (0.92–1.01)

Tao 1988

0.96 (0.94–0.99)

Hu 1997

0.96 (0.91–1.02)

Zheng 2001

0.96 (0.91–1.01)

Kuru 2002

0.95 (0.93–0.98)

Layde 1989

0.95 (0.93–0.97)

Lopez-Carillo 1997

0.95 (0.92–0.99)

Wenten 2001

0.95 (0.88–1.02)

Romieu 1996

0.95 (0.92–0.97)

Hirose 1999

0.94 (0.90–0.98)

Furberg 1999

0.94 (0.89–0.99)

Olaya-Contreras 1999

0.94 (0.88–0.99)

Park 2000

Lee 2004

0.87 (0.79–0.86)

Summary estimate

0.98 (0.97–0.98)

0.8

1

1.2

1.4

Relative risk, per 5 months

355 701 702 712 714 730 731 739 741 743 745 746

Total duration

Four cohort studies showed decreased risk with increased
total duration of lactation,164 177 721-723 which was statistically significant in two.177 721 One study showed no effect on
risk.724 Meta-analysis was possible on four cohort studies,giving a summary effect estimate of 0.98 (95% CI 0.97–1.00)
per 5 months of total breastfeeding, with no heterogeneity

The general mechanisms through which lactation could
plausibly protect against cancer are outlined in 6.3.3. In
addition to the hormonal effects of amenorrhea, the strong
exfoliation of the breast tissue during lactation, and the massive epithelial apoptosis at the end of breastfeeding, could
contribute to risk decrease by elimination of cells with potential initial DNA damage.
There is abundant epidemiological evidence from bothprospective and case-control studies, which isconsistent and shows a dose-response relationship.

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There is robust evidence for plausible mechanisms that
operate in humans. The evidence that lactation
protects against both premenopausal andpostmenopausal breast cancer is convincing.

One cohort study750 and 10 case-control studies254 751-760
investigated lactation and ovarian cancer.
The single cohort study showed non-significant decreased
risk with increased total duration of lactation. The effect estimate was 0.79 (95% CI 0.25–2.56) for five or more children
breastfed compared with never breastfeeding. However, thisstudy was relatively small, with only 97 cases.750
Seven case-control studies showed decreased risk withincreased total duration of lactation,254 753 754 756-760 which
was statistically significant in three.753 756 759 760 Three studies showed non-significant increased risk.751 752 755 Metaanalysis was possible on six case-control studies, giving asummary effect estimate of 0.96 (95% CI 0.93–0.99) per
6 months of total breastfeeding, with high heterogeneity(figure 6.3.2).
A dose-response relationship is apparent from case-control
data, but cohort data are insufficient.
As described in 6.3.2, substantial heterogeneity could be
expected when assessing breastfeeding when, for example,
exclusivity of breastfeeding is not always assessed.
The general mechanisms through which lactation could
plausibly protect against cancer are outlined in 6.3.3. Thereis evidence that the reduced number of menstrual cycles
associated with breastfeeding protects against some cancers.
There are sparse prospective epidemiological data,
though some evidence for a dose response. The
mechanistic evidence is speculative. There is limited
evidence suggesting that lactation protects against
ovarian cancer.

Total duration of lactation and ovarian cancer;
case-control studies
Relative risk (95% CI)

Booth 1989

1.09 (0.95–1.24)

Chiaffarino 2005

1.03 (0.97–1.10)

Yen 2003

0.96 (0.92–1.00)

Hirose 1999

0.90 (0.72–1.13)

Greggi 2000

0.84 (0.78–0.91)

Zhang 2004

0.80 (0.69–0.94)

Summary estimate

0.96 (0.93–0.99)

0.5

1
Relative risk, per 6 months

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The Panel is aware that since the conclusion of the SLR, one
case-control study761 has been published. This new information
does not change the Panel judgement (see box 3.8).

6.3.4 Comparison with previous report

Ovary

Figure 6.3.2

2

1.5

2

The previous report noted evidence that breastfeeding(meaning lactation) protected against breast cancer, but it
did not review the literature or make a judgement.

6.3.5 Conclusions
The Panel concludes:
The evidence on lactation and breast cancer — the mostcommon female hormone-related cancer — is impressive.
Much of this has been published since the mid-1990s.
The evidence that lactation protects against breast cancer,
at all ages, is convincing. There is limited evidence suggesting that lactation protects against ovarian cancer.

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7Cancers
Every year an estimated 11 million people are
diagnosed with cancer (excluding skin cancers) andnearly 7 million people are recorded as dying fromcancer. Projections for 2030 predict that thesefigures will double. Cancer is increasing at rates
faster than the increase in global population. It is
becoming more common in high-income but also —and most of all — in middle- and low-income
countries, absolutely and also relative to otherdiseases.
The scientific community is convinced that
inherited high susceptibility to cancer accounts for
only a small proportion of cases. Although we are
all more or less susceptible to various diseases,
most adult cancers are caused mainly byenvironmental factors. This means that mostcancers are at least in theory preventable.
One important cause of cancer is smoking, orother exposure to, tobacco. Infection, infestation,
solar radiation, and other factors are also
important. Food and nutrition, physical activity,
body composition, and other associated factors arealso individually and collectively important
modifiers of cancer risk. But there is a difference.
Smoking and exposure to tobacco, and these otherfactors, are all causes of cancer. By contrast, thisand the previous chapters show that food andnutrition, and physical activity can protect against
cancer. When we are able to do so, we can choose
ways of life that protect both ourselves and thenext generation against cancer. So our nutritional
state — what we eat and drink, how active we are,and how much body fat we carry — not only as
adults but also from and before birth, vitally affects
our risk of many cancers.
This chapter follows those on foods and drinks,
physical activity, and body composition, growth,and development. Its purpose is to summarise theevidence derived from independently commissioned
and presented systematic literature reviews (SLRs),
and the Panel’s judgements and conclusions, as they
relate to cancers of 17 sites. Together, these amountto roughly 80 per cent of the incidence of, anddeaths from, all cancers worldwide. Evidence on anumber of other cancers is also summarised briefly,
based on narrative reviews.

244

The sequence of the sections of this chapter
corresponds roughly with the body’s systems, orwith sites that have anatomical, metabolic,hormonal, or other features in common, andgenerally follows the sequence of the previous
report.
The structure of all the sections, where evidence
derives from these systematic reviews, is identical.
After brief introductions, matrices display the
Panel’s judgements. In this chapter, the Panel’s
judgements also include the ‘Limited — noconclusion’ category, where evidence is, in the
Panel’s view, of such poor quality, or too sparse,
confused, or conflicting, to allow a conclusion.
Footnotes to these matrices include important
explanations or qualifications.
Then follow subsections on trends, incidence, andsurvival; pathogenesis; and other establishedcauses. The next subsection concerns interpretationof the evidence, in which issues and problems
related to specific cancer sites are summarised.
‘Evidence and judgements’ are the central
subsections throughout this chapter. Here, theevidence from the SLRs, reported more extensively
with graphics in Chapters 4, 5, and 6, is also
summarised. The sequence of these subsections is
the same as that of Chapters 4–6. The strongest
evidence on protection from cancer comes first,
followed by the strongest evidence on causation,and so on. Within each passage, summaries of thestatistically most powerful epidemiological studies
come first, followed by other epidemiologicalstudies, and then summaries of the experimental
literature and evidence of biological plausibility.
This is followed by the Panel’s judgements, whichtake into account matters of quality andinterpretation.
Then follows a subsection comparing thejudgements of this Report with those of theprevious report, with indications of why thesediffer when they do. All sections conclude with thePanel’s judgements for each cancer site.

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7.1 Mouth, pharynx, and larynx
Cancers of the mouth, pharynx, and larynx, taken together,
are the seventh most commonly occurring types of cancer
worldwide. These cancers are three times more common inmen than in women. Over 550 000 cases were recorded in
2002, accounting for around 5 per cent of cancer cases
overall. In general, the rates of these cancers are
decreasing. These cancers tend to recur. Survival rates arevariable and average around 50 per cent at 5 years.
Cancers of the mouth, pharynx, and larynx are the seventh
most common cause of death from cancer.
Overall, the Panel judges that food and nutrition play animportant role in the prevention and causation of cancersof the mouth, pharynx, and larynx.
The Panel judges as follows:
The evidence that alcoholic drinks are a cause of cancersof the mouth, pharynx, and larynx is convincing. The risk
is multiplied when drinkers of alcohol also smoke tobacco.
Non-starchy vegetables, fruits, and also foods containing
carotenoids probably protect against these cancers.
There is limited evidence suggesting that maté, a herbal
infusion traditionally drunk scalding hot through a metal
straw in parts of South America, is a cause of oral cancer.
The main single cause of these cancers is smoking
tobacco. It has been estimated that up to half of thesecancers are preventable by appropriate diets andassociated factors.
In final summary, the strongest evidence, corresponding
to judgements of “convincing” and “probable”, shows that
alcoholic drinks are a convincing cause of these cancers;
and that non-starchy vegetables, fruits, and foods
containing carotenoids are probably protective.

There are several different tissues and organs in and aroundthe mouth, pharynx, and larynx. These include the lips, thetongue, the inside lining of the cheeks (buccal mucosa), thefloor of the mouth, the gums (gingiva), the palate, and thesalivary glands. The pharynx (or throat) is the muscular cavity leading from the nose and mouth to the larynx, which
includes the vocal cords.
Ninety per cent of cancers of the mouth, pharynx, and larynx are squamous cell carcinomas, the type discussed here.
Cancers of the oropharynx (including the tonsils) and thehypopharynx are also included. For cancer of the nasopharynx,
the cavity from the back of the mouth to the nose, see 7.2.

FOOD, NUTRITION, PHYSICAL ACTIVITY, AND
CANCERS OF THE MOUTH, PHARYNX, AND LARYNX
In the judgement of the Panel, the factors listed below modify the risk ofcancers of the mouth, pharynx, and larynx. Judgements are gradedaccording to the strength of the evidence.

DECREASES RISK
Convincing
Probable

INCREASES RISK
Alcoholic drinks

Non-starchy
vegetables1
Fruits1
Foods containing
carotenoids2
Maté3

Limited —suggestive
Limited —no conclusion

Substantial
effect on risk
unlikely

1
2
3

Cereals (grains) and their products; starchy roots,
tubers, and plantains; dietary fibre; pulses (legumes);
meat; poultry; fish; eggs; milk and dairy products;
total fat; animal fats; plant oils; coffee; tea; frying;grilling (broiling) and barbecuing (charbroiling);
protein; vitamin A; retinol; thiamin; riboflavin;niacin; folate; vitamin C; vitamin E; calcium; iron;selenium; body fatness; energy intake

None identified

Judgements on vegetables and fruits do not include those preserved bysalting and/or pickling.
Includes both foods naturally containing the constituent and foods whichhave the constituent added (see chapter 3.5.3).
As drunk traditionally in parts of South America, scalding hot through ametal straw. Any increased risk of cancer is judged to be caused by epithelial
damage resulting from the heat, and not by the herb itself.

For an explanation of all the terms used in the matrix,
please see chapter 3.5.1, the text of this section,and the glossary.

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7.1.1 Trends, incidence, and survival
Rates of cancers of the mouth and pharynx (age adjusted)
are stable or decreasing in many high-income countries.
There was a sharp increase between 1950 and 1980 in several European countries, such as Germany and France,
although this has since reached a plateau and started todecrease. Laryngeal cancer rates appear to have been
generally stable or decreasing since 1970.1
Age-adjusted incidence rates of oral cancers range from
20–40 per 100 000 people in parts of south-central Asia,
Europe, Oceania, and southern Africa, to less than 3 per
100 000 in parts of eastern Asia, northern and western
Africa, and Central America. Pharyngeal cancers (other thanthose of the nasopharynx) follow broadly similar incidence
patterns, although the overall incidence is lower, with highsof more than 10 per 100 000 in south-central Asia and western Europe, to a low of less than 1 per 100 000 in northern
Africa. Age-adjusted incidence rates of laryngeal cancer
range from more than 10 per 100 000 in South America,
south-central and western Asia, and southern, central, andwestern Europe to less than 1 per 100 000 in many Africancountries.2 Rates are higher in men than in women byapproximately three to one.2 In the USA, rates are higher
among African-American people than in white people.3
Risk increases with age, and diagnoses of these three typesof cancer are most common in people aged 50 or over.4
Although cure rates are high for early-stage cancers of themouth, pharynx, and larynx, second primary tumours are relatively common at these sites.5 More than 60 per cent ofpatients do not seek medical advice until the disease is at anadvanced stage; in these cases, long-term survival rates arepoor, especially if the cancer site is inaccessible.4 Five-year
survival rates are around 60 per cent in the USA and 50 per
cent in the UK.3 6 These cancers account for just over 5 per

Box 7.1.1

Cancer incidence and survival

The cancer incidence rates and figures given in this Report arethose reported by cancer registries, now established in many
countries. These registries record cases of cancer that have been
diagnosed. However, many cases of cancer are not identified orrecorded: some countries do not have cancer registries; regionsof some countries have few or no records; records in countries
suffering war or other disruption are bound to be incomplete;and some people with cancer do not consult a physician.
Altogether, this means that the actual incidence of cancer is higher than the figures given here.
The cancer survival rates given in this chapter and elsewhereare usually overall global averages. Survival rates are generally
higher in high-income countries and other parts of the world
where there are established services for screening and early
detection of cancer and well established treatment facilities.
Survival also is often a function of the stage at which a cancer isdetected and diagnosed. The symptoms of some internal cancers
are often evident only at a late stage, which accounts for relatively low survival rates. In this context, ‘survival’ means that theperson with diagnosed cancer has not died 5 years after diagnosis. Also see chapter 9.

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cent of all cancer incidence, but just under 5 per cent of allcancer deaths.2 Also see box 7.1.1.

7.1.2 Pathogenesis
Mouth, pharynx, and larynx cancers, like other types, are theresult of genetic alterations that lead to small, localised
lesions in the mucous membranes that grow in an abnormalway (dysplasia). These lesions may then progress to carcinoma in situ, and then become invasive cancers.
Exposure to carcinogens, such as those in tobacco, can be
prolonged and consistent. The mouth and pharynx are
directly exposed to both inhaled carcinogens and those thatare ingested by drinking and chewing — including, in thecase of chewing tobacco and betel quid, when it is spat out
after chewing. Chronic damage and inflammation caused bystomach acid are also implicated; some studies have foundthat laryngopharyngeal reflux (where stomach acid flows
upwards to the larynx and/or pharynx) is associated withlaryngeal cancers.7 8
Cancers of the mouth, pharynx, and larynx frequently
show multiple, independent, malignant foci — with second
primary cancers occurring relatively frequently. This phenomenon occurs when an entire region of tissue is repeatedly exposed to carcinogens. Around 90 per cent of oral
cancers occur after exposure to tobacco or alcohol, or a combination of both.9

7.1.3 Other established causes
7.1.3.1 General(Also see chapter 2.4.)
Throughout this chapter, this section lists factors outside thescope of this Report, identified as established causes of cancer by the World Health Organization International Agency
for Research on Cancer, and other authoritative bodies.
These factors are as listed in chapter 2.4: tobacco use; infectious agents; radiation; industrial chemicals; and some medications. Other diseases may also increase the risk of cancer.
In the same way, life events that modify the risk of cancer— causative and protective — are also included.
‘Established’ effectively means ‘beyond reasonable doubt’— roughly the equivalent of the judgement of ‘convincing’
used in this Report. Occasionally, authoritative findings thatperhaps fall short of ‘established’ are also included here.
Where possible, a note of interactive or multiplicative
effects with food, nutrition, and the other factors covered bythis Report is added, as is any indication of scale or relative
importance. The factors here are almost all causative, whereas much of the evidence on food, nutrition, physical activity, and related factors shows or suggests protection against
cancer.
7.1.3.2 Specific
Other diseases. There is substantial evidence that gastricreflux increases the risk of oral cancers.

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C A N C E R S

Tobacco use. Smoking, and other use of and exposure totobacco, is the most important cause of oral cancers, including those of the mouth, pharynx, and larynx. These factors
are estimated to cause around 60 per cent per cent of alllaryngeal cancers. While alcoholic drinks are an independentcause of these cancers, risk is multiplied if drinkers smoke
tobacco and if smokers drink .10 Chewing of betel quid (withor without added tobacco) also causes oral cancers.11
Infection and infestation. Human papilloma viruses (HPVs)

are a cause of oral cancers.12-14

7.1.4 Interpretation of the evidence
7.1.4.1 General
For general considerations that may affect interpretation of
the evidence, see chapters 3.3 and 3.5, and boxes 3.1, 3.2,
3.6 and 3.7.
‘Relative risk’ is used in this Report to denote ratio measures of effect, including ‘risk ratios’, ‘rate ratios’, ‘hazard
ratios’, and ‘odds ratios’.
7.1.4.2 Specific
Considerations specific to cancers of the mouth, pharynx,
and larynx include:
Classification. Some studies did not report separately on can-cers of the mouth, pharynx, or larynx, but grouped thesecancers with others as ‘head and neck cancers’ or ‘upper
aerodigestive tract cancers’. The term ‘head and neck cancer’ includes all of these sites plus cancers of the middle ear,the nasal cavity, and the paranasal sinuses. The term ‘upper
aerodigestive tract cancer’ includes all head and neck cancers and oesophageal cancer (see 7.3).
Confounding. High-quality studies adjust for smoking but
may still be subject to residual confounding. Because of thesize of the effect of smoking, and the tendency for the dietsof smokers to be low in vegetables and fruits, and for smokers to have relatively lower body mass indices, residual confounding is a particular concern for these exposures.
Wherever possible, detailed stratification of the data according to smoking status was obtained.

7.1.5 Evidence and judgements
In total, 238 publications were included in the systematic literature review (SLR) for cancers of the mouth, pharynx, andlarynx. Fuller summaries of the epidemiological, experimental, and mechanistic evidence are in Chapters 4–6.
The full SLR is contained on the CD included with thisReport.
7.1.5.1 Non-starchy vegetables(Also see chapter 4.2.5.1.)
A total of 31 case-control studies and 3 ecological studies
examined non-starchy vegetables. Other groupings exam-

ined were non-starchy vegetables and fruits (in combination)(1 cohort, 6 case-control); raw vegetables (23 case-control);cruciferous vegetables (1 cohort, 14 case-control, and 1 ecological); green, leafy vegetables (1 cohort, 10 case-control);carrots (3 cohort, 18 case-control); and tomatoes (1 cohort,
12 case-control). Most of the studies for the exposuresgrouped under non-starchy vegetables showed a decreased
risk with increased intake. Meta-analysis showed a 28 percent decreased risk per 50 g per day (figure 4.2.2). The
dose-response relationship suggested that the greatest effect
was produced by the first increment; that is, that somevegetable consumption confers a protective effect compared with none (figure 4.2.3). However, it is not clear thatthe effect continues in a linear fashion. It is possible that
this is an artificial phenomenon produced by residual
confounding due to smoking. There is some unexplained
heterogeneity.
This is a wide and disparate category, and many different
plant food constituents are represented that could contributeto a protective effect of non-starchy vegetables. These include
dietary fibre, carotenoids, folate, selenium, glucosinolates,
dithiolthiones, indoles, coumarins, ascorbate, chlorophyll,
flavonoids, allylsulphides, flavonoids, and phytoestrogens,some of which are potentially antioxidants. Antioxidants trap
free radicals and reactive oxygen molecules, protecting
against oxidation damage. It is difficult to unravel the relative importance of each constituent and is likely that any protective effect may result from a combination of influences on
several pathways involved in carcinogenesis.
A substantial amount of consistent evidence on nonstarchy vegetables, including specific subtypes mostly
from case-control studies, shows a dose-response
relationship. There is evidence for plausible
mechanisms. Non-starchy vegetables probably protect
against mouth, pharynx, and larynx cancers.

The Panel is aware that since the conclusion of the SLR, twocohort15 16 and two case-control studies17 18 have been published. This new information does not change the Panel judgement. Also see box 3.8.
7.1.5.2 Fruits(Also see chapter 4.2.5.2.)
A total of 1 cohort study, 35 case-control studies, and 2 ecological studies investigated fruits. Other groupings examined
were citrus fruits (1 cohort, 23 case-control, 1 ecological),and non-starchy vegetables and fruits (in combination)(1 cohort, 6 case-control). Most studies showed decreased
risk. Meta-analysis showed a 18 per cent decreased risk per
100 g per day for general fruits, or 24 per cent per 50 g per
day for citrus fruits (figures 4.2.17 and 4.2.18). The doseresponse relationship suggested that the greatest effect was
produced by the first increment; that is, that some fruit consumption confers a protective effect compared to none.
However, it is not clear that the effect continues in a linear
fashion (figures 4.2.19 and 4.2.20). It is possible that this is
an artificial phenomenon produced by residual confounding
due to smoking.

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Studies that reported on combined intake of non-starchy
vegetables and fruits showed evidence of an association withdecreased risk (see 7.1.5.1).
Fruits are sources of vitamin C and other antioxidants suchas carotenoids, phenols, and flavonoids, as well as otherpotentially bioactive phytochemicals. Antioxidants trap free
radicals and reactive oxygen molecules, protecting against
oxidation damage. It is difficult to unravel the relative importance of each constituent, and is likely that any protective
effect may result from a combination of influences on several pathways involved in carcinogenesis.

7.1.5.4 Maté
(Also see chapter 4.7.5.6.1.)
Six case-control studies were examined. All reported
increased risk from drinking maté, which was statistically significant in four.
There is some biological plausibility. Maté is a herbal infusion traditionally drunk very hot through a metal straw. This
produces heat damage in the mouth, pharynx, and larynx.
Repeated damage of this nature could lead to cancer.
Chemical carcinogenesis from constituents of maté has also
been postulated.19 20

The evidence, including that on fruit subtypes, thoughmostly from case-control studies, is consistent, with adose-response relationship. There is evidence forplausible mechanisms. Fruits probably protect against
mouth, pharynx, and larynx cancers.

The evidence is sparse. There is limited evidence
suggesting that maté is a cause of mouth, pharynx, andlarynx cancers.

The Panel is aware that since the conclusion of the SLR, twocohort studies15 16 and one case-control study18 have been published. This new information does not change the Panel judgement. Also see box 3.8.
7.1.5.3 Foods containing carotenoids(Also see chapter 4.2.5.3.)
Two cohort studies investigated total serum carotenoids, 10case-control studies investigated pro-vitamin A carotenoids,
and 2 case-control studies investigated total dietary
carotenoids. Other groupings examined were dietary alphacarotene (1 cohort); serum alpha-carotene (3 cohort);
dietary beta-carotene (1 cohort, 7 case-control); serum betacarotene (3 cohort, 2 case-control); dietary lycopene (1cohort, 4 case-control); and serum lycopene (1 cohort, 1
case-control). All of the serum studies and most of the
dietary studies showed decreased risk with increased measures of carotenoids. Meta-analysis was not possible.
Information comes predominantly from dietary sources, notsupplements; therefore no effect can be attributed tocarotenoids separate from foods.
In trials, carotenoids have been effective at reducing cellular damage within the mouth, which may act as a precursor to cancers in this region. Carotenoids are antioxidants.
Oxidative damage is linked to the formation of tumours
through several mechanisms. Oxidative stress damages DNA.
This might be prevented or limited by dietary antioxidants
found in fruits and vegetables.
There is a considerable amount of evidence, andthough it is for different carotenoid types, it isgenerally consistent, with a dose-response
relationship. There is evidence for plausible
mechanisms. Foods containing carotenoids probably
protect against mouth, pharynx, and larynx cancers.

The Panel is aware that since the conclusion of the SLR, onecohort study15 has been published. This new information does
not change the Panel judgement. Also see box 3.8.

248

7.1.5.5 Alcoholic drinks(Also see chapter 4.8.5.1.)
Five cohort studies, 89 case-control studies, and 4 ecological studies investigated alcoholic drinks. All cohort studies
and nearly all case-control studies showed increased risk.
Meta-analysis of cohort data showed a 24 per cent increased
risk per drink/week; case-control data showed a 3 per centincreased risk per drink/week (figure 4.8.2). The cohort
studies showed a curvilinear dose-response relationship.
It is biologically highly plausible that alcoholic drinks area cause of mouth, pharynx, and larynx cancers. IARC classifies alcohol as a Class 1 carcinogen. Reactive metabolitesof alcohol such as acetaldehyde can be carcinogenic. Thereis also an interaction with smoking. Tobacco may induce specific mutations in DNA that are less efficiently repaired in thepresence of alcohol. Alcohol may also function as a solvent,enhancing penetration of other carcinogenic molecules into
mucosal cells. Additionally, the effects of alcohol may be
mediated through the production of prostaglandins, lipid
peroxidation, and the generation of free radical oxygen
species. High consumers of alcohol may also have diets
low in essential nutrients, making tissues susceptible tocarcinogenesis.
There is ample and consistent evidence, both fromcase-control and cohort studies, with a dose-response
relationship. There is robust evidence for mechanisms
operating in humans. The evidence that alcoholic
drinks are a cause of mouth, pharynx, and larynx
cancers is convincing. Alcohol and tobacco together
increase the risk of these cancers more than either
acting independently. No threshold was identified.

The Panel is aware that since the conclusion of the SLR, onecohort15 and four case-control studies21-24 have been published.
This new information does not change the Panel judgement.
Also see box 3.8.
7.1.5.6 Other exposures
Other exposures were evaluated. However, the data were
either of too low quality, too inconsistent, or the number ofstudies too few to allow conclusions to be reached. These
were as follows: cereals (grains) and their products; starchy

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roots, tubers, and plantains; pulses (legumes); foods containing dietary fibre; meat; poultry; fish; eggs; milk and dairy
products; total fat; foods containing animal fat; plant oils;
coffee; tea; frying, grilling (broiling), and barbecuing; protein; vitamin A; retinol; thiamin; riboflavin; niacin; folate;vitamin C; vitamin E; iron; calcium; selenium; energy intake;and body fatness.
Fourteen case-control studies examined body fatness, asmeasured by body mass index (BMI). Meta-analysis produced a statistically significant decreased risk with increased
BMI, and a dose-response relationship, but reverse causality
was implicated. That is, cancers of the mouth, pharynx, andlarynx cause significant weight loss, often before diagnosis.
Smoking is also associated with low BMI. For these reasons,the data were judged insufficient to allow any conclusion to
be drawn.

the mouth, pharynx, and larynx is convincing. The risk ismultiplied when drinkers of alcohol also smoke tobacco.
Non-starchy vegetables, fruits, and foods containing
carotenoids probably protect against these cancers.
There is limited evidence suggesting that maté, a herbal
infusion, when drunk scalding hot through a metal straw, as
is traditional in some parts of South America, is a cause oforal cancer.
The main cause of these cancers is smoking and other useof and exposure to tobacco.

7.1.6 Comparison with previous report
The main differences between this Report and the previous
report are summarised here, together with any reasons forthese differences. When the findings here and in the previous report are similar, this is usually not mentioned. Minor
differences are not always mentioned.
7.1.6.1 General
The criteria used by the previous report for gauging thestrength of the evidence were not identical to the criteria
used for this Report. In particular, a judgement of ‘convincing’ causal association was not conditional on supportive evidence from prospective studies. This Report does make that
requirement. It also emphasises the special importance ofrandomised controlled trials when applied appropriately,
especially where the results are positive. In these respects,
the criteria used for this Report are more stringent. See box
3.8 in chapter 3.
7.1.6.2 Specific
The previous report separated cancers of the mouth andpharynx from cancer of the larynx. The panel responsible forthe previous report judged the evidence that vegetables andfruits protect against cancers of the mouth and pharynx tobe convincing. It also judged that these foods probably protect against cancer of the larynx. Vitamin C was judged to
be possibly protective against cancers of the mouth and larynx. There is still little information from cohort studies,
which weakens the evidence base.
Evidence accumulated since the mid-1990s confirms theprevious judgement that the evidence that alcoholic drinks
are a cause of oral cancers is convincing. And in the previous report, the evidence that maté is a cause of oral cancers
was judged possible for cancers of the mouth and pharynx.

7.1.7 Conclusions
The Panel concludes:
The evidence that alcoholic drinks are a cause of cancers of249

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7.2 Nasopharynx
Cancer of the nasopharynx is the 23rd most common typeof cancer worldwide. About 80 000 cases were recorded in
2002, accounting for less than 1 per cent overall. In mostparts of the world, this cancer is rare. It is relatively
common on and near the southern Chinese littoral, andamong communities who have migrated from that part ofChina to other countries. It is twice as common in men as
in women. It is the 20th most common cause of deathfrom cancer.
Overall, the Panel judges that there is a specific role for
Cantonese-style salted fish in the causation of cancer ofthe nasopharynx.
The Panel judges as follows:
Cantonese-style salted fish is probably a cause ofnasopharyngeal cancer. This judgement does not apply tofish salted or fermented by any other method.
There is limited evidence suggesting that non-starchy
vegetables and fruits protect against this cancer.
Other causes of this cancer include tobacco smoking andinfection with the Epstein-Barr virus.
In final summary, the strongest evidence, corresponding
to judgements of “convincing” and “probable”, shows that
Cantonese-style salted fish is a probable cause of thiscancer.

The nasopharynx is the top portion of the pharynx, the muscular cavity leading from the nose and mouth to the larynx.
Cancers in this area arise predominantly from epithelial
cells, with squamous cell carcinomas being the most common. Carcinomas constitute 75–90 per cent of nasopharyngeal cancers in low-risk populations, and virtually 100 per
cent in high-risk populations.25 Nasopharyngeal squamouscell carcinomas are included here; other types are not.

7.2.1 Trends, incidence, and survival
Age-adjusted rates of nasopharyngeal cancer are decreasing
in areas of high incidence, such as Hong Kong andSingapore.25
This cancer is predominantly a disease of low-income
countries, with overall rates more than three times higher in
middle- to low- than in high-income countries. Incidence isalso higher in certain ethnic groups — for instance Chinese
and also Malay and Filipino people living in south-eastern
Asia.
Around the world, age-adjusted incidence rates range
from 20–30 per 100 000 people in parts of Hong Kong andsouth-eastern Asia, to less than 1 per 100 000 across mostof the Americas and Europe.
This cancer also occurs in northern Africa, parts of the
Middle East, and Micronesia and Polynesia. However, thehighest rates are among Cantonese people who live in the250

FOOD, NUTRITION, PHYSICAL ACTIVITY,
AND CANCER OF THE NASOPHARYNX
In the judgement of the Panel, the factors listed below modify the risk ofcancer of the nasopharynx. Judgements are graded according to thestrength of the evidence.

DECREASES RISKINCREASES RISK

Convincing
Probable

Cantonese-stylesalted fish1

Limited —suggestiveNon-starchy vegetables2

Limited —no conclusion

Cereals (grains) and their products; nuts and seeds;
herbs, spices, and condiments; meat; fish; shellfish
and seafood; eggs; plant oils; tea; alcohol; salted
plant food; Chinese-style pickled cabbage; pickled
radish; pickled mustard leaf; Chinese-style preserved
salted eggs; fermented tofu and soya products

Substantial
effect on risk
unlikely

1

2

Fruits2

None identified

This style of preparation is characterised by treatment with less salt thantypically used, and fermentation during the drying process due to relatively
high outdoor temperature and moisture levels. This conclusion does not
apply to fish prepared (or salted) by other means.
Judgements on vegetables and fruits do not include those preserved bysalting and/or pickling.

For an explanation of all the terms used in the matrix,
please see chapter 3.5.1, the text of this section,and the glossary.

central region of Guangdong Province in southern China,
which includes Hong Kong.25 Migrant populations from thisprovince carry the risk levels of the original population, but
this decreases over generations.26 Rates are approximately
twice as high in men as in women.2
The age profile of nasopharyngeal cancer is different inareas of high compared with low incidence. Risk increases
with age in most of the world, but in Guangdong Province
it peaks between the ages of 45 and 54. In populations
where there is a moderate incidence of this cancer, riskpeaks in young adults.25 Overall 5-year survival rates arearound 50 per cent.27 Also see box 7.1.1.
There are two variants of nasopharyngeal squamous cell
carcinoma: keratinising and non-keratinising. The non-keratinising variant can be further divided into differentiatedor undifferentiated. In North America, the proportions ofeach are 25, 12, and 63 per cent, respectively. In southern
China, the distribution is different: 2, 3, and 95 per cent.27

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Box 7.2.1

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Epstein-Barr virus

Most adults are infected with the Epstein-Barr virus, but relatively few will ever develop the cancers of which this virus is acontributory or necessary cause. Other factors beyond infection
with the virus are needed to lead to the development of cancer. Environmental factors including some dietary factors arethought to render precancerous epithelial cells sensitive to
Epstein-Barr virus infection, which then triggers malignancy.29
Epstein-Barr virus is a DNA virus of the herpes family. It primarily infects B lymphocytes (white blood cells that produce
antibodies), though it can also infect epithelial cells. Infection
usually occurs in childhood and does not usually produce symptoms, but in adults it can cause infectious mononucleosis or glandular fever. It is particularly associated with undifferentiatednasopharyngeal carcinoma, the most prevalent type.30 31
In nasopharyngeal carcinoma, all of the tumour cells carryviral DNA in a monoclonal form. This means that Epstein-Barrvirus infection must have occurred quite early in the cancer
process, before rapid growth.32 It is not normally possible todetect Epstein-Barr virus infection in non-cancerous nasopharyngeal cells.31‘Relative risk’ is used in this Report to denote ratio measures of effect, including ‘risk ratios’, ‘rate ratios’, ‘hazard
ratios’, and ‘odds ratios’.
7.2.4.2 Specific
Considerations specific to cancer of the nasopharynx and to
Cantonese-style salted fish, include:
Classification. The term ‘salted’ is an incomplete and perhaps

misleading term, given that the fish is also fermented. See
the footnote of the matrix for this section, and also 7.2.5.3.
Confounding. It is not possible to exclude a genetic compo-

nent. Those at highest risk are Cantonese-speaking communities living in or originally from Guangdong Province.
Production, preservation, processing, preparation. The
method of salting or the type of fish salted varies between
regions. The presence of nitrates and nitrosamines (see box
4.3.2) in the fish also varies.

7.2.5 Evidence and judgements
7.2.2 Pathogenesis
Variation in the distribution of keratinising squamous cell
carcinoma and the two forms of non-keratinising carcinoma
in North America and southern China, together with the different age profiles in the two regions, suggests that different disease paths may occur in high-incidence populations.
Patches of dysplasia are the first recognisable precancerous lesions; latent infection with the Epstein-Barr virus (seebox 7.2.1) leads to severe dysplasia. The subsequent genetic and chromosomal changes in these lesions lead to invasive carcinoma.28

7.2.3 Other established causes(Also see chapter 2.4 and 7.1.3.1.)
Tobacco use. Smoking tobacco is a cause of nasopharyngeal

cancer.
Occupational exposure. Occupational exposure to formalde-

hyde is also a cause of this cancer.33-35
Infectious agents. Epstein-Barr virus infection is a cause ofnasopharyngeal cancer (see box 7.2.1).30 It may be necessary but is not a sufficient cause.

7.2.4 Interpretation of the evidence
7.2.4.1 General
For general considerations that may affect interpretation of
the evidence, see chapters 3.3 and 3.5, and boxes 3.1, 3.2,
3.6 and 3.7.

In total, 74 publications were included in the SLR for
nasopharyngeal cancer. Fuller summaries of the epidemiological, experimental, and mechanistic evidence are to befound in Chapters 4–6.
The full SLR is contained on the CD included with thisReport.
7.2.5.1 Non-starchy vegetables(Also see chapter 4.2.5.1.)
Five case-control studies and two ecological studies investigated non-starchy vegetables; a further four case-control
studies investigated green vegetables. Preserved vegetables
were excluded from all categories. Nearly all of the studies
showed decreased risk with increased intake.
This is a wide and disparate category, and many different
plant food constituents are represented that could contributeto a protective effect of non-starchy vegetables. These
include dietary fibre, carotenoids, folate, selenium, glucosinolates, dithiolthiones, indoles, coumarins, ascorbate,chlorophyll, flavonoids, allylsulphides, flavonoids, and phytoestrogens, some of which are potentially antioxidants.
Antioxidants trap free radicals and reactive oxygen molecules, protecting against oxidation damage. It is difficult tounravel the relative importance of each constituent and it
is likely that any protective effect may result from a
combination of influences on several pathways involved in
carcinogenesis.
The evidence on non-starchy vegetables is sparse but
generally consistent. There is limited evidence
suggesting that non-starchy vegetables protect against
nasopharyngeal cancer.

7.2.5.2 Fruits(Also see chapter 4.2.5.2.)

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Six case-control studies investigated general fruits and afurther five case-control studies investigated citrus fruits.
Preserved fruits were excluded from all categories. Most of
the studies for general fruits and all of the studies for citrus
fruits showed a decreased risk.
This is a wide and disparate category, and many different
plant food constituents are represented that could contributeto a protective effect of fruits. These include dietary fibre,
carotenoids, folate, selenium, glucosinolates, dithiolthiones,
indoles, coumarins, ascorbate, chlorophyll, flavonoids, allylsulphides, flavonoids, and phytoestrogens, some of which arepotentially antioxidants. Antioxidants trap free radicals andreactive oxygen molecules, protecting against oxidation damage. It is difficult to unravel the relative importance of eachconstituent and likely that a protective effect may result froma combination of influences on several pathways involved in
carcinogenesis. In addition, some components of citrus fruits
have been shown directly to inhibit Epstein-Barr virus activation.36
The evidence, from case-control studies only, is sparse.
There is limited evidence suggesting that fruits protect
against nasopharyngeal cancer.

7.2.5.3 Cantonese-style salted fish
(Also see chapter 4.3.5.3.1.)
One cohort study and 21 case-control studies of adult diets
were examined. The single cohort study and most of thecase-control studies showed increased risk with higher
intake. Meta-analysis showed a 28 per cent increased risk pertime eaten per week (figure 4.3.9). There is some heterogeneity, not all readily explained. Childhood diet data implicate an increased risk with early-life exposure.
Cantonese-style salted fish is dried in natural conditions
outdoors. As prepared on the southern Chinese littoral, it ischaracterised by treatment with less salt than used on thenorthern littoral; it is also subject to fermentation during thedrying process in the warm, damp climate of southern China.
The high content of nitrate and nitrosamines may accountfor some of the increased risk associated with salted fish
intake. Nitrosamines are known mutagens and animal carcinogens that induce gene mutation. The direct role ofnitrosamines in the carcinogenic process is supported by theincreased risk for nasopharyngeal cancer development inpeople who have a variant allele of CYP2E1. This enzyme isexpressed in the nasopharynx and is involved in the metabolic activation of nitrosamines to carcinogenic adducts.37
Additional evidence has suggested a component of salted
fish may contain Epstein-Barr virus-activating substances,although the specific agents of action have not been
identified.38
Evidence from several case-control studies is
consistent and shows a dose-response effect. There isevidence for plausible mechanisms. Cantonese-stylesalted fish is probably a cause of nasopharyngeal
cancer.

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7.2.5.4 Other exposures
Other exposures were evaluated. However, the data were
either of too low quality, too inconsistent, or the number ofstudies too few to allow conclusions to be reached. These
were as follows: cereals (grains) and their products; nuts andseeds; meat; fish; shellfish and seafood; eggs; herbs, spices,and condiments; tea; alcohol; plant oils; salted plant foods;
Chinese-style pickled cabbage; pickled radish; pickled mustard leaf; Chinese-style preserved salted eggs; and fermented tofu/soya products.

7.2.6 Comparison with previous report
7.2.6.1 GeneralSee 7.1.6.1, and box 3.8.
7.2.6.2 Specific
The previous report judged the evidence that Cantonese-stylesalted fish is a cause of nasopharyngeal cancer to be convincing. No further cohort studies have been conducted since
the mid-1990s.

7.2.7 Conclusions
The Panel concludes:
Cantonese-style salted fish is probably a cause of nasopharyngeal cancer. This does not apply to fish salted or
fermented by any other method.
There is limited evidence suggesting that non-starchy
vegetables, and also fruits, protect against this cancer.

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7.3 Oesophagus
Cancer of the oesophagus is the eighth most common typeof cancer worldwide. Around 460 000 cases occurred in
2002, accounting for over 4 per cent overall. There are two
common types of oesophageal cancer, adenocarcinoma
and squamous cell carcinoma, which have different
patterns of occurrence. In general this cancer is notincreasing, except for adenocarcinomas, which are
increasing in high-income countries. Oesophageal cancer
is twice as common in men as in women. It is usually fatal
and is the sixth most common cause of death from cancer.
Overall, the Panel judges that food and nutrition andbody fatness play an important role in the prevention andcausation of cancer of the oesophagus.

FOOD, NUTRITION, PHYSICAL ACTIVITY, AND
CANCER OF THE OESOPHAGUS
In the judgement of the Panel, the factors listed below modify the risk ofcancer of the oesophagus. Judgements are graded according to thestrength of the evidence.

DECREASES RISK
Convincing

INCREASES RISK
Alcoholic drinks
Body fatness1

ProbableMaté4

Non-starchy
vegetables2
Fruits2

The Panel judges as follows:
The evidence that alcoholic drinks are a cause of cancer ofthe oesophagus is convincing. The risk is multiplied when
drinkers of alcohol also smoke tobacco. The evidence that
greater body fatness is a cause of oesophageal
adenocarcinoma is also convincing. Maté, a herbal
infusion, when drunk scalding hot through a metal straw,
as is traditional in parts of South America, is probably acause of this cancer.
Non-starchy vegetables, fruits, and foods containing
beta-carotene and/or vitamin C probably protect against
oesophageal cancer.
There is limited evidence suggesting that foods
containing dietary fibre, folate, pyridoxine, or vitamin E
protect against this cancer, and that red meat, processed
meat, and high-temperature drinks are causes of thiscancer.
See chapter 8 for evidence and judgements on factorsthat modify the risk of body fatness, including physicalactivity and sedentary ways of life, the energy density offoods and drinks, and breastfeeding.
Other causes of this cancer include smoking tobacco andchewing betel quid. It has been estimated that most casesof oesophageal cancer are preventable by appropriate diets
and associated factors, together with not smoking.
In final summary, the strongest evidence, corresponding
to judgements of “convincing” and “probable”, shows that
alcoholic drinks and body fatness are a cause of thiscancer (adenocarcinoma only); that non-starchy
vegetables, fruits, and foods containing beta-carotene
and/or vitamin C are probably protective; and that maté,
as traditionally drunk in parts of South America, isprobably a cause of this cancer.

Foods containing
beta-carotene3
Foods containing
vitamin C3
Limited —suggestive

Processed meat7

Foods containing
folate3

High-temperaturedrinksFoods containing
pyridoxine3 5
Foods containing
vitamin E3
Limited —no conclusion

Substantial
effect on risk
unlikely

1
2
3

4

5
6
7

The oesophagus is the muscular tube through which foodpasses from the pharynx to the stomach.
The oesophagus is lined over most of its length by squamous epithelial cells, where squamous cell carcinomas occur.
The portion just above the gastric junction (where theoesophagus meets the stomach) is lined by columnar

Red meat6

Foods containing
dietary fibre3

Cereals (grains) and their products; starchy roots,
tubers, and plantains; pulses (legumes); soya andsoya products; herbs, spices, and condiments;
poultry; fish; eggs; milk and dairy products; total
fat; saturated fatty acids; monounsaturated fatty
acids; polyunsaturated fatty acids; sugary foods anddrinks; salt; salting; fermenting; pickling; smokedand cured foods; nitrates and nitrites; frying;grilling (broiling) and barbecuing (charbroiling);
protein; vitamin A; retinol; thiamin; riboflavin;calcium; iron; zinc; pro-vitamin A carotenoids;beta-cryptoxanthin; Seventh-day Adventist diets;
adult attained height; energy intake

None identified

For oesophageal adenocarcinomas only.
Judgements on vegetables and fruits do not include those preserved bysalting and/or pickling.
Includes both foods naturally containing the constituent and foods whichhave the constituent added (see chapter 3.5.3). Dietary fibre is contained inplant foods (see box 4.1.2 and chapter 4.2).
As drunk traditionally in parts of South America, scalding hot through ametal straw. Any increased risk of cancer is judged to be caused by epithelial
damage resulting from the heat, and not by the herb itself.
Vitamin B6.
The term ‘red meat’ refers to beef, pork, lamb, and goat from domesticatedanimals.
The term ‘processed meat’ refers to meats preserved by smoking, curing,or salting, or addition of chemical preservatives.

For an explanation of all the terms used in the matrix,
please see chapter 3.5.1, the text of this section,and the glossary.

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epithelial cells, from which adenocarcinomas can develop.4
Adenocarcinoma of the oesophagus shows similarities withadenocarcinoma of the gastric cardia (see 7.5). Each typeaccounts for around half of all cases and both types areincluded in this Report.

7.3.1 Trends, incidence, and survival
Age-adjusted rates of oesophageal squamous cell carcinomas
are generally declining, although in some high-income
regions, overall rates of oesophageal cancer are increasing.
For instance, the incidence of oesophageal adenocarcinoma
is rising rapidly in Europe and North America.39 In the USA,adenocarcinomas in white men increased fivefold between
1974 and the end of the 20th century, making it the fastest
increasing cancer studied in that country.40
Oesophageal cancer is, however, mainly a disease of lowincome countries, occurring around four times more commonly in low- to middle- than in high-income countries.
Around the world, age-adjusted incidence rates range from
more than 20 per 100 000 people in parts of eastern andsouthern Africa and eastern and south-central Asia to lessthan 5 per 100 000 in northern, western, and middle Africa,
Central America, and south-eastern Asia. Localised peaks inincidence have been reported to exceed 100 per 100 000. For
instance, in rural Linxian, China, oesophageal cancer is theleading cause of death.41 In the USA, rates are higher among
African-American people than in white people. Worldwide,
rates are higher in men than in women, by around five totwo. In most populations, risk increases with age, with few
cases diagnosed in people under 40.
Oesophageal cancer does not usually produce symptoms
at the early stages, so the disease is generally at an advanced
stage when diagnosed. Survival rates are poor: around 10
per cent at 5 years.3 6 This type of cancer accounts for a little over 4 per cent of all cancer incidence, but almost 6 percent of all cancer deaths worldwide. Also see box 7.1.1.

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nocarcinomas in people with Barrett’s oesophagus.4
Some people have an abnormally strong lower
oesophageal sphincter (a condition called oesophageal
achalasia), which means swallowed food is retained in theoesophagus. It causes a 15-fold increase in the risk of squamous cell carcinomas, which may be due to chronic irritation of the lining of the oesophagus or its increased contact
with food-borne carcinogens.45 46
Tylosis A is the late-onset, inherited familial disease where
the outer horny layer of the skin thickens, affecting the palms
and soles (hyperkeratosis). Palmar and plantar hyperkeratosis is the single proven genetic abnormality associatedwith a 25 per cent lifetime incidence of squamous cell cancer of the oesophagus.47

7.3.3 Other established causes(Also see chapter 2.4 and 7.1.3.1.)
Other diseases. Gastric reflux and oesophageal achalasia
both increase the risk of, and thus can be seen as a cause of,this cancer. Barrett’s oesophagus can be seen as a precancerous condition.
Tobacco use. Smoking is a cause both of oesophageal squa-mous cell carcinoma and of adenocarcinomas, increasing therisk approximately twofold.10 39 Smoking is estimated tocause around 40 per cent of all cases. Chewing betel quid
(on its own and also with tobacco quid) is also a cause ofoesophageal cancers.11
Infectious agents. HPV (see box 7.13.1) is also a cause of thiscancer, and is estimated to be a cause of almost 25 per centof squamous cell carcinomas. Like other infectious agents, it
may be a necessary cause but is not a sufficient cause. It may
also play a role in the divergent geographical distributionsof this cancer.48

7.3.2 Pathogenesis

7.3.4 Interpretation of the evidence

The epithelial cells lining the oesophagus are exposed directly to carcinogens in food. Repeated exposures, for instance,
to burns from very high-temperature drinks or irritation fromthe direct action of alcohol, may cause inflammation.
The role of irritation and inflammation in the developmentof oesophageal cancer is supported by the finding that gastro-oesophageal reflux (where stomach acid flows upwards
to the oesophagus) increases the risk of adenocarcinomas by
as much as 40-fold.42 Barrett’s oesophagus is a probableintermediate stage between gastro-oesophageal reflux disease, with repeated gastro-oesophageal reflux, and developing oesophageal adenocarcinoma.43 Barrett’s oesophagus
is an acquired condition in which squamous cells are
replaced by columnar epithelial cells; autopsy studies suggest that it usually remains undiagnosed.44 The increasinguse of endoscopes to investigate abdominal symptoms has
resulted in the earlier detection of a small proportion of ade-

7.3.4.1 General
For general considerations that may affect interpretation of
the evidence, see chapters 3.3 and 3.5, and boxes 3.1, 3.2,
3.6 and 3.7.
‘Relative risk’ is used in this Report to denote ratio measures of effect, including ‘risk ratios’, ‘rate ratios’, ‘hazard
ratios’, and ‘odds ratios’.

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7.3.4.2 Specific
Considerations specific to cancer of the oesophagus include:
Classification. There are different types of oesophageal cancer. Squamous cell carcinomas have different geographicaland time trends from adenocarcinomas. Each follows a different disease path, and may have different associated risk
factors. However, there were only sufficient data to conduct
separate analyses for body fatness. Therefore the ratio of

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squamous cell carcinomas to adenocarcinomas in each study
is a potential cause of heterogeneity in all other summaries.
The oesophageal-gastric junction and gastric cardia are also
lined with columnar epithelial cells. Cancers in these areas
are often grouped with oesophageal cancers, although they
may also be classed as stomach cancers (see 7.5).4 Different
approaches or definitions in different studies are anotherpotential source of heterogeneity.
Confounding. Smoking is the main single cause of this cancer. High-quality studies adjust for smoking.

This is a wide and disparate category, and many different
plant food constituents are represented that could contributeto a protective effect of non-starchy vegetables. These
include dietary fibre, carotenoids, folate, selenium, glucosinolates, dithiolthiones, indoles, coumarins, ascorbate,chlorophyll, flavonoids, allylsulphides, flavonoids, and phytoestrogens, some of which are potentially antioxidants.
Antioxidants trap free radicals and reactive oxygen molecules, protecting against oxidation damage. It is difficult tounravel the relative importance of each constituent and it islikely that any protective effect may result from a combination of influences on several pathways involved in carcinogenesis.

7.3.5 Evidence and judgements
In total, 262 publications were included in the SLR for
oesophageal cancer. Fuller summaries of the epidemiological, experimental, and mechanistic evidence are to be foundin Chapters 4–6.
The full SLR is contained on the CD included with thisReport.
7.3.5.1 Foods containing dietary fibre(Also see chapter 4.1.5.3.)
One cohort study, nine case-control studies, and two ecological studies investigated dietary fibre. Most were suggestive of a relationship with decreased oesophageal cancer
incidence. Data come predominantly from dietary sources,
not supplements; therefore no specific effect can be attributed specifically to dietary fibre itself, which is interpreted
simply as a marker of consumption of foods containing it.
It is not clear whether there is an as yet unknown mechanism through which dietary fibre could exert a direct effecton oesophageal cancer, or whether the effect is mediatedthrough other constituents of the foods (such as cereals(grains), vegetables, and fruits) that contain dietary fibre.
There is limited evidence, from sparse and inconsistentcase-control studies only, suggesting that foods
containing dietary fibre protect against oesophageal
cancer.

7.3.5.2 Non-starchy vegetables(Also see chapter 4.2.5.1.)
A total of 5 cohort studies, 37 case-control studies, and 6 ecological studies investigated non-starchy vegetables. Other
groupings examined were vegetable and fruit consumption(combined) (8 case-control), raw vegetables (16 case-control), cruciferous vegetables (1 cohort, 5 case-control), allium vegetables (1 cohort, 8 case-control), green, leafy
vegetables (1 cohort, 11 case-control), and tomatoes (1cohort, 9 case-control). All of the studies of raw vegetables
and most of the other studies showed decreased risk withincreased intake. Meta-analysis of case-control data showeda 31 per cent decreased risk per 50 g of raw vegetables perday (figures 4.2.6 and 4.2.7). Raw vegetables have a moreconsistent definition than non-starchy vegetables, which may
include preserved vegetables and a variety of cooking methods, leading to increased heterogeneity.

There is more evidence, including on vegetable
subtypes, from case-control studies than from cohort
studies, but both are moderately consistent, and there
is some evidence for a dose-response relationship.
There is evidence for plausible mechanisms (seechapter 4.2.5.1). Non-starchy vegetables probably
protect against oesophageal cancer.

The Panel is aware that since the conclusion of the SLR, onecohort49 and two case-control studies17 50 have been published.
This new information does not change the Panel judgement.
Also see box 3.8.
7.3.5.3 Fruits(Also see chapter 4.2.5.2.)
A total of 4 cohort studies, 36 case-control studies, and 7
ecological studies investigated fruits; and 1 cohort study, 16case-control studies, and 1 ecological study investigated citrus fruits. All of the cohort studies and most of the otherstudies showed decreased risk with increased intake. Metaanalysis of case-control data showed a 22 per cent decreased
risk per 50 g of fruit per day, and 30 per cent decreased risk
per 50 g of citrus fruit per day (figures 4.2.22 and 4.2.24).
A dose-response relationship was apparent. Heterogeneity
could not be fully explained.
Fruits are sources of vitamin C and other antioxidants,
such as carotenoids, phenols, and flavonoids, as well as otherpotentially bioactive phytochemicals. Antioxidants trap free
radicals and reactive oxygen molecules, protecting against
oxidation damage.
It is difficult to unravel the relative importance of eachconstituent and it is likely that any protective effect may
result from a combination of influences on several pathways
involved in carcinogenesis.
The evidence, including that on fruit subtypes, thoughmostly from case-control studies, is consistent, with adose-response relationship. There is evidence forplausible mechanisms. Fruits probably protect against
oesophageal cancer.

The Panel is aware that since the conclusion of the SLR, onecohort49 and two case-control studies50 51 have been published.
This new information does not change the Panel judgement.
Also see box 3.8.

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7.3.5.4 Foods containing folate(Also see chapter 4.2.5.4.)
Eight case-control studies investigated dietary folate and twocase-control studies investigated red-cell and plasma folate.
All studies showed a relationship with decreased cancer incidence. Data come predominantly from dietary sources, notsupplements; therefore no effect can be attributed to folate
separate from foods.
Folate plays an important role in the synthesis, repair, andmethylation of DNA. Abnormal DNA methylation has been
linked to aberrant gene expression and to cancers at several sites. Folate may also reduce HPV proliferation in cells.

7.3.5.7 Foods containing vitamin E(Also see chapter 4.2.5.7.)
One cohort study, nine case-control studies, and one ecological study investigated dietary vitamin E; three cohort
studies and four case-control studies investigated serum vitamin E. All cohort studies and most case-control studies
showed decreased risk with increased intake; serum casecontrol data were inconsistent.
Vitamin E is a family of eight compounds collectively
referred to as tocopherols. They can act as antioxidants andfree radical scavengers; however, few animal studies support
an anti-cancer effect.

The evidence, from case-control studies only, is sparse.
There is limited evidence suggesting that folate
protects against oesophageal cancer.

Much of the evidence on vitamin E, mostly from casecontrol studies, was of poor quality. There is limited
evidence suggesting that foods containing vitamin E
protect against oesophageal cancer.

The Panel is aware that since the conclusion of the SLR, one
case-control study52 has been published. This new information
does not change the Panel judgement. Also see box 3.8.
7.3.5.5 Foods containing pyridoxine (vitamin B6)(Also see chapter 4.2.5.5.)
Six case-control studies investigated foods containing pyridoxine and oesophageal cancer.
All six studies showed a relationship between pyridoxine
consumption and reduced risk of oesophageal cancer, withnone reporting contrary results.
Together with folate and cobalamin (vitamin B12), vitamin B6 is involved in one-carbon metabolism and is important for DNA synthesis, repair, and methylation.
The evidence, from case-control studies only, wassparse. There is limited evidence suggesting thatpyridoxine protects against oesophageal cancer.

The Panel is aware that since the conclusion of the SLR, one
case-control study52 has been published. This new information
does not change the Panel judgement. Also see box 3.8.
7.3.5.6 Foods containing vitamin C(Also see chapter 4.2.5.6.)
One cohort study, 19 case-control studies, and 3 ecologicalstudies investigated vitamin C. The single cohort study andnearly all of the case-control studies showed decreased risk
with increased intake.
Vitamin C traps free radicals and reactive oxygen molecules, protecting DNA from mutagenic attack, protecting
against lipid peroxidation, reducing nitrates, and stimulating the immune system.

7.3.5.8 Foods containing beta-carotene(Also see chapter 4.2.5.3.)
Ten case-control studies investigated dietary beta-carotene;
three cohort studies and one case-control study investigated serum beta-carotene; and one cohort study and threecase-control studies investigated dietary pro-vitamin A
carotenoids. Most of these studies showed a relationshipwith decreased risk.
Data come predominantly from dietary sources, not supplements; therefore no effect can be attributed to carotenoids
separate from foods.
Carotenoids are antioxidants, which can prevent lipid oxidation and related oxidative stress. Some, such as betacarotene, are also pro-vitamin A carotenoids.
There is a substantial amount of consistent evidence
available from both cohort and case-control studies.
Foods containing beta-carotene probably protect
against oesophageal cancer.

7.3.5.9 Red meat
(Also see chapter 4.3.5.1.1.)
Twelve case-control studies investigated red meat. Most weresuggestive of increased risk.
There are several potential underlying mechanisms for apositive association of red meat consumption with
oesophageal cancer, including the generation of potentiallycarcinogenic N-nitroso compounds (see box 4.3.2). Somemeats are also cooked at high temperatures, resulting in the
production of heterocyclic amines and polycyclic aromatichydrocarbons (see box 4.3.4). Red meat contains haem iron.
Free iron can lead to the production of free radicals (see box
4.3.3).

A substantial amount of consistent evidence isavailable, both from cohort and from case-control
studies. Foods containing vitamin C probably protect
against oesophageal cancer.

There is limited evidence, from case-control studies,some of which were poor quality, suggesting that redmeat is a cause of oesophageal cancer.

The Panel is aware that since the conclusion of the SLR, one
case-control study53 has been published. This new information
does not change the Panel judgement. Also see box 3.8.

The Panel is aware that since the conclusion of the SLR, onecohort study54 has been published. This new information does
not change the Panel judgement. Also see box 3.8.

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7.3.5.10 Processed meat
(Also see chapter 4.3.5.1.2.)
Two cohort studies and eight case-control studies investigated processed meat. Both cohort studies were suggestiveof increased risk; case-control data were inconsistent. The
definition of processed meat varies (see box 4.3.1), which
may increase heterogeneity.
Nitrates are produced endogenously in gastric acid and are
added as preservatives to processed meats (see box 4.3.2).
This may contribute to production of N-nitroso compounds
and increased exposure. These compounds are suspectedmutagens and carcinogens.55
Many processed meats also contain high levels of salt andnitrite. Meats cooked at high temperatures can contain heterocyclic amines and polycyclic aromatic hydrocarbons (seebox 4.3.4). Haem promotes the formation of N-nitroso compounds and also contains iron. Free iron can lead to the production of free radicals (see box 4.3.3).
There is limited evidence, mostly from case-control
studies, suggesting that processed meat is a cause ofoesophageal cancer.

The Panel is aware that since the conclusion of the SLR, onecohort study54 has been published. This new information does
not change the Panel judgement. Also see box 3.8.
7.3.5.11 Maté
(Also see chapter 4.7.5.6.1.)
Eight case-control studies and one ecological study investigated maté. Most were suggestive of an increased incidencewith higher maté consumption. Meta-analysis of casecontrol data showed a 16 per cent increased risk per cup/day (figure 4.7.5). A dose-response relationship wasapparent.
There is some biological plausibility. Maté is a tea-likebeverage typically drunk very hot through a metal straw.
This produces heat damage in the oesophagus. Repeateddamage of this nature can lead to cancer (see chapter
2.4.1.3). Chemical carcinogenesis from constituents of maté
has also been postulated.19 20
The evidence from case-control studies is consistentand a dose-response relationship is apparent. There isrobust evidence for plausible mechanisms. Regularconsumption of maté, as drunk in the traditional stylein South America, is a probable cause of oesophageal
cancer.

7.3.5.12 High-temperature foods and drinks(Also see chapter 4.7.5.7.)
Three cohort studies and 15 case-control studies investigated high-temperature foods and drinks. Most were suggestiveof a relationship between them and increased incidence ofoesophageal cancer but many were inadequately adjusted foralcohol and smoking.
High-temperature foods and drinks can produce heat damage in the oesophagus. Repeated damage of this nature canpredispose to the development of oesophageal cancer.

The evidence is inconsistent. There is limited evidence
suggesting that high-temperature drinks are a cause ofoesophageal cancer.

The Panel is aware that since the conclusion of the SLR, twocase-control studies50 51 have been published. This new information does not change the Panel judgement. Also see box 3.8.
7.3.5.13 Alcoholic drinks(Also see chapter 4.8.5.1.)
Eight cohort studies, 56 case-control studies, and 10 ecological studies investigated alcoholic drinks. Most studies
showed a relationship between increased consumption andincreased cancer incidence. Meta-analysis of case-control
data showed a 4 per cent increased risk per drink/week (figure 4.8.6). A dose-response relationship is apparent fromcase-control data, with no clear threshold.
It is biologically highly plausible that alcoholic drinks area cause of oesophageal cancer. Reactive metabolites of alcohol such as acetaldehyde can be carcinogenic. Tobacco may
induce specific mutations in DNA that are less efficiently
repaired in the presence of alcohol. Alcohol may also function as a solvent, enhancing penetration of other carcinogenic molecules into mucosal cells. Additionally, the effectsof alcohol may be mediated through the production of
prostaglandins, lipid peroxidation, and the generation of free
radical oxygen species. Lastly, heavy consumers of alcohol
may have diets low in essential nutrients, making tissues susceptible to carcinogenesis.
There is ample and consistent evidence, both fromcohort and case-control studies, with a dose-response
relationship. There is robust evidence for mechanisms
operating in humans. The evidence that alcoholic
drinks are a cause of oesophageal cancer is convincing.
No threshold was identified.

The Panel is aware that since the conclusion of the SLR, onecohort56 and four case-control studies50 51 53 57 have been published. This new information does not change the Panel judgement. Also see box 3.8.
7.3.5.14 Body fatness(Also see chapter 6.1.3.1.)
A sufficient number of studies investigated BMI to allow
squamous cell carcinomas and adenocarcinomas to beanalysed separately. While results were inconsistent for squamous cell carcinomas and for all oesophageal cancers,
adenocarcinomas, when analysed separately, showed a consistent increased risk with greater BMI. Three cohort studies and eight case-control studies investigated body fatness,as measured by BMI and adenocarcinomas. All of the cohort
studies and most of the case-control studies showed
increased risk with increased BMI. Meta-analysis of case-control data showed a 55 per cent increased risk per 5 kg/m2(figure 6.1.2). A dose-response relationship is apparent. Thisis consistent with known geographical and time trends forboth BMI and adenocarcinomas.
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oesophageal cancer. High body fatness is associated withincreased gastro-oesophageal reflux and Barrett’s oesophagus. It also directly affects levels of many circulating hormones, such as insulin, insulin-like growth factors, andoestrogens, creating an environment that encourages carcinogenesis and discourages apoptosis (see box 2.4) Body
fatness stimulates the body’s inflammatory response, which
may contribute to the initiation and progression of several
cancers (see chapter 2.4.1.3).
The epidemiology is consistent with evidence of adose-response relationship. There is evidence forplausible mechanisms that operate in humans. The
evidence that greater body fatness is a cause ofoesophageal adenocarcinoma is convincing.

The Panel is aware that since the conclusion of the SLR, twocohort58 59 and five case-control studies51 53 60-62 have been published. This new information does not change the Panel judgement. Also see box 3.8.
7.3.5.15 Other exposures
Other exposures were evaluated. However, the data were
either too sparse, too inconsistent, or the number of studies
too few to allow conclusions to be reached. These were as
follows: cereals (grains) or their products; starchy roots,
tubers, and plantains; pulses (legumes); soya and soya products; herbs, condiments or spices; poultry; fish; eggs; milk
and dairy products; sugary foods and drinks; fermenting;pickling; salt; salting; smoked and cured foods; nitrates andnitrites; frying, grilling (broiling), and barbecuing; total fat;saturated fatty acids; monounsaturated fatty acids; polyunsaturated fatty acids; protein; vitamin A; retinol; pro-vitamin
A carotenoids; beta-cryptoxanthin; thiamin; riboflavin; iron;calcium; zinc; energy intake; adult attained height; andSeventh-day Adventist diets.

7.3.6 Comparison with previous report
7.3.6.1 General
See section 7.1.6.1 of this chapter, and box 3.8 in chapter 3.
7.3.6.2 Specific
The previous report judged the evidence that vegetables andfruits protect against oesophageal cancer to be convincing.
Data published since then have been somewhat less consistent.
At the time of the previous report, the evidence on bodyfatness was unclear, because data on adenocarcinomas wasinadequate and not analysed separately.
The previous report judged it possible that carotenoids orvitamin C protect against this cancer. The evidence base forfoods containing these nutrients is now stronger. The previous report judged it possible that maté and other very hot
drinks cause oesophageal cancer. The evidence on maté isnow stronger.

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7.3.7 Conclusions
The Panel concludes:
The evidence that alcoholic drinks and body fatness (adenocarcinomas only) are causes of cancer of the oesophagus
is convincing. The risk is multiplied when drinkers of alcohol also smoke tobacco.
Non-starchy vegetables, fruits, and foods containing betacarotene and/or vitamin C probably protect against
oesophageal cancer.
Maté, a herbal infusion, when drunk scalding hot througha metal straw as is traditional in South America, is probably
a cause of this cancer.
There is limited evidence suggesting that foods containing dietary fibre, folate, pyridoxine, or vitamin E protect
against this cancer; and that red meat, processed meat, andhigh temperature drinks are causes of this cancer.

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7.4 Lung
Cancer of the lung is the most common type of cancer
worldwide (excluding non-melanoma skin cancer). Around
1.4 million cases were recorded in 2002, accounting forover 12 per cent of all cancers. Three-quarters of all cases
occur in men. The disease is most common in high-income
countries and is increasing in some low-income countries
such as China. It is almost always fatal, and is the chief
cause of death from cancer: nearly 18 per cent of alldeaths from cancer are from this type.
Overall, the Panel emphasises that the principal cause oflung cancer is smoking tobacco.
The Panel judges as follows:
The evidence that arsenic in drinking water and (insmokers only) pharmacological doses of beta-carotene area cause of this cancer is convincing.
Fruits, and also foods containing carotenoids, probably
protect against lung cancer.
There is limited evidence suggesting that non-starchy
vegetables, selenium and foods containing it, foods
containing quercetin, and physical activity protect against
lung cancer.
There is also limited evidence suggesting that red meat,
processed meat, total fat, butter, pharmacological doses ofretinol (smokers only), and low body fatness are causes oflung cancer.
In final summary, the strongest evidence, corresponding
to judgements of “convincing” and “probable”, shows that
arsenic in drinking water and pharmacological doses ofbeta-carotene (smokers only) are causes of lung cancer;
and that fruits and foods containing carotenoids probably
protect against this cancer.

FOOD, NUTRITION, PHYSICAL ACTIVITY,
AND CANCER OF THE LUNG
In the judgement of the Panel, the factors listed below modify the risk ofcancer of the lung. Judgements are graded according to the strength ofthe evidence.

DECREASES RISK
Convincing

Arsenic in drinking
water1
Beta-carotene
supplements2

Probable

Fruits3
Foods containing
carotenoids4

Limited —suggestiveNon-starchy vegetables3

Red meat7

Foods containing
selenium4

Processed meat8

Foods containing
quercetin4

Butter5

Selenium

Limited —no conclusion

1

2

3
4
5
6
7
8

Total fat
Retinol supplements2
Low body fatness

Physical activity6

Substantial
effect on risk
unlikely

The lungs are part of the aerodigestive system. They containhundreds of lobules, and each lobule contains a bronchiole,its branches, and clusters of alveoli. This is where carbon
dioxide (a product of respiration) is removed from the bloodand replaced with oxygen, to fuel further respiration, producing energy.
About 90–95 per cent of lung cancers are either small-cellcarcinoma or non-small-cell carcinoma. The latter has threemajor subtypes: squamous cell carcinoma, adenocarcinoma,
and large-cell carcinoma.4 Squamous cell carcinomas accountfor 30–35 per cent, adenocarcinomas 30–45 per cent, andlarge-cell carcinomas about 9 per cent of all lung cancers.
Small cell lung cancer (SCLC) accounts for 10–15 per centof all lung cancers; this form is considered a distinct clinicalpathological entity due to its characteristic aggressive biology, diffuse nature, propensity for early metastasis, and overall poor prognosis. Mesothelioma, which affects the pleura(layer of cells covering the lung and chest cavity), is almost
always caused by previous exposure to asbestos.

INCREASES RISK

Cereals (grains) and their products; starchy tubers;
dietary fibre; pulses (legumes); poultry; fish; eggs;
milk and dairy products; total fat; animal fats; plant
oils; soft drinks; coffee; tea; alcohol; preservation,
processing, and preparation; carbohydrate; protein
vitamin A; thiamin; riboflavin; niacin; vitamin B6;
folate; vitamin C; vitamin E; multivitamins; calcium;
copper; iron; zinc; pro-vitamin A carotenoids;
lycopene; flavonoids; culturally-defined diets;
body size, shape, and composition (except low
body fatness); energy intake

None identified

The International Agency for Research on Cancer has graded arsenic andarsenic compounds as Class 1 carcinogens. The grading for this entry applies
specifically to inorganic arsenic in drinking water.
The evidence is derived from studies using high-dose supplements(20 mg/day for beta-carotene; 25 000 international units/day for retinol)
in smokers.
Judgements on vegetables and fruits do not include those preserved bysalting and/or pickling.
Includes both foods naturally containing the constituent and foods whichhave the constituent added (see chapter 3.5.3).
The evidence is derived from studies using supplements at a dose of
200 µg/day.
Physical activity of all types: occupational, household, transport, andrecreational.
The term ‘red meat’ refers to beef, pork, lamb, and goat from domesticatedanimals.
The term ‘processed meat’ refers to meats preserved by smoking, curing,or salting, or addition of chemical preservatives.

For an explanation of all the terms used in the matrix,
please see chapter 3.5.1, the text of this section,and the glossary.

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7.4.1 Trends, incidence, and survival
Smoking and other exposure to tobacco smoke are the principal causes of lung cancer. The trend and incidence patterns
are explained largely by these exposures. Age-adjusted rates
of lung cancer are decreasing in many high-income countries
due to decreased smoking. Global and regional trends in incidence have mirrored the prevalence of smoking, with a time
lag of around 35 years.63 Lung cancer was rare until the endof the 19th century, with only 140 cases reported in theworld literature before 1898, and only 374 by 1912.63
Incidence peaked in most high-income countries in the second half of the 20th century, and later for women than men.
The relative incidence of the various types of lung cancer
is gradually changing. Between 1980 and 2000, the proportion of squamous cancers decreased as the proportion of
adenocarcinomas increased, possibly due to changes insmoking habits or products.64 Adenocarcinoma is now themost frequently diagnosed type in the USA and Japan; while
it is also showing signs of increasing in Europe, squamouscell carcinoma continues to be the predominant type.
Lung cancer is mainly a disease of high-income countries,
where the smoking epidemic began earlier, and overall rates
are nearly double those in middle- to low-income countries.
Around the world, age-adjusted incidence ranges from morethan 60 per 100 000 people in North America and acrossmuch of Europe, to less than 5 per 100 000 in much of middle Africa. Within Europe, rates are highest in eastern
European countries. In the USA, rates are higher among
African-American people than in white people. Worldwide,
rates are higher in men than in women, by around three toone. The incidence of lung cancer increases with age. Rates
will continue to rise in middle- and low-income countries astobacco smoking increases.
The early stages of lung cancer do not usually produce symptoms, so the disease is generally at an advanced stage when it
is diagnosed. Survival rates are poor, around 10 per cent at
5 years, and are usually higher in women than men.3 6 SCLC
has a worse prognosis than non-SCLC (a survival rate of onlyaround 5 per cent at 5 years), because SCLC has a tendency to metastasise (spread) early, and surgery is not usually
successful.4 65 Lung cancer accounts for somewhat over 12
per cent of all cancer incidence, but for nearly 18 per centof all cancer deaths. Also see box 7.1.1.

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The division of these new cells increases, and this eventually is followed by dysplasia of the lung mucosa. When thisprocess involves the full thickness of the mucosa, these dysplastic lesions become carcinoma in situ. Further invasion to
the depth of the basement membrane, and the subsequent
infiltration of the underlying stroma by malignant cells, signals invasive cancer. This process may take 10–20 years.4
People with adenocarcinomas may have an associated history of chronic lung disease, such as scleroderma, rheumatoid disease, sarcoidosis, or tuberculosis.4

7.4.3 Other established causes(Also see chapter 2.4 and section 7.1.3.1.)
Tobacco use. Smoking is the principal cause of lung cancer; itis estimated to be responsible for 85 per cent of all types of thiscancer.66 In populations with a history of long-term cigaretteuse, the proportion has reached 90 per cent.10 Involuntary
exposure to tobacco smoke (‘passive smoking’) is also a causeof lung cancer, including in people who have never smoked.10
Industrial chemicals. Carcinogens that are causes of lung can-cer include aluminium; arsenic; asbestos (both lung cancer
and mesothelioma); chloromethyl methyl ether and/or bischloromethyl ether; coal-tar fumes; erionite (mesothelioma); pollutants from iron and steel founding; untreatedmineral oils; mustard gas; soot; talc containing asbestiform
tremolite; and vinyl chloride.67

7.4.4 Interpretation of the evidence
7.4.4.1 General
For general considerations that may affect interpretation of
the evidence, see chapters 3.3 and 3.5, and boxes 3.1, 3.2,
3.6 and 3.7.
‘Relative risk’ is used in this Report to denote ratio measures of effect, including ‘risk ratios’, ‘rate ratios’, ‘hazard
ratios’, and ‘odds ratios’.
7.4.4.2 Specific
Considerations specific to cancer of the lung include:
Measurement. Due to low survival rates, both incidence and7.4.2 Pathogenesis
Carcinogens in tobacco smoke, or other inhaled particles
such as coal tar or asbestos, can interact directly with the
DNA of lung cells. Because the whole lung is exposed toinhaled carcinogens, several sites may accumulate different
cancerous changes, leading to multiple cancers originating
in different types of cell.4
Inflammation may also play a role in the development oflung cancer, with cancerous changes occurring as a responseto chronic exposure to irritants and repeated injury.
Columnar epithelial cells are replaced with stratified squamous epithelial cells, which may also increase cancer risk.

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mortality can be assessed. Low survival times and rates
decrease the reliability of case-control studies, which often
rely on proxy reporting.
Confounding. Smoking tobacco is the predominant cause oflung cancer, and smokers tend also to have less healthy diets,
more sedentary ways of life, and to be leaner than non-smokers. Therefore a central task in assessing the results of dietarystudies is to evaluate the degree to which observed associations
in smokers may be due to confounding/residual confoundingby cigarette smoking; that is, not a direct result of the dietary
exposure examined. A high proportion of the studies assessed
below are appropriately adjusted for smoking.

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7.4.5 Evidence and judgements
In total, 561 publications were included in the SLR for lungcancer. Fuller summaries of the epidemiological, experimental, and mechanistic evidence are to be found in
Chapters 4–6.
The full SLR is contained on the CD included with thisReport.
7.4.5.1 Non-starchy vegetables(Also see chapter 4.2.5.1.)
A total of 17 cohort studies, 27 case-control studies, and 6
ecological studies investigated total vegetables. Other groupings examined were non-starchy vegetables specifically (3cohort, 1 case-control); green, leafy vegetables, excluding
cruciferous (5 cohort, 17 case-control); non-starchy root vegetables and tubers (2 cohort); and carrots (6 cohort, 21 casecontrol, 1 ecological). Most studies showed decreased risk
with increased intake. Data are particularly consistent whenstratified for carrots. A pooled analysis of 8 cohort studies(more than 430 000 participants, followed up for 6–16 years,
with more than 3200 lung cancer cases) showed a non-significant decreased risk for the groups that ate the most vegetables. There was considerable heterogeneity, not all
readily explained.
This is a wide and disparate category, and many different
plant food constituents are represented that could contributeto a protective effect of non-starchy vegetables. These include
dietary fibre, carotenoids, folate, selenium, glucosinolates,
dithiolthiones, indoles, coumarins, ascorbate, chlorophyll,
flavonoids, allylsulphides, flavonoids, and phytoestrogens,some of which are potentially antioxidants. Antioxidants trap
free radicals and reactive oxygen molecules, protecting
against oxidation damage. It is difficult to unravel the relative importance of each constituent and it is likely that any
protective effect may result from a combination of influences
on several pathways involved in carcinogenesis.
A substantial amount of evidence is available but somestudies were not adjusted for smoking. A dose
response is apparent from both cohort and casecontrol studies. There is limited evidence suggestingthat non-starchy vegetables protect against lungcancer.

7.4.5.2 Fruits(Also see chapter 4.2.5.2.)
Twenty-five cohort studies, 32 case-control studies, and 7
ecological studies investigated fruit consumption. Most ofthese showed decreased risk with increased intake. Metaanalysis of cohort data showed a 6 per cent decreased risk
per 80 g serving/day; meta-analysis of case-control data
showed a 20 per cent decreased risk per serving/day (figure
4.2.25). A pooled analysis of 8 cohort studies (more than 430
000 participants, followed up for 6–16 years, with more than
3200 lung cancer cases) showed a 23 per cent decreased risk
for the groups that ate the most fruit. There is considerable
heterogeneity, perhaps explained by the broad and disparate
nature of this category.

Fruits are sources of vitamin C and other antioxidants,
such as carotenoids, phenols, and flavonoids, as well as otherpotentially bioactive phytochemicals. Antioxidants trap free
radicals and reactive oxygen molecules, protecting against
oxidation damage. In addition, flavonoids found in fruit
directly inhibit the expression of a cytochrome P450
enzyme. This helps to metabolise toxins and has been associated with increased risk of lung cancer, primarily in smokers.68 It is difficult to unravel the relative importance of eachconstituent, and it is likely that any protective effect may
result from a combination of influences on several pathways
involved in carcinogenesis.
The evidence is ample and consistent. A dose-response
relationship is apparent from both cohort and casecontrol studies and there is evidence for plausible
mechanisms operating in humans. The evidence thatfruits protect against lung cancer is convincing.

The Panel is aware that since the conclusion of the SLR, one
case-control study69 has been published. This new information
does not change the Panel judgement. Also see box 3.8.
7.4.5.3 Foods containing carotenoids(Also see chapter 4.2.5.3.)
A total of 11 cohort studies, 16 case-control studies, and 1
ecological study investigated total dietary carotenoids; 4cohort studies and 5 case-control studies investigated serumor plasma carotenoids. Other groupings examined weredietary beta-cryptoxanthin (7 cohort, 8 case-control, 1 ecological), and serum/plasma beta-cryptoxanthin (6 cohort, 1
case-control). Nearly all cohort studies and most case-control studies showed decreased risk with increased intake.
Meta-analysis of cohort data showed a 2 per cent decreased
risk per 1 mg dietary carotenoid intake per day, or per
10 µg beta-cryptoxanthin intake per day (figure 4.2.28). A
pooled analysis of 7 cohort studies (almost 400 000 participants, followed up for 7–16 years, with more than 3100
lung cancer cases) showed a 24 per cent decreased risk forthe groups that consumed the most beta-cryptoxanthin.
Several case-control studies did not adjust for smoking. Data
come predominantly from dietary sources, not supplements;
therefore no effect can be attributed to carotenoids separate
from foods.
Carotenoids are antioxidants, which can prevent lipid oxidation and related oxidative stress. Some, such as betacarotene, are also pro-vitamin A carotenoids.
There is a substantial amount of evidence available
from both cohort and case-control studies. A clear
dose-response relationship is apparent from cohort
studies. Foods containing carotenoids probably protect
against lung cancer.

7.4.5.4 Foods containing selenium(Also see chapter 4.2.5.8.)
Two cohort studies, 2 case-control studies, and 2 ecologicalstudies investigated dietary selenium; 10 cohort studies, 7case-control studies, and 4 ecological studies investigated261

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plasma or serum selenium; and 3 cohort studies investigated selenium levels in nails. Most studies showed decreased
risk with increased intake. Meta-analysis of cohort data on
plasma or serum selenium produced evidence of decreased
risk with a clear dose-response relationship.
Dietary selenium deficiency has been shown to cause alack of selenoprotein expression. Twenty-five selenoproteins
have been identified in animals and a number of these haveimportant anti-inflammatory and antioxidant properties.
Four are glutathione peroxidases, which protect against
oxidative damage to biomolecules such as lipids, lipoproteins, and DNA. Three are thioredoxin reductases and,among other functions, these regenerate oxidised ascorbic
acid to its active antioxidant form.
The evidence available is sparse. There is limited
evidence to suggest that foods containing selenium
protect against lung cancer.

7.4.5.5 Foods containing quercetin(Also see chapter 4.2.5.9.)
Two cohort studies and three case-control studies investigated quercetin intake. Both cohort studies showed statistically significant decreased risk for the highest intake groups.
Data from case-control studies were more heterogeneous.
Quercetin is a flavonoid which directly inhibits expressionof a cytochrome P450 enzyme that helps to metabolise toxins, resulting in decreased DNA damage in laboratory experiments.70
The evidence available is sparse and inconsistent.
There is limited evidence suggesting that foods
containing quercetin protect against lung cancer.

7.4.5.6 Red meat
(Also see chapter 4.3.5.1.1.)
One cohort study and nine case-control studies investigated
red meat. The single cohort study and most of the case-control studies showed increased risk with increased intake.
Red meat contains haem iron (see box 4.3.3). Free iron canlead to the production of free radicals. When cooked at hightemperatures, red meat can also contain heterocyclic aminesand polycyclic aromatic hydrocarbons (see box 4.3.4).
There is limited evidence, mostly from inconsistentcase-control studies, suggesting that red meat is a
cause of lung cancer.

7.4.5.7 Processed meat
(Also see chapter 4.3.5.1.2.)
Four cohort studies and 10 case-control studies investigatedprocessed meat, most of which showed increased risk withincreased intake.
N-nitroso compounds are suspected mutagens and carcinogens that are found in processed meats, and producedin the stomach from nitrates, including those used to preserve meats.55 Many processed meats also contain high levels of salt and nitrite (see box 4.3.2). When cooked at hightemperatures, meats can also contain heterocyclic amines

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and polycyclic aromatic hydrocarbons (see box 4.3.4). Haem
promotes the formation of N-nitroso compounds and also
contains iron. Free iron can lead to production of free radicals (see box 4.3.3).
There is limited, inconsistent evidence suggesting thatprocessed meat is a cause of lung cancer.

7.4.5.8 Total fat(Also see chapter 4.5.5.1.)
Nine cohort studies, 17 case-control studies, and 4 ecological studies investigated total fat intake. Most studies showed
increased risk with increased intake, although cohort data
were less suggestive of an effect, and few studies were statistically significant. No evidence for plausible mechanisms
was found.
The mixed results from cohort studies contrast withthe more consistent results from other studies. Overall,there is limited evidence suggesting that consumptionof total fat is a cause of lung cancer. The Panelemphasises that the principle cause of lung cancer issmoking tobacco.

7.4.5.9 Butter(Also see chapter 4.5.5.1.1.)
Two cohort studies and eight case-control studies investigated butter consumption. Most studies showed increased
risk with increased intake, but cohort data were inconsistent.
No evidence for plausible mechanisms was found.
There is a limited amount of inconsistent evidence
suggesting that consumption of butter is a cause oflung cancer.

7.4.5.10 Arsenic in drinking water(Also see chapter 4.7.5.1.1.)
Two cohort studies, 2 case-control studies, and 12 ecological studies investigated arsenic in drinking water. All cohortand case-control studies, and most ecological studies,
showed a relationship between increased levels of arsenic indrinking water and increased incidence. Meta-analysis was
not possible, but effect estimates tended to be large (anincreased risk of over 300 per cent for the highest levels).
Soluble arsenic in drinking water induces lung cancers inanimal models.71 In humans, arsenic is a chromosomal mutagen (an agent that induces mutations involving more than
one gene, typically large deletions or rearrangements). It canalso act as a synergistic co-mutagen. Arsenic exposure also
causes chronic lung disease.71 The Joint FAO/WHO Expert
Committee on Food Additives has set a provisional tolerable
weekly intake of 0.015 mg/kg of body weight.72
The evidence is ample and consistent, from cohort andcase-control as well as ecological studies. There is adose-response relationship, and the effect size isrelatively large. There is robust evidence formechanisms. The evidence that arsenic in drinking
water is a cause of lung cancer is convincing.

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7.4.5.11 Retinol supplements (in smokers)(Also see chapter 4.10.6.4.1.)
Two trials (one randomised controlled, one non-randomised),two cohort studies, and two case-control studies investigated retinol or retinol supplements. The single randomised controlled trial, performed in current and former smokers only,
showed a statistically significant increased risk with a highdose supplement. There was a suggestion of further elevated incidence in heavy smokers and asbestos workers. The
non-randomised trial was inconclusive. One cohort, also stratified by smoking status, showed a relationship with increased
incidence only in current smokers. All other studies failed to
stratify by smoking status and were inconclusive.
It is possible that some protective effect present at dietaryintake amounts of vitamins is lost or reversed by the higher
levels supplied by pharmacologic supplementation.
The evidence is sparse and inconsistent. There islimited evidence suggesting that high-dose vitamin A
supplements are a cause of lung cancer in current
smokers.

7.4.5.12 Beta-carotene supplements (in smokers)(Also see chapter 4.10.6.4.2.)
Four randomised controlled trials and two cohort studies
investigated beta-carotene supplements. Of these, one randomised controlled trial was performed in smokers. This
study showed a statistically significant increased risk of 17
per cent with a daily 20 mg beta-carotene supplement. It alsosuggested that heavy smoking elevated the risk further.
Other trials and studies, either in non-smokers or not stratified according to smoking status, were inconclusive.
There is a marked interaction between beta-carotene,
heavy smoking, and glutathione S-transferase (GST) genotype. GST is a carcinogen-detoxifying enzyme (see chapter
2.5). Beta-carotene supplementation among people without
GSTM1 (one of the variants of the GST gene) who smoked
more than 42 cigarettes per day was compared to betacarotene supplementation among those without GSTM1 who
smoked less than 37 cigarettes per day. A relative risk of 6.01
(95% confidence interval 1.90–19.08) was observed.
It is possible that a protective association present at dietaryintake amounts of carotenoids is lost or reversed by the higher levels that pharmacological supplementation may supply.
In one animal study, low-dose beta-carotene was protective
against smoking-induced changes in the tumour-suppressor
p53 gene (see box 2.2), while high doses promoted thesechanges.73 A second explanation could relate to disturbanceof the complex nature of naturally occurring carotenoids. It
is possible that the protective associations are not due to thespecific agent used in supplement studies, but rather to othercarotenoids present in dietary exposure,74 or other associated dietary or health-related behaviour.
There is strong evidence from good-quality trials,
consistent with cohort studies. An interaction between
smoking, genotype, and beta-carotene is apparent. The
evidence that beta-carotene supplements cause lungcancer in current smokers is convincing.

7.4.5.13 Selenium supplements(Also see chapter 4.10.6.4.5.)
One randomised controlled trial investigated selenium supplements and lung cancer.
The single trial of more than 1300 participants given
200 µg/day of selenium for 13 years showed a non-significant decreased risk with supplementation, adjusted for age
and smoking. Subgroup analysis indicated that this risk differed according to baseline plasma selenium level, with a statistically significant decreased risk for those with the lowest
initial plasma selenium. This is suggestive that selenium supplementation may decrease cancer risk in those who havepoor selenium status, but that this effect may not extend to
those who do not.
Dietary selenium deficiency has been shown to cause alack of selenoprotein expression. Twenty-five selenoproteins
have been identified in animals and a number of these haveimportant anti-inflammatory and antioxidant properties.
Four are glutathione peroxidases, which protect against
oxidative damage to biomolecules such as lipids, lipoproteins, and DNA. Three are thioredoxin reductases and,among other functions, these regenerate oxidised ascorbic
acid to its active antioxidant form.
The evidence is sparse. There is limited evidence
suggesting that selenium protects against lung cancer.

7.4.5.14 Physical activity(Also see chapter 5.4.4.)
In total, 5 cohort studies investigated total physical activity; 2 cohort studies investigated non-recreational activity; 4cohort studies and 2 case-control studies investigated occupational activity; and 11 cohort studies and 4 case-control
studies investigated recreational activity. Overall, moststudies showed decreased risk with increased physical activity. No studies showed a statistically significant increased
risk. Of the categories analysed, consistent protective relationships were reported for total physical activity, non-recreational activity, and recreational activity. Increased
heterogeneity in occupational physical activity may be due
to either the extreme variation in exposure definition, or thegenerally lower levels of occupational activity, meaning that,as a percentage of daily activity, occupational activity is of
reduced importance in many high-income countries (wherethese studies were generally performed).
Sustained, moderate physical activity raises metabolic rateand increases maximal oxygen uptake. In the long term,
regular periods of such activity increase the body’s metabolic
efficiency and capacity (the amount of work that it canperform), as well as reducing blood pressure and insulin
resistance.
There is evidence from prospective and case-control
studies showing lower risk of lung cancer with higher
levels of physical activity, but there is no evidence ofplausible mechanisms. The relationship between activity,
BMI, and lung cancer makes the evidence difficult tointerpret. There is limited evidence suggesting thatphysical activity protects against lung cancer.

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The Panel is aware that since the conclusion of the SLR, onecohort study75 has been published. This new information does
not change the Panel judgement. Also see box 3.8.

matrix entry for beta-carotene supplements. The previous
report did not review arsenic.

7.4.5.15 Body fatness(Also see chapter 6.1.3.1.)
Twenty-one cohort studies, 24 case-control studies, and 1
ecological study investigated body fatness, as measured by
BMI. Nearly all of the cohort and case-control studies showeddecreased risk with increased BMI. Meta-analysis of cohortand case-control data provided evidence of a statistically significant reduced risk, with no heterogeneity in cohort data.
Smoking is the principal cause of lung cancer and may also
be associated with lower BMI. There is a high potential for
confounding due to tobacco smoking, and residual confounding is therefore possible. In addition, it is possible thatpeople with undiagnosed lung cancer may lose weight, so
giving a spurious association (reverse causation).
There is no known mechanism through which greater bodyfatness could plausibly protect against lung cancer, or
through which low body fatness could increase risk.

7.4.7 Conclusions

Although the epidemiological evidence suggests aninverse relationship, this could be caused by
confounding by cigarette smoking or reverse causation
due to weight loss from undiagnosed cancer. There islimited evidence suggesting that low body fatness is a
cause of lung cancer.

7.4.5.16 Other exposures
Other exposures were evaluated. However, the data were
either of too low quality, too inconsistent, or the number ofstudies too few to allow conclusions to be reached. These
were as follows: cereals (grains) or their products; starchy
tubers; pulses (legumes); meat; poultry; fish; eggs; animal
fats; milk and dairy products; soft drinks; coffee; tea; alcohol; processing, preservation, and preparation; carbohydrate;
dietary fibre; total fat; protein; vitamin A; retinol; pro-vitamin A carotenoids; lycopene; thiamin; riboflavin; niacin; vitamin B6; folate; vitamin C; vitamin E; multivitamins; iron;zinc; copper; calcium; selenium; flavonoids; energy intake;plant oils; body size, shape, and composition (except low
body fatness); and culturally defined diets.

7.4.6 Comparison with previous report
7.4.6.1 General
See section 7.1.6.1 of this chapter, and box 3.8 in chapter 3.
7.4.6.2 Specific
The previous report judged the evidence that vegetables andfruits protect against lung cancer to be convincing. Evidence,
particularly from cohort studies published since the mid1990s, is more consistent for fruits than for vegetables.
The findings of the previous report for carotenoids, and forpharmaceutical doses of beta-carotene given to smokers,
were identical to the current findings (for foods containing
carotenoids), although the previous report did not include a

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The Panel concludes:
The evidence that arsenic in drinking water and (in smokers only) pharmacological doses of beta-carotene are causes of lung cancer is convincing.
Fruits, and also foods containing carotenoids, probably
protect against lung cancer.
There is limited evidence suggesting that non-starchy vegetables, selenium and foods containing it, foods containing
quercetin, and physical activity protect against lung cancer.
There is also limited evidence suggesting that red meat,
processed meat, total fat, butter, pharmacological doses ofretinol (in smokers only), and low body fatness are causesof lung cancer.
Smoking tobacco is the main cause of lung cancer.

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7.5 Stomach
Cancer of the stomach is the fourth most common type ofcancer worldwide. Almost one million cases were recorded
in 2002. Two out of three cases occur in men. Overall, it isdecreasing rapidly in high-income countries, but remains
very common elsewhere in the world. It is usually fatal
and is the second most common cause of death fromcancer.
Overall, the Panel judges that food and nutrition play animportant role in the prevention and causation of stomach
cancer.

FOOD, NUTRITION, PHYSICAL ACTIVITY,
AND CANCER OF THE STOMACH
In the judgement of the Panel, the factors listed below modify the risk ofcancer of the stomach. Judgements are graded according to the strengthof the evidence.

DECREASES RISK
Convincing
Probable

The Panel judges as follows:
Non-starchy vegetables, including specifically allium
vegetables, as well as fruits probably protect against
stomach cancer.
Salt, and also salt-preserved foods, are probably causesof this cancer.
There is limited evidence suggesting that pulses(legumes), including soya and soya products, and also
foods containing selenium protect against stomach cancer.
There is also limited evidence suggesting that chilli,
processed meat, smoked foods, and grilled (broiled) andbarbecued (charbroiled) animal foods are causes ofstomach cancer.
Infection with the bacterium Helicobacter pylori isestablished as a necessary cause of almost all cases ofstomach cancer. It has been estimated that most casesof this cancer are preventable by appropriate diets andassociated factors.
In final summary, the strongest evidence, corresponding
to judgements of “convincing” and “probable”,shows that
non-starchy vegetables, allium vegetables, and fruits
protect against stomach cancer; and that salt and alsosalt-preserved foods are causesof this cancer.

Salt2

Non-starchy
vegetables1
Allium vegetables1

Salted and salty
foods

Fruits1
Limited —suggestive

Pulses (legumes)3

Chilli1

Foods containing
selenium4

Processed meat5
Smoked foods6
Grilled (broiled)or barbecued(charbroiled) animal
foods6

Limited —no conclusion

Substantial
effect on risk
unlikely1

The stomach is the sac-like part of the digestive system
between the oesophagus and the small intestine. The bodyof the stomach is lined by a mucous membrane consistingof columnar epithelial cells and glands, surrounded bymuscle.
There are two main types of stomach cancer. Distal gastriccancers (those of the lower portion of the stomach) are thepredominant type. The other type is cancer of the gastriccardia or of the gastro-oesophageal junction.4 The latter are
sometimes grouped with oesophageal adenocarcinomas.
Distal gastric cancers may be classified depending on theirappearance under the microscope as intestinal or diffuse(from mucus-producing cells). The former is more common
and predominates in areas of high incidence; the latter has
a poorer prognosis, tends to occur at a younger age, and may
also occur in the cardia.76 More than 95 per cent of gastriccancers are adenocarcinomas.77

INCREASES RISK

2
3
4
5
6

Cereals (grains) and their products; dietary fibre;
potatoes; starchy roots, tubers, and plantains; nuts
and seeds; herbs, spices, and condiments; meat
(unprocessed); poultry; eggs; milk and dairy
products; fats and oils; total fat; fatty acidcomposition; cholesterol; sugars; sugar (sucrose);fruit juices; coffee; tea; alcohol; dietary nitrate andnitrite, N-nitrosodimethylamine; drying or dried
food; protein; thiamin; riboflavin; vitamin C;
vitamin D; multivitamin/mineral supplements;
calcium; iron; selenium supplements; carotenoids;
culturally defined diets; meal frequency; eating
speed; body fatness; energy intake

None identified

Judgements on vegetables and fruits do not include those preserved bysalting and/or pickling.
‘Salt’ here means total salt consumption, from processed foods, including
salty and salted foods, and also salt added in cooking and at the table.
Including soya and soya products.
Includes both foods naturally containing the constituent and foods whichhave the constituent added (see chapter 3.5.3).
The term ‘processed meat’ refers to meats preserved by smoking, curing,or salting, or addition of chemical preservatives.
The evidence is mostly from meats preserved or cooked in these ways.

For an explanation of all the terms used in the matrix,
please see chapter 3.5.1, the text of this section,and the glossary.

7.5.1 Trends, incidence, and survival
Age-adjusted rates of stomach cancer are decreasing, and in
2002 (in many countries) were half what they were 30 years
earlier. However, during the same period, two types of cancer affecting the upper (proximal) section of the stomach —those of the gastro-oesophageal junction and gastric cardia

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P A R T— increased, notably in high-income countries.78 The
decline in stomach cancer incidence is likely to have been
due partly to the increased availability of refrigeration (seebox 4.6.4). This has had the effect of increasing availability
and consumption of fresh foods such as vegetables and fruits,
and decreasing consumption of foods preserved by salt andother relevant methods.79 80
Age-adjusted incidence rates range from more than 60 per
100 000 people in Japan and other countries in eastern Asia,
to less than 10 per 100 000 in much of Africa and North
America. Chile and other Latin American countries, as well
as Portugal and eastern Europe, have moderately high ratesof 30 per 100 000. Rates are also higher in some ethnic
groups, for instance, Asian and Pacific Islanders living in theUSA, and African-American, and Hispanic-American people;
rates are also twice as high in men as women. Rates of different types of stomach cancer also vary, both geographicallyand between ethnic groups. Cancers affecting the lower (distal) section of the stomach are most common in low- to middle-income countries and in people of African origin;proximal tumours are predominant in high-income countries
and in white people.78 Risk increases with age; stomach cancer is rarely diagnosed in people under 50.
The 5-year survival rate for stomach cancer is approximately 20 per cent.3 6 Survival rates are higher in countries
which have screening programmes that lead to early detection, and where distal cancer (which has a better prognosis)
predominates.81 Stomach cancer accounts for nearly 9 percent of all cancer incidence, but somewhat over 10 per centof all cancer deaths worldwide. Also see box 7.1.1.

Box 7.5.1

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Helicobacter pylori

H pylori is a bacterium that lives in the human stomach. Infection
does not usually produce symptoms, and spreads through saliva
and faecal material. Prevalence increases with age, but differs
dramatically among populations.82 In the USA, prevalence is lessthan 20 per cent at 20 years old and about 50 per cent at 50
years, which may be typical of high-income countries,83 while in
Korea, it is 50 per cent at 5 years and 90 per cent at 20 years,
and in Japan it reaches 85 per cent by middle age.84
H pylori colonises the gastric mucosa and elicits both inflammatory and immune lifelong responses, including the release ofvarious bacterial and host-dependent cytotoxic substances.85
H pylori infection greatly reduces the bioavailability of vitamin
C. This may play a role in the development of stomach cancer inthe presence of dietary and other factors that are a cause of thiscancer. In studies of precancerous lesions or gastric atrophy, eradication of H pylori promoted regression of these cancer precursors.86-88
Some people develop stomach cancer without apparent infection with H pylori. Reported percentages of non-cardia cancers
that test positive for H pylori range from approximately 60 to 95
per cent, averaging around 86 per cent,89 but those with distal
stomach cancer who test negative for H pylori may have undergone a loss of infection associated with the atrophic gastritis, andconsequently a decline in antibody titre. It can be regarded as anecessary cause for those stomach cancers arising in the distal
region of the stomach.90
The longer the time of infection, and the greater the impact
on the gastric mucosa, the more likely it is that stomach cancer
will develop and take a severe form. The exact site of the cancer is most likely to be where the mucosa is most affected.91
Those who develop extensive gastritis and gastric atrophy are atincreased risk of developing cancer.81

7.5.2 Pathogenesis
Changes in the stomach mucosa, brought about by a varietyof environmental factors and ageing, can eventually lead toatrophic gastritis. The chronic form of this condition, and theresulting changes in the characteristics of the stomach cells,
appear to be precursor conditions to the development of distal stomach cancer.4 Food carcinogens can also potentiallyinteract directly with the epithelial cells that line the stomach. However, cancer can also develop without these precursors, particularly when the bacterium H pylori is present
in the stomach (see box 7.5.1).81
Three independent cohort studies have shown the progression of gastritis from the non-atrophic to the atrophic
form. Epidemiological studies of atrophic gastritis have also
shown an association with dietary factors, especially a highintake of salt (mostly in the form of salty and salted foods).90
N-nitrosamines are known carcinogens produced in thestomach from nitrate in foods, and via nitrite from endogenous nitric oxide production in chronic inflammation (seebox 4.3.2). They may be potential causes of stomach cancer92 (see chapter 2.4.2.6).
Cancers of the gastric cardia show many similarities tooesophageal cancer (see 7.3.1). There is a clear association
between Barrett’s oesophagus and adenocarcinoma of thelower (distal) oesophagus and of the gastric cardia, causedby chronic acid damage.

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The diffuse type of distal stomach cancers (those thatdevelop from mucus-producing cells) show some genetic predisposition, with an increased risk for people with bloodgroup A. Genetic predisposition is thought to be a factor in
5–10 per cent of diffuse cancers.93 Stomach cancer is part ofthe spectrum of cancers associated with the germ line mismatch repair (MMR) gene alterations that give rise to hereditary nonpolyposis colorectal cancer (HNPCC).77 Also see
chapter 7.9.2.

7.5.3 Other established causes(Also see chapter 2.4 and 7.1.3.1.)
Infection and infestation. The bacterium H pylori is an
important cause of distal stomach cancers (see box 7.5.1).
Also, Epstein-Barr virus is carcinogenic to humans and has
been linked to stomach cancers (particularly gastric lymphoepithelial carcinomas and a smaller proportion of gastricadenocarcinomas) in some studies.30
Industrial chemicals. Industrial exposure to ethylene oxide

is carcinogenic to humans and has led to increased risk ofstomach cancer in some studies.94

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7.5.4 Interpretation of the evidence
7.5.4.1 General
For general considerations that may affect interpretation of
the evidence, see chapters 3.3 and 3.5, and boxes 3.1, 3.2,
3.6 and 3.7.
‘Relative risk’ is used in this Report to denote ratio measures of effect, including ‘risk ratios’, ‘rate ratios’, ‘hazard
ratios’, and ‘odds ratios’.
7.5.4.2 Specific
Considerations specific to cancer of the stomach include thefollowing.
Classification. Most evidence relates to distal stomach cancers, although cancers of the gastric cardia and gastrooesophageal junction might be included in an outcome of‘stomach cancer’. It is now well recognised that proximal anddistal stomach cancers are quite different, but relatively few
studies stratified results on the basis of subsite. For many
early studies, most stomach cancer was probably distal in origin, so the lack of stratification was less important. As theincidence and overall proportion of proximal cancer haveincreased in recent years in high-income countries, there isa greater likelihood that the general term ‘stomach cancer’
will represent a combination of the two subsites and therefore results will be less informative.
Measurement. Owing to low survival rates, both incidence
and mortality can be assessed. Low survival times and rates
decrease the reliability of case-control studies, which often
rely on proxy reporting.
Confounding. H pylori infection is a necessary cause of dis-

tal stomach cancer. This has only been established relatively recently. Only recent studies have incorporated H pylori
status into their design and have adjusted or stratified for
infection.

7.5.5 Evidence and judgements
In total, 722 publications were included in the SLR for stomach cancer. Fuller summaries of the epidemiological, experimental, and mechanistic evidence are to be found in
Chapters 4–6.
The full SLR is contained on the CD included with thisReport.
7.5.5.1 Non-starchy vegetables(Also see chapter 4.2.5.1.)
A total of 10 cohort studies, 45 case-control studies, and 19
ecological studies investigated total vegetables. Other groupings examined were green-yellow vegetables (11 cohort, 21
case-control, 8 ecological); green, leafy vegetables (6 cohort,
13 case-control, 2 ecological); tomatoes (3 cohort, 19 casecontrol); white or pale vegetables (2 cohort, 6 case-control);raw vegetables (6 cohort, 25 case-control, 3 ecological); or
non-starchy vegetables and fruits (5 cohort, 6 case-control).

Most studies showed decreased risk with increased intake.
However, cohort data were less consistent than case-control
data. Meta-analysis of cohort data showed a 19 per centdecreased risk per 50 g green-yellow vegetables/day; no othersubcategory analyses were statistically significant. Case-control data showed a 15 per cent decreased risk per 50 g vegetables/day (figures 4.2.8. and 4.2.9); a 21 per centdecreased risk per 50 g green-yellow vegetables/day; a 57 percent decreased risk per 50 g green, leafy vegetables/day; a
30 per cent decreased risk per 50 g tomatoes/day; and a 25
per cent decreased risk per 50 g raw vegetables/day (figure
4.2.12). There was unexplained heterogeneity.
This is a wide and disparate category, and many different
plant food constituents are represented that could contributeto a protective effect of non-starchy vegetables. These include
dietary fibre, carotenoids, folate, selenium, glucosinolates,
dithiolthiones, indoles, coumarins, ascorbate, chlorophyll,
flavonoids, allylsulphides, flavonoids, and phytoestrogens,some of which are potentially antioxidants. Antioxidants trap
free radicals and reactive oxygen molecules, protecting
against oxidation damage. It is difficult to unravel the relative importance of each constituent and it is likely that any
protective effect may result from a combination of influences
on several pathways involved in carcinogenesis.
A substantial amount of evidence is available,
including on specific subtypes, particularly greenyellow vegetables, with a dose-response relationship incase-control, but not cohort, data. There is evidence
for plausible mechanisms. Non-starchy vegetables
probably protect against stomach cancer.

The Panel is aware that since the conclusion of the SLR, one
case-control study95 has been published. This new information
does not change the Panel judgement. Also see box 3.8.
7.5.5.2 Allium vegetables(Also see chapter 4.2.5.1.1.)
A total of 2 cohort studies, 27 case-control studies, and 2
ecological studies investigated allium vegetables; and 1
cohort study, 16 case-control studies, and 2 ecological studies investigated garlic. There was also one relevant intervention study that combined allitridium (a garlic extractcontaining triallylsulphides) and selenium supplements.
Most of the studies showed decreased risk with increased
intake. Meta-analysis of cohort data showed a 23 per centdecreased risk per 50 g allium vegetables/day. Meta-analysis of case-control data showed a 20 per cent decreased risk
per 50 g allium vegetables/day (figure 4.2.14), and a 59 percent decreased risk per serving of garlic/day. The single trialof combined selenium and allitridium supplements showeda statistically significant decreased risk in men but not
women, after 5 years of follow-up.
Allium vegetables, particularly garlic, have antibiotic properties. Although this may act directly against H pylori, studies in humans have not shown this effect. It is also possiblethat antibacterial effects of garlic might inhibit the secondarycolonisation of the stomach after H pylori-induced atrophy.
At present, there is no evidence to support or refute this idea.

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The evidence, though not copious and mostly fromcase-control studies, is consistent, with a doseresponse relationship. There is evidence for plausible
mechanisms. Allium vegetables probably protect
against stomach cancer.

7.5.5.3 Fruits(Also see chapter 4.2.5.2.)
Sixteen cohort studies, 51 case-control studies, and 23 ecological studies investigated fruits. Most studies showeddecreased risk with increased intake, but there was unexplained heterogeneity. Cohort studies suggested a non-significant relationship with decreased risk. Meta-analysis ofcase-control data showed a 17 per cent decreased risk per
50 g fruits per day (figure 4.2.27).
Fruits are sources of vitamin C and other antioxidants,
such as carotenoids, phenols, and flavonoids, as well as otherpotentially bioactive phytochemicals. Antioxidants trap free
radicals and reactive oxygen molecules, protecting against
oxidation damage. In addition, flavonoids found in fruits
directly inhibit the expression of a cytochrome P450 enzyme,
which helps to metabolise toxins and has been associatedwith increased risk of lung cancer, primarily in smokers.68 It
is difficult to unravel the relative importance of each constituent and it is likely that a protective effect may result froma combination of influences on several pathways involved in
carcinogenesis.
The evidence is ample and more consistent, with adose-response relationship, for case-control studies
than for cohorts. There is evidence for plausible
mechanisms. Fruits probably protect against stomach
cancer.

The Panel is aware that since the conclusion of the SLR, threecase-control studies95-97 have been published. This new information does not change the Panel judgement. Also see box 3.8.
7.5.5.4 Pulses (legumes) including soya and soya
products(Also see chapter 4.2.5.10.)
A total of 3 cohort studies, 22 case-control studies, and16 ecological studies investigated pulses (legumes) andstomach cancer; and 2 cohort studies, 9 case-control studies, and 2 ecological studies investigated soya and soya products. All of the cohort studies and most of the case-control
studies showed decreased risk with increased intake.
Ecological studies showed decreased risk for soya and soya
products, but were inconsistent for pulses (legumes).
Meta-analysis of cohort studies showed a non-significant
relationship with decreased risk. Meta-analysis of case-control studies produced evidence for a relationship withdecreased risk.
Pulses (legumes), particularly soya, contain high levels of
isoflavones that have shown anti-cancer properties in laboratory experiments. Saponins and other bioactive constituents of soya (and to a lesser extent, other pulses) may
also have anti-cancer properties, although these are less welldemonstrated.

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The evidence, mostly from case-control studies, isinconsistent. There is limited evidence suggesting that
pulses (legumes), including soya and soya products,
protect against stomach cancer.

7.5.5.5 Foods containing selenium(Also see chapter 4.2.5.8.)
One case-control study and 5 ecological studies investigateddietary selenium; 3 cohort studies, 9 case-control studies and3 ecological studies investigated blood selenium; and 1 cohort
study and 1 case-control study investigated selenium in toenails or hair. All of the studies for blood, nail, or hair selenium levels showed decreased risk with increased selenium
intake. Meta-analysis of cohort data showed a non-significant
decreased risk, and meta-analysis of case-control data produced statistically significant evidence of decreased risk.
Dietary selenium deficiency has been shown to cause alack of selenoprotein expression. Twenty-five selenoproteins
have been identified in animals and a number of these haveimportant anti-inflammatory and antioxidant properties.
Four are glutathione peroxidases, which protect against
oxidative damage to biomolecules such as lipids, lipoproteins, and DNA. Three are thioredoxin reductases, which,among other functions, regenerate oxidised ascorbic acid to
its active antioxidant form. Selenoproteins with powerfulantioxidant activity may provide protection against the
inflammatory effect of H pylori that can lead to gastric cancer in infected individuals.
A substantial amount of evidence was available on
selenium, from dietary questionnaires as well as blood,nails, and hair, mostly from case-control studies. Thereis limited evidence suggesting that foods containing
selenium protect against stomach cancer.

7.5.5.6 Chilli(Also see chapter 4.2.5.12.1.)
Fourteen case-control studies investigated chilli use. Most ofthese reported increased risk with increased use, although
results were heterogeneous and data were not suitable formeta-analysis.
Anecdotally, chilli may be used to disguise ‘off’ flavours infoods, so these data may be confounded by socioeconomic
status, the availability of refrigeration, and H pylori infection.
Some constituents of chilli are irritants, which could therefore plausibly increase inflammation in the stomach (also see
chapter 2.4.1.3).
The evidence, from case-control studies only, isinconsistent. There is limited evidence suggesting thatchilli is associated with an increased risk of stomach
cancer.

7.5.5.7 Processed meat
(Also see chapter 4.3.5.1.2.)
Eight cohort studies, 21 case-control studies, 1 cross-sectional study, and 1 ecological study investigated processed
meat. Most of these showed increased risk with higher
intake. Meta-analysis of cohort data showed a non- signifi-

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cant relationship with increased risk. Meta-analysis of casecontrol data produced evidence of a statistically significant
dose-response relationship. Heterogeneity is likely to becaused by the diverse nature of definitions for processedmeat in different studies.
Nitrates are produced endogenously in gastric acid, and are
added as preservatives to processed meats. They may contribute to N-nitroso compound production and exposure. Nnitroso compounds are suspected mutagens and carcinogens(see box 4.3.2).55 Many processed meats also contain highlevels of salt and nitrite. Meats cooked at high temperatures
can contain heterocyclic amines and polycyclic aromatichydrocarbons (see box 4.3.4). Haem promotes the formationof N-nitroso compounds and also contains iron. Free iron canlead to the production of free radicals (see box 4.3.3).

specified the foods studied). Most studies showed increased
risk with increased intake.
Cooking methods involving grilling above a heat sourceand barbecuing can produce marked differences in levels ofcarcinogens in foods cooked in these ways (see chapter
4.9.4). For example, fat dripping on hot surfaces can form
polycyclic aromatic hydrocarbons and heterocyclic amines(see box 4.3.4), while oven grilling prevents this from happening, resulting in much lower levels of these compounds
in the cooked foods.

The evidence is inconsistent. There is limited evidence
suggesting that processed meat is a cause of stomach
cancer.

7.5.5.10 Salt
(Also see chapter 4.6.5.2.)
Three cohort studies, 21 case-control studies, and 12 ecological studies investigated total salt use. Other groupings
examined were salt added at the table (2 cohort, 13 case-control) and sodium intake (1 cohort, 8 case-control). Most studies showed increased risk with increased intake, but there issome unexplained heterogeneity. Meta-analysis of case-control data showed an 18 per cent increased risk per gram of
sodium per day; the meta-analyses for total salt indicatedincreased risk but were not statistically significant (figure
4.6.1).
Assessment of salt intake is complicated as the small proportion added during preparation or at the table is very variable and difficult to quantify. Higher-quality studies, which
are better adjusted, tend to report a greater or more significant effect. However, residual confounding is possible: salt
intake may be inversely related to the availability of refrigeration in a population, and so to socioeconomic status,
which is itself related to stomach cancer risk.
Salt has been shown to directly damage the stomach lining in animal trials. It has also been shown to increase
endogenous N-nitroso compound formation (see box 4.3.2).
Salt may enhance the action of carcinogens in the stomach.
In addition, salt intake may facilitate H pylori infection.101

The Panel is aware that since the conclusion of the SLR, onecohort98 and two case-control studies95 99 have been published.
This new information does not change the Panel judgement.
Also see box 3.8.
7.5.5.8 Smoked foods(Also see chapter 4.3.5.7.)
Seventeen case-control studies and two ecological studies
investigated smoked foods. Most of these showed increased
risk with increased intake, with none reporting statisticallysignificant reduced risk.
Definitions of smoked foods varied between studies,
although most included smoked meats and/or fish. Smokedfoods are often salted. High rates of mortality from stomach
cancer are found in countries such as Iceland, Hungary, andLatvia, where diets include a regular intake of meat and/or
fish preserved by smoking.
Smoked foods, particularly meats, may contain polycyclicaromatic hydrocarbons, depending on the fuel burned to produce the smoke.100 (Also see box 4.3.4.) Smoked meats arealso often salted or cured, meaning that they are likely toraise endogenous production of N-nitroso compounds in thestomach (see box 4.3.2). These are suspected causes of stomach cancer.
There is limited evidence from case-control andecological studies, some of which were of poor quality,that smoked foods are causes of stomach cancer.

The Panel is aware that since the conclusion of the SLR, threecase-control studies95 96 99 have been published. This new information does not change the Panel judgement. Also see box 3.8.
7.5.5.9 Grilled (broiled) or barbecued(charbroiled) animal foods(Also see chapter 4.3.5.8.)
Three cohort studies and 12 case-control studies investigated grilled (broiled) or barbecued (charbroiled) foods (thesewere predominantly meats or fish, although not all studies

There is limited, inconsistent evidence, mostly fromcase-control studies, that grilled (broiled) orbarbecued (charbroiled) animal foods are causes ofstomach cancer.

There is a substantial amount of evidence from studies
on total salt use, salt added at the table, and sodium
intake. For total salt use, a dose-response relationshipwas apparent from cohort but not case-control studies.
For sodium intake, a dose response was also apparent
from case-control studies. The mechanistic evidence isstrong. Salt is a probable cause of stomach cancer.

The Panel is aware that since the conclusion of the SLR, onecohort102 and two case-control studies95 99 have been published.
This new information does not change the Panel judgement.
Also see box 3.8.
7.5.5.11 Salted and salty foods(Also see chapter 4.6.5.2.1.)
Four cohort studies, 17 case-control studies, and 1 ecological study investigated salty or salted foods. Nearly all of the269

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studies showed increased risk with increased intake. Metaanalysis of cohort data showed a non-significant increased
risk; meta-analysis of case-control data showed a 5.2-foldincreased risk per serving per day (figure 4.6.2).
Heterogeneity may be partly explained by variation between
studies in the precise foods being assessed.
As stated above, assessment of salt intake is complicated.
Again, higher-quality studies report a greater or more significant effect.
Again, salt has been shown to directly damage the stomach lining in animal trials. It has also been shown to increase
endogenous N-nitroso compound formation (see box 4.3.2).
The evidence, both from case-control and cohort
studies, is consistent. A dose-response relationship isapparent from case-control but not cohort studies.
There is robust evidence for mechanisms operating inhumans. Salted and salty foods are probable causes ofstomach cancer.

The Panel is aware that since the conclusion of the SLR, twocase-control studies95 99 have been published. This new information does not change the Panel judgement. Also see box 3.8.
7.5.5.12 Other exposures
Other exposures were evaluated. However, the data were
either of too low quality, too inconsistent, or the number ofstudies too few to allow conclusions to be reached. These
were as follows: cereals (grains) and their products; starchy
roots, potatoes, and other tubers; plantains; nuts and seeds;
herbs, spices, and condiments; meat; poultry; eggs; fats andoils; milk and dairy products; sugar; fruit juices; coffee; tea;
alcohol; nitrosodimethylamine/dietary nitrate/nitrite; drying
or dried food; dietary fibre; sugars; total fat; fatty acid composition; cholesterol; protein; carotenoids; thiamin;
riboflavin; vitamin C; vitamin D; multivitamin/mineral supplements; selenium supplements; iron; calcium; energy
intake; body fatness; culturally defined diets; meal frequency; and eating speed.

7.5.6 Comparison with previous report
7.5.6.1 GeneralSee 7.1.6.1, and box 3.8.
7.5.6.2 Specific
The previous report judged the evidence that vegetables andfruits protect against stomach cancer to be convincing. Since
then, the evidence from cohort studies has been rather equivocal, whereas evidence from case-control studies remains
strong and consistent. Previously, the compounds found inallium vegetables were judged possibly to protect against
stomach cancer; more recent evidence for allium vegetables
is stronger.
The previous report found the evidence that refrigeration
protects against stomach cancer to be convincing. Also seebox 4.6.4.
Before the mid-1990s there were no published trials of

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selenium supplements. Two trials are now available, as wellas increased numbers of cohort and case-control studies, but
the evidence is still limited and only suggestive of a protective effect.

7.5.7 Conclusions
The Panel concludes:
Non-starchy vegetables, and specifically allium vegetables,
as well as fruits probably protect against stomach cancer.
Salt and salt-preserved foods are probably causes of thiscancer.
There is limited evidence suggesting that pulses (legumes)
including soya and soya products and foods containing selenium protect against stomach cancer.
There is also limited evidence suggesting that chilli,
processed meat, smoked foods, and grilled (broiled) and barbecued (charbroiled) animal foods are causes of stomach
cancer.
Infection with the bacterium H pylori is a necessary but
not sufficient cause of stomach cancer.

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7.6 Pancreas
Cancer of the pancreas is the thirteenth most common
type of cancer worldwide. About 230 000 cases wererecorded in 2002, accounting for around 2 per cent ofcancers overall. The incidence is somewhat morecommon in men than in women. It is generally
increasing, particularly in high-income countries,
where it is most frequent. It is rare in Africa and Asia.
This cancer is almost always fatal and is the ninth mostcommon cause of cancer death.
Overall, the Panel is impressed by the strength of theevidence that body fatness, abdominal fatness, and thefactors that lead to greater adult attained height, or its
consequences, are causes of cancer of the pancreas.

FOOD, NUTRITION, PHYSICAL ACTIVITY,
AND CANCER OF THE PANCREAS
In the judgement of the Panel, the factors listed below modify the risk ofcancer of the pancreas. Judgements are graded according to the strengthof the evidence.

DECREASES RISK
Convincing
Probable

INCREASES RISK
Body fatness

Foods containing
folate1

Abdominal fatness
Adult attainedheight2

Limited —suggestive

Fruits3

Red meat5

Limited —no conclusion

Cereal (grains) and their products; dietary fibre;
vegetables; pulses (legumes); soya and soya
products; processed meat; poultry; fish; eggs; milk
and dairy products; total fat; butter; plant oils;
margarine; cholesterol; sugar (sucrose); black tea;green tea; alcohol; nitrate and nitrite; total
carbohydrate; folic acid supplements; vitamin C;
vegetarianism; age at menarche; lactation; energy
intakeThe Panel judges as follows:
The evidence that body fatness is a cause of cancer ofthe pancreas is convincing; abdominal fatness is probably
a cause of this cancer.
Foods containing folate probably protect against
this cancer.
The factors that lead to greater adult attained height,
or its consequences, are probably a cause of pancreaticcancer.
It is unlikely that coffee has any substantial effect on
the risk of this cancer.
There is limited evidence suggesting that fruits andphysical activity protect against this cancer, and that redmeat is a cause of this cancer.
See chapter 8 for evidence and judgements on factorsthat modify the risk of body fatness and abdominal
fatness, including physical activity and sedentary waysof life, the energy density of foods and drinks, andbreastfeeding.
Tobacco smoking is an established cause ofthis cancer.
In final summary, the strongest evidence,corresponding to judgements of “convincing” and“probable”, shows that body fatness and (probably)
abdominal fatness are both causes of cancer of thepancreas, and that the factors that lead to greater adultattained height, or its consequences, are probably also a
cause of this cancer. Foods containing folate are probably
protective. It is unlikely that coffee has any substantial
effect on the risk of this cancer.

7.6.1 Trends, incidence, and survival

The pancreas is an elongated gland located behindthe stomach. It contains two types of tissue, exocrineand endocrine. The exocrine pancreas produces digestive
enzymes that are secreted into the small intestine. Cells in
the endocrine pancreas produce hormones including insulin
and glucagon, which influence glucose metabolism.
Over 95 per cent of pancreatic cancers are adenocarcinomas of the exocrine pancreas, the type included in thisReport.

Age-adjusted rates of pancreatic cancer have been generally stable since the 1970s, following an approximate threefold rise over the preceding 50 years in the countries forwhich data are available.103 104
This is mainly a disease of high-income countries, where
overall rates are nearly three times higher than in middleand low-income countries. Around the world, age-adjusted
incidence rates range from 10–15 per 100 000 people inparts of northern, central, and eastern Europe to less than
1 per 100 000 in areas of Africa and Asia, although rates are

Substantial
effect on risk
unlikely

1
2

3
4
5

Physical activity4

CoffeeIncludes both foods naturally containing the constituent and foods whichhave the constituent added (see chapter 3.5.3).
Adult attained height is unlikely directly to modify the risk of cancer. It is amarker for genetic, environmental, hormonal, and also nutritional factors
affecting growth during the period from preconception to completion of
linear growth (see chapter 6.2.1.3).
Judgements on vegetables and fruits do not include those preserved bysalting and/or pickling.
Physical activity of all types: occupational, household, transport, andrecreational.
The term ‘red meat’ refers to beef, pork, lamb, and goat from domesticatedanimals.

For an explanation of all the terms used in the matrix,
please see chapter 3.5.1, the text of this section,and the glossary.

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relatively high in some countries in these areas, for example, Japan and Korea. In the USA, rates are higher among
African-American people than in white people.3 The risk ofpancreatic cancer increases with age, with most diagnoses
made in people between the ages of 60 and 80.
The early stages of this cancer do not usually produce
symptoms, so the disease is generally advanced when it isdiagnosed. Survival rates are therefore low — around 4 percent at 5 years. This cancer accounts for around 2 per centof all cancer incidence, but somewhat over 3 per cent of allcancer deaths.4 Also see box 7.1.1.

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rates decrease the reliability of case-control studies, which
often rely on proxy reporting.
Confounding. High-quality studies adjust for smoking.

7.6.5 Evidence and judgements
In total, 318 publications were included in the SLR for thiscancer. Fuller summaries of the epidemiological, experimental, and mechanistic evidence are in Chapters 4–6.
The full SLR is contained on the CD included with thisReport.

7.6.2 Pathogenesis
The ductal cells in the head of the pancreas are exposed topancreatic secretions, as well as bile, and environmental carcinogens can reach these cells through those fluids or in the
blood (see 7.7).
The pancreas is relatively inaccessible to routine medical
examination, so the progression of this cancer through precursor lesions is not well understood. However, inflammation is implicated in this process through chronic pancreatitis,which is a risk factor for pancreatic cancer. The role of infection with H pylori (see box 7.5.1) is the subject of ongoing
research.105 Conditions that lead to high insulin levels in pancreatic secretions, such as insulin resistance and type 2 diabetes, may increase the risk of this cancer.106
More than 90 per cent of pancreatic cancer cases are sporadic (due to spontaneous rather than inherited mutations),
although a family history increases risk, particularly wheremore than one family member is involved.105 Around 75–90
per cent of pancreatic cancer cases involve a point mutationin the K-ras oncogene107 (see box 2.2 in chapter 2).

7.6.3 Other established causes(Also see chapters 2.4 and 7.1.3.1.)
Tobacco use. Approximately 25 per cent of cases of pancreatic cancer are attributable to tobacco smoking.

7.6.4 Interpretation of the evidence
7.6.4.1 General
For general considerations that may affect interpretation of
the evidence, see chapters 3.3 and 3.5, and boxes 3.1, 3.2,
3.6 and 3.7.
‘Relative risk’ is used in this Report to denote ratio measures of effect, including ‘risk ratios’, ‘rate ratios’, ‘hazard
ratios’, and ‘odds ratios’.
7.6.4.2 Specific
Considerations specific to cancer of the pancreas include:
Measurement. Owing to very low survival rates, both incidence and mortality can be assessed. Low survival times and272

7.6.5.1 Fruits(Also see chapter 4.2.5.2.)
Six cohort studies, 16 case-control studies, and 8 ecologicalstudies investigated fruits. All cohort studies and most otherstudies showed decreased risk with increased intake. Metaanalysis of cohort data showed a non-significant decreased
risk. Meta-analysis of case-control data showed a statisticallysignificant decreased risk.
Fruits are sources of vitamin C and other antioxidants,
such as carotenoids, phenols, and flavonoids, as well as otherpotentially bioactive phytochemicals. Antioxidants trap free
radicals and reactive oxygen molecules, protecting against
oxidation damage. In addition, flavonoids found in fruit
directly inhibit the expression of the cytochrome P450
enzyme, which helps to metabolise toxins and has been associated with increased risk of lung cancer, primarily in smokers.68 It is difficult to unravel the relative importance of eachconstituent and is likely that a protective effect may result
from a combination of influences on several pathways
involved in carcinogenesis.
The evidence is inconsistent. There is limited evidence
suggesting that fruits protect against pancreatic cancer.

The Panel is aware that since the conclusion of the SLR, onecohort study108 has been published. This new information does
not change the Panel judgement. Also see box 3.8.
7.6.5.2 Foods containing folate(Also see chapter 4.2.5.4.)
Three cohort studies, two case-control studies, and one ecological study investigated folate from foods and/or folic acidfrom supplements. Meta-analysis of all three cohort studies
showed a non-significant decreased risk, with high heterogeneity. When stratified according to the source, both dietarystudies showed a non-significant decreased risk, and threestudies of supplements showed a non-significant increased
risk. One cohort study also analysed serum folate levels,
showing a significant decreased risk of 55 per cent for thehighest levels compared with the lowest. Both the case-control studies and the ecological study showed decreased risk
with increased intake. Folic acid supplements do not show
a protective effect.
Folate plays an important role in the synthesis and repair
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alcohol and the risk of some cancers (see chapter 4.8). Folate
intake is strongly correlated with intake of non-starchy polysaccharide or dietary fibre.
The evidence available is sparse but a dose-response
relationship was apparent from cohort studies. There islimited evidence suggesting that foods containing
folate protect against pancreatic cancer.

The Panel is aware that since the conclusion of the SLR, onecohort study109 has been published. This new information does
not change the Panel judgement. Also see box 3.8.
7.6.5.3 Red meat
(Also see chapter 4.3.5.1.1.)
Seven cohort studies and four case-control studies investigated red meat. Nearly all of the studies showed increased
risk with increased intake.
Red meat contains haem iron. Free iron can lead to the production of free radicals (see box 4.3.3). When cooked at hightemperatures, red meat can also contain heterocyclic aminesand polycyclic aromatic hydrocarbons (see box 4.3.4).
Evidence from cohort studies is less consistent thanthat from case-control studies. There is limited
evidence suggesting that red meat is a cause ofpancreatic cancer.

The Panel is aware that since the conclusion of the SLR, onecohort study110 has been published. This new information does
not change the Panel judgement. Also see box 3.8.
7.6.5.4 Coffee(Also see chapter 4.7.5.4.)
Eighteen cohort studies, 37 case-control studies, and 11 ecological studies investigated coffee. Analysis of cohort data
showed an effect estimate close to null with low heterogeneity. Data for case-control studies were less consistent.
There is ample evidence, including prospective data,
which is consistent and with low heterogeneity, andwhich fails to show an association. It is unlikely thatcoffee has a substantial effect on the risk of pancreaticcancer.

7.6.5.5 Physical activity(Also see chapter 5.4.5.)
A total of three cohort studies and one case-control study
investigated total physical activity; three cohort studies andtwo case-control studies investigated occupational activity;and nine cohort studies and three case-control studies investigated recreational activity. Several studies also examinedwalking and transportation. Most of the studies showeddecreased risk with increased physical activity, though there
was heterogeneity in the direction of effect and no clear
dose-response relationship.
Sustained moderate physical activity raises the metabolic
rate and increases maximal oxygen uptake. In the long term,
regular periods of such activity increase the body’s metabolic

efficiency and capacity (the amount of work that it can perform), as well as reducing blood pressure and insulin resistance. In addition, low levels of physical activity decrease
gastrointestinal transit times. This alters bile content andsecretion, as well as affecting pancreatic activity.111
There is evidence from prospective studies showing
lower risk of pancreatic cancer with higher levels of
various types of physical activity, but it is rather
inconsistent. There is limited evidence suggesting thatphysical activity protects against pancreatic cancer.

The Panel is aware that since the conclusion of the SLR, onecohort study112 has been published. This new information does
not change the Panel judgement. Also see box 3.8.
7.6.5.6 Body fatness(Also see chapter 6.1.3.1.)
Twenty-three cohort studies and 15 case-control studies
investigated body fatness, as measured by BMI. Most cohort
studies showed increased risk with increased body fatness,but case-control studies were inconsistent. Meta-analysis ofcohort data showed a 14 per cent increased risk per 5 kg/m2(figure 6.1.4). Heterogeneity appeared to be explained by anumber of studies failing to adjust for smoking, which is separately associated with both BMI and pancreatic cancer.
It is biologically plausible that body fatness is a cause ofpancreatic cancer. There is an established connection
between increasing BMI or body fatness and insulin resistance and diabetes. The risk of this cancer is increased inpeople with insulin resistance or diabetes. It also directly
affects levels of many circulating hormones, such as insulin,
insulin-like growth factors, and oestrogens, creating an environment that encourages carcinogenesis and discourages
apoptosis (see box 2.4). Body fatness stimulates the inflammatory response, which may contribute to the initiation andprogression of several cancers (see chapter 2.4.1.3).
There is ample epidemiological evidence, which is
generally consistent, and there is a dose-response
relationship. There is evidence for plausible
mechanisms that operate in humans. The evidence
that greater body fatness is a cause of pancreaticcancer is convincing.

The Panel is aware that since the conclusion of the SLR, twocohort studies58 112 have been published. This new information
does not change the Panel judgement. Also see box 3.8.
7.6.5.7 Abdominal fatness(Also see chapter 6.1.3.2.)
Three cohort studies investigated waist circumference, twocohort studies investigated waist to hip ratio, and one cohort
study investigated patterns of weight gain, all of whichshowed increased risk with increasing measures of abdominal fatness. Half of all studies were statistically significant.
The general mechanisms through which abdominal fatness
could plausibly cause cancer are outlined in chapter 6.1.3(also see box 2.4). The hormonal and other biological effects

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of being overweight or obese are outlined in chapter 8. Manyof these, such as increased circulating oestrogens anddecreased insulin sensitivity, are associated with abdominal
fatness independently of overall body fatness.
There is a substantial amount of epidemiologicalevidence that is generally consistent, and there isevidence for plausible mechanisms. Abdominal fatness
is a probable cause of pancreatic cancer.

The Panel is aware that since the conclusion of the SLR, onecohort study112 has been published. This new information does
not change the Panel judgement. Also see box 3.8.

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7.6.6 Comparison with previous report
7.6.6.1 GeneralSee 7.1.6.1, and box 3.8 in chapter 3.
7.6.6.2 Specific
Apart from vegetables and fruits, the strongest evidence andjudgements here are remarkably different from the previous
report. Much of the evidence on body fatness, abdominal fatness, attained adult height (tallness), and physical activity
is recent.

7.6.7 Conclusions
7.6.5.8 Adult attained height(Also see chapter 6.2.3.1.)
Eight cohort studies, 12 case-control studies, and 1 ecological study investigated adult attained height. Most cohort
studies and the single ecological study showed increased risk
with greater adult attained height. Case-control studies wereinconsistent. Meta-analysis of cohort data showed an 11 percent increased risk per 5 cm of height (figure 6.2.5). There
was considerable heterogeneity in case-control data, not all
readily explained. However, the cohort studies showed a linear dose-response relationship (figure 6.2.6).
The general mechanisms through which the factors thatlead to greater adult attained height, or its consequences,
could plausibly influence cancer risk are outlined in chapter
6.2.1.3 (for more detail see box 2.4). Many of these, such as
early-life nutrition, altered hormone profiles, and the rate ofsexual maturation, could plausibly increase cancer risk.
There is ample prospective epidemiological evidence,
though there is some inconsistency. There is evidence
for a dose-response relationship, and evidence forplausible mechanisms. The factors that lead to greater
adult attained height, or its consequences, areprobably a cause of pancreatic cancer. The causal
factor is unlikely to be tallness itself, but factors that
promote linear growth in childhood.

The Panel is aware that since the conclusion of the SLR, onecohort study112 has been published. This new information does
not change the Panel judgement. Also see box 3.8.
7.6.5.9 Other exposures
Other exposures were evaluated. However, the data were
either of too low quality, too inconsistent, or the number ofstudies too few to allow conclusions to be reached. These
were as follows: cereals (grains) and their products; vegetables; pulses (legumes); soya and soya products; processed
meat; poultry; fish; eggs; milk and dairy products; butter;margarine; black tea; green tea; alcoholic drinks;
nitrate/nitrite; total carbohydrate; dietary fibre; sucrose;
total fat; cholesterol; folic acid supplements; plant oils; energy intake; age at menarche; vegetarianism; and lactation.
In the case of alcoholic drinks, although low-to-moderate levels of drinking were unlikely to have an effect on risk, it could
not be excluded that heavy drinking might have an effect.

274

The Panel concludes:
The evidence that body fatness is a cause of cancer of thepancreas is convincing; abdominal fatness is probably acause of this cancer.
Foods containing folate (but not folic acid supplements)
probably protect against pancreatic cancer.
The factors that lead to greater adult attained height, or
its consequences, are probably a cause of this cancer. Greater
height is unlikely to directly modify the risk of cancer; it isa marker for genetic, environmental, hormonal, and also
nutritional factors affecting growth during the period frompreconception to completion of linear growth.
It is unlikely that coffee has any substantial effect on risk.
There is limited evidence suggesting that fruits and also
physical activity protect against this cancer, and that redmeat is a cause of this cancer.

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7.7 Gallbladder
Cancer of the gallbladder accounts for somewhat over
2 per cent of all cancer incidence and rates are generally
declining. The highest rates occur in eastern Asia andeastern Europe, but it is rare in Africa. This cancer isusually fatal and is the 17th most common cause ofcancer death.
The Panel judges as follows:
Body fatness is probably a cause of cancer of thegallbladder and people with gallstones are more likely todevelop gallbladder cancer.
See chapter 8 for evidence and judgements on factorsthat modify the risk of body fatness, including physicalactivity and sedentary ways of life, the energy density offoods and drinks, and breastfeeding.
In final summary, the strongest evidence, corresponding
to judgements of “convincing” and “probable”, shows thatbody fatness is probably a cause of gallbladder cancer,
both directly and indirectly, through the formation ofgallstones.

FOOD, NUTRITION, PHYSICAL ACTIVITY,
AND CANCER OF THE GALLBLADDERIn the judgement of the Panel, the factors listed below modify the risk ofcancer of the gallbladder. Judgements are graded according to thestrength of the evidence.

DECREASES RISK
Convincing

Body fatness1

Probable
Limited —suggestive
Limited —no conclusion

Peppers (capsicums); fish; coffee; tea; alcohol;
vitamin C.

Substantial
effect on risk
unlikely

1

The gallbladder is a small sac-like organ that forms part ofthe biliary tract. Bile, produced in the liver, flows into thegallbladder, where it is stored and concentrated until
released into the small intestine.
More than 90 per cent of gallbladder cancers are adenocarcinomas, while only a small proportion are squamous cell
carcinomas.4

INCREASES RISK

None identified

Directly and indirectly, through the formation of gallstones.

For an explanation of all the terms used in the matrix,
please see chapter 3.5.1, the text of this section,and the glossary.

7.7.1 Trends, incidence, and survival

7.7.2 Pathogenesis

Age-adjusted rates of gallbladder cancer are decreasing.1
Even in many of the countries where incidence had been relatively high, such as in eastern Asia and eastern Europe, rates
have decreased and continued to fall, following a dramaticrise in the 1970s and 1980s.
There is no clear geographical pattern to the distributionof gallbladder cancer. Age-adjusted incidence rates range
from 5–10 per 100 000 people in parts of eastern Asia andeastern Europe to less than 1 per 100 000 in parts of Africa.
In the USA, rates are higher among both Native- andHispanic-American people than in white people.113 Aroundmost of the world, gallbladder cancer is slightly more common in women than men. In Japan and Korea, this trend isreversed, with around 60 per cent of cases in men.103 Risk
increases with age, with more than two thirds of cases occurring in people aged 65 years or older.114
Gallbladder cancer is usually advanced at diagnosis.
Survival rates are poor: at 5 years less than 12 per cent foradvanced disease, but this is much higher (by up to 20 percent) when the cancer is caught early. Gallbladder cancer
accounts for just over 2 per cent of all cancer incidence, andthe same proportion of all cancer deaths. Also see box 7.1.1.

The pathogenesis of gallbladder cancer is not well understood, partly because it is often diagnosed at a late stage.
Having gallstones increases the risk of this cancer. The
associated inflammation decreases the speed at which bile
empties from the gallbladder; gallstones may also have a
direct effect by blocking the transit of bile.115 Gallstones, likegallbladder cancers, are more common in women than men,and the risk of cancer is proportional to the size of the gallstones.116 However, other factors must also be involved: inhigh-income countries up to 1 person in 10 has gallstones(many asymptomatic),117 whereas gallbladder cancer is diagnosed in only around 1 in 50 000.
Many toxins, whether they come from diet, smoke inhalation, or other environmental sources (and their metabolic
products) are excreted and concentrated in the bile.
Early stages of the disease include plaque-like lesions andsmall ulcerations in the mucosal lining of the gallbladder,which are associated with chronic inflammation (cholecystitis). This may progress to carcinoma in situ, and then toinvasive tumours. This process probably takes at least 20
years (cholecystitis is seldom seen in people under 40),
hence the age profile of gallbladder cancer. Chronic inflam-275

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mation caused by other factors (such as in ‘porcelain gallbladder’ or from chronic bacterial infection) may be a necessary stage in the development of gallbladder cancer,
although the evidence is not conclusive.4 118 119
A congenital deformity to the pancreatic ducts is associated with most gallbladder cancers in eastern Asia.120 This
may account for the different epidemiology in this region,and could imply a distinct pathogenesis with different risk
factors. Mutations of the tumour-suppressor p53 gene are frequent in gallbladder cancers (see box 2.2).121

7.7.3 Other established causes(Also see chapter 2.4 and 7.1.3.1 of this chapter.)Other diseases. Having gallstones increases the risk of gallbladder cancer and can be identified as a cause of this cancer.

Other causes are not established; see 7.7.2.

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case-control data showed a 19 per cent increased risk per 5kg/m2. Heterogeneity could be partly attributed to differences in the study participants’ ethnicity or sex, or to thenumber of adjustments made in the study.
Body fatness directly affects levels of many circulating hormones, such as insulin, insulin-like growth factors, andoestrogens, creating an environment that encourages carcinogenesis and discourages apoptosis (see box 2.4). It also
stimulates the body’s inflammatory response, which may
contribute to the initiation and progression of several cancers (see chapter 2.4.1.3). In addition, obesity is a known
cause of gallstone formation, and having gallstones increases the risk of gallbladder cancer, possibly through bile cholesterol supersaturation.
Because having gallstones is a cause of gallbladder cancer, the Panel also reviewed the dietary causes of gallstones,
especially in relation to body fatness. Having a relatively highBMI increases the risk of gallstones in a linear fashion; waist
circumference is associated with gallstone risk in men, independently of BMI. Gallstone formation is associated withrepeated dieting, especially where it involves rapid weight
loss, such as that from very low-energy diets and bariatricsurgery.

7.7.4 Interpretation of the evidence
7.7.4.1 General
For general considerations that may affect interpretation of
the evidence, see chapters 3.3 and 3.5, and boxes 3.1, 3.2,
3.6 and 3.7.
‘Relative risk’ is used in this Report to denote ratio measures of effect, including ‘risk ratios’, ‘rate ratios’, ‘hazard
ratios’, and ‘odds ratios’.
7.7.4.2 Specific
Considerations specific to cancer of the gallbladder include:
Confounding. Having gallstones increases the risk of gallbladder cancer. Exposures with an apparent link to gallbladder cancer may act indirectly, through gallstones, ordirectly, either after gallstone formation or in their absence.
It is not yet possible to separate these effects. See 7.7.7.

7.7.5 Evidence and judgements
In total, 48 publications were included in the SLR for gallbladder cancer. Fuller summaries of the epidemiological,
experimental, and mechanistic evidence are to be found in
Chapters 4–6.
The full SLR is contained on the CD included with thisReport.
7.7.5.1 Body fatness(Also see chapter 6.1.3.1.)
Five cohort studies, seven case-control studies, and twocross-sectional studies investigated body fatness, as measured by BMI. Most studies showed increased risk withincreased body fatness. Meta-analysis of cohort data showeda 23 per cent increased risk per 5 kg/m2; meta-analysis of276

There is a substantial amount of generally consistentepidemiological evidence with some evidence of adose-response relationship. There is evidence forseveral plausible mechanisms. Greater body fatness is
a probable cause of gallbladder cancer, directly andalso indirectly through the formation of gallstones.

7.7.5.2 Other exposures
Other exposures were evaluated. However, the data were
either of too low quality, too inconsistent, or the number ofstudies too few to allow conclusions to be reached. These
included capsicums, fish, coffee, tea, alcohol, and vitamin C.

7.7.6 Comparison with previous report
7.7.6.1 GeneralSee 7.1.6.1, and box 3.8 of chapter 3.
7.7.6.2 SpecificSince publication of the previous report, the evidence thatbody fatness is an indirect and a direct cause of gallbladdercancer has strengthened.

7.7.7 Conclusions
The Panel concludes:
Greater body fatness is probably a cause of cancer of the gallbladder. People with gallstones are more likely to develop
gallbladder cancer.

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7.8 LiverCancer of the liver is the sixth most common type ofcancer worldwide. Around 625 000 cases were recorded in
2002, accounting for around 6 per cent of all cancers.
About half of all cases occur in China, and it is morecommon in middle- and low-income countries. It is almost
always fatal, and is the third most common cause of deathfrom cancer, accounting for around 9 per cent of alldeaths.
Overall, the Panel notes that toxic compounds are themain causes of primary liver cancer related to foods anddrinks.
The Panel judges as follows:
The evidence that aflatoxins, which contaminate mostly
cereals (grains) and pulses (legumes) stored in hot, wetconditions, are a cause of liver cancer is convincing.
Alcoholic drinks are probably a direct cause of this cancer.
There is limited evidence suggesting that fruits areprotective, and that body fatness is a cause of this cancer.
Other causes of this cancer include infection with
hepatitis viruses B or C, the development of cirrhosis fromany cause, and infestation with liver flukes.
In final summary, the strongest evidence, corresponding
to judgements of “convincing” and “probable”, shows thataflatoxins, and probably alcoholic drinks, are causes ofliver cancer.

The liver is the body’s largest organ. It processes and stores
nutrients, and produces cholesterol and proteins such as
albumin, clotting factors, and the lipoproteins that carry cholesterol. It also secretes bile and performs many metabolic
functions, including detoxification of several classes of carcinogen.
Different types of tumour occur in the liver. Each has
potentially different causes and natural history. Around75–90 per cent of liver cancers are hepatocellular carcinoma. This starts in hepatocytes, which are the commonest
type of liver cell, and has various subtypes. Cholangiocarcinomas account for 10–20 per cent of primary liver cancers. These cancers start in the small bile ducts (tubes thatcarry bile to the gallbladder) within the liver. Hepatoblastoma and angiosarcoma are less common types of livercancer. Hepatocellular carcinoma is the main type included
here. Secondary tumours of the liver are not included.

FOOD, NUTRITION, PHYSICAL ACTIVITY,
AND CANCER OF THE LIVERIn the judgement of the Panel, the factors listed below modify the risk ofcancer of the liver. Judgements are graded according to the strength ofthe evidence.

DECREASES RISKINCREASES RISK

Convincing

Aflatoxins1

Probable

Alcoholic drinks2

Limited —suggestive

Fruits3

Limited —no conclusion

Cereals (grains) and their products1; non-starchy
vegetables; peanuts (groundnuts)1; fish; salted fish;
water source; coffee; tea

Substantial
effect on risk
unlikely

12

3

Body fatness

None identified

Foods that may be contaminated with aflatoxins include cereals (grains),
and also pulses (legumes), seeds, nuts, and some vegetables and fruits(see chapter 4.2).
Cirrhosis is an essential precursor of liver cancer caused by alcohol. The
International Agency for Research on Cancer has graded alcohol as a Class 1
carcinogen for liver cancer. Alcohol alone only causes cirrhosis in thepresence of other susceptibility factors.
Judgements on vegetables and fruits do not include those preserved bysalting and/or pickling.

For an explanation of all the terms used in the matrix,
please see chapter 3.5.1, the text of this section,and the glossary.

7.8.1 Trends, incidence, and survival
Age-adjusted rates of liver cancer are either increasing or stable in most countries for which data are available.6 122 However,a recent report on trends in the USA between 1975 and 2001
suggested that these increases may now be reversing.3
This is predominantly a disease of middle- to low-income
countries, where overall rates are more than double thosein high-income countries. Around the world, age-adjusted
incidence rates range from more than 40 per 100 000 people in eastern Asia and parts of Africa to less than 5 per
100 000 in the Americas and northern Europe.2 In the USA,rates are higher among African-American and HispanicAmerican people, and Asian and Pacific Islanders, than inwhite people.3 Globally, rates are higher in men than womenby five to two.
Risk tends to increase with age, although the diseasedevelops at a younger age (typically around the age of 40,
or below) in people living in Asia and Africa compared withthose in high-income countries.123

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Box 7.8.1

Hepatitis viruses

Hepatitis B and hepatitis C viruses are causes of liver cancer. The
former appears to act directly by damaging cells and their DNA.
The latter shows an indirect effect, mediated by cirrhosis. For
both, there is potential for nutrition status to have an effect atseveral stages: susceptibility to and duration of infection, liver
damage, DNA damage, and cancer progression.129
Around 7–8 per cent of the world’s population is estimated to
be infected with hepatitis B virus. It is mostly spread by bloodand sexual transmission. In endemic areas, the carrier rate may
be 10–20 per cent.130 It is often acquired at birth or in childhood,and is endemic in areas of Africa and Asia. Chronic hepatitis B
virus carriers have a 100-fold greater chance of developing livercancer than non-carriers. Those infected in adulthood have alower risk of this cancer than those infected in childhood because
there is less time for the virus to cause inflammation.130
Vaccination against hepatitis B virus has been shown to reduce
the prevalence of liver cancer by 60 per cent.131
Liver cancer in hepatitis B virus carriers is not necessarily connected with cirrhosis: up to 40 per cent of associated liver cancer cases are non-cirrhotic. Hepatitis B virus carries its genetic
code as DNA rather than RNA. Viral DNA can insert itself into liver
cells and alter their DNA.
Around 3 per cent of the world’s population is estimated to
be infected with hepatitis C virus. It is more prevalent in highincome countries. Approximately 80 per cent of these infections
become chronic, of which 15–20 per cent develops into cirrhosis. Of those, 1–4 per cent develops into liver cancer each year.
Interruption of the sequence of chronic hepatitis developing into
cirrhosis prevents liver cancer. Also, there is an interaction
between hepatitis C virus infection, liver cancer risk, and consumption of alcoholic drinks.132 There is no vaccine against
hepatitis C. It is mostly spread by blood.

The early stages of liver cancer do not usually produce
symptoms, so the disease is generally advanced when it isdiagnosed. Survival rates are poor: at 5 years, approximately
5 per cent.124 This cancer accounts for almost 6 per cent of
all cancer incidence, but around 9 per cent of all cancer
deaths.2 Also see box 7.1.1.

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7.8.3 Other established causes(Also see chapter 2.4 and 7.1.3.1.)
Other diseases. Cirrhosis of the liver increases the risk of, andso can be seen as a cause of, liver cancer.
Infection and infestation. Chronic viral hepatitis is a causeof liver cancer (see box 7.8.1).130 Infestation with liver flukes
is a cause of cholangiocarcinoma.
Medication. Oral contraceptives containing high doses of oestro-

gen and progesterone may be a cause of this cancer.90 133

7.8.4 Interpretation of the evidence
7.8.4.1 General
For general considerations that may affect interpretation of
the evidence, see chapters 3.3 and 3.5, and boxes 3.1, 3.2,
3.6 and 3.7.
‘Relative risk’ is used in this Report to denote ratio measures of effect, including ‘risk ratios’, ‘rate ratios’, ‘hazard
ratios’, and ‘odds ratios’.
7.8.4.2 Specific
Considerations specific to cancer of the liver include:
Classification. Most of the data is on hepatocellular carcinoma, the most well characterised (and most common) formof liver cancer. However, different outcomes are reported forunspecified primary liver cancer, compared with hepatocellular carcinoma or cholangiocarcinoma. This suggests
different causation and so may therefore be a cause ofheterogeneity.
Confounding. Hepatitis B and C viruses are possible confounders or effect modifiers; high-quality studies adjust forthem. Not all studies do so.
Measurement. Owing to low survival rates, both incidence

7.8.2 Pathogenesis
Liver cancer generally follows cirrhosis, so any cause of cirrhosis — either viral (see box 7.8.1) or chemical — is likely to increase cancer risk. Approximately 80 per cent of
hepatocellular carcinoma cases develop in cirrhotic livers.123
As for cancers at most sites, accumulated sequentialchanges (see chapter 2.5), specifically in mature hepatocytes,
lead to the development of dysplastic nodules; over thecourse of around 5 years, 30 per cent may develop into
tumours.125 Hepatocellular carcinoma cells show numerous
genetic changes, perhaps accumulated during cellular proliferation, which is part of the normal liver repair process.126
The hepatitis B virus-related type (see box 7.8.1) appears to
be more genetically unstable than others.127 128
The liver is a common site for metastasis of tumours originating in other organs.

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and mortality can be assessed. Low survival times and rates
decrease the reliability of case-control studies, which often
rely on proxy reporting.

7.8.5 Evidence and judgements
In total, 273 publications were included in the SLR for livercancer. Fuller summaries of the epidemiological, experimental, and mechanistic evidence are to be found in
Chapters 4–6.
The full SLR is contained on the CD included with thisReport.
7.8.5.1 Fruits(Also see chapter 4.2.5.2.)
One cohort study and five case-control studies investigatedfruits. The cohort study and most of the case-control stud-C H A P T E R

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ies showed decreased risk with increased fruit intake. No
studies showed statistically significant increased risk.
Fruits are sources of vitamin C and other antioxidants,
such as carotenoids, phenols, and flavonoids, as well as otherpotentially bioactive phytochemicals. Antioxidants trap free
radicals and reactive oxygen molecules, protecting against
oxidation damage.
In addition, flavonoids found in fruit directly inhibit theexpression of a cytochrome P450 enzyme, which helps tometabolise toxins and has been associated with increased
risk of lung cancer, primarily in smokers.68 It is difficult tounravel the relative importance of each constituent andis likely that a protective effect may result from a combination of influences on several pathways involved in
carcinogenesis.
The evidence is sparse and inconsistent. There islimited evidence suggesting that fruits protect against
liver cancer.

The Panel is aware that since the conclusion of the SLR, one
case-control study134 has been published. This new information
does not change the Panel judgement. Also see box 3.8.
7.8.5.2 Aflatoxins(Also see chapter 4.1.5.4.)
Five cohort studies and seven case-control studies investigated biomarkers of exposure to aflatoxins. All of the cohort
studies and most of the case-control studies showed
increased risk with elevated measures of exposure. Most
cohort studies showed significant dose-response relationships, although the variety of measures used prevented metaanalysis. Effect estimates ranged from a three- to sevenfold
increased risk for the highest measures of exposure.
There is strong mechanistic evidence through the metabolic product of aflatoxin B1, which is known to be genotoxic and is formed in the liver. It directly damages DNA,
forming adducts. The activity of GST enzymes can result in
lower levels of adducts with varying efficiency between
genotypes. There is clear and consistent evidence that GSTpositive genotypes protect against the increased risk of livercancer from hepatitis infection combined with aflatoxin
exposure. This supports a causal role for aflatoxin B1 inhepatocellular carcinoma.
The evidence is ample and consistent and is supported
by strong evidence for mechanisms operating inhumans. A dose-response relationship is apparent fromboth cohort and case-control studies. The evidence thataflatoxins and aflatoxin-contaminated foods are acause of liver cancer is convincing.

7.8.5.3 Alcoholic drinks(Also see chapter 4.8.5.1.)
A total of 15 cohort studies and 33 case-control studies investigated alcoholic drinks, and 14 cohort studies and 21 casecontrol studies investigated total ethanol intake. Most studies
showed increased risk with increased alcohol intake, withnone reporting statistically significant decreased risk. Meta-

analysis of cohort data showed a 10 per cent increased risk
per 10 g ethanol/day. Meta-analysis of case-control data
showed an 18 per cent increased risk per drink/week, or a
17 per cent increased risk per 10 g ethanol/day (figures
4.8.18–4.8.19).
Heterogeneity in case-control studies may be explained byalcoholic behaviour, by proxy reporting, or by failure toadjust for hepatitis virus status. Several studies used participants judged to be at high risk of developing liver cancer(people who already had liver cirrhosis). These results are
particularly difficult to interpret as cirrhosis status affects
drinking behaviour. Also, the cancer disease path may be different in people with cirrhosis.
It is biologically highly plausible that alcoholic drinks area cause of liver cancer. Reactive metabolites of alcohol suchas acetaldehyde can be carcinogenic. DNA mutations may beless efficiently repaired in the presence of alcohol. Alcohol
may also function as a solvent, enhancing penetration ofother carcinogenic molecules into cells. Additionally, theeffects of alcohol may be mediated through the productionof prostaglandins, lipid peroxidation, and the generation offree radical oxygen species. Lastly, heavy consumers of alcohol may have diets low in essential nutrients, making tissues
susceptible to carcinogenesis. In addition, regular, high levels of alcohol consumption are known to cause liver damage. Tumour promotion has been linked to inflammation in
the liver through alcohol-associated fibrosis and hepatitis.
Alcohol consumption, even at moderate levels, is associated with increases in levels of circulating hepatitis C virus
RNA in carriers of this infection. This infection is highly
prevalent among alcoholics with chronic liver disease, andappears to accelerate the course of alcoholic liver disease.
There is ample, generally consistent evidence fromboth cohort and case-control studies. A dose-response
relationship is apparent. Alcohol is a cause of cirrhosis,
which predisposes to liver cancer, but the factors that
determine why some people are susceptible tocirrhosis are not known. Alcoholic drinks are aprobable cause of liver cancer. No threshold was
identified.

The Panel is aware that since the conclusion of the SLR, one
case-control study135 has been published. This new information
does not change the Panel judgement. Also see box 3.8.
7.8.5.4 Body fatness(Also see chapter 6.1.3.1).
Six cohort studies and two case-control studies investigatedbody fatness, as measured by BMI, or obesity. All cohort studies showed increased risk with increased body fatness, except
in one subgroup of African-American men. There was substantial heterogeneity and none of the studies adjusted forhepatitis virus status. The two case-control studies provided no clear evidence of any effect.
Body fatness directly affects levels of many circulating hormones, such as insulin, insulin-like growth factors, andoestrogens, creating an environment that encourages carcinogenesis and discourages apoptosis (see box 2.4). It stim-

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ulates the body’s inflammatory response, which may contribute to the initiation and progression of several cancers(see chapter 2.4.1.3).
The epidemiological evidence shows someinconsistencies and the mechanistic evidence is
speculative. There is limited evidence suggesting that
greater body fatness is a cause of liver cancer.

The Panel is aware that since the conclusion of the SLR, twocohort studies58 136 have been published. This new information
does not change the Panel judgement. Also see box 3.8.
7.8.5.5 Other exposures
Other exposures were evaluated. However, the data were
either of too low quality, too inconsistent, or the number ofstudies too few to allow conclusions to be reached. These
were as follows: cereals (grains) and their products; nonstarchy vegetables; peanuts; fish; salted fish; water source;
coffee; and tea.
In cases of cereals (grains) and peanuts, there are data connecting these foods to liver cancer, but the Panel judges thatany causative factor is likely to be aflatoxins.

7.8.6 Comparison with previous report
7.8.6.1 GeneralSee 7.1.6.1, and box 3.8 in chapter 3.
7.8.6.2 SpecificSince publication of the previous report, the evidence thataflatoxin contamination of food is a cause of liver cancer isstronger and now justifies a judgement of ‘convincing’.

7.8.7 Conclusions
The Panel concludes:
The evidence is convincing that aflatoxins, which contaminate mostly cereals (grains) and pulses (legumes), usually
as a result of long storage in hot, wet conditions, are a causeof liver cancer.
Alcoholic drinks are probably a cause of liver cancer.
There is limited evidence suggesting that fruits are protective, and that body fatness is a cause of this cancer.

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7.9 Colon andrectumCancers of the colon and rectum are the third mostcommon type worldwide. Around 1 million cases wererecorded in 2002, accounting for around 9 per centoverall. Rates of this cancer increase with industrialisation
and urbanisation. It has been much more common in highincome countries but is now increasing in middle- andlow-income countries. It remains relatively uncommon in
Africa and much of Asia. It is somewhat more common inmen than in women. It is fatal in just under half of allcases and is the fourth most common cause of death fromcancer.
Overall, the Panel judges that food and nutrition have ahighly important role in the prevention and causation ofcancers of the colon and rectum (here termedcolorectum).
The Panel judges as follows:
The evidence that physical activity protects against
colorectal cancer is convincing, although the evidence isstronger for colon than for rectum. The evidence that red
meat, processed meat, substantial consumption of alcoholic
drinks (in men), body fatness and abdominal fatness, andthe factors that lead to greater adult attained height, or its
consequences, are causes of colorectal cancer isconvincing. Substantial consumption of alcoholic drinks isprobably a cause of this cancer in women. Foods containing
dietary fibre, and garlic, milk, and calcium probably protect
against this cancer.
There is limited evidence suggesting that non-starchy
vegetables, fruits, foods containing folate, fish, foods
containing vitamin D, and selenium and foods containing it
protect against colorectal cancer, and that foods containing
iron, cheese, foods containing animal fats, and foods
containing sugars are causes of this cancer.
See chapter 8 for evidence and judgements on factorsthat modify the risk of body fatness and abdominal fatness,
including physical activity and sedentary ways of life, theenergy density of foods and drinks, and breastfeeding.
It has been estimated that this cancer is mostly
preventable by appropriate diets and associated factors.
In final summary, the strongest evidence, corresponding
to judgements of “convincing” and “probable”,shows thatphysical activity protects against colorectal cancer. The
evidence also shows that red meat and processed meat,
substantial consumption of alcoholic drinks (by men andprobably by women), body fatness and abdominal fatness,and the factors that lead to greater adult attained height,
or its consequences, are causes of this cancer. Foods
containing dietary fibre, and also garlic, milk, and calcium,probably protect against this cancer.

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FOOD, NUTRITION, PHYSICAL ACTIVITY, AND CANCERS OF THE COLON AND THE RECTUM
In the judgement of the Panel, the factors listed below modify the risk of cancers of the colon and the rectum. Judgements are graded according to thestrength of the evidence.

DECREASES RISK
Convincing

12

Physical activity

INCREASES RISKRed meat3 4Processed meat4 5
Alcoholic drinks (men)6
Body fatness
Abdominal fatness
Adult attained height7

Probable

Foods containing dietary fibre8

Alcoholic drinks (women)6

Garlic9
Milk10 11
Calcium12
Limited —suggestiveNon-starchy vegetables9

Foods containing iron4 8

Fruits9

Cheese10

Foods containing folate8

Foods containing animal fats8

Foods containing selenium8

Foods containing sugars15

Fish
Foods containing vitamin D8 13
Selenium14
Limited —no conclusion

Cereals (grains) and their products; potatoes; poultry; shellfish and other seafood; other dairy products; total fat; fatty acidcomposition; cholesterol; sugar (sucrose); coffee; tea; caffeine; total carbohydrate; starch; vitamin A; retinol; vitamin C; vitamin E;
multivitamins; non-dairy sources of calcium; methionine; beta-carotene; alpha-carotene; lycopene; meal frequency; energy intake

Substantial
effect on risk
unlikely

1
2
3
4
5
6
7
8
9
10
11
12
13
14
15

None identified

Physical activity of all types: occupational, household, transport, and recreational.
Much of the evidence reviewed grouped colon cancer and rectal cancer together as ‘colorectal’ cancer. The Panel judges that the evidence is stronger for colon
than for rectum.
The term ‘red meat’ refers to beef, pork, lamb, and goat from domesticated animals.
Although red and processed meats contain iron, the general category of ‘foods containing iron’ comprises many other foods, including those of plant origin.
The term ‘processed meat’ refers to meats preserved by smoking, curing, or salting, or addition of chemical preservatives.
The judgements for men and women are different because there are fewer data for women. Increased risk is only apparent above a threshold of 30 g/day of
ethanol for both sexes.
Adult attained height is unlikely directly to modify the risk of cancer. It is a marker for genetic, environmental, hormonal, and also nutritional factors affecting
growth during the period from preconception to completion of linear growth (see chapter 6.2.1.3).
Includes both foods naturally containing the constituent and foods which have the constituent added (see chapter 3.5.3). Dietary fibre is contained in plant foods(see box 4.1.2 and chapter 4.2).
Judgements on vegetables and fruits do not include those preserved by salting and/or pickling.
Although both milk and cheese are included in the general category of dairy products, their different nutritional composition and consumption patterns may
result in different findings.
Milk from cows. Most data are from high-income populations, where calcium can be taken to be a marker for milk/dairy consumption. The Panel judges that ahigher intake of dietary calcium is one way in which milk could have a protective effect.
The evidence is derived from studies using supplements at a dose of 1200 mg/day.
Found mostly in fortified foods and animal foods.
The evidence is derived from studies using supplements at a dose of 200 µg/day. Selenium is toxic at high doses.
‘Sugars’ here means all ‘non-milk extrinsic’ sugars, including refined and other added sugars, honey, and as contained in fruit juices and syrups. It does not include
sugars naturally present in whole foods such as fruits. It also does not include lactose as contained in animal or human milks.

For an explanation of all the terms used in the matrix, please see chapter 3.5.1, the text of this section, and the glossary.

The colon is the lower part of the intestinal tract. It extends
from the caecum to the rectum. In the colon, water and salts
are absorbed from undigested foods, and muscles move thewaste products towards the rectum. The colon contains a vast
population of many types of bacteria, which have potentially important functions. These include the fermentation ofunabsorbed carbohydrate (non-starch polysaccharides andresistant starch) to release energy and short chain fatty acids
that influence the health of the colonic mucosa. It may also
be infected with harmful types of bacteria. The colon is linedwith mucous membranes, and also contains lymphoid cells
that form part of the body’s immune defences.
Approximately 95 per cent of colorectal cancers are adenocarcinomas. Other types of cancer that can occur here281

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include mucinous carcinomas and adenosquamous carcinomas.4 Adenocarcinomas are covered here. A systematic
review of colorectal adenomas was conducted to understandthe contribution of food, nutrition, and physical activity tothe pathogenesis of colorectal cancer, and contributed tointerpretation of the underlying mechanisms.

7.9.1 Trends, incidence, and survival
There is no clear trend in global age-adjusted rates of colorectal cancer. There has, however, been a rapid increase inrates in high-income countries that have recently made thetransition from a relatively low-income economy, such as
Japan, Singapore, and eastern European countries. Rates
have at least doubled in many of these countries since themid-1970s.137 Colorectal cancer is mainly a disease of highincome countries, where overall rates are nearly four times
higher than in middle- to low-income countries. Around theworld, age-adjusted incidence rates range from more than
40 per 100 000 people in North America, parts of Europe,
Australia, New Zealand, and Japan to less than 5 per
100 000 in much of Africa, Central America, and parts ofAsia.2 In the USA, rates are higher among African-American
people than in white people.3 This disease is slightly morecommon in men than in women, by seven to five. Risk
increases with age until old age, when it levels off.6
Colorectal cancer often produces symptoms at an earlyenough stage to make it treatable, meaning that survival
rates are relatively high. In addition, regular screening iscommon in some countries such as the USA. The 5-year overall survival rate averages 50 per cent, with 55 per cent inhigh-income countries and 39 per cent in middle- to lowincome countries.124 This cancer accounts for somewhat over
9 per cent of all cancer incidence, but around 8 per cent of
all cancer deaths. Also see box 7.1.1.

7.9.2 Pathogenesis
Carcinogens ingested as part of, or with, foods and drinks
can interact directly with the cells that line the colon and rectum if they are not metabolised or absorbed in the small
intestine. Colorectal cancer can also develop from a background of inflammatory bowel disease (ulcerative colitis or
Crohn’s disease).138
Between 5 and 10 per cent of colorectal cancers are a consequence of recognised hereditary conditions. The two major
ones are familial adenomatous polyposis (FAP) and
HNPCC139 (also see 7.5.2). A further 20 per cent of cases
occur in people who have a family history of colorectal cancer.139 People with FAP develop a large number of adenomas
at a relatively young age; if left untreated, nearly all willdevelop colorectal cancer by the time they reach 40.140
On average, people develop HNPCC in their mid-40s140;
having this form of the disease increases the risk of a numberof other gastrointestinal cancers. HNPCC involves mutations
in DNA repair genes, a recognised step in the developmentof many colorectal cancers.

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There are two characterised pathways to colorectal cancer,
although they are likely to be linked — the ‘gatekeeper’ andthe ‘caretaker’ pathways.141 The gatekeeper pathway is
involved in 85 per cent of sporadic colorectal cancers, andis the one associated with FAP.140 It involves the disruptionof genes that regulate growth, and for colorectal cancer, thekey one is the tumour-suppressor gene APC. The caretaker
pathway is characterised by disruption to genes that maintain genetic stability. It leads to 15 per cent of sporadic cancers, and is involved in the development of HNPCC.140
Several tumour-suppressor genes are mutated in this pathway142 (also see box 2.2 in chapter 2).

7.9.3 Other established causes(Also see chapter 2.4 and 7.1.3.1.)
Other diseases. Inflammatory bowel disease (Crohn’s disease
and ulcerative colitis) increase the risk of, and so may beseen as a cause of, colon cancer.
Medication. Non-steroidal anti-inflammatory drugs such as
aspirin and hormone replacement therapy in postmenopausal women have been shown to decrease colon cancer
risk.143 144

7.9.4 Interpretation of the evidence
7.9.4.1 General
For general considerations that may affect interpretation of
the evidence, see chapters 3.3 and 3.5, and boxes 3.1, 3.2,
3.6 and 3.7.
‘Relative risk’ is used in this Report to denote ratio measures of effect, including ‘risk ratios’, ‘rate ratios’, ‘hazard
ratios’, and ‘odds ratios’.
7.9.4.2 Specific
Considerations specific to colorectal cancer include:
Classification. Cancers in different parts of the colon and in
the rectum could have different pathogeneses and different
causal agents.

7.9.5 Evidence and judgements
In total, 752 publications were included in the SLR for cancers of the colon and rectum. Fuller summaries of the epidemiological, experimental, and mechanistic evidence are to
be found in Chapters 4–6.
The full SLR is contained on the CD included with thisReport.
7.9.5.1 Foods containing dietary fibre(Also see chapter 4.1.5.3.)
Sixteen cohort studies and 91 case-control studies investigated dietary fibre. Most studies showed decreased risk with

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increased intake. Meta-analysis of cohort data showed a 10
per cent decreased risk per 10 g/day (see figure 4.1.1).
Heterogeneity may be caused by variation in the definitionof dietary fibre between studies. A pooled analysis of 8100
colorectal cancer cases among 730 000 participants, followed up for 6–20 yeas, showed a non-significant decreased
risk for the groups that consumed the most dietary fibre.
Data come predominantly from dietary sources, not supplements; therefore no effect can be attributed specifically tofibre, which is interpreted simply as a marker of consumption of foods containing it, although specific mechanisms
have been identified.
Fibre exerts several effects in the gastrointestinal tract, but
the precise mechanisms for its probable protective role arestill not clearly understood. Fibre dilutes faecal content,
decreases transit time, and increases stool weight.
Fermentation products, especially short-chain fatty acids, areproduced by the gut flora from a wide range of dietary carbohydrates and mucins that reach the colon. Short-chain
fatty acids, such as butyrate, induce apoptosis, cell cycle
arrest, and differentiation in experimental studies. Fibre
intake is also strongly correlated with intake of folate, thoughadjusting for this often does not affect the risk reduction
attributed to fibre.
A clear dose-response relationship is apparent fromgenerally consistent cohort studies, supported byevidence for plausible mechanisms, but residual
confounding could not be excluded. Foods containing
dietary fibre probably protect against colorectal cancer.

The Panel is aware that since the conclusion of the SLR, sevencohort studies145-151 and one case-control study152 have been
published. This new information does not change the Panel
judgement. Also see box 3.8.

7.9.5.2 Non-starchy vegetables(Also see chapter 4.2.5.1.)
Seventeen cohort studies and 71 case-control studies investigated non-starchy vegetables. Although meta-analysis ofcohort data produced no evidence of an association, a comparison of the groups with the highest intakes against thosewith the lowest was suggestive of an association.
This is a wide and disparate category, and many different
plant food constituents are represented that could contributeto a protective effect of non-starchy vegetables. These include
dietary fibre, carotenoids, folate, selenium, glucosinolates,
dithiolthiones, indoles, coumarins, ascorbate, chlorophyll,
flavonoids, allylsulphides, flavonoids, and phytoestrogens,some of which are potentially antioxidants. Antioxidants trap
free radicals and reactive oxygen molecules, protecting
against oxidation damage. It is difficult to unravel the relative importance of each constituent and it is likely that any
protective effect may result from a combination of influences
on several pathways involved in carcinogenesis.
A substantial amount of evidence is available but it isinconsistent. There is limited evidence suggesting that

non-starchy vegetables protect against colorectal cancer.

The Panel is aware that since the conclusion of the SLR, threecase-control studies17 152 154 have been published. This new
information does not change the Panel judgement. Also see box
3.8.
7.9.5.3 Garlic(Also see chapter 4.2.5.1.2.)
Two cohort studies and six case-control studies investigatedgarlic. All studies reported decreased risk with increased
intake, with none reporting contrary results. Most studies did
not reach statistical significance, and meta-analysis was notpossible.
There is considerable preclinical evidence with model carcinogens and transplantable tumours that supports an anticancer effect of garlic and some of its allyl sulphur
components. Animal studies demonstrate that allyl sulphides
effectively inhibit colon tumour formation, and also caninhibit cell growth in laboratory experiments.
The evidence, though not copious and mostly fromcase-control studies, is consistent, with a doseresponse relationship. There is evidence for plausible
mechanisms. Garlic probably protects against
colorectal cancer.

The Panel is aware that since the conclusion of the SLR, one
case-control study17 has been published. This new information
does not change the Panel judgement. Also see box 3.8.
7.9.5.4 Fruits(Also see chapter 4.2.5.2.)
Twenty cohort studies and 57 case-control studies investigated fruits. More than half of the cohort studies showeddecreased risk with increased intake. Meta-analysis of cohort
data produced no clear evidence of an overall association.
However, stratification by sex did show a statistically significant decreased risk with increased intake among women,
but not men.
This difference could be hormone-related, speculating
a connection with the protective effects observed in
postmenopausal women provided by hormone replacement
therapy. Another possibility is that this could be artefactual:
men may have not reported their diets as accurately as
women.
Because of the abundant prospective data from cohort
studies, case-control studies were not summarised.
Fruits are sources of vitamin C and other antioxidants,
such as carotenoids, phenols, and flavonoids, as well as otherpotentially bioactive phytochemicals. Antioxidants trap free
radicals and reactive oxygen molecules, protecting against
oxidation damage. In addition, flavonoids found in fruit
directly inhibit the expression of a cytochrome P450
enzyme, which helps to metabolise toxins and has been associated with increased risk of lung cancer, primarily in smokers.68 It is difficult to unravel the relative importance of eachconstituent and it is likely that a protective effect may result
from a combination of influences on several pathways
involved in carcinogenesis.

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There is a substantial amount of evidence but it isinconsistent. There is limited evidence suggesting thatfruits protect against colorectal cancer.

The Panel is aware that since the conclusion of the SLR, onecohort147 153 155 and five case control studies152 154 156-158 havebeen published. This new information does not change thePanel judgement. Also see box 3.8.
7.9.5.5 Foods containing folate(Also see chapter 4.2.5.4.)
Nine cohort studies investigated dietary folate and twocohort studies investigated serum folate. Most studies
showed decreased risk with increased intake. Meta-analysis
of cohort data produced evidence of decreased risk with aclear dose-response relationship. Both studies that investigated serum folate levels, which may be a more accurate andprecise measure than dietary estimates, showed decreased
risk for colon cancer, but not rectal cancer; this was statistically significant in one study. Data come predominantly fromdietary sources, not supplements; therefore no effect can be
attributed specifically to folate, which is interpreted simply
as a marker of consumption of foods containing it.
Folate plays an important role in the synthesis, repair, andmethylation of DNA. Abnormal DNA methylation has been
linked to aberrant gene expression and also to cancers at several sites. Folate may also reduce HPV proliferation in cells(also see box 7.13.1). In addition, folate intake is also strongly correlated with intake of dietary fibre, which probably protects against colorectal cancer (see 7.9.5.1).
The evidence from cohort studies is plentiful, with adose-response relationship, but there is unexplainedinconsistency. Residual confounding from dietary fibreis possible. There is limited evidence suggesting thatfoods containing folate protect against colorectal
cancer.

The Panel is aware that since the conclusion of the SLR, fourcohort159-163 and two case control studies152 164 have been published. This new information does not change the Panel judgement. Also see box 3.8.
7.9.5.6 Foods containing selenium(Also see chapter 4.2.5.8.)
Fifteen case-control studies investigated dietary selenium, allof which showed decreased risk with increased intake. Metaanalysis of case-control data produced evidence of decreased
risk with increased serum selenium levels, showing a clear
dose-response relationship.
Dietary selenium deficiency has been shown to cause alack of selenoprotein expression. Twenty-five selenoproteins
have been identified in animals, and a number of these haveimportant anti-inflammatory and antioxidant properties.
Four are glutathione peroxidases, which protect against
oxidative damage to biomolecules such as lipids, lipoproteins, and DNA. Three are thioredoxin reductases, which
regenerate oxidised ascorbic acid to its active antioxidant
form, among other functions.

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A substantial amount of data was available, from casecontrol studies only. There is limited evidence
suggesting that foods containing selenium protect
against colorectal cancer.

7.9.5.7 Red meat
(Also see chapter 4.3.5.1.1.)
Sixteen cohort and 71 case-control studies investigated redmeat. Nearly all cohort studies showed increased risk withhigher intake. Meta-analysis of cohort data showed a 43 percent increased risk per time consumed/week (figure 4.3.2) ora 15 per cent increased risk per 50 g/day (figure 4.3.3).
Heterogeneity could not be fully explained but some studies
could have included processed meats in the ‘red meat’ category.
There are several potential underlying mechanisms for apositive association of red meat consumption with colorectal
cancer, including the generation of potentially carcinogenic
N-nitroso compounds (see box 4.3.2). Some meats are also
cooked at high temperatures, resulting in the production ofheterocyclic amines and polycyclic aromatic hydrocarbons(see box 4.3.4). Red meat contains haem iron. Free iron canlead to the production of free radicals (see box 4.3.3).
A substantial amount of data from cohort and casecontrol studies showed a dose-response relationship,
supported by evidence for plausible mechanisms
operating in humans. Red meat is a convincing causeof colorectal cancer.

The Panel is aware that since the conclusion of the SLR, sixcohort165-173 and four case-control studies154 156 157 174 have been
published. This new information does not change the Panel
judgement. Also see box 3.8.
7.9.5.8 Processed meat
(Also see chapter 4.3.5.1.2.)
Fourteen cohort studies and 44 case-control studies investigated processed meat. Nearly all cohort studies showed
increased risk with higher intake. Meta-analysis of cohort
data showed a 21 per cent increased risk per 50 g/day (figure 4.3.6). Heterogeneity was low and explained by the disparity in category definitions between studies, as well as byimproved adjustment for confounders in recent studies.
Nitrates are both produced endogenously in gastric acidand added as preservatives to processed meats. They may
contribute to N-nitroso compound production and exposure.
These compounds are suspected mutagens and carcinogens(see box 4.3.2).55 Many processed meats also contain highlevels of salt and nitrite. Meats cooked at high temperatures
can contain heterocyclic amines and polycyclic aromatichydrocarbons (see box 4.3.4). Haem promotes the formationof N-nitroso compounds and also contains iron. Free iron canlead to production of free radicals (see box 4.3.3).
There is a substantial amount of evidence, with a doseresponse relationship apparent from cohort studies.
There is strong evidence for plausible mechanisms
operating in humans. Processed meat is a convincing
cause of colorectal cancer.

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The Panel is aware that since the conclusion of the SLR, fivecohort153 165-169 171 173 175 and two case-control studies154 157 havebeen published. This new information does not change thePanel judgement. Also see box 3.8.
7.9.5.9 Fish
(Also see chapter 4.3.5.3.)
Nineteen cohort studies and 55 case-control studies investigated fish. Most cohort studies showed decreased risk withhigher intake. Meta-analysis showed a non-significant
decreased risk. Heterogeneity may be partially explained byvarying definitions of fish in different studies to include fresh
and/or salted and dried fish. Also, high fish intake may be
associated with low meat intake, which is a potential confounder that has not been adjusted for.
Because of the abundant prospective data from cohort
studies, case-control studies were not summarised.
It is biologically plausible that long-chain fish n-3 polyunsaturated fatty acids (PUFAs) protect against cancer (seechapter 2.4.1.3). Fish oils reduce tumours in animal studies.176 Likely mechanisms are thought to include their role
in reduction of n-6 PUFA-derived eicosanoid biosynthesis(eicosanoids influence inflammation) and direct inhibitionof cyclo-oxygenase-2, also implicated in the cancer processThis mechanism, though plausible, is not well supported.177
Alternative suggestions include the relatively high selenium
or vitamin D content of fish.
A substantial amount of data is available but theresults are inconsistent, and residual confounding bymeat could not be excluded. There is limited evidence
suggesting that eating fish protects against colorectal
cancer.

The Panel is aware that since the conclusion of the SLR, sixcohort147 165 167-169 171 178 and two case-control studies152 154 havebeen published. This new information does not change thePanel judgement. Also see box 3.8.
7.9.5.10 Foods containing vitamin D(Also see chapter 4.3.5.5.)
Eleven cohort studies and 17 case-control studies investigated total vitamin D and/or dietary vitamin D. Four cohort
studies investigated plasma or serum vitamin D. Most of thestudies of intake, and all of the studies of plasma or serum
vitamin D, showed decreased risk as measures of intake
increased.
The effects of vitamin D and calcium are strongly interrelated because both are growth restraining, both induce differentiation and apoptosis in intestinal cells, andcalcium-mediated effects are strongly dependent on vitaminD levels. Data from observational studies were limited by thefact that levels of the biologically active form are not only
dependent on diet but also on supplements, and ultraviolet(UV) exposure of the skin.
The evidence on vitamin D was inconsistent. There islimited evidence suggesting that foods containing vitamin
D or vitamin D status protect against colorectal cancer.

The Panel is aware that since the conclusion of the SLR, twocase-control studies152 179 have been published. This new information does not change the Panel judgement. Also see box 3.8.
7.9.5.11 Foods containing iron
(Also see chapter 4.3.5.6.)
Four cohort studies and 23 case-control studies investigatediron intake. All cohort studies showed increased risk withincreased intake, which was statistically significant in two.
It is biologically plausible that iron increases colorectal cancer risk due to its catalytic activity on the formation of reactive oxygen species. However, this role has not been
confirmed in animal studies. Another hypothesis relates todietary haem, which can induce colonic cytotoxicity andhyperproliferation.180 Iron overload also activates oxidative
responsive transcription factors, pro-inflammatory cytokines
and iron-induced hypoxia signalling.181 Also see box 4.3.3.
The evidence is sparse, of poor quality, andinconsistent. There is limited evidence suggesting thatfoods containing iron are in general a cause ofcolorectal cancer. (Also see chapter 4.3 for evidence
specifically on red and processed meat, which areclassified as convincing causes of colorectal cancer.)

The Panel is aware that since the conclusion of the SLR, twocohort studies175 182 have been published. This new information
does not change the Panel judgement. Also see box 3.8.
7.9.5.12 Milk
(Also see chapter 4.4.5.1.2.)
Thirteen cohort studies and 36 case-control studies investigated milk; 15 cohort studies and 58 case-control studies
investigated dietary calcium. Most cohort studies showeddecreased risk with increased intake. A pooled analysis of 10
cohort studies (nearly 5000 colorectal cancer cases among
more than 530 000 participants) showed a 15 per centdecreased risk for the groups that drank the most milk, anda 14 per cent decreased risk for the groups with the highest
dietary calcium intakes.183
Most of the evidence used here comes from Western countries, where dietary calcium intake can be taken as a marker for dairy consumption.
Any effect of milk in reducing colorectal cancer risk is likely
to be mediated at least in part by calcium, which has direct
growth-restraining and differentiation- and apoptosis-inducing
actions on normal and tumour colorectal cells.184 Milk includes
many bioactive constituents, which may also play a role.
The evidence on milk from cohort studies is reasonably
consistent, supported by stronger evidence from dietarycalcium, as a dietary marker. There is evidence forplausible mechanisms. Milk probably protects against
colorectal cancer.

The Panel is aware that since the conclusion of the SLR, threecohort185-188 and three case-control studies154 158 189 have been
published. This new information does not change the Panel
judgement. Also see box 3.8.

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7.9.5.13 Cheese(Also see chapter 4.4.5.1.2.)
Eleven cohort studies and 25 case-control studies investigated cheese. Most cohort studies showed increased risk withincreased intake. Meta-analysis showed a non-significant
increased risk.
The potential mechanisms for the association of cheesewith cancers of the colon and rectum are unclear. Saturated
fatty acids can induce expression of inflammatory mediatorsand stimulate increased insulin production.
The evidence is inconsistent. There is limited evidence
suggesting that cheese is a cause of colorectal cancer.

The Panel is aware that since the conclusion of the SLR, twocohort studies185-188 and one case-control study189 have been
published. This new information does not change the Panel
judgement. Also see box 3.8.
7.9.5.14 Foods containing animal fats
(Also see chapter 4.5.5.2.)
Five cohort studies investigated animal fats. Most studies
showed increased risk with increased intake but there ispotential for residual confounding. Meta-analysis of cohort
data showed a non-significant increased risk.
Diets high in fat lead to increased levels of bile acids inthe colon. Bile acids are metabolised by the bacterial flora
to deoxycholic acid, which can promote cancer in rodents.
The conversion of bile acids to secondary bile acids such as
deoxycholic acid is decreased by the lower pH induced byshort-chain fatty acids produced in diets high in non-starchpolysaccharides. Also, deoxycholic acid is less soluble at alower pH, which may limit its adverse effects.190
There is a limited amount of fairly consistent evidence
suggesting that consumption of foods containing
animal fats is a cause of colorectal cancer.

The Panel is aware that since the conclusion of the SLR, onecohort study167 has been published. This new information does
not change the Panel judgement. Also see box 3.8.
7.9.5.15 Foods containing sugars(Also see chapter 4.6.5.1.)
A total of one cohort study and seven case-control studies
investigated sugars as foods. Seven cohort studies and 16
case-control studies investigated sugars as nutrients, defined
as total sugar, sucrose, or fructose. Most studies showed
increased risk with increased total sugars, sucrose, or fructose intake. Data were particularly suggestive for fructose.
In most, though not all, animal experiments, sucrose andfructose are associated with increased colonic proliferation
and aberrant crypt foci, which are precursors of colon cancers (see chapter 2).
The evidence is sparse and inconsistent. There islimited evidence suggesting that foods containing
sugars are a cause of colorectal cancer.

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7.9.5.16 Alcoholic drinks(Also see chapter 4.8.5.1.)
Twenty-four cohort studies investigated alcoholic drinks; 13
cohort studies and 41 case-control studies investigatedethanol intake. Nearly all cohort studies showed increased
risk with increased intake, with none reporting statisticallysignificant contrary results. Meta-analysis of cohort data
showed a 9 per cent increased risk per 10 g ethanol/day (figure 4.8.10). A pooled analysis of more than 4600 colorectal
cancer cases among more than 475 000 participants, followed up for 6–16 years, showed a 41 per cent increased risk
for the groups that drank the most alcohol.191 There wassome suggestion of sexual dimorphism, with a possibly
greater effect in men than in women. This more elevated risk
may be because of the generally higher consumption of alcohol among men. Also, men and women may prefer different
types of alcoholic drinks, there may be hormone-related differences in alcohol metabolism, or susceptibility to alcohol
may exist. Data also suggested a ‘J ’-shaped dose-response
relationship, with low intake being associated with lower risk
compared with no intake.
Because of the abundant prospective data from cohort
studies, case-control studies were not summarised.
Reactive metabolites of alcohol such as acetaldehyde canbe carcinogenic. There is also an interaction with smoking.
Tobacco may induce specific mutations in DNA that are lessefficiently repaired in the presence of alcohol. Alcohol may
also function as a solvent, enhancing penetration of othercarcinogenic molecules into mucosal cells. Additionally, theeffects of alcohol may be mediated through the productionof prostaglandins, lipid peroxidation, and the generation offree radical oxygen species. Lastly, high consumers of alcohol may have diets low in essential nutrients, making tissues
susceptible to carcinogenesis.
There is ample and generally consistent evidence fromcohort studies. A dose-response relationship isapparent. There is evidence for plausible mechanisms.
The evidence that consumption of more than about
30 g per day of ethanol from alcoholic drinks is a causeof colorectal cancer in men is convincing; and it isprobably a cause in women.

The Panel is aware that since the conclusion of the SLR, fourcohort studies159 192-194 and four case-control studies154 195-197
have been published. This new information does not change thePanel judgement. Also see box 3.8.
7.9.5.17 Calcium(Also see chapter 4.10.6.4.4.)Seven cohort studies investigated calcium supplements. All
but one reported decreased risk with calcium supplementation. A pooled analysis of 10 cohort studies (nearly 5000 colorectal cancer cases among more than 530 000 participants,
followed up for 6–16 years) showed a 22 per cent decreased
risk for the groups with the highest calcium intakes (dietaryand supplemental sources).183 In addition, two randomised
controlled trials and four cohort studies investigated calcium supplements and the risk of adenomas. Both trials andC H A P T E R

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most of the cohort studies showed decreased risk with
supplementation.
Because of the abundant prospective data from cohort
studies, case-control studies were not summarised.
Calcium from diet is an important nutrient; intracellular
calcium is a pervasive second messenger acting on many cellular functions including cell growth. Calcium has direct
growth-restraining and differentiation- and apoptosis-inducing actions on normal and tumour colorectal cells.184
There is generally consistent evidence from several
cohort studies, and evidence from trials for colorectal
adenomas. There is evidence for plausible
mechanisms. Calcium probably protects against
colorectal cancer.

7.9.5.18 Selenium(Also see chapter 4.10.6.4.5.)
One randomised controlled trial and one cohort study investigated selenium supplements. The trial showed a statisticallysignificant decreased risk with a daily supplement of 200 gof selenium. This was a relatively small study (1321 participants; 8 cases in the supplement group and 19 in the control
group) and colorectal cancer was a secondary outcome. The
cohort study showed non-significant decreased risk.
Dietary selenium deficiency has been shown to cause alack of selenoprotein expression. Twenty-five selenoproteins
have been identified in animals and a number of these haveimportant anti-inflammatory and antioxidant properties.
Four are glutathione peroxidases, which protect against
oxidative damage to biomolecules such as lipids, lipoproteins, and DNA. Three are thioredoxin reductases and,among other functions, these regenerate oxidised ascorbic
acid to its active antioxidant form.
The evidence is sparse. There is limited evidence tosuggest that selenium protects against colorectal
cancer.

7.9.5.19 Physical activity(Also see chapter 5.4.1.)
Eleven cohort studies investigated total physical activity; 12cohort studies investigated occupational physical activity;and 24 cohort studies investigated recreational activity. Most
studies reported an association between increased physicalactivity and decreased cancer risk. Most studies were unsuitable for meta-analysis due to the disparate measures used
to assess physical activity. The data also suggested that theeffect was reduced or removed for rectal cancer. The evidence, overall, was broad and consistent. A published metaanalysis of 19 cohort studies reported a statisticallysignificant decreased risk for physical activity for colon cancer, but not for rectal cancer.
Sustained moderate physical activity raises the metabolic
rate and increases maximal oxygen uptake. In the long term,
regular periods of such activity increase the body’s metabolic
efficiency and capacity (the amount of work that it can perform), as well as reducing blood pressure and insulin resistance. In addition, physical activity increases gut motility.

There is abundant epidemiological evidence fromprospective studies showing lower risk of colorectal
cancer with higher overall levels of physical activity, as
well as with greater frequency and intensity, and thereis evidence of a dose-response effect. There is little
heterogeneity, except that the effect is not as clear forrectal cancer as it is for colon cancer. There is plausible
evidence for mechanisms operating in humans. The
evidence that higher levels of physical activity, within
the range studied, protect against colon cancer isconvincing.

The Panel is aware that since the conclusion of the SLR, fourcohort198-201 and four case-control studies154 202-204 have been
published. This new information does not change the Panel
judgement. Also see box 3.8.
7.9.5.20 Body fatness(Also see chapter 6.1.3.1.)
Sixty cohort studies and 86 case-control studies investigated body fatness, as measured by BMI. Most of the cohort
studies showed increased risk with increased body fatness.
Meta-analysis of cohort data showed a 15 per cent increased
risk per 5 kg/m2 (figure 6.1.6). Heterogeneity is explained
partially by sexual and geographical differences, and also bycancer site. When stratified according to cancer site, data are
more consistent and suggest a larger increased risk for coloncancer (figure 6.1.7) than for rectal cancer (figure 6.1.8).
Because of the abundant prospective data from cohort
studies, case-control studies were not summarised.
Body fatness directly affects levels of many circulating hormones, such as insulin, insulin-like growth factors, andoestrogens, creating an environment that encourages carcinogenesis and discourages apoptosis. It also stimulates the
body’s inflammatory response, which may contribute to theinitiation and progression of several cancers. Also see chapter 6.1.3 and box 2.4.
There is abundant and consistent epidemiologicalevidence with a clear dose-response relationship, andevidence for plausible mechanisms that operate inhumans. The evidence that greater body fatness is a
cause of colorectal cancer is convincing.

The Panel is aware that since the conclusion of the SLR, 15
cohort58 59 151 205-215 and 2 case-control studies216-218 have been
published. This new information does not change the Panel
judgement. Also see box 3.8.
7.9.5.21 Abdominal fatness(Also see chapter 6.1.3.2.)
Seven cohort studies and two case-control studies investigated waist circumference; six cohort studies and four casecontrol studies investigated waist to hip ratio. All cohort
studies showed increased risk with either increased waist circumference or increased waist to hip ratio. Meta-analysis was
possible on four cohort studies measuring waist circumference and five cohort studies measuring waist to hip ratio.
This showed a 5 per cent increased risk per inch of waist cir-287

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cumference, or a 30 per cent increased risk per 0.1 incrementof waist to hip ratio (figures 6.1.22 and 6.1.23).
The general mechanisms through which abdominal fatness
could plausibly influence cancer risk are outlined in chapter
6.1.3 (for more detail see box 2.4). The hormonal and otherbiological effects of being overweight or obese are outlined
in chapter 8. Many of these, such as increased circulatingoestrogens and decreased insulin sensitivity, are associatedwith abdominal fatness independently of overall bodyfatness.
There is ample consistent epidemiological evidencewith a clear dose-response relationship and robust
evidence for mechanisms that operate in humans. The
evidence that abdominal fatness is a cause ofcolorectal cancer is convincing.

The Panel is aware that since the conclusion of the SLR, threecohort studies146 205 209 have been published. This new information does not change the Panel judgement. Also see box 3.8.
7.9.5.22 Adult attained height(Also see chapter 6.2.3.1.)
Twenty-one cohort studies and 16 case-control studies
investigated adult attained height. Most cohort studies
showed increased risk with increased height. Meta-analysis
of cohort data showed a 9 per cent increased risk per 5 cmof height (figure 6.2.1).
Because of the abundant prospective data from cohort
studies, case-control studies were not summarised.
The general mechanisms through which the factors thatlead to greater adult attained height, or its consequences,
could plausibly influence cancer risk are outlined in chapter
6.2.1.3 (for more detail see box 2.4). Many of these, such as
early-life nutrition, altered hormone profiles, and the rate ofsexual maturation, could plausibly increase cancer risk.
There is ample prospective epidemiological evidence,
which is consistent, and there is a clear dose-response
relationship, with evidence for plausible mechanisms
operating in humans. The evidence that the factorsthat lead to greater adult attained height, or its
consequences, are a cause of colorectal cancer isconvincing. The causal factor is unlikely to be tallness
itself, but factors that promote linear growth inchildhood.

The Panel is aware that since the conclusion of the SLR, fourcohort studies146 151 206 207 209 have been published. This new
information does not change the Panel judgement. Also see box
3.8.
7.9.5.23 Other exposures
Other exposures were evaluated. However, the data were
either of too low quality, too inconsistent, or the number ofstudies too few to allow conclusions to be reached. These
were as follows: cereals (grains) or their products; potatoes;
poultry; shellfish and other seafood; dairy products otherthan cheese or milk; non-dairy sources of calcium; coffee;

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caffeine; tea; total carbohydrate; starch; sugar; total fat; fatty
acid composition; cholesterol; vitamin A; retinol; betacarotene; alpha-carotene; lycopene; vitamin C; vitamin E;
methionine; multivitamins; meal frequency; and energy
intake.

7.9.6 Comparison with previous report
7.9.6.1 GeneralSee 7.1.6.1, and box 3.8 in chapter 3.
7.9.6.2 Specific
The previous report judged the evidence that vegetables protect against colorectal cancer to be convincing. The resultsof cohort studies since then have generally not been supportive of this judgement.
Evidence that red meat and, in particular, processed meat
are causes of colorectal cancer is now stronger.
The previous report noted the evidence showing that
greater adult height was a possible cause of colorectal cancer. The evidence now is stronger, as is that for body fatness
and for abdominal fatness. The previous report found thatfrequent meals or snacks possibly increased the risk of colorectal cancer; this was not found here.
The evidence that dietary fibre protects against colorectal
cancer is here judged to be stronger than it was previously.
Evidence that garlic, milk, and calcium supplements areprobably protective was not found previously.

7.9.7 Conclusions
The Panel concludes:
The evidence that physical activity protects against colorectal cancer is convincing, although the evidence is stronger
for colon than for rectum.
The evidence that red meat, processed meat, substantial
consumption (more than about 30 g per day ethanol) of alcoholic drinks (by men, and probably by women), body fatness
and abdominal fatness, and the factors that lead to greater
adult attained height, or its consequences, are causes of colorectal cancer is convincing.
Foods containing dietary fibre, as well as garlic, milk, andcalcium, probably protect against this cancer.
There is limited evidence suggesting that non-starchy vegetables, fruits, foods containing folate, as well as fish, foods
containing vitamin D, and also selenium and foods containing it, protect against colorectal cancer, and that foods containing iron, and also cheese, foods containing animal fats,
and foods containing sugars are causes of this cancer.

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7.10 Breast
FOOD, NUTRITION, PHYSICAL ACTIVITY,
AND CANCER OF THE BREAST (PREMENOPAUSE)

FOOD, NUTRITION, PHYSICAL ACTIVITY, AND
CANCER OF THE BREAST (POSTMENOPAUSE)In the judgement of the Panel, the factors listed below modify the risk ofcancer of the breast (premenopause). Judgements are graded according
to the strength of the evidence.

In the judgement of the Panel, the factors listed below modify the risk ofcancer of the breast (postmenopause). Judgements are graded according
to the strength of the evidence.

Convincing
Probable

DECREASES RISKINCREASES RISK

Lactation

Alcoholic drinks

Body fatness

DECREASES RISK
Convincing

Lactation

Alcoholic drinks
Body fatness

Adult attainedheight1

Adult attainedheight1

Greater birth weight
Probable
Limited —suggestive

Physical activity2

Limited —no conclusion

Cereals (grains) and their products; dietary fibre;
potatoes; vegetables; fruits; pulses (legumes); soya
and soya products; meat; poultry; fish; eggs; milk
and dairy products; fats and oils; total fat;vegetable fat; fatty acid composition, trans-fatty
acids; cholesterol; sugar (sucrose); other sugars;
sugary foods and drinks; coffee; tea; carbohydrate;
starch; glycaemic index; protein; vitamin A; riboflavin;vitamin B6; folate; vitamin B12; vitamin C; vitamin
D; vitamin E; calcium; iron; selenium; carotenoids;
isoflavones; dichlorodiphenyldichloroethylene;
dichlorodiphenyltrichloroethane; dieldrin;
hexachlorobenzene; hexachlorocyclohexane;
trans-nonachlor; polychlorinated biphenyls; dietary
patterns; culturally defined diets; adult weight
gain; energy intake; being breastfed

Substantial
effect on risk
unlikely

1

2

INCREASES RISK

Physical activity2

Abdominal fatness
Adult weight gain

None identified

Adult attained height is unlikely directly to modify the risk of cancer. It is amarker for genetic, environmental, hormonal, and also nutritional factors
affecting growth during the period from preconception to completion of
linear growth (see chapter 6.2.1.3).
Physical activity of all types: occupational, household, transport, andrecreational.

For an explanation of all the terms used in the matrix,
please see chapter 3.5.1, the text of this section,and the glossary.

Cancer of the breast is the most common cancer in women
worldwide. Around 1.15 million cases were recorded in
2002, accounting for around 23 per cent of all cancers inwomen (11 per cent overall).
Observed rates of this cancer increase withindustrialisation and urbanisation, and also with facilities
for early detection. It remains much more common in
high-income countries but is now increasing rapidly in
middle- and low-income countries, including within Africa,much of Asia, and Latin America. Breast cancer is fatal inunder half of all cases and is the leading cause of death

Limited —suggestive
Limited —no conclusion

Substantial
effect on risk
unlikely

12

Total fat

Cereals (grains) and their products; dietary fibre;
potatoes; vegetables and fruits; pulses (legumes);soya and soya products; meat; poultry; fish; eggs;
milk and dairy products; fats and oils; vegetable fat;fatty acid composition; cholesterol; sugar (sucrose);sugary foods and drinks; coffee; tea; carbohydrate;
starch; glycaemic index; protein; vitamin A; riboflavin;vitamin B6; folate; vitamin B12; vitamin C; vitamin
D; vitamin E; calcium; iron; selenium; carotenoids;
isoflavones; dichlorodiphenyldichloroethylene;
dichlorodiphenyltrichloroethane; dieldrin;
hexachlorobenzene; hexachlorocyclohexane; transnonachlor; polychlorinated biphenyls; dietary
patterns; culturally defined diets; birth weight;
birth length; energy intake; being breastfed

None identified

Adult attained height is unlikely directly to modify the risk of cancer. It is amarker for genetic, environmental, hormonal, and also nutritional factors
affecting growth during the period from preconception to completion of
linear growth (see chapter 6.2.1.3).
Physical activity of all types: occupational, household, transport, andrecreational.

For an explanation of all the terms used in the matrix,
please see chapter 3.5.1, the text of this section,and the glossary.

from cancer in women (fifth overall), accounting for 14
per cent of all cancer deaths worldwide.
Breast cancer is hormone related, and the factors thatmodify the risk of this cancer when diagnosed
premenopausally and when diagnosed (much morecommonly) postmenopausally are not the same.
Overall, the Panel is impressed by the pattern ofevidence showing the importance of early life events,
including food and nutrition, as well as factors that affecthormone status, in modification of the risk of breast
cancer.

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The Panel judges as follows:
The evidence that lactation protects against breast cancer
at all ages is convincing.
Physical activity probably protects against breast cancer
postmenopause, and there is limited evidence suggestingthat it protects against this cancer diagnosed
premenopause. The evidence that alcoholic drinks are acause of breast cancer at all ages is convincing. The
evidence that the factors that lead to greater adultattained height, or its consequences, are a cause of
postmenopausal breast cancer is convincing, and these areprobably also a cause of breast cancer diagnosed
premenopause.
The factors that lead to greater birth weight, or its
consequences, are probably a cause of breast cancer
diagnosed premenopause. Adult weight gain is probably acause of postmenopausal breast cancer. The evidence thatbody fatness is a cause of postmenopausal breast cancer isconvincing, and abdominal body fatness is probably also a
cause. On the other hand, body fatness probably protects
against breast cancer diagnosed premenopause. There islimited evidence suggesting that total dietary fat is a causeof postmenopausal breast cancer.
Life events that protect against breast cancer include
late menarche, early pregnancy, bearing children, andearly menopause, all of which have the effect of reducing
the number of menstrual cycles, and therefore lifetime
exposure to oestrogen. The reverse also applies.
See chapter 8 for evidence and judgements on factorsthat modify the risk of body fatness and abdominal
fatness, including physical activity and sedentary ways oflife, the energy density of foods and drinks, andbreastfeeding.
In final summary, the strongest evidence, corresponding
to judgements of “convincing” and “probable”, shows that
lactation protects against breast cancer; that alcoholic
drinks are a cause of this cancer; that the factors that leadto greater adult attained height, or its consequences, are acause of postmenopausal and probably alsopremenopausal breast cancer; that factors that lead togreater birth weight, or its consequences, are probably acause of premenopausal breast cancer; and that
abdominal body fatness and adult weight gain areprobably a cause of postmenopausal breast cancer. Body
fatness is a cause of postmenopausal breast cancer but
probably protects against premenopausal breast cancer.

Breast tissue comprises mainly fat, glandular tissue (arranged
in lobes), ducts, and connective tissue. Breast tissue develops
in response to hormones such as oestrogens, progesterone,
insulin, and growth factors. The main periods of development
are during puberty, pregnancy, and lactation. The glandular tissue atrophies after menopause.
Breast cancers are almost all carcinomas of the epithelial cells
lining the ducts (the channels in the breast that carry milk to
the nipple).219 Premenopausal and postmenopausal breast cancers are considered separately in this Report. Although rare,breast cancer can occur in men, but it is not included here.

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7.10.1 Trends, incidence, and survival
Age-adjusted rates of breast cancer in women are increasing
in most countries, particularly in areas where the incidence
had previously been low, such as Japan, China, and southern and eastern Europe.124 137
This is predominantly a disease of high-income countries,
where overall rates are nearly three times higher than in middle- to low-income countries. Around the world, age-adjusted incidence rates range from 75–100 per 100 000 womenin North America, northern Europe, and Australia, to less than
20 per 100 000 in parts of Africa and Asia.2 In the USA, rates
are higher among white women than those from other ethnic groups, although mortality is highest in black women.3
Overall risk doubles each decade until the menopause,
when the increase slows down or remains stable. However,breast cancer is more common after the menopause. Studies
of women who migrate from areas of low risk to areas of highrisk show that rates of breast cancer in migrants assume therate in the host country within one or two generations. Thisshows that environmental factors are important in the progression of the disease.220
Breast cancers can often be detected at a relatively earlystage. In countries that provide or advocate screening, mostof these cancers are diagnosed when the disease is still at a
localised stage.221 Survival rates range from more than 90 toless than 50 per cent, depending on the characteristics of thetumour, its size and spread, and the availability of treatment.4
Average 5-year survival rates are higher in high-income countries: around 73 per cent, compared with 57 per cent in middle- to low-income countries. Breast cancer accounts fornearly 23 per cent of all cancer incidence in women and 14
per cent of all cancer deaths (all sites except for skin (nonmelanoma) and in women only). Also see box 7.1.1.

7.10.2 Pathogenesis
Breast tissue, as well as hormones and hormone-receptor status, varies at different stages of life. It is therefore possiblethat individual risk factors will have different effects at different life stages (see 7.10.5). Early menarche, latemenopause, not bearing children, and late (over 30) firstpregnancy all increase breast cancer risk.220 222 The age whenbreasts develop, and menopause, are both influenced bynutrition, with overnutrition leading to early puberty andlate menopause; undernutrition delays puberty and advances
menopause (see chapter 6.2).
Hormones play an important role in breast cancer progression because they modulate the structure and growth ofepithelial tumour cells.4 Different cancers vary in hormone
sensitivity. Many breast cancers also produce hormones, suchas growth factors, that act locally, and these can both stimulate and inhibit the tumour’s growth.223 224
Between 4 and 9 per cent of breast cancer cases are hereditary, and are usually caused by inherited mutations in either
the BRCA1 or BRCA2 gene.225 226 In addition, growth factor
receptor genes, as well as some oncogenes, are overexpressedin many breast cancers4 (see box 2.2).

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7.10.3 Other established causes

7.10.5 Evidence and judgements(Also see chapter 2.4 and 7.1.3.1.)

In total, 873 publications were included in the SLR for breast
cancer. Fuller summaries of the epidemiological, experimental, and mechanistic evidence are to be found in
Chapters 4–6.
The full SLR is contained on the CD included with thisReport.

Life events. As stated above, lifetime exposure to oestrogen,influenced by early menarche, late natural menopause, notbearing children, and late (over 30) first pregnancy all
increase the risk of, and may be seen as causes of, breast cancer.220 222 The reverse also applies: late menarche, earlymenopause, bearing children, and early pregnancy all reduce
the risk of, and may be seen as protective against, breast cancer. Age of breast development and menopause are influenced by nutrition, with high-energy diets promoting
earlier puberty and late menopause, and low-energy diets
delaying puberty and advancing menopause.
Radiation. Ionising radiation exposure from medical treat-ment such as X-rays, particularly during puberty, increases
risk, even at low doses.227
Medication. Hormone replacement therapy is a cause ofbreast cancer. The increased risk appears to disappear a few
years after cessation.144 Oral contraceptives containing bothoestrogen and progesterone cause a small, transient,increased risk of breast cancer; the increased risk disappears
after cessation.133

7.10.4 Interpretation of the evidence
7.10.4.1 General
For general considerations that may affect interpretation of
the evidence, see chapters 3.3 and 3.5, and boxes 3.1, 3.2,
3.6 and 3.7.
‘Relative risk’ is used in this Report to denote ratio measures of effect, including ‘risk ratios’, ‘rate ratios’, ‘hazard
ratios’, and ‘odds ratios’.
7.10.4.2 Specific
Considerations specific to breast cancer include:
Patterns. The preponderance of data from high-income

countries is a special issue with breast cancer. Breast cancer
is hormone related, and factors that modify risk have different effects on cancers diagnosed pre- and postmenopause.
Classification. Because of the importance of menopause as
an effect modifier, studies should stratify for menopause status. Many do not.
Confounding. Hormone replacement therapy is an importantpossible confounder in postmenopausal breast cancer. A few
studies also reported results separately for different hormone
receptor profiles within cancers. High-quality studies adjust
for age, number of reproductive cycles, age at which children
were born, and the taking of hormone-based medications.

7.10.5.1 Alcoholic drinks(Also see chapter 4.8.5.1.)
A total of 11 cohort studies, 31 case-control studies, and 2
ecological studies investigated alcoholic drinks; 25 cohort
studies, 29 case-control studies, and 4 ecological studies
investigated ethanol intake and all-age breast cancer.
Further studies investigated the relationship with alcoholic
drinks in either pre- or postmenopausal breast cancer. Most
studies showed increased risk with increased intake. Metaanalysis of cohort data showed a 10 per cent increased risk
per 10 g ethanol/day; meta-analysis of case-control data
showed a 5 per cent increased risk per 5 drinks/week, anda 6 per cent increased risk per 10 g ethanol/day (figures
4.8.13, 4.8.15, and 4.8.16). Menopausal status did not significantly alter the association. Two pooled analyses also
showed statistically significant increased risks of 9 and 7 percent per 10 g ethanol/day. The first was based on 6 cohort
studies with more than 320 000 participants, followed up
for up to 11 years, with more than 4300 breast cancer cases.
The other analysed 53 case-control studies, with more than
58 000 cases and more than 95 000 controls.228 229
Reactive metabolites of alcohol, such as acetaldehyde,
may be carcinogenic. Additionally, the effects of alcohol may
be mediated through the production of prostaglandins, lipid
peroxidation, and the generation of free radical oxygen
species. Alcohol also acts as a solvent, enhancing penetration of carcinogens into cells. High consumers of alcohol
may have diets deficient in essential nutrients, making tissues susceptible to carcinogenesis. In addition, most experimental studies in animals have shown that alcohol intake
is associated with increased breast cancer risk. Alcohol interferes with oestrogen metabolism and action in multiple
ways, influencing hormone levels and oestrogen receptors.
There is an interaction between folate and alcohol affecting breast cancer risk: increased folate status partially mitigates the risk from increased alcohol consumption.230
There is ample, generally consistent evidence fromcase-control and cohort studies. A dose-response
relationship is apparent. There is robust evidence formechanisms operating in humans. The evidence that
alcoholic drinks are a cause of premenopausal andpostmenopausal breast cancer is convincing. No
threshold was identified.

The Panel is aware that since the conclusion of the SLR, one
case-control study231 has been published. This new information does not change the Panel judgement. Also see box 3.8.

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7.10.5.2 Lactation(Also see chapter 6.3.3.)
One cohort study and 37 case-control studies investigatedever having breastfed as compared to never having breastfed; and 5 cohort studies and 55 case-control studies investigated the total duration of lactation. The single cohort
study and most case-control studies showed decreased risk(age unspecified) with ever having breastfed compared withnever. Most studies showed decreased risk with increasing
duration of breastfeeding. Meta-analysis of case-control data
showed a 3 per cent decreased risk per 5 months of total
breastfeeding (figure 6.3.1); meta-analysis of cohort data
showed a non-significant decreased risk. Pooled analysis
from 47 epidemiological studies in 30 countries (more than
50 000 controls and nearly 97 000 breast cancer cases)
showed a statistically significant decreased risk of breast cancer of 4.3 per cent for each 12 months of breastfeeding.
Menopause status was not an effect modifier.228 386
Lactation is associated with increased differentiation ofbreast cells and with lower exposure to endogenous sex hormones during amenorrhea accompanying lactation. In addition, the strong exfoliation of breast tissue during lactation,and the massive epithelial apoptosis at the end of lactation,
could decrease risk by elimination of cells with potential
DNA damage.
There is abundant epidemiological evidence from bothprospective and case-control studies, which isconsistent and shows a dose-response relationship.
There is robust evidence for plausible mechanisms that
operate in humans. The evidence that lactation
protects against both premenopausal andpostmenopausal breast cancer is convincing.

7.10.5.3 Physical activity(Also see chapter 5.4.2.)
Six cohort studies and 8 case-control studies investigatedtotal physical activity; 5 cohort studies and 7 case-control
studies investigated occupational activity; and 14 cohort
studies and 11 case-control studies investigated recreational activity.
Menopause age unspecified

Most studies showed decreased risk with increased physicalactivity. Meta-analysis of case-control data showed a 10 per
cent decreased risk per 7 MET-hours recreational activity/week (figure 5.4.5).
Premenopause

Data were inconsistent for most categories, but data on occupational activity were suggestive of decreased risk.
Postmenopause

Nearly all of the cohort studies and most case-control studies showed decreased risk with increased physical activity.
Meta-analysis of cohort data showed a 3 per cent decreased
risk per 7 MET-hours recreational activity/week (figure 5.4.6).
Sustained moderate physical activity raises the metabolic
rate and increases maximal oxygen uptake. In the long term,

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regular periods of such activity increase the body’s metabolic
efficiency and capacity (the amount of work that it can perform), as well as reducing blood pressure and insulin resistance. In addition, it decreases levels of oestrogens andandrogens in postmenopausal women. Some trials have also
shown decreases in circulating oestrogens, increased menstrual cycle length, and decreased ovulation in premenopausal women with a high level of physical activity.
Premenopause: There is ample evidence fromprospective studies, but it is inconsistent. There is limited
evidence suggesting that physical activity protects
against premenopausal breast cancer.
Postmenopause: There is ample evidence fromprospective studies showing lower risk of
postmenopausal breast cancer with higher levels ofphysical activity, with a dose-response relationship,
although there is some heterogeneity. There is little
evidence on frequency, duration, or intensity of activity.
There is robust evidence for mechanisms operating inhumans. Physical activity probably protects against
postmenopausal breast cancer.

The Panel is aware that since the conclusion of the SLR, one
case-control study232 has been published. This new information
does not change the Panel judgement. Also see box 3.8.
7.10.5.4 Body fatness(Also see chapter 6.1.3.1.)
Forty-three cohort studies, more than 100 case-control studies, and 2 ecological studies investigated body fatness, asmeasured by BMI. When grouped for all ages, data wereinconsistent. However, a consistent effect emerged when
they were stratified according to menopausal status. Most
studies showed a decreased risk for premenopausal breast
cancer and an increased risk for postmenopausal breast cancer with increased body fatness. For cancer diagnosed premenopause, meta-analysis of cohort data showed a 15 percent decreased risk per 5 kg/m2; meta-analysis of case-control data showed a 15 per cent increased risk per 5 kg/m2.
For cancer diagnosed postmenopause, meta-analysis ofcohort data showed an 8 per cent increased risk per 5 kg/m2;
meta-analysis of case-control data showed a 13 per centincreased risk per 5 kg/m2 (figures 6.1.11–6.1.16).
Two pooled analyses showed statistically significant
increased risk for postmenopausal cancer. One of these also
showed a statistically significant decreased risk for premenopausal breast cancer. One pooled analysis was basedon 7 cohort studies with more than 337 000 participants, followed up for up to 11 years, with more than 4300 breast cancer cases. It showed a 14 per cent decreased risk per 5 kg/m2
for cancer diagnosed premenopause and a 9 per centincreased risk per 5 kg/m2 for cancer diagnosed postmenopause. The other pooled analysis, based on 53 casecontrol studies with more than 58 000 cases and more than
95 000 controls, showed a 19 per cent increased risk per 5kg/m2 for postmenopausal breast cancer.233 234
Body fatness directly affects levels of many circulating hor-C H A P T E R

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mones, such as insulin, insulin-like growth factors, andoestrogens, creating an environment that encourages carcinogenesis and discourages apoptosis (see box 2.4). It also
stimulates the body’s inflammatory response, which may
contribute to the initiation and progression of several cancers (see chapter 2.4.1.3). Adjusting for serum levels ofoestradiol diminishes or destroys the association with BMI,
suggesting that hormones are a predominant mechanism.235
There is no single well established mechanism throughwhich body fatness could prevent premenopausal breast cancer. According to the oestrogen plus progesterone theory,
overweight premenopausal women would be protected
because they would be more frequently anovulatory, andtherefore less exposed to endogenous progesterone.
However, this theory is not well supported by recent studies, which suggest that natural progesterone could be protective.236 Normal levels of natural progesterone are likely tobe protective, and well nourished, or perhaps overnourishedwomen, who may become slightly overweight in adulthood,
may be protected by their natural fertile condition. Anotherpossible mechanism is that the increased adipose tissuederived oestrogen levels in overweight children could
induce early breast differentiation and eliminate some targets for malignant transformation.237 Anovulation andabnormal hormone profiles are commonly associated withobesity.238 The age-specific pattern of association of breast
cancer with BMI, therefore, is largely explained by its relationship with endogenous sex hormone levels.
Breast cancer diagnosed postmenopause is much morecommon. Therefore, throughout life, a decreased risk of premenopausal breast cancer would be expected to be outweighed by an increased risk of postmenopausal breast
cancer.
Premenopause: There is a substantial amount ofconsistent epidemiological evidence with a doseresponse relationship, but the mechanistic evidence is
speculative. Greater body fatness probably protects
against premenopausal breast cancer.
Postmenopause: There is abundant and consistentepidemiological evidence and a clear dose-response
relationship with robust evidence for mechanisms
operating in humans. The evidence that greater bodyfatness is a cause of postmenopausal breast cancer isconvincing.

The Panel is aware that since the conclusion of the SLR, onecohort239 and one case-control study240 have been published.
This new information does not change the Panel judgement.
Also see box 3.8.
7.10.5.5 Adult attained height(Also see chapter 6.2.3.1.)
Thirty-three cohort studies, 56 case-control studies, and 3
ecological studies investigated adult attained height.
Age unspecified

Twenty cohort studies and 29 case-control studies investi-

gated adult attained height and breast cancer at all ages, or
unspecified menopausal status. Most of the studies showed
increased risk. Meta-analysis of cohort data showed a 9 percent increased risk per 5 cm of height; meta-analysis of casecontrol data showed a 3 per cent increased risk per 5 cm ofheight (figure 6.2.2).
Premenopause

Seventeen cohort studies and 38 case-control studies investigated adult attained height and premenopausal breast cancer. Most of the studies showed increased risk. Meta-analysis
of cohort data showed a 9 per cent increased risk per 5 cmof height; meta-analysis of case-control data showed a 4 percent increased risk per 5 cm of height (figure 6.2.4). A
pooled analysis of 7 cohort studies (more than 337 000 participants, followed up for up to 11 years, with more than
4300 breast cancer cases) showed a non-significant increased
risk with greater adult attained height.234
There are fewer data for premenopausal than forpostmenopausal breast cancer. The epidemiologicalevidence is generally consistent, with a dose-response
relationship and evidence for plausible mechanisms.
The factors that lead to greater adult attained height,
or its consequences, are probably a cause of
premenopausal breast cancer. The causal factor isunlikely to be tallness itself, but factors that promote
linear growth in childhood.
Postmenopause

Twenty-two cohort studies and 34 case-control studies investigated adult attained height and postmenopausal breast
cancer. Nearly all of the cohort studies and most of the casecontrol studies showed increased risk, with no studies showing statistically significant contrary results. Meta-analysis ofcohort data showed an 11 per cent increased risk per 5 cmof height; meta-analysis of case-control data showed a 2 percent increased risk per 5 cm of height (figure 6.2.3). A
pooled analysis of 7 cohort studies (more than 337 000 participants, followed up for up to 11 years, with more than
4300 breast cancer cases) showed a statistically significant
7 per cent increased risk per 5 cm of height.234 The ecological studies provided supporting data.
The general mechanisms through which the factors thatlead to greater adult attained height, or its consequences,
could plausibly influence cancer risk are outlined in chapter
6.2.1.3 (for more detail see box 2.4). Many of these, suchas early-life nutrition, altered hormone profiles, and the rateof sexual maturation, could plausibly increase cancer risk.
There is abundant prospective epidemiologicalevidence, which is generally consistent, with a clear
dose-response relationship, and evidence for plausible
mechanisms operating in humans. The evidence thatthe factors that lead to greater adult attained height,
or its consequences, are a cause of postmenopausal
breast cancer is convincing. The causal factor isunlikely to be tallness itself, but factors that promote
linear growth in childhood.

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The Panel is aware that since the conclusion of the SLR, onecohort study241 has been published. This new information does
not change the Panel judgement. Also see box 3.8.
7.10.5.6 Abdominal fatness (postmenopause)(Also see chapter 6.1.3.2.)
Eight cohort studies and three case-control studies investigated waist circumference and postmenopausal breast
cancer; eight cohort studies and eight case-control
studies investigated waist to hip ratio. All of the waist-circumference studies and most of those on waist to hip ratio
showed increased risk with increased measures of abdominal fatness. Meta-analysis of cohort data showed a 19 percent increased risk per 0.1 increment in waist to hip ratio(figure 6.1.24).
The general mechanisms through which abdominal fatness
could plausibly cause cancer are outlined in chapter 6.1.3 (formore detail see box 2.4). The hormonal and other biologicaleffects of being overweight or obese are outlined in chapter
8. Many of these, such as increased levels of circulatingoestrogens and decreased insulin sensitivity, are associatedwith abdominal fatness independently of overall body fatness.
There is a substantial amount of epidemiologicalevidence but some inconsistency. There is robust
evidence for mechanisms that operate in humans.
Abdominal fatness is a probable cause of
postmenopausal breast cancer.

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Meta-analysis of cohort data showed an 8 per cent increased
risk per kg (figure 6.2.8).
The general mechanisms through which the factors thatlead to greater birth weight, or its consequences, could
plausibly influence cancer risk are outlined in chapter
6.2.1.1. Many of these, such as long-term programming ofhormonal systems, could plausibly increase cancer risk.
Greater birth weight raises circulating maternal oestrogenlevels and may increase insulin-like growth factor (IGF)-1
activity; low birth weight raises both fetal and maternal levels of IGF-1 binding protein. The action of both oestrogens
and IGF-1 are thought to be important in fetal growth andmammary gland development, and play a central, synergistic role in the initiation and promotion of breast cancer.242
Animal experiments also provide evidence that exposure tooestrogens during fetal and early postnatal development canincrease the risk of mammary cancers.243
There is general consistency amongst the relatively few
epidemiological studies, with some evidence for adose-response relationship. The mechanistic evidenceis speculative. The factors that lead to greater birthweight, or its consequences, are probably a cause of
premenopausal breast cancer.

The Panel is aware that since the conclusion of the SLR, onecohort study239 and one case-control study244 have been published. This new information does not change the Panel judgement. Also see box 3.8.

7.10.5.7 Adult weight gain (postmenopause)(Also see chapter 6.1.3.3.)
Seven cohort studies and 17 case-control studies investigated adult weight gain and postmenopausal breast cancer.
Nearly all of the studies showed increased risk withincreased weight gain in adulthood. Meta-analysis of casecontrol data showed a 5 per cent increased risk per 5 kg
gained (figure 6.1.26). Heterogeneity may be explained by
failure to separate postmenopausal participants taking hormone replacement therapy.
Body fatness directly affects levels of many circulating hormones, such as insulin, insulin-like growth factors, andoestrogens, creating an environment that encourages carcinogenesis and discourages apoptosis (see chapter 2.7.1.3).
It also stimulates the body’s inflammatory response, which
may contribute to the initiation and progression of several
cancers.

7.10.5.9 Total fat (postmenopause)(Also see chapter 4.5.5.1.)
Nine cohort studies and 16 case-control studies investigated total fat intake and postmenopausal breast cancer. Most
studies showed increased risk with increased intake. Metaanalysis of cohort data showed a non-significant increased
risk; meta-analysis of case-control data showed a statisticallysignificant increased risk. A pooled analysis (more than
350 000 participants and more than 7300 breast cancer
cases) showed an overall non-significant decreased risk withincreased fat intake. Menopausal status did not significantly alter the result.245
Higher endogenous oestrogen levels after menopause area known cause of breast cancer.235 246 Dietary fat may also
increase endogenous oestrogen production.247

There is ample, consistent epidemiological evidence
from both cohort and case-control studies. A doseresponse relationship was apparent from case-control
and cohort studies. Adult weight gain is a probablecause of postmenopausal breast cancer.

Evidence from prospective epidemiological studies ofdifferent types on the whole shows inconsistent effects,
while case-control studies show a significant positive
association. Mechanistic evidence is speculative.
Overall, there is limited evidence suggesting that
consumption of total fat is a cause of postmenopausal
breast cancer.

7.10.5.8 Greater birth weight (premenopause)(Also see chapter 6.2.3.2.)
Six cohort studies and four case-control studies investigated birth weight. All cohort studies and most case-control
studies showed increased risk with greater birth weight, withnone reporting statistically significant contrary results.

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7.10.5.10 Other exposures
For premenopausal breast cancer, other exposures were evaluated. However, the data were either of too low quality, too
inconsistent, or the number of studies too few to allow conclusions to be reached. These were as follows: cereals

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C A N C E R S(grains) and their products; potatoes; vegetables; fruits;pulses (legumes); soya and soya products; meat; poultry;
fish; eggs; fats and oils; vegetable fat; sugar; sugary foods
and drinks; milk and dairy products; coffee; tea; carbohydrate; starch; dietary fibre; sugars; total fat; fatty acid composition; trans-fatty acids; cholesterol; protein; vitamin A;
carotenoids; folate; riboflavin; vitamin B6; cobalamin;
vitamin C; vitamin D; vitamin E; iron; calcium; selenium;
isoflavones; dieldrin; trans-nonachlor; dichlorodiphenyltrichloroethane; dichlorodiphenyldichloroethylene; polychlorinated biphenyls; hexachlorocyclohexane; hexachlorobenzene; energy intake; adult weight gain; adult attainedheight; dietary patterns; culturally defined diets; glycaemic
index; and being breastfed.
For postmenopausal breast cancer other exposures were
evaluated. However, the data were either of too low quality, too inconsistent, or the number of studies too few to allow
conclusions to be reached. These were as follows: cereals(grains) and their products; potatoes; vegetables and fruits;pulses; soya and soya products; meat; poultry; fish; eggs; fats
and oils; sugar; sugary drinks and foods; milk and dairy
products; coffee; tea; carbohydrate; starch; dietary fibre; vegetable fat; fatty acid composition; cholesterol; protein; vitamin A and carotenoids; riboflavin; vitamin B6; vitamin B12;
folate; vitamin C; vitamin D; vitamin E; isoflavones; iron;calcium; selenium; dieldrin; trans-nonachlor; dichlorodiphenyltrichloroethane; dichlorodiphenyldichloroethylene;
polychlorinated biphenyls; hexachlorocyclohexane; hexachlorobenzene; energy intake; birth length; culturally
defined diets; dietary patterns; glycaemic index; beingbreastfed; and birth weight.
There is considerable speculation around a biologicallyplausible interaction of soya and soya products with breast
cancer development, due to their high phytoestrogen content. Data on pulses (legumes) were sparse and inconsistent,
and there were insufficient studies available on soya consumption to allow a conclusion to be reached.

not make a judgement on rates of growth. The previous
report did not make judgments on birth weight.
The previous report judged it probable that vegetables andfruits decrease breast cancer risk. Cohort findings since thenhave been equivocal.

7.10.7 Conclusions
The Panel concludes:
The evidence that lactation protects against breast cancer at
all ages therafter is convincing. Physical activity probably
protects against postmenopausal breast cancer, and there islimited evidence suggesting that it protects against premenopausal breast cancer. The evidence that alcoholic drinks
are a cause of breast cancer at all ages is convincing. The
evidence that the factors that lead to greater attained adultheight or its consequences are a cause of postmenopausal
breast cancer is convincing; these are probably a cause of
premenopausal breast cancer.
The factors that lead to greater birth weight or its consequences are probably a cause of breast cancer diagnosed premenopause. Adult weight gain is probably a cause of
postmenopausal breast cancer. The evidence that body fatness is a cause of postmenopausal breast cancer is convincing, and abdominal body fatness is probably a cause of thiscancer. On the other hand, body fatness probably protects
against breast cancer diagnosed premenopause. There is limited evidence suggesting that total dietary fat is a cause of
postmenopausal breast cancer.

7.10.6 Comparison with previous report
7.10.6.1 GeneralSee 7.1.6.1, and box 3.8.
7.10.6.2 Specific
One of the most striking differences between the two reports
is the finding here on lactation. The previous report mentioned studies indicating that breastfeeding may protect
against breast cancer, but it did not review or judge thisevidence.
The previous report found that high body mass probably
increases the risk for breast cancer diagnosed after themenopause, while this Report found the evidence for bodyfatness to be convincing. While the previous report made no
judgement on high body mass and premenopausal breast
cancer, this Report found that greater body fatness probably
decreases the risk. The previous report judged the evidence
to be convincing that rapid growth, together with greater
adult height, are causes of breast cancer. This Report does

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7.11 Ovary
Ovarian cancer is the seventh most common cancer inwomen (and the 16th most common cancer overall)worldwide. Around 200 000 cases were recorded in 2002,
accounting for around 4 per cent of all new cases ofcancer in women (2 per cent overall). It is most frequentin high-income countries. This cancer is usually fatal, andis the seventh most common cause of cancer death inwomen worldwide (15th overall).
The Panel judges as follows:
The factors that lead to greater adult attained height, or
its consequences, are probably a cause of cancer of theovary. There is limited evidence suggesting that nonstarchy vegetables, and also lactation, protect against thiscancer.
Life events that protect against ovarian cancer include
late menarche, bearing children, and early menopause, allof which have the effect of reducing the number of
menstrual cycles, and therefore lifetime exposure tooestrogen.
In final summary, the strongest evidence, corresponding
to judgements of “convincing” and “probable”, shows thatthe factors that lead to greater adult attained height, or its
consequences, are probably a cause of cancer of the ovary.

FOOD, NUTRITION, PHYSICAL ACTIVITY,
AND CANCER OF THE OVARY
In the judgement of the Panel, the factors listed below modify the risk ofcancer of the ovary. Judgements are graded according to the strength ofthe evidence.

DECREASES RISK
Convincing
Probable

7.11.1 Trends, incidence, and survival
There is no clear global trend in ovarian cancer incidence.
Rates appear to be high in high-income countries, and rising in countries undergoing economic transition.137 For
instance in Japan, there was a fourfold increase in the ageadjusted mortality rate (from 0.9 to 3.6 per 100 000 women)between 1950 and 1997.248
Ovarian cancer rates are nearly three times higher in highthan in middle- to low-income countries. Around the world,
age-adjusted incidence rates range from more than 10 per
100 000 women in Europe and North America, to less than
5 per 100 000 in parts of Africa and Asia. But rates are relatively high elsewhere in Asia, for example in Singapore and
the Philippines.2 In the USA, rates are higher among white
women than in those from other ethnic groups; rates are also
higher in Jewish women of Ashkenazi descent.3 249
Risk increases with age, although the rate of increase slows

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Adult attainedheight1

Limited —suggestiveNon-starchy vegetables2

Limited —no conclusion

Dietary fibre; fruits; pulses (legumes); meat;
poultry; fish; eggs; milk and dairy products; total
fat; cholesterol; coffee; tea; alcohol; carbohydrate;
lactose; protein; vitamin A; folate; vitamin C;
vitamin E; recreational activity; body fatness;
abdominal fatness; weight change; energy intake

Lactation

Substantial
effect on risk
unlikely1

The ovaries are the sites of egg production in women. They
are also the main source of the hormones oestrogen and progesterone.
There are three types of ovarian tissue that can produce
cancers: epithelial cells, which cover the ovary; stromal cells,
which produce hormones; and germ cells, which become
eggs. Many different types of ovarian cancers can occur.
About 85–90 per cent of ovarian cancers are carcinomas,4 thetype included here.

INCREASES RISK

2

None identified

Adult attained height is unlikely directly to modify the risk of cancer. It is amarker for genetic, environmental, hormonal, and also nutritional factors
affecting growth during the period from preconception to completion of
linear growth (see chapter 6.2.1.3).
Judgements on vegetables and fruits do not include those preserved bysalting and/or pickling.

For an explanation of all the terms used in the matrix,
please see chapter 3.5.1, the text of this section,and the glossary.

after the menopause, with most ovarian cancers occurring
after menopause. Only 10–15 per cent of cases occur before
the menopause, although germ cell cancers peak in women
aged between 15 and 35.4
Ovarian cancer often has no symptoms at the early stages,
so the disease is generally advanced when it is diagnosed.
The 5-year survival rate ranges from approximately 30 to 50
per cent.3 6 This cancer accounts for about 7 per cent of allcancer incidence and 4 per cent of cancer deaths in women
worldwide. Also see box 7.1.1.

7.11.2 Pathogenesis
The pathogenesis of this disease is not well characterised,although various mechanisms have been suggested. Over
many cycles of ovulation, the ovarian surface epithelium
undergoes repeated disruption and repair. The epithelial cells

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are stimulated to proliferate, which increases the probability of spontaneous mutations. Alternatively, following ovulation, these cells may become trapped within the connective
tissue surrounding the ovary, which can lead to the formation of inclusion cysts. If this happens, the epithelial cells are
subjected to a unique pro-inflammatory microenvironment,
which may increase the rate of DNA damage.
Most ovarian cancers occur spontaneously, although 5–10
per cent of cases develop due to a genetic predisposition.104
The latter, involving dysfunctional BRCA1 or BRCA2 genes(see chapter 2.4.1.1), produces high-grade carcinomas, witha poorer prognosis.250

7.11.3 Other established causes(Also see chapter 2.4 and 7.1.3.1.)
Life events. The risk of ovarian cancer is affected by the number of menstrual cycles during a woman’s lifetime. Not bearing children increases the risk of, and may be seen as a causeof, ovarian cancer. The reverse also applies: bearing children
reduces the risk of, and may be seen as protective against,
ovarian cancer.251-253 There is also substantial evidence that,as with breast cancer, early menarche and late natural
menopause increase the risk of, and may be seen as causesof, ovarian cancer. The reverse also applies: late menarcheand early menopause reduce the risk of, and may be seen asprotective against, ovarian cancer.251-253
Medication. Oral contraceptives protect against this cancer.133

7.11.4 Interpretation of the evidence
7.11.4.1 General
For general considerations that may affect interpretation of
the evidence, see chapters 3.3 and 3.5, and boxes 3.1, 3.2,
3.6 and 3.7.
‘Relative risk’ is used in this Report to denote ratio measures of effect, including ‘risk ratios’, ‘rate ratios’, ‘hazard
ratios’, and ‘odds ratios’.
7.11.4.2 Specific
Considerations specific to cancer of the ovary include:
Patterns. Because ovarian cancer is hormone related, factorsthat modify risk might have different effects at different
times of life. If so, this might partly explain heterogeneous
results.
Confounding. High-quality studies adjust for age, number ofreproductive cycles, age at which children were born, and thetaking of hormone-based medications.
Classification. There are different histological subtypes ofovarian cancer, which may have independent risk factors anddisease progression patterns. Most studies combine thesesubtypes.

7.11.5 Evidence and judgements
In total, 187 publications were included in the SLR for ovarian cancer. Fuller summaries of the epidemiological, experimental, and mechanistic evidence are to be found in
Chapters 4–6.
The full SLR is contained on the CD included with thisReport.
7.11.5.1 Non-starchy vegetables(Also see chapter 4.2.5.1.)
A total of five cohort studies, eight case-control studies, andtwo ecological studies investigated non-starchy vegetables;
three cohort studies and two case-control studies investigated green, leafy vegetables. All showed decreased risk withincreased intake, with none reporting contrary results. Metaanalysis of cohort data showed a statistically significant
decreased risk for non-starchy vegetables, with a clear doseresponse relationship. A pooled analysis of 12 cohort studies (more than 560 000 participants, followed up for 7–22
years, with more than 2100 ovarian cancer cases) showed anon-significant decreased risk for the highest intake groupof non-starchy vegetables.254
This is a wide and disparate category, and many different
plant food constituents are represented that could contributeto a protective effect of non-starchy vegetables. These
include dietary fibre, carotenoids, folate, selenium, glucosinolates, dithiolthiones, indoles, coumarins, ascorbate,chlorophyll, flavonoids, allylsulphides, flavonoids, and phytoestrogens, some of which are potentially antioxidants.
Antioxidants trap free radicals and reactive oxygen molecules, protecting against oxidation damage. It is difficult tounravel the relative importance of each constituent and it islikely that any protective effect may result from a combination of influences on several pathways involved in
carcinogenesis.
Evidence from cohort and case-control studies issparse. There is limited evidence suggesting that nonstarchy vegetables protect against ovarian cancer.

The Panel is aware that since the conclusion of the SLR, one
case-control study17 has been published. This new information
does not change the Panel judgement. Also see box 3.8.
7.11.5.2 Adult attained height(Also see chapter 6.2.3.1.)
Seven cohort studies, nine case-control studies, and two ecological studies investigated adult attained height. All cohort
studies and most other studies showed increased risk withgreater adult attained height. Meta-analysis of cohort data
showed an 8 per cent increased risk per 5 cm of height (figure 6.2.7); meta-analysis of case-control data showed no statistically significant relationship. Heterogeneity in the latter
was derived almost entirely from one study.
The general mechanisms through which the factors thatlead to greater adult attained height, or its consequences,
could plausibly influence cancer risk are outlined in chapter
6.2.1.3 (see box 2.4). Many of these, such as early-life297

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nutrition, altered hormone profiles, and the rate of sexual
maturation, could plausibly increase cancer risk.
There is some inconsistency, but the better quality
epidemiological data show a clearer effect, with adose-response relationship. There is evidence forplausible mechanisms operating in humans. The
factors that lead to greater adult attained height, or its
consequences, are probably a cause of ovarian cancer.
The causal factor is unlikely to be tallness itself, but
factors that promote linear growth in childhood.

The Panel is aware that since the conclusion of the SLR, onecohort study255 and one case-control study256 have been published. This new information does not change the Panel judgement. Also see box 3.8.
7.11.5.3 Lactation(Also see chapter 6.3.3.)
One cohort study and 10 case-control studies investigatedlactation, most of which showed an association with
reduced risk. Meta-analysis of case-control data showed statistically significant decreased risk with increased accumulated lifetime duration of breastfeeding, with a clear
dose-response relationship. Substantial heterogeneity is partially explained by variation in the assessment of breastfeeding when, for example, exclusivity of breastfeeding is notalways assessed.
Lactation delays the return of menstruation and ovulation
after childbirth. The general mechanisms through which lactation could plausibly protect against cancer are outlined inchapter 6.3.3. There is evidence that the reduced number of
menstrual cycles associated with breastfeeding protect
against some cancers.
There are sparse prospective epidemiological data,
though some evidence for a dose-response
relationship. The mechanistic evidence is speculative.
There is limited evidence suggesting that lactation
protects against ovarian cancer.

The Panel is aware that since the conclusion of the SLR, one
case-control study257 has been published. This new information
does not change the Panel judgement. Also see box 3.8.
7.11.5.4 Other exposures
Other exposures were evaluated. However, the data were
either of too low quality, too inconsistent, or the number ofstudies too few to allow conclusions to be reached. These
were as follows: pulses (legumes); fruits; meat; poultry; fish;
eggs; milk and dairy products; coffee; tea; alcohol; carbohydrate; dietary fibre; lactose; total fat; cholesterol; protein;vitamin A; folate; vitamin C; vitamin E; recreational activity; energy intake; body fatness; weight change; and abdominal fatness.

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7.11.6 Comparison with previous report
7.11.6.1 GeneralSee 7.1.6.1, and box 3.8 in chapter 3.
7.11.6.2 Specific
The finding here on adult attained height is new.

7.11.7 Conclusions
The Panel concludes:
The factors that lead to greater adult attained height, or its
consequences, are probably a cause of cancer of the ovary.
There is limited evidence suggesting that non-starchy vegetables, and also lactation, protect against this cancer.

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7.12 Endometrium
Endometrial cancer is the eighth most common cancer inwomen (and the 17th most common cancer overall)worldwide. Around 200 000 cases were recorded in 2002,
accounting for around 4 per cent of all new cases ofcancer in women (2 per cent overall). It is most frequentin high-income countries. Around three quarters of womenwith this cancer survive for 5 years. It is the 13th mostcommon cause of cancer death in women worldwide (21stoverall).
Overall, the Panel is impressed by the pattern of evidence
showing the importance of physical activity and bodyfatness, as well as factors that affect hormone status, inmodification of the risk of endometrial cancer.
The Panel judges as follows:
The evidence that body fatness is a cause of cancer of theendometrium is convincing; abdominal fatness is probably
a cause. Physical activity probably protects against thiscancer. There is limited evidence suggesting that nonstarchy vegetables protect against endometrial cancer, andthat red meat, and also the factors that lead to greater
adult attained height, or its consequences, are causes ofthis cancer.
Life events that protect against endometrial cancer
include bearing children and early menopause, which havethe effect of reducing the number of menstrual cycles andtherefore lifetime exposure to oestrogens. The reverse also
applies.
See chapter 8 for evidence and judgements on factorsthat modify the risk of body fatness and abdominal
fatness, including physical activity and sedentary ways oflife, the energy density of foods and drinks, andbreastfeeding.
In final summary, the strongest evidence, corresponding
to judgements of “convincing” and “probable”, shows thatbody fatness and probably abdominal fatness are causes ofendometrial cancer, and that physical activity is protective.

The endometrium is the lining of the uterus. It is subject toa process of cyclical change during the fertile years of awoman’s life.
The majority of cancers that occur in the body of the womb
are endometrial cancers, mostly adenocarcinomas,4 the typeincluded here.

7.12.1 Trends, incidence, and survival
Age-adjusted rates of endometrial cancer are increasing incountries undergoing transition from low- to high-income
economies, although there is no clear, overall trend in highincome countries.
This is mainly a disease of high-income countries, where
overall rates are nearly five times higher than in middle- to

FOOD, NUTRITION, PHYSICAL ACTIVITY,
AND CANCER OF THE ENDOMETRIUM
In the judgement of the Panel, the factors listed below modify the risk ofcancer of the endometrium. Judgements are graded according to thestrength of the evidence.

DECREASES RISK
Convincing

INCREASES RISK
Body fatness

Probable

Physical activity1

Limited —suggestiveNon-starchy vegetables2

Limited —no conclusion

Cereals (grains) and their products; dietary fibre;
fruits; pulses (legumes); soya and soya products;
poultry; fish; eggs; milk and dairy products; total
fat; animal fats; saturated fatty acids; cholesterol;
coffee; alcohol; carbohydrates; protein; retinol;
vitamin C; vitamin E; beta-carotene; lactation;energy intake

Substantial
effect on risk
unlikely1234Abdominal fatness
Red meat3
Adult attained height4

None identified

Physical activity of all types: occupational, household, transport,
and recreational.
Judgements on vegetables and fruits do not include those preserved bysalting and/or pickling.
The term ‘red meat’ refers to beef, pork, lamb, and goat fromdomesticated animals.
Adult attained height is unlikely directly to modify the risk of cancer. It is amarker for genetic, environmental, hormonal, and also nutritional factors
affecting growth during the period from preconception to completion of
linear growth (see chapter 6.2.1.3).

For an explanation of all the terms used in the matrix,
please see chapter 3.5.1, the text of this section,and the glossary.

low-income countries. Around the world, age-adjusted incidence rates range from more than 15 per 100 000 womenin North America and parts of Europe to less than 5 per
100 000 in most of Africa and Asia. In the USA, rates arehigher in white women than among those from other ethnic groups, although mortality rates are higher in black
women.3 258 Risk increases with age, with most diagnoses
made postmenopause.
Endometrial cancer often produces symptoms at relatively early stages, so the disease is generally diagnosed early.
At around 73 per cent, the overall 5-year survival rate is relatively high, although it is lower in middle- than in highincome countries (67 compared with 82 per cent).124 259
Endometrial cancer accounts for almost 2 per cent of allcancer incidence (around 4 per cent in women), but justunder 1 per cent of all cancer deaths (nearly 2 per cent in
women). Also see box 7.1.1.

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7.12.2 Pathogenesis
Type 1 endometrial tumours are oestrogen driven, accountfor around 80 per cent of endometrial cancers, and have afavourable prognosis.260 They follow a clear development
pathway, starting with endometrial hyperplasia (an increasein the number of cells), and are relatively well differentiated. Type 2 tumours are less common, accounting for around
10 per cent of endometrial cancers. Most are associated withendometrial atrophy (wasting), tend to metastasise, andhave a less favourable prognosis.
Up to 70 per cent of endometrial cancers are reported inwomen who have no recognised risk factors — such as thosethat might disrupt endocrine (hormone) processes.4 Somestudies have shown that polycystic ovary syndrome andinsulin sensitivity, which are both components of metabolic
syndrome, may play a role in the pathogenesis of endometrial cancer, perhaps through hormonal disruption.261
The tumour-suppressor gene PTEN is also involved in
the development of endometrial cancers.260 Also see also
box 2.2.

7.12.3 Other established causes(Also see chapter 2.4 and 7.1.3.1.)
Life events. Not bearing children increases the risk of, andmay be seen as a cause of, endometrial cancer.262 The reverse
also applies: bearing children reduces the risk of, and may
be seen as protective against, endometrial cancer.258-261 Thereis also substantial evidence that, as with breast and ovariancancer, late natural menopause increases the risk of, and may
be seen as a cause of, endometrial cancer. The reverse also
applies: early menopause reduces the risk of, and may beseen as protective against, this cancer.133

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Confounding. High-quality cohort studies eliminate women
who have had hysterectomies from ‘at-risk’ populations.
High-quality case-control studies assess the levels of hysterectomies in control groups.

7.12.5 Evidence and judgements
In total, 282 publications were included in the SLR for
endometrial cancer. Fuller summaries of the epidemiological, experimental, and mechanistic evidence are to be foundin Chapters 4–6.
The full SLR is contained on the CD included with thisReport.
7.12.5.1 Non-starchy vegetables(Also see chapter 4.2.5.1.)
Ten case-control studies investigated non-starchy vegetables,and seven case-control studies investigated cruciferous vegetables. Most studies showed decreased risk with increased
intake. Meta-analysis of case-control data produced evidence
of decreased risk with non-starchy or cruciferous vegetableintake, with a clear dose-response relationship. There were
no cohort data.
This is a wide and disparate category, and many different
plant food constituents are represented that could contributeto a protective effect of non-starchy vegetables. These
include dietary fibre, carotenoids, folate, selenium, glucosinolates, dithiolthiones, indoles, coumarins, ascorbate,chlorophyll, flavonoids, allylsulphides, flavonoids, and phytoestrogens, some of which are potentially antioxidants.
Antioxidants trap free radicals and reactive oxygen molecules, protecting against oxidation damage.
It is difficult to unravel the relative importance of eachconstituent and it is likely that any protective effect may
result from a combination of influences on several pathways
involved in carcinogenesis.

Medication. Oral contraceptives protect against this can-cer.133 Oestrogen-only hormone replacement therapy is a
cause of this cancer,144 as is tamoxifen.

7.12.4 Interpretation of the evidence
7.12.4.1 General
For general considerations that may affect interpretation of
the evidence, see chapters 3.3 and 3.5, and boxes 3.1, 3.2,
3.6 and 3.7.
‘Relative risk’ is used in this Report to denote ratio measures of effect, including ‘risk ratios’, ‘rate ratios’, ‘hazard
ratios’, and ‘odds ratios’.
7.12.4.2 Specific
Considerations specific to cancer of the endometrium
include:Patterns. Because endometrial cancer is hormone related,factors that modify risk might have different effects at different times of life.

300

Evidence comes from case-control studies only. Thereis limited evidence suggesting that non-starchy
vegetables protect against endometrial cancer.

7.12.5.2 Red meat
(Also see chapter 4.3.5.1.1.)
One cohort study and seven case-control studies investigated red meat. Most studies showed increased risk with higher intake. Meta-analysis of case-control data produced
evidence of increased risk with higher intake, with a clear
dose-response relationship.
There are several potential underlying mechanisms for apositive association of red meat consumption with endometrial cancer, including the generation of potentially carcinogenic N-nitroso compounds (see box 4.3.2).
Some meats are also cooked at high temperatures, resulting in the production of heterocyclic amines and polycyclicaromatic hydrocarbons (see box 4.3.4). Red meat contains
haem iron. Free iron can lead to the production of free radicals (see box 4.3.3).

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The evidence, mostly from case-control studies, issparse. There is limited evidence suggesting that redmeat is a cause of endometrial cancer.

The Panel is aware that since the conclusion of the SLR, one
case-control study263 has been published. This new information
does not change the Panel judgement. Also see box 3.8.
7.12.5.3 Physical activity(Also see chapter 5.4.3.)
Two cohort studies and 4 case-control studies investigatedtotal physical activity; 3 cohort studies and 10 case-control
studies investigated occupational activity; and 4 cohort studies and 10 case-control studies investigated recreational
activity. Nearly all of the cohort studies and most of the otherstudies showed decreased risk with increased physical activity. Although meta-analysis was not possible due to the wide
variety in measures used, comparisons of high with low
activity levels showed a consistent association withdecreased risk (figures 5.4.8 and 5.4.9).
Sustained moderate physical activity raises the metabolic
rate and increases maximal oxygen uptake. In the long term,
regular periods of such activity increase the body’s metabolic
efficiency and capacity (the amount of work that it can perform), as well as reducing blood pressure and insulin resistance. In addition, physical activity has been found to affectserum levels of oestradiol, oestrone, and androgens in postmenopausal women, even after adjusting for BMI. More generally, effects on oestrogen metabolism may operate directly,or through decreasing body fat stores. Physical activity is also
known to have favourable effects on insulin resistance, which
may also result in decreased risk of endometrial cancer.
Physical activity also results in decreased risk of diabetes andhigh blood pressure, which are risk factors for endometrial
cancer.
There is generally consistent evidence, mostly fromcase-control studies, showing lower risk of cancer ofthe endometrium with higher levels of physical activity.
There is evidence for mechanisms operating inhumans. Physical activity probably protects against
cancer of the endometrium.

7.12.5.4 Body fatness(Also see chapter 6.1.3.1.)
Twenty-three cohort studies, 41 case-control studies and2 cross-sectional studies investigated body fatness, as measured by BMI. Three cohort studies and six case-control studies investigated BMI as a young adult. Nearly all of thestudies showed increased risk with increased body fatness,more than half of which were statistically significant. Metaanalysis of cohort data showed an overall 52 per centincreased risk per 5 kg/m2, or a 31 per cent increased risk
per 5 kg/m2 as a young adult; meta-analysis of case-control
data showed an overall 56 per cent increased risk per 5kg/m2, with a non-significant increased risk for BMI as ayoung adult (figures 6.1.17 and 6.1.18). Heterogeneity existed in the size, but not direction, of the effect.
Body fatness directly affects levels of many circulating hor-mones, such as insulin, insulin-like growth factors, andoestrogens, creating an environment that encourages carcinogenesis and discourages apoptosis (see box 2.4). It also
stimulates the body’s inflammatory response, which may
contribute to the initiation and progression of several cancers (see chapter 2.4.1.3).
There is abundant, consistent epidemiologicalevidence with a clear dose-response relationship, androbust evidence for mechanisms operating in humans.
The evidence that greater body fatness is a cause ofendometrial cancer is convincing.

The Panel is aware that since the conclusion of the SLR, onecohort study215 and one case-control study264 have been published. This new information does not change the Panel judgement. Also see box 3.8.
7.12.5.5 Abdominal fatness(Also see chapter 6.1.3.2.)
One cohort study and four case-control studies investigatedwaist circumference; one cohort study and six case-control
studies investigated waist to hip ratio. Both cohort studies
and most case-control studies showed statistically significant
increased risk with increased abdominal fatness. Meta-analysis of case-control data showed a non-significant increasedrisk.
The general mechanisms through which abdominal fatness
could plausibly cause cancer are outlined in chapter 6.1.3(for more detail see box 2.4). The hormonal and other biological effects of being overweight or obese are outlined inchapter 8. Many of these, such as increased circulatingoestrogens and decreased insulin sensitivity, are associatedwith abdominal fatness independently of overall bodyfatness.
There is a substantial amount of generally consistentepidemiological evidence, but limited prospective
data. There is evidence for plausible mechanisms.
Greater abdominal fatness is a probable cause ofendometrial cancer.

7.12.5.6 Adult attained height(Also see chapter 6.2.3.1.)
Ten cohort studies, 16 case-control studies and 1 ecologicalstudy investigated adult attained height. Most studies
showed increased risk with greater adult attained height.
Meta-analysis of cohort and case-control data showed nonsignificant increased risk.
The general mechanisms through which the factors thatlead to greater adult attained height, or its consequences,
could plausibly influence cancer risk are outlined in chapter
6.2.1.3 (for more detail see box 2.4). Many of these, suchas early-life nutrition, altered hormone profiles, and the rateof sexual maturation, could plausibly increase cancer risk.
Although there is generally consistent evidence forprospective epidemiological data, there is someinconsistency in the evidence between cohort and301

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case-control studies, and the mechanistic evidence is
speculative. There is limited evidence that greater
adult attained height, or the factors that lead to it, area cause of endometrial cancer. The causal factor isunlikely to be tallness itself, but factors that promote
linear growth in childhood.

7.12.5.7 Other exposures
Other exposures were evaluated. However, the data were
either of too low quality, too inconsistent, or the number ofstudies too few to allow conclusions to be reached. These
were as follows: cereals (grains) and their products; fruits;pulses (legumes); tofu and soya; poultry; fish; eggs; milk anddairy products; coffee; alcohol; carbohydrates; dietary fibre;
total fat; animal fats; saturated fatty acids; cholesterol; protein; retinol; beta-carotene; vitamin C; vitamin E; energy
intake; and lactation.

7.12.6 Comparison with previous report
7.12.6.1 GeneralSee 7.1.6.1, and box 3.8 in chapter 3.
7.12.6.2 Specific
The finding here on physical activity is new. The evidence
on body fatness and on abdominal fatness (not consideredseparately in the previous report’s matrices) has strengthened.

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7.13 Cervix
Cervical cancer is the second most common cancer inwomen worldwide. Around half a million cases wererecorded in 2002, accounting for around 10 per cent of all
new cases of cancer in women (5 per cent overall). It is
most common in Africa, some parts of Asia including
India, and in Latin America. It is most common in
relatively young women. Five-year survival rates arearound 50 per cent. It is the third most common cause ofcancer death in women.
Overall, the Panel notes that food and nutrition andassociated factors are not significant factors inmodification of the risk of cancer of the cervix, althoughgeneral nutritional status may affect a woman’svulnerability to infection.
Life events that protect against cervical cancer include
having relatively few sexual partners. The reverse also
applies. Infection with HPV is a necessary cause of thiscancer, and smoking tobacco increases risk.
The Panel judges as follows:
There is limited evidence suggesting that carrots protect
against cervical cancer.
In final summary, there is no strong evidence,corresponding to judgements of “convincing” and“probable”, to conclude that any aspect of food, nutrition,and physical activity modifies the risk of cervical cancer.

7.12.7 Conclusions
The Panel concludes:
The evidence that body fatness is a cause of cancer of theendometrium is convincing; abdominal fatness is probably
also a cause.
Physical activity probably protects against this cancer.
There is limited evidence suggesting that non-starchy vegetables protect against endometrial cancer, and that red
meat, and also the factors that lead to greater adult attainedheight, or its consequences, are causes of this cancer.

The cervix is the neck of the womb. The part of the cervix
inside the cervical canal is called the endocervix. The part on
the outside is the ectocervix. Most cervical cancers start wherethese two parts meet. There are two main types, squamouscell carcinoma and adenocarcinoma. Occasionally, mixed carcinomas, with features of both types, occur. Approximately
80 per cent of cervical cancers are squamous cell carcinomas,
with most of the rest being adenocarcinomas.265 Both typesof cervical cancer are covered in this Report.

7.13.1 Trends, incidence, and survival
Age-adjusted rates of cervical cancer are decreasing, particularly in high- and middle-income countries, although there
are insufficient data to derive trends in low-income countries.
In high-income countries, the incidence of adenocarcinomas
has increased since the 1970s, both absolutely and relative
to squamous cell carcinomas. The prevalence appears to be
increasing disproportionately in young women.266
Cervical cancer is predominantly a disease of low-income
countries, with overall rates nearly twice as high in middleto low- as in high-income countries. Around the world, ageadjusted incidence rates range from more than 40 per
100 000 women in parts of Africa, South America, andMelanesia, to less than 10 per 100 000 in North America andparts of Asia. However, rates are relatively high elsewhere302

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FOOD, NUTRITION, PHYSICAL ACTIVITY,
AND CANCER OF THE CERVIXIn the judgement of the Panel, the factors listed below modify the risk ofcancer of the cervix. Judgements are graded according to the strength ofthe evidence.

DECREASES RISKINCREASES RISK

Convincing
Probable
Limited —suggestive

Carrots1

Limited —no conclusion

Non-starchy vegetables; fruits; milk; retinol; vitamin E;
alcoholism2; body fatness; adult attained height.

Substantial
effect on risk
unlikely

None identified

1
2

Judgements on vegetables and fruits do not include those preserved bysalting and/or pickling.
Although data suggest that alcoholism is related to increased risk, the Panelconcludes that this is likely to be due to factors other than alcohol intake
itself.

For an explanation of all the terms used in the matrix,
please see chapter 3.5.1, the text of this section,and the glossary.

in Asia, for example in India and Bangladesh. In the USA,rates are higher among both African-American and HispanicAmerican women than in white women. The incidence ofmany cancers rises with age, but cervical cancer peaks inyounger women, between the ages of 30 and 45.6 However,Box 7.13.1

mortality does not follow the same pattern, and rises withage. Most women in high-income countries, and to varying
degrees in other countries, have access to preventive
screening programmes that are designed to detect precancerous lesions. If these are identified and removed, the incidence of this cancer is reduced. After a screening programme
was implemented in the UK in 1988, cervical cancer incidence (age-standardised rate) has fallen by nearly 60 per
cent.6 It is generally well accepted that better access to cervical screening programmes worldwide would decrease boththe incidence and mortality rates for this cancer.267 Morerecently vaccination against HPV has become a preventive
option.
The overall 5-year survival rate is approximately 50 per
cent: 61 per cent in high-income countries compared with
41 per cent in middle- to low-income countries.124 This cancer accounts for somewhat over 4 per cent of all cancer incidence (around 10 per cent in women) but only around 4 percent of all cancer deaths (just over 9 per cent in women).
Also see box 7.1.1.

7.13.2 Pathogenesis
Virtually all cervical cancers are associated with HPV
infection (see box 7.13.1), and a woman’s nutrition
status may influence her susceptibility to this infection.268
However, the majority of women with HPV do not develop
cervical cancer. Therefore, HPV infection is a necessary but
not a sufficient cause of cervical cancer. Women become susceptible to developing cervical cancer following HPV infection, but other environmental factors are required for thecancer to develop.
These factors may include toxins such as polycyclic aromatic hydrocarbons (see box 4.3.4) from tobacco smoke,
food, or other environmental sources, which have beenfound in the mucus lining the cervix.269

Human papilloma viruses

Human papilloma viruses (HPVs) are common. They infect squamous epithelia andgenerate warts. They are passed by directcontact; genital HPV infections are sexually transmitted. HPV infection rates arehigher in women who have had a higher
number of sexual partners (particularly
male partners); do not use barrier methodsof contraception; and who started having
sex at a younger age.
There are more than 100 types of HPV.
All can interfere with host-cell machinerythat prevents cells from growing andreplicating excessively, which are some of
the cellular mechanisms that help protect
the body against cancer development.
Low-risk HPVs cause genital warts; highrisk HPVs cause squamous intra-epithelial

lesions that can progress to invasive squamous cell carcinoma. The majority ofhuman cervical cancers are associated withhigh-risk HPV infections. Four subtypes ofthis virus account for 80 per cent of all cervical cancer.
HPV infection tends to remain dormant,
and with repeated infection, the HPV
genome becomes integrated within thehost cell genome and some cells may
become cancerous.
Most HPV infections do not become persistent, and most persistent HPV infections
do not lead to cancer. However, HPV infection is demonstrably present in 99 per centof women with cervical cancer, and may bepresent but undetected in the remainder.
HPV is a necessary while not sufficientcause of cervical cancer.
There are several stages at which foods
or nutrition status could influence progression. Dietary factors influence susceptibility to infection; infection can alter
nutrition status; diet may affect the likelihood of infections becoming persistent;
and dietary factors have been shown to
alter
DNA
stability
andrepair.
Unfortunately, there is a shortage of epidemiological evidence specific to HPV ateach of these stages. There is some limited evidence that eating vegetables andfruits can protect against persistence.268
There is also evidence that folate canreduce persistence and independently
reduce the risk of precancerous lesions inhigh-risk-HPV infected women.270-272

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7.13.3 Other established causes(Also see chapter 2.4 and 7.1.3.1.)
Life events. Early sexual experience and a relatively highnumber of sexual partners increase the risk and severity of
HPV infection, and may be seen as indirect causes of cervical cancer.220 222
Tobacco use. Smoking tobacco makes a woman twice as likely to develop cervical cancer.10 Tobacco by-products have beenfound in the cervical mucus of women who smoke. The effectof smoking is independent of that of viral infection.10 273
Infectious agents. HPV infection (see box 7.13.1) is a necessary but not sufficient cause of cervical cancer.273 274
Medication. Dethylstilboestrol (a synthetic oestrogen, now
withdrawn) used by women during pregnancy is a cause ofvaginal and cervical clear-cell adenocarcinoma in theirdaughters.275

7.13.4 Interpretation of the evidence
7.13.4.1 General
For general considerations that may affect interpretation of
the evidence, see chapters 3.3 and 3.5, and boxes 3.1, 3.2,
3.6 and 3.7.
‘Relative risk’ is used in this Report to denote ratio measures of effect, including ‘risk ratios’, ‘rate ratios’, ‘hazard
ratios’, and ‘odds ratios’.

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Some carotenoids, including beta-carotene and alphacarotene, which are found at high levels in carrots, are precursors of vitamin A. They also have properties independentof their pro-vitamin A activity. Carotenoids are recognised
antioxidants, and low blood levels of dietary antioxidants areassociated with HPV persistence.276
The evidence, from case-control studies only, is sparse
but consistent. There is limited evidence suggestingthat carrots protect against cervical cancer.

7.13.5.2 Other exposures
Other exposures were evaluated. However, the data were
either of too low quality, too inconsistent, or the number ofstudies too few to allow conclusions to be reached. These
were as follows: non-starchy vegetables; fruits; milk; retinol;
vitamin E; alcoholism; body fatness; and adult attainedheight.
Although data suggest that alcoholism is related toincreased risk, the Panel concludes that this is likely to be due
to factors other than alcohol intake itself.
7.13.5.3 Exposures as related to non-invasivecancer outcomes
The following exposures were evaluated. However, the data
were either too sparse, too inconsistent, or the number ofstudies too few to allow conclusions to be reached: vitamin
A (as beta-carotene, alpha-carotene, or retinol); folate; vitamin C; vitamin E; and lycopene.

7.13.6 Comparison with previous report

7.13.4.2 Specific
Considerations specific to cancer of the cervix include:

7.13.6.1 GeneralSee 7.1.6.1, and box 3.8 in chapter 3.

Confounding. High-quality studies adjust for HPV infection.
Early studies that failed to adjust for HPV status have
reduced validity.

7.13.6.2 Specific
The previous report found that vegetables and fruits, andcarotenoids (not carrots specifically), and also vitamins C
and E possibly protect against cervical cancer.

7.13.5 Evidence and judgements
7.13.7 Conclusions
In total, 154 publications were included in the SLR for cervical cancer. Fuller summaries of the epidemiological,
experimental, and mechanistic evidence are to be found in
Chapters 4–6.
The full SLR is contained on the CD included with thisReport.
7.13.5.1 Carrots(Also see chapter 4.2.5.1.3.)
Five case-control studies and one ecological study investigated carrots. All of the case-control studies showeddecreased risk for the highest levels of intake compared withthe lowest, statistically significant in three. The case-control
studies all used hospital-based controls and none adjusted for
HPV status. The single ecological study showed non-significant increased risk with high intake of carrots.

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The Panel concludes:
There is limited evidence suggesting that carrots protect
against cervical cancer. The evidence is too limited to conclude that any aspect of food, nutrition, and physical activity directly modifies the risk of this cancer.

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7.14 Prostate
Prostate cancer is the second most common cancer in men(and the sixth most common cancer overall) worldwide.
Around 680 000 cases were recorded in 2002, accounting
for around 12 per cent of all new cases of cancer in men(6 per cent overall). It is most commonly diagnosed inhigh-income countries, where screening is common. Fiveyear survival rates are around 60 per cent. It is the sixth
most common cause of cancer death in men worldwide.
Overall, the Panel notes the impressive recent evidence
from cohort studies and trials demonstrating effects, orabsence of effect, of specific foods and nutrients on
prostate cancer.
The Panel judges as follows:
Foods containing lycopene, as well as selenium or foods
containing it, probably protect against prostate cancer.
Foods containing calcium are a probable cause of thiscancer. It is unlikely that beta-carotene (whether fromfoods or supplements) has a substantial effect on the riskof this cancer. There is limited evidence suggesting that
pulses (legumes) including soya and soya products, foods
containing vitamin E, and alpha-tocopherol supplements
are protective; and that processed meat, and milk anddairy products are a cause of this cancer.
In final summary, the strongest evidence, corresponding
to judgements of “convincing” and “probable”, shows thatfoods containing lycopene, as well as selenium or foods
containing it, probably protect against prostate cancer,
and that foods containing calcium are a probable cause ofthis cancer. It is unlikely that beta-carotene (whether fromfoods or supplements) has a substantial effect on the riskof this cancer.

The prostate is a walnut-sized gland in men that surrounds
the top of the urethra; it produces seminal fluid. Its growthand function are controlled by male hormones such as
testosterone.
Almost all prostate cancers are adenocarcinomas,4 the typeincluded here.

7.14.1 Trends, incidence, and survival

FOOD, NUTRITION, PHYSICAL ACTIVITY,
AND CANCER OF THE PROSTATEIn the judgement of the Panel, the factors listed below modify the risk ofcancer of the prostate. Judgements are graded according to the strengthof the evidence.

DECREASES RISK
Convincing
Probable

Foods containing
lycopene1 2
Foods containing
selenium1

Diets high incalcium4 5

Selenium3
Limited —suggestive

Limited —no conclusion

Substantial
effect on risk
unlikely

1
2
3
4
5

6
7
8

Age-adjusted incidence rates of prostate cancer increased dramatically between 1988 and 1992.137 This was largely
because of the increased availability of screening for prostatespecific antigen (PSA) in men without symptoms of the disease. This test leads to the detection of many prostate cancers
that are small and/or would otherwise remain unrecognised,
and which may or may not develop further into higher stage
disease (see 7.14.2). Rates were already increasing before theavailability of PSA testing, and have continued to increase in
middle-income countries where screening is still not widely
available.124 This suggests that prostate cancer is influenced

INCREASES RISK

9

Pulses (legumes)6
Foods containing
vitamin E1

Processed meat8

Alpha-tocopherol7

Milk and dairy
products5

Cereals (grains) and their products; dietary fibre;
potatoes; non-starchy vegetables; fruits; meat;
poultry; fish; eggs; total fat; plant oils; sugar(sucrose); sugary foods and drinks; coffee; tea;
alcohol; carbohydrate; protein; vitamin A; retinol;
thiamin; riboflavin; niacin; vitamin C; vitamin D;
gamma-tocopherol; vitamin supplements;
multivitamins; iron; phosphorus; zinc; othercarotenoids; physical activity; energy expenditure;
vegetarian diets; Seventh-day Adventist diets;
body fatness; abdominal fatness; birth weight;
energy intake

Beta-carotene1 9

Includes both foods naturally containing the constituent and foods whichhave the constituent added (see chapter 3.5.3).
Mostly contained in tomatoes and tomato products. Also fruits such as
grapefruit, watermelon, guava, and apricot.
The evidence is derived from studies using supplements at a dose of
200 µg/day. Selenium is toxic at high doses.
Includes diets that naturally contain calcium and that contain foods
fortified with calcium. See box 4.10.1.
Effect only apparent at high calcium intakes (around 1.5 g/day or more).
Evidence for milk and dairy products (but not calcium) was derived only
from countries with populations that have high calcium and dairy
consumption.
Including soya and soya products.
The evidence is derived from studies using supplements at a dose of
50 mg/day.
The term ‘processed meat’ refers to meats preserved by smoking, curing,or salting, or addition of chemical preservatives.
The evidence is derived from studies using supplements at doses of 20, 30,
and 50 mg/day.

For an explanation of all the terms used in the matrix,
please see chapter 3.5.1, the text of this section,and the glossary.

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by environmental factors. Although screening is increasingly
popular in many high-income countries, its value, for example in reducing mortality, is controversial. There has been adecline in incidence and mortality in several high-income
countries since the 1990s although rates remain higher thanthose recorded before screening became available. This trend
may be due to elimination of early stage disease andimproved treatment.277
Prostate cancer is mainly a disease of high-income countries, where overall rates are nearly six times higher than in
middle- to low-income countries. Around the world, ageadjusted incidence rates range from more than 100 per
100 000 men in North America, parts of the Caribbean, andOceania, to less than 10 per 100 000 in Melanesia and muchof Asia.2 This wide range is partly, but not entirely, attributable to the increased availability of screening in high-income
countries. In the USA, rates are higher among AfricanAmerican men than in white men.3
Risk increases with age, rising sharply after 40. In mosthigh-income countries, incidence in men below 40 is typically less than 1 per 100 000, rising to more than 1000 per
100 000 in those aged 65 and over.278
Average survival for prostate cancer is relatively highworldwide, although markedly more so in high-income countries. The 5-year survival rate is approximately 60 per centoverall: 76 per cent in high-income countries compared with
45 per cent in middle- to low-income countries.124 This cancer accounts for around 6 per cent of all cancer incidence(nearly 12 per cent in men) but around 3 per cent of all cancer deaths (almost 6 per cent in men; all sites except for nonmelanoma skin). Also see box 7.1.1.

7.14.2 Pathogenesis
The disease usually develops slowly and dysplastic lesions
may precede cancer by many years or even decades.
Extrapolations from autopsy studies suggest that most men
would have prostate cancer if they lived to be more than
100.278 The number of prostate cancers found incidentally
at autopsy, which had been asymptomatic and not a causeof death, suggests that small, localised prostate cancers canremain unrecognised for many years before progressing to aclinically significant form. Men are more likely to die with,rather than from, prostate cancer.279 280
The increased prostate cancer incidence in first-degree
male relatives of women who have early onset breast cancer suggests a genetic predisposition.281 Some studies propose that this may be linked to the BRCA genes.282
Growth factors, particularly IGF, as well as androgens havealso been implicated in the development of prostate cancers.
Serum levels of IGF-1 can be associated with prostate cancer independently of PSA levels.283 High levels of testosterone promote cell differentiation, which could protect
against the development of this cancer. Therefore, declining
levels of this hormone in older age may contribute to thedevelopment of this cancer.284

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7.14.3 Other established causes(Also see chapter 2.4 and 7.1.3.1.)
There are no other established causes of prostate cancer.

7.14.4 Interpretation of the evidence
7.14.4.1 General
For general considerations that may affect interpretation of
the evidence, see chapters 3.3 and 3.5, and boxes 3.1, 3.2,
3.6 and 3.7.
‘Relative risk’ is used in this Report to denote ratio measures of effect, including ‘risk ratios’, ‘rate ratios’, ‘hazard
ratios’, and ‘odds ratios’.
7.14.4.2 Specific
Considerations specific to cancer of the prostate include:
Confounding. Screening is associated with relatively highsocioeconomic status and also with ‘health-conscious’ behaviour such as taking exercise or following dietary guidelines.
High-quality studies adjust for these factors. Some case-control studies use cases that have been detected by screening.
If so, it is important that control groups are also from ascreened population.

7.14.5 Evidence and judgements
In total, 558 publications were included in the SLR for
prostate cancer. Fuller summaries of the epidemiological,
experimental, and mechanistic evidence are to be found in
Chapters 4–6.
The full SLR is contained on the CD included with thisReport.
7.14.5.1 Pulses (legumes) including soya and soya
products(Also see chapter 4.2.5.10.)
A total of 3 cohort studies, 11 case-control studies, and 6 ecological studies investigated pulses (legumes); 4 cohort studies, 4 case-control studies, and 2 ecological studies
investigated soya and soya products. Most studies showeddecreased risk with increased intake. Meta-analysis of casecontrol data produced evidence of an association withlegume intake, with a clear dose-response relationship.
Pulses (legumes), particularly soya foods, contain various
compounds that may have anti-cancer effects. These compounds could plausibly influence oestrogen metabolism. In
addition, phytoestrogens in pulses and soya can have an
androgenic effect, potentially inhibiting testosterone-induced
growth of the prostate.
The evidence, mostly from case-control studies, isinconsistent. There is limited evidence suggesting that
pulses (legumes), including soya and soya products,
protect against prostate cancer.

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7.14.5.2 Processed meat
(Also see chapter 4.3.5.1.2.)
Four cohort studies and six case-control studies investigated processed meat. All cohort studies reported increased risk
with higher intake; and most case-control studies also
showed this effect.
Nitrates are both produced endogenously in gastric acidand added as preservatives to processed meats (box 4.3.2).
They may contribute to N-nitroso compound production andexposure. These compounds are suspected mutagens andcarcinogens.55
Many processed meats also contain high levels of salt andnitrite. Meats cooked at high temperatures can contain heterocyclic amines and polycyclic aromatic hydrocarbons (box
4.3.4). Haem promotes the formation of N-nitroso compounds and also contains iron. Free iron can lead to production of free radicals (box 4.3.3).
There is limited evidence from sparse and inconsistentstudies suggesting that processed meat is a cause of
prostate cancer.

The Panel is aware that since the conclusion of the SLR, twocohort studies285 286 have been published. This new information
does not change the Panel judgement. Also see box 3.8.
7.14.5.3 Milk and dairy products(Also see chapter 4.4.5.1.)
A total of 10 cohort studies, 13 case-control studies, and 2
ecological studies investigated milk and dairy foods; 16
cohort studies, 11 case-control studies, and 11 ecologicalstudies investigated milk. Most of the studies showed
increased risk with increased intake. Meta-analysis of cohort
data produced evidence of a clear dose-response relationshipbetween advanced/aggressive cancer risk with milk intake,and between all prostate cancer risk and milk and dairy
products.
Most other meta-analyses show non-significant increased
risk. Ecological studies consistently report a relationship inthe direction of increased risk between milk or dairy consumption and prostate cancer.
High calcium intake downregulates the formation of 1,25dihydroxy vitamin D3 from vitamin D, thereby increasing cellproliferation in the prostate.287 Prostate cancer tumours inrats treated with 1,25-dihydroxy vitamin D3 were significantly smaller, and presented smaller numbers of lung metastases.288 Also, consumption of milk increases blood levels of
IGF-1, which has been associated with increased prostatecancer risk in some studies.283 289
The evidence is inconsistent from both cohort andcase-control studies. There is limited evidence
suggesting that milk and dairy products are a cause of
prostate cancer.

The Panel is aware that since the conclusion of the SLR, twocohort studies290 291 and one case-control study189 have been
published. This new information does not change the Panel
judgement. Also see box 3.8.

7.14.5.4 Diets high in calcium(Also see chapter 4.4.5.2.)
Nine cohort studies, 12 case-control studies, and 2 ecological studies investigated dietary calcium. Most cohort studies showed increased risk with increased calcium intake;case-control studies were inconsistent. Meta-analysis ofcohort data showed an increased risk of 27 per cent per
g/day; meta-analysis of cohort data on advanced or aggressive prostate cancer showed an increased risk of 32 per centper g/day. Meta-analyses of case-control data showed nonsignificant increased risk.
Calcium can be taken to be a marker for dairy intake inhigh-income populations. In areas outside the USA, Europe,and Oceania, dairy products are not as widely consumed,
and the range of calcium intakes is smaller.
High calcium intake downregulates the formation of 1,25dihydroxy vitamin D3 from vitamin D, thereby increasingcell proliferation in the prostate.287 Prostate cancer tumoursin rats treated with 1,25-dihydroxy vitamin D3 were significantly smaller and presented fewer lung metastases.288
The evidence, from both cohort and case-control
studies, is substantial and consistent, with a doseresponse relationship. There is evidence for plausible
mechanisms. Diets high in calcium are a probablecause of prostate cancer.

The Panel is aware that since the conclusion of the SLR, twocohort studies290 291 have been published. This new information does not change the Panel judgement. Also see box 3.8.
7.14.5.5 Foods containing selenium(Also see chapter 4.2.5.8.)
A total of 1 cohort study, 7 case-control studies, and 2 ecological studies investigated dietary selenium; 12 cohort
studies and 4 case-control studies investigated serum or
plasma selenium; and 3 cohort studies, 3 case-control studies, and 1 ecological study investigated levels in nails. Most
studies, including all of those that reported separately on
advanced/aggressive prostate cancer, showed decreased risk
with increased intake. Meta-analysis of cohort data on
advanced or aggressive prostate cancer showed a decreased
risk of 13 per cent per 10 µg selenium/litre of serum or
plasma (figure 4.2.37), or 20 per cent per 100 ng selenium
per g of nail clippings. Meta-analyses of cohort data that
included all prostate cancer diagnoses showed non-significant decreased risk. Case-control studies were inconsistent.
Dietary selenium deficiency has been shown to cause alack of selenoprotein expression. Twenty-five selenoproteins
have been identified in animals, and a number of these haveimportant anti-inflammatory and antioxidant properties.
Four are glutathione peroxidases, which protect against
oxidative damage to biomolecules such as lipids, lipoproteins, and DNA. Three are thioredoxin reductases; among
other functions, these regenerate oxidised ascorbic acid to
its active antioxidant form.
In addition, selenoproteins are involved in testosterone
production, which is an important regulator of both normal
and abnormal prostate growth.

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The evidence from cohort and case-control studies is
consistent, with a dose-response relationship. There isevidence for plausible mechanisms. Foods containing
selenium probably protect against prostate cancer.

7.14.5.6 Foods containing lycopene(Also see chapter 4.2.5.3.)
A total of 5 cohort studies, 9 case-control studies, and 3 ecological studies investigated tomatoes; 3 cohort studies and14 case-control studies investigated dietary lycopene; and 6
cohort studies and 2 case-control studies investigated serumor plasma lycopene. Most of the studies showed decreased
risk with increased intake. Studies of cumulative lycopene
intake, or of tomato sauce products (from which lycopene ishighly bioavailable), showed statistically significant
decreased risk. Meta-analysis of cohort data on serum or
plasma lycopene, which are likely to be more precise andaccurate than dietary assessments, showed a 4 per centdecreased risk per 10 µg lycopene/litre.
Lycopene is best absorbed from vegetables and fruits that
contain it after they are cooked and pureed. The best measures, that take the degree of absorption into account, aretherefore from studies on tomato sauce or serum/plasma
lycopene. The Panel also gave emphasis to studies on
advanced or aggressive cancers, which may be better linked
to prognosis than studies that include early stage or
unrecognised disease.
Lycopene is the most potent carotenoid antioxidant, has
an antiproliferative effect, reduces plasma low-density
lipoprotein cholesterol, improves immune function, andreduces inflammation.
There is a substantial amount of consistent evidence,in particular on tomato products, from both cohort andcase-control studies. There is evidence for plausible
mechanisms. Foods containing lycopene probably
protect against prostate cancer.

The Panel is aware that since the conclusion of the SLR, twocohort studies292 293 and one case-control study294 have been
published. This new information does not change the Panel
judgement. Also see box 3.8.
7.14.5.7 Selenium(Also see chapter 4.10.6.4.5.)
One randomised controlled trial and two cohort studies
investigated selenium supplements. The randomised controlled trial was conducted in 974 men with a history of skincancers, randomised to receive a daily supplement of 200 µg
selenium or a placebo. Prostate cancer was not a prior stated outcome, and was assessed as a secondary endpoint. The
trial showed a 63 per cent decreased risk from selenium supplementation. Both cohort studies showed non-significant
decreased risk with selenium supplementation.
Dietary selenium deficiency has been shown to cause alack of selenoprotein expression. Twenty-five selenoproteins
have been identified in animals and a number of these haveimportant anti-inflammatory and antioxidant properties.
Four are glutathione peroxidases, which protect against

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oxidative damage to biomolecules such as lipids, lipoproteins, and DNA. Three are thioredoxin reductases; among
other functions, these regenerate oxidised ascorbic acid to
its active antioxidant form. In addition, selenoproteins are
involved in testosterone production, which is an important
regulator of both normal and abnormal prostate growth.
There is strong evidence from trials and cohort studies.
Selenium probably protects against prostate cancer.

7.14.5.8 Foods containing vitamin E(Also see chapter 4.2.5.7.)
A total of 2 cohort studies, 13 case-control studies, and 1 ecological study investigated dietary vitamin E; and 4 cohort
studies and 1 case-control study investigated serum vitamin
E. Other groupings examined were serum or plasma alphatocopherol (8 cohort, 2 case-control) and serum gammatocopherol (6 cohort, 1 case-control). Most studies showeddecreased risk with increased intake. Meta-analysis ofcohort data on serum gamma-tocopherol produced evidenceof an association with decreased risk, with a clear doseresponse relationship.
Vitamin E is an antioxidant that has been reported to prevent DNA damage, enhance DNA repair, prevent lipid peroxidation, and prevent activation of carcinogens such as
nitrosamines. Vitamin E protects vitamin A and selenium inthe body. In addition to acting as a free-radical scavenger,
vitamin E enhances the body’s immune response, which may
play a role in cancer defences.
The evidence on vitamin E, mostly from case-control
studies, was inconsistent. There is limited evidence
suggesting that foods containing vitamin E protect
against prostate cancer.

The Panel is aware that since the conclusion of the SLR, twocohort studies293 295 have been published. This new information
does not change the Panel judgement. Also see box 3.8.
7.14.5.9 Beta-carotene(Also see chapters 4.2.5.3 and 4.10.6.4.2.)
Six cohort studies and 21 case-control studies investigateddietary beta-carotene; 10 cohort studies and 5 case-control
studies investigated serum or plasma beta-carotene; 3 randomised controlled trials and 2 cohort studies investigatedbeta-carotene supplements. Meta-analyses of 6 cohort studies and 15 case-control studies that investigated betacarotene from food and 7 cohort studies that investigatedserum or plasma beta-carotene produced evidence for there
being no association with prostate cancer risk. One randomised controlled trial produced evidence of no association; the other two showed that it was unlikely thatbeta-carotene reduced incidence, but did not exclude aneffect of increasing incidence.
There is strong evidence from good quality trials
and from cohort studies, which consistently failto demonstrate a protective effect. Beta-carotene
supplements are unlikely to have a substantial

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protective effect against prostate cancer. The evidence
is too limited to draw a conclusion on a harmful
effect. It is unlikely that beta-carotene or foods
containing it have a substantial effect on the risk of
prostate cancer.

The Panel is aware that since the conclusion of the SLR, twocohort studies293 295 have been published. This new information
does not change the Panel judgement. Also see box 3.8.
7.14.5.10 Alpha-tocopherol (vitamin E)(Also see chapter 4.10.6.4.3.)
One randomised controlled trial investigated alpha-tocopherol supplements and prostate cancer. The large randomised controlled trial of male smokers given daily
supplements of 50 mg of alpha-tocopherol and 20 mg ofbeta-carotene showed a statistically significant 34 per centdecreased risk for alpha-tocopherol supplements. Prostatecancer was not a prior-stated outcome for this trial.
Vitamin E exists in eight different forms (isomers): four
tocopherols and four tocotrienols. There is an alpha, beta,
gamma, and delta form of each. Each form has slightly different biological properties but all are antioxidants. Alphatocopherol is thought to be the most biologically active
isomer of vitamin E. It inhibits cell proliferation, can directly activate certain enzymes, and exerts transcriptional control on several genes. Vitamin E may have a direct effect on
prostate growth by decreasing cellular concentrations of
testosterone, which could impair differentiation.

reflecting the recent intense research interest in prostate cancer, including randomised controlled supplementation trials.

7.14.7 Conclusions
The Panel concludes:
Foods containing lycopene, as well as selenium and foods
containing it, probably protect against prostate cancer. Dietshigh in calcium are a probable cause of this cancer. It is
unlikely that beta-carotene (whether from foods or supplements) has a substantial effect on the risk of this cancer.
There is limited evidence suggesting that pulses (legumes)
including soya and soya products, foods containing vitamin
E, and alpha-tocopherol supplements are protective, and thatprocessed meat, and milk and dairy products are a cause ofthis cancer.

The evidence is sparse. There is limited evidence thatalpha-tocopherol supplements protect against prostatecancer in smokers.

7.14.5.11 Other exposures
Other exposures were evaluated. However, the data were
either of too low quality, too inconsistent, or the number ofstudies too few to allow conclusions to be reached. These
were as follows: culturally defined diets (vegetarian,Seventh-day Adventist); cereals (grains) and their products;
potatoes; fruit and (non-starchy) vegetables; poultry; meat;
fish; eggs; all fats; plant oils; sugar; confectionery; dietary
fibre; fat; protein; carbohydrate; coffee; tea; alcoholic drinks;
vitamin supplements; multivitamins; vitamin A; retinol;
carotenoids; thiamine; riboflavin; niacin; vitamin C; vitamin
D; vitamin E from foods; iron; zinc; phosphorus; physicalactivity; energy intake; energy expenditure; body composition; size and shape; and birth weight.

7.14.6 Comparison with previous report
7.14.6.1 GeneralSee 7.1.6.1, and box 3.8 in chapter 3.
7.14.6.2 Specific
The findings here on foods containing lycopene and/or calcium, and on selenium or foods containing it, are new,309

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7.15 Kidney
Cancer of the kidney is the 15th most common typeworldwide. Around 200 000 cases were recorded in 2002,
accounting for around 2 per cent of all cancers. Averageoverall survival rates are around 50 per cent at 5 years. It
is the 16th most common cause of death from cancer.
Overall, the Panel is impressed by the pattern of evidence
showing the importance of body fatness as a cause ofcancer of the kidney.
The Panel judges as follows:
The evidence that body fatness is a cause of this cancer isconvincing. It is unlikely that coffee has a substantial
effect, or that alcoholic drinks have an adverse effect, on
the risk of this cancer. There is limited evidence suggestingthat arsenic in drinking water is a cause of this cancer.
Smoking is a cause of cancer of the kidney.
In final summary, the strongest evidence, corresponding
to judgements of “convincing” and “probable”,shows that
greater body fatness is a cause of kidney cancer; and that it
is unlikely that coffee has a substantial effect, or alcoholic
drinks an adverse effect, on the risk of this cancer.

The kidneys are at the back of the abdomen and outside theperitoneal cavity. They filter waste products and water fromthe blood, producing urine, which empties into the bladderthrough the ureter. They are also important endocrine organs
concerned with salt and water metabolism, and convert vitamin D to its active form.
Renal cell carcinoma is the most common kidney cancer,
accounting for approximately 85 per cent. The majority ofthese are adenocarcinomas,4 the type included here. Kidneycancers also include transition cell carcinomas of the renal
pelvis, sarcomas, and Wilms’ tumour (nephroblastoma), a
childhood cancer. This section refers mainly to renal cell
carcinomas; some studies also examined transitional cell
carcinomas.

7.15.1 Trends, incidence, and survival
Age-adjusted rates of kidney cancer are increasing worldwide. Rates have doubled in many high-income countries
since the mid-1970s, with some of the largest increases incountries in eastern Europe, for example, that are undergoing profound economic transition.137
This is mainly a disease of high-income countries, whererates are nearly five times higher overall than in middle- to
low-income countries. Around the world, age-adjusted incidence rates range from 10–20 per 100 000 people in North
America, parts of Europe, and Australia to less than 2 per
100 000 in parts of Africa.2 In the USA, rates are higher
among African-American people than in white people.
Globally, rates are higher in men than in women, by five tothree.3 Risk increases with age, with most diagnoses made

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AND CANCER OF THE KIDNEY
In the judgement of the Panel, the factors listed below modify the risk ofcancer of the kidney. Judgements are graded according to the strengthof the evidence.

DECREASES RISK
Convincing

INCREASES RISK
Body fatness

Probable
Limited —suggestive
Limited —no conclusion

Substantial
effect on risk
unlikely12Arsenic in drinking
water1
Cereals (grains) and their products; vegetables;
fruits; meat; poultry; fish; eggs; milk and dairy
products; total fat; soft drinks; tea; alcoholic drinks(protective effect)2; carbohydrate; protein; vitamin
A; retinol; vitamin C; vitamin E; beta-carotene;
flavonol; Seventh-day Adventist diets; physicalactivity; body fatness at age 18–20; weight at age
18–20; birth weight; adult attained height; age at
menarche; energy intake.

Coffee; alcoholic drinks (adverse effect)2

The International Agency for Research on Cancer has graded arsenic andarsenic compounds as Class 1 carcinogens. The grading for this entry
applies specifically to inorganic arsenic in drinking water.
The evidence was sufficient to judge that alcoholic drinks were unlikely tohave an adverse effect on the risk of kidney cancer; but it was inadequate
to draw a conclusion regarding a protective effect.

For an explanation of all the terms used in the matrix,
please see chapter 3.5.1, the text of this section,and the glossary.

in people between the ages of 60 and 80.296
Kidney cancer is diagnosed at an early stage in more thanhalf of cases. The 5-year survival rate is about 95 per centfor early stage cancers, and about 20 per cent at the mostadvanced stages.296 Overall, 5-year survival rates are morethan 50 per cent in high-income countries, but lower in middle- to low-income countries.3 6 This cancer accounts foralmost 2 per cent of all cancer incidence, and somewhat over
1 per cent of all cancer deaths. Also see box 7.1.1.

7.15.2 Pathogenesis
Urine contains many waste products from food, drinks, andother environmental sources, and some of these are potential carcinogens, such as carcinogens from cigarette smoke,and may play a role in kidney cancer.
It is not clear whether benign renal adenomas are a precursor of renal cell carcinoma. They are similar histologicallyand are frequently distinguished predominantly by their size.
Most adult kidney cancers are sporadic renal cell carcino-

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mas, which can be divided into two main types. The conventional (or clear cell) type accounts for 75 per cent; 12
per cent of cases are of the papillary form,296 which are lesslikely to metastasise. In 60 per cent of conventional carcinoma cases, there is a mutation in the von Hippel–Lindau
tumour suppressor gene (VHL) (see box 2.2).297 VHL diseaseis also a cause of some familial kidney cancers.

7.15.3 Other established causes(Also see chapter 2.4 and 7.1.3.1.)
Tobacco use. Smoking is a cause of kidney cancer, increas-

ing the risk approximately twofold.10 The association isstronger for cancers of the renal pelvis.298
Medication. Analgesics containing phenacetin are a cause ofcancer of the renal pelvis.299 Dialysis is a cause of kidney cancer, perhaps through its role in the development of acquired
renal cystic disease.300 301

7.15.4 Interpretation of the evidence
7.15.4.1 General
For general considerations that may affect interpretation of
the evidence, see chapters 3.3 and 3.5, and boxes 3.1, 3.2,
3.6 and 3.7.
‘Relative risk’ is used in this Report to denote ratio measures of effect, including ‘risk ratios’, ‘rate ratios’, ‘hazard
ratios’, and ‘odds ratios’.
7.15.4.2 Specific
Considerations specific to cancer of the kidney include:
Classification. The subtype of kidney cancer may also be

important. Papillary renal cell carcinomas may follow a different disease path from other renal cell carcinomas. Somestudies also included transitional cell carcinomas or lookedat both renal and urinary tract tumours.
Confounding. High-quality studies adjust for smoking.

7.15.5 Evidence and judgements
In total, 187 publications were included in the SLR for kidney cancer. Fuller summaries of the epidemiological, experimental, and mechanistic evidence are to be found in
Chapters 4–6.
The full SLR is contained on the CD included with thisReport.
7.15.5.1 Arsenic in drinking water(Also see chapter 4.7.5.1.1.)
Three cohort studies, one time-series study, and nine ecological studies investigated arsenic in drinking water. All
studies showed increased risk for the highest intake levels

compared with the lowest. Effect sizes, particularly from ecological studies in areas of high exposure levels, tend to berelatively large.
Arsenic is carcinogenic to humans and causes chromosomal abnormalities.217 Arsenic biotransformation is thought
to lead to a state of oxidative stress. In addition, arsenic indrinking water is well absorbed in the gastrointestinal tract,
and both inorganic arsenic and its methylated metabolites
are excreted in urine. Arsenic can modify the urinary excretion of porphyrins in animals and humans.
The evidence is sparse. There is limited evidence
suggesting that arsenic in drinking water is a cause ofkidney cancer.

7.15.5.2 Coffee(Also see chapter 4.7.5.4.)
Five cohort studies, 18 case-control studies, and 1 ecological study investigated coffee. None of the cohort studies andonly 1 of the case-control studies reported a statistically significant association. Meta-analysis of case-control data produced evidence of no association.
There is substantial evidence, both from cohort andcase-control studies, which is consistent and of low
heterogeneity, and which fails to show an association.
It is unlikely that coffee has a substantial effect on therisk of kidney cancer.

The Panel is aware that since the conclusion of the SLR, onecohort study302 has been published. This new information does
not change the Panel judgement. Also see box 3.8.
7.15.5.3 Alcoholic drinks(Also see chapter 4.8.5.1.)
A total of 3 cohort studies and 16 case-control studies investigated alcoholic drinks; 4 cohort and 5 case-control studies
investigated ethanol intake. Studies showed no consistent
direction of effect. Meta-analysis of cohort data on ethanol
produced evidence of a dose-response relationship withdecreased risk; cohort data on alcoholic drinks were heterogeneous. Meta-analyses of case-control data showed nonsignificant decreased risk.
It is unlikely that alcoholic drinks increase the risk ofkidney cancer, though a protective effect cannot be
excluded.

The Panel is aware that since the conclusion of the SLR, onecohort study302 has been published. This new information does
not change the Panel judgement. Also see box 3.8.
7.15.5.4 Body fatness(Also see chapter 6.1.3.1.)
Seventeen cohort studies and 20 case-control studies investigated body fatness, as measured by BMI. Nearly all of themshowed increased risk with increased body fatness, withnone showing a statistically significant decreased risk. Metaanalysis of cohort data showed a 31 per cent increased risk

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per 5 kg/m2; meta-analysis of case-control data showed a
205 (adjusted for smoking) or 42 (unadjusted) per centincreased risk per 5 kg/m2 (figures 6.1.19 and 6.1.20).
There was little heterogeneity in the former two analyses;
the heterogeneity in the latter could be partially explainedby failure to adjust for smoking.
Body fatness directly affects levels of many circulating
hormones, such as insulin, insulin-like growth factors, andoestrogens, creating an environment that encourages carcinogenesis and discourages apoptosis (box 2.4). It also
stimulates the body’s inflammatory response, which may
contribute to the initiation and progression of several cancers (see chapter 2.4.1.3). In addition, laboratory studies
point to a potential role for insulin and leptin in renal cell
carcinoma.303 304
There is abundant and consistent epidemiologicalevidence with a dose-response relationship and evidenceof plausible mechanisms. The evidence that greater bodyfatness is a cause of kidney cancer is convincing.

The Panel is aware that since the conclusion of the SLR, threecohort studies58 213 305 and one case-control study306 have been
published. This new information does not change the Panel
judgement. Also see box 3.8.

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7.16 Bladder
Cancer of the bladder is the 10th most common typeworldwide. Around 350 000 cases were recorded in 2002,
accounting for around 3 per cent of all cancers. It is mostcommon in high-income countries. Rates are much higher
in men than in women. Overall rates of this cancer are notchanging much. Average overall survival rates varydepending on how soon the cancer is detected. It is the
11th most common cause of death from cancer.
Overall, the Panel notes the evidence that food,nutrition, and physical activity are not significant factors
in the development of cancer of the bladder.
The Panel judges as follows:
There is limited evidence suggesting that milk protects
against bladder cancer; and that arsenic in drinking water
is a cause.
Smoking tobacco and schistosomiasis are other causesof this cancer.
In final summary, the evidence is too limited to conclude
that any aspect of food, nutrition, and physical activity
directly modifies the risk of bladder cancer.

7.15.5.5 Other exposures
Other exposures were evaluated. However, the data were
either of too low quality, too inconsistent, or the numberof studies too few to allow conclusions to be reached. These
were as follows: cereals (grains) or their products; vegetables; fruits; meat; poultry; fish; eggs; milk and dairy products; soft drinks; tea; alcoholic drinks (protective effect);carbohydrate; total fat; protein; vitamin A; retinol; betacarotene; vitamin C; vitamin E; flavonol; physical activity;
energy intake; body fatness at age 18–20; weight at age
18–20; age at menarche; adult attained height; birthweight; and Seventh-day Adventist diets.

The bladder is a sac-like organ that is the reservoir for urine.
The inside of the bladder is lined by transitional epithelial
cells known as the urothelium.
The term ‘urothelial cancers’ includes predominantly transition cell carcinomas of the bladder and cancers of the upper
part of the urinary tract. Transitional cell carcinoma is themost common form, accounting for more than 90 per centof bladder cancers, the type mainly included here. Other
types (in order of incidence) include squamous cell carcinomas, adenocarcinomas, and small cell cancers.4

7.15.6 Comparison with previous report

7.16.1 Trends, incidence, and survival

7.15.6.1 GeneralSee 7.1.6.1, and box 3.8.

There is no clear global trend in bladder cancer incidence.
While rates increased in many countries during the 20th century, this rise has generally slowed since the mid-1980s or
stopped.137 However, there are exceptions, such as in Japanand countries in eastern Europe that are in economic transition.
Bladder cancer is predominantly a disease of high-income
countries, where overall rates are slightly more than threetimes higher than in middle- to low-income countries.
Around the world, age-adjusted incidence rates range from
20–30 per 100 000 men in southern and western Europe andNorth America to less than 1 per 100 000 in much of Middle
Africa and Asia.2 It is five times more common in men thanin women, and risk increases with age. In northern Africa
and parts of Asia, where schistosomiasis (a parasitic disease,also known as bilharzia) is prevalent, bladder cancer rates
are high and squamous cell carcinomas of the bladder are

7.15.6.2 Specific
The previous report judged that high body mass is probably a cause of kidney cancer. Since then the evidence forbody fatness has become stronger.

7.15.7 Conclusions
The Panel concludes:
The evidence that body fatness is a cause of kidney cancer
is convincing. It is unlikely that coffee has a substantial
effect, or alcoholic drinks an adverse effect, on the risk ofthis cancer. There is limited evidence suggesting that
arsenic in drinking water is a cause of this cancer.

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FOOD, NUTRITION, PHYSICAL ACTIVITY,
AND CANCER OF THE BLADDERIn the judgement of the Panel, the factors listed below modify the risk ofcancer of the bladder. Judgements are graded according to the strengthof the evidence.

DECREASES RISKINCREASES RISK

Limited —suggestive

Milk1

Arsenic in drinking
water2

Limited —no conclusion

Cereals (grains) and their products; vegetables; fruits;pulses (legumes); meat; poultry; fish; eggs; total fat;butter; dietetic foods; soft drinks; diet drinks; fruit
juices; coffee; tea; caffeine; alcohol; chlorinatedsurface water; total fluid intake; sweeteners; frying;carbohydrate; protein; vitamin A; folate; vitamin C;
vitamin E; multivitamin supplements; selenium;
beta-carotene; alpha-carotene; lycopene; betacryptoxanthin; lutein; zeaxanthin; flavonoids;
physical activity; body fatness; energy intake

Convincing
Probable

Substantial
effect on risk
unlikelyso the bladder lining is exposed to these toxins.
Urothelial cell carcinomas start as superficial bladder carcinomas. The majority have low rates of progression,
although they can occur at multiple sites. Low-risk lesions
may never progress, but they have a poor prognosis if they
become invasive cancers.
The superficial lesion that carries the highest risk, carcinoma in situ, progresses to invasive cancer in more than 50
per cent of cases if it is not treated. These high-risk lesions
are often found with multiple papillary tumours, but
because they may involve different molecular changes, they
are likely to have a different natural history to low-risk
lesions.308
Squamous cell carcinoma may be caused by chronic
inflammation, for instance from latent schistosomiasis,chronic infections, or long-term catheter use.
Mutations in the tumour-suppressor p53 gene, as well as
abnormalities in chromosome 9, are common in invasive
bladder cancer (see box 2.2). Inherited mutations of twoother genes, GSTM1 (glutathione S-transferase null) and
NAT2 (n-acetyltransferase; slow acetylation) also cause bladder cancer. NAT2 interacts with cigarette smoke, and may
be responsible for 20–46 per cent of bladder cancers.309

None identified

7.16.3 Other established causes
1

2

Milk from cows. Most data are from high-income populations, where
calcium can be taken to be a marker for milk/dairy consumption. The Panel
judges that a higher intake of dietary calcium is one way in which milk
could have a protective effect.
The International Agency for Research on Cancer has graded arsenic andarsenic compounds as Class 1 carcinogens. The grading for this entry applies
specifically to inorganic arsenic in drinking water.

For an explanation of all the terms used in the matrix,
please see chapter 3.5.1, the text of this section,and the glossary.

(Also see chapter 2.4 and 7.1.3.1.)
Tobacco use. Smoking is a major cause of bladder cancer. It

is estimated that more than half of all cases in men andaround a third in women are caused by smoking.10 310
Infection and infestation. Infestation with schistosomes (par-ticularly Schistosoma haematobium) is a cause of bladdercancer, particularly squamous cell carcinomas.311 This is estimated to be responsible for 10 per cent of bladder cancer
cases in middle- and low-income countries, and 3 per centof cases overall.312
Industrial chemicals. Occupational exposure to aromaticthe most common type. In Egypt, it is the most common cancer among men and the third most common among
women.307 In the USA, rates are higher in white people thanamong other ethnic groups.3
Five-year survival rates vary according to the stage of thecancer when it is diagnosed. They range from 63 to 88 percent in cases of superficial bladder carcinoma, and from 47
to 63 per cent in muscle-invasive bladder cancer.4 However,recurrence rates for this cancer are relatively high.308 This disease accounts for just over 3 per cent of all cancer incidence,
and around 2 per cent of all cancer deaths. Also see box
7.1.1.

7.16.2 Pathogenesis
Dietary carcinogens, as well as those from tobacco smoke orother environmental sources, are often excreted in the urine,

amines, such as 2-naphthylamine (used in dyes), also
increases the risk of bladder cancer.313

7.16.4 Interpretation of the evidence
7.16.4.1 General
For general considerations that may affect interpretation of
the evidence, see chapters 3.3 and 3.5, and boxes 3.1, 3.2,
3.6 and 3.7.
‘Relative risk’ is used in this Report to denote ratio measures of effect, including ‘risk ratios’, ‘rate ratios’, ‘hazard
ratios’, and ‘odds ratios’.
7.16.4.2 Specific
Considerations specific to cancer of the bladder include:
Confounding. High-quality studies adjust for smoking.

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7.16.5 Evidence and judgements
In total, 349 publications were included in the SLR for bladder cancer. Fuller summaries of the epidemiological, experimental, and mechanistic evidence are to be found in
Chapters 4–6.
The full SLR is contained on the CD included with thisReport.
7.16.5.1 Milk
(Also see chapter 4.4.5.1.1.)
Five cohort studies, 14 case-control studies, and 1 ecological study investigated milk. All of the cohort studies and halfof the case-control studies showed decreased risk withincreased intake of milk. Meta-analysis of cohort data produced evidence of an association with decreased risk, witha clear dose-response relationship. Meta-analysis of case-control data was inconclusive.
The possible effect of milk in reducing bladder cancer risk
is likely to be mediated at least in part by calcium, which has
direct growth-restraining and differentiation- and apoptosisinducing actions on normal and tumour cells.184 However,milk includes many bioactive constituents, which may also
play a role.
The evidence is inconsistent and comes mainly fromevidence on dietary calcium. There is limited evidence
suggesting that milk protects against bladder cancer.

7.16.5.2 Arsenic in drinking water(Also see chapter 4.7.5.1.1.)
Six cohort studies, 1 time-series study, 7 case-control studies, and 11 ecological studies investigated arsenic in drinking water. Most studies showed increased risk for groups
with the highest intakes when compared with the lowest.
Soluble arsenic in drinking water induces lung cancers inexperimental animal models.71 In humans, arsenic is a chromosomal mutagen (an agent that induces mutations involving more than one gene, typically large deletions or
rearrangements). It can also act as a synergistic co-mutagen.
Arsenic exposure also causes chronic lung disease.71 Thesemechanisms may also apply to bladder cancer. The Joint
FAO/WHO Expert Committee on Food Additives has set a
provisional tolerable weekly intake of 0.015 mg per kg bodyweight.72
The evidence is inconsistent. There is limited evidence
suggesting that arsenic is a cause of bladder cancer.

7.16.5.3 Other exposures
Other exposures were evaluated. However, the data were
either of too low quality, too inconsistent, or the number ofstudies too few to allow conclusions to be reached. These
were as follows: cereals (grains) and their products; vegetables; fruits; pulses (legumes); meat; poultry; fish; eggs;
butter; dietetic foods; soft drinks; diet drinks; fruit juices;
coffee; caffeine; tea; alcohol; chlorinated surface water;
sweeteners; frying; carbohydrate; total fat; protein; vitamin
A; beta-carotene; alpha-carotene; lycopene; beta-cryptox-

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anthin; lutein; zeaxanthin; folate; vitamin C; vitamin E; selenium; multivitamin supplements; flavonoids; energy intake;physical activity; body fatness; and total fluid intake.

7.16.6 Comparison with previous report
7.16.6.1 GeneralSee 7.1.6.1, and box 3.8.
7.16.6.2 Specific
The previous report judged that vegetables and fruits probably protect against bladder cancer. As with other sites, theevidence for these foods is now considered to be weaker, in
this case, very much so. The previous finding that coffee(more than five cups per day) is a possible cause of bladdercancer was not found here.

7.16.7 Conclusions
The Panel concludes:
There is limited evidence suggesting that milk protects
against bladder cancer and that arsenic in drinking water isa cause.

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7.17 Skin
Cancer of the skin in its various forms is the most common
type of cancer worldwide. Around 90 per cent of all skincancers are non-melanoma. Around 4 million cases wererecorded in 2002, but it is likely that many cases are notreferred, and this cancer is not included in the rankings inthis Report. Around 160 000 cases of melanoma skincancer were recorded in 2002, accounting for around 1.5
per cent of all cancers. Skin cancers are more common in
high-income countries and among light-skinned people.
Overall rates of this cancer are increasing. Survival rates
of melanoma are high and also depend on access totreatment. Five-year survival rates for non-melanoma skincancer are more than 99 per cent. Melanoma is the 22nd
most common cause of death from cancer.
Overall, the Panel emphasises that the main cause of skincancer is over-exposure to radiation from sunlight.
The Panel judges as follows:
Arsenic in drinking water is probably a cause of skincancer. There is limited evidence suggesting that retinol
protects against squamous cell carcinomas of the skin, andthat selenium is a cause of skin cancer. It is unlikely thatbeta-carotene or foods containing it have a substantial
effect on the risk of non-melanoma skin cancer.
In final summary, the strongest evidence, corresponding
to judgements of “convincing” and “probable”, shows that
arsenic in drinking water is probably a cause of skincancer. It is unlikely that beta-carotene or foods containing
it have a substantial effect on the risk of non-melanoma
skin cancer.

The skin is the outer covering of the body. There are twomain types of skin cancer: melanoma and non-melanoma.
Non-melanoma is more common. The most common nonmelanoma tumours are basal cell carcinoma and squamouscell carcinoma, which together account for 90 per cent ofskin cancers.4 Melanomas are nearly always pigmented andusually develop from pigmented lesions such as moles.
Melanoma accounts for 4 per cent of skin cancers. Other skincancers such as Kaposi’s sarcoma and cutaneous lymphomas
are not included here.

7.17.1 Trends, incidence, and survival
Age-adjusted rates of both melanoma and non-melanoma
skin cancers are increasing. Rates have doubled since themid-1950s in many high-income countries, particularly thosethat already had high rates. This trend is restricted to countries where a high proportion of the population is fairskinned.137 The incidence of non-melanoma skin cancer isalso increasing.4 It is estimated that there are more than amillion new cases each year in the USA alone,314 and inAustralia the reported incidence is even higher.315

FOOD, NUTRITION, PHYSICAL ACTIVITY,
AND CANCER OF THE SKIN
In the judgement of the Panel, the factors listed below modify the risk ofcancer of the skin. Judgements are graded according to the strength ofthe evidence.

DECREASES RISKINCREASES RISK

Convincing
ProbableArsenic in drinking
water1

Limited —suggestive

Retinol2

Limited —no conclusion

Potatoes; non-starchy vegetables; fruits; fish; eggs;
milk; total fat; cholesterol; coffee; tea; alcohol;
protein; vitamin A; retinol (foods); folate; vitamin C;
vitamin D; vitamin E; multivitamins; selenium;
carotenoids; beta-carotene (melanoma); alphacarotene; lycopene; physical activity; body fatness;
energy intake

Substantial
effect on risk
unlikely1234Selenium supplements3

Beta-carotene4 (non-melanoma)

The International Agency for Research on Cancer has graded arsenic andarsenic compounds as Class 1 carcinogens. The grading for this entry
applies specifically to inorganic arsenic in drinking water.
The evidence is derived from studies using supplements at a dose of 25 000
international units/day. Applies only to squamous cell carcinoma.
The evidence is derived from studies using supplements at a dose of
200 µg/day.
The evidence is derived from studies using supplements at doses of 30, and
50 mg/day, and from foods containing beta-carotene. See chapter 4.2.

For an explanation of all the terms used in the matrix,
please see chapter 3.5.1, the text of this section,and the glossary.

Skin cancer is mainly a disease of high-income countries,
where overall melanoma rates are more than 10 times higher
than in middle- to low-income countries. Age-adjusted incidence rates range from more than 30 per 100 000 people inAustralia and New Zealand to less than 1 per 100 000 acrossmuch of Africa and Asia. Rates are relatively high (around
15 per 100 000) in North America, Israel, and many northern European countries.2 In the USA, rates are higher inwhite people than among other ethnic groups.3 Nonmelanoma skin cancer is the most common cancer in theworld, and correlates with lighter skin colour and accumulated sun exposure.316
Although both melanoma and non-melanoma skin cancer
incidence increases with age, melanoma causes a disproportionate number of cancers in young and middle-aged
people.317 Melanomas are most common on exposed areasof the body, and are relatively rare on areas that are usually covered by clothing.

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Despite the considerably higher incidence of nonmelanoma skin cancer compared with melanoma (around 20
to 1 in the USA), this less common type accounts for 79 percent of skin cancer deaths.318 The 5-year survival rate is
between 80 and 90 per cent in high-income countries, butjust over half that in middle- to low-income countries.124 Thisdifference is partly due to a different, prevalent type ofmelanoma (acral melanoma, on the soles of the feet), which
has a poorer prognosis. Melanoma accounts for somewhat
over 1 per cent of all cancer incidence, but only around 0.5
per cent of all cancer deaths. Non-melanoma skin cancers arealmost never fatal.319 Also see box 7.1.1.

7.17.2 Pathogenesis
The skin changes with age and is affected by hormonal influences and exposure to the sun and wind. Skin pigmentation
varies between individuals and its structure also differs,
depending, for instance, on whether it covers the lips, thesoles of the feet, or the eyelids. All of these aspects influenceskin cancer risk. Both melanoma and non-melanoma skincancers are thought to be caused largely by UV irradiation
mainly from sunlight. There is a clear relationship between
accumulated sun exposure and non-melanoma skin cancer,
but melanoma is more common in office workers than in outdoor workers, suggesting that damage from episodic exposure and extreme occasional sun damage (blisteringsunburn) may be more important.4 The role of sun damage
is supported by the association between measures of sun sensitivity and skin cancer incidence, which is higher in people
who have freckles and skin that burns without tanning, moremoles, blue eyes, and red hair.320 321
UV-damaged cells are usually removed by apoptosis (programmed cell death, see chapter 2.5.2) in a process involving the p53 protein. However, in non-melanoma skin cancer,
the p53 tumour-suppressor gene is often damaged by UVB
irradiation, so faulty cells are not removed from the skin.
Both UVB and UVA irradiation also have direct and indirect
effects on the cutaneous immune system, lowering the skin’scell-mediated immunity,322 which is another factor that may
influence carcinogenesis.
People who have a family history of melanoma may be predisposed to this type of skin cancer, although only one major
inherited mutation has been found, and less than 2 per centof melanomas are attributable to this inherited mutation.323

7.17.3 Other established causes(Also see chapter 2.4 and 7.1.3.1.)
Radiation. Over-exposure to UV radiation (mainly from sun-light) is the chief cause of both non-melanoma andmelanoma skin cancers.324 In the case of melanoma, themain cause is episodic skin exposure involving severe sunburn, particularly in fair-skinned white people.317
Medication. Immune suppression in organ-transplant and

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J U D G E M E N T SAIDS patients is also associated with an increased risk of skincancer (in addition to Kaposi’s sarcomas).325
Infection and infestation. HPV can cause squamous cell car-cinomas, especially in immune-compromised people.325

7.17.4 Interpretation of the evidence
7.17.4.1 General
For general considerations that may affect interpretation of
the evidence, see chapters 3.3 and 3.5, and boxes 3.1, 3.2,
3.6 and 3.7.
‘Relative risk’ is used in this Report to denote ratio measures of effect, including ‘risk ratios’, ‘rate ratios’, ‘hazard
ratios’, and ‘odds ratios’.
7.17.4.2 Specific
Considerations specific to cancer of the skin include:
Classification. Melanoma and non-melanoma cancers may

have different causes; this would explain heterogeneity instudies that do not distinguish between these two types ofskin cancer. Non-melanoma skin cancer cases are commonly not recorded by cancer registries, and are therefore underestimated in many reports.
Confounding. High-quality studies adjust for sun exposureand distinguish between cancer types.

7.17.5 Evidence and judgements
In total, 167 publications were included in the SLR for skincancer. Fuller summaries of the epidemiological, experimental, and mechanistic evidence are in Chapters 4–6.
The full SLR is contained on the CD included with thisReport.
7.17.5.1 Arsenic in drinking water(Also see chapter 4.7.5.1.1.)
Two cohort studies, 5 case-control studies, 1 cross-sectional
study, and 11 ecological studies investigated arsenic in drinking water. Nearly all studies showed an association between
increased arsenic and skin cancer. Two case-control studies
used toenail and fingernail measurements, which are thought
to be more reliable than dietary estimates. These studies bothshowed increased risk, which was statistically significant inone. The single cross-sectional study and all ecological studies showed increased risk, with several reporting relatively
large and statistically significant effect estimates.
Soluble arsenic in drinking water induces lung cancers inexperimental animal models.71 In humans, arsenic is a chromosomal mutagen (an agent that induces mutations involving
more than one gene, typically large deletions or rearrangements). It can also act as a synergistic co-mutagen. Arsenic
exposure also causes chronic lung disease.71 These mechanisms
may also be applicable to skin cancer. The Joint FAO/WHO
Expert Committee on Food Additives has set a provisional tol-C H A P T E R

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erable weekly intake of 0.015 mg per kg body weight.72
The evidence is consistent, from cohort, case-control,and ecological studies. There is robust mechanistic
evidence. Arsenic in drinking water is a probable causeof skin cancer.

7.17.5.2 Retinol(Also see chapter 4.10.6.4.1.)
Two randomised controlled trials investigated retinol supplements. Both trials included only participants at risk ofdeveloping non-melanoma skin cancer, and both gave results
stratified according to this type. While neither trial reported a statistically significant association to basal cell carcinoma, one of the two studies did report a statisticallysignificant relationship with decreased squamous cell carcinoma risk.
The mechanism of anti-tumour action of the retinoids is
not completely understood, but retinol is known to bind tocell receptors with promotion of differentiation, alteration of
membranes, and immunological adjuvant effects.326
The evidence is sparse and studies were conducted ona narrowly defined population group (people at risk ofdeveloping skin cancer). There is limited evidence
suggesting that retinol supplements protect againstsquamous cell skin cancer.

The Panel is aware that since the conclusion of the SLR, one
case-control study327 has been published. This new information
does not change the Panel judgement. Also see box 3.8.
7.17.5.3 Selenium supplements(Also see chapter 4.10.6.4.5.)
One randomised controlled trial and one cohort study investigated selenium supplements. The trial showed a statistically significant increased risk of total non-melanoma skincancer with daily supplementation of 200 µg selenium.
Subgroup analysis indicated that this risk might differ
according to cancer type, with a statistically significant
increased risk for squamous cell carcinoma but not basal cell
carcinoma. The single cohort study stated that there was no
statistically significant association.
No plausible mechanisms for how selenium might increaserisk of skin cancer have been suggested.
The evidence is sparse, and no plausible mechanisms
have been identified. There is limited evidence
suggesting that selenium supplements are a cause ofskin cancer.

All three randomised controlled trials that investigatedbeta-carotene supplement interventions against placebo withrespect to non-melanoma skin cancer reported results very
close to null. Meta-analysis of the three trials produced evidence of no association. Two trials that investigated betacarotene supplement interventions against placebo withrespect to melanoma stated that there was no association
with risk.
Meta-analysis of cohort data on plasma or serum betacarotene and non-melanoma skin cancer, and cohort datathat investigated the same exposure in melanoma, showedno clear association. No clear association was shown withdietary beta-carotene.
There is strong evidence from good quality trials thatconsistently fail to show an effect. It is unlikely thatbeta-carotene has a substantial effect on the risk ofnon-melanoma skin cancer. It is unlikely that foods
containing beta-carotene have any substantial effecton the risk of non-melanoma skin cancer.

7.17.5.5 Other exposures
Other exposures were evaluated. However, the data were
either of too low quality, too inconsistent, or the number ofstudies too few to allow conclusions to be reached. These
were as follows: potatoes; non-starchy vegetables; fruits;
fish; eggs; milk; coffee; tea; alcohol; foods containing selenium; total fat; cholesterol; protein; vitamin A; retinol(foods); beta-carotene (melanoma); alpha-carotene;
carotenes; lycopene; folate; vitamin C; vitamin D; vitamin
E; multivitamins; physical activity; energy intake; and bodyfatness.

7.17.6 Comparison with previous report
Skin cancers were not reviewed in the previous report.

7.17.7 Conclusions
The Panel concludes:
Arsenic in drinking water is probably a cause of skin cancer.
There is limited evidence suggesting that retinol protects
against squamous cell carcinomas of the skin and that selenium is a cause of skin cancer. It is unlikely that betacarotene or foods containing it have a substantial effect on
the risk of non-melanoma skin cancer. The main cause ofskin cancer is over-exposure to UV radiation from sunlight.

7.17.5.4 Beta-carotene (non-melanoma)(Also see chapters 4.2.5.3 and 4.10.6.4.2)
Four randomised controlled trials and one cohort study
investigated beta-carotene supplements; two cohort studies
and seven case-control studies investigated dietary betacarotene; three cohort studies and one case-control study
investigated beta-carotene from food and supplements combined; and eight cohort studies and three case-control studies investigated serum or plasma beta-carotene.

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7.18 Other cancers
The Panel also considered other cancers, not generally
recognised to have a relationship to food, nutrition, andphysical activity. These are cancers of the thyroid glandand testis, and cancers of the lymphoid and haemopoietic
systems, the musculoskeletal system, and the nervous
systems.
Five narrative reviews were commissioned. This method
was not systematic, and the Panel decided not to make any
judgements regarding the causality of any associations in
the text or matrices.
Some of the evidence that emerged may merit morethorough investigation and further studies.
The Panel noted as follows:
Some of these cancers are known to have as establishedcauses other diseases, tobacco use, radiation, infection, or
industrial chemicals, or else not to have establishedcauses. Some details are given in the following sections.
From the reviews commissioned, some evidence emerges.

Thyroid cancer. Non-cruciferous, non-starchy vegetables
and fish show an association with decreased risk. Body fatness and adult attained height show an association withincreased risk.
Lymphoid and haemopoietic cancers. Vegetables and fruits

are associated with decreased risk. Alcoholic drinks have anassociation with decreased risk. Meat, total fat, and body fatness are associated with increased risk. Milk and dairy
products show an association with increased risk of nonHodgkin’s lymphoma.
Other cancers. The evidence on food, nutrition, physicalactivity, and cancers of the musculoskeletal and nervous systems is too limited to draw any conclusions.

7.18.1 Thyroid
Thyroid cancer is the 21st most common type worldwide. An
estimated 141 000 cases occurred in 2002, accounting forjust over 1 per cent overall. This cancer type is the 23rd mostcommon cause of cancer death. It is more common in highincome countries, with rates more than twice those of middle- to low-income countries.
Thyroid cancer is not usually fatal, with a 5-year survival
rate of approximately 70 per cent.2 It is increasing in incidence worldwide, although this may be partly explained bychanging diagnostic practices.124 137
Thyroid cancer rates peak between the ages of 25 and 55,
then decline and rise again in the elderly. This cancer is morecommon in women than in men. Also see box 7.1.1.
Differentiated carcinomas account for 94 per cent of thesecancers (80 per cent papillary and 14 per cent follicular car-318

cinomas). Medullary carcinoma and the highly aggressive
anaplastic carcinoma comprise the remainder.4
Exposure to ionising radiation, especially during childhood, is a cause of this cancer.328
7.18.1.1 Evidence
The evidence from the narrative review is summarised below.
7.18.1.1.1 Vegetables

One pooled analysis of 11 case-control studies (2241 casesand 3716 controls) investigated consumption of vegetables.
It showed a statistically significant reduced incidence withhigher intakes of vegetable other than cruciferous types.
Cruciferous vegetables were not significantly associated with
reduced incidence.
Vegetables contain many potentially protective substances,including several antioxidants, as well as phytochemicals
with antiproliferative capabilities. They are also a rich sourceof folate, which plays an important role in the synthesis,
repair, and methylation of DNA.
7.18.1.1.2 Fish

One pooled analysis of 13 case-control studies (2497 cases
and 4337 controls) and 2 case-control studies investigatedfish consumption. These were consistent in showing a significantly reduced incidence with increased consumption inareas of endemic iodine deficiency, but none in areas whereiodine intakes are high.
Fish is known to be an important natural source of iodinein the diets of different populations, and therefore an association between fish intake and thyroid cancer risk may be
mediated by iodine.
7.18.1.1.3 Body fatness

One pooled analysis of 12 case-control studies (cases: 2056
women and 417 men; controls: 3358 women and 965 men)and 1 cohort study investigated BMI or obesity. Obesity was
associated with a statistically significant increased incidence
in women, with a clear dose-response relationship. No association was observed in men (although this could have been
influenced by the relatively small number of cases). The
cohort study also showed a relationship with increased
incidence.
Body size might affect iodine requirement and therefore,
indirectly, influence thyroid cancer risk.
7.18.1.1.4 Adult attained height

One pooled analysis of 12 case-control studies (cases: 2056
women and 417 men; controls: 3358 women and 965 men)investigated adult attained height. Greater height was associated with a statistically significant increased incidence inboth women and men, with a clear dose-response relationship. The effect was greater in men than in women.
Body size might affect iodine requirement and therefore,
indirectly, influence thyroid cancer risk. The association with

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height in both men and women may indicate a potential
influence of some growth factor or hormone during childhood or adolescence, but the potential role of growth factors on thyroid carcinogenesis is still poorly defined.
7.18.1.2 Conclusions
Thyroid cancer was reviewed in the previous report. It judgedthat both iodine deficiency (probably) and iodine excess(possibly) were causes of this cancer, and also that vegetables and fruits were possibly protective.
The Panel concludes that the associations identified warrant
more investigation into food, nutrition, and thyroid cancer.

7.18.2 Testis
Cancer of the testis is the 19th most common type in men.
An estimated 49 000 cases occurred in 2002, accounting foraround 0.5 per cent overall. This cancer is increasing worldwide, with rapid rises in many high-income countries andsome transition countries.124 Rates are more than five times
higher than in middle- to low-income countries.
Cancer of the testis is usually not fatal where chemotherapy is available, with a 5-year survival rate of more than 90
per cent in high-income countries, but less than 60 per centin middle- to low-income countries.2 6 Also see box 7.1.1.
Most (95 per cent) testicular cancers are germ cell cancers,
with seminomas being the other main subtype.4
The most well established risk factor for testicular cancer
is the failure of one testis or both to descend into the normal position during fetal development.4 Rates peak in young
adulthood.
7.18.2.1 Evidence
The evidence from the narrative review is summarised below.
7.18.2.1.1 Milk and dairy products

Five case-control studies, one twin study, and four ecological studies investigated milk and dairy consumption. All ecological studies and two of the case-control studies showedstatistically significant relationships between increased milk
and dairy consumption and increased testicular cancer
incidence.
None of the other studies reported statistically significant
associations, although non-significant associations were
heterogeneous.
There are no well established mechanisms through whichmilk could influence testicular cancer development. Milk anddairy products contain fat, protein, and calcium, all of which
may have an effect on testicular cancer risk.
7.18.2.2 Conclusions
Cancer of the testis was not reviewed in the previous report.
The Panel concludes that the evidence does not warrant
significant investigation into food, nutrition, and testicularcancer.

7.18.3 Lymphoid and haemopoietic
systemCancers of the lympho-haemopoietic system are predominantly lymphomas (Hodgkin’s or non-Hodgkin’s), leukaemias, and multiple myelomas. These cancers havedifferent non-dietary causes and there is no reason to believethat they might be affected by food, nutrition, and physicalactivity in the same ways.
If taken together, this group of cancers would be the sixth
most common type worldwide. An estimated 749 000 cases
occurred in 2002, accounting for around 7 per cent overall.
Approximately 48 per cent of these cancers were lymphomas(83 per cent non-Hodgkin’s; 17 per cent Hodgkin’s), and40 per cent were leukaemias, with multiple myelomas
accounting for the remaining 12 per cent.2
Non-Hodgkin’s lymphoma is the 11th most common causeof cancer incidence. It is increasing in incidence worldwide.124 Non-Hodgkin’s lymphoma is most frequent in highincome countries, with rates more than twice those of
middle- to low-income countries. It is usually fatal, with a
5-year survival rate of less than 35 per cent.4 This is not asingle cancer, but a wide group of cancers (such as Burkitt’s
lymphoma and diffuse large B-cell lymphoma), each with adistinct geographical distribution, development path, age
profile, and prognosis.
Hodgkin’s lymphoma is the 25th most common type. It is
most frequent in high-income countries, where rates are
more than twice those of middle- to low-income countries.
It is not usually fatal, with a 5-year survival rate of approximately 75 per cent in high-income countries and less than
60 per cent in middle- to low-income countries.2 4 This cancer occurs mainly in children, young adults, and the elderly (tending to occur at a younger age or in old age in middleto low-income countries).124
Leukaemias are the 12th most common type and the 10th
most common cause of cancer death. They are gradually
increasing in incidence worldwide. They are most frequentin high-income countries, with rates more than twice thoseof middle- to low-income countries. Leukaemias are usually fatal, with a 5-year survival rate of approximately 40 per
cent in high-income countries, and less than 20 per cent in
middle- to low-income countries.124 However, childhood
leukaemias have a very high survival rate. This is not a single cancer, but a wide group of both acute and chronic
leukaemias.
Multiple myeloma is the 24th most common type and the19th most common cause of cancer death. It is gradually
increasing in incidence worldwide, and is most frequent inhigh-income countries with rates more than three times higher than in middle- to low-income countries. It is usually fatal,
with a 5-year survival rate of less than 50 per cent in highincome countries and less than 30 per cent in middle- to lowincome countries.2
Infection with Epstein-Barr virus (see box 7.2.1) is a risk
factor for developing Hodgkin’s lymphoma.329 HIV-1 infection, immune suppression (whatever the cause), and infection with Epstein-Barr and human T-cell leukaemia virus all
increase the risk of developing non-Hodgkin’s lymphoma.330

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Tobacco use, infection with human T-cell leukaemia virus,
radiation, and benzene are established causes ofleukaemia.10 67 328 331 Exposure to ionising radiation is a causeof multiple myeloma. Also see chapter 2.4.
7.18.3.1 Evidence
The evidence from the narrative review is summarised below.
7.18.3.1.1 Vegetables and fruits

One cohort study and six case-control studies investigatedvegetables and fruits. The cohort study and five of the casecontrol studies showed statistically significant associations
with increased vegetable and fruit intake and reduced incidence of lymphoid and haemopoietic cancers. However, thecohort study and two of the case-control studies reported on
non-Hodgkin’s lymphoma only. The sixth case-control study
reported increased incidence with consumption of ‘vegetables other than cruciferous, leafy, or yellow/orange’.
Vegetables and fruits contain many potentially protective
substances, including several antioxidants, as well as phytochemicals with antiproliferative capabilities. They are also
a rich source of folate, which plays an important role in thesynthesis, repair, and methylation of DNA.
7.18.3.1.2 Milk and dairy products

One cohort study, nine case-control studies, and one ecological study investigated milk and dairy products, with mostreporting on non-Hodgkin’s lymphoma. The cohort study, theecological study, and most of the case-control studies reported statistically significant associations between increased
milk and dairy consumption and increased incidence.
There are no well established mechanisms by which milk
could increase lymphoma incidence. Hypotheses include calcium restricting the bioavailability of vitamin D (this vitaminpromotes differentiation and apoptosis and inhibits cancer
cell growth in the laboratory). Alternatively, organochlorines(which are potential carcinogens) may accumulate in dairy
fat. A final hypothesis is that bovine leukaemia virus mighttransmit through milk to humans, although there is no direct
evidence for this.

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One animal study has shown that fish oils can inhibit theformation of lymphoid and haemopoietic cancers.
7.18.3.1.5 Fat

Two cohort studies and four case-control studies investigated fat consumption. All showed statistically significant relationships with increased incidence. One case-control study
that reported separately on PUFAs described a significantly
reduced incidence for that fatty acid type, while confirminga significant increased incidence for saturated fatty acids.
There are no postulated mechanisms by which fat could
increase lymphoid and haemopoietic cancers.
7.18.3.1.6 Alcoholic drinks

One pooled analysis of case-control studies representing
15 175 participants, with 6492 non-Hodgkin’s lymphoma
cases, showed a statistically significant reduced incidence forthis type, particularly Burkitt’s lymphoma.
There are no postulated mechanisms by which alcohol
could decrease the incidence of lymphoid and haemopoietic cancers.
7.18.3.1.7 Body fatness

Nine cohort studies and 11 case-control studies investigated BMI or obesity and non-Hodgkin’s lymphoma, leukaemia,
or multiple myeloma. In each case, most studies reported an
association with increased incidence, with several reporting
statistically significant relationships.
Obesity results in pathological states of inflammation andaltered immune responses, both of which are factors that can
influence lymphoid and haemopoietic cell function.
7.18.3.2 Conclusions
These cancers were not reviewed in the previous report.
The Panel concludes that more work into mechanisms thatmight underlie the associations identified is warranted. A
more comprehensive and systematic review might also clarify the epidemiology. The different cancer types should be
investigated separately unless there is reason to believe thatthey have common causes.

7.18.3.1.3 Meat

One cohort study, seven case-control studies, and one ecological study investigated meat or red meat. The cohort
study, the ecological study, and most of the case-control studies showed an association with increased incidence, with several reaching statistical significance. A review article cameto the same conclusion.
There are no postulated mechanisms by which meat
could increase the incidence of lymphoid and haemopoietic
cancers.
7.18.3.1.4 Fish

Two cohort studies and seven case-control studies investigated fish and lymphoid and haematopoietic cancers. Most
studies showed a non-significant relationship with reduced
incidence. This reached statistical significance in two casecontrol studies that reported results separately for nonHodgkin’s lymphoma.

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7.18.4 Musculoskeletal system
Cancers of the musculoskeletal system are a diverse group,
including those of the bones, muscles, and related tissues,
all around the body. These include liposarcomas, fibrosarcomas, osteosarcomas, and myosarcomas.
These cancers are all uncommon or rare, each accounting
for less than 1 per cent — usually much less — of all cancers. There is no reason to think that they have causes incommon.
The narrative review did not produce any findings.
Because these cancers are uncommon, any study investigating their possible links with food, nutrition, and physicalactivity would be unlikely to be fruitful. Because they are
diverse, any investigation that grouped all of them together
would also be unlikely to show consistent results.

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7.18.4.1 Conclusions
These cancers were not reviewed in the previous report.
The Panel concludes that it is unlikely that any further investigation would be warranted.

7.18.5 Nervous system
Cancers of the brain and central nervous system are the 18th
most common type worldwide. An estimated 189 000 cases
occurred in 2002, accounting for around 2 per cent overall.
These cancers are most frequent in high-income countries,
with rates more than twice those of middle- to low-income
countries. Brain tumours are relatively common amongchildhood cancers. They are the 13th most common causeof cancer death, and are usually fatal. The overall 5-year survival rate is less than 25 per cent, with higher rates for many
brain tumours that occur during childhood, and in highrather than in middle- to low-income countries.2 Also see box
7.1.1.
Tumours of neural tissue account for approximately halfof these cancers, with most of these being glioblastomas.4
Meningiomas are the other major type of central nervous system tumour, with sellar tumours, cranial and spinal nerve
tumours, central nervous system lymphomas, and other rarebrain tumour types comprising the remainder.
The incidence of these cancers appears to be increasing
worldwide, although the trend is not entirely clear.124 The
causes of brain and central nervous system cancers have notbeen well established.
The narrative review did not produce any findings.
Because these cancers are uncommon, any study investigating their possible links with food, nutrition, and physicalactivity would be unlikely to be fruitful. Because they are
diverse, any investigation that grouped all of them together
would also be unlikely to show consistent results.
7.18.5.1 Conclusions
These cancers were not reviewed in the previous report.
The Panel concludes that it is unlikely that any further investigation is warranted.

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8Determinants of weight gain,
overweight, and obesity
This chapter examines food, nutrition, and physicalactivity as factors that modify the risk of weight gain,
overweight, and obesity, which themselves influencecancer risk.
The Panel agreed that as for the other systematic
literature reviews elsewhere in this Report, a review of theepidemiological literature should be amplified byconsideration of established knowledge on mechanisms,
including basic thermodynamics and mechanisms ofenergy input, output, and balance.
As shown in Chapters 6 and 7 of this Report, theevidence that obesity, weight gain, and also overweightshort of obesity increase the risk of anumber of cancers, is more impressive than was the casein the mid-1990s. Also, it is now generally agreed that the
rapid rise in the incidence ofoverweight and obesity is a public health nutrition
emergency worldwide. In most countries in Asia, Latin
America, and the Middle East, and some in Africa, chronic
diseases including obesity are now more prevalent thannutritional deficiencies and infectious diseases.
The Panel agreed therefore that any comprehensive
report on the prevention of cancer must also deal with theprevention of overweight, obesity, and weight gain. Expert
reports that inform public health policy on cardiovasculardiseases have, for many years, accepted that factors
identified as causes of obesity are also causes ofcardiovascular diseases. The Panel agrees that the same
applies to cancer. So unless there is reason to thinkotherwise, anything that modifies the risk of weight gain,
overweight, and obesity also modifies the risk of thosecancers whose risk is increased by weight gain,
overweight, and obesity.
The Panel judges that the evidence that regular andsustained physical activity of all types protects against
weight gain, overweight, and obesity is convincing.
Correspondingly, the evidence thatsedentary living is a cause of these conditions is also
convincing. Television viewing, a particular form of very
sedentary behaviour, which may be associated withsnacking on energy-dense foods, is probably also a cause.
Low energy-dense foods — typically foods that are highin fibre and bulky because of their water content — areprobably protective. Such foods include cereals (grains),
pulses (legumes), and vegetables and fruits, and are also
often micronutrient-dense, meaning high in vitamins,

322

minerals, and other bioactive compounds.
Correspondingly, the Panel judges that high energy-dense
foods, in particular sugary drinks and ‘fast foods’, areprobably a cause of weight gain, overweight, and obesity.
Such foods are typically high in fats and/or sugars, containlittle water or dietary fibre, and are often low in
micronutrients.
The Panel also judges that sustained breastfeeding
probably protects infants and young children against
overweight and obesity, which tend to track into laterchildhood and adult life.
The Panel’s conclusions and judgements on the dietary
and associated determinants of weight gain, overweight,
and obesity also apply to cancers for which the risk isincreased by weight gain, overweight, and obesity, unlessthere is reason to think otherwise.
Within the remit of this Report, the strongest
evidence, corresponding to judgements of ‘convincing’ and‘probable’, shows that physical activity of all types protects
against weight gain, overweight, and obesity, whereas
sedentary living is causative; that low energy-dense foods
are probably protective and high energy-dense foods areprobably causative; that being breastfed is probably
protective; and that sugary drinks, ‘fast foods’, andtelevision watching are probably causative.
Environmental factors (physical, economic, political, andsociocultural) are extremely important in determining
health behaviour, including that which affects bodyfatness. Such factors are the subject of a further report tobe published in late 2008.

C H A P T E R

8•

D E T E R M I N A N T S

O F

W E I G H T

G A I N ,FOOD, NUTRITION, PHYSICAL ACTIVITY, AND
WEIGHT GAIN, OVERWEIGHT, AND OBESITYIn the judgement of the Panel, the factors listed below modify the risk ofweight gain, overweight, and obesity. Judgements are graded according
to the strength of the evidence.
Factors that decrease risk promote appropriate energy intake,and those that increase risk promote excess energy intake,relative to the level of energy expenditure.

DECREASES RISKINCREASES RISK

Convincing

Physical activity

Sedentary living1

Probable

Low energy-dense
foods2

Sugary drinks5

Being breastfed4‘Fast foods’6

Energy-dense foods2 3

Television viewing7
Limited —suggestive
Limited —no conclusion

Substantial
effect on risk
unlikely

1

2

3

4

5

6
7

Refined cereals (grains) and their products; starchy
roots, tubers, and plantains; fruits; meat; fish; milk
and dairy products; fruit juices; coffee; alcoholic
drinks; sweeteners

None identified

Sedentary living comprises both high levels of physical inactivity and low
levels of physical activity (in terms of intensity, frequency, and duration).
Also see box 5.2.
The direct epidemiological evidence for low energy-dense foods is fromwholegrain cereals (grains) and cereal products, non-starchy vegetables,and dietary fibre. The direct epidemiological evidence for energy-dense
foods is from animal fat and fast foods. These are interpreted as markersof the energy density of diets, based on compelling physiological andmechanistic evidence (box 8.1).
Some relatively unprocessed energy-dense foods (which tend to be eaten
sparingly), such as nuts, seeds, and some vegetable oils, are valuable sourcesof nutrients.
The evidence relates principally to obesity in childhood, but overweight andobesity in children tend to track into adult life: overweight children are
liable to become overweight and obese adults.
The evidence relates to all drinks containing added caloric sweeteners,
notably sucrose and high-fructose corn syrup. Fruit juices are also sugary
drinks and could have similar effects, but the evidence is currently limited.
‘Fast foods’ characteristically are consumed often, in large portions, and areenergy dense (box 8.2).
Television viewing (box 8.4) is here identified as a sedentary activity (box5.2). It is also associated with consumption of energy-dense foods (box 8.1).
The evidence relates specifically to childhood and adolescence, and is taken
also to apply to adults.

For an explanation of all the terms used in the matrix,
please see chapter 3.5.1, the text of this section,and the glossary.

Recent and current research shows that degree of body fatness (often characterised as overweight and obesity) is amore important cause of cancer than was evident in the mid1990s.5 As stated in Chapters 6 and 7, the evidence that bodyfatness is a cause of cancers of the oesophagus, pancreas,O V E R W E I G H T,

A N D

O B E S I T Y

colon and rectum, breast (postmenopause), endometrium,and kidney is convincing; and it is probably a cause of cancer of the gallbladder. In addition, the evidence that abdominal fatness is a cause of cancer of the colon is convincing;and it is also probably a cause of cancers of the breast (postmenopause) and endometrium. Body fatness probably protects against breast cancer that becomes evident before themenopause.
Further, rates of overweight and obesity have greatly
increased since the 1990s, not only throughout high-income
countries, but also in urban and even rural areas of many if
not most middle- and many low-income countries; and not
only in adults, but also in children and young people. Obesity
in both childhood and adult life can now be seen more as adisease of poverty than of affluence. In 2005, the World
Health Organization estimated the number of overweight
adults (age 15+) to be approximately 1.6 billion, with projections for 2015 increasing this figure to 2.3 billion.6
The evidence showing that body fatness is, or probably is,a cause of a number of cancers, as well as a large numberof disorders and diseases (see 8.2.2), is impressive; and overweight and obesity are now pandemic, including among children and young people. For these reasons, the Panel decided
to commission this chapter, and also decided that its assessments and judgements should be based on the same principles underlying their assessments of the links between food,nutrition, and physical activity with specific cancers.
The Panel agrees that any factor related to food, nutrition,and physical activity that increases the risk of weight gain,
overweight, and obesity, can also be taken to increase the riskof cancers associated with excess body fatness, unless there
is reason to think otherwise. Thus if regular, sustained physical activity of all types and regular consumption of low energy-dense foods protect against weight gain, overweight, andobesity, then they would also be expected to protect indirectly against those cancers identified in Chapter 7 as being
associated with body fatness.
Social and environmental (underlying and basic) factorsthat modify the risk of weight gain, overweight, and obesity are critically important and the subject of an associatedreport to be published in late 2008.7

8.1 Definitions
Humans take in energy from food and drinks, which is used
for the body’s natural processes and for physical activity.
People gain weight if they take in more energy than they use
and lose weight if they take in less energy than they use.
Excess energy is stored mostly as body fat, laid down at various sites around the body, regardless of whether the excessenergy comes from carbohydrates, fats, or proteins, or fromethanol from alcoholic drinks. Conversely, with a deficiencyof energy, carbohydrates are initially released in the form of323

P A R T

Box 8.1•

E V I D E N C E

A N D

J U D G E M E N T S

Energy density

A concept central to the Panel’s thinking,assessments, and judgements in this chapter is that of the energy density of foods
and drinks.
Energy density describes the amount ofenergy per unit weight of foods or diets.
The units of measure are kilocalories (kcal)
or kilojoules (kJ) per 100 grams (g). The
body derives energy from the macronutrients in foods and drinks. The metabolisable energy of carbohydrate and protein isaround 4 kcal (17 kJ)/g; of fat, 9 kcal (38kJ)/g; and of ethanol — from alcoholic
drinks — 7 kcal (29 kJ)/g. It follows that of
the macronutrients in pure form, fats andoils are the most energy-dense, followedby ethanol; and protein and carbohydrate
are least energy-dense.1 By contrast,
dietary fibre generates around 1.5 kcal (6.3
kJ)/g.2 Water, like all foods and drinks,
requires some energy for its absorption
and metabolism, but its energy value can,for practical purposes, be counted as nil.
The energy density of foods and dietsvaries depending on the water content
and concentration of the different
macronutrients, and of dietary fibre. In
general, low energy-dense foods and diets
are high in fibre, and also in water.
Therefore, in terms of weight, they are
relatively ‘dilute’ in energy-providing
macronutrients. Cereals (grains) and vegetables cooked in water, and most fruits,
are examples of low energy-dense foods.
By contrast, high energy-dense diets tend
to contain fewer fibre-rich foods and to berelatively concentrated in macronutrients.
Many processed foods are energy dense.

Energy-dense foods are usually high in fatsor oils, and/or processed starches andadded sugars. ‘Fast foods’ (box 8.2), certain
baked goods, and confectionery are examples of high energy-dense foods. The energy density of meat depends on the amountof fat it contains and how it is cooked. Low
energy-dense foods are often high in vitamins and minerals and other bioactive constituents. Processed, high energy-dense
foods are often low in micronutrients.
There is no evidence that drinking a lotof water with the consumption of energydense foods mimics the intake of low
energy-dense foods.
In general, people tend to consume
roughly the same amount of food from day
to day, measured by bulk and weight.
Several human clinical studies have shownthat high energy-dense diets can undermine normal appetite regulation — a
process that has been termed ‘passive overconsumption’.3 4 Higher energy density
diets tend to lead to greater energy intake.
Energy consumed in drinks appears to beless easily recognised by appetite control
systems than energy in foods. Drinks bytheir nature are generally high in waterand so, compared to foods, have low energy density. However, altering the energy
density of drinks, for instance by adding
sugar, nevertheless does influence the overall amount of energy consumed, just as it
does for foods, even though the absolutelevels of energy density for drinks are lower
than that for foods. For this reason, caloric
drinks may play a special role in contributing to positive energy balance.

immediately available glycogen, followed by use of body fat
and of protein in the form of lean tissue. Balance (no weightloss or gain) is achieved when energy input equals output,
over time. When body fat stores increase or decrease, there
is an accompanying change in lean body mass, with aroundthree quarters of progressive weight gain or loss representing changes in body fat stores.
As stated in Chapter 6, body mass index (BMI) is the conventional indicator of body fatness, and takes account of bothheight and weight. BMI is calculated as weight in kilograms
divided by height in metres squared (BMI = kg/m2). Thismethod does not always provide an accurate measure ofbody fatness. Unusually lean but muscular people have a relatively high BMI, even if they have little fat. The BMI criteria for risk are now supplemented by measures of excess
abdominal fat, because this selective accumulation is a particular risk to health. But the BMI method provides a simple
measure of body fatness for most people, most of the time.8
See table 8.1 and also Chapter 6.

324

2

The Panel has given special emphasis tothe substantial body of robust experimental evidence, both in humans and in relevant animal models, underpinned by theprinciples of thermodynamics. To reach its
conclusions, the Panel interpreted the epidemiological findings in the light of thisexperimental evidence. Thus, the Panelnotes the associations between specificfoods and food groups with weight gain,
overweight, and obesity, and has interpreted them, in the light of the experimental evidence, as indicating a generaleffect of energy density rather than as
several different specific effects of particular foods and drinks. The Panel concludes
that energy density is a probable causal
factor underlying the observed associations
with specific foods and food groups,
and therefore has decided that energy
density is entered into the matrix as
such. Similar principles apply to physicalactivity although, unlike energy density,
epidemiological studies estimate this more
directly.
The evidence, compelling on physiological grounds and supported by experimental and observational evidence, is for dietswith plenty of low energy-dense foods tolimit weight gain; and for diets with substantial amounts of high energy-dense
foods to promote weight gain — especially when there is frequent consumption oflarge portions of energy-dense foods anddrinks. Although drinks are characteristically high in water and less energy dense
than foods, the same principles apply,
within the drink category.

8.2 Trends and incidence
Brief summaries of the worldwide trends in BMI are given
in Chapter 1. The more historical and detailed perspectivethat follows provides an important evolutionary context forinterpretation of the clinical, epidemiological, and experimental data reviewed.
8.2.1 Human evolution and adaptation
Overweight and obesity became a public health issue only
relatively recently in human history. Before industrialisation,
underweight and weight loss, leading to debility caused byshortage or deficiency of energy from food, were the main
nutritional issues.10 Food insecurity is still a feature of life
for the remaining gatherer–hunter and pastoralist communities, and for many agricultural communities in adverse
social or environmental circumstances. Periodic episodes offood shortage are a defining characteristic of any type of
nomadic life. It is likely that the human species has evolved

C H A P T E R8

Box 8.2•

D E T E R M I N A N T S

W E I G H T

G A I N ,and are frequently offered in large portion
sizes. In the literature, the term usuallyrefers to ‘fast food’ served in transnational restaurants and the many ‘fast foods’
created in each country and region that
imitate those served in such transnational
restaurants.
Studies assessed in this chapter (see 8.8)
show an association between the consumption of ‘fast foods’ as defined in theliterature and a higher risk of weight gain
and obesity. These studies examined peo-

Body mass index as a measure ofbody fatness

A body mass index (BMI) of between 18.5 and 24.9 is generally regarded
as ‘acceptable’ or ‘normal’. This is roughly equivalent to 15–20 per centbody fat in adult men and 25–30 per cent in adult women.1 The ‘underweight’ or ‘thin’ range is a BMI of below 18.5. Above 25, the common
gradings for overweight and obesity are as follows:
Classification

Normal range

O V E R W E I G H T,

A N D

O B E S I T Y

Fast food

The term ‘fast food’ is used in lay publications and in common discourse, as well as
in the scientific literature. It is also used asa category in research studies of food,nutrition, and the risk of diseases, including cancer. In the literature, the term does
not refer to all foods that can be consumed
immediately or quickly, and certainly does
not refer to foods such as fruits. In general, the term refers to readily available,energy-dense meals, snacks, foods, anddrinks. These tend to be consumed often

Table 8.1

O F

BMI (kg/m2)
Principal
Additional
cut-off points
cut-off points
18.50–24.99
18.50–22.99
23.00–24.99

Overweight≥ 25.00≥ 25.00
25.00–27.49
27.50–29.99

Obese
Obese class I≥ 30.00
30.00–34.99

Obese class II

35.00–39.99

Obese class III≥ 40.00≥ 30.00
30.00–32.49
32.50–34.99
35.00–37.49
37.50–39.99≥ 40.00

Adapted with permission from WHO9

The principal cut-off points have been proposed to classify
overweight and obesity. The additional cut-off points are used insome countries as useful public health references.9 Also see
chapter 6.1.1.

and adapted to favour the deposition of body fat in orderto survive food shortages.11 12
Famines still occur in regions of the world ravaged by wars
and droughts, particularly in Africa. In children, poor maternal nutrition, inadequate and inappropriate feeding of
infants and young children, and recurrent infections stillcause millions of deaths every year. Therefore it is unlikelythat the United Nations Millennium Development Goal, tohalve the 1990 global rate of malnutrition in under-5s by
2015, will be achieved.13 14
In the past, people in most settled communities possibly
lived a large part of their lives in approximate energy

ple who ate at ‘fast-food’ restaurants orfrom takeaway outlets: most of the foods
they consumed were high energy-dense
products. There is no plausible basis forweight gain being caused by the speedwith which a food is prepared or madeavailable. Indeed, many foods can be prepared speedily without also being energy
dense. These studies support the Panel’s
conclusion that the energy density offoods and drinks is an important determinant of body mass.

balance, with adults usually remaining lean, neither losing
nor gaining much weight from year to year. This pattern isstill evident in food-secure agricultural communities inAfrica, Asia, and Latin America, as well as in those urban
areas where ways of life involve a substantial amount ofphysical labour and where energy-dense foods are scarce.
Historically, being overweight has been seen as a sign ofwealth, the ability to provide, and a social advantage. Thisis still the case in countries where food insecurity remains
endemic or is a living memory.
8.2.2 Obesity as a public health issue
Even in the highest-income countries, obesity was uncommon until the 19th century, except among wealthy people
who had access to plentiful amounts of food. But with industrialisation and urbanisation in Europe, and then in North
America and other countries, issues of food insecurity disappeared, food supplies became more plentiful, and foodgenerally became more energy dense (in particular, increasingly processed and higher in fats and sugars). At the sametime, occupations gradually became more sedentary.15
Consequently, from the latter part of the 19th century,
overweight and obesity were not unusual among middleaged, middle-class adults in high-income countries; from the
middle of the 20th century, they became fairly common in
adults in high-income countries. In low-income countries,and even most high-income countries, there has been a rapid
increase in the prevalence of obesity in the period from 1990
to the present. The rate of increase of the prevalence of obesity globally has accelerated during this period.16
Although obesity was recognised as a public health problem in higher-income countries in the 1970s,17 18 until fairly recently it was generally not taken seriously. It was
typically seen by health professionals and the public as beingcaused by bad habits and weak will — obese patients would
simply be advised to follow a low-energy diet. Only in thepast decade has there been a growing and wide recognitionof the significance of the social and environmental forces that
influence the quality and quantity of food and drink consumed and physical activity undertaken.19
Further, until recently, the causal role of obesity in increasing the risk of other diseases was not well understood. Since
the 1980s, however, obesity has increasingly been recognised325

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Table 8.2

Approximate relative risk of physicalhealth problems associated with obesity

Relative risk
greater than 3

Relative risk 2–3

Type 2 diabetes

Coronary heart disease

CancerGallbladder disease

Hypertension

Reproductive
hormoneabnormalities

Dyslipidaemia

Osteoarthritis (knees)

Polycystic ovary
syndrome

Insulin resistanceHyperuricaemia
and gout

Impaired fertility

Relative risk 1–2

Breathlessness

Low back pain

Sleep apnoea

Increased risk ofanaesthesia
complications
Fetal defects(associated withmaternal obesity)

Adapted with permission from WHO1

as a disease in itself, and also as a cause of several disorders
and diseases (table 8.2). Many people who are obese suffer
several of these diseases, disorders, or disabilities. Obese people, women in particular, are also more likely to experience
personal, social, and professional difficulties20 and reduced
opportunities for employment and advancement.21
Obesity also lowers life expectancy. It is estimated that at
40 years of age, an obese person can expect to live 6 to 7
years less than someone defined as being of ‘normal’ weight.
The UK government has suggested that the average life

Box 8.3•

E V I D E N C E

A N D

J U D G E M E N T S

expectancy of men living in England has fallen because
so many are obese.22 23 It is also now generally accepted that,to a lesser degree, overweight short of obesity as usually
defined is a cause of many of these pathologies (table 8.2).24
8.2.3 Obesity as a global pandemic
Now, at the beginning of the 21st century, overweight andobesity are common, and their prevalence is increasing rapidly. WHO estimated in 2005 that 1.6 billion adults worldwide
were overweight, of whom 300 million were obese.25 About
one sixth of the adult population worldwide was overweight
and a further 7 per cent obese. The very rapid rise in overweight and obesity in children, together with a fast andaccelerating rise in type 2 diabetes in young people (box8.3), are particularly striking.
Although the very rapid rise in obesity throughout theworld was not expected, there is now general agreement on
why obesity has become pandemic. The demographic, nutritional, and epidemiological shifts that affected the populations of the first countries to be industrialised in the 19th
century are now occurring worldwide, and at a faster rate.
In 1975, of a global population of around 4 billion, about
35 per cent (or 1.4 billion people) lived in cities or urban
areas. In 2005, of a global population of 6.5 billion, about
49 per cent (or 3.2 billion people) lived in urban areas: soin three decades the world’s urban population has more thandoubled. The projections for 2030 are a world population ofperhaps 8.2 billion, of which 60 per cent (or 4.9 billion people) will live in urban areas: an increase of over three times
the 1975 figure within the space of one lifetime.34
Living in cities does not of itself predispose people toweight gain, overweight, and obesity; this depends on how
people work and live, and what they eat and drink. Daily

Body fatness in childhoodChildhood overweight and obesity are
becoming increasingly common, not onlyin high-income countries, but in industrialised areas in most countries around theworld.26 The most widely used definition ofchildhood obesity is that of Cole et al.27
Ten per cent of the world’s children were
estimated to be overweight in 2000.
Recent evidence suggests that this problem
affects almost all countries and is escalating.28 In many countries, an additional 1
per cent of children are becoming overweight or obese every year. From the 1970s
to the end of the 1990s, the prevalence ofoverweight and obesity in children doubled or tripled in several large countries inmost regions, such as Canada and theUnited States in North America; Brazil andChile in Latin America; Australia and Japanin the Western Pacific region; and Finland,
France, Germany, Italy, and Spain in
Europe. Projections estimate that by 2010,
half of all school-age children will be over-326

2weight in the Americas, along with some
44 per cent of children in the eastern
Mediterranean region, and 35 per cent in
the European region (including the countries of the former Soviet Union) and in thewestern Pacific region.29
Children who are overweight are liable
to remain overweight as adults or to
become obese.26 30 The likelihood of an
overweight or obese child becoming or
remaining obese in adulthood is increasedby their degree of body fatness and the age
at which they are assessed. Below about
the age of 10, the degree of overweight orobesity is only partly related to adult fatness, while by 18 years of age, obesity islargely fixed.30 Even when adults are notoverweight, they may retain an increased
risk of morbidity and mortality from having
been overweight in adolescence.31
As with overweight and obesity in adulthood, childhood overweight and obesity
are causes of other chronic diseases. Mostof the consequences of obesity take years,
or even decades, to become clinically evident, but some are apparent in childhood.
Over half of overweight 5–10-year-old-children have been reported to have one cardiovascular disease risk factor, such as
high blood pressure, hyperlipidaemia, or
elevated insulin level.32 Children who areeven only moderately overweight haveelevated low-density lipoprotein cholesterol levels. Type 2 diabetes, almost
unknown in early life until recently, is rising rapidly in children as obesity increases.
Some areas in the USA experienced a 10fold increase in this form of diabetes inchildren between the 1980s and 1990s.33
Children who experienced growth
restriction or very low-energy diets in very
early life (and in utero), but who thengained weight rapidly in infancy or earlychildhood, are especially likely to become
obese and to develop type 2 diabetes aschildren and as adults.

C H A P T E R

Figure 8.1

8•

D E T E R M I N A N T S

O F

W E I G H T

G A I N ,Estimates of the prevalence of obesity andoverweight in selected countries

O V E R W E I G H T,

Figure 8.2

A N D

O B E S I T Y

Estimates of the annual increases inprevalence of overweight and obesity inselected countries

Per cent
Per cent

80
BMI ≥25
BMI ≥30
BMI 25–29.9
GDP = $US

70
60
50

2.5
BMI ≥25
BMI ≥30
BMI 25–29.9
GDP = $US

2.0
1.5

40
30

1.0

20
10

0.5

0

M F M F M F

F M F M F M F M F M F M F M F

UK Mexico Brazil Morocco Egypt S. Africa Thailand China Indonesia
USA Australia
1999–
2000
2003 1999 2003 1998–1999 1998
1998
1996
2000
2000
(GDP
(GDP (GDP (GDP
(GDP
(GDP
(GDP
(GDP
(GDP
(GDP
2002
(GDP $20 640) $21 410)$3840) $4630) $1240) $1290) $3310) $2160) $750)$640)$29 240)

Reproduced with permission from the American Journal of
Clinical Nutrition37

0.0

M

F M

F

USA
Australia
1999–2002
2000
(GDP
(GDP
$29 240)$20 640)

M

F

F

M

F

UK
Mexico Brazil
2003 1988–1999 2003
(GDP
(GDP
(GDP
$21 410) $3840) $4630)

M

F

M

F

Morocco Thailand
1995–1999 1991–1996
(GDP
(GDP
$1240)$2160)

M

F

China
2000
(GDP
$750)

M

F

Indonesia
2000
(GDP
$640)

Reproduced with permission from the American Journal of
Clinical Nutrition37

Estimates are given by country for men and women, for three BMI
ranges: ≥ 25; ≥ 30; and 25–29.9. GDP = gross domestic product percapita ($US). UK = United Kingdom. USA = United States of America.

Estimates are given by country for men and women, for three BMI
ranges: ≥ 25; ≥ 30; and 25–29.9. GDP = gross domestic product percapita ($US). UK = United Kingdom. USA = United States of America.

ways of life for non-industrialised populations typicallyinvolve relatively high levels of physical activity. This
includes manual labour and walking, even when food supplies are secure and plentiful; and staple foods — cereals(grains) or roots and tubers — which are almost always of
relatively low energy density (box 8.1). In contrast, ways oflife in industrialised cities are more likely to be sedentary.
Modern urban food supplies are increasingly processed, withproducts that are relatively energy dense: low in dietary fibre
and relatively high in fats and oils, and refined starches andsugars. Modern urban food supplies also include more meatand energy-dense alcoholic and soft drinks. An additional
factor, in what has been termed this ‘obesogenic’ environment, is the ready availability and low price of very many
processed foods and drinks. This makes it easy for poor aswell as rich people to consume more energy than their bodies require.20 35
Obesity is still more common in high-income countries,
where about 22 per cent of the adult population (185 million people) are now obese, compared with less than 4 percent (115 million people) in middle- to low-income countries.36 However, of the six countries where more than 60 per
cent of the adult population are overweight or obese, while
three are higher income (the United States, Australia,
and Great Britain), three are lower-income (Mexico, Egypt,and South Africa).37 In middle- and low-income countries,
obesity, and the diseases caused by weight gain leading
to obesity, coexist with diseases and disorders of undernutrition in the same communities and families.38 See figures 8.1
and 8.2.
In general, obesity is more common in women than in men,
although more men are overweight.1 Overweight and obesity rates usually increase up to middle age and then are lower
in old age. Obesity rates rise first in cities and urban areas;
rural communities are slower to show this increase.1 Of 38

nationally representative studies among the very lowest
income countries, women of child-bearing age were more
likely to be overweight than underweight, even in rural
areas.39
Obesity rates vary with socioeconomic status. In a crosscountry analysis, as national income rose, BMI increased
rapidly, then flattened, and eventually declined.40
It increased most rapidly until an annual income of about$US 5000, and peaked at about $US 12 500 for women and$US 17 000 for men. In countries whose gross national product (GNP) per head is less than $US 2500, obesity in women
is more common among those with a high income.41 But
even in a number of countries with GNP per capita below$US 2 500, such as China, more women of lower comparedto higher socioeconomic status are overweight. As countries
use more money (measured by rises in national GNP), obesity is increasingly becoming a disease of the poor.41

8.3 Regulation of body fatness
As stated, the physiological cause of weight gain, overweight, and obesity is the consumption of more energy fromfoods and drinks than is used. Therefore both dietary intake
and energy expended, and physical activity, are determinantsof energy balance. In particular, the systems responsible forregulating appetite to match energy intake to expenditureare crucial. This section summarises relevant points about
thermodynamics and the physiological mechanisms involvedin energy intake, expenditure, and balance.
8.3.1 Thermodynamics
The first law of thermodynamics states that energy cannot
be created or destroyed, but only transformed. In humans
and other animals, energy is supplied by the metabolism of327

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food, using up oxygen in the process. Of the energy the body
liberates from food, about 10 per cent is used in its digestion, absorption, and metabolism.
Energy expenditure can be measured in a calorimeter, asealed chamber designed for this purpose, either directly asheat production or indirectly by measuring the amounts ofoxygen used and carbon dioxide produced. The amount ofenergy metabolised can then be calculated. Studies using
calorimeters prove that the principles of thermodynamics,
manifest as energy balance, with weight loss and weight gainas described in this chapter, apply both in humans and in animals.42 Such studies were the first to prove that restrictionof energy from food results in weight loss.43
Energy restriction to less than is expended will result inweight loss, independent of the type of macronutrients supplied in the diet. Recent trials,44-47 however, show that different macronutrients may have different effects on
metabolism, independent of their energy content. For
instance, low-carbohydrate diets cause the body tometabolise carbohydrate stored in the body as glycogen; theassociated water excreted leads to loss of weight but not,unless there is a deficit in total energy, of tissue. Foods highin dietary fibre, such as wholegrain cereals and vegetables,
promote satiety and therefore may influence weight regulation by improving appetite regulation and tending to constrain excess energy consumption.48
8.3.2 Energy intake and output
Human energy needs comprise the amount of energy used
to maintain the body’s functions (measured as basal metabolic rate or BMR); to digest and assimilate food (dietinduced thermogenesis); and to provide fuel for physicalactivity. This energy comes originally from foods anddrinks, and is sourced by the body from stores of carbohydrate, fat, and protein.
Human basal energy needs vary largely as a function of
the total mass of lean tissue, which in turn relates to sex, size,
and age. Physical activity levels vary from day to day, as does
energy intake from foods and drinks. Excess intake is stored;
these stores are used to meet the needs of a higher output— as a result of extra physical activity, for example. In premenopausal women, basal needs vary to some extent with
ovulatory and other cyclical hormonal changes.
Usually, body weight and energy stores balance over amonth or so. Short-term changes in weight are mostly causedby fluctuations in the body’s store of water, not in stored
energy. Thus between meals and overnight, the short-termstores of carbohydrate (glycogen in liver and muscles) aremobilised and oxidised, with associated water. This causes
weight loss, but mostly of water. Longer-term changes inweight, by contrast, are due to alterations in the body’s fat
tissue. Therefore substantial daily fluctuations in weight do
not reflect changes in energy stores, whereas consistentweight gain (or weight loss) over a substantial period of time
does. In undernourished people with negligible fat stores,
weight loss reflects loss of lean tissue, used for energy. In
sedentary adults who are not undernourished, changes inweight over a period of time reflect changes mainly in the
body’s stores of fat.

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8.3.3 Energy requirement and balance
The energy used to maintain the body’s functions (basal
metabolism) fuels many physiological processes. These
include maintenance of the balance of minerals within cells
and the electrical potential difference across membranes.
Energy is also required for processes such as DNA repair andthe production of new cells, and for the synthesis of proteins
and other structural and functional molecules. The assimilation of food involves the production and secretion of various enzymes and hormones that control the flow of nutrient
molecules through different metabolic pathways.
The regulation of these interrelated processes depends on
factors such as general health, age, and also genetic andother factors that vary between people.49
Tissue deposition during growth in childhood, puberty,
and pregnancy and lactation, has additional energy costs.
Pregnant women have modestly increased energy requirements, but many are less physically active during pregnancy. Lactating women require about an extra daily 750 kcal
(3150 kJ) of energy from food.
The major energy cost above BMR comes from physicalactivity (see Chapter 5).
For any given weight, BMR is largely a function of the proportion of lean body mass to total body mass; this varies with
sex and age, and also health and nutrition status. In sedentary adults, lean mass (and so BMR) decreases with age:older adolescents and young adults usually have higher energy requirements than middle-aged and elderly people. Thismeans that as they age, people need to consume less energy from foods and drinks if they are to stay in energy balance
and not gain weight.
Energy requirements — the energy expended by the body— vary between people. A small, lean, elderly man weighing 50 kg living in the tropics, who takes only light exercise,might be in energy balance at around 1750 kcal (7350 kJ)
per day; whereas a young man weighing 80 kg, who isextremely active as a manual labourer, is likely to need over3500 kcal (14.6 MJ) per day. A sedentary, elderly woman
weighing 55 kg might be in energy balance at 1500 kcal
(6300 kJ) per day; whereas a young woman who trains withweights daily might need up to 2750 kcal (11.5 MJ). Positiveenergy balance means consuming more energy than isexpended, in which case, the body will gain weight — mainly as fat, but also as lean tissue, which increases BMR.
Negative energy balance means consuming less energy thanis expended, in which case the body will lose weight — again
mainly fat, but also lean tissue. This, together with otheradaptations such as reducing physical activity, tends tomitigate weight loss.
In obesity there is excess stored energy, mainly as fat but
also as lean tissue, which leads to increased energy expenditure, so that higher energy intake is needed to maintainenergy balance.
As people gain weight and their BMR increases, they needmore energy from foods and drinks to maintain theirincreased weight. Over time, a new balance may beachieved, so that no more weight is gained, or the balance
may remain positive even at the heavier weight, so thatweight continues to be gained.50

•

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O F

W E I G H T

G A I N ,8.3.4 Appetite and weight control
Humans have many physiological control systems to helpbalance energy input and output. Underfeeding leads toincreased appetite. Eating a meal normally leads to satiation,a feeling of fullness which stops the eating, and satiety, which
inhibits the desire to begin to eat. However, humans varywith regard to the extent to which they are able to maintainbody weight over years or decades; some appear to maintain energy balance readily, others can only do so with difficulty. The maintenance of energy balance involves various
processes including satiety responses, appetite control systems, and other homeostatic mechanisms. In the main, thecontrol systems are most effective in responding to underfeeding, by increasing appetite, and are less effective at
reducing intake with long-term overfeeding. Psychological,
social, and cultural factors are important underlying influences on dietary patterns and physical activity.
Control seems to be least effective at relatively low levelsof physical activity, meaning that sedentary people tend to
gain weight more readily than active people. Conversely,
although high levels of physical activity increase energy
requirements and appetite, the likelihood of consuming
more than is needed is lower. In addition, both increased
energy density51 and portion size appear to promote overconsumption.52-54
In rodents, various mechanisms have been identified that
affect appetite control and weight. Some of these, involving
the hormones leptin and ghrelin, for example, may turn out
to be important for humans. But in humans, energy homeostasis is most reliably achieved by relatively active ways oflife, together with low energy-dense diets. It is likely, inhumans at least, that energy homeostasis operates mosteffectively within a range of physical activity and so also ofenergy expenditure, to which humans have evolved since theemergence of Homo sapiens about 250 000 years ago, and towhich they are adapted.11 55

O V E R W E I G H T,

A N D

O B E S I T Y

8.5 Risks of overweight and obesity
The risk of ill health and of death rises with increasing BMI, froma point well below a BMI of 30 (figures 8.3 and 8.4).61-67
The effects of overweight and obesity in the USA havebeen thought to be declining because of improvements in the
medical treatment of complications such as high blood pressure, type 2 diabetes, and abnormal blood lipids. But large

Figure 8.3

Relationship between BMI andrisk of death

Death from cardiovascular disease (684 cases)
11.86

8.0

Relative risk of death

8

6.0
4.0

2.0

0.0
<21.0

21.0–
22.9

23.0–
24.9

25.0–
26.9

27.0–
29.9

30.0–
32.9

33.0–
34.9

35.0–
39.9

≥40.0

BMI (kg/m2)
Death from cancer (1740 cases)
3.62

3.0

Relative risk of deathC H A P T E R

2.5
2.0
1.5
1.0
0.5
0.0
<21.0

21.0–
22.9

23.0–
24.9

25.0–
26.9

27.0–
29.9

30.0–
32.9

33.0–
34.9

35.0–
39.9

≥40.0

BMI (kg/m2)

8.4 Other causes

5.84

5.0

Relative risk of death

Genetic, social, and environmental factors over the life
course influence the prevalence of weight gain, overweight,
and obesity. A large number of genes are involved with complex gene–gene and gene–environment interactions.
Estimates of the extent to which relative body mass is inherited, derived from studies of identical (monozygotic) twinsor adopted children and their biological parents, are consistently high, ranging between 64 and 84 per cent.56
Correspondingly, relatively high energy intake and/or relatively low energy expenditure, as well as levels of habitualphysical activity, also tend to run in families.57-59
Genetically determined obesity, such as the single-gene
defects that cause Prader-Willi syndrome, Bardet-Biedl syndrome, and congenital leptin deficiency, is rare.
Polymorphisms, in particular chromosomal locations linked toobesity in various populations, are now being investigated.60
The study of genetic determinants of weight gain is tending
to show that appetite regulation and spontaneous physicalactivity, rather than metabolism, have the dominant role.56

Death from other causes (838 cases)

4.0
3.0
2.0
1.0
0.0
<21.0

21.0–
22.9

23.0–
24.9

25.0–
26.9

27.0–
29.9

30.0–
32.9

33.0–
34.9

35.0–
39.9

≥40.0

2

BMI (kg/m )Figures relate to US women who have never smoked
Reproduced with permission from The New England Journalof Medicine67
Copyright © 2004 Massachusetts Medical Society. All rights reserved.

Relative risks of death were adjusted for: age; presence orabsence of a parental history of coronary heart disease;menopausal status and hormone use; physical activity; andalcohol consumption. Bars denote 95% confidence intervals.

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Figure 8.4

Relationship between BMI and diabetes,
hypertension, and hypercholesterolaemia

Per cent

Adults by BMI category

60
50

Type 2 diabetes
Hypertension
Hypercholesterolaemia

40
30
20
10
0
18.5–24.9

25.0–26.9

27.0–29.9

30.0–34.9

35+

BMI (kg/m2)
Risk of type 2 diabetes, hypertension, and hypercholesterolaemia
increases with increasing BMI, with no apparent threshold

Reproduced with permission from the National Centre for
Health Statistics (USA)66

prospective studies with direct long-term monitoring of US
women show increases in death rates when BMI exceeds 25(except in smokers who tend to be thin and die earlier thannon-smokers).67
Figure 8.3 shows relative risks for death among women
who had never smoked. The monotonic relationship held fordeaths from cancer and, more strongly, for deaths from cardiovascular causes. For other deaths, the increased risk in theleanest group was primarily due to chronic obstructive pulmonary disease and cirrhosis.
When death rate is plotted graphically against BMI, U- or
J-shaped curves imply that having a low BMI both increases the risk of death and reduces life expectancy. But careneeds to be taken to exclude the impact of smoking and ofundiagnosed diseases such as cancer, which can lead to unintended weight loss well before a diagnosis is made.68

8.6 Method
As already stated (see Chapter 3), a full understanding of thebiological factors that modify the risk of chronic diseases
such as obesity requires a synthesis of several types of evidence. Each type has advantages and disadvantages, and allcontribute to an overall picture. But there are special considerations that need to be taken into account for weight
gain, overweight, and obesity.
First, this chapter includes consideration of thermodynamics, and the mechanisms of energy input, output, andbalance, to complement evidence from observational andexperimental studies. Evidence on the physiological mechanisms, including robust experimental evidence in humans,
is abundant. Reliable evidence for mechanisms by which aparticular factor affects energy balance is an especially
important consideration when assessing and judging evidence on biological causation.
Next, clinical and epidemiological evidence in this area has
specific problems. Studies on obese subjects based on their

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retrospective assessment (recall) of diet and physical activity
are prone to serious bias. Also, interventions that may workin the short term are often ineffective in the longer term.
Further, even if specific interventions are shown to cause
weight loss, they are not necessarily the same factors thatcaused the weight gain originally. Finally, because of the crucial importance of environmental (economic, social, cultural, and political) factors in determining weight-related
behaviour, interventions which focus on individual behaviour in isolation from the environment may fail to show longterm impact.
The Panel therefore decided to exclude data from such studies that are inherently problematic from the systematic literature review (SLR) of the clinical and epidemiologicalevidence. The literature review included trials or studies thatran for, or included follow-up of, less than a year in thereview of underlying mechanisms. These were interpreted ascontributing to understanding of mechanisms underpinning
regulation of body fatness, though not in themselves as evidence of long-term impact on body fatness. The failure ofinterventions that are successful in the short term to translate to the long term is probably due to the powerful influences of sociocultural and other environmental factors indetermining behaviour. Case-control studies were excluded,
due to the special bias inherent in retrospective dietary
reports related to weight gain. Trials that prescribed energyrestricted diets as the intervention were also excluded; only
trials using ad libitum (unrestricted) diets as the intervention were included. Studies in children under 5 years old
were also excluded. The restriction to include only studies
in free-living participants means that results from this SLR
are relatively robust and generalisable.

8.7 Interpretation of the evidence
Energy balance and body composition
Measuring energy intake and expenditure in free-living participants taking part in prospective observational studies iscomplex. Interpretation of measures of energy intake per seis problematic, due to inaccuracies in assessment and thecomplexity of its relationships with body mass and physicalactivity. Current techniques are not sufficiently precise to reliably detect the small imbalances that lead to weight gain,
against a background of much higher levels of total energy
intake and expenditure. Studies addressing the effectivenessof interventions designed to encourage weight loss are alsodifficult to interpret from the point of view of what causes
weight gain in the first place. Interventions in free-living
populations tend to have relatively low compliance.
Initial weight loss is hard to sustain in the long term, andso long-term studies tend to show less weight loss than predicted by short-term interventions. While the causes of shortterm weight loss or maintenance can be identified andunderstood physiologically, the causes of long-term weightloss or maintenance may be different. Weight-loss trials were
included in the review and informed the judgements reported here, but the causes of weight loss are not necessarily theconverse of the causes of weight gain and obesity.

C H A P T E R8

Box 8.4•

D E T E R M I N A N T S

O F

W E I G H T

G A I N ,O V E R W E I G H T,

A N D

O B E S I T Y

Television viewing

The Panel decided to include evidence on
television viewing, which is a discrete andmeasurable pastime associated with obesity. Subjective methods such as diaries orquestionnaires, and more objective methods such as accelerometers, pedometers, orheart rate monitoring, can be used to measure relatively complex patterns of physicalactivity. However, all such methods areprone to imprecision and bias. On theother hand, the time spent on single, simple activities such as viewing television canbe recalled more precisely, and it is rela-

tively straightforward to measure the number of hours someone spends watching
television.
As shown in 8.8.8, watching television isassociated with the development of obesity (as well as with metabolic and cardiovascular pathology). Such adverse effects
are unlikely to be caused simply by the actof watching television. Television watchingis a sedentary behaviour; the degree ofphysical inactivity during television watching appears to be profound compared withother sedentary activities such as reading,Several of the studies that contributed data to this reportused self-reported body weight, which correlates well withmeasured body weight, although under-reporting is common, particularly among more overweight subjects.
Self-reported information on food consumption has also
been used; this is prone to similar bias. Consumption of foods
or drinks regarded as ‘unhealthy’, for instance, those containing fat, sugars, and alcohol, tend to be under-reported
more than others.
Designs and reporting methods vary between studies, making it difficult to combine data. For most of the exposuresassessed, many different measures are used. Study results can,and have been compared, but meta-analysis was not usuallypossible. Nevertheless, when epidemiological and trial data
are interpreted appropriately, and the results are assessed
together in the light of biological evidence, this research does
identify aspects of food and nutrition, and ways of life suchas being physically active, that are the most important determinants of overweight, weight gain, and obesity.
Social (including economic and political) and environmental factors are important determinants of behaviour,
including that which affects body fatness. Such factors are
the subject of a further report to be published one year after
this Report.
Physical activity

Measurement of physical activity is complex (also see
Chapter 5). When exposure measurement is less precise thanoutcome measurement, the apparent effect is attenuated.
Most cohort studies used subjective assessment methods.
Although all studies are prospective, some studies do notallow reverse causality to be excluded. That is, a high BMI
at the start of the study may be a cause of decreasing physical activity and may also be independently associated withan increased risk of weight gain. Although many studies
adjusted for potential confounders, the complexity of thisarea makes residual confounding difficult to exclude.
Trials of physical activity interventions and cohort studies
that investigated the effects of physical activity on weightgain vary greatly in size, length, follow-up, intervention
details, and study design, making comparisons problematicand precluding meta-analysis. In the case of physical activity and obesity, cross-sectional data may also be valuable.69

or sitting and talking. Also, time spent
watching television displaces opportunities
for more active pursuits and increases
exposure to promotion of foods that may
promote weight gain. Further, watching
television may be accompanied byrelatively uninhibited consumption ofenergy-dense foods, which may be eaten
in large portion sizes. Measuring the number of hours someone spends watching
television not only measures physical inactivity, but also a collection of related
behaviour.70

More recent studies report an inverse relationship between
physical activity and weight gain. While this could be
explained by improvements in study design, publication bias
may be present.
Being breastfed

The definition and classification of breastfeeding varied
between studies. Some studies included mixed feeding, perhaps in a ‘predominantly breastfed’ group; some reported
mixed feeding separately to exclusive feeding. In other studies, it was unclear what level of exclusiveness was used. The
duration of exclusive breastfeeding varied and was notalways reported. Intervention trials of the effect of breastfeeding are impossible for practical and ethical reasons.
Results may remain confounded, because in high-income
countries where most studies are undertaken, mothersfrom higher socio-economic groups tend to breastfeed for
longer periods, and it is difficult to correct for social classcompletely.

8.8 Evidence and judgements
A total of 207 publications were included in the SLR for thedeterminants of weight gain, overweight, and obesity. The
evidence from these studies is summarised here and is followed by the Panel’s assessments and judgements.
The evidence included observational epidemiology, trials,
and mechanistic data, with particularly strong and robust
evidence in humans, including data from short-term trials,
which were interpreted as evidence of underlying mechanisms rather than of long-term impact. Each of these typesof evidence is presented according to the particular exposures in the matrix. The exposures in the matrix reflect thePanel’s interpretation of the causal pathway by which theexposures/interventions might influence the risk of obesity.
The Panel agreed that in the particular case of weight gain,
overweight, and obesity, the epidemiological and trial evidence on cereals (grains), on vegetables, and on foods highin dietary fibre, should be interpreted in the light of, and asa marker of, their low energy density. It also agreed that, correspondingly, epidemiological and trial evidence on animalfats should be interpreted on the basis of their high energy

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density (box 8.1). Therefore, the Panel concludes that the epidemiological associations between specific foods, and weightgain and obesity, were probably due to a general effect of
the relative energy density of such foods and drinks rather
than any other characteristic.
The full SLR is contained on the CD included with thisReport.
8.8.1 Physical activity
Three randomised controlled trials (RCTs)71-73 and 16
cohort studies74-89 investigated total physical activity andweight maintenance or change in adults. Nine RCTs investigated combined physical activity and diet interventions inadults.90-100 Ten cohort studies101-110 and 1 case-cohort
study111 investigated occupational activity; 19 cohort studies.73 78 86 87 102 104 106 111-121 and 1 case-cohort study111 investigated recreational activity in adults; 2 cohort studies
investigated household activity86 122; 1 cohort study investigated frequency of physical activity in adults107; 3 cohort
studies investigated intensity of physical activity in adults.78
102 123
Two long-term RCTs,124 125 3 short-term RCTs,126-128 and
15 cohort studies.129-145 investigated total physical activity inchildren, and 4 cohort studies investigated frequency of physical activity in children.145-148
Total physical activity in adults

Two trials showed at least one statistically significant
decreased measure of weight gain/body fatness with a physical activity intervention.71 73 One trial showed no effect onweight maintenance.72 (See table 8.3.)
In the Schmitz trial, at 39 weeks, the intervention groupgained significantly more fat-free mass (0.89 kg, p = 0.009)
and lost more body fat (1.63 per cent, p = 0.006) comparedwith controls.71 There was no statistically significant
effect on weight or waist measurements. The Fogelholm
trial showed lower weight regain and waist-circumference
measures in the moderate walking group than in either
the control or high-intensity groups.73 The Borg trial showedno statistically significant difference to weight maintenance.72 However, resistance training attenuated theregain of body fat mass during the maintenance phase,2•

E V I D E N C E

A N D

J U D G E M E N T S

though not after follow-up.
Also see 8.8.4, 8.8.5, 8.8.6, and 8.8.7 for dietary interventions.
All nine trials showed a decreased risk of at least one measure of weight gain with interventions that included physical activity and diet advice. This tended to be removed orattenuated as follow-up periods extended past 12 months(table 8.4).
The first Pound of Prevention trial showed that 82 per centof the intervention group maintained or lost weight, compared with 56 per cent of the control group.90 The second
showed a statistically significant higher weight loss or maintenance in high-income women and men than in low-income
women from intervention, but no statistically significant difference overall between intervention and control.91 At 3
years, there was no statistically significant difference.92 In the
Women’s Healthy Lifestyle Project, the intervention group
showed statistically significant reductions in weight andwaist to hip ratio levels compared with baseline. The control group showed no statistically significant difference.93 94
In Leermarker’s trial,95 both intervention groups showed statistically significant reductions in weight (-1.6 kg, whereas
controls gained 0.2 kg; p < 0.01). (The 54-month follow-up
showed statistically significant lower increases in low-density lipoprotein cholesterol in the intervention group than in
the control group.95) In the Harrell trial, the intervention
group showed statistically significant lesser body fat than thecontrol group.96
The Patient-centred Assessment and Counselling for
Exercise trial showed no difference in BMI, but a non-significant lower percentage of body fat in the intervention groupcompared with the control group.97 The Burke trial showedno statistically significant effect on BMI, but fewer individuals in the high-intensity group became overweight orobese.98 The Pritchard trial showed a statistically significant
greater weight loss in the diet than in the exercise group.99
However, dual energy X-ray absorptiometry scans showedthat 60 per cent of weight loss in dieters was fat tissue,compared to 80 per cent in the exercise group, which also
showed better preservation of lean tissue. In the King trial,
the exercise-focused intervention showed statistically significant better weight maintenance than diet or control.100
Cohort studies in adults

Table 8.3

Physical activity interventions in adults

AuthorNumber ofparticipants

Intervention

Length ofintervention

Length offollow-up

Schmitz 2003

56 women

Strength-training
programme or control(aimed at weight loss)

15 weeks

6 months

Fogelholm
2000

85 women who
had undergone
a 12-week very
low-calorie diet

Moderate or highintensity walking
programme (aimed atweight-loss maintenance),or control

40 weeks

33 months

Borg 2002

90 men who
had undergone
a 2-month very
low-energy diet

Walking programme,
resistance training(aimed at weight-loss
maintenance) or control

8 months

31 months

332

All 16 cohort studies showed decreased risk
for at least one measure of weight gain,
overweight, or obesity with increased physical activity, which was statistically significant in 12.74-85
Effect estimates (not all studies reported
effect estimates) were a 0.77 per centdecrease in annual percentage change inweight (95% confidence interval (CI)
0.53–1.01) per one-unit increase in physicalactivity level89; a 0.32 kg/m2 greater increasein BMI (95% CI 0.19–0.46) for not taking
exercise, compared to taking exercise inmen, and a 0.30 kg/m2 (95% CI 0.16–0.44)
for the same comparison in women85; a0.03 kg/m2 decrease in BMI (95% CI

C H A P T E R

8•Table 8.4

D E T E R M I N A N T S

O F

W E I G H T

G A I N ,O V E R W E I G H T,

A N D

O B E S I T Y

Diet and physical activity interventions in adults

Trial

Number ofparticipants

Intervention

Length ofintervention

Length offollow-up

Pound of Prevention(Forster 1988)

219

Monthly education newsletters, with andwithout incentives, monitoring postcards,
optional education course.
Advice on healthy diet and exercise

12 months–

Pound of Prevention II(Jeffery 1997, 1999)

288 men, 594 highincome women, and404 low-income women

Newsletters with and without lottery
incentives, or control

12 months

3 years

Women’s Healthy

535 women

Behavioural programme or control

5 years

6–54 months

Lifestyle Project(Kuller 2001, Simkin-Silverman 1995)
Leermarkers 1998

67 sedentary men

Clinic or home-based intervention or control–

4 months

Harrell 1996

1504 police trainees‘Health and fitness programme’ or theusual training

9 weeks–

Patient-centred Assessment
and Counselling for Exercise

299 municipal service
workers

Intervention or control

9 months–(Proper 2003) Burke 2003

137 couples

High- or low-intensity intervention or control

4 months

12 months

Pritchard 1997

58 overweight men

A worksite programme comparing diet to
exercise interventions–

12 months

King 1989

90 men who hadparticipated in a 1-year
weight-loss trial

Comparing diet or exercise programmes
against control in maintenance of previous
weight loss––

0.005–0.0001; p = 0.049) per 1-unit increase in metabolic
equivalent (MET) hours per day83; a 0.91 kg decrease in men(95% CI 0.42–1.4) per physical activity score unit and a 2.14
kg decrease in women (95% CI 1.35–2.93)81; a 0.12 kg
decrease (95% CI 0.07–0.16) per 0.10 MET change in physical activity level80; a 0.29 kg decrease (± 0.12 kg; p < 0.02)
per log physical activity score in women only79; a 0.38 cm
decrease in waist circumference (95% CI 0.16–0.60) for an
increase in vigorous physical activity from baseline of 25
MET hours per week (this effect was reduced to 0.19 cm(95% CI 0.03–0.35 cm) after controlling for change inBMI)78; a 2.98 kg decrease (95% CI 1.41–4.55) per 200 exercise units in white women, and change in physical activity
was inversely associated with change in body weight in all
four race and sex subgroups (p < 0.0005)77; a 0.32 kg
decrease (95% CI 0.16–0.48; p < 0.0001) per 1-unit, within-woman increase in sports/exercise scale86; a 0.41 kg/m2
decrease in current BMI (95% CI 0.02–0.81; p value for trend
0.042) per 1-unit increase in past sport participation75; a
1.09 risk of increased BMI (95% CI 1.01–1.17) for the inactive group compared with the referent in the overweight, anda 0.95 risk of increased BMI (95% CI 0.91–0.99) in the average compared to the active reference group in the overweightsubgroup.74 One study showed that the baseline physicalactivity index was a significant predictor of weight gain (correlation coefficient of 0.39; p value for trend < 0.05) and
fat mass gain (correlation coefficient of 0.40; p value fortrend < 0.05) when one outlier was removed (weight regainof approximately 40 kg).82 One study stated that there wasa non-significant trend for lower increases in BMI withincreased physical activity.84
One study showed a non-significant association between

increased physical activity energy expenditure (correlation
coefficient of -0.03; p value for trend 0.77) and physicalactivity level (correlation coefficient of -0.03; p value fortrend 0.80) and subsequent weight gain.88
Other physical activity assessments in adults

Two cohort studies showed a statistically significant
decreased risk of weight gain, overweight, or obesity withincreased occupational activity108 110; two studies showedstatistically significant decreased risk in women only102 105;
four studies showed no significant association103 104 107 109;
two studies had mixed results101 106; and one study showeda statistically significant increased risk (exposure was ‘lifting’).111 There was considerable heterogeneity.
Six cohort studies showed a decreased risk of weight gain,
overweight, or obesity with increased recreational activity.73
86 118-121
Six studies showed no significant association87 102 104
111 115 116; five studies had mixed results,78 106 112-114 and one
study showed a statistically significant increased risk.118
One cohort study showed a statistically significant
decreased risk of weight gain, overweight, or obesity withincreased household activity.122 One study showed no significant association.86
One cohort study showed no statistically significant association between frequency of physical activity and risk ofweight gain, overweight, or obesity.107
Two cohort studies showed a statistically significant
decreased risk of weight gain, overweight, or obesity withincreased frequency of high-intensity physical activity.78 102
One study showed no significant association.123
One cohort study showed a statistically significant
decreased risk of weight gain, overweight, or obesity with333

P A R T

Table 8.5

2•

E V I D E N C E

A N D

J U D G E M E N T S

Physical activity interventions in children

AuthorNumber ofparticipants

Intervention

Length ofintervention

Length offollow-up

Mo-Suwan 1998

292 kindergarten children

Randomised by class (n=10) into exercise orcontrol group29–30 weeks

12 months

Sallis 1993

549 school children(mean age 9.25)

Randomised by school to specialist-led orteacher-led physical activity programme, or
control condition–

18 months

Flores 1995

110 children(mean age 12.6)

Randomised by class to Dance for Healthor control conditions

12 weeks–

Pangrazi 2003

606 children(mean age 9.8)

Randomised by school to usual physicaleducation, PLAY (Promoting Lifetime Activity
for Youth) (intervention) and PLAY plus usualphysical education and control (no physicaleducation or PLAY)

12 weeks–

Neumark-Sztainer 2003

201 physically inactive
girls (mean age 14.9(intervention) and15.8 (control))Randomised by school to multicomponent
physical education class or control.
Intervention included 8-week maintenancecomponent of weekly meetings

24 weeks–increased number of steps climbed in a day.87 One study
showed a statistically significant decreased risk of weight
gain, overweight, or obesity with increased routine, daily
physical activity level, and a non-significant decreased risk
with change in daily physical activity level.86
Both long-term trials showed statistically significant
decreased risk of at least one measure of weight gain, overweight, or obesity.124 125 However, one of the trials also
reported statistically significant lower BMIs in the control
group (table 8.5).125
Two short-term trials showed no statistically significant difference with physical activity interventions.127 128 One shortterm trial showed a decreased risk of weight gain,
overweight, or obesity with a dance-based physical activity
intervention, which was statistically significant in girls.126
The Mo-Suwan trial showed a non-significant decreased
prevalence of obesity in the intervention group (p = 0.057).
Girls had a statistically significant decreased risk of increasing BMI of 0.32 (95% CI 0.18–0.56); boys had a non-significant increased risk of 1.08 (95% CI 0.62–1.89). At 1 year,
the prevalence of obesity (defined by 95th skinfold percentile)
decreased by 2.7 per cent in the intervention group andincreased by 1.4 per cent in the controls.124 The Sallis trial
showed statistically significant lower BMI at 6 and 12
months (p value for trend < 0.05), but not at 18 months, inthe control group. However, boys in the specialist-led group
had thinner skinfold measurements at 6 and 12 months, but
not at 18 months. Girls in the control group had lower BMI
at each time point and this was statistically significant at 18
months (p < 0.01).125
The Flores trial showed a decreased risk of weight gain
with intervention, which was statistically significant in girls
only (BMI change -0.8 kg/m2 in intervention and 0.3 kg/m2
control). Boys showed similar, though non-significant,trends.126 The Pangrazi trial showed no statistically significant difference between the intervention and control
schools. However, girls showed a statistically significant
higher activity in two out of three of the interventions than334

control girls.128 The Neumark-Stzainer trial showed nostatistically significant difference in BMI between the intervention and control schools, with non-significant improvements in several analyses.127
Twelve cohort studies showed decreased risk for at least
one measure of weight gain, overweight, or obesity withincreased physical activity in children, which was statisticallysignificant in 11 (including the 2 cohort studies that used
objective measures to assess physical activity).132-145 Threestudies stated that there was no statistically significant
association.129-131
General mechanisms

The general mechanisms through which physical activity
could plausibly protect against weight gain, overweight, andobesity are outlined in 8.3 and in Chapter 5. In addition, an
important physiological consequence of physical activity is
fat oxidation, although this effect may be attenuated in obese
people. Regular exercise has been shown to increase fat
oxidation in both healthy and obese people, a mechanismthat is thought to occur as a result of improved insulin
sensitivity,149 although this effect may be attenuated in obese
people. Evidence has shown that physical activity could
potentially influence appetite control by: increasing thesensitivity of satiety signals; altering food choice or macronutrient preference; and modifying the pleasure response tofood, which may elevate hunger, food intake, and bodyweight. Short- and medium-term studies have, however,shown that individuals can tolerate substantial negative
energy balance during sustained physical activity, thus resulting in weight loss. Eventually, food intake will increase tocompensate for the exercise-induced energy loss, although
the degree of compensation may vary greatly between
individuals.150
The epidemiological evidence on physical activity is
substantial and consistent. There is robust mechanistic
evidence, particularly in relation to its impact on

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O F

W E I G H T

G A I N ,appetite regulation and energy balance. Overall, theevidence that all types of physical activity protect
against weight gain, overweight, and obesity isconvincing. It has this effect by promoting appropriate
energy intake. Conversely, the evidence can beinterpreted as showing that sedentary living is a causeof weight gain, overweight, and obesity.

The Panel is aware that since the conclusion of the SLR, nine
RCTs151-159 and four cohort studies160-163 have been published.
This new information does not change the Panel judgement (seebox 3.8).
8.8.2 Sedentary living
One RCT investigated physical inactivity in children164 (seetable 8.6) and three cohort studies investigated physical inactivity in adults.87 122 165 In addition, one RCT164 and 16 cohort
studies129 143 147 166-178 investigated television viewing. These
data are summarised separately in 8.8.8. Television viewing
is a behaviour that usually involves being highly sedentary,although other activities, such as snacking, are also associated with it (see box 8.4).
Sedentary living involves a high level of inactivity, withlow levels of activity. The data reviewed here relate to physical inactivity, which is only one component of sedentary living. Somebody who is inactive for considerable periods oftime might also engage in regular, moderate, or vigorous
physical activity at other times, and therefore not be sedentary. The strong mechanistic evidence on the effects ofsedentary living, particularly in an environment with easy
access to frequent, large portions of high energy-dense foods,
contribute to the Panel’s judgement on sedentary living.
The single trial showed no significant relationship between
sedentary living and BMI. Post-intervention, BMI was
unchanged, but behaviour such as the number of children
watching more than 2 hours of television per day was significantly lower in the intervention group, as was total number of hours watched.164
Two cohort studies showed increased risk of weight gain
with increased sitting time.122 165 One study stated that there
was no statistically significant relationship.87 Effect estimates
were 1.28 (95% CI 1.04–1.58) for the risk of becoming obesein those sitting at work, or away from home, or driving for
more than 40 hours per week compared with less than 1hour a week; 1.11 (95% CI 0.85–1.45) in those who spent> 40 hours a week sitting at home compared with 0–1 hours
per week122; and 0.80 (95% CI 0.70–0.91) for the likelihoodof weight maintenance (vs weight gain) with a low (< 33O V E R W E I G H T,

A N D

O B E S I T Y

hours per week) compared with high (/ 52 hours per week)sitting time.165
The general mechanisms through which sedentary living
could plausibly cause weight gain, overweight, and obesity
are outlined above and in Chapter 5.
The epidemiological evidence that sedentary living
causes weight gain, overweight, and obesity isrelatively sparse, but there is robust mechanistic
evidence in humans. The Panel concludes that theevidence that sedentary living causes weight gain,
overweight, and obesity is convincing.

The Panel is aware that since the conclusion of the SLR, onecohort study179 and one case-control study180 have been published. This new information does not change the Panel judgement (see box 3.8).

8.8.3 Being breastfed
Two published SLRs181 182 and three subsequent cohort
studies98 171 183 investigated being breastfed.
The larger literature review included 61 studies that investigated being breastfed and later risk of obesity, of which 43
were cohort studies, 15 were cross-sectional studies, and 3
were case-control studies.182 It showed a statistically significant decreased risk of obesity with breastfeeding. Metaanalysis was possible on 28 studies, giving a summary effectestimate of 0.87 (95% CI 0.85–0.89) for breastfeeding compared with formula feeding.
Only two studies looked at adult obesity; the rest assessed
obesity in those under 18 years. This effect was attenuated,but still statistically significant, when only the six studies that
adjusted for parental obesity, maternal smoking, and social
class were included, with an effect estimate of 0.93 (95% CI
0.88–0.99).182
The smaller literature review included 28 studies thatinvestigated being breastfed and risk of obesity in later childhood.181 It showed a statistically significant decreased riskof obesity with breastfeeding. Meta-analysis was possible onnine studies (two cohort studies and seven cross-sectional
studies), giving an adjusted summary effect estimate of 0.78
(95% CI 0.71–0.85) for breastfeeding compared with not.
The assessment of exposure to breastfeeding differed
between studies. One study compared children who were
mostly or only breastfed in their first 6 months with those
who were mostly or only formula-fed, while most of the studies compared children who were never breastfed with children always breastfed. Again, the effect was attenuatedwhen only maximally adjusted studies were
included.
All three cohort studies published after the
Table 8.6
Sedentary behaviour interventions in children
conclusion of the above-mentioned literaAuthor
Number ofIntervention
Length ofLength ofture reviews showed decreased risk of obeparticipantsintervention follow-up
sity with breastfeeding.98 171 183 However, theeffect was not statistically significant when
Dennison
176 children
Randomised by daycare
12 weeks–
fully adjusted in two studies,171 183 and one
2004
from middlecentre (n=18) into
income families
intervention that addressed
study showed a decreased risk of obesity,(mean age 4.0)
nutrition, reducing sedentary
which was statistically significant in adolesbehaviours, or control groupcence but not adulthood.98 Effect estimates335

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were 0.70 (95% CI 0.54–0.91; minimally adjusted) but 1.22
(95% CI 0.87–1.71) in the final model171; and 0.15 (95% CI
0.03–0.72) for being obese in adolescence and 0.34 (95%
CI 0.12–1.01) for being obese in adulthood.98 One study
reported a regression coefficient of -0.30 (95% CI -0.053 to-0.007; p value for trend 0.012) and BMI at age 8 years after
adjustment for sex.183 The study stated that breastfeeding
was not a statistically significant predictor of BMI after multivariate adjustment.
General mechanisms

Exclusively breastfed children show different growth patterns
from those of formula-fed infants (also see chapter 6.2).
Breastfed infants consume less total energy and less protein
than formula-fed infants.184 It is possible that the bioactive
factors in human milk could modulate energy metabolism,a process in which leptin (present in human milk but not formula) may be implicated. Alternatively, the effect of elevated protein intake and plasma insulin concentrations informula-fed babies could stimulate fat deposition and early
adipocyte development.
The epidemiological and mechanistic evidence thatbeing breastfed protects against overweight andobesity is substantial and generally consistent. While
there are some issues to do with measurement andconfounding, there is evidence for plausible
mechanisms. Being breastfed is probably protective.
The epidemiological evidence relates to childhood
overweight and obesity; overweight children tend to
become obese adults.

The Panel is aware that since the conclusion of the SLR, threecohort studies185-187 have been published. This new information
does not change the Panel judgement (see box 3.8).

8.8.4 Low energy-dense foods
The Panel decided to group the epidemiological evidence
on foods that are low in energy (box 8.1) into this generalcategory. This decision was informed by the mechanistic
evidence.
Nutrition interventions

Fourteen randomised controlled trials investigated dietaryinterventions and weight loss, and prevention of weight gain,
overweight, or obesity.45 188-200 Most trials increased the proportion of low energy-dense foods and drinks in people’s
diets. However, the stated aims of trials varied and some may
not be directly relevant. In particular, low-carbohydrate dietsseem to lead to energy reduction with high energy density,
but the long-term health impact of such diets is not known(see table 8.7).
All trials showed that restricted energy diets decreased therisk of weight gain, overweight, and obesity. All trials also
showed that increasing the consumption of low energy-dense
foods and decreasing the consumption of high energy-dense
foods in diets decreased risk of weight gain, overweight, andobesity. Some found that these varied approaches were more

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effective than general energy restriction; some did not.
Most trials with sufficient follow-up periods also showedthat weight loss was not commonly maintained after theintervention ended.
The Matvienko trial showed no significant difference fromanalysis of the whole dataset, although participants withhigher initial BMI showed improved weight maintenancewith intervention, with statistically significant weight gainin the control group.200 The Epstein trial showed nonsignificant weight loss in both intervention groups, with anon-significantly greater weight loss in the decreased fat andsugar group.199 The Swinburn trial showed statisticallysignificant weight loss with the low-fat diet at one year, but
no significant difference at five years.195 The Flemming trial
showed statistically significant weight loss with the low-fat
diet and calorie-controlled interventions.197 The Dansinger
trial showed statistically significant weight loss for all dietsand no significant difference between them.198 The HarveyBerino trial showed statistically significant greater weightloss with calorie restriction than with the low-fat diet.196 The
Jeffery trial showed statistically significant greater weightloss with the low-fat diet at the end of the intervention; after
follow-up, both groups had returned to their original
weights.194 The Sheppard trial showed statistically significant
greater weight loss in the low-fat diet group.193 The Shahtrial showed no statistically significant difference in weightloss between the low-fat and low-calorie diets.192 The Foster
trial showed statistically significant greater weight loss forthe low carbohydrate diet at three and six months, but a nonsignificant greater weight loss at one year.45 The Stern trial
showed a non-significant greater weight loss with the lowcarbohydrate diet than the calorie-restricted diet.191 The
Ebbeling trial showed statistically significant greater weightloss with the reduced glycaemic load trial.190 The SimkinSilverman trial showed statistically significant greater weightloss and/or maintenance for the intervention group.189 The
Toubro trial showed no significant difference between thetwo weight-loss regimes, but did show statistically significant
maintenance (less regained weight) in the ad libitum maintenance regime than in the fixed energy group.188
8.8.4.1 Wholegrain cereals and cereal products

Four cohort studies investigated wholegrain cereals andcereal products.
All four cohort studies showed decreased risk of weightgain and/or obesity for the highest intake group when compared with the lowest, which was statistically significant in
two.201-204 The two statistically significant results were bothfrom studies that investigated all food sources of wholegrains. Effect estimates for higher wholegrain intake were0.81 (95% CI 0.73–0.91; p value for trend 0.0002) for obesity and 0.77 (95% CI 0.59–1.01; p value for trend 0.03) for
major weight gain204; decreased weight gain with greater
total wholegrain intake (p value for trend < 0.0001)203;
regression coefficients of -0.07 (95% CI -0.30 to 0.17) for
men and -0.20 (95% CI -0.49 to 0.09) for women for the
relationship between wholegrain bread intake and waist circumference202; and 0.91 (95% CI 0.79–1.05; p value fortrend 0.13) for the relationship between wholegrain break-C H A P T E R

8•Table 8.7

D E T E R M I N A N T S

O F

W E I G H T

G A I N ,O V E R W E I G H T,

A N D

O B E S I T Y

Nutrition interventions

AuthorNumber ofparticipants

Intervention

Length ofintervention

Length offollow-up

Matvienko 2001

40 female young adults

Nutrition education

4 months

16 months

Epstein 2001

26 children with at least one
obese parent – and theirfamilies

Increased vegetables and fruits of decreased
fat and sugar intake

12 months–

Dansinger 2005

160 adults with one obesityrelated comorbidity

Low-carbohydrate diet, low-fat diet, calorie
restriction, and macronutrient balance

12 months–

Flemming 2002

100 otherwise healthy overweightor obese adults

High, moderate, and low-fat diet comparedwith a calorie-controlled group

12 months–

Harvey-Berino 1999

80 otherwise healthy overweightor obese adults

Low-fat diet or low-calorie diet

24 weeks–

Swinburn 2001

103 adults with one obesityrelated comorbidity

Low-fat diet or general dietary advice

12 months

5 years

Jeffery 1995

74 moderately obese but
otherwise healthy womenLow-fat diet or low-calorie intervention

18 months–

Sheppard 1991

303 women at increased
risk of breast cancer

Low-fat diet or other intervention

12 months–

Shah 1996

122 overweight but otherwise
healthy women (data only
available for 75)

Low-fat diet or low-calorie diet

6 months

12 months

Foster 2003

63 obese but otherwise
healthy people

Low-carbohydrate diet (Atkins) comparedwith low-calorie diet

6 months

12 months

Stern 2004

87 obese adults

Low-carbohydrate diet or calorie-restricted
diet

12 months–

Ebbeling 2003

14 obese adolescents/
young adults

Reduced glycaemic load diet compared with
reduced energy and reduced-fat diet

6 month intensive–
phase + 6 month
maintenance phase

Simkin-Silverman 1998

489 women, 50% were
not over or underweightat baseline

Meetings led by behavioural psychologists
and nutritionists compared with control

18 months–

Toubro 1997

43

First randomised to rapid or slow weight-loss
programmes, then re-randomised to a fixedenergy or ad lib maintenance programme

12 months–

fast cereal intake and risk of being overweight.201
Definitions of wholegrain foods remain contentious (seebox 4.1.1).
Wholegrains (consisting of the grain endosperm, germ,and bran) provide an abundant source of dietary fibre, resistant starch, phytoestrogens, antioxidants, and other micronutrients (see chapter 4.1). The primary mechanism for aneffect on weight gain is through low-energy density.
However, there are other mechanisms through which wholegrains may have a physiological effect on weight gain. For
instance, several studies have demonstrated a positive relation between wholegrain consumption and improved blood
insulin profiles, which could provide an indirect mechanism.
Wholegrain cereals and cereal products are assessed
here as high-fibre foods and as a marker for low
energy-dense foods. For this reason, no separate
judgement is made for wholegrain cereals and cereal
products.
8.8.4.2 Foods containing dietary fibre

Six cohort studies investigated foods containing fibre, fourin adults and two in children.115 173 203-206
Five cohort studies showed decreased risk of weight gain
and/or obesity for the highest intake group when comparedwith the lowest,115 203-206 which was statistically significant
in three.203-205 One study (in children) showed a non-significant decreased risk in boys and a non-significant increased
risk in girls.173 Of the two studies that showed non-significant decreased risk, one investigated the relationshipbetween infant diets and adolescent obesity.206 Effect estimates in adults were 0.51 (95% CI 0.39–0.67; p value fortrend < 0.0001) for overweight and 0.66 (95% CI
0.58–0.74; p value for trend < 0.0001) for obesity204;
p value for trend / 0.001 for weight gain (no effect estimate)205; 0.39 standard deviation (SD) g per day weightchange (± 0.2) for the highest intake group and 1.4 SD g
per day weight change (± 0.2) for the lowest, p value fortrend < 0.0001203; and the univariate model (adjusted for
retirement (yes/no); type of job (sedentary or active); interaction between retirement and type of job; age; smoking;and the base level of the behaviour) showed a regression
coefficient of -0.31, p value for trend < 0.01, and the multivariable model (additionally adjusted for all other behav-

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iours examined, including physical activity and dietary variables) showed a regression coefficient of -0.17, p value fortrend 0.10.115 Effect estimates in children were 0.78 (95%
CI 0.60–1.02) for adolescent obesity with the highest intake
group of fibre foods at 3 years old206; and regression coefficients of 0.0011 (95% CI -0.0073 to 0.0095; p value for trend0.80) in girls and -0.0046 (95% CI -0.014 to 0.0046; p value
for trend 0.320) in boys.173
Residual confounding is possible, as indicated by the maximally adjusted cohort study above. People whose diets arehigh in fibre from food often also have other habits regarded as healthy, which may be difficult to characterise precisely.
On the other hand, there is considerable evidence for a specific effect of dietary fibre on satiety and on mechanisms
relating to appetite regulation, such as gastric emptying.48
Fibre from food has a low energy density, as it is not digested in the small bowel and can only undergo partial fermentation in the large bowel. Fibre consumption may increasesatiation by increasing chewing, slowing gastric emptying
and elevating stomach distension, and stimulation of cholecystokinin. The increased viscosity of soluble fibre can reduce
the overall rate and extent of digestion, which may also
result in reduced energy from protein and fat and a blunted
post-prandial glycaemic and insulinaemic response to carbohydrates. Fibre-induced delayed absorption and the resultant presence of macronutrients in the distal small intestine,
known as the ileal brake, mediate the release of several gut
hormones.207
The evidence on foods containing dietary fibre isassessed here as a marker for low energy-dense foods,
although there are specific mechanisms beyond energy
density. For this reason, no separate judgement ismade for dietary fibre.
8.8.4.3 Non-starchy vegetables

Five cohort studies investigated non-starchy vegetables, fourin adults and one in children.114 208-211
All five cohort studies showed decreased risk of weightgain and/or obesity for the highest group of non-starchy vegetables intake when compared with the lowest, which wasstatistically significant in two.114 210 Effect estimates in adults
were 0.84 (95% CI 0.75–0.93; p value for trend < 0.0001)
for becoming obese and 0.76 (95% CI 0.59–0.99; p value fortrend 0.01) for major weight gain210; -0.12 kg/m2 meanchange in BMI (95% CI -0.22 to -0.02; p value for trend
0.012)114; regression coefficient of -0.05 (95% CI -1.24 to-0.63) with change in BMI211; and 0.99 (95% CI 0.87–1.13)
for weight gain.209 Weight and height were measured in thetwo statistically significant studies, and were self-reported in
the two non-significant studies. The study in children showeda statistically significant decreased risk of raised BMI z-scoresin boys (regression coefficient of -0.003, 95% CI -0.004 to-0.001) but no relationship in girls.208
Increased consumption of non-starchy vegetables, which
are generally low in energy density, may result in a compensatory decrease in the consumption of more energy-dense
foods. Most non-starchy vegetables tend to have a low glycaemic index and contain soluble dietary fibre, which may

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result in slowed gastric emptying and increased satiety. Fruits
and vegetables contain high concentrations of a range ofimportant micronutrients such as antioxidants and phytoestrogens that may also have a beneficial influence upon theenergy homeostatic pathways.
Non-starchy vegetables are assessed here as high fibre
foods and as a marker for low energy-dense foods. For
this reason, no separate judgement is made for nonstarchy vegetables.
Overall, the epidemiological evidence that low
energy-dense foods protect against weight gain,
overweight, and obesity is substantial and generally
consistent. The mechanistic evidence, particularly thaton appetite regulation and energy balance, iscompelling. Taking all types of evidence together, lowenergy-dense foods probably protect against weight
gain, overweight, and obesity. They have this effect bypromoting appropriate energy intake.

The Panel is aware that since the conclusion of the SLR, two
RCTs,212 213 three cohort studies,179 214 215 and one case-cohort
study216 have been published. This new information does notchange the Panel judgement (see box 3.8).
8.8.5 Energy-dense foods
The Panel decided to group the epidemiological evidence on
foods that are high in energy (box 8.1) into this generalcategory. This decision was informed by the mechanistic
evidence.
In addition to the evidence summarised below, several of
the trials reviewed in 8.8.4 investigated the effect of reducing intake of energy-dense foods and drinks, which generally decreased the risk of weight gain during theintervention. The evidence on sugary drinks and ‘fast foods’
are also relevant to the judgement for this general category(see 8.8.6 and 8.8.7).
8.8.5.1 Animal fatsThree cohort studies investigated animal fats, two in adults
and one in children.211 217 218
All three cohort studies showed increased risk of weightgain for the highest intake group when compared to the lowest, which was statistically significant in one study,218 andin one analysis of data on children.217 Regression coefficientsin adults were 0.0032 (95% CI 0.0063–0.00006) linking animal fat intake and increased risk of weight gain (height andweight were self-reported)218; and 4.85 (95% CI -3.5 to 13.2;
p value for trend 0.26) linking animal fat intake and weightchange (measured).211 The study in children (recording animal fat intake from 1 to 7 years of age) showed a statistically significant greater weight at 7 years for the highest
intake group of 29.3 kg (SD±2.0) compared with 23.7 kg(SD±1.2) in the lowest (p value for trend < 0.05).217 Whenanimal fat intake was measured as g/1000 kcal, g/kg bodyweight, or compared to Roher index (weight in g 3
100/height in cm3), no statistically significant difference wasapparent.
As the most energy-dense macronutrient, there are several

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O F

W E I G H T

G A I N ,plausible mechanisms by which dietary fat could lead to positive energy balance and obesity. The efficiency of nutrient
use is higher for fat than carbohydrate or protein. Whenenergy balance is positive and fat is being stored, the storage of this fat only requires a small degree of oxidation(approximately 3 per cent of the energy stored). The highenergy density of fat may promote passive overconsumption.
Prolonged consumption of a high-fat diet may desensitise theindividual to a number of appetite controls. The palatability of fat may induce voluntary overconsumption.
The evidence on animal fats is assessed here as amarker for energy-dense foods. For this reason, no
separate judgement is made for animal fats.
High energy-dense foods are probably a cause ofweight gain, overweight, and obesity, particularly
when large portion sizes are consumed regularly. They
have this effect by promoting excess energy intake.
Also see entries on sugary drinks (8.8.6), ‘fast foods’(8.8.7), and television viewing (8.8.8).

The Panel is aware that since the conclusion of the SLR, onecohort219 and one case-control study180 have been published.
This new information does not change the Panel judgement (seebox 3.8).
8.8.6 Sugary drinks
The evidence on sugary drinks is reviewed separately due toits independent effect on body fatness. It also contributes tothe judgement on energy-dense foods and drinks.
One RCT220 and four cohort studies investigated sugary
drinks.115 221-223 Two cohort studies were in adults115 223; thetrial and two other cohort studies were in children.221 222
The single trial included 644 children randomised by class
to receive teaching sessions to discourage consumption ofsugary, carbonated drinks or to control. After 12 months,
change in BMI z-score was non-significantly lower in theintervention group, with a change of 0.7 (SD 0.2) comparedwith 0.8 (SD 0.3) in the control group.220
Three cohort studies showed increased risk of weight gain
when frequency of sugary drink intake increased,115 222 223
which was statistically significant in two.115 222 One study
showed no association.221 This study was in children, andinvestigated intake of ‘fruit drinks’, but excluded fruit juice,soda (fizzy drinks), or diet soda. The effect estimates for thetwo adult studies were mean weight gain of 4.69 kg for 1991
to 1995 and 4.20 kg for 1995 to 1999 in women who
increased their sugar-sweetened soft drink consumption, and1.34 kg and 0.15 kg in women who decreased their consumption223; regression coefficients of 0.20 (p value for trend< 0.01) for the univariate model relating weight gain to
increase in intake of sugar-sweetened soft drinks and 0.12
(p value for trend 0.05) for the multivariable model (thisstudy also reported a statistically significant relationship withincreased waist circumference).115 The cohort study in children that reported an effect estimate showed that BMI
increased by 0.24 kg/m2 (95% CI 0.10–0.30; p value fortrend 0.03) per sugary drink (not including fruit juice)/dayand the effect estimate for the frequency of obesity was 1.60

O V E R W E I G H T,

A N D

O B E S I T Y(95% CI 1.14–2.24; p value for trend 0.02), also per drink/day.222
There is considerable variation in the definition of ‘sugary
drinks’ between studies. The study that reported no association excluded fizzy drinks.
Studies have demonstrated that, when consumed as partof a soft drink, the energy from sugars may not be compensated for in the same way as when consumed as part of asolid meal.224 Limited studies have shown that in adults,
short-term (10-week) intake of sugar-sweetened foods anddrinks (of which 80% were drinks) promoted weight gain,
whilst consumption of artificially sweetened foods resulted
in weight loss.28
The epidemiological and mechanistic evidence thatdrinks containing added sugars, including sucrose andhigh-fructose corn syrup, are a cause of weight gain,
overweight, and obesity is substantial and consistent.
Sugary drinks probably cause weight gain, overweight,
and obesity. Like energy-dense foods and drinks, they
have this effect by promoting excess energy intake.

The Panel is aware that since the conclusion of the SLR, one
RCT,225 one cohort,226 and one case-control study180 have been
published. This new information does not change the Panel
judgement (see box 3.8).
8.8.7 ‘Fast foods’
The evidence on ‘fast foods’ is reviewed separately due totheir independent effect on body fatness. It also contributes
to the judgement on energy-dense foods and drinks.
Six cohort studies investigated ‘fast foods’ (see box 8.2),
four in adults and two in children.165 227-231
All six cohort studies showed increased risk of weight gain
with increased intake of ‘fast foods’, which was statisticallysignificant in four,165 227 229 230 and in women but not men in
an additional study.231 Effect estimates in adults were aregression coefficient of 0.85 (95% CI 0.43–1.27; p value fortrend < 0.05) in low-income women and 0.39 (95% CI
0.15–0.64; p value for trend < 0.05) for the association
between number of ‘fast-food meals’ per week and BMI231;
a 0.85 (95% CI 0.75–0.96) chance of maintaining weight(equivalent to a 15 per cent increased risk of weight gain)165;
a weight gain of 1.72 kg (95% CI 0.52–2.92; p value fortrend 0.005) greater for black people who visited ‘fast-foodrestaurants’ frequently compared to those who visited infrequently, and 1.84 kg (95% CI 0.86–2.82; p value for trend< 0.0013) greater for the same comparison in white people230; and a 0.72 kg (95% CI 0.33–1.11; p value for trend< 0.01) greater weight gain for people who visited fast-foodrestaurants more than twice a week compared to those who
visited infrequently.229 One study in children showed a statistically significant greater increase in BMI z-scores of 0.82
for those who ate food from quick-service outlets more than
twice a week compared to 0.28 for those who never ate
quick-service foods (p value for trend 0.0023).227 One study
in children stated that there was a statistically significant
association between increased ‘takeaway food’ intake and
BMI at the age of 8, but that after multivariable adjustment

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there was no statistically significant relationship.228
The energy density of a food reflects the energy content
per unit weight (box 8.1). Many of the highly consumed
processed and ‘fast foods’ have a high energy density, often
due to a high content of fat and refined starches and sugars
and a correspondingly low water content.232
The evidence that ‘fast foods’ as defined in theliterature are a cause of weight gain, overweight, andobesity is strong and consistent. This epidemiologicalevidence reinforces the Panel’s judgement on energydense foods. Other factors are that ‘fast foods’ arepromoted vigorously, are cheap, and are often
available in large portion sizes at low cost. ‘Fast foods’
probably cause weight gain, overweight, and obesity.
They have this effect by promoting excess energy
intake.

The Panel is aware that since the conclusion of the SLR, twocohort studies226 233 and one case-control study180 have been
published. This new information does not change the Panel
judgement (see box 3.8).
8.8.8 Television viewing
The evidence on television viewing is reviewed separately
due to its independent effect on body fatness. It also
contributes to the judgement on sedentary living (8.8.2)
and may be a marker for other behaviour, such as
consumption of energy-dense foods (box 8.1).70
One RCT234 and 16 cohort studies129 143 147 166-178 investigated television viewing, all in children, adolescents, or young
adults. Some studies grouped other sedentary leisure-time
activities, such as playing videogames, together with television viewing.
The single RCT showed a statistically significant decreased
risk of body fatness with decreased television viewing. The
trial included 198 children randomised by school into anintervention or control group for six months. The intervention aimed to reduce television, videotape, and videogame
use with supporting lessons, encouragement not to eat meals
whilst watching television, and a seven hours per week television budget. The intervention group showed a 0.45 kg/m2
greater decrease in BMI (95% CI -0.73 to -0.17) than the control group. Statistically significant greater decreases werealso seen in skinfold measurement, waist circumference, andwaist to hip ratio. The intervention group showed statistically significant fewer hours of television viewing (p value
for trend < 0.001) and fewer meals eaten in front of the television (p value for trend < 0.02).234
Ten cohort studies showed increased risk of weight gain
and/or obesity with increased television viewing,143 166-168 170-175
which were statistically significant in nine.143 166-168 170-174 Fourstudies stated that there was no significant association129
176-178
and an additional study found an association withvideogame-playing in girls but not boys, but no association
with television viewing.147 One study showed a non-significant decreased risk.169 Effect estimates (four studies did notreport effect estimates) were a regression coefficient of 0.029(p value for trend < 0.001) for the relationship between

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hours spent watching television and the risk of obesity (asdefined by triceps skinfolds on or above the 85th percentile)and 0.14 (p value for trend < 0.001) for triceps skinfolds
on or above the 95th percentile174; regression coefficients of
0.037 (95% CI 0.011–0.058; p value for trend 0.001) for the
relationship between time spent watching television or playing videogames in girls and 0.038 (95% CI 0.018–0.059; pvalue for trend 0.001) for the same relationship in boys173;
correlation coefficient of 0.14 (95% CI 0.01–0.27; p value
for trend < 0.05) for the relationship between time spent
watching television and subscapular skinfold thickness (asa measure of body fatness)143; a regression coefficient of
0.054 (p value for trend 0.82) for the relationship between
television viewing and BMI175; a regression coefficient of
0.48 (standard error 0.19; p value for trend 0.012) for relationship between television viewing in adolescence and BMI
at 26 years in a maximally adjusted model167; a regression
coefficient of 0.47 (SE 0.21; p value for trend 0.02) for the
relationship between television viewing and BMI166; a regression coefficient of 0.19 (p value for trend < 0.01) for the
relationship between time spent watching television or playing videogames and BMI172; an effect estimate of 1.55 (95%
CI 1.13–2.12) for the group that watched the most television when compared to the lowest.171 Watching television orvideos, playing computer games, or listening to audio tapes
was a positive predictor of body fat in 2 out of 4 models
investigating variables related to percentage body fat at age
8 years170; a regression coefficient of 0.05 (95% CI
0.02–0.07; p value for trend < 0.01) for the relationshipbetween time spent watching television and BMI168; and a
BMI of 19.5 kg/m2 (95% CI 19.3–19.7) in the group thatwatched the most television compared to a BMI of 19.6
kg/m2 (95% CI 19.4–19.9) in the group that watched theleast.169
Television viewing is a form of very sedentary
behaviour. The epidemiological evidence is mostly
consistent and generally free of methodological issues.
Results from the intervention trial are impressive, andthere is evidence of a dose-response relationship.
Television viewing may also be associated with
consumption of energy-dense foods and drinks.
Studies were of children and adolescents, but these canbe taken to apply also to adults. Given that televisionviewing is a sedentary behaviour, the mechanistic
evidence, particularly that on energy input, output,
and turnover, is compelling. Television viewing isprobably a cause of weight gain, overweight, andobesity. It has this effect by promoting an energy intake
in excess of the relatively low level of energy
expenditure.

8.8.9 Other exposures
The following exposures were evaluated: total fat, refinedcereals (grains)/cereal products, starchy roots, tubers andplantains, fruits, fruit juices, fish, milk and dairy products,
alcoholic drinks, sweeteners, and coffee. However, the data
were either too low quality, too inconsistent, or the numberof studies too few to allow conclusions to be reached.

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8.9 Comparison with previous report
The panel responsible for the previous report made recommendations on body mass and on weight gain, based on theevidence that high body mass increases the risk of some cancers (also see Chapter 6). The report did not review thedeterminants of weight gain, overweight, and obesity.

8.10 Conclusions
The Panel concludes:
Throughout this Report, our conclusions and judgements
derive from a balance of different types of evidence, including epidemiological, clinical trial, and mechanistic data (asset out in Chapter 3). Compared to evidence on the factorsthat modify the risk of cancer, there is more and better evidence from clinical trials, and less from observational epidemiology, while there is a large and robust body ofexperimental evidence in humans on mechanisms of energybalance. Factors that increase (or decrease) risk of weightgain do this through promoting (or discouraging) excessenergy intake. The interaction of energy density of diets andlevel of physical activity is fundamental.
In light of this, we have taken an integrated approach in
our interpretation of the evidence relating to weight gain,
overweight, and obesity, much of which has focused on specific foods, drinks, and dietary constituents. The various
foods and dietary constituents have therefore been interpreted in the context of the energy density of foods and diets.
The evidence showing that regular, sustained physicalactivity of all types protects against weight gain, overweight,
and obesity is convincing. Being breastfed is probably protective. While the evidence is from studies of infants andyoung children, childhood overweight and obesity tend to
track into adult life. Low energy-dense foods, especiallythose containing dietary fibre, are probably also protective.
The evidence that sedentary living is a cause of weight
gain, overweight, and obesity is convincing. Energy-dense
foods are probably also a cause. Sugary drinks (those containing added caloric sweeteners, notably sucrose and highfructose corn syrup); ‘fast foods’ (which are readily available
and may be energy dense and frequently consumed, often
in large portions); and television viewing (a sedentary
behaviour associated with consumption of energy-dense
foods) are all probable causes of weight gain, overweight,
and obesity.
The evidence reviewed in this chapter does not include theimportant role played by sociocultural and other environmental factors, which will be the subject of a further report
to be published in late 2008. Nevertheless, given theevidence summarised in Chapter 7 on the role of body fatness in causing various cancers, the factors identified here
should be considered to be additional, indirect causes of
those cancers.

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9Cancer survivors
Cancer survivors are people who are living witha diagnosis of cancer, including those who haverecovered.
Awareness of cancer survival has increased greatly
since the 1990s. So has the number of people livingwith a diagnosis of cancer. The total number ofrecorded cancer survivors in the world in 2002 wasestimated to be just under 25 million, and by 2050
may approach 70 million.
The term ‘cancer survivor’ covers a very wide
variety of circumstances. Thus, the needs of people
currently undergoing therapy are likely to bedifferent from those of people whose metabolic
functions have been altered as a result of therapy
and from those of people who are evidently fully
recovered and whose functions are intact.
Nevertheless, the Panel accepts the validity of theconcept of cancer survivor, welcomes the rising consciousness that cancer is a disease best spoken of
and dealt with openly, and agrees that the best way
to improve quality of life and increase the chancesof prolonged life and recovery from cancer is whencancer survivors take responsibility for themselves,supported by associates, friends, and family, while
always also consulting their professional advisorsand making best use of available medical care systems and qualified social support.
Correspondingly, we the Panel collectively haveaccepted a special responsibility to give our best
advice, having examined the evidence derived fromsystematic reviews of the scientific literature done
according to our agreed methodology, and also
from our knowledge of the whole range of evidence
and consideration of the precautionary principle
and best clinical and public health practice.
Research on food, nutrition, physical activity, andcancer survival is at an early stage. Overall, thePanel agrees that it is not possible to make judgements that apply specifically to cancer survivors,
based on the evidence reviewed for this Report. The
available evidence on cancer survivors has a numberof limitations: it is of variable quality; it is difficult
to interpret; and it has not yet produced any impressive results. Definite general judgements are mademore problematic because of differences in thehealth of cancer survivors at various stages;342

between cancers of various sites; and between theeffects of the many types of conventional and othertherapies used.
The Panel notes as follows:
Regular physical activity and other measures that
control body weight may help prevent recurrence, atleast of breast cancer. In any case, when able to doso, cancer survivors are likely to gain general healthbenefit, and a sense of control over theircircumstances, from regular physical activity.
The evidence does not support the use of highdose supplements of microconstituents as a meansof improving outcome in people with a diagnosis ofcancer. Cancer survivors should consult their
physician and/or a qualified nutrition professional,
who can evaluate the safety and efficacy of specificdietary supplements, and counsel an appropriate
action based on current research relevant to their
particular clinical situation.
In summary, evidence that some aspects of food,nutrition, or physical activity specifically modify thecondition of cancer survivors is emerging, but is not
yet sufficiently developed to enable the Panel tomake judgements that apply specifically to cancer
survivors, as distinct from people without cancer.

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The concept of ‘cancer survivor’ first gained currency in the
USA in the 1990s, particularly among advocacy groups
formed to give information, advice, and support to people
with cancer. The term here refers to people living with a diagnosis of cancer, including those believed to have recovered.
Consciousness of cancer survival has increased greatly
since the 1990s, especially in high-income countries. This is
only partly because of the increase in numbers. Another reason is that cancer is increasingly a disease spoken of openly, and seen less as the visitation of a death sentence.
Cancer survivors, and their families and friends, areincreasingly determined to take responsibility for living withcancer. They do this individually and collectively, usually incollaboration with their medical and surgical advisors, andoften with practitioners offering complementary and alternative therapies, regimens, and advice.
Cancer survivors as an overall group, together with those
who are closest to them, are especially concerned to learn
about and act on helpful recommendations. These should beleast likely to do harm, and most likely to help limit the
progress of the cancer. They should also help prevent a recurrence of that or another cancer, and help prevent other diseases, as well as improve the quality of survivors’ lives. This
places a special responsibility on professionals in this field,
to consider carefully what can be recommended.
The Panel’s recommendations for cancer survivors are inPart 3, Chapter 12.

9.1 Definitions
The term ‘cancer survivors’ denotes all people who are livingwith a diagnosis of cancer, and those who have recoveredfrom the disease. In this definition, then, cancer survival
begins at the point of diagnosis.
Cancer survivors include the following population groups;
these are often not discrete, because people may fall into several of the groups below.
After diagnosis, before treatment• People with cancer who have chosen to have treatment• People with cancer who choose to have no treatment.
During treatment• People being treated with modern conventional therapies• Radiation• Chemotherapy• Surgery• Combinations of radiation, chemotherapy, and surgery.
• People treated with therapies that are alternative orcomplementary to conventional ones (box 9.1), usually
as well as, but sometimes instead of, conventional
therapies• Naturopathy• Radical diets (very low fat, raw food, other)• Energy restriction• Orthomolecular nutrition (including all forms ofsupplementation)• Gerson therapy, Hoxsey therapy, antineoplastons,
Coley’s toxins, other• Traditional therapies (Ayurvedic, Chinese herbal,
other)• Combinations of these, with or without conventional
therapy• Other.
After treatment• People whose treatment has been said to be successful,and who have undamaged metabolic functions• People whose treatment has been said to be successful,and who have damaged metabolic functions• People who have had parts of their digestive tract
surgically removed (mouth, oesophagus, stomach,small intestine, colon)• As above, also with colostomy, ileostomy• Other.
People with secondary cancer or cancer ofa different site
• Where treatment has been unsuccessful, and who haveundamaged metabolic functions• Where treatment has been unsuccessful, and who havedamaged metabolic functions• Those who have had parts of their digestive tract
surgically removed (mouth, oesophagus, stomach,small intestine, colon)• As above, also with colostomy, ileostomy• Other• People with metastasised or disseminated cancer, withor without cachexia• People with terminal cancer.

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After recovery• People who are alive 5–10 years after successful treatment• People who are alive 10+ years after successful treatment(including those who had cancer as a child).
The definition of ‘cancer survivor’ here does not include people living with a diagnosis of a benign tumour, or tumours
defined as premalignant, such as premalignant cervicallesions or polyps in the colon.
‘Cancer survivors’ as defined here also does not include
those living with people who are living with a diagnosis of cancer. Sometimes this wider definition is used, and from the public, community, and family health points of view, issues thatconcern cancer survivors are also of vital importance to theirpartners, family members, and close friends.1 Such loved ones
are most likely to want to know what to do, and will seek professional guidance, both for the person with diagnosed cancer, and also for themselves and family members.
This becomes most important practically when decisions
need to be made about family shopping and meal preparation, and eating out. Should the family member with cancer
be treated differently? Or should the whole family follow thesame recommendations and advice? These are not questionsof direct professional concern to cancer researchers, but doconcern physicians, and other health professionals, whose
responsibility includes passing on authoritative recommendations, or else giving the best available advice and guidance.

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tinues to increase, and follows predictions made in the USA,and given a further increasing global population, the numberof recorded cancer survivors worldwide in 2025 will approach
50 million, and in 2050 will approach 70 million. Such projections may be conservative, and also do not take into accountpeople with cancer that is not diagnosed or recorded.
Among cancer survivors in the USA in 2002, the mostcommon cancer diagnosed was breast cancer among women(22 per cent), prostate cancer among men (18 per cent), andcolorectal cancer among men and women combined (10 percent).1 These figures are not proportional to incidence rates
because the average time of survival after diagnosis of different cancers varies. In Europe, breast cancer was the mostprevalent cancer in women (34 per cent), followed by colorectal cancer (10 per cent). In men, colorectal cancer (15per cent), prostate cancer (12 per cent), and lung cancer (10per cent) were most prevalent.2

9.3 Interpretation of the evidence
9.3.1 General
For general considerations that may affect interpretation of
the evidence, see chapters 3.3 and 3.5, and boxes 3.1, 3.2,
3.6 and 3.7.
9.3.2 SpecificNature of the field. The main problem faced by reviews of

9.2 Occurrence
The number of cancer survivors has greatly increased inrecent decades, especially in high-income countries. This ispartly because the general prevalence of cancer continues torise, within a world population that is also rising. In addition, screening programmes for common cancers are identifying many more cases, usually at relatively early stages. As
already stated, the rapid rise in the recorded incidence of
prostate cancer in recent years is largely because of increased
use of methods of detection (see chapter 7.14.1). Also, forsome cancers, medical and surgical treatments and followup care are increasing the time that people live with cancer;
these interventions are also improving rates of recovery. In
the USA, estimates of the number of cancer survivors haveincreased from around 3 million (1.5 per cent of the population) in 1970 to over 10 million (close to 4 per cent of the
population) in 2002. The absolute number of cancer survivors aged 65 years and older is predicted to double in the
USA by the year 2050.1
Calculations of the type made in the USA have not been
made in Europe as a whole. European Union countries
together now have a larger population than the USA, but
given the overall differences between the two (somewhat
lower rates of screening, detection, and years of survival after
diagnosis in Europe), a rough guess of 5 million European
survivors (or 1 per cent of the population) seems reasonable.2 In 2002, the total number of recorded cancer survivors
in the world was estimated to be just under 25 million.3
If prevalence of, and survival with, cancer worldwide con-344

cancer survivors, as indicated in 9.1, is the scale and heterogeneity of the field. The interventions reviewed werestudied in people with a number of different cancers, at different stages, and for different outcomes.
Classification. There are many groups of cancer survivors.
Some have been diagnosed but have not yet received treatment. Others are undergoing treatments that have damaging effects and which, for some, have damaged the physicalfunction of the body. Others have been overtly free from cancer for several or many years. As yet, there are no generally agreed classifications of cancer survivors, or the different
stages of cancer survival, which makes comparisons of studies problematic.
Study design. Studies should take into account and report
the stage of treatment participants are at, and give detailsof this treatment. Studies need to have sufficient statisticalpower to address the research question being examined.
Confounding. Clinical and pathological characteristics of thecancer, such as tissue of origin, stage at diagnosis, and specific molecular characteristics, are the strongest predictors ofoutcome, and are powerful confounding factors, especiallyin observational studies. Cancer treatments and their consequences may change the effects of interventions in ways thatare not well understood. Different cancers may be modified
in different ways by food, nutrition, and physical activity.
This complexity is increased by the effects of treatment
and the disease itself, both of which can affect foodconsumption, digestion, absorption, and metabolism, andC H A P T E R

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Conventional and unconventional therapies

Conventional medicine is also known as
modern or Western medicine. It is allopathic, meaning that it relies on diagnosis
of disease, by examinations and tests, andtreatment. With cancer, treatment includes
surgery, chemotherapy, and radiotherapy.
Conventional medicine is based on investigation of the biology (including anatomy,
physiology, and biochemistry) of bodyorgans, tissues, and cells. It includes anunderstanding of the pathological processes that lead to disease, and testing ofinterventions for efficacy and safety.
Conventional practitioners undergo externally validated and structured educationand training programmes, and continuing
professional development, and they are
subject to statutory regulation.

Complementary and alternative medicine includes many diverse medical andhealthcare systems, practices, and products— some traditional, some modern. Training
and regulation of providers exist, but
often vary between therapies and nations.
Some orthodox scientific evidence is available regarding some of these therapies,
although the efficacy of many remains
unclear and often controversial.
These therapies include mind–bodyinterventions, such as meditation; biologically based treatments, such as radical
nutritional regimens, micronutrient supplements, and herbal products; manipulative and body-based techniques, suchas massage and osteopathy; ‘energy
therapies’, such as the use of magnets oralso a person’s physical condition or behaviour. This is particularly important for studies that relate body fatness to cancer risk, as cancer often causes weight loss. In some cases,
surgery may have been performed to remove parts of thegastrointestinal tract affected by cancer. Cancer often
results in loss of appetite, and cancer treatments may cause
nausea or a decreased ability to absorb nutrients from food.4
An important strength of randomised trials, provided they
are sufficiently large, is that confounding variables, both
known and unknown, will on average be distributed equally between the treatment and control groups, and will therefore not bias the study results (also see chapter 3.1.6).

9.4 Evidence and judgements
A systematic literature review (SLR) was undertaken toassess the role of food, nutrition, and physical activity in thecase of cancer survivors. This review addressed the efficacy
of nutritional and physical activity interventions in cancer
survivors in relation to mortality, disease-free survival, cancer recurrence, secondary cancers, quality of life, andadverse effects of treatment regimens.5
This SLR was designed differently from those on the causes of cancer in people assumed to be free from the disease,and used as the bases for judgements in previous chapters.
This decision was taken because the focus of the researchquestions was not on causation, but on the efficacy of particular interventions. In addition, people with cancer are ina clinical situation and will often be receiving, or will havereceived, medical, surgical, or other treatments that may
affect their nutritional status; this limits the value of somekinds of observational evidence.
For these and other reasons, it was decided in the case ofcancer survivors to give pre-eminence to randomised controlled trials (RCTs), which are least likely to be confounded, and are best suited to investigate the relatively short-term
efficacy of specific interventions. The review undertaken wastherapeutic touch; and alternative medical
systems, such as traditional Chinese andAyurvedic medicine.
‘Integrative medicine’ is a recent
approach that uses some complementary
and alternative therapies within conventional medicine. Physical activity programmes and dietary interventions arecommonly used in integrative medicine,
together with counselling.
Cancer survivors should consult their
physician or qualified health professional
before initiating any therapies that arealternative or complementary to conventional therapies. Cancer survivors should
keep all of the health professionals involvedin providing any treatment fully informedof their choices in these areas.

of 53 nutritional intervention trials and 23 physical activity
trials. It assessed the quality of all the studies reviewed,
including the size of the study populations; the length of
the interventions and of the follow-up programmes; themethods used to ensure randomisation; and the methods ofstatistical analysis.
There were usually insufficient numbers of any type ofstudy to allow useful combining of data for meta-analysis.
Overall, data were also insufficient to allow for separate
analyses of survivors before, during, and after treatment. The
Panel’s standard criteria used to grade the strength of evidence, and the matrices used to record the Panel’s judgements, used in previous chapters, were not used in the caseof cancer survivors.
A narrative review of observational studies was also conducted. As stated above, these are less suited in the study ofefficacy of treatments, and so in studies of cancer survivors
their results should be treated with caution. Also see 9.3.
The full SLR is contained on the CD included with thisReport.
9.4.1 Randomised controlled trials
9.4.1.1 ‘Healthy’ diets

Food-based RCTs were defined as those using interventions
that offered advice about ‘healthy eating’ (variously defined)or specific diets such as high-fibre diets and/or weight-loss
programmes. Twelve trials met the criteria for inclusion in
the review of food-based interventions. Study designs tended to be of poor quality, and insufficient information wasavailable about the methods used for randomisation andblinding. Duration of interventions varied between sevenweeks and three years.
Small trials conducted in Russia, the Netherlands, andPoland reported on the effects of ‘healthy diet’ interventions
for breast cancer survivors, either during or after treatment,
and cancer recurrence. A reduced fat and energy dietdecreased the recurrence of breast cancer in the Russian
study.6 A study conducted both in the Netherlands and in

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Box 9.2

Use of supplements by cancer survivors

In the USA and in other high-income countries, the use of supplements in physiological (low dose) and also pharmacological (highdose) amounts is common among the general population andalso among cancer survivors.
At least 50 per cent of the US population take vitamin and mineral supplements.52 Supplement use among US cancer survivors
has been shown in two studies published in 2004 to be similar to
the average, but high-dose supplements may be more commonlyused by cancer survivors.53 54 Survivors are also reported to be highusers of complementary and alternative medicines and othertreatments.55 Several hundred web sites promote high-dose supplements with unsupported claims that they are active cancer
cures or can prevent recurrence.

Poland examined the effect of dietary advice and psychological support to achieve weight loss, but no significant
effect on breast cancer recurrence was reported, perhaps
because of the small size and limited power of the study.7
Six trials reported on the effect of ‘healthy diets’ on ‘qualityof life’. Of these, one study of people surviving breast, ovary,
prostate, or testicular cancers showed a positive effect, in a programme that combined general dietary information with physical training and coping skills.8 A study of people surviving headand neck or gastrointestinal cancers showed a beneficial effectwith a programme of dietary counselling compared to usualcare.9 The other studies reported no effect.10-13
Only one trial investigated food-based interventions andside-effects of treatment. This study found that individual
nutritional advice, adapted to the patient’s own needs andtastes, reduced adverse effects from radiotherapy in people
with head and neck cancers.14
Three small trials examined food-based interventions andall-cause mortality. The studies were conducted in survivorsof non-melanoma skin cancer,15 colorectal or lung cancer,16
and breast, ovary, prostate, or testicular cancer.8 None of thetrials reported a significant association between the intervention and all-cause mortality.
No conclusions can be derived from these results.

The Panel is aware of two large, multicentre, randomised trials of breast cancer survivors, the WINS study, published in
2006, and the WHEL study, published in 2007. The WINS trial
tested a dietary intervention to reduce fat intake in over 2000
women with early stage breast cancer. After 5 years of followup, the women in the intervention group had a 24 per centreduced risk of recurrence compared with the control group (relative risk 0.76, 95% CI 0.60–0.98).17 However, these findings
cannot be easily translated into recommendations for breast
cancer survivors, for several reasons. First, women in the intervention group had more extensive surgical procedures. Also,
they lost weight during the trial and it is possible that weightloss was responsible for their improved outcome. Finally,
dietary fat reduction was most beneficial in women with oestrogen- or progesterone-receptor negative tumours, a finding that
may be due to chance.18
The WHEL study tested the effect of a dietary intervention high

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in vegetables, fruits, and dietary fibre, and low in fat, in over 3000
women with early stage breast cancer. After 7.3 years of followup, there was no difference in breast cancer recurrence, new breast
cancer, or all-cause mortality between the intervention and control groups.19 Unlike the WINS study, in the WHEL study womenin both the intervention group and the control group experienced
small increases in weight, and this may partially account for thedifferent results in these two trials.
9.4.1.2 Supplements

Data from 39 RCTs were assessed. The review included trials on supplements of retinol,20-26 beta-carotene,27-30 vitamin
B6,31 32 vitamin C,31 32 multivitamins,27 33 34 vitamin E,35-37
selenium,35-38 and isoflavones.39 40 Additionally, single trialsof each of evening primrose oil,41 glutamine,42 and N-acetylcysteine26 and nine trials of commercial supplements werereviewed.43-51 Also see box 9.2.
Trial quality and number of participants tended to behigher in supplement trials than in the dietary-intervention
trials. Compliance was monitored in the majority of trials,
and placebos were usually given to the control group.
However, the controls in all seven retinol trials and in fiveof the nine commercial supplement interventions were given‘usual treatment’ or an ‘unrestricted’ diet.
There was considerable variation in the methods andlength and type of intervention used, and the overall quality of many studies was poor. Furthermore, the disparate vitamins and other bioactive substances used in these studies
make comparison difficult. Results were null or non-significant in almost all cases.
Trials where data were sufficient and the exposures were
homogeneous enough to allow meta-analysis included thoseexamining retinol and all-cause or cancer mortality.
Comparing the intervention to usual treatment, the summary
estimate from four trials that examined all-cause mortality
was 0.97 (95% CI 0.83–1.13)23-26; from three trials thatexamined cancer mortality, the summary estimate was 0.92
(95% CI 0.65–1.31).23 24 26
One small trial of bladder cancer survivors showed a significant reduction in cancer recurrence. This trial compared
supplementation with a multivitamin plus a high-dose
combination of vitamins A, B6, C, and E and zinc against amultivitamin alone.33
A larger trial designed to test the effect of 200 micrograms
per day of selenium supplementation on recurrent nonmelanoma skin cancer showed no effect on skin cancer, but
a protective effect on prostate cancer.36 37
Fifteen trials investigated types of supplementation andside-effects of cancer treatment. One small study reported
higher treatment toxicity in survivors of haematological cancers with vitamin A supplementation (as retinol or betacarotene).23 No significant results were reported in the otherstudies.27 29 31 32 34 35 38-40 48 56-58
The evidence from this review of trials does not showthat micronutrient supplements have any benefits incancer survivors. High-dose supplements may be
harmful. Some micronutrients and other bioactive
compounds are known to be toxic at high doses.

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9.4.1.3 Physical activity

Twenty-three physical activity RCTs met the criteria for inclusion in the review. Interventions ranged from simple advice
to increase physical activity, to enrolment in supervised exercise programmes. These were mostly small trials and of shortduration. In half of the studies, compliance levels were
unclear, and the majority failed to record physical activity
levels in the control group, which severely limits their value.
Only three of the physical activity intervention trials
reported on mortality or cancer recurrence.8 59 60 None ofthese studies reported significant effects.
Twenty trials investigated quality of life outcomes with physical activity interventions. Nine of these trials were in survivorsof haematological cancer,61 lung cancer,62 prostate cancer,63
and in a combination of cancers.8 12 64-68. Eleven trials were inbreast cancer survivors.62-73 Two of the interventions in thesetrials included nutrition components.12 64
The physical activity interventions, assessment instruments, and outcomes studied were varied. The interventions
included many types of supervised or home-based exercise
programmes. Several studies assessed well-being and quality of life using a version of the Functional Assessment ofCancer Therapy scale,69 although other questionnaires andscales were also used. Quality of life outcomes included a
range of measures of physical, functional, and emotional
well-being, as well as measures of physical fitness.
Of the 20 physical activity trials that investigated qualityof life, 18 reported a benefit from the intervention on at least
one of the outcome measures reported in the study. None of
the trials reported harmful effects of the physical activity
interventions on any of the outcomes studied.
Taken together, these trials provide some evidence forthe benefit of physical activity on post-treatment
quality of life in cancer survivors.

9.4.2 Observational data
Three reviews that examined data from 26 observational
cohort or case-control studies met the criteria for inclusionin the review of observational data.70-72
All of these compared breast cancer outcomes in cancer
survivors to ‘body fatness’, as measured by body mass index(BMI) (see chapter 6.1). The results of these studies weregenerally consistent. An overall increased risk of mortality
with increasing BMI was reported, although there was someheterogeneity in study results.
Of 21 studies that followed cases for at least 5 years, 12
showed statistically significant associations between higher
BMI and worse outcome, while others showed insignificant
results or were null. One study found that mortality risk
decreased as BMI increased. Physical activity was associated with an enhanced quality of life in cancer survivors.

The Panel is aware of two large observational studies thatinvestigated physical activity in breast cancer survivors. A studyof nearly 3000 breast cancer survivors in the Nurses’ HealthStudy reported reduced risk of breast cancer mortality inwomen who were physically active, compared with sedentary
women.73 In a second study of over 1200 women, physicalactivity measured before diagnosis of breast cancer was associated with reduced all-cause mortality; this association was
statistically significant in women who were overweight or obese
at diagnosis.74

9.5 Comparison with the previous report
The previous report did not include any review, assessment,or recommendations directed at cancer survivors. The panel
responsible for that report stated that its recommendations
were especially important for population groups and people
most susceptible to cancer.

9.6 Conclusions
The Panel concludes:
Research into the effects of food, nutrition, and physicalactivity in cancer survivors is in its early stages. For this reason, and also because of the scale and heterogeneity of the
field, the evidence reviewed here is inconclusive.
Regular physical activity and other measures that control
weight may help prevent recurrence of breast cancer andimprove quality of life. When able to do so, cancer survivors
may gain general health benefit and a sense of control overtheir circumstances from regular physical activity.
The evidence does not support the use of high-dose
supplements of microconstituents as a means of improving
outcomes in people with a diagnosis of cancer.
Cancer survivors should consult their physician and/or aqualified nutrition professional who can evaluate the safety
and efficacy of specific dietary supplements, and offer advice
based on current research relevant to their particular clinical situation.
As with all the chapters in Part 2 of this Report, thePanel’s recommendations for cancer survivors are in Part 3,
Chapter 12.

While this information suggests that higher bodyfatness before diagnosis leads to a worse outcome, andalso that physical activity may be beneficial in breast
cancer survivors, it is nevertheless insufficient tojustify any firm judgement on body fatness specificallyin relation to cancer survivors.

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Findings of other reports
The assessments and judgements made by the Panelshown in the preceding chapters are based onevidence from systematic literature reviews oforiginal research studies, compiled according to
specified criteria, on food, nutrition, physicalactivity, and the risk of cancer. However, the Panel
recognises that recommendations on food, nutrition,and physical activity are also made in relation toother diseases. These include recommendations
designed to control and prevent chronic diseases
other than cancer, and those designed to influence
the dietary and activity patterns of populations andindividuals. Recommendations that address
nutritional adequacy (prevention of deficiencies),and prevention and management of infectious
diseases (vulnerability to which is affected bynutritional status) should also be taken into account.
The Panel has therefore decided that its
recommendations designed to control and preventthe incidence of cancer, made in the following
chapters, should take into account the judgements
and recommendations of authoritative reports
related to the prevention and control of otherdiseases. Any potential conflicts that might arise
between its own recommendations and others thatcover the same aspects of food, nutrition, andphysical activity are identified in this chapter.
As stated in its title, the present Report has a
global perspective. The importance of dietary issues
related to chronic diseases, relative to those fornutritional adequacy and infectious diseases, varies
both between countries and between
subpopulations within countries. The approach takenby this Report, to consider recommendations fromother reports, is particularly relevant for those partsof the world now suffering the ‘double burden’ ofendemic deficiencies and infection — especially of
infancy and childhood — as well as increasing
incidence of cancers of various sites, and of otherchronic diseases. Nevertheless, people, as well as
public health authorities, need integrated messages.
In Chapter 12 we state whether any recommendation
is affected as a result of the findings of other suchreports.
This chapter has also assembled the findings ofother recent reports on food, nutrition, physical348

activity, and cancer. These show where judgements
and recommendations are consistent, and where
they have changed, as science has developed and as
views on relative weight of evidence from different
types of research have evolved. In addition,comparisons have been made in Chapters 4 to 7
between the findings of this Report and the previous
report, published in 1997.

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Dietary guidelines produced by expert bodies have been partof national and international public health nutrition policies
since the early 20th century. At first, the recommended
dietary intakes for the planning of food supplies were
designed to prevent specific nutritional deficiencies. Fromthe 1960s, a different type of guidance began to emerge,
designed to prevent food and nutrition-related chronic
diseases, including heart disease and cancer.
A previous review analysed the findings of 100 expert
reports published between 1961 and 1991 that include
guidelines and recommendations to prevent various chronic diseases.1 Some of the landmark reports produced overthis period are ‘The Causes of Cancer’,2 ‘The US Surgeon
General’s Report on Nutrition and Health’,3 ‘Nutritional Goals
for Health in Latin America’,4 ‘Medical Aspects of Dietary
Fibre’ published by the Royal College of Physicians of
London,5 and ‘Diet and Health’ and ‘Diet, Nutrition, andCancer’ published by the US National Research Council.6 7
Towards the end of this 30-year period, dietary guidelines
to prevent chronic diseases tended to move the emphasis
away from dietary constituents (such as saturated fat or vitamins). Instead, the focus shifted to foods and drinks, andsometimes to dietary patterns as a whole.
The 1961–1991 review1 shows consistent agreement on
the types of diet recommended to protect against obesity, cardiovascular disease (CVD), cancer of a number of sites, type2 diabetes, gut disorders and diseases, osteoporosis, dental
caries, and other chronic diseases. Compared with diets typically consumed in high-income countries, the recommended diets are high in wholegrain or minimally processedcereals (grains), vegetables and fruits, and are therefore highin dietary fibre and bioactive microconstituents, relatively
high in fish, and contain lean meat. These recommended
diets are also correspondingly low in total fat and saturated
fatty acids, sugars, and salt; fatty and salty foods; sugary
foods and drinks in general; and alcoholic drinks. The review
also shows that the expert reports consistently recommend
regular, sustained, physical activity.
However, almost without exception, expert reports onchronic diseases treated these issues independently to thoseof nutritional adequacy (and the prevention of nutritional
deficiencies), or of the prevention and management of infectious diseases, notably of infancy and childhood, and viceversa. The separate consideration of these issues usuallyreflected the focus either on national concerns in highincome societies, or the specific interests of specialists.

10.1 Method
This chapter is based on a systematic review of secondary
literature that examines recommendations for dietary andphysical activity produced since 1990 for the prevention of
a number of diseases. Therefore, this chapter carries forward
the work of the 1961–1991 review. The purpose is to givean account of the recommendations of other reports and not
to assess the evidence therein. The full systematic literature
review is contained on the CD included with this Report.
10.1.1 Diseases and exposures
The diseases in this present review are categorised as nutritional deficiencies, infectious diseases, chronic diseases otherthan cancer, and cancer. These are diseases identified by theUnited Nations and other authoritative bodies as being
causally linked with food, nutrition, and physical activity.
They are also identified as significant contributors to theglobal burden of preventable disease in terms of prevalence
and cost.
The ‘exposures’ covered in this review are those identified
in the report that preceded this one8 as convincing or probable modifiers of cancer risk — together with those judged
by other reports to justify a recommendation designed to prevent or control other diseases. The reports analysed include
recommendations on relevant foods and drinks (including
food production, preservation, processing, and preparation),and dietary constituents, physical activity, and energybalance.
10.1.2 Reports reviewed
The reports reviewed were published between 1990 and
31 December 2004 in the English language. To be includedin the review, reports needed to:• Involve an expert panel• Include an original review of relevant literature• Include explicit disease-specific conclusions andrecommendations• Base their conclusions on published peer-reviewed
literature specified as a bibliography.
This approach eliminated reports that simply restated previous recommendations. It also ensured that the review
included only reports with the main aim of developing or
updating nutrition-related recommendations. Reports
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other interested parties were excluded.
The criteria used for and timing of this review meant thatsome important reports were not included. The Panel is awareof these exclusions and has supplemented the text wheresuch an omission would have given an incomplete picture.
Of more than 10 000 documents identified initially by database searches, applying these criteria reduced thenumber to 207. All of these reports were read and 94 were
included in the review: 16 reports from international organisations,8-23 39 from North American organisations,24-62 22
from the European Union,63-84 14 from Australasia,85-98
2 from India,99 100 and 1 report from South Africa.101 The
recommendations in the 113 that were finally excluded are
generally consistent with those in the included reports.
The Panel is aware that other important reports have been
published, which were either published subsequent to thereview for this chapter or did not meet the criteria for inclusion. The organisations that produced these reports are: theAmerican Cancer Society,102 the International Agency for
Research on Cancer,103 the National Institute for Health andClinical Excellence,104 and the US Department of Health andHuman Services and the Department of Agriculture,105 andthe National Heart, Lung and Blood Institute and the World
Health Organization.106 106B The recommendations fromthese reports were also taken into consideration during theformulation of the recommendations for this Report.

10.2 Interpretation of the data
Some caution is needed when interpreting the information
presented here. Most of the reports included have been commissioned by and for high-income countries and so reflect
the nutrition concerns of such countries. Producing thesereports is expensive and is likely to be beyond the means ofmost individual middle- and low-income countries. Where a
recommendation is made for diets high in vegetables andfruits, for example, this means high in relation to the diets
typical of high-income countries. Meeting such recommendations might mean increases in intake in some countries andmaintaining already high intakes in others. Recommendations for vegetables and fruits usually do not include potatoes, which are generally grouped with roots and tubers (seechapter 4.1.1).
Many of these reports are concerned with what are now
pandemic diseases of the circulatory system (ischaemic heart
and cerebrovascular diseases and their determinants such as
obesity, high levels of blood fats, and high blood pressure).
Fewer reports are concerned specifically with cancer or diseases of other systems of the body, although an increasing
number now link obesity with type 2 diabetes, and cancer.
Only a minority of the reports reviewed attempt to be comprehensive, and the terms of reference of these reports may
be limited. For example, of the 15 reports addressing cancer, just 4 are concerned solely with cancers in general. Of
the rest, 4 focus on chronic diseases including cancer, 2 areconcerned only with colorectal cancer, 2 with vitamin supplementation, 1 with oral health, 1 with children’s health,and 1 with fats and oils. Also, some reports on cancer do not

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review alcohol, food additives and contaminants, or breastfeeding. For such reasons, most reports say nothing about
many of the aspects of food, nutrition, and physical activity
addressed in this Report. The summary below states where
there is significant disagreement between reports. The Paneldecided not to include a tabulated summary of the recommendations from reports on cancer because, in view of ourown Report, this would be non-contributory.
Until recently, few reports have used a systematic approachto assess the prevention of nutritional deficiencies in general. Although it has been established that vulnerability toinfectious diseases — especially of infancy and childhood —is crucially affected by nutritional status, only in the past few
years has there been an extensive analysis and a coherent
approach to the recognition of the role of individual micronutrients such as vitamin A, zinc, and selenium in reducing lifethreatening infections, for example, of the respiratory andgastrointestinal tracts, which continue to exact a huge burden of disability and premature death.
Many reports concerned with food, nutrition, and physical activity also stress the importance of not smoking or using
tobacco. This information is not included here.

10.3 Nutritional deficiencies
10.3.1 Background
Undernutrition and hunger remain common in parts of theworld where populations are impoverished and food is insecure, largely for social (including political and economic) andenvironmental reasons. Global rates of malnutrition (inadequate energy intake) and micronutrient deficiencies remain
high, especially in low-income countries.
Many diseases are caused by deficiencies of specific or
combined essential nutrients. These diseases, when severe
and prolonged, can be fatal. In the 1990s, relevant UN agencies specified that certain micronutrient deficiencies were themost important global public health problems.107 108 Those
identified included deficiencies of iron (causing anaemia, lassitude, and learning difficulties), iodine (causing goitre andcretinism), and vitamin A (causing xerophthalmia, impaired
night vision, and eventually blindness).
Infants, young children, and pregnant and lactating
women have been, and remain, the main focus of recommendations designed to prevent and control nutritional
deficiencies. Recommendations for combating specific deficiencies include programmes of salt iodisation (iodine); consumption of foods containing readily absorbable iron,including meat and other foods of animal origin (iron); andconsumption of foods high in carotenoids or retinol (vitamin
A). Supplementation and fortification are also recommended.107 108 Other recommendations continue to promote exclusive breastfeeding, as well as the supply of adequate andvaried weaning foods (preferably indigenous or local), andwater and food free from infectious agents.
A number of trials and systematic analyses have assessedthe value of interventions with micronutrients. The results
are sometimes different when tested in African, Asian, or
Latin American children, and this probably reflects the

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different prevailing nutritional conditions. The results
emphasise the importance of ensuring that micronutrient
intakes are adequate and that dietary factors that enhancemicronutrient status form an important part of the diet ofboth children and adults, with particular attention being paid
to women before and during pregnancy.
10.3.2 Introduction
Few reports concerning nutritional deficiencies qualified forinclusion in this review. Of the 95 included, 2 make recommendations on preventing rickets,28 52 4 on preventing irondeficiency anaemia,11 13 51 92 and 4 on preventing vitamin A
deficiency.14 19 21 79 These reports come from 10 different
organisations: 1 from Europe, 6 from international agencies,and 3 from North America. No reports were included whose
recommendations relate to malnutrition in general, or toiodine deficiency.
10.3.3 Foods and drinks
Vegetables, fruits, pulses (legumes), nuts, seeds, herbs,
and spices. Three reports recommended that various

vegetables and fruits — being those high in vitamin C
and folates — should be included with meals to boost
iron absorption and hence prevent iron deficiency
anaemia.11 13 51 Another report recommended that the complementary diets of infants and young children should include
vegetables and fruits high in vitamin A to prevent vitamin A
deficiency.21
Meat, fish, and eggs. One report recommended including
foods that are high in absorbable iron, such as lean meat, toprevent iron deficiency anaemia.51
Dietary constituents and supplements. For vitamin C, folicacid, and iron, see chapter 4.10. Also, one report recommended that after the age of 6 months, infants receiving
breastmilk or cow’s milk as their main drink, or those consuming less than 500 ml/day of infant or follow-on formula, should receive a vitamin A supplement to prevent vitamin
A deficiency.79 Two reports include recommendations for vitamin A supplementation,14 19 and two recommended vitamin
D to prevent rickets.28 52

and reports on cancer and other chronic diseases do
not recommend diets without red meat.
The Panel agrees that these matters of emphasis andconsiderations should be taken into account in its
recommendations. See Chapter 12. Also see the Panel’s
conclusions in 10.7.

10.4 Infectious diseases
10.4.1 Background
Vulnerability to a number of common infectious diseases isaffected by nutritional status; this is especially important ininfants and young children.109 Interaction between nutrition
and infection occurs with ‘classic’ malnutrition — inadequate
energy from food — and also with deficiencies of a range ofvitamins and minerals. Relevant diseases include diarrhoeal
diseases, respiratory infections, measles, whooping cough,and chickenpox.109 On a global basis, rates of dangerous
infectious diseases — especially of infancy and childhood —remain high, particularly in low-income countries. Conversely, repeated infections impair nutritional status,
particularly during childhood.
The usual recommendations in previous reports concerning food, nutrition, and infectious diseases of infants andyoung children have been for exclusive breastfeeding, adequate and varied weaning foods (preferably indigenous or
local), and water and food supplies free from infectious
agents.107
10.4.2 Introduction
Few reports concerned with infections qualified for inclusionin the review. Of the 95 reports accepted, 3 included recommendations for the prevention or management of diarrhoea,10 17 91 3 for the management of HIV and AIDS,9 12 25
1 for the management of measles,85 and 1 for respiratory diseases.91 These 7 reports were published by 6 organisations:
2 from Australasia, 3 from international agencies, and 1 from
North America. No reports were found that make dietary
recommendations to help prevent or manage dysentery,malaria, or tuberculosis.
10.4.3 Foods and drinks

Breastfeeding. One report recommended that mothers

Cereals (grains), roots, tubers, and plantains. One report

should breastfeed exclusively for the first 4–6 months of theirchild’s life to prevent iron deficiency in the child.19

recommended that people with HIV or AIDS should include
staple foods with every meal.9 This report specified refined
starchy foods such as white rice, maize meals, white bread,
noodles, and potatoes to avoid gastric aggravation.9

10.3.4 Comparison of reports
One difference in emphasis between these reports and thoseon cancer (and other reports not included in the review) is
the stress given to the importance of extended, exclusive
breastfeeding (see 10.4.3), and the importance of safe watersupplies.
Differences in recommendations for supplementation ofdiets of infants and young children are not substantial.
An apparent difference between these reports, and thoseon cancer and other chronic diseases, is the recommendation to consume meat as a source of absorbable iron to prevent anaemia. However, only modest amounts are proposed,

Vegetables, fruits, pulses (legumes), nuts, seeds, herbs,
and spices. One report recommended that people with HIV

or AIDS should eat a wide variety of vegetables, fruits, andpulses (legumes) every day.9
Meat, fish, and eggs. One report recommended thatpeople with HIV or AIDS should eat meat, poultry, andfish regularly.9 It advised that meat should be cooked
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Milk and dairy products. One report recommended thatpeople with HIV or AIDS should consume milk products
regularly.9
Fats and oils. One report recommended that people withHIV or AIDS should include fats and oils in their diet tomaintain their weight.9
Salt and sugar. One report recommended that people withHIV or AIDS should include sugar and sugary foods in theirdiet to maintain their weight.9
Water, fruit juices, soft drinks, and hot drinks. One report
recommended that people with HIV or AIDS should drink
plenty of clean and safe water. If in doubt, and during an
episode of diarrhoea, water should be boiled before use, andcoffee and tea avoided.9
Food production, processing, preservation, and preparation. Also see 10.5.3. Two reports made recommendations

on preventing diarrhoea: contaminated food and drink
should be avoided; clean utensils should be used during
preparation and serving; and food should be stored safely
and served immediately after preparation.10 17 One of thesereports also recommended that foods should be covered andrefrigerated where possible, for the same reason.17 Similarly,
another report recommended storing fresh food and leftovers
in a cool place or a refrigerator.9 Two reports recommended
that foods should be cooked thoroughly and leftovers reheated to a high temperature to prevent diarrhoea.9 17
Dietary constituents and supplements. One report rec-ommended that some people with measles should receive
vitamin A supplements.85
Breastfeeding. Three reports recommended that womenshould breastfeed exclusively for the first 4–6 months of theirchild’s life to prevent the child having diarrhoea.10 17 91 Of
these, one further advised non-exclusive breastfeeding up to
2 years of age and beyond if possible.17 Another report madethe same recommendation to prevent respiratory disease in
the infant.91 Two reports recommended that women infected with HIV should avoid breastfeeding where possible toprevent transmission of the virus to their child, and shouldcease breastfeeding as soon as is feasible.12 25 One report
recommended that clean, nutritious weaning foods should
be introduced to an infant at 4–6 months of age, beginning
initially with soft mashed foods to prevent the childhaving diarrhoea.17
10.4.4 Physical activity
One report recommended that people with HIV or AIDS
should take light exercise.9
10.4.5 Comparison of reports
As with reports on nutritional deficiencies, one difference inemphasis between these reports and those on cancer is thestress given to the importance of extended, exclusive breastfeeding and the importance of safe water supplies.

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The Panel agrees that these matters of emphasis should betaken into account in its recommendations. On the important issue of mothers with HIV or AIDS, the Panel endorses
the position of the WHO that ‘exclusive breastfeeding is recommended for HIV-infected women for the first 6 monthsof life unless replacement feeding is acceptable, feasible,
affordable, sustainable and safe for them and their infants
before that time’. Also see Chapter 12.
Many of the specific recommendations to protect against
deficiencies and infections in these reports (and others) are
in harmony with those designed to prevent chronic diseases;
few are inconsistent. On salt and the prevention of goitre,
and meat/iron and the prevention of deficiency, and the promotion of physical and mental health, see 10.5.7.
The recommendations made by the Panel in Chapter 12,
when these take into account prevention of nutritional deficiencies and infectious diseases, are based additionally on
the expert judgement of Panel members experienced in theseareas. Many such reports were excluded by the criteria forinclusion for systematic review. These usually emphasise theneed for food security — the constant availability of adequate, appropriate, and nourishing food. This fundamental
priority does not contradict the findings of reports concernedwith chronic diseases. Similarly, reports concerned with
deficiencies and infections, especially of infancy and childhood, emphasise the need for safe water (and safe watersupply and reliable sewage systems). This also does notcontradict the findings of reports concerned with chronic
diseases.

10.5 Chronic diseases other than cancer
10.5.1 BackgroundIn general, chronic diseases such as obesity, type 2 diabetes,and cardiovascular disease (CVD), as well as some cancers,
appear to have been uncommon, even in older people, until
recent history. With urbanisation and industrialisation, they
have become more prevalent, even among younger people.
It is now generally accepted that the main causes of chronic diseases are environmental factors, including inappropriate food and nutrition, and physical inactivity.
Expert reports concerning the impact of unbalanced foodand nutrition on the risk of chronic diseases began to appear
in the 1970s.110 At first, these were concerned mostly withcoronary heart disease (CHD), which had become the mostcommon cause of total and premature mortality in various
high-income countries. Later reports began to consider otherchronic diseases, or chronic diseases in general. For example, a report published by WHO in 1990 considered that a
number of diseases could be prevented by appropriate foodand nutrition. These include cerebrovascular disease, CHD,
dental caries, type 2 diabetes, obesity, osteoporosis, various
cancers, and various gut disorders.111
Forty-two reports published mostly in high-income countries between 1973 and 1988 were reviewed in 1990.111
These made recommendations for reducing the risk of chronic diseases. They proposed that changes in consumption ofcertain foods and drinks were causing the rise in chronic

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diseases, as was physical inactivity. They identified foods anddrinks relatively concentrated in total fat and saturated fatty
acids, sugar and salt, and alcohol, as well as diets low in relatively unprocessed grains and other starchy foods, vegetables and fruits, and dietary fibre. Later reports noted thatobesity and type 2 diabetes in particular were becoming
more common in middle-income countries, and that these
diseases were no longer ‘diseases of affluence’.
More or less the same dietary recommendations weremade for the prevention of all of these chronic diseases,
including cancer.1 For high-income countries, this has beensummarised as diets with: ‘moderately low levels of fat, withspecial emphasis on restriction of saturated fatty acids andcholesterol; high levels of complex carbohydrates; only moderate levels of protein, especially animal protein; and only
low levels of added sugars’.7
Global population average nutrient goals for the prevention of chronic diseases were published by WHO in 1990 as
follows: total fats 15–30 per cent, saturated fats 0–10 per
cent, and polyunsaturated fatty acids 3–7 per cent of totalenergy intake; cholesterol 0–300 g/day; sugar 0–10 per centof total energy intake; salt less than 6 g/day; starch/complex
carbohydrates 50–70 per cent of total energy intake; dietary
fibre 27–40 g/day; and dietary protein 10–15 per cent of
total energy intake.111
10.5.2 Introduction
This section presents the recommendations made since 1990
on chronic diseases other than cancer. Of the 95 reports
reviewed, 60 made recommendations relating to the prevention of obesity, type 2 diabetes, or CVD. These were produced by 34 different organisations: 6 from Australasia, 10
from Europe, 2 from India, 2 from international agencies, 13
from North America, and 1 from South Africa. Of these, 33
discussed the prevention of CVD in general,16 22 30 32 34 36 37
39-47 57 61-63 68 69 71 72 77 78 80 84 91 92 94 97 98
24 the prevention ofCHD,8 22 24 26 30 35 36 53 62 64 66 73 75 81 88 91-93 95-97 99-101 14 theprevention of type 2 diabetes,22 30 31 45 53 57 62 69 76 77 88 89 91 92
8 the prevention of dyslipidaemia,16 30 53 57 77 87 91 98 16 theprevention of hypertension,16 22 30 34 36 44 46 56 57 62 69 71 88 91 92
98
12 the prevention of overweight/obesity,8 16 18 22 27 53 62 69
76 91 92 98
and 11 the prevention of stroke,30 36 38 40 42 62 70 77 88
91 111
Nine reports included recommendations to prevent
osteoporosis22 23 33 48 58 59 88 91 92 and 10 to prevent dental
caries.22 49 50 52 53 65 69 74 91 92 Two reports referred to theprevention of skeletal disorders in general30 82 and 3 to theprevention of dental diseases in general.62 79 88 These havebeen produced by 16 different organisations: 1 from
Australasia, 4 from Europe, 1 from an international agency,
and 10 from North America. Some 5 reports made recommendations to prevent gut diseases and disorders, producedby 4 organisations: 2 from Australasia, 1 from Europe, and1 from North America. Of these, 3 referred to the preventionof constipation,9 60 91 2 to the prevention of diverticulardisease,91 92 and 1 to the prevention of Crohn’s disease92 andulcerative colitis.92 Recommendations regarding foodintolerances were found in 4 reports,79 86 91 92 of which 1 wasconcerned with lactose intolerance88 and 1 with coeliac
disease.92

10.5.3 Foods and drinks
Cereals (grains), roots, tubers, and plantains. Fourteen
reports recommended including wholegrain cereals in thediet.16 18 24 36 40 41 43 66 70 78 91 92 95 98 Four of these recommended
that people should consume 3–6 servings per day to prevent
CVD,36 40 78 98 and those at risk of CVD should eat 6–12 servings per day.98 Three recommended that people should limit
their intake of refined carbohydrates, particularly from cereals (grains).36 41 98
Vegetables, fruits, pulses (legumes), nuts, seeds, herbs,
and spices. Sixteen reports recommended consuming rela-

tively high amounts of vegetables and fruits22 35 36 40 69 70 73
75 77 78 80 91 92 95 98 100with 13 recommending at least 400 g
per day (at least 5 servings).22 35 36 40 69 73 75 77 78 83 95 98 100
Eleven reports recommended the consumption of pulses(legumes).16 22 24 36 37 41 43 70 88 91 98
Meat, fish, and eggs. Eight reports recommended that con-sumption of red meat should be moderated and lean meat
preferred (unspecified amount).16 24 40 41 66 78 98 101 Seven
reports recommended including fish in the diet.16 24 41 43 66 80
91
Nine reports recommended consuming oily fish.22 39 40 72
78 80 91 93 98
Eleven reports recommended that people should
consume 1–3 servings of fish a week.22 30 39 40 70 72 78 83 93 96 98
Two reports recommended that egg consumption should be
limited.16 98
Fats and oils. Twenty-five reports recommended that total

dietary fat intake should be limited.8 22 24 26 34 35 46 53 56 62 64 69
Thirty-three reports recommended
that intake of saturated fatty acids should be limited.8 16 22 24
26 30 31 34-36 40 41 43 53 56 62 63 66 69 70 76-78 80 88 89 91 94 95 98-101
Threereports recommended that dietary fat intake should not be
restricted in children under 2 years of age.26 41 83 Seven reports
recommended moderate intake of polyunsaturated fatty
acid.24 30 35 66 70 80 93 One report recommended that if total fat
intake is restricted, people who are inactive and overweightshould still include some polyunsaturated fatty acids in theirdiet to prevent CHD.98 One report recommended that n-6
fatty acids should form 5–8 per cent of energy intake to prevent stroke,70 while another suggested they should form 4–8
per cent to prevent CVD.69 One report recommended that toprevent CHD, linoleic acid should make up no more than 10
per cent of total energy, at a ratio of between 5:1 and 10:1
with alpha-linolenic acid.8 Five reports recommended theconsumption of n-3 fatty acids.70 72 80 91 93 Two reports recommended that eicosapentaenoic acid and docosahexaenoic
acid should be included in the diet.23 39 Nine reports recommended restricting intake of trans-fatty acids.22 30 36 40 41 43 69
83 98
Three reports recommended restricting the combined
intake of trans- and saturated fatty acids.93 97 98 Four reports
recommended limiting the intake of hydrogenated, vegetable,and partially hydrogenated fats.24 62 66 91 Three reports recommended restricting myristic acid intake (including coconut
products).66 91 101
70 77 78 80 84 87 89 91 94 98-101

Salt and sugar. Twenty reports recommended that salt

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adults,16 30 35 36 40 41 44 46 56 62 63 69-71 73 80 88 91 98 100 while another recommended that people should consume less than
5 g/day.22 Ten reports recommended that people should limit
their sodium intake.30 40 41 44 46 56 59 66 80 88 Seven reports recommended that consumption of sugary foods should be limited,36 41 62 69 91 92 98 with six specifying the prevention ofdental disease.22 62 65 74 79 92 Four of these reports made thisrecommendation only in relation to dental disease.22 65 74 79
Ten reports recommended that the proportion of energy inthe diet from sugar should be limited (either total, added,
or non-milk extrinsic sugars).36 41 53 62 73 87 91 92 98 101
Milk and dairy products. Eleven reports recommended that

low-fat dairy products should be chosen in preference tohigh-fat versions.16 24 36 40 41 46 56 66 83 98 101
Water, fruit juices, soft drinks, and hot drinks. Threereports recommended that water should be chosen as a drink
to prevent overweight/obesity and dental damage.22 65 92 One
report recommended that individuals (particularly older people) should consume between 1.5 and 2 litres of water each
day to prevent constipation.60 One report recommended thatpeople with HIV or AIDS should drink plenty of fluids to prevent constipation.9 Three reports recommended that people
should limit their consumption of sugary drinks to prevent
dental damage.22 65 92 Three reports recommended against
using sugary drinks in babies’ bottles to prevent dental damage.49 65 92 Two recommended that people should limit theircaffeine intake to no more than four cups of coffee per day
to prevent osteoporosis.48 59 One report recommended that
caffeine should be eliminated to prevent constipation.60
Alcoholic drinks. Sixteen reports recommended that men

should drink no more than two alcoholic drinks per day andthat women should drink no more than one.22 31 36 40 44 46 56
62 70 73 75 77 88 91 96 97
Two reports recommended that people
with dyslipidaemia should limit their intake of alcoholic
drinks.64 96 Five reports recommended that if people choose
to drink, they should do so only with meals.40 56 62 70 91 Fivereports recommended that alcohol intake should be limited.34 44 64 96 99 Three reports recommended that men should
drink no more than 21 units of alcohol/week (equivalent tothree drinks a day), and women no more than 14 (equivalent to two drinks a day).73 75 76 One report recommended
avoiding high intakes of alcohol to prevent osteoporosis.23
Two reports recommended that alcohol should be eliminated completely to prevent constipation60 and stroke.70
Food production, processing, preservation, and preparation. Also see 10.4.3. Two reports recommended that foodshould be grilled (broiled) or steamed, rather than fried.62 101
Dietary constituents and supplements. Eight reports rec-ommended that carbohydrates should provide between 45
and 65 per cent of total energy intake as part of a healthy
diet.24 53 63 64 69 80 87 99 Three reports recommended including
complex carbohydrates in the diet.16 87 99 Fifteen reports recommended a diet relatively high in dietary fibre.9 16 35 36 40 41
53 60 63 64 69 70 95 98 101
Sixteen recommended restricting dietary

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cholesterol intake.8 16 24 26 30 35 36 40 43 62 63 66 70 78 80 93 Thirteen
reports recommended that ‘at risk’ groups, and also people
with type 2 diabetes, should limit dietary cholesterol to lessthan 200 mg/day to prevent CVD.30 34-36 40 41 43 44 46 63 64 99 101
These groups of people include those at risk of or with preexisting CVD, or those with elevated levels of low-density
lipoprotein (LDL) cholesterol. Two reports recommended
that there should be no restriction of dietary cholesterol forchildren under 2 years of age.26 80 One report recommended that more than 400 micrograms/day of folate should be
consumed to prevent CVD.98 Three reports recommended theconsumption of vitamin D to prevent osteoporosis,22 48 59 andanother made this recommendation for preventing skeletal
disorders in general.82 One report recommended that children with inflammatory bowel disease should have at least
400 international units (IU) of vitamin D per day to prevent
osteoporosis.58 Another report recommended that vitamin D
intakes for people with gastrointestinal diseases should be
800 IU/day to prevent osteoporosis.33 Various reports recommended that people should ensure that they have an adequate intake of calcium,16 22 30 33 46 48 58 59 70 82 potassium,22 46
56 80
and magnesium.46 70 Three recommended that people
should brush their teeth with a fluoride toothpaste to prevent dental damage.50 65 74 With regard to supplements, one
report recommended against the use of antioxidant supplements to prevent CVD,43 while two recommended against
beta-carotene supplements.61 73 One report recommended
against using vitamin E supplements to prevent CHD,61 73 andanother to prevent CVD.47
Breastfeeding. One report recommended that womenshould breastfeed to prevent dyslipidaemia in the infant.87
Two gave this advice as a means of preventing overweight/obesity in the infant,27 92 and one of these specified
exclusive breastfeeding for 6 months.92 Four reports recommended that women should breastfeed exclusively for 6
months to prevent food intolerance in the infant,27 79 91 92 ofwhich two made this recommendation to prevent Crohn’s disease,27 92 and ulcerative colitis.27 92 One report also recommended breastfeeding as a way of reducing the risk ordelaying the onset of coeliac disease92 in the infant.

10.5.4 Physical activity
Twenty-four reports recommended that people should
undertake at least 30 minutes of moderate intensity physical activity on most days of the week.16 22 30 33-36 40 43 45 56 57
62 64 68 69 73 76 78 80 89 96 97 101
One of these recommended 60 minutes/day of moderate, or 30 minutes/day of vigorous activity,69 while two reports recommended 60 minutes/day ofmoderate activity.22 53 Three reports recommended that children and adolescents should perform 60 minutes of activity
on most days of the week.16 41 62 Seventeen reports recommended that people should be physically active for general
good health and to prevent chronic diseases.9 16 23 27 30 34 4042 59 62 64 75 77 82 88 91
Two reports recommended that weightbearing activity should be included to prevent skeletal
disorders including osteoporosis.59 82 Four reports recommended that people, especially children, should limit
sedentary activities.27 41 62 82

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10.5.5 Growth, development, body composition
Two reports recommended that people should avoid being
underweight to prevent skeletal disorders, including
osteoporosis.23 82
10.5.6 Weight gain, overweight, obesity
Fifteen reports recommended that a body mass index (BMI)of less than 25 is healthy.35 36 38 40 41 43 46 56 62 69 80 91 96 98 101 Eightof these reports specified a BMI range of 18.5–24.9.35 38 40 43
46 56 62 91
Two reports recommended a BMI range of 18.5–23
for Asian people.99 100 Twelve reports recommended that people should achieve and maintain a healthy weight.16 18 23 34 41
46 62 69 82 91 98 111
Six reports recommended that people shouldlose weight if they have a BMI of 25 or above.34 40 44 46 77 78
One report recommended that people who are overweight orobese should lose 5–10 kg to prevent CHD.73 One recommended that overweight people at risk of type 2 diabetes
should lose 5–10 per cent of their bodyweight to prevent thisdisease.31 Nine reports recommended that men maintain awaist circumference of no more than 40 inches (102 cm) andwomen no more than 35 inches (89 cm).34-36 40 43 44 78 89 98 Two
recommended that Asian men should have a waist to hip ratio
of not more than 0.88; for Asian women this should not exceed
0.85.99 100 Three reports recommended that people should
limit their intake of energy-dense foods.36 62 89
10.5.7 Comparison of reports
There is one significant difference between the reports that
focus specifically on cancer (see 10.6) and those concernedwith chronic diseases other than cancer. The discussion in a
number of these reports noted the evident protective effectof modest alcohol consumption against CHD (but not cerebrovascular disease or other chronic diseases). However, noreport included in this review explicitly recommended theconsumption of alcoholic drinks.
There are some significant differences — at least in emphasis — between reports that make recommendations to prevent chronic diseases other than cancer, and those that makerecommendations for preventing cancer specifically. Reports
concerned with preventing chronic diseases other than cancer, particularly CVD, give more prominence to the importance of diets high in cereals (grains) — preferablywholegrain or minimally processed — as well as diets highin vegetables, fruits, and fish. High-fat milk and dairy products are judged to increase the risk of CVD, but these foods
are not thought to be a major factor in the development ofcancer.
The iodisation of salt supplies, which is necessary to prevent
goitre, need not be in conflict with recommendations on maximum levels of salt intake. Recommendations to limit consumption of red meat need not conflict with recommendations
for iron intake to prevent clinical and subclinical deficiency,
and to promote physical and mental development.
The Panel agrees that these differences and considerations
be taken into account in its recommendations which, when
they are based partly on findings on diseases other than cancer, are clearly identified as such. See Chapter 12.
In general, the Panel notes the impressive consistency of findings apparent from a systematic review of expert reports pub-lished since 1990 on food, nutrition, physical activity, and theprevention of chronic diseases, which reinforce the findingsof earlier, less formally conducted work. The main evidencebased recommendations made by expert reports on cancer,
and by reports on chronic diseases other than cancer, aremostly harmonious and often practically identical. This includes reports on obesity, type 2 diabetes, CVD, and disordersof the digestive system, osteoporosis, and dental diseases.

10.6 Cancer
10.6.1 Background
Throughout recorded history, cancer has been attributed —at least in part — to food and nutrition, as well as to otherenvironmental factors. Until the beginning of the 20th
century, high consumption of meat and salt, and low
consumption of bulky plant foods, vegetables, and fruits
were thought to increase the risk of cancer in general. In thefirst two thirds of the 20th century, a series of laboratory andecological studies found that energy restriction protectedagainst cancer in laboratory animals, and that diets low infibre and high in meat, fat, salt, salty foods, and/or alcoholic
drinks seemed to increase the risk of some cancers inparticular.15
From the late 1970s, reports began to be published thatsummarised the scientific literature on food, nutrition, andcancer, and provided dietary recommendations for the prevention of cancer. Between 1977 and 1989, 12 such reports
were published in, or for, Canada (1), Europe (2), Japan (1),Latin America (1), and USA (7). These reports have beenreviewed previously.1 They tended to recommend relatively
high consumption of cereals (grains), vegetables, and fruits(and so of dietary fibre and micronutrients); relatively low
consumption of red meat, and smoked and cured meats; lowconsumption of salted and salty foods; low or no consumption of alcoholic drinks; maintenance of a healthy bodyweight; and regular physical activity.
10.6.2 Introduction
Following this work, this section presents the recommendations made for controlling and preventing cancer since 1990.
The order of the passages below follows that of the contentsof the present Report. Overall, of the 95 reports reviewed,
15 include recommendations on preventing cancer. These
reports have been produced by 12 different organisations: 1
from Australasia, 3 from Europe, 5 in or for North America,and 3 from international agencies. There are no such reports
from middle- or low-income countries. Of the 15 reports, 12
present recommendations relating to the prevention of cancer in general 8 15 22 29 47 61 62 67 83 88 91 92 and 11 of these also
make recommendations on preventing site-specific cancers.
These include cancers of the bladder (3)15 88 91; breast (7)15
29 62 67 88 91 92; 2 for cervix, endometrium, kidney, larynx, liver,nasopharynx, oesophagus, pancreas, and stomach15 67; colonand rectum (9)15 20 29 62 67 88 90-92; lung (3)15 47 67; mouth/pharynx (3)15 65 67; and 1 for ovary and prostate.15 The recommendations summarised in this section (10.6) are forpreventing cancer in general, unless stated otherwise.

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Table 10.1

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Recommendations to prevent food-related diseases

The table below summarises recommendations from reports published since 1991 for the management, control, and prevention of chronic diseases, nutritional
deficiencies, and relevant infectious diseases. Recommendations related to cancer are not included here. Unless indicated otherwise, there is no disagreement
between reports. To present the findings of the review more easily, recommendations have only been included if they are made in three or more reports.
However, the Panel does not intend this as a measure of the quality of the recommendations themselves. For more detailed information, please refer to theappropriate sections in this chapter.
EXPOSURE

RECOMMENDATIONSTO PREVENT OR MANAGE

Cereals (grains), roots,
tubers, and plantains

Include wholegrain cereals in the diet (unspecified amount)

CVD,36 41 43 78 98 CHD16 24 66 91 92 95

Suggested intake of 3–6 or more servings/day of wholegrain cereals

CVD36 40 78 98

Foods high in iron should be eaten in combination with foods that enhancerather than inhibit iron absorption: cereals (grains) should be consumed withmeals of low iron content, and foods high in ascorbic acid, such as tubers,
should be included with meals

Iron deficiency anaemia11 13 51

Include 400 g (5 or more servings)/day of vegetables and fruits

CVD,36 40 69 77 78 80 98 111 CHD,35 40 73 75 95 100 111
hypertension35 36 73 95 100 111

Include pulses (legumes) in the diet (unspecified amount)

CVD,36 41 43 91 98 CHD16 24 88

Foods high in ascorbic acid, such as orange juice, carrots, and cauliflower,should be included with meals

Iron deficiency anaemia11 13 51

Red meat consumption should be moderated and lean meat preferred(unspecified amount)

CVD,16 40 41 78 98 CHD24 66 101

Include fish in the diet (unspecified amount)

CVD,16 41 43 80 CHD24 66 91

Consume between 1 and 3 servings/week of fish

CVD,39 40 72 78 80 98 CHD22 30 40 93 96

Choose oily fish (unspecified amount)

CVD,39 40 72 78 80 98 CHD22 36 91 93

Limit intake of hydrogenated/partially hydrogenated vegetable oils
and hard margarines (unspecified amount)

CHD24 62 66 91

Total dietary fat intake should be limited (unspecified amount)

CVD46 77 84

Total dietary fat to provide no more than 35% of total energy

CHD,8 53 66 overweight/obesity22 53 69

Total dietary fat to provide no more than 30% of total energy

CVD,22 69 78 CHD24 26 34 35 62 64 101

Dietary fat intake should not be restricted

In children under 2 years of age26 41 80

Limit/reduce intake of saturated fats (unspecified amount)

CHD53 88 98

Intake of saturated fat should be no more than 10% of energy

CVD16 22 36 40 41 63 69 78 80 94
CHD8 24 26 62 66 91 92 95 101

Intake of saturated fat should be no more than 7% of energy

CVD,34 36 41 43 44 CHD,35 99 100 people with,or at risk of, CVD or with elevated LDLcholesterol (including those withdiabetes)31 34-36 40 41 43 44

Intake of saturated fatty acid intake should be limited (unspecified amount)

CHD53 88 98

Restrict intake of myristic acid (including coconut products)

CHD66 91 101

Limit intake of dietary cholesterol to <300 mg/day

CVD,16 36 40 43 63 78 CHD8 24 26 35 62 66 93

Limit intake of dietary cholesterol to <200 mg/day

CVD in people with diabetes, people atrisk of, or with pre-existing, CVD or thosewith elevated LDL cholesterol,34 36 41 43 44 63
CHD in people with diabetes, people atrisk of, or with pre-existing, CVD or thosewith elevated LDL cholesterol35 64 101

Limit intake of polyunsaturated fatty acids to no more than 10% of energy

CHD24 66 93 101

Limit intake of trans-fatty acids (unspecified amount)

CVD36 40 41 43 98

Vegetables, fruits, pulses(legumes), nuts, seeds,
herbs, and spices

Meat, fish, and eggs

Fats and oils

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Continued

EXPOSURE

RECOMMENDATIONSTO PREVENT OR MANAGE

Salt and sugar

Limit intake of sodium to no more than 100 mmol/day

Hypertension30 46 56 80 88

Limit/reduce sodium intake (unspecified amount)

CVD in children at risk of CVD and in
adults with hypertension40 41 44 46

Limit/reduce consumption of salt and salted foods to no morethan 6 g of salt/day

CVD,16 36 40 41 63 69 71 80 91 CHD,35 73 80 100
hypertension,30 46 56 62 69 71 80 88 91 98
stroke40 70 80

Limit the proportion of energy in the diet from sugar (unspecified amount)

CVD,36 41 98 overweight/obesity62 91 92

Limit consumption of sugary foods (unspecified amount)

CVD,36 41 98 overweight/obesity62 69 91 92

Avoid consumption of sugary foods and drinks between meals

Dental caries22 65 74 92

Limit sugar intake

Dental caries22 65 74 91 92

Milk and dairy products

Eat low-fat versions of dairy products in preference to high-fat versions

CVD,16 36 40 43 46 80 98 CHD24 66 101

Water, fruit juices, softdrinks, and hot drinks

Avoid using sugary drinks in baby bottles

Dental disease49 65 92

Alcoholic drinks

Limit intake of alcoholic drinks to two drinks for men and
one drink for women per day

CVD,22 36 40 44 46 77 97 CHD,31 73 75 88 96
hypertension,31 46 56 62 91 stroke31 40 62 70 77 91

If drinking, do so only with meals

Hypertension,56 62 91 stroke40 62 70 91

Food production,
processing, preservation,and preparation

Limit/reduce intake of refined carbohydrates/grain products and foods

CVD36 41 98

Dietary constituents andsupplements

Include fibre in the diet (unspecified amount)

CVD36 69 98

Brush teeth with fluoride toothpaste twice daily

Dental caries50 65 74

Ensure an adequate intake of vitamin D

Osteoporosis22 48 59

Ensure an adequate intake of calcium

Osteoporosis22 33 48 58 59 88

Encourage exclusive breastfeeding for first 4–6 months

Diarrhoea10 17 91

Women should breastfeed exclusively for 6 months

Food intolerances in the infant27 79 91 92

Be physically active

CVD,30 34 40-42 44 CHD,64 75 88 91
osteoporosis23 59 88

Minimum of 30 minutes of moderate-intensity physical activity on
most days of the week

CVD16 22 34 36 40 43 45 57 62 68 78 80
CHD22 35 64 73 96 97 101
type 2 diabetes22 30 31 57 62 69 76 89
hypertension16 56 57 62
overweight/obesity16 57 62 69

60 minutes of physical activity for children and adolescents onmost days of the week

CVD16 41 62

Achieve/maintain a healthy weight (unspecified)Type 2 diabetes22 62 69 91
hypertension34 46 62 98

Achieve/maintain a BMI of 18.5–24.9 kg/m2

Stroke,38 40 62 hypertension46 56 91

If BMI is ≥25 kg/m2, lose weight

CVD34 40 44 46 77 78

Achieve/maintain a waist circumference of no more than 35 inches (89 cm)
for women and 40 inches (102 cm) for men

CVD34-36 40 43 44 78 89 98

Dietary patterns

Physical activity

Weight gain, overweight,
and obesity

BMI, body mass index; CHD, coronary heart disease; CVD, cardiovascular disease; LDL, low density lipoprotein

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10.6.3 Foods and drinks
Cereals (grains), roots, tubers, and plantains. Six reports
recommended diets high in cereals (grains),15 20 29 90-92 withsome emphasising relatively unprocessed grains. One recommended 600–800 g/day of a variety of cereals (grains),
pulses (legumes), roots, tubers, and plantains, stating that
this is based more on the evidence for other chronic
diseases.15
Vegetables, fruits, pulses (legumes), nuts, seeds, herbs,
and spices. Nine reports recommended diets relatively highin vegetables and fruits,15 20 22 29 65 67 83 90 91 with five specifying five or more portions a day.15 22 29 67 83 One report recommended the consumption of five portions of vegetables
and two portions of fruits each day.91 Four reports recommended diets relatively high in pulses (legumes).15 29 88 91
Meat, fish, and eggs. Five reports recommended limiting

red meat15 20 22 29 83; two of these advised opting for leanvarieties.22 29 Three reports recommended that meat should
be baked, grilled (broiled), or poached rather than fried or
flame grilled (charbroiled).15 22 29 One recommended minimal
intake of smoked and cured meats.15 Four recommended
choosing poultry15 20 22 29 and fish.15 20 22 29 One recommended limiting Cantonese-style fermented salted fish.22

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saccharides.83 Another recommended 1000–1200 mg/day ofcalcium to prevent colorectal cancer.90 Two stated that
dietary supplements are unnecessary and possibly evenharmful.15 83
10.6.4 Physical activity
Ten reports recommended regular, sustained physical activity.15 20 22 29 62 67 83 88 90 91 Those that specify the intensity andduration, recommend moderate physical activity for around
30–60 minutes per day.
10.6.5 Growth, development, body composition
One report recommended that women should breastfeed
exclusively to prevent them from developing breast cancer— ideally until the child is 6 months old.91
10.6.6 Weight gain, overweight, obesity
Five reports recommended maintaining a BMI of between
18.5 and 24.9.15 29 67 83 91 One of these advised that people
should not gain more than 5 kg during their adult life.15 One
report recommended avoiding energy-dense foods.29
10.6.7 Comparison of reports
There is no substantial disagreement between any of thesereports. The Panel also notes the general consistency with its
own findings and recommendations.

Fats and oils. Three reports recommended limiting total fat

intake: upper limits vary between 15 and 30 per cent,15
25 and 30 per cent,15 90 and 30 and 35 per cent.8 Two recommended restricting saturated fatty acid intake to 10 per
cent or less of total energy intake.8 67 One recommended limiting animal fats,15 and another limiting linoleic acid.53
Salt and sugar. Two reports recommended that consumptionof salt, salty, and salted foods should be limited to a total
intake of less than 6 g of salt/day.15 22 Two reports recommended limiting sugars and refined carbohydrates.15 29 Oneof these advised limiting sugars to less than 10 per cent of
total energy intake.15
Water, fruit juices, soft drinks, and hot drinks. One report
recommended drinking plenty of water to prevent cancersof the colon and rectum and bladder.91 Two reports recommended limiting sugars and syrups from sources such as softdrinks.15 29 Another recommended avoiding very hot andscalding drinks.22
Alcoholic drinks. Six reports recommended limiting alcoholic drinks.15 22 29 62 91 92 When an amount was specified, thiswas usually a maximum of 1–2 drinks per day.
Food production, processing, preservation, and preparation. (Also see meat, fish, and eggs.) Two reports recom-

mended avoiding contaminants (in particular aflatoxins andmycotoxins).15 22 One of these recommended that perishable
foods should be refrigerated.15
Dietary constituents and supplements. One report

recommended diets high in dietary fibre/non-starch poly-358

10.7 Conclusions
The Panel concludes:
We are impressed by the similarity of the conclusions and recommendations in all types of expert report reviewed here.
For reports that recommended diets high in cereals (grains)(preferably relatively unrefined), and in vegetables andfruits, and pulses (legumes), no conflicting recommendations
were found. These reports also include recommendations fordiets low in red and processed meats; and correspondingly
high in dietary fibre and micronutrients, including bioactive
microconstituents; and low in fats, saturated fatty acids,
added sugars, salt, and alcoholic drinks.
We are also impressed by the consistency between reports
on deficiencies and infections that stress the vital importanceof extended, exclusive breastfeeding for the sake of the child;and reports on chronic diseases that make the same recommendation, for the sake of both children and mothers. We
are also impressed by the agreement of the reports on thebenefits of all forms of regular, sustained physical activity,
and the corresponding risks of sedentary ways of life.
Evidence on micronutrient supplements is less clear. We
consider this largely reflects the clinical needs of populations
vulnerable to deficiencies.

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1 1

Research issues
The evidence of causal relationships between food,nutrition, physical activity, body composition, andcancer is and always will be incomplete. New
methods of research, and new issues to study, arealways being developed. However, this ongoingwork does not mean that the response to every
question is ‘more research is needed’. The previous
chapters in this Report show that in many areas, theevidence of causal relationships is already strong
enough to justify public health goals and personal
recommendations, which are specified in Chapter 12.
This chapter outlines future strategic research
directions that the Panel sees as especially promising
to build on this current base of knowledge.
In many areas, as shown in the matrices
introducing each section of Chapter 7, the evidence
may be suggestive but inconclusive. These particularareas are those in which new efforts to answer
research questions may be most likely to result infindings that can advance scientific knowledge orchange public health practice. The research directions
identified here are often cross-cutting andinterdisciplinary. These could increase understandingof the cancer process, and provide new evidence toclarify and strengthen the recommendations made in
Chapter 12.
There are also many fields of study that are only
now beginning to be explored. These include
exposures in early life including before birth that
affect birth weight, growth in childhood, age at
menarche, and attained adult height. They also
include interactions between food and nutrition andother factors, notably smoking, inflammation, andinfectious agents. There is as yet relatively little
epidemiological research on broad patterns of diets,and the inter-relationship between elements ofdiets: more understanding here will enable
recommendations to be made with increasing
confidence.
More needs to be known about the levels of
exposure that are critical as modifiers of cancer risk,
and the extent to which risk is decreased orincreased at different levels. In some areas,
understanding will be improved by generalagreement on the nature and definition of
exposures; examples include physical activity,

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processed meat, and breastfeeding.
Until recently, epidemiological and experimental
research studies were typically carried out
separately, and with different objectives. But to beconvincing, epidemiological evidence, howeverconsistent, needs to be supported by concrete
evidence of biological mechanisms. A promisingdevelopment is an increased tendency for
epidemiologists and basic scientists to work as teammembers, to mutual benefit. Future research should
encourage this.
One broad category of research, not reviewed forthis Report, concerns the underlying social(including economic and political) and broad
environmental determinants of patterns of food,nutrition, and physical activity. This area is also
critical to the successful translation of theknowledge of the causes of cancer into improved
health. This crucially important aspect of research iscontained in a separate report dedicated to this
topic to be published in late 2008.

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11.1 Principles

11.2 Research issues

The principles applied when identifying the researchquestions specified here are as follows:

How can the evidence for specific nutritional or
physical activity exposures in relation to cancer bestrengthened?

Interdisciplinary
The research directions discussed here are focused not on
issues that are specific to separate disciplines, such as
epidemiology or cancer biology, but on interdisciplinary
issues and questions that concern the relationships
between cancer and food, nutrition, physical activity, andobesity.
Important
The benefit of conducting more research where theevidence is already convincing and well understood islikely to be small. Research that investigates areas where
the evidence is unclear is likely to be of especial value.
Research is also of most value when the results have alarge potential impact on the overall burden of disease.
This may be because the exposure under consideration has
a potentially profound effect on cancer risk or because thecancer site in question is particularly common.
Innovative
Research questions need to be practical and yet innovative,
which implies that they should not be constrained byconventional wisdom. More innovative research is needed.
Investigators should be imaginative and collaborate acrossdisciplines, and be willing to engage in research
programmes most likely to benefit public health.

Box 11.1

Updating the evidence

Research findings continue to accumulate. This evidence needs
to be identified, analysed, and interpreted. The World Cancer
Research Fund International, together with the American
Institute for Cancer Research, the organisations responsible forcommissioning this Report, have now commissioned a processof continuous updating of the literature. This will be the basis
for periodic updates of this Report’s findings. The process willcontinue to make use of systematic literature reviews and isbeing overseen by an international expert steering group,
including members of the Panel responsible for this Report.

Exposures judged ‘probable’ or ‘limited — suggestive’ inthe matrices of this Report are most promising as a focus
of further research when evidence is scant. Examples ofsuch exposures include calcium and dairy products as
related to cancer of the prostate; vitamin D and cancer ofthe colon; folate and cancers of the oesophagus,
pancreas, and colorectum; and selenium and cancers of
the lung, colorectum, and prostate. Those already judged
convincing, by their very nature, are less likely to be
influenced by new research. Also, people are increasingly
using non-traditional therapies, and these should also be
a topic for more systematic research.
Study design options include pooling of prospective
data (especially for rarer cancers), longer follow-up of
existing cohorts, investigations with biomarker
measurements of intake and biomarker endpoints, andnew randomised controlled trials (RCTs).

For exposures where strong evidence exists of a causal
relationship, what are the effect sizes with respect totiming, dose, and duration of exposure?
The evidence currently available for various exposuresand cancer risk is limited in terms of timing, dose,
duration, and size of effect. This kind of evidence isimportant for healthcare providers and policy-makers tomake informed decisions on public health programmes,and for people to make better-informed choices.
Study design options include pooling of prospective
data (especially for less common cancers), longer followup of existing cohorts, and obtaining more information
on early life dietary exposures. This research direction
applies to a number of the questions addressed in thisReport. For example, more information on timing, dose,and duration of exposure is needed on the effects of bodysize and fatness at different times of life in relation to
future risk of breast cancer and colorectal cancer; theeffects of timing, dose, and duration of use of alcohol andbreast cancer risk; and detailed dose-response361

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information on red meat and processed meat in relation
to colorectal and other cancers.

How do environmental and genetic factors modify theeffects of exposures on cancer risk?
Further investigation into the presence of effectmodification is needed to deepen understanding of risk
among different population groups and to help healthprofessionals and policy-makers provide more precise
recommendations. Factors that should be studied as
potential effect modifiers include tobacco, exogenous
hormones, medications (such as non-steroidal antiinflammatory drugs), metabolising genes, genes
associated with various cancers, and other food,nutrition, and body composition exposures.

What mechanisms link foods and drinks, dietary
constituents, or other nutritional and physical activity
factors to cancer risk?
There is general agreement that nutritional factors, bodycomposition, and physical activity are important
determinants of cancer risk. However, it has been difficult
to identify with confidence the precise pathways whereby
such exposures influence the process of cancer
development. Inevitably, the impact of nutrition will
ultimately be at the level of DNA and gene expression,
but the ways in which this occurs, either via genetic
mutation or epigenetic events, is only now beginning to
be explored. There are many nutritional factors for which
epidemiological data suggest that a relationship exists,
but where complete understanding of the biologicalpathways is lacking. Examples include adiposity, physicalactivity, height, red meat, processed meat, vegetables,
alcoholic drinks, lactation, arsenic, dairy products, andwhole grains.
Dietary constituents that are especially favourable tothis type of mechanistic investigation include betacarotene, calcium, vitamin D, folate, selenium, polycyclicaromatic hydrocarbons, and dietary fibre. Intermediate
biological mechanisms potentially relevant to mechanistic
understanding include inflammation, insulin resistance,
growth factors, oxidation, gut flora, hormonal changes,
and various cellular metabolic and molecular processes.
Such mechanisms may vary by the histopathological andmolecular characteristics of the tumours. Intermediatemarkers may clarify questions of causation and serve as
surrogate endpoints for observational and intervention
studies.
Study designs that may be useful to examine thesequestions include human metabolic studies with cancerrelated endpoints and metabolic studies added onto
existing nutrient RCTs. Intermediate endpoints should beincorporated into large, prospective, observational orintervention studies to better understand their links toboth nutritional factors and cancer endpoints.

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Increasingly with greater understanding of the interplayof nutritional state and genetic expression, programmesof study that incorporate elements of different disciplines
and technologies should illuminate the fundamental
processes underpinning diet–cancer links.

Which genetic polymorphisms and nutritional
exposures that influence gene expression are useful forunderstanding the relationship between nutrition or
physical activity and cancer?
Certain genetic polymorphisms (genetic variants thatappear in at least 1 per cent of the population) may
increase, while others may decrease, the extent to which
nutritional factors affect cancer risk. Studying
gene–nutrient interactions is likely to yield better results
as technology allows the simultaneous examination ofmultiple gene–nutrient interactions, and as bettersystems evolve for synthesising the large amounts of datathat are generated by these newer techniques.
Genetic make up can impact the extent to which ourbodies respond to nutritional factors. Also, genes express
themselves (or switch on) to varying degrees dependingon the nutritional environment. Understanding the extent
to which nutrients affect gene expression in such a way as
to impact on both cancer risk itself and thenutrient/cancer risk relationship is very important.
Examples of gene–nutrient interactions include Nacetyl transferase and meat. In certain cases, genetic
polymorphisms (for example, MTHFR 677 TT for low
folate intake and LCT — lactase persistence — for dairy
food intake) can act as proxies for nutritional exposures.
This can be examined using a Mendelian randomisation
study design, controlling for confounding factors. For
example, the effects of folate may be demonstrated bylooking at the differences in cancer outcome between
people who have the MTHFR gene variant that mimics
low folate intake (MTHFR 677 TT) and people who donot. Carrying this form of the gene is unlikely to berelated to other potential confounding factors such as
smoking or socioeconomic status.

Does weight loss in overweight or obese people reducecancer risk?
Body fatness and weight gain increase the risk of several
cancers. But the effects of weight loss on cancer risk arepoorly understood. Study design options for investigating
this question include model systems with caloric
restriction and weight loss, human metabolic studies withintermediate endpoints, and cohort studies with explicit
inquiries about intentional weight loss.

What are the relevant milestones in the timing of growthand development that affect cancer risk and how canthey be modified by food, nutrition, and physical activity?

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Critical periods for exposure to factors that lead toincreased cancer risk during the life course should be
identified. For example, high birth weight and rapid
growth in height during adolescence are both associatedwith an increased risk of breast cancer. Some countries
have extensive child and adolescent growth data that canbe examined in relation to cancer outcomes using
registries.

How can factors related to food production, processing,preservation, and cooking methods, which may affectcancer risk, best be studied in humans?
Current methods used to produce food are changing fasterthan at any other point in history. It is most important tounderstand how old and new methods might affect therisk of cancer. In addition to changes in agricultural
practices, both rapid urbanisation and economic
globalisation have transformed food systems. Methods
used to evaluate the changes in cancer risk that might betied to these new patterns need to be developed. Relevant
factors may include exogenous hormone administration in
the production of meat, production of heterocyclic aminesand polycyclic aromatic hydrocarbons by high-temperature
cooking, use of food additives, use of pesticides, novel
processing methods, and storage conditions.

How do food, nutrition, body composition, andphysical activity affect outcomes in cancer survivors?

How do relationships between food, nutrition, andphysical activity and cancer risk differ in various partsof the world?
In areas of the world where patterns of cancer andpatterns of diet are different, the relationship between
nutrition and cancer risk can also vary. For example, in
middle- and low-income countries, the inverse relation
between body mass and premenopausal breast cancer isusually not seen. It could be that there are factors such as
genes, body composition, or physical activity that modify
the effect of body mass on cancer risk in some
populations.

How can measures of food, nutrition, physical activity,and body composition, as they relate to cancer risk, be
improved?
Better ways of characterising and measuring the shortand long-term exposures most relevant to determining
cancer risk are needed. These may include incorporating
new instruments in prospective studies, whether internetbased or telephone-based recalls, dietary records, with, if
possible, strong validation studies using biomarkers. Also,
additional development of intake biomarkers, where
feasible, and their incorporation in large prospective
studies would be helpful.
Finally, expanded investigation of dietary indexes andpatterns, which have the potential to capture the effect ofmultiple, interconnected dietary factors, may further
enhance our understanding of nutrition and cancer.

The extent to which cancer survivors are similar to or
different from people without cancer, in terms of theextent to which their cancer risk is sensitive to changes in
diet, body composition, and physical activity, needs to beinvestigated.
A number of further questions arise:• Are any effects of food, nutrition, and physical activity
additive?
• Are the type and the progression of the cancer
important in this regard?
• Is the extent to which cancer survivors have had
exposure to chemotherapeutic or radiologicaltreatment important?
There are two broad contexts for these questions: do diet,nutrition, or physical activity before diagnosis affectoutcome after treatment? And do changes in these after
diagnosis and treatment affect outcome?
In addition to RCTs among survivors, existing cohort
studies can examine some of these questions since there
are now fairly large numbers of cancer survivors in somecohorts. Pooling of the data from these studies could bevaluable. Good information on clinical–pathologicalfactors and treatments is necessary in observational
studies because these potentially confounding factors
affect cancer prognosis and may be related to nutritional
exposures.

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, i V  i  ` > Ì  Ã

Chapter 12
Public health goals and personal
recommendations

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3

Introduction to Part 3
The culmination of the five-year process resulting in this Report is Chapter 12, in
which the Panel’s public health goals and personal recommendations are
specified. These are preceded by a statement of the principles that have guided
the Panel in its thinking.
The goals and recommendations are based on judgements made by the Panel inPart 2, as shown in the introductory matrices. Such judgements are of a‘convincing’ or ‘probable’ causal effect, either of decreased or increased risk.
Judgements of ‘convincing’ or ‘probable’ generally justify goals andrecommendations. These are proposed as the basis for public policies and for
personal choices that, if effectively implemented, will be expected to reduce theincidence of cancer for people, families, and communities.
Eight general and two special goals and recommendations are specified. In eachcase a general recommendation is followed by public health goals and personal
recommendations, together with footnotes when further explanation or
clarification is required. These are all shown in boxed text. The accompanying
text includes a summary of the evidence; justification of the goals andrecommendations; and guidance on how to achieve them.
Reliable judgements are carefully derived from good evidence. But specificpublic health and personal goals and recommendations do not automaticallyfollow from the evidence, however strong and consistent. The process of movingfrom evidence to judgements and to recommendations has been one of the
Panel’s main responsibilities, and has involved much discussion and debate until
final agreement has been reached. The goals and recommendations here havebeen unanimously agreed.
Food, nutrition, body composition, and physical activity also affect the risk of
diseases other than cancer. Informed by the findings of other reportssummarised in Chapter 10, the goals and recommendations have therefore been
agreed with an awareness of their wider public health implications.
The goals and recommendations are followed by the Panel’s conclusions on the
dietary patterns most likely to protect against cancer. As conventionally
undertaken, epidemiological and experimental studies are usually sharply
focused. In order to discern the ‘big picture’ of healthy and protective diets, it isnecessary to integrate a vast amount of detailed information. This also has beenpart of the Panel’s task.
The main focus of this Report is on nutritional and other biological andassociated factors that modify the risk of cancer. The Panel is aware that, as withother diseases, the risk of cancer is critically influenced by social, cultural,
economic, and ecological factors. Thus the foods and drinks that people consume
are not purely because of personal choice; often opportunities to accessadequate food or to undertake physical activity can be constrained, either forreasons of ill health or geography, economics, or equally powerfully, by culture.

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There is a limit to what can be achieved by individuals, families, communities,
and health professionals.
Identifying not only the nutritional and associated factors that affect the risk ofcancer but also the deeper factors enables a wider range of policy
recommendations and options to be identified. This is the subject of a separate
report to be published in late 2008.
The members of the Panel and supporting secretariat, and the executives of the
WCRF global network responsible for commissioning this Report, have been
constantly reminded of the importance of their work during its five-year
duration. The public health goals and personal recommendations of the Panelthat follow are offered as a significant contribution towards the prevention andcontrol of cancer throughout the world.

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1 2

Public health goals andpersonal recommendations
This Report is concerned with food, nutrition,
physical activity, body composition, and theprevention of cancer, worldwide. Chapter 12 is theculmination of the Report. It explains the principles
that guide the Panel’s decisions; lists and explains
the Panel’s recommendations to prevent cancer; andidentifies appropriate dietary patterns. The
recommendations are in the form of a series ofgeneral statements; public health goals designed to
be used by health professionals; andrecommendations for people — as communities,
families, and individuals — who can also be guided
by the goals. Footnotes are included when needed
for further explanation or clarity.
Most cancer is preventable. The risk of cancers isoften influenced by inherited factors. Nevertheless,
it is generally agreed that the two main ways toreduce the risk of cancer are achievable by mostwell informed people, if they have the necessary
resources. These are not to smoke tobacco and to
avoid exposure to tobacco smoke; and to consume
healthy diets and be physically active, and tomaintain a healthy weight. Other factors, inparticular infectious agents, and also radiation,industrial chemicals, and medication, affect the riskof some cancers.
The Panel notes that previous reports haveattributed roughly one third of the world’s cancer
burden to smoking and exposure to tobacco, androughly another one third to a combination of
inappropriate food and nutrition, physicalinactivity, and overweight and obesity. By theirnature, these estimates are approximations, but thePanel judges that avoidance of tobacco in any form,
together with appropriate food and nutrition,
physical activity, and body composition, have thepotential over time to reduce much and perhaps
most of the global burden of cancer. This is in thecontext of general current trends towards
decreased physical activity and increased bodyfatness, and projections of an increasing and ageing
global population.
The recommendations here are derived from theevidence summarised and judged in Part 2 of thisReport. They have also taken into account relevant

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dietary and associated recommendations made inother reports commissioned by United Nations
agencies and other authoritative international andnational organisations, designed to promotenutritional adequacy and prevent cardiovascularand other chronic diseases. They therefore
contribute to diets that are generally protective,
and that also provide adequate energy andnutrients. The recommendations can therefore be
the basis for policies, programmes, and choices thatshould prevent cancer, and also protect against
deficiency diseases, infections especially of early
life, and other chronic diseases.
Throughout its work, the Panel has also been
conscious that enjoyment of food and drink is acentral part of family and social life, and that foodsystems that generate adequate, varied, anddelicious diets are one central part of humancivilisation. From the cultural and culinary, as wellas the nutritional point of view, therecommendations here amount to diets similar to
cuisines already well established and enjoyed inmany parts of the world.

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12.1 Principles
The recommendations presented in this chapter aredesigned as the basis for policies, programmes, andpersonal choices to reduce the incidence of cancer ingeneral. These are guided by a number of separate
principles and also by one overall principle, which is,that taken together, the recommendations provide an
integrated approach to establishing healthy patterns ofdiet and physical activity, and healthy ways of life.
In order to be useful both for health professionals who
advise on cancer, and for people who are interested in
reducing their own risk of cancer, the recommendations
are quantified wherever possible and appropriate.
See box 12.1.

12.1.1 Integrated
The Panel, in making its recommendations, has been concerned to ensure that most people in most situations
throughout the world will be able to follow its advice. The
recommendations are framed to emphasise aspects of foodand nutrition, physical activity, and body composition that
protect against cancer. They are also integrated with existing advice on promoting healthy ways of life, such as thatto prevent other diseases. At the same time, the Panel has
given special attention to making recommendations that canform the basis for rational policies, effective programmes,
and healthy personal choices.
12.1.2 Broad based
In assessing the evidence, making its judgements, and inframing its recommendations, the Panel has, where appropriate, chosen to take a broad view. It has also agreed to baseits advice on foods and whole diets rather than on specificnutrients. Thus, recommendations 4 and 5 concern plantfoods and animal foods in general, while their specific public health goals and personal recommendations are mostly
concerned with vegetables and fruits, and then with redmeat and processed meat, where the evidence on cancer isstrongest.
The same applies to physical activity. The evidence showsthat all types and degrees of physical activity protect orprobably protect against some common cancers. Recommendation 2 therefore does not specify any particular physical activity (of which sport and exercise are
one type). Rather, it recommends sustained physical activity as part of active ways of life. What type of physicalactivity is most appropriate and enjoyable depends on individual abilities and preferences, as well as the settings inwhich populations, communities, families, and individuals
live.
The Panel has taken the same approach in considering therecommendations altogether. As a whole, the recommendations contribute to whole diets and overall levels of physical activity most likely to prevent cancer. This does not
imply one particular diet, or a specific form of physical activity, but rather key elements designed to be incorporated into
existing and traditional diets and ways of life around theworld. This is emphasised in section 12.3 of this chapter, on
patterns of food, nutrition, and physical activity.
12.1.3 Global
This Report has a global perspective. It is therefore appropriate that the recommendations here are for people andpopulations all over the world; that they apply to people
irrespective of their state of health or their susceptibility tocancer; and that they include cancer survivors.
Some factors that modify the risk of cancer are more common, and so of more concern, in some parts of the world
than others. It is possible that such factors might become
more widespread, but the recommendations on them in thisReport are in the context of their current local importance.
Just as people’s susceptibility to cancer varies, so will theextent to which they will benefit from following these recommendations, though most people can expect to benefit
to some extent from each of them.
Recommendations for whole populations are usually now
identified as also being of importance for people who, while
not being clinically symptomatic, have known risk factors
for disease. People at higher risk of various cancers include
smokers and people regularly exposed to tobacco smoke;
people infected with specific micro-organisms; overweight
and obese people; sedentary people; people with highintakes of alcoholic drinks; people who are immunosuppressed; and those with a family history of cancer. Such people are often at higher risk of diseases other than cancer.
The Panel agrees that the recommendations here apply tothese people.
They also apply to cancer survivors, meaning people living with a diagnosis of cancer, including those identified ashaving recovered from cancer (see Chapter 9). This is subject to important qualifications, stated in the special recommendations for this group of people.

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12.1.4 Cancer in general
This Report is concerned with the prevention of cancer ingeneral. Evidence for particular cancer sites provided thebuilding blocks. A key task for the Panel was to take this specific evidence and formulate recommendations that would,
in general, lead to a lower burden from cancer regardlessof site.
This broad approach is appropriate from the public healthpoint of view. International agencies, national governments,
other policy-makers, health professionals, and people within communities and families, and also as individuals, wantto know how to prevent cancer in general.

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12.1.5 Designed to have major impact
Every case of cancer is important. But the responsibility of
those concerned with public health is to encourage policies,
programmes, and choices that will have the greatest impact.
For this reason, the Panel has paid special attention to themore common cancers; cancers where there is the most clearcut evidence of modification of risk by food, nutrition, physical activity, and body composition; and cancers that may
most readily be prevented by achievable recommendations.
Special attention has also been paid to those aspects of foodand nutrition, physical activity, and body composition thatseem most likely to prevent cancers of a number of sites.

FOOD, NUTRITION, PHYSICAL ACTIVITY, AND THE PREVENTION OF CANCEROVERVIEW OF THE PANEL’S KEY JUDGEMENTS

Convincing
decreasedrisk

Probabledecreasedrisk

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risk

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Includes evidence on foods containing
carotenoids for mouth, pharynx, larynx; foods
containing beta-carotene for oesophagus; foods
containing vitamin C for oesophagus
2
Includes evidence on foods containing
carotenoids for mouth, pharynx, larynx andlung; foods containing beta-carotene foroesophagus; foods containing vitamin C for
oesophagus
3
Includes evidence from supplements forprostateBre
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Summary of ‘convincing’ and ‘probable’ judgements

4

Evidence is from milk and studies using
supplements for colorectum
Includes 'fast foods'
Convincing harm for men and probable harm for
women for colorectum
7
The evidence is derived from studies using
supplements for lung8
Includes evidence on televison viewing
9
Judgement for physical activity applies to colonand not rectum
56This matrix displays the Panel’s most confident judgements on the strength of the evidence causally relating food, nutrition, and physicalactivity to the risk of cancer. It is a synthesis of all the matrices introducing the text of Chapters 4, 5, 6, 7, and 8 of this Report, but shows
only judgements of ‘convincing’ and ‘probable’, on which the following recommendations are based. It does not show a detailed
breakdown of the individual foods, drinks, and their constituents. The full matrix, which also includes judgements of ‘limited —suggestive’, is on the fold-out section, which can be found inside the back cover of this Report.
In this matrix, the columns correspond to the cancer sites that are the subject of Chapter 7 and body fatness that is the subject ofChapter 8. The rows correspond to factors that the Panel judges to be ‘convincing’ or ‘probable’, either as protective against or causativeof cancer of the sites specified, or of weight gain, overweight, or obesity. Such judgements usually justify public health goals andpersonal recommendations. The strength of the evidence is shown by the height of the blocks in this matrix — see the key.

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Quantification

Public health professionals who advise on
preventing cancer, including those responsible for planning food supplies or exercise
programmes (for example, for schools, hospitals, or canteens), or those working inclinical settings, need to be able to give specific, actionable, and relevant advice that
includes prevention of cancer.
To do this they need to know how muchof what foods and drinks, what levels ofbody fatness, and how much physical activity are most likely to protect against cancer.
So do people in general, as members ofcommunities and families, as well as individuals. For these reasons, the personal
and public health goals in each of the recommendations are quantified wherever
possible.
Translation of an overall body of current
evidence into quantified recommendations
is a challenge for all expert panels responsible for recommendations designed to
guide public policy, and professional andpersonal decisions. This process is not andcannot be ‘an exact science’. Within any
population, people differ from one another, and there are differences between populations as well. A single, numerical
recommendation is not able to encompass
these differing needs and so will necessarily be imprecise.
Furthermore, the evidence rarely showsa clear point above or below which riskchanges suddenly. Rather, there is usually acontinuous relationship between the exposure, be it body fatness, physical activity, orlevel of consumption of a food or drink,and cancer risk. The shape of this ‘dose
response’ may vary — sometimes it is astraight line, or it may be curved, forinstance J-shaped or U-shaped. All of thesefactors need to be taken into account. The
quantified recommendations are therefore
based on the evidence but are also a matter of judgement.
For example, the evidence on alcoholic
drinks and breast cancer, as shown in chapters 4.8 and 7.10, does not show any ‘safe
threshold’. The risk evidently increases,
albeit modestly, at any level of intake ofany alcoholic drink. And there is no nutritional need to consume alcohol. So in thiscase, the appropriate recommendation
based solely on the evidence for breast cancer would be not to consume alcoholic
drinks; the quantified recommendation
would be zero.
However, the integrated approach thatguides these recommendations means that
the Panel has taken into account evidence
for a likely protective effect of modest
amounts of alcohol against coronary heartdisease, and has not made this recommendation based only on the evidence for cancer (see recommendation 6).
In addition, in some cases, there is evidence for adverse effects unrelated to cancer risk that might help to quantify
recommendations. Physical activity is a casein point. The evidence, as shown in
Chapters 5 and 7, shows that high levels of
all types of physical activity protect or may
protect against some cancers, and also that
low levels increase the risk of these cancers.
But there is also evidence (not derived fromthe systematic literature reviews), thatabove certain high levels, which varydepending on people’s general state of fitness, physical activity can provoke an undesirable inflammatory response.
The Panel also used such an approach inconsidering the minimum limit for healthy

12.1.6 Prevention of other diseases taken into
account
Chapter 10 of this Report is based on a systematic review of
secondary sources — other reports — on other diseases where
the risk is modified by food and nutrition and related factors.
These diseases are nutritional deficiencies; relevant infectious
diseases, especially diarrhoea and respiratory infections ofearly childhood; and chronic diseases other than cancer.
As stated above, the recommendations here are designed
to prevent cancer as a whole. For similar reasons of publichealth, the Panel, in considering and judging the secondary
evidence presented in Chapter 10, has made sure that therecommendations here take the prevention of other diseases
into account.
Often recommendations to prevent cancer are much thesame as recommendations to control or prevent otherdiseases. When this is evidently so, the Panel has statedbody mass index, which does not derivefrom the evidence on cancer. The implication is that upper as well as lower limits
may need to be recommended.
These quantified recommendations arealso guided by the ranges of foods anddrinks, physical activity, and body composition identified in the studies whose results,
taken together, form the basis for the
Panel’s judgements. High and low limits canbe set by simply following the ranges in thestudies themselves, mostly cohort studies.
The case for doing this is quite strong;
this prospective evidence provides a robust
basis for defining the dose response. On theother hand, many studies have been carriedout among populations who have only arather narrow range of dietary intakes, levels of physical activity, and degree of bodyfatness, which makes detection of associations difficult. Further, these ranges may
not themselves be optimal, and this makes
it difficult to define what is healthy. In suchcases, a recommended range based only on
the results of such studies would be flawed.
Ecological studies, which often address amuch wider range of intakes, were alsopart of this review and, though not central
to the judgement of causality, neverthelessinform the quantification of the recommendations.
As well as considering the evidence fromstudies on cancer, the Panel, in common
with others, has also used its collective
knowledge of other relevant considerations
in making the quantified recommendationsin this chapter. It has also taken into
account the ranges of intake of foods anddrinks, and the ranges of advisable bodycomposition and physical activity recommended in other reports.

that its recommendations are supported or reinforced.
Occasionally, recommendations to prevent other diseases
include factors that evidently do not apply to cancer: forexample, saturated fatty acids, contained mostly in animal
foods, are accepted to be a cause of coronary heart disease,
but have no special relevance to the risk of cancer.
There are also some cases where recommendations to prevent other diseases conflict, or seem to conflict, with thosefor cancer. One example is alcoholic drinks. While no reporton cardiovascular disease has ever recommended consumption of alcoholic drinks, low levels of consumption of alcoholic drinks are likely to protect against coronary heartdisease; whereas there is no evidence that alcoholic drinks
at any level of consumption have any benefit for any cancer. In cases like this, the Panel’s recommendations may be
modified to take such a conflict into account; this is clearly
indicated in the recommendations.

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12.1.7 Challenging
The Panel emphasises that food and life should be enjoyed.
The Panel recognises that for many people, these recommendations will involve change. People tend to enjoy ways of lifethat they have become used to. However, when they change,
people often enjoy their new ways of life as much or more.
The Panel is aware of the importance of aspirational goals
and recommendations. To achieve substantial public and personal health gain, some of these need to be challenging.
For many populations and people, especially in industrialised or urban settings, achieving all of these recommendations will not be easy. Levels of physical activity withinsocieties that are basically sedentary, and energy density ofdiets, are often well outside the ranges recommended here.
But the Panel believes that populations and people whoachieve these recommendations will not only reduce theirrisk of cancer, as well as of other diseases, but are also likely to improve their positive health and well-being.
Sometimes it may take time for people to achievechanges. The Panel has taken this into account when
applying the evidence to framing these recommendations.
See box 12.2.
Some people will not be able to follow some or all of theseBox 12.2

Making gradual changes

The evidence reviewed by the Panel more often than not does
not show thresholds of food and drink consumption, body fatness, or physical activity below or above which the risk of cancer suddenly changes. In such cases, any change in the exposure
would be expected to lead to a change in cancer risk, whatever the starting level, and no single point lends itself to being an
obvious recommended level. Recommendations might then simply state ‘the less the better’ or ‘the more the better’. However,while that would be faithful to the evidence, it is less helpful
for people trying to implement change — the question arisesof how much more or less, or of what level should be a target.
These judgements take account of several factors — the rangeof foods and drinks consumed, the level of physical activity or
degree of body fatness found in the studies reviewed, or the
possibility of adverse effects at particularly high or low levels,
but also the precise nature of the relationship between themand the risk of cancer. In some cases, this may be a relatively
straight line, in others it may be curved, for instance either Ushaped or J-shaped. Therefore the Panel has chosen to makequantified recommendations that in its judgement would resultin a real health gain, and are achievable yet challenging.
However, it would be wrong to interpret this as meaning thatany movement towards them, but which did not reach them,was valueless. On the contrary, these recommendations should
act as a spur to change of any amount. While it is true that asmaller change than recommended would lead to less reduction
in risk, any change at all would nevertheless provide at least
some benefit.
A perceived inability to achieve the targets should not be adisincentive to making changes to move in that direction. So achange from eating two portions of vegetables daily to three,or a reduction in body mass index from 29 to 27, while not meeting the goals, would nevertheless be valuable.

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recommendations because of their situation or circumstances. For such people, the recommendations as stated here
may be unattainable, but working towards them will also
reduce the risk of cancer, although to a lesser degree.

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12.2 Goals and recommendations
The Panel’s goals and recommendations, the culminationof five years of work, are guided by the principles above.
They are based on the best available evidence, which has
been identified, collected, analysed, displayed,summarised, and judged systematically, transparently, andindependently. The public health goals are for populations
and are therefore principally for health professionals; therecommendations are for people, as communities,
families, and individuals. The eight generalrecommendations are followed by two special
recommendations. Together they are designed to be
integrated and to contribute to healthy dietary patterns,
healthy ways of life, and general well-being.

The Panel emphasises that the setting of recommendations is
not and cannot be ‘an exact science’. Recommendations
derive from judgements based on the best evidence but that
evidence and those judgements may still not be such that
only one possible recommendation would follow. Several
aspects of recommendations designed to improve health canbe questioned. The Panel believes nevertheless that its recommendations are as firmly based as the science currently
allows, and therefore represent a sound base for developing
policy and action.
The 10 recommendations here derive from the evidence
on food, nutrition, and physical activity but not on theirwider socioeconomic, cultural, and other determinants. The
Panel is aware that patterns of diet and physical activity, as
well as the risk of diseases such as cancer, are also crucially influenced by social and environmental factors. These
broader factors, and recommendations designed as the basis
for policies and programmes that can create healthier societies and environments, are the subject of a further report
to be published in late 2008.
The Panel has agreed that its recommendations normallyderive from evidence that justifies judgements of ‘convincing’ and ‘probable’, as shown in the top halves of the matrices in the chapters and sections of Part 2. This means thatthe evidence is sufficiently strong to make recommendations
designed as the basis for public health policies andprogrammes. Therefore judgements that evidence is ‘limited — suggestive’ do not normally form the basis for recommendations.
As shown in the following pages, the goals and recommendations themselves are boxed. They begin with a general statement. This is followed by the public health goals
and the personal recommendations, together with any necessary footnotes. These footnotes are an integral part of therecommendations. The boxed texts are followed by passages
summarising the relevant judgements made by the Panel.
Then the specifications made in the public health goals andpersonal recommendations are explained. This is followed bypassages of further clarification and qualification as necessary: in special circumstances, the points made here are also

RECOMMENDATIONSBODY FATNESSBe as lean as possible within thenormal range of body weight
PHYSICAL ACTIVITY
Be physically active as part of everyday life
FOODS AND DRINKS THAT PROMOTE WEIGHT GAIN
Limit consumption of energy-dense foods
Avoid sugary drinks
PLANT FOODSEat mostly foods of plant origin
ANIMAL FOODS
Limit intake of red meat and avoid processed meat
ALCOHOLIC DRINKS
Limit alcoholic drinks
PRESERVATION, PROCESSING, PREPARATION
Limit consumption of salt
Avoid mouldy cereals (grains) or pulses (legumes)
DIETARY SUPPLEMENTS
Aim to meet nutritional needs through diet alone
BREASTFEEDING
Mothers to breastfeed; children to be breastfed
CANCER SURVIVORS
Follow the recommendations for cancer prevention

integral to the recommendations. Finally, guides showing
how people can sustain the recommendations are included.
The public health goals are for populations and so are primarily for health professionals, and are quantified whereappropriate. ‘Population’ includes the world population,national populations, and population groups such as schoolchildren, hospital patients, and staff who eat in canteens,generally or in specific settings. The personal recommendations are for people as communities, families, and as individuals. This allows for the fact that decisions on the choiceof foods and drinks are often taken communally or withinfamilies, or by the family members responsible for buying
and preparing meals and food, as well as by individuals.
Personal recommendations are best followed in conjunction
with public health goals. For example, the recommendationthat people walk briskly for at least 30 minutes every day is373

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to enable them to increase their average physical activity
level (PAL) by about 0.1.
The Panel concludes that the evidence that high body fatness and also physical inactivity are causes of a number ofcancers, including common cancers, is particularly strong.
For this reason, the first three sets of goals and recommendations are designed as a basis for policies, programmes, andchoices whose purpose is to maintain healthy body weights
and to sustain physical activity, throughout life. The remaining five general recommendations are not in any order of priority; instead, they follow the order that their subjects
appear in the chapters in Part 2. After the eight general recommendations, there are two special recommendations, one
on breastfeeding and one for cancer survivors, that are targeted at specific groups of people.
These goals and recommendations are concerned withfood and nutrition, physical activity, and body fatness. Other
factors that modify the risk of cancer outside the remit ofthis Report, such as smoking, infectious agents, radiation,industrial chemicals, and medication, are specified in
Chapter 2 and throughout Chapter 7.
The Panel emphasises the importance of not smoking andof avoiding exposure to tobacco smoke.

BODY FATNESSBe as lean as possible within
the normal range1 of body weight
PUBLIC HEALTH GOALSMedian adult body mass index (BMI) to be
between 21 and 23, depending on thenormal range for different populations2
The proportion of the population that is overweightor obese to be no more than the current level,or preferably lower, in 10 years

PERSONAL RECOMMENDATIONS
Ensure that body weight throughchildhood and adolescent growth projects3 towards thelower end of the normal BMI range at age 21
Maintain body weight within
the normal range from age 21

Greater birth weight, and adult attained height
The evidence that the factors that lead to greater adult attainedheight, or its consequences, increase the risk of cancers of thecolorectum and breast (postmenopause) is convincing; and they
probably also increase the risk of cancers of the pancreas, breast(premenopause) and ovary. In addition, the factors that lead togreater birth weight, or its consequences, are probably a causeof premenopausal breast cancer. Also see chapter 6.
The Panel has agreed that height and birth weight are themselves unlikely directly to modify the risk of cancer. They aremarkers for genetic, environmental, hormonal, and nutritional
factors affecting growth during the period from preconception
to completion of linear growth. However, the precise mechanisms by which they operate are currently unclear. In addition,
they are known to have different associations with other chronic diseases such as cardiovascular disease. For these reasons, they
are not the subject of recommendations in this chapter.
Understanding the factors that influence growth, and how
they might modify the risk of cancer and other chronic diseases,
is an important question for future research, including the relative importance of genetic and environmental factors, andwhen in the life course nutritional factors might be most relevant. Identifying optimal growth trajectories that protect
health not only in childhood but also throughout life is a major
challenge for the research and public health communities.

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Avoid weight gain and increases inwaist circumference throughout adulthood
1‘Normal range’ refers to appropriate ranges issued by national governments or
the World Health Organization
To minimise the proportion of the population outside the normal range
3‘Projects’ in this context means following a pattern of growth (weight andheight) throughout childhood that leads to adult BMI at the lower end of thenormal range. Such patterns of growth are specified in International Obesity
Task Force and WHO growth reference charts
2

Evidence
The evidence that overweight and obesity increase the riskof a number of cancers is now even more impressive thanin the mid-1990s. Since that time, rates of overweight andobesity, in adults as well as in children, have greatly
increased in most countries.

The evidence that greater body fatness is a cause of cancersof the colorectum, oesophagus (adenocarcinoma), endometrium, pancreas, kidney, and breast (postmenopause) isconvincing. It is a probable cause of cancer of the gallbladder. Body fatness probably protects against premenopausal
breast cancer, but increases the risk of breast cancer overall.
This is because postmenopausal breast cancer is more common. The evidence that abdominal (central) fatness is a
cause of cancer of the colorectum is convincing; and it is a
probable cause of cancers of the pancreas and endometrium,and of postmenopausal breast cancer. Adult weight gain isa probable cause of postmenopausal breast cancer. Greaterbirth weight is a probable cause of premenopausal breast
cancer. Also see Chapters 6 and 7.

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Justification
Maintenance of a healthy weight throughout life may be oneof the most important ways to protect against cancer. This
will also protect against a number of other common chronic diseases.

P E R S O N A L

R E C O M M E N D AT I O N S

Box 12.3

Height, weight, and ranges ofbody mass index (BMI)

Height (ft, in)Public health goals

The points here are additional to those made in the footnotes
to the goals above.

5’2” 5’4” 5’6” 5’8” 5’10”

6’6’2” 6’4” 6’6”

275

120

264

110

253
242

40

231

105
100

35

37.5

95
90

32.5

85

220
209

30

198

27.5

80
75

187

25

176
165

23

70

18.5

Weight (lb)

5’

115

Weight (kg)Weight gain, overweight, and obesity are now generally
much more common than in the 1980s and 1990s. Rates ofoverweight and obesity doubled in many high-income countries between 1990 and 2005. In most countries in Asia andLatin America, and some in Africa, chronic diseases including obesity are now more prevalent than nutritional deficiencies and infectious diseases.
Being overweight or obese increases the risk of some cancers. Overweight and obesity also increase the risk of conditions including dyslipidaemia, hypertension and stroke, type2 diabetes, and coronary heart disease. Overweight in childhood and early life is liable to be followed by overweight andobesity in adulthood. Further details of evidence and judgements can be found in Chapters 6 and 8. Maintenance of ahealthy weight throughout life may be one of the mostimportant ways to protect against cancer.

4’10”

125

154

65

143

60

132

55

121

50

110

45

99

40
88
145 150 155 160 165 170 175 180 185 190 195 200
Height (cm)Underweight

Overweight

Extremely (morbidly) obese

NormalObese

Proposed additional cut offs
for Asian populations

Median adult BMI for different populations tobe between 21 and 23, depending on the normal range

To date, the range of normal weight has been usually identified as a BMI between 18.5 and 24.9; overweight and obesity has been identified as a BMI of 25 or over 30, respectively.
However, the evidence that is the basis for this Report does
not show any threshold at a BMI of 25. The relationshipbetween BMI and risk of disease varies between different populations (see chapter 8.4), and so the median population BMI
that accompanies lowest risk will vary. The Panel therefore recommends that the population median lies between 21 and 23,
which allows for this variation. Within any population, therange of individual BMIs will vary around this.
The proportion of the population that is overweight orobese to be no more than the current level,or preferably lower, in 10 years

The context for this goal, which like the others specified here
is designed as a guide for national and other population policies, is the current general rapid rise in overweight and obesity. The goal proposes a time-frame. Policy-makers areencouraged to frame specific goals according to their own
circumstances. The implications of the goal for countries
where there is a current increasing trend are that over the
10-year period, the increase would stop, and then rates ofoverweight and obesity would begin to drop.
While it is clear that obesity itself is a cause of some cancers and of other diseases, it is also a marker for dietary andphysical activity patterns that independently lead to poor
health.

In the chart above, a BMI between 18.5 and 25 is highlighted.
A BMI between 18.5 and 25 has conventionally been regarded as normal or healthy. BMIs under 18.5 represent underweight, which is unhealthy; BMIs between 25 and 30 are called
overweight; BMIs over 30 are called obesity; and BMIs over 40
are designated as extremely (morbidly) obese.
However, different cut-off points for overweight and obesity have been agreed in some countries; these cut-offs usually specify overweight at BMI less than 25, and obesity at BMI
less than 30. Such specifications should be used for and by people living in those countries. These are shown in dotted lines.
BMI is calculated using weight and height. Using the graphabove, a person who is 170 cm tall and weighs 68 kg has a BMI
within the normal range. To calculate BMI, divide weight (kg)by height (m) squared. Therefore, a person who is 1.7 m talland who weighs 68 kg has a BMI of 23.5.
It should be noted that BMI should be interpreted with caution, as in some cases it may be misleading, for instance in muscular people such as manual workers and some athletes, andolder people, children, or people less than 5 feet tall (152 cm).

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Personal recommendations

RECOMMENDATION 2

The points here are additional to those made in the footnotes
to the recommendations above.

PHYSICAL ACTIVITY
Be physically active as part of everyday life

Ensure that body weight through childhood andadolescent growth projects towards the lower end of thenormal BMI range at age 21

PUBLIC HEALTH GOALS

Maintain body weight within
the normal range from age 21

The proportion of the population that is sedentary1
to be halved every 10 years

These two related recommendations emphasise the importance of prevention of excess weight gain, overweight, andobesity, beginning in early life — indeed, in infancy andchildhood. As stated, the normal range of BMI is within 18.5
to 25, with some variation between countries; where theagreed range is different this should be used as the guide.
See box 12.3.
These recommendations do not mean that all healthy people within the normal range of BMI need necessarily aim tolower their BMI. However, people who have gained weight,
even within the normal range, are advised to aim to returnto their original weight.
People above the normal range of BMI are recommended
to lose weight to approach the normal range. See ‘Guidance’
and also recommendations 2 and 3.

Average physical activity levels (PALs)1 to be above 1.6

PERSONAL RECOMMENDATIONS
Be moderately physically active, equivalent
to brisk walking,2 for at least 30 minutes every day
As fitness improves, aim for 60 minutes or moreof moderate, or for 30 minutes or more ofvigorous, physical activity every day2 3Limit sedentary habits such as watching television

1

Avoid weight gain and increases inwaist circumference throughout adulthood

There may be specific adverse effects from gaining weight
during adulthood (see chapter 6.1.1.3), and so maintenanceof weight within the normal range throughout adult life isrecommended.
The World Health Organization reference values for waist
circumferences of 94 cm (37 inches) in men and 80 cm (31.5
inches) in women (on a population basis) are based on theirrough equivalence to a BMI of around 25, whereas waist circumferences of 102 cm (40.2 inches) in men and 88 cm(34.6 inches) in women are equivalent to a BMI of around
30. For Asian populations, cut-offs for waist circumferencesof 90 cm (35.4 inches) for men and 80 cm (31.5 inches) for
women have been proposed.
Guidance
This overall recommendation can best be achieved by being
physically active throughout life, and by choosing diets
based on foods that have low energy density and avoiding
sugary drinks.

People who are already outside the normal BMI range shouldseek advice from appropriately qualified professionals
with a view to returning towards the normal range.
However, for weight control, recommendations 1, 2, and 3
can be followed.

The term ‘sedentary’ refers to a PAL of 1.4 or less. PAL is a way of representing
the average intensity of daily physical activity. PAL is calculated as total energy
expenditure as a multiple of basal metabolic rate2
Can be incorporated in occupational, transport, household, or leisure activities
3
This is because physical activity of longer duration or greater intensity is more
beneficial

Evidence
The evidence that physical activity of all types protects
against cancer and also against obesity, and therefore indirectly those cancers whose risk is increased by obesity, hascontinued to accumulate since the early 1990s.

The evidence that physical activity protects against coloncancer is convincing. It probably protects against postmenopausal breast cancer and endometrial cancer. Also see
Chapter 5.
The evidence that physical activity protects against weight
gain, overweight, and obesity is convincing. The evidence
that sedentary living increases the risk of weight gain, overweight, and obesity is also convincing. Television viewing, aform of very sedentary behaviour, is probably a cause ofweight gain, overweight, and obesity. Also see Chapter 8.
Justification
Most populations, and people living in industrialised andurban settings, have habitual levels of activity below levels
to which humans are adapted.

With industrialisation, urbanisation, and mechanisation,
populations and people become more sedentary. As withoverweight and obesity, sedentary ways of life have been376

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usual in high-income countries since the second half of the20th century. They are now common if not usual in mostcountries.
All forms of physical activity protect against some cancers,
as well as against weight gain, overweight, and obesity; correspondingly, sedentary ways of life are a cause of these cancers and of weight gain, overweight, and obesity. Weight
gain, overweight, and obesity are also causes of some cancers independently of the level of physical activity. Further
details of evidence and judgements can be found in
Chapters 5, 6, and 8.
The evidence summarised in Chapter 10 also shows thatphysical activity protects against other diseases and thatsedentary ways of life are causes of these diseases.

P E R S O N A L

Average PALs for people in high income populations are
between around 1.4 and 1.6. PALs for people in the normal
range of BMI often average around 1.6. The Panel emphasises that the goal is to move above a PAL of 1.6. Levels of
1.7 and more are readily achieved by active and fit people.
See Chapter 5.
Personal recommendations

The points here are additional to those made in the footnotes
to the recommendations above.
Be moderately physically active, equivalent to brisk
walking for at least 30 minutes every day
As fitness improves, aim for 60 minutes or more ofmoderate, or for 30 minutes or more ofvigorous, physical activity every day

Public health goals

The points here are additional to those made in the footnotes
to the goals above.
The proportion of the population that is sedentary
to be halved every 10 years

As above, the context for this goal, which like the others specified here is designed as a guide for national and other population policies, is the current general rapid rise in sedentary
ways of life. Again as above, the goal proposes a time-frame.
Its achievement will require leadership from governments,
city planners, school boards, and others. Policy-makers areencouraged to frame goals according to their specific circumstances.
The recommendation takes account of the magnitude ofhealth gain expected from moving, even modestly, fromsedentary ways of life, compared to increasing the level ofactivity for already active people.
Average physical activity levels to be above 1.6

Table 12.1

R E C O M M E N D AT I O N S

These recommendations are linked. The first derives fromthe evidence on cancer. The second derives from the evidence on overweight and obesity, themselves a cause ofsome cancers. In making these two recommendations, thePanel also recognises that for people who have been habitually sedentary for some time, a first recommendation,
which is also meant to be intermediary, is sensible. Levelsof activity above those recommended here are likely to be
additionally beneficial, unless excessive, which may lead toan acute inflammatory response indicated by muscle pain
and vulnerability to infections.
Limit sedentary habits such as watching television

Watching television is a form of very sedentary behaviour.
Children may commonly watch television for more than
three hours a day, and are often also exposed to heavy marketing of foods that are high in energy and of sugary drinks
on television.

How to achieve a healthy physical activity level (PAL)

This table provides guidance on the impact of specific periods of activity on overall physical activity levels. Increasing activity can be achieved in manydifferent ways. See Chapter 5.
The table lists some examples of the effect on average daily PAL of doing different activities for different periods of time. The estimates are approximate
and rounded.
So for a person with a PAL of 1.6, an extra 30 minutes daily of moderate activity would increase PAL to around 1.7.
Category

Sedentary
Lying down quietly
Light
Walking slowly,
light gardening, housework
Moderate
Walking briskly, cycling,
dancing, swimming
Vigorous
Running, tennis, football

Increase in daily PAL Increase in daily PAL Increase in daily PAL Increase in daily PAL Increase in daily PAL(for 40 minutes(for an hour of(for 30 minutes(for 20 minutes of(for an hour ofactivity a week)
activity a day)of activity a day)of activity a day)
activity a day)
0

0

0

0

0

0.01

0.03

0.05

0.06

0.09

0.03

0.07

0.10

0.13

0.20

0.07

0.17

0.25

0.35

0.50

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Guidance
Most people can readily build regular moderate, and somevigorous, physical activity into their everyday lives.

Moderate physical activity can readily be built into everyday
life. It is not necessary to devote a continuous half hour every
day to moderate activity. With walking as an example, walkbriskly all or part of the way to and from work, or on local
errands, or at school; take a break for a walk in the middleof the day or the evening; use stairs rather than the elevator. The same applies to other moderate activities.
The best choice of vigorous physical activity is that which
is most enjoyable for the family or the individual — be it
swimming, running, dancing, rowing, cycling, hill walking,aerobic workouts, or team games such as football and badminton. Resistance and balance training are also beneficial.
Some sports and recreations such as golf are not vigorously
active. A good test that activity is vigorous is that it involves
sweating and raises heart rate to 60–80 per cent of its maximum.
People whose work is sedentary should take special careto build moderate and vigorous physical activity into theireveryday lives.
It is also important to avoid long periods of sedentary
behaviour, such as watching television. This behaviour is also
often associated with consumption of energy-dense food andsugary drinks.
A common misconception is that sport or exercise is the only
way in which to be physically active. Physical activity includes
that involved with transport (such as walking and cycling),
household (chores, gardening), and occupation (manual andother active work), as well as recreational activity.
See table 12.1 for guidance on how to achieve and maintain a healthy PAL. This table provides guidance on theimpact of specific periods of activity on overall PALs.
Increasing activity can be achieved in many different ways.
The table lists some examples of the effect on average daily
PAL of doing different activities for different periods of time.
The estimates are approximate and rounded. So for a person with a PAL of 1.6, an extra 30 minutes daily of moderate activity would increase their PAL to around 1.7.

3

FOODS AND DRINKS THATPROMOTE WEIGHT GAIN
Limit consumption of energy-dense foods1
Avoid sugary drinks2
PUBLIC HEALTH GOALS
Average energy density of diets3 to be lowered
towards 125 kcal per 100 g
Population average consumption of sugary drinks2
to be halved every 10 years

PERSONAL RECOMMENDATIONS
Consume energy-dense foods1 4 sparingly
Avoid sugary drinks2
Consume ‘fast foods’5 sparingly, if at all
1

Energy-dense foods are here defined as those with an energy content of morethan about 225–275 kcal per 100 g
This principally refers to drinks with added sugars. Fruit juices should also be
limited
3This does not include drinks
4
Limit processed energy-dense foods (also see recommendation 4). Relatively
unprocessed energy-dense foods, such as nuts and seeds, have not been shownto contribute to weight gain when consumed as part of typical diets, and theseand many vegetable oils are valuable sources of nutrients
5
The term ‘fast foods’ refers to readily available convenience foods that tend to
be energy-dense and consumed frequently and in large portions
2

Evidence
Evidence shows that foods and diets that are high in energy,
particularly those that are highly processed, and sugary drinks,
increase the risk of overweight and obesity. Some foods low
in energy density probably protect against some cancers.

Energy-dense foods and sugary drinks probably promoteweight gain, especially when consumed frequently and inlarge portions. Correspondingly, low energy-dense foods,(often relatively unprocessed) probably protect against weight
gain, overweight, and obesity. Specific types of low energydense foods, such as vegetables and fruits and foods containing dietary fibre, probably protect against some cancers.
Also see recommendation 4, Chapter 8, and box 12.4.
Justification
Consumption of energy-dense foods and sugary drinks isincreasing worldwide and is probably contributing to theglobal increase in obesity.

This overall recommendation is mainly designed to prevent andto control weight gain, overweight, and obesity. Further details

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of evidence and judgements can be found in Chapter 8.
‘Energy density’ measures the amount of energy (in kcal orkJ) per weight (usually 100 g) of food. Food supplies that are
mainly made up of processed foods, which often contain substantial amounts of fat or sugar, tend to be more energy-dense
than food supplies that include substantial amounts of fresh
foods. Taken together, the evidence shows that it is not specific dietary constituents that are problematic, so much as thecontribution these make to the energy density of diets.
Because of their water content, drinks are less energy-dense
than foods. However, sugary drinks provide energy but do notseem to induce satiety or compensatory reduction in subsequent energy intake, and so promote overconsumption ofenergy and thus weight gain.
Public health goals

The points here are additional to those made in the footnotes
to the goals above.
Average energy density of diets to belowered towards 125 kcal per 100 g

Diets appropriately low in energy density are identified as
supplying around 125 kcal (or 525 kJ) per 100 g, excluding
any drinks. These of course will include foods whose energy
density is higher than this average.
Population average consumption of sugary drinks
to be halved every 10 years

The context for this goal, which like others specified here isdesigned as a guide for national and other population policies,
is the current general rapid rise in weight gain, overweight,
and obesity, especially in children and young people, and therapid rise in consumption of sugary drinks. As above, the goal
proposes a time-frame. Achievement of this challenging goal
implies support from regulatory authorities and from manufacturers of sugary drinks. Policy-makers are encouraged toframe goals according to their specific circumstances.
Personal recommendations

The points here are additional to those made in the footnotes
to the recommendations above.
Consume energy-dense foods sparingly

Energy-dense foods are here defined as those supplying morethan about 225–275 kcal (950–1150 kJ) per 100 g. Foods naturally high in dietary fibre or water, such as vegetables andfruits, and cereals (grains) prepared without fats and oils, areusually low in energy density. Non-starchy vegetables, roots andtubers, and fruits provide roughly between 10 and 100 kcal per
100 g, and cereals (grains) and pulses (legumes) between
about 60 and 150 kcal per 100 g. Breads and lean meat, poultry, and fish usually provide between about 100 and 225 kcal
per 100 g. Most foods containing substantial amounts of fats,oils, or added sugars, including many ‘fast foods’ as defined
here, as well as many pre-prepared dishes and snacks, baked
goods, desserts, and confectionery, are high in energy density.

P E R S O N A L

R E C O M M E N D AT I O N SThis recommendation does not imply that all energy-dense
foods should be avoided. Some, such as certain oils of plantorigin, nuts, and seeds, are important sources of nutrients;
their consumption has not been linked with weight gain, andby their nature they tend to be consumed sparingly.
Avoid sugary drinks

This recommendation is especially targeted at soft drinks(including colas, sodas, and squashes) with added sugars.
Consumption of such drinks, including in ‘super-sizes’, hasgreatly increased in many countries. The evidence that suchdrinks ‘fool’ the human satiety mechanism, thereby promoting
weight gain, is impressive. They are best not drunk at all. The
implication of this recommendation is to prefer water. Lowenergy soft drinks, and coffee and tea (without added sugar),are also preferable. Fruit juices, even with no added sugar, arelikely to have the same effect and may promote weight gain,
and so they should not be drunk in large quantities.
Consume ‘fast foods’ sparingly, if at all

As already stated, ‘fast foods’ does not refer to all foods (anddrinks) that are readily available for consumption. The term
refers to readily available convenience foods that tend to beenergy-dense, and that are often consumed frequently and inlarge portions. Most of the evidence on ‘fast foods’ is fromstudies of such foods, such as burgers, fried chicken pieces,
French fries (chips), and fatty or sugary drinks, as served ininternational franchised outlets.
Guidance
Foods and diets that are low in energy density, and avoidanceof sugary drinks, are the best choices, in particular for people who lead generally sedentary lives.

The recommendation above can be best achieved by replacing energy-dense foods, such as fatty and sugary processed
foods and ‘fast foods’, with those of low energy density, suchas plant foods including non-starchy vegetables, fruits, and relatively unprocessed cereals (grains) (see recommendation 4),
and replacing sugary drinks with unsweetened drinks such as
water, and unsweetened tea or coffee.
The total energy content of diets is related not only to theenergy density of individual foods consumed, but also to thefrequency with which they are eaten and the portion size. The
physical capacity of the human stomach and digestive system
is limited. In general, people usually consume roughly thesame amount of food from day to day, measured by weight.
Energy-dense diets can undermine normal appetite regulationand therefore lead to greater energy intake.
Sugary drinks are a particular problem as these canbe drunk in large quantities without a feeling of satiety.
By replacing these foods and drinks with those of low energy
density, such as vegetables and fruits, relatively unprocessedcereals (grains) and pulses (legumes), water and non-caloric
drinks, the risk of weight gain is reduced, which therefore would be expected to reduce the risk of developing somecancers.

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RECOMMENDATION 4

PLANT FOODSEat mostly foods of plant origin

PUBLIC HEALTH GOALS
Population average consumption of non-starchy1
vegetables and of fruits to be at least 600 g (21 oz) daily2
Relatively unprocessed cereals (grains) and/or pulses(legumes), and other foods that are a natural source of
dietary fibre, to contribute to a population averageof at least 25 g non-starch polysaccharide daily

3•

R E C O M M E N D AT I O N S

carotenoids probably protect against cancers of the mouth,
pharynx, larynx, and lung; foods containing beta-carotene
probably protect against oesophageal cancer; and foods containing lycopene probably protect against prostate cancer.
Foods containing vitamin C probably protect against
oesophageal cancer; and foods containing selenium probably protect against prostate cancer. It is unlikely that foods
containing beta-carotene have a substantial effect on the riskof cancers of the prostate or skin (non-melanoma). It cannot be confidently assumed that the effects of these foods
can be attributed to the nutrient specified, which may be acting as a marker for other constituents in the foods. Also see
chapter 4.2.
Justification
An integrated approach to the evidence shows that mostdiets that are protective against cancer are mainly made up
from foods of plant origin.

PERSONAL RECOMMENDATIONS
Eat at least five portions/servings(at least 400 g or 14 oz) of a variety2 of
non-starchy vegetables and of fruits every day
Eat relatively unprocessed cereals (grains)
and/or pulses (legumes) with every meal3
Limit refined starchy foods
People who consume starchy roots or tubers4
as staples also to ensure intake of sufficientnon-starchy vegetables, fruits, and pulses (legumes)

1This is best made up from a range of various amounts of non-starchy vegetables
and fruits of different colours including red, green, yellow, white, purple, andorange, including tomato-based products and allium vegetables such as garlic
2
Relatively unprocessed cereals (grains) and/or pulses (legumes) to contribute toan average of at least 25 g non-starch polysaccharide daily
3
These foods are low in energy density and so promote healthy weight
4
For example, populations in Africa, Latin America, and the Asia-Pacific region

Evidence
The evidence that diets high in vegetables and fruits protect
against cancer is overall less compelling than in the mid1990s. However, vegetables and fruits, and other foods containing dietary fibre, probably protect against a number ofcancers.

Non-starchy vegetables probably protect against cancers ofthe mouth, pharynx, larynx, oesophagus, and stomach.
Allium vegetables in particular probably protect against cancer of the stomach. Garlic probably protects against cancersof the colon and rectum. Fruits probably protect against cancers of the mouth, pharynx, larynx, oesophagus, lung, andstomach. Also see chapter 4.2.
Foods containing dietary fibre probably protect against
cancers of the colorectum. Foods containing folate probably
protect against cancer of the pancreas. Foods containing

380

Higher consumption of several plant foods probably protects
against cancers of various sites. What is meant by ‘plantbased’ is diets that give more emphasis to those plant foods
that are high in nutrients, high in dietary fibre (and so in
non-starch polysaccharides), and low in energy density.
Non-starchy vegetables, and fruits, probably protect
against some cancers. Being typically low in energy density,
they probably also protect against weight gain. Further
details of evidence and judgements can be found in
Chapters 4 and 8.
Non-starchy vegetables include green, leafy vegetables,
broccoli, okra, aubergine (eggplant), and bok choy, but not,for instance, potato, yam, sweet potato, or cassava. Nonstarchy roots and tubers include carrots, Jerusalem artichokes, celeriac (celery root), swede (rutabaga), andturnips.
The goals and recommendations here are broadly similar
to those that have been issued by other international andnational authoritative organisations (see Chapter 10). They
derive from the evidence on cancer and are supported by evidence on other diseases. They emphasise the importance ofrelatively unprocessed cereals (grains), non-starchy vegetables and fruits, and pulses (legumes), all of which contain
substantial amounts of dietary fibre and a variety of micronutrients, and are low or relatively low in energy density. These,and not foods of animal origin, are the recommended centre for everyday meals.
Public health goals

The points here are additional to those made in the footnotes
to the goals above.
Population average consumption of non-starchy
vegetables and of fruits to be at least 600 g (21 oz) daily

This goal represents amounts well above average population
intakes in almost all parts of the world. Non-starchy vegetables exclude starchy roots and tubers (such as potatoes
and potato products).
In populations where most people consume at least 400 g

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of vegetables and fruits daily (see below), the average
consumption is likely to correspond roughly to at least
600 g per day.
Relatively unprocessed cereals (grains) and/or pulses(legumes), and other foods that are a natural source of
dietary fibre, to contribute to a population averageof at least 25 g non-starch polysaccharide daily

All cereals (grains) and pulses (legumes) undergo some formof processing before they can be consumed. Cooking is a formof processing. This goal is designed to emphasise the valueof wholegrains, and generally of plant foods naturally containing substantial amounts of dietary fibre. This does notinclude processed foods with forms of dietary fibre added, forwhich evidence of a protective effect is lacking. A total of 25
g of non-starch polysaccharide is roughly equivalent to 32 gof dietary fibre. Also see box 4.1.2 in chapter 4.1.
Personal recommendations

The points here are additional to those made in the footnotes
to the recommendations above.
Eat at least five portions/servings(at least 400 g or 14 oz) of a variety of
non-starchy vegetables and of fruits every day
Eat relatively unprocessed cereals (grains)
and/or pulses (legumes) with every meal
Limit refined starchy foods

These three linked recommendations also relate to the public health goals above. It is likely that there is further protective benefit from consuming more than five portions/servings of non-starchy vegetables and fruits. The recommendation on relatively unprocessed cereals (grains) andpulses (legumes) is designed to ensure that these become afeature of all meals. Refined starchy foods include products
made from white flour such as bread, pasta, pizza; white
rice; and also foods that are fatty and sugary, such as cakes,
pastries, biscuits (cookies), and other baked goods.
People who consume starchy roots and tubers
as staples to ensure intake of sufficientnon-starchy vegetables, fruits, and pulses (legumes)

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Other plant foods
Some plant foods are not the subject of goals or
recommendations.
Nuts, seeds, plant oils. The evidence on nuts, seeds, and plant oils,
and the risk of cancer, is not substantial. However, nuts and seeds
are sources of dietary fibre, essential fatty acids, and vitamins
and minerals. Though they are energy-dense, and so should be
eaten sparingly, they have not been associated with weight gain.
Similarly, modest amounts of appropriate plant oils can be usedas the primary form of fat for use in cooking and food preparation. See chapter 4.2.
Sugars. Sugars and also syrups in their various forms are refinedfrom cane, beet, or corn. The evidence on sugary drinks is strong
enough to generate goals and recommendations (3, above). The
evidence suggesting that foods containing substantial amountsof added sugars increase the risk of colorectal cancer is limited,and so the Panel has made no recommendation. However, thegeneral implication of the goals and recommendations madehere is that consumption of foods containing added sugars
would be limited. See chapter 4.6.

Guidance
Maintaining plant-based diets is easily done by planningmeals and dishes around plant foods rather than meat andother foods of animal origin.

Meat and other animal foods became centrepieces of meals
as a result of industrialisation, one consequence of which isthat meat becomes cheap. As stated above, foods of plantorigin are recommended to be the basis of all meals. A
healthy plate is one that is at least two thirds full of plantfoods; and instead of processed cereals and grains, wholegrain versions are better choices.
As stated in recommendation 3, vegetables and fruits are
generally low in energy density. Therefore, by consuming theamount of vegetables and fruits recommended above, andlimiting the amount of energy-dense foods consumed, people can reduce their risk of cancer directly, as well as the riskof overweight and obesity.
One portion of vegetables or fruits is approximately 80 g
or 3 oz. If consuming the recommended amount of vegetables and fruits stated above, average consumption will be atleast 400 g or 14 oz per day.

In many parts of the world, traditional food systems are
based on roots or tubers, such as cassava, sweet potato,yam, or taro. Traditional food systems should be protected:
as well as their cultural value, and their suitability to local
climate and terrain, they are often nutritionally superior to
the diets that tend to displace them. However, monotonoustraditional diets, especially those that contain only small
amounts of non-starchy vegetables, fruits, and pulses(legumes), are likely to be low in nutrients, which may
increase susceptibility to infection and so be relevant to therisk of some cancers.

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RECOMMENDATION 5

ANIMAL FOODS
Limit intake of red meat1 andavoid processed meat2

PUBLIC HEALTH GOAL
Population average consumption of red meat
to be no more than 300 g (11 oz) a week,
very little if any of which to be processed

PERSONAL RECOMMENDATION
People who eat red meat1
to consume less than 500 g (18 oz) a week,
very little if any to be processed2
1‘Red meat’ refers to beef, pork, lamb, and goat from domesticated animals
including that contained in processed foods
2‘Processed meat’ refers to meat preserved by smoking, curing or salting, oraddition of chemical preservatives, including that contained in processed foods

Evidence
The evidence that red meat, and particularly processed
meat, is a cause of colorectal cancer is stronger now than it
was in the mid-1990s.

The evidence that red meat is a cause of colorectal cancer isconvincing. The evidence that processed meat is a cause ofcolorectal cancer is also convincing. Cantonese-style salted
fish (see chapter 4.3, box 4.3.5, and also box 12.5) is a probable cause of nasopharyngeal cancer: this conclusion does
not apply to fish prepared (or salted) by other means. Milkfrom cows probably protects against colorectal cancer. Dietshigh in calcium are a probable cause of prostate cancer; thiseffect is only apparent at high calcium intakes (around 1.5
g per day or more). Also see chapters 4.3 and 4.4.
Justification
An integrated approach to the evidence also shows thatmany foods of animal origin are nourishing and healthy if
consumed in modest amounts.

People who eat various forms of vegetarian diets are at low
risk of some diseases including some cancers, although it is
not easy to separate out these benefits of the diets from otheraspects of their ways of life, such as not smoking, drinking
little if any alcohol, and so forth. In addition, meat can bea valuable source of nutrients, in particular protein, iron,zinc, and vitamin B12. The Panel emphasises that this overall recommendation is not for diets containing no meat —or diets containing no foods of animal origin. The amounts
are for weight of meat as eaten. As a rough conversion, 300
g of cooked red meat is equivalent to about 400–450 g raw

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weight, and 500 g cooked red meat to about 700–750 g raw
weight. The exact conversion will depend on the cut of meat,
the proportions of lean and fat, and the method and degreeof cooking, so more specific guidance is not possible.
Red or processed meats are convincing or probable causes of some cancers. Diets with high levels of animal fats areoften relatively high in energy, increasing the risk of weightgain. Further details of evidence and judgements can befound in Chapters 4 and 8.
Public health goal

The points here are additional to those made in the footnotes
to the goal above.
Population average consumption of red meat
to be no more than 300 g (11 oz) a week,
very little if any of which to be processed

This goal is given in terms of weekly consumption to encourage perception that red meat need not be a daily food. The
goal of 300 g or 11 oz a week corresponds to the level ofconsumption of red meat at which the risk of colorectal cancer can clearly be seen to rise. The evidence on processedmeat is even more clear-cut than that on red meat, and thedata do not show any level of intake that can confidently beshown not to be associated with risk.

Other animal foods
Many animal foods are not the subject of goals or recommendations.
Poultry, fish. The evidence on poultry and the risk of cancer is
not substantial. The evidence suggesting that fish protects
against colorectal cancer is limited. (Cantonese-style salted fish
is a special case — see chapter 4.3.) However, people who eat
flesh foods are advised to prefer poultry, and all types of fish, to
red meat. Flesh from wild animals, birds, and fish, whose nutritional profiles are different from those of domesticated andindustrially reared creatures, is also preferred. See chapter 4.3.
Eggs. The evidence on eggs and the risk of cancer is not substantial. There is no basis for recommending avoidance of eggs
to prevent cancer. See chapter 4.3.
Milk, cheese, other dairy products. The evidence on cow’s milk,cheese, and foods high in calcium, and the risk of cancer, is hardto interpret. The evidence on colorectal cancer and on prostatecancer seems to be in conflict. After long discussion, the Panelchose to make no recommendations here. See chapter 4.4.
Animal fats. The evidence suggesting that animal fats are a causeof colorectal cancer is limited. Animal fats are high in energy and
the Panel integrated the limited evidence suggesting that animal fats are a cause of overweight and obesity into its findings
on energy-dense foods. The implication is that it is best to limit
consumption of animal fats, as part of meat and also as contained in processed foods, in part because of the relation withcardiovascular disease. See chapter 4.5.

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R E C O M M E N D AT I O N SRECOMMENDATION 6

Personal recommendation

The points here are additional to those made in the footnotes
to the recommendation above.

ALCOHOLIC DRINKS
Limit alcoholic drinks1

People who regularly eat red meat
to consume less than 500 g (18 oz) a week,
very little if any to be processed

PUBLIC HEALTH GOAL

This recommendation relates to the goal above. In populations where most people consume less than 500 g (18 oz) a
week, the population average is likely to correspond to no
more than roughly 300 g (11 oz) a week.

Proportion of the population drinking
more than the recommended limits to be
reduced by one third every 10 years1 2

Guidance
There are many ways to enjoy meat and other animal foods
as part of plant-based diets.

For those who eat flesh foods, the amount of red meat consumed can be limited by choosing poultry and fish instead.
It is better also to consume the lean parts of red meat.
It is best that processed meats are avoided. They are generally energy-dense and can also contain high levels of salt(see recommendation 7). They also tend to be preserved bysmoking, curing, or salting, or with the addition of chemical preservatives. Some of these methods of preservation are
known to generate carcinogens; while the epidemiologicalevidence that these are causes of cancer is limited, it is a wise
precaution to avoid them. Processed meat includes ham,bacon, pastrami, and salami. Sausages, frankfurters, and ‘hotdogs’, to which nitrates/nitrites or other preservatives areadded, are also processed meats. Minced meats sometimes,
but not always, fall inside this definition if they are preserved
chemically. The same point applies to ‘hamburgers’. Freshmeats that have simply been minced or ground and thenshaped and cooked are not considered to be ‘processed’.
Substantial amounts of meat are not needed to sustain
adequate consumption of protein and iron. All flesh foods
are high in protein, and for people who consume varied diets
without any flesh foods, more than adequate protein can bederived from a mixture of pulses (legumes) and cereals(grains). Iron is present in many plant foods, as well as inmeat.

PERSONAL RECOMMENDATION
If alcoholic drinks are consumed,
limit consumption to no more than two drinks a day
for men and one drink a day for women1 2 3

1This recommendation takes into account that there is a likely protective effectfor coronary heart disease2Children and pregnant women not to consume alcoholic drinks
3
One ‘drink’ contains about 10–15 grams of ethanol

Evidence
The evidence that all types of alcoholic drink are a cause of
a number of cancers is now stronger than it was in the mid1990s.

The evidence that alcoholic drinks are a cause of cancers ofthe mouth, pharynx, and larynx, oesophagus, and breast(pre- and postmenopausal) is convincing. The evidence that
alcoholic drinks are a cause of colorectal cancer in men isconvincing. Alcoholic drinks are a probable cause of livercancer, and of colorectal cancer in women. It is unlikely that
alcoholic drinks have a substantial adverse effect on the riskof kidney cancer. Also see chapter 4.8.
Justification
The evidence on cancer justifies a recommendation not todrink alcoholic drinks. Other evidence shows that modest
amounts of alcoholic drinks are likely to reduce risk of coronary heart disease.

The evidence does not show a clear level of consumption of
alcoholic drinks below which there is no increase in risk of
the cancers it causes. This means that, based solely on theevidence on cancer, even small amounts of alcoholic drinks
should be avoided. Further details of evidence and judgements can be found in Chapter 4. In framing the recommendation here, the Panel has also taken into account theevidence that modest amounts of alcoholic drinks are likely
to protect against coronary heart disease, as described in
Chapter 10.
The evidence shows that all alcoholic drinks have the same
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depending on the type of drink. This recommendation therefore covers all alcoholic drinks, whether beers, wines, spirits (liquors), or other alcoholic drinks. The important factor
is the amount of ethanol consumed.
The Panel emphasises that children and pregnant womenshould not consume alcoholic drinks.

PRESERVATION, PROCESSING,
PREPARATION
Limit consumption of salt1
Avoid mouldy cereals (grains) or pulses (legumes)

Public health goal

The points here are additional to those made in the footnotes
to the goal above.

PUBLIC HEALTH GOALS

Proportion of the population drinking
more than the recommended limits to be
reduced by one third every 10 years

The context for this goal, which like the others specified here
is designed as a guide for national and other population policies, is the current common rise in regular and heavy consumption of alcoholic drinks, including among young
people. The focus of the goal is especially on those consuming above the recommended limits, rather than regularmodest drinkers. Again as above, the goal proposes a timeframe. Achievement of this goal requires substantial support
from regulatory authorities, the manufacturers of alcoholic
drinks, and from the owners of bars and other locations
where alcoholic drinks are sold and consumed. Policy-makers
are encouraged to frame goals according to their specificcircumstances.

Population average consumption of salt fromall sources to be less than 5 g (2 g of sodium) a day
Proportion of the population consuming more than 6 gof salt (2.4 g of sodium) a day to be halved every 10 years
Minimise exposure to aflatoxinsfrom mouldy cereals (grains) or pulses (legumes)

PERSONAL RECOMMENDATIONS
Avoid salt-preserved, salted, or salty foods;
preserve foods without using salt1
Limit consumption of processed foods with added salt
to ensure an intake of less than 6 g (2.4 g sodium) a day

Personal recommendation

The points here are additional to those made in the footnotes
to the recommendation above.
If alcoholic drinks are consumed,
limit consumption to no more than two drinks
a day for men and one drink a day for women

Modest consumption of alcoholic drinks has been shown tobe protective against coronary heart disease compared to no
drinking, with higher levels of drinking in some cases showing increased risk. Nevertheless, no authoritative body has
made specific recommendations for alcohol consumption to
avoid coronary heart disease because of the adverse biological, behavioural, physical, social, and other effects of higher levels of consumption.
For those who do consume alcoholic drinks, no more than
two drinks per day (men) and no more than one drink per
day (women) are the recommended limits. These limits are
expressed as amounts per day, because occasional heavy
drinking (say, at weekends) while at other times alcoholic
drinks are not consumed, is particularly likely to lead toadverse outcomes.
Guidance
For those people who choose to consume alcoholic drinks,
the Panel endorses the advice of other authoritative bodies.
These generally advise an upper limit of around two drinks
per day for men and one for women.

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Do not eat mouldy cereals (grains) or pulses (legumes)
1

Methods of preservation that do not or need not use salt include refrigeration,
freezing, drying, bottling, canning, and fermentation

Evidence
Some methods of food preservation, processing, and preparation affect the risk of cancer. The strongest evidence concerns processed meats, preserved by salting, smoking,pickling, addition of chemicals, and other methods (see recommendation 5, above); salt from all sources; and salt-preserved foods.

Salt and salt-preserved foods are probably a cause of stomach cancer: see chapter 4.6.
The Panel judges that refrigeration, while not likely to haveany direct effect on the risk of cancer, indirectly protects
against some cancers because it affects consumption of foods
which themselves influence the risk of cancer. For instance,
it may increase the availability and nutrient content of fresh,
perishable foods (vegetables and fruits; meat; milk; seechapters 4.2, 4.3, and 4.4); and decrease the need forprocessed foods (preserved by salting, smoking, curing, andpickling; see chapters 4.3 and 4.9). Also see recommendations 4 and 5, and box 4.6.4 in chapter 4.6.
Some plant foods, notably cereals (grains) and pulses(legumes), may be contaminated with aflatoxins, producedby moulds (fungi) during storage in hot and humid condi-

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tions. The evidence that aflatoxins are a cause of liver cancer is convincing. Also see chapter 4.1.

Limit consumption of processed foods with added salt
to ensure an intake of less than 6 g (2.4 g sodium) a day

Justification
The strongest evidence on methods of food preservation,
processing, and preparation shows that salt and salt-preserved foods are probably a cause of stomach cancer, andthat foods contaminated with aflatoxins are a cause of livercancer.

For most people, these two linked recommendations aredesigned to reduce salt consumption substantially. Usuallymost salt in diets is contained in processed foods. Some such
foods are obviously salty. Others, bread for example, usually do not taste salty, but bread and other cereal products area major source of salt in high-income countries, together
with many other industrially processed foods that may notappear ‘salty’. When preserving foods at home, methods thatminimise use of salt are recommended. Avoid the use of salt
at table.

Salt is necessary for human health and life itself, but at levels very much lower than those typically consumed in mostparts of the world. At the levels found not only in highincome countries but also in those where traditional diets arehigh in salt, consumption of salty foods, salted foods, andsalt itself, is too high. The critical factor is the overall amountof salt.
Microbial contamination of foods and drinks and of watersupplies, remains a major public health problem worldwide.
Specifically, the contamination of cereals (grains) and pulses (legumes) with aflatoxins, produced by some moulds
when such foods are stored for too long in warm temperatures is an important public health problem, and not only intropical countries.
Salt and salt-preserved foods are a probable cause of somecancers. Aflatoxins are a convincing cause of liver cancer.
Further details of evidence and judgements can be found in
Chapter 4.
Public health goals

The points here are additional to those made in the footnotes
to the goal above.
Population average consumption of salt fromall sources to be less than 5 g (2 g of sodium) a day
Proportion of the population consuming more than 6 gof salt (2.4 g of sodium) a day to be halved every 10 years

The reason for these linked goals, which like the others specified above are designed as a guide for national and otherpopulation policies, is the very high consumption of salt inmost countries. Again as above, one of the goals proposes atime-frame. This time-frame implies a continuing effort into
the future to achieve levels that might seem difficult within
a single decade. Its achievement implies support from regulatory authorities and from the manufacturers of salty andsalted foods. Policy-makers are encouraged to frame goals
according to their specific circumstances.
Minimise exposure to aflatoxinsfrom mouldy cereals (grains) or pulses (legumes)
Personal recommendations

The points here are additional to those made in the footnotes
to the recommendations above.
Avoid salt-preserved, salted, or salty foods;
preserve foods without using salt

Do not eat mouldy cereals (grains) or pulses (legumes)

The prudent approach is to avoid consumption of any cereals (grains) or pulses (legumes) that may have been stored

Other methods of preservationand preparation
Most methods of food preservation, processing, and preparation
are not the subject of goals or recommendations. Some of theseare of public interest and some are mentioned here.
Drying, fermenting, canning, bottling. There is no good evidence
that these methods of food preservation in themselves have any
effect on the risk of cancer. When they do not involve the use ofsalt, they are preferable to methods that do add salt. See chapter 4.9.
Refrigeration. The epidemiological evidence associating use ofrefrigeration with reduction of the risk of stomach cancer is substantial. The previous report judged this evidence to be convincing. The Panel responsible for this Report judged that the effectof refrigeration as such on cancer risk was not likely to be directly causative. Nevertheless, the benefits of industrial and domestic freezing, refrigeration, and chilling include availability ofperishable foods, including vegetables and fruits, all year round,protection against microbial contamination, and reduced need topreserve food by salting. In these respects, refrigeration is beneficial. Also see box 4.6.4 in chapter 4.6.
Additives, contaminants. There is little epidemiological evidence
on any relationship between food additives and contaminants,
whose use is subject to regulation, and the risk of cancer. Also see
chapter 4.9.
Steaming, boiling, stewing, baking, roasting, frying, grilling (broiling), barbecuing (charbroiling). While evidence suggesting that
grilled (broiled) and barbecued (charbroiled) animal foods are acause of stomach cancer is limited, there is evidence from experimental settings showing that carcinogens are formed whenmeats, animal foods, and some other foods are cooked at very
high temperatures, and most of all when they are exposed todirect flame. While the epidemiological evidence that these arecauses of cancer is limited, it is a wise precaution to avoid foods
cooked in this way. This effect is not found when foods are cookedby use of boiling water. Also see chapter 4.9.

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for a relatively long time in warm, ambient temperatures,
even if they show no visible signs of mould.

DIETARY SUPPLEMENTS
Guidance
At all stages in the food chain, from production to purchaseand storage ready for food preparation, prefer methods offood preservation, processing, and preparation that keep
perishable foods relatively fresh, and that do not involve theuse of salt.

Aim to meet nutritional needs
through diet alone1

PUBLIC HEALTH GOAL

Salt is just one way to add savour to foods. Many herbs andspices can be used instead. After a period of time of limiting the use of salt, taste sensitivity to it increases, preference
decreases, and the natural savour of food becomes apparent.
Food labels give some guidance. Products advertised as‘reduced salt’ may still be high in salt.
Keep food fresh by use of refrigeration. Discard food showing signs of mould (other than those such as some cheeses
manufactured by use of benign moulds).

Maximise the proportion of the population achieving
nutritional adequacy without dietary supplements

PERSONAL RECOMMENDATION
Dietary supplements are not recommended
for cancer prevention
1

This may not always be feasible. In some situations of illness or dietary
inadequacy, supplements may be valuable

Evidence
Randomised controlled trials have produced strong evidence
that high-dose supplements of some nutrients modify therisk of some cancers.

The evidence that high-dose beta-carotene supplements area cause of lung cancer in smokers is convincing. Calcium
probably protects against cancers of the colorectum.
Selenium in high doses probably protects against prostatecancer. It is unlikely that beta-carotene, or foods fortified
with this constituent, have a substantial effect on the risk ofcancers of the prostate or skin (non-melanoma). Also see
chapters 4.2 and 4.10.
Justification
The evidence shows that high-dose nutrient supplements
can be protective or can cause cancer. The studies that
demonstrate such effects do not relate to widespread use
among the general population, in whom the balance of risks
and benefits cannot confidently be predicted. A general recommendation to consume supplements for cancer prevention might have unexpected adverse effects. Increasing theconsumption of the relevant nutrients through the usual dietis preferred.

The recommendations of this Report, in common with its
general approach, are food based. Vitamins, minerals, andother nutrients are assessed in the context of the foods anddrinks that contain them. The Panel judges that the bestsource of nourishment is foods and drinks, not dietary supplements. There is evidence that high-dose dietary supplements can modify the risk of some cancers. Although somestudies in specific, usually high-risk, groups have shown evidence of cancer prevention from some supplements, thisfinding may not apply to the general population. Their level386

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of benefit may be different, and there may be unexpected
and uncommon adverse effects. Therefore it is unwise to recommend widespread supplement use as a means of cancer
prevention. Further details of evidence and judgements canbe found in Chapter 4.
In general, for otherwise healthy people, inadequacy of
intake of nutrients is best resolved by nutrient-dense dietsand not by supplements, as these do not increase consumption of other potentially beneficial food constituents. The
Panel recognises that there are situations when supplements
are advisable. See box 12.4.
Public health goal

P E R S O N A L

R E C O M M E N D AT I O N S

consuming nutritionally inadequate diets. In such cases ofimmediate need, supplementation is necessary. See box 12.4.
Personal recommendation

The points here are additional to that in the footnote above.
Dietary supplements are not recommended
for cancer prevention

This recommendation applies to self-administration of low(physiological) as well as high (pharmacological) doses ofsupplements, unless on the advice of a qualified health professional who can assess potential risks and benefits.

The points here are additional to that in the footnote above.
Maximise the proportion of the population achieving
nutritional adequacy without dietary supplements

In many parts of the world, nutritional inadequacy is endemic. In cases of crisis, it is necessary to supply supplements ofnutrients to such populations or to fortify food to ensure atleast minimum adequacy of nutritional status. The best
approach is to protect or improve local food systems so thatthey are nutritionally adequate. The same applies in highincome countries, where impoverished communities andfamilies, vulnerable people including those living alone, theelderly, and the chronically ill or infirm, are also liable to be

Box 12.4

Guidance
Choose nutrient-rich foods and drinks instead of dietary supplements.

This can be done by following all the recommendations
made here, in the context of appropriate general recommendations on food, nutrition, physical activity, and bodycomposition, designed to protect against disease and to promote health and well-being.

When supplements are advisable

The Panel judges that the use of supplements as possible protection against colorectal and prostate cancer should not be routinely recommended.
In general, as already stated, with secure food supplies andaccess to a variety of foods and drinks, when people follow therecommendations here in the context of general dietary recommendations, supplements are normally unnecessary.
Furthermore, in diets, nutrients are present in combinations
often not found in ‘multi’-supplements, and with other bioactive substances.
The Panel recognises, however, that dietary supplements, inaddition to varied diets, may at times be beneficial for specificpopulation groups. Examples include vitamin B12 for people
over the age of 50 who have difficulty absorbing naturally occurring vitamin B12, folic acid supplements for women who may
become or are pregnant, and vitamin D supplements for people who are not exposed to sufficient sunlight or some people(such as the elderly or people with dark skin) who do not synthesise adequate vitamin D from sunlight.
The Panel advises against self-administration of supplements asprotection against specific cancers. The findings on calcium andselenium apply in specific settings and specific doses. A recommendation for routine consumption in the general population
might show a different balance of risks and benefits. Advice forindividuals whose particular circumstances have been assessedis best given in a clinical setting in consultation with an appropriately qualified professional.

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SPECIAL RECOMMENDATION 1

BREASTFEEDING
Mothers to breastfeed; children to be breastfed1
PUBLIC HEALTH GOAL
The majority of mothers to breastfeed
exclusively, for six months2 3
PERSONAL RECOMMENDATION
Aim to breastfeed infants exclusively2
up to six months and continue
with complementary feeding thereafter3

1

Breastfeeding protects both mother and child‘Exclusively’ means human milk only, with no other food or drink, includingwater3
In accordance with the UN Global Strategy on Infant and Young Child Feeding
2

Evidence
The evidence on cancer supports the evidence on well-being,
positive health, and prevention of other diseases: at the
beginning of life, human milk is best.

The evidence that lactation protects the mother against
breast cancer at all ages is convincing. There is limited evidence suggesting that lactation protects the mother against
cancer of the ovary. Having been breastfed probably protects
children against overweight and obesity, and therefore thosecancers for which weight gain, overweight, and obesity area cause. Overweight and obesity in children tend to track
into adult life. Also see recommendation 1 and chapters 6.3,
7.10, and 8.
Justification
The evidence on cancer as well as other diseases shows thatsustained, exclusive breastfeeding is protective for the mother as well as the child.

This is the first major report concerned with the preventionof cancer to make a recommendation specifically on breastfeeding, to prevent breast cancer in mothers, and to prevent
overweight and obesity in children. Further details of evidence and judgements can be found in Chapters 6 and 8.
Other benefits of breastfeeding for mothers and their children are well known. Breastfeeding protects against infections in infancy, protects the development of the immature
immune system, protects against other childhood diseases,
and is vital for the development of the bond between mother and child. It has many other benefits. Breastfeeding is especially vital in parts of the world where water supplies are notsafe and where impoverished families do not readily have themoney to buy infant formula and other infant and young
child foods.

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need to be directed throughout the whole life course, fromthe beginning of life.
Public health goal

The points here are additional to those made in the footnotes
to the goal above.
The majority of mothers to breastfeed
exclusively, for six months

Sustained, exclusive breastfeeding was the norm until thedevelopment and marketing of infant formulas, which largely replaced breastfeeding in high-income and then in mostcountries by the second half of the 20th century.
While the practice of breastfeeding and exclusive breastfeeding has been increasing in many countries in recent
decades, in most countries now only a minority of mothers
exclusively breastfeed their babies until four months, and an
even smaller number until six months.
This is the context for this goal, which like the others specified here, is designed as a guide for national and otherpopulation policies. It does not imply that in any population
where over half of all mothers breastfeed exclusively forsix months that the ultimate goal has been reached: thegreater the proportion, the better. Its achievement will
require increased support from regulatory authorities andfrom the manufacturers of infant formulas. Policy-makers
are encouraged to frame goals according to their specificcircumstances.
The Panel emphasises the importance of exclusive breastfeeding (other than vitamin drops where locally recommended), with no other sustenance, including water.
There are special situations where breastfeeding is recommended with caution or is not advised. The main special
situation is when mothers have HIV/AIDS. On this, the UN
Global Strategy as revised in late 2006 states: ‘Exclusive
breastfeeding is recommended for HIV-infected women for
the first six months of life unless replacement feeding is
acceptable, feasible, affordable, sustainable, and safe forthem and their infants before that time.’
Personal recommendation

The points here are additional to those made in the footnotes
to the recommendations above.
Aim to breastfeed infants exclusively
up to six months and continue
with complementary feeding thereafter

This and the population goal are references to the UN Global
Strategy on Infant and Young Child Feeding, which isendorsed by the Panel. None of the phrasing of the goals andrecommendations here is designed to modify the Strategy,
which allows for special circumstances, including those inwhich mothers are not able to breastfeed their babies or mayotherwise be well advised not to do so.

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Guidance
On breastfeeding, the Panel endorses the UN Global
Strategy on Infant and Young Child Feeding.

SPECIAL RECOMMENDATION 2

It is universally agreed, by UN agencies, national governments, health professionals, civil society organisations, andthe infant formula and milk industries, that human milk is
the best food for infants and young children. Therefore, thisReport recommends that mothers breastfeed exclusively, forsix months, as recommended in the Strategy.

Follow the recommendations
for cancer prevention2

CANCER SURVIVORS1RECOMMENDATIONSAll cancer survivors3 to receive nutritional carefrom an appropriately trained professional
If able to do so, and unless otherwise advised,
aim to follow the recommendations for
diet, healthy weight, and physical activity2
1

Cancer survivors are people who are living with a diagnosis of cancer, including
those who have recovered from the disease2
This recommendation does not apply to those who are undergoing active
treatment, subject to the qualifications in the text
3
This includes all cancer survivors, before, during, and after active treatment

Evidence
The available evidence on cancer survivors has limitations.
It is of variable quality; it is difficult to interpret; and it has
not yet produced impressive results. The evidence for thisreview does not include the active treatment period.

The term ‘cancer survivor’ denotes people in a very wide
range of circumstances. It is unlikely that specific recommendations based on evidence applying to any one groupof people would apply to all cancer survivors.
In no case is the evidence specifically on cancer survivors
clear enough to make any firm judgements or recommendations that apply to cancer survivors as a whole, or to those
who are survivors of any specific cancer.
Justification
Subject to the qualifications made here, the Panel has agreed
that its recommendations apply also to cancer survivors.
There may be specific situations where this advice may not
apply, for instance, where treatment has compromised gastrointestinal function.

If possible, when appropriate, and unless advised otherwise
by a qualified professional, the recommendations of thisReport also apply to cancer survivors. The Panel has madethis judgement based on its examination of the evidence,
including that specifically on cancer survivors, and also on
its collective knowledge of the pathology of cancer and its
interactions with food, nutrition, physical activity, and bodycomposition. In no case is the evidence specifically on cancer survivors clear enough to make any firm judgements orrecommendations to cancer survivors. Further details of evidence and judgements can be found in Chapter 9.
Treatment for many cancers is increasingly successful, andso cancer survivors increasingly are living long enough todevelop new primary cancers or other chronic diseases. The

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recommendations in this Report would also be expected toreduce risk of those conditions, and so can also be recommended on that account.
Recommendations

In the special circumstances of cancer survivors, who until
they have recovered from the disease are in a clinical setting,the Panel decided not to separate public health goals and personal recommendations. The points here are additional tothose made in the footnotes above.
All cancer survivors to receive nutritional care froman appropriately trained professional

The circumstances of cancer survivors vary greatly. Given theincreased importance of food, nutrition, physical activity, andbody composition in cancer survival, people who havereceived a diagnosis of cancer should consult an appropriately trained health professional as soon as possible. The
advice received will be designed to take their personal situation and circumstances into account.
People who are undergoing surgical, chemical, or radiotherapy for cancer are likely to have special nutritional
requirements; as are people after treatment whose ability toconsume or metabolise food has been altered by treatment;
and people in the later stages of cancer whose immediateneed is to arrest or slow down weight loss. These are all clinical situations where the advice of an appropriately trained
health professional is essential.
The evidence does not support the use of high-dose supplements of microconstituents as a means of improving outcome. Cancer survivors should consult their physician and/or
a qualified nutrition professional, who can evaluate the safety and efficacy of specific dietary supplements, and counsel
appropriate action based on current research relevant to their
particular clinical situation.
All cancer survivors to aim to follow the recommendations
for diet, healthy weight, and physical activity

This general approach is for cancer survivors who are able,
and have not been advised otherwise, to follow the recommendations of this Report.
There is growing evidence that physical activity and othermeasures that control weight may help to prevent cancer
recurrence, particularly breast cancer. These findings are inline with the recommendations of this Report. Cancer survivors are also likely to gain health benefit, and a sense ofcontrol, from regular physical activity at levels that they cansustain.
Guidance

The general purpose of the recommendations made in thisReport is to ‘stop cancer before it starts’. Crucial support will
be given to cancer survivors who decide to follow the overall recommendations made in this chapter, when the people
living closest to them also make this choice. As well as giving crucial support and improving the quality of life of thecancer survivor, they will also be reducing their own risk ofcancer.
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12.3 Patterns of food, nutrition,and physical activity
Those responsible for reports such as this are faced with anumber of challenges. Information, even from highincome countries where most research is carried out, isincomplete and often patchy, and that from many
countries is fragmentary. Most modern research in the
nutritional and other biological sciences is highly focused.
Many researchers address not just what foods affect therisk of disease, but what specific agent or agents in thefood are responsible, or the exact biological pathway
involved. The amount of data produced by such studies ismultiplying and its sheer volume can obscure the generalview needed as a basis for public health goals andpersonal recommendations.
As a result, until relatively recently, expert reports
concerned with the prevention of disease tended to frame
their conclusions and recommendations in terms ofspecific dietary constituents being the most relevant
factors modifying the risk of disease. Thus, since the1960s, reports concerned with prevention of coronary
heart disease have recommended cuts in consumption ofsaturated fats and of dietary cholesterol. Such
recommendations, while staying closer to the science asusually carried out, and of value to planners of foodsupplies and in the formulation of manufactured food, areless effective as ways of encouraging healthy choices offoods and drinks. People consume foods and drinks, rather
than nutrients.
Also, what people eat and drink and how they behave
are only partly a matter of choice. Many other factors are
involved including income, climate, and culture. Althoughfood supplies are now becoming increasingly globalised,
the people of South India are not likely to move to meatbased diets, nor will most people in the USA adopt lentils
as staple foods.
More recently, some reports have adopted a food-based
approach to the prevention of disease and the promotionof well-being. This has presented the expert panels
responsible for reports such as this one with anotherchallenge. This is to review, assess, and judge the evidence
in ways that respect its nature, yet at the same time alsoseek to discern ‘the bigger picture’. A further challenge is
to identify healthy patterns of food, nutrition, and physicalactivity that allow for — indeed encourage — the diversity
both of traditional and modern food systems and cuisines.

12.3.1 The integrated approach
Since its work began, five years before publication of thisReport, the Panel has used a broad, integrative approach.
This, while largely derived from conventional ‘reductionist’research, has sought to find patterns of consumption of foods
and drinks, degrees of physical activity, and scale of bodycomposition that lead to recommendations designed to prevent cancer at personal and population levels.
This approach has proved to work. As recommendation 2
indicates, meticulous examination of the many studies on
physical activity and the risk of cancer shows that all types ofactivity — occupational, transport, domestic, recreational —do or may protect against some cancers. The type of activity
is evidently unimportant. Given the general tendency of populations living in industrialised and urbanised societies tobecome increasingly sedentary, this enables clear recommendations designed to encourage increased levels of physicalactivity.
At a more detailed level, the same point applies to alcoholic drinks, as indicated in recommendation 6. Many studies have been undertaken to examine the relationship of beer,wine, and spirits (liquor) to the risk of cancer — and to otherdiseases. Taken all together, these show that it is alcoholic
drinks in general — which is to say, the amount of ethanol
consumed — that are or may be a cause of some cancers.
Again, this enables the framing of clear recommendations
that take into account the effect of modest amounts of alcoholic drinks on the risk of coronary heart disease.
Recommendations 3, 4, and 5 also show how the integrated approach stays with the science and, by looking forpatterns, can create broad public and personal health messages. After particularly careful discussions, the Panel agreed
that a key factor determining vulnerability to weight gain,
overweight, and obesity, and thus to those cancers whose risk
is increased in these ways, is not so much specific foods,
drinks, or nutrients, but the relative energy density of diets.
This is not an obvious conclusion from the studies whose
results form the basis for this judgement. Up to now, epidemiologists have rarely used energy density as a concept in
the design of their studies.
Comparably, the vast amount of evidence on specific foods
and drinks does indeed show a more general pattern withvegetables and fruits, and with red and processed meat. In
framing recommendations 4 and 5, the Panel agreed that recommendations on these types of food should be seen in the
broader context of plant and animal foods. This is not a newconclusion. Plant-based diets, which is to say diets within
which foods of plant origin are more central than is typicalin industrialised and urbanised settings, are now commonly recognised as protective against some cancers. Again, thejudgement requires qualification, as has been done in thefootnotes and text. Many foods of animal origin are nour-391

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ishing, and only the evidence on red meat and on processedmeat is strong enough to justify specific recommendations.
Nevertheless, with such precautions, the Panel has agreed
that dietary patterns in which foods of plant origin are more
central, with red meat less so, are protective.
12.3.2 Nutritional patterns
The recommendations made in this Report do not specify
every major type of food and drink. In this sense they donot, taken together, amount to whole diets. Nevertheless,combined with the text that accompanies them, they arelikely to promote the nutritional adequacy of diets andhealthy body composition. For this and other reasons, they
will also be expected to help prevent nutritional deficiencies and related infectious diseases.
Thus, a diet based on these recommendations is likely tohave modest fat content (through limiting energy-dense
foods), especially in saturated fatty acids (limiting red andprocessed meat); to be relatively high in starch and fibre(from emphasis on relatively unprocessed plant foods
including cereals (grains)), while being low in sugar (dueto limiting energy-dense foods and sugary drinks). Overall,
the macronutrient profile is likely to be similar to that recommended in authoritative reports concerned more gener-Box 12.5•

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ally with prevention of other chronic diseases.
A number of the positive recommendations derive fromevidence on foods that contribute various micronutrients tothe diet. These, including relatively unprocessed cereals(grains), vegetables and fruits, and pulses (legumes), as wellas various foods of animal origin, would be expected to supply ample vitamin A (mostly in the form of carotenoids),
folate, other B vitamins including vitamin B12, vitamin C,
vitamin E, selenium, iron, zinc, potassium, and indeed
sodium.
12.3.3 Integration with national
recommendations
In national settings, the recommendations of this Report will
be best used in combination with recommendations issued
by governments or on behalf of nations, designed to prevent
chronic and other diseases. Also see box 12.5.
In the Panel’s judgement, based on its collective knowledge of food, nutrition, physical activity, and disease prevention, and also experience of national contexts, therecommendations here are likely to be harmonious withthose designed to prevent disease in specific countries, whichtake local and national dietary patterns, food cultures, andsocial and other circumstances into account.

Regional and special circumstances

The goals and recommendations specified
in 12.2 are generally relevant worldwide.
In three cases, evidence that is strong
enough to be the basis for goals and recommendations is of importance only in discrete geographical regions. That is not to
say that if the same foods or drinks wereconsumed elsewhere they would not havethe same effect, but rather that currently,
people in the rest of the world do not consume them. These are the herbal drink
maté, probably a cause of oesophageal cancer; Cantonese-style salted fish, probably acause of nasopharyngeal cancer; and contamination of water supplies with arsenic, acause of lung cancer and (probably) skincancer. The Panel considers that detailed
goals and recommendations in these cases
are most appropriately set by local and/or
regional regulatory authorities, other policy-makers, and health professionals in the
countries affected.
Maté
As stated in chapter 4.7 and elsewhere,
maté is a herbal infusion originally cultivated and drunk by the original inhabitantsin Argentina, Uruguay, and Rio Grande do
Sul in Brazil, where it is now adopted as astaple drink. Reports on the prevention ofcancer have identified maté as a cause or
possible cause of cancers of the oral cavity392

3

and oesophagus. The product is commonly
available in supermarkets in many countries, but the evidence shows that the causal
factor is maté drunk very hot through ametal straw often left resting on the lip, theform traditional within Latin America. It is
probable that the cause of cancer is not the
herb but the thermic effect.

RECOMMENDATION
Avoid consumption of maté as drunkin parts of Latin America, very hot andthrough a metal straw.
Cantonese-style salted fish
Cantonese-style salted fish, as stated inchapter 4.3 and elsewhere, is part of the
traditional diet consumed by people living
around the Pearl River Delta region insouthern China, and has been given to children, even as part of a weaning diet. This
style of fish is prepared with less salt thanused on the northern Chinese littoral, isallowed to ferment, and so is eaten in a
decomposed state. While it is also consumed by communities of emigrants fromthe Pearl River Delta in other countries, thisparticular preparation of fish is not otherwise an issue, and there is no goodevidence that other forms of preserved fish
affect the risk of cancer.

RECOMMENDATIONS
Avoid consumption of Cantonese-stylesalted fish.
Children not to eat this type of fish.

Arsenic in waterContamination of water supplies witharsenic is a different type of special case.
This may happen as a result of release ofindustrial effluents, and also because ofgeological and other environmental circumstances. High concentrations of arsenic
in drinking water have been found in areasof Bangladesh, China, and West Bengal(India); and also in more localised areas ofArgentina, Australia, Chile, Mexico, Taiwan,
China, the USA, and Vietnam. Arsenic isclassed as a carcinogen by the International
Agency for Research on Cancer.

RECOMMENDATIONS
Avoid use of any source of waterthat may be contaminated with arsenic.
Authorities to ensure thatsafe water supplies are available
where such contamination occurs.

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12.3.4 General patterns
The Panel has not been able to base its recommendations on
general patterns of food and nutrition, as stated above, on
evidence specifically directed towards that question. Reasonsfor this, as summarised in chapter 4.9, are that relatively few
epidemiological studies examine diets in an integrated form;
and of these, most do not define the nature of such diets ina way that can be compared with other studies. Those that
do, such as studies of Seventh-day Adventists, often examine the effects of whole ways of life, including factors that
may confound findings specifically on food, nutrition, andphysical activity.
For the future, the Panel recommends that protocols be
agreed to enable well conducted epidemiological studies tobe carried out on patterns of food, nutrition, and of physical activity, using agreed definitions and methods that allow
comparisons and detailed analyses.
A number of traditional and more modern food systems
generate a variety of climatically and culturally appropriate,
delicious, and nourishing cuisines that are harmonious withthe recommendations made here. These include the many
traditional cuisines of the Mediterranean littoral, and ofSouth-East and East Asia, and some diets devised since theindustrialisation and internationalisation of food systems.
The latter are often adaptations of traditional diets, enjoyedby people in higher income countries as part of generally
healthy ways of life.

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late 2008 will deal with the social and environmental factors that influence the risk of cancer, with appropriate recommendations.

12.3.5 Health, well-being, and ways of life
Throughout our work we, the members of this Panel, havebeen aware that prevention of cancer through changes tofood and nutrition, physical activity, and body composition
is a major global, regional, and national task; and also that
this work is one part of a greater task, to prevent disease andto promote well-being throughout the world, sustainably andequitably.
As part of this task, integrated and comprehensive programmes should be developed on cancer prevention, together with prevention of other chronic diseases, such as type 2
diabetes, cardiovascular diseases, osteoporosis, other chronic diseases, and also nutrient deficiencies and relevant infectious diseases, especially of early childhood. This approach,broader than any now undertaken within the UN system,
would need to be coordinated by relevant international andnational organisations.
All reports on the prevention of cancer must emphasise thefundamental importance of tobacco control, as we do here.
The one habit that most unequivocally is a cause of cancer
is smoking, and other use of and exposure to tobacco. Partly
because of its addictive nature, and for other reasons, tobacco smoking is not a simple matter of personal choice. Its
reduction requires vigilant commitment from governments
and civil society at all levels.
In general, ways of life — patterns of behaviour withinsocieties — are never just personal matters. In this Report,
we have concentrated our attention on nutritional and associated factors that affect the risk of cancer, and our goals andrecommendations here for populations and for people areframed accordingly. An associated report to be published in393 «« i  ` Vi Ã

Appendix A
Project process

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Appendix B
The first WCRF/AICR Expert Report

398

Appendix C
WCRF Global Network

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Glossary

402

References

410

Index

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AProject process
How this Report has been achieved

This Report follows, develops, and replaces Food, Nutrition
and the Prevention of Cancer: a global perspective, the firstreport commissioned by the World Cancer Research Fund
together with the American Institute for Cancer Research,which was published in 1997.
In 2001, WCRF and AICR agreed that it was time to commission a new report. Since the mid 1990s, the amount ofscientific literature on this subject has dramaticallyincreased. New methods of analysing and assessing evidence
have been developed, facilitated by advances in electronic
technology. There is more evidence, in particular on overweight and obesity and on physical activity. Examining food,nutrition, and physical activity in relation to cancer survivors
is a new field of study. The need for a new report was obvious, and a multilevel process involving global collaboration
was put in place.
Commissioning this Report

The goal of this second Report, Food, Nutrition, Physical
Activity, and the Prevention of Cancer: a Global Perspective,
has been to identify, review, and assess all the relevant
research to date. It has used the most meticulous methods
for assessment and review in order to generate a comprehensive series of recommendations on food, nutrition, andphysical activity suitable for all societies and designed toreduce the risk of cancer. The process has also been devisedas the basis for a continuous review that will keep the evidence updated into the future.
The process was organised into overlapping stages,
designed to ensure objectivity and transparency as well as
separation between the collection of evidence and the business of assessing and judging it. First, an expert task force
developed a method for systematic review of the voluminous
scientific literature. Second, research teams collected andreviewed the literature based upon this methodology. Third,
an expert Panel assessed and judged this evidence andagreed recommendations. The results are published in thisReport.
The whole project has taken six years, with the launch anddistribution of the second Report taking place in November
2007.
Agreeing the methodology

As a first stage, WCRF International developed an appropriate method for collecting, synthesising, analysing, and396

reporting the evidence. In 2002, a Methodology Task Forceof experts in nutrition, cancer, epidemiology, methodology,
and statistics was convened. This Task Force drew on theaccumulated experience of existing techniques to develop aunique new process. The methodology is described in a
Systematic Literature Review Specification Manual, which contains the instructions for conducting the systematic reviews.
The methods specified in the manual were tested at twocentres, one in the USA and the other in the UK, and as aresult the manual was modified. It has formed the basis of
all the reviews of the literature on food, nutrition, physicalactivity, and the risk of cancer for all relevant cancer sites
and on weight gain, overweight, and obesity.
Reviewing the literature

WCRF International then invited scientific centres to bid forthe work of systematic literature review (SLR), and contracted with nine institutions in Europe and North America
to conduct reviews of the literature on all cancer sites where
evidence of links with food, nutrition, and associated factors
was already apparent, as well as that on determinantsof overweight and obesity, and on authoritative reports concerned with other diseases. The project team from eachcentre included expertise in epidemiology, nutrition, cancer,
mechanisms, statistics, and project management. Teams
have been supported by a review coordinator — a memberof the WCRF International Secretariat. All reviews haveincluded the relevant epidemiological and experimental
literature.
Using the specification manual to ensure a comprehensive
and consistent approach to the analysis plus a common format for displaying the evidence, each centre undertook one
or more SLRs and produced a report on the evidence for eachcancer site. The reports were subject to peer review both at
the initial protocol stage and when the reports were submitted in complete form. They were then revised before
being summarised and submitted to the Panel. The systematic reviews present the findings of the review teams basedon the agreed protocol. They stop short of assessing or judging the strength and implications of the evidence.
Judging the evidence

The Panel of 21 experts was convened by WRCF
International in 2003 to develop the second Report.
Members of the Panel come from all the main continents andfrom 11 countries. Its collective expertise includes nutrition,

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cancer, obesity, other chronic diseases, physical activity, epidemiology, biochemistry, statistics, public health, and public policy. The Panel includes members of the Panel from thefirst WCRF/AICR report and relevant World HealthOrganization expert consultations, as well as observers from
the Methodology Task Force and the Mechanisms Working
Group and from six relevant United Nations and other international organisations. The Panel convened twice a year for
three- or four-day meetings between 2003 and 2007.
The Panel has been responsible for assessing the evidence
from the SLRs, for agreeing judgements based on theirassessments, and for agreeing a comprehensive set of recommendations. The Panel has also been responsible for identifying issues arising from this work that would beappropriate topics for future research.
For the next stage, the Panel, supplemented by additional expertise, examined the evidence on the determinants of
dietary and activity patterns, and of obesity, and the effectiveness of interventions from personal to population level.
Publication of this separate report is due in late 2008.
Managing the project

The second Report was commissioned by WCRF Internationaland has been funded and published by WCRF/AICR. WCRF

International set up a multilevel process to manage the project, and an Executive Team was established with the specific responsibility of directing it.
Executive Team:

Secretariat:
Advisory Group:

Executive body responsible for Report.
Composed of WCRF International and
AICR executives and advisors.
Manages the whole report process.
Guides the Executive Team and thePanel on policy and strategic andtechnical issues

The Secretariat has included WCRF International staff in the
UK, AICR staff in the USA, and consultants, including in thefollowing positions:
Project Director:

Overall responsibility for the reportand its scientific content. Chair of
Executive Team.
Chief Editor:
Responsible for editorial quality of thereport. Chair of Advisory Group.
Project Manager: Responsible for day-to-day
management of the project; Chair ofSecretariat.
Chapter Managers: Drive progress on chapters of thereport.
In addition to the work of producing the second Report, aCommunications Strategy Group from within the WCRF
global network was set up to be responsible for all aspectsof the promotion of the report before, during, and after its
launch in November 2007.
Keeping up to dateThis Report is meant to guide future scientific research, cancer prevention education programmes, and health policy
around the world. It provides a solid evidence base for policy-makers, health professionals, researchers, and informed
and interested people to draw on and work with.
WCRF International has been mindful that the literature
is continually expanding, and has commissioned a continuous review of the evidence. This process will be overseen by
an expert panel convened by WCRF International, responsible for assessing and judging the updated evidence as a basis
for recommendations and action to prevent cancer worldwide.

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BThe first WCRF/AICR
Expert Report
In September 1997, the World Cancer Research Fund and its
affiliate in the USA, the American Institute for Cancer
Research, jointly published Food, Nutrition and the Preventionof Cancer: a global perspective.
On publication, this 670-page WCRF/AICR report, in its
distinctive blue cover, and with its accompanying summary,
was immediately recognised as the most authoritative andinfluential in its field. It became the standard text worldwide
for policy-makers in government at all levels, for civil society and health professional organisations, and in teaching
and research for centres of academic excellence.
Responsibility for the first report and its conclusions andrecommendations was taken by a panel of scientists convened by WCRF/AICR, chaired by Professor John Potter.
Panel members came from Africa, Asia (India, China, Japan)
and Latin America, as well as Europe and the USA. The collective knowledge of the panel included nutrition, cancer,
other chronic diseases, energy balance, epidemiology,
biochemistry, toxicology, statistics, public health, and public
policy.
Official observers came from the World HealthOrganization, the International Agency for Research on
Cancer, the Food and Agriculture Organization of the United
Nations, and the US National Cancer Institute. The Panel,
supported by a WCRF Secretariat, held a series of seventhree-day meetings between 1993 and 1997.
Special features

The first report had a number of special features, adaptedand developed in this second Report. All its findings wereintroduced and summarised in plain language, to make thescience and its significance as clear and accessible as possible. This facilitated its use as a tool for policy-makers at alllevels from international government to municipalities,
schools, and hospitals, as well as the standard basis for academic teaching and practice.
The panel responsible for the first report concluded thatworldwide, around 4 million deaths each year are preventable by adoption of its recommendations. Part of the
purpose of the report was to show that prevention of cancer
by means of food, nutrition, and associated factors is as feasible and crucial as prevention of coronary heart disease. Its
recommendations take into account prevention of otherchronic diseases, and also prevention of nutritional deficiencies and food-related infectious diseases.
The conclusions of the first report were based on method-398

ical reviews of the epidemiological, experimental, and otherrelevant expert literature. The judgements of the panel were
presented in the form of matrices, adapted for this second
Report. This matrix approach, in which judgements such as‘convincing’ and ‘probable’ were displayed according to common specified criteria on the relative strength of evidence,
was pioneered in the first WCRF/AICR report.
The 14 recommendations of the 1997 report are foodbased. Taken together, they amount to whole diets judged
to give the best protection against cancer, other chronic diseases, and also other food-related diseases. The first report
also included a chapter on the public policy implications of
its recommendations. As part of the second Report process,this aspect is the subject of a separate report to be publishedin late 2008.
Impact and influence

WCRF/AICR has a special commitment to ensure that thework for which it is responsible has a global impact and thatits reports are placed in the right hands. Accordingly, over
30 000 copies of the first report and of its summary havebeen distributed throughout the world, to policy-makers ingovernment, to health professional and civil society organisations, to scientists responsible for research and prevention,and to all other qualified and interested people.
In addition, the report and its summary have been translated or adapted for a number of regions and countries,
including Latin America, China, Japan, India, Germany,
France, Italy, and the Asia-Pacific region.
The report has had a powerful impact on cancer prevention at all levels. Governments and authoritative organisations around the world use it to shape public health policy.
The 2003 WHO report, Diet, Nutrition and the Prevention ofChronic Diseases, the scientific basis for the WHO Global
Strategy on Diet, Physical Activity and Health, adapted themethods pioneered by WCRF to classify the strength of scientific evidence and to display evidence-based judgementsin the form of matrices.
Research scientists use the first report as a basis for theirwork. Academics and public health educators use it as thepre-eminent textbook. Having set the agenda in its field, it
is frequently cited in the academic and professional literature and at international scientific conferences. It has stimulated debate about how best to engage in a systematic andobjective interpretation of the scientific data on food, nutrition, and the prevention of cancer.

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T H E

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E X P E R T

R E P O R T

Directly, and also indirectly through its influence on professionals, it guides communities, families, and individuals
throughout the world as they make choices about their foodand nutrition, physical activity, and weight management.
The report has also been used as the basis for the research,education, and associated programmes of the WCRF global
network in the USA, the UK, the Netherlands, China (HongKong), and France, which together distribute tens of millionsof brochures and newsletters each year to assist their supporters and to fulfil their missions.
The first report laid solid foundations for this second
Report, which has developed its methods and made use of
the latest electronic technology in compiling, displaying, andassessing the evidence. The overall purpose of both reports
has been, and will remain, that of WCRF and AICR: to prevent cancer, worldwide.

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CThe World Cancer Research
Fund global network
Since its foundation in 1982, the World Cancer Research
Fund global network has been dedicated to the preventionof cancer. All the members of the global network have thesame mission: to prevent cancer worldwide.
Cancer is a global disease. Some types of cancer are morecommon in the higher income countries of Europe, North
America, and elsewhere. Other types are more common in
Africa and Asia and other lower-income parts of the world;
and as shown in Chapter 1 of this Report, these are among
the many compelling reasons why it is necessary to study
cancer from a global perspective in order to understand how
best to prevent cancer in any one country.
The WCRF global network consists of WCRF International
and its member organisations. These are national charities
based in the USA, the UK, the Netherlands, France, and Hong
Kong.
Each member organisation is supported by donations fromthe public and is independent of government. Each is a separate legal entity, responsible to its own board and accountable to the donors who support it. All member organisations
determine their own programmes, which are designed to be
most effective in national and local environments. Throughnational education and research programmes, a primary goalof the WCRF global network is to help promote changes thatwill decrease rates of cancer incidence. WCRF International
provides each member with financial, operational, and scientific services and support.

and support for individuals and their families to adopt
healthy ways of life. Public seminars and specific materials
for dieticians, scientists, parents, and children all ensure that
relevant information reaches these specific groups in appropriate formats and language. National websites provide
an immediate and interactive communication tool withthe facility for nutrition hot lines, recipe corners, and dailytips, in addition to access to the wide range of educational
materials.
Research

The global network funds research worldwide on the role offood, nutrition, physical activity, and associated factors in thecausation and prevention of cancer. There are two research
grant programmes within the network. One is operated by
WCRF International in London; the other is based with theAmerican Institute for Cancer Research, a member of the network, in Washington, DC. The programmes support epidemiological studies and basic laboratory research. In 2007,
the cumulative research funding by all members of the WCRF
global network amounts to over $US 105 million, supporting almost 800 projects and involving over a thousand scientists from 23 countries.
The research issues raised in Chapter 11 of this Report willbe the basis for setting new research priorities for the global network.
Global impact

Education

The extensive education programmes of the global network
encourage and enable individuals, families, and communities to make healthy choices. Until 2007, these were basedon the six Diet and Health Guidelines for Cancer Prevention,
developed from the recommendations made in the firstexpert report published in 1997 (see Appendix B).
All the global network’s education programmes reflect themost current research and the latest scientific agreements.
A prime purpose of this second Report is to provide the basis
for the WCRF global network’s education programmes from2007.
All network member organisations produce a wide varietyof publications. Collectively, these are the most extensive intheir field. They include a quarterly newsletter, booklets,
brochures, and leaflets covering many themes, from the latest information on antioxidants to suggestions for the quick
preparation of healthy meals. The emphasis is on easy tips

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In its first year in 1982, AICR, with the agreement of the US
National Academy of Sciences, reprinted the pioneering NAS
report on Diet, Nutrition and Cancer and distributed it to policy-makers, opinion-formers, and health professionals
throughout the USA. The findings and recommendations of
the NAS report became the first basis for the education andother programmes of AICR.
Following the foundation of WCRF in the UK in 1990, thedecision was taken to commission a new report with a global perspective. This work took five years. The result was thefirst report, published by WCRF together with AICR in 1997(see Appendix B). With the development of the global network, the science in the field, and new understanding of thecauses of cancer, the decision was taken in 2001 to commission this second Report, which has also been a five-year
task. This Report will enable the global network to deliver
the most current and reliable advice on food, nutrition, physical activity, body composition, and associated factors, inA P P E N D I X

C •

T H E

W O R L D

C A N C E R

R E S E A R C H

order to reduce the risk of cancer. It replaces the 1997 reportas the leading work of reference and basis for action in thefield, throughout the world.
The global network is already committed to continue thiswork by continuous updating and evaluation of the scientific evidence. This commitment means that the network is
now able to offer the best and most reliable advice now andalso in the future.
The global network is also proud of its work done in association with United Nations and other authoritative international and national organisations. This work is concernedwith the prevention of cancer, and also the prevention ofother diseases. The methods and findings of the first and
now this Report are offered as a basis for the work of otherorganisations that are also committed to the prevention of
disease and the promotion of health and well-being, worldwide.
Our membership

World Cancer Research Fund International is the associationthat coordinates the global network. The greatest impact canbe achieved when allied organisations work together.
Founded in 1999 and based in London and the USA, WCRF
International maximises the potential of each member organisation, and strengthens their work. The commissioning andfunding of this Report, and provision of the secretariat, is an
example of all members of the global network combining
together. This has required collaboration on a global basis,in the interests of the network and all its members, and tofurther their joint mission.
Founded in 1982, The American Institute for Cancer
Research was the first organisation to focus exclusively on thelink between diet and cancer, and became the first memberof the WCRF global network. Located in Washington, DC,
AICR is now one of the largest cancer charities in the USA,funding scientific research and offering a wide range of education programmes.
World Cancer Research Fund UK became the second member of the global network when it was established in 1990.
Based in London, it is the UK’s leading charity in the field of
diet, nutrition, and cancer prevention, and is responsible forraising awareness of the diet and cancer link among scientists, public health officials, media, and the general public.
Wereld Kanker Onderzoek Fonds (WCRF NL) began workin 1994 in the Netherlands as the third member of the global network. Based in Amsterdam, it is the only Dutch char-F U N DG L O B A L

N E T W O R K

ity specialising in cancer prevention by means of food, nutrition, physical activity, and associated factors, and has alreadymade a major contribution to the acceptance of this message
in the Netherlands.
World Cancer Research Fund Hong Kong (WCRF HK) beganwork in 2002. As traditional Chinese diets have been
replaced by more western diets, patterns of cancer incidence
are changing. WCRF HK is playing a vital role, especially inworking with government health departments in Hong Kong,
to disseminate education and research programmes on cancer prevention.
Fonds Mondial de Recherche contre le Cancer (WCRF FR),
founded in 2004, is the latest member of the WCRF global
network. Based in Paris, WCRF FR is building its researchand education programmes, working with like-mindedorganisations to disseminate the vital information to help
people to make healthy choices and so reduce their risk ofcancer.
From its beginnings in the early 1980s, the WCRF global
network has consistently been a pioneer and a leader of
research and education on food, nutrition, physical activity,
and the prevention of cancer. The network has a special commitment to creation of the most reliable science-based recommendations and their translation into messages that form
the basis for action by professionals, communities, families,
and individuals.
This work is being done for these organisations in the USA,the UK, the Netherlands, France, and Hong Kong, and on
behalf of people in all countries. The global network willremain one of the leaders of the international cancer prevention movement, in the broader context of better personal and public health, worldwide.

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Glossary
Terms here are defined in the context of
this Report. Some terms may have othermeanings in other contexts.
Absorption
The movement of nutrients and other foodconstituents from the gut into the blood.
Acid-base balance
The appropriate acidity of the blood andtissues. Abnormal acid-base balance may
indicate a change in respiratory or metabolicstatus.
Adduct (see DNA adduct)
Adenocarcinoma
Cancer of glandular epithelial cells.
Adenosine triphosphate (ATP)The principal molecule used for storage andtransfer of energy in metabolic processes.
Adipose tissue
Body fat. Tissue comprising mainly cells(adipocytes) containing triglyceride. It acts as
an energy reserve, provides insulation andprotection, and secretes metabolically active
hormones.
Adiposity rebound
The age at which body mass index (BMI)
increases after reaching a nadir at around 4–6
years of age. Earlier age of adiposity reboundhas been linked to later development ofobesity.
Adjustment
A statistical tool for taking into account theeffect of known confounders (see box 3.1).

Age-adjusted incidence
The number of events in a population, usually
expressed per 100,000 people, over a defined
period of time, adjusted for the varying
proportion of people in each age groupbetween populations and over time. It allows
for comparisons between countries withdifferent age structures (see box 7.1.1).
Alpha-linolenic acidAn essential n-3 polyunsaturated fatty acid
(C18:3 n3).
Amenorrhoea
The absence of menstruation.
Amino acidAn organic compound containing an aminogroup and a carboxylic acid group. The basic
building blocks of proteins such as enzymes.
Anaerobic metabolism
The process of producing ATP as a source ofenergy without oxygen, resulting in lactic acidaccumulation.
AndrogenAny masculinising sex hormone, such as
testosterone.
Angiogenesis
The process of generating new blood vessels.
Antioxidants
Any substance that inhibits oxidation or traps
or quenches reactive oxygen species
generated during metabolism.
Anthropometric measures
Measures of body dimensions.

Adrenarche
The period, typically between age 6 and 10
years, characterised by an increase in secretionof androgens from the adrenal cortex.

ATP (see adenosine triphosphate)

Aerobic metabolism
The normal process of producing ATP as asource of energy using oxygen.

Basal metabolic rate (BMR)
The amount of energy required to maintainthe essential body functions in resting andfasting conditions, expressed as megajoules,
kilojoules, or kilocalories per minute, hour, orday.

Aflatoxins
Naturally-occurring mycotoxins that are
produced by many species of Aspergillus, afungus, most notably Aspergillus flavus andAspergillus parasiticus. Aflatoxins are toxic andcarcinogenic to animals, including humans (seebox 4.1.4).

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Basal energy expenditure (see basal
metabolic rate)

Begg’s test
A statistical test for small study effects such as
publication bias.

Beta-glucans
Non-starch polysaccharides composed of
glucose subunits linked in such a way as torender them indigestible by pancreaticamylase. A major component of the cell wall
polysaccharides of oats (see non-starchpolysaccharides and dietary fibre).
Bias
In epidemiology, deviation of an observed
result from the true value in a particular
direction (systematic error) due to factors
pertaining to the observer or to study designor analysis. See also selection bias.
Bile
A greenish-yellow fluid secreted by the liverand stored in the gallbladder. Bile plays animportant role in the intestinal absorption offats. Bile contains cholesterol, bile salts, andwaste products such as bilirubin.
Biliary tract
The biliary tract includes the bile ducts within
the liver, the common bile duct, whichconnects the liver and gallbladder to the small
intestine, and the cystic duct, which connects
the gallbladder to the common bile duct.
Bioavailability
The degree to which a nutrient (or othersubstance) can be absorbed and used by thebody.
BMI (see body mass index)
BMR (see basal metabolic rate)
Body mass index (BMI)
Body weight expressed in kilograms divided by
the square of height expressed in metres (BMI
= kg/m2). It provides an indirect measure ofbody fatness. Also called Quetelet’s Index.
Caffeine
An alkaloid found in coffee, tea, kola nuts,
chocolate, and other foods that acts as a
stimulant and a diuretic.
Cancer survivor
Any person who has received a diagnosis ofcancer

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Cantonese-style salted fish
Fish that has been treated with varying
amounts of salt and dried in natural
conditions outdoors. It is characterised bytreatment with less salt than typically used
and is also subject to fermentation during
the drying process due to relatively highoutdoor temperature and moisture levels (seebox 4.3.5).
Carcinogen
Any substance or agent capable of causingcancer.
Carcinoma
Malignant tumour derived from epithelial
cells, usually with the ability to spread into thesurrounding tissue (invasion) and produce
secondary tumours (metastases).
Carcinoma in situ
The first stage of carcinoma in which themalignant tumour has not spread beyond theepithelium.
Cardiovascular disease
A group of diseases that involve the heart
and/or blood vessels (arteries and veins). While
the term technically refers to any disease that
affects the cardiovascular system, it is usuallyused to refer to those related toatherosclerosis.
Case-control study
An epidemiological study in which theparticipants are chosen based on their diseaseor condition (cases) or lack of it (controls) totest whether past or recent history of an
exposure such as smoking, genetic profile,alcohol consumption, or dietary intake isassociated with the risk of disease (see box
3.4).

Cerebrovascular disease
A group of diseases of the brain due todamage to the blood vessels, in which an areaof the brain is transiently or permanently
affected by ischaemia or bleeding.
Cholesterol
The principal sterol in animal tissues,
synthesised in the body; an essential
component of cell membranes and theprecursor of the steroid hormones andvitamin D.
Chromatin
Mass of genetic material in the nucleus of acell, composed of DNA and proteins thatcondense to form chromosomes.
Chronic disease
A disease that develops or persists over a long
period of time. Includes noncommunicablediseases such as cancer, cardiovasculardisease, and diabetes, and some infectious
diseases such as tuberculosis.
CI (see confidence interval)
Coeliac disease
Intolerance to the gliadin fraction of theprotein gluten from wheat, rye, and barley.
The villi of the small intestine atrophy andnutrient absorption from food is poor.
Stools are often bulky and contain a large
amount of unabsorbed fat.

CE
Common Era — the period of measured time
beginning with the year one on the Gregoriancalendar. The notations CE and BCE (Before
Common Era) are alternative notations for AD
and BC, respectively.

Cohort study
A study of a (usually large) group of people
whose characteristics are recorded atrecruitment (and sometimes later), followed
up for a period of time during which
outcomes of interest are noted. Differences in
the frequency of outcomes (such as disease)
within the cohort are calculated in relation todifferent levels of exposure to factors ofinterest, for example smoking, alcohol
consumption, diet, and exercise. Differencesin the likelihood of a particular outcome arepresented as the relative risk comparing one
level of exposure to another (see box 3.4).

Cell cycle
The sequence of stages that a cell passes
through between one cell division and thenext.

Compliance
The extent to which people such as study
participants follow an allocated treatment
programme.

Cell signalling
Mechanisms whereby cells send messages to,or respond to external stimuli from, othercells.

Computed tomography (CT)A form of X-ray that produces cross-sectionalor other images of the body.

Confidence interval (CI)A measure of the uncertainty in an estimate,usually reported as 95% confidence interval(CI), which is the range of values within which
there is a 95% chance that the true value lies.
For example the effect of smoking on therelative risk of lung cancer in one study may
be expressed as 10 (95% CI 5–15). This meansthat in this particular analysis, the estimate of
the relative risk was calculated as 10, and that
there is a 95% chance that the true value lies
between 5 and 15.
Confounder
A variable, within a specific epidemiologicalstudy, that is associated with an exposure, isalso a risk factor for the disease, and is not in
the causal pathway from the exposure to thedisease. If not adjusted for, this factor may
distort the apparent exposure–disease
relationship. An example is that smoking isrelated both to coffee drinking and to risk oflung cancer and thus, unless accounted for(controlled) in studies, might make coffee
drinking appear falsely as a possible cause oflung cancer (see box 3.1).
Confounding factor (see confounder)
Confounding variable (see confounder)
Cretinism
Underactivity of the thyroid gland(hypothyroidism) in infancy, resulting in poor
growth, severe mental retardation, anddeafness.
CT (see computed tomography)
CuringVarious preservation and flavouring processes,
especially of meat or fish, by the addition of a
combination of salt, sugar, and either nitrateor nitrite. Curing processes often involve
smoking. The addition of saltpetre (sodium
nitrate) gives a pinkish colour to meat.
Bacteria convert the nitrates in cured meats tonitrites and nitrosamines, which arepotentially carcinogenic to humans (see box
4.3.2).
Cytotoxic
Poisonous to living cells.
Deoxyribonucleic acid (DNA)The double-stranded, helical molecular chain
found within the nucleus of each cell thatcarries the genetic information.

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DEXA (see dual energy X-ray
absorptiometry)
Diabetes mellitus
A metabolic disorder involving impaired
metabolism of glucose due either to failure of
secretion of the hormone insulin (type 1
diabetes) or to impaired responses of tissues toinsulin (type 2 diabetes), which results incomplications including kidney failure,
blindness, and increased risk ofcardiovascular disease.
Dietary fibre
Constituents of plant cell walls that are notdigested in the small intestine. Several
methods of analysis are used, which identify
different components. The many constituentsthat are variously included in the definitions
have different chemical and physiologicalfeatures that are not easily defined under asingle term. The different analytical methods
do not generally characterise the physiologicalimpact of foods or diets. Non-starchpolysaccharides are a consistent feature andare fermented by colonic bacteria to produce
energy and short chain fatty acids including
butyrate. The term dietary fibre is increasingly
seen as a concept describing a particular aspectof some dietary patterns (see box 4.1.2).
Dietary supplement
A substance, often in tablet or capsule form,
which is consumed in addition to the usual
diet. Dietary supplements typically refer tovitamins or minerals, thoughphytochemicals or other substances may be
included.
Differentiation
The process of development of cells to take on
the structural and functional characteristics
specific to a particular tissue. Also, the degree
to which tumour cells have the structure orfunction of the organ from which the tumour
arose. Tumours can be described as well,moderately, or poorly differentiated: welldifferentiated tumours appear similar to thecells of the organ in which they arose; poorly
differentiated tumours do not. The degree ofdifferentiation is often of prognostic
significance.
Disaccharide
A carbohydrate composed of twomonosaccharides.
Diverticular disease
The presence of pouch-like hernias(diverticula) through the muscle layer of thecolon, associated with a low intake of dietary
fibre and high intestinal pressure due tostraining. Faecal matter may be trapped inthese diverticula, causing them to become
inflamed, causing pain and diarrhoea(diverticulitis).

DNA adducts
DNA adducts are compounds formed by thereaction of a chemical with DNA, which may
damage the DNA. If repaired, some adducts
can be excreted and measured in the urine as amarker of DNA damage. If not repaired, DNAmay function abnormally and may therefore
be a stage in carcinogenesis.
Docosahexaenoic acid (DHA)
A long-chain n-3 polyunsaturated fatty acid
(C22:6 n3).

Energy adjustment
The use of statistical methods to ‘adjust’intakes of a dietary factor under study for totalenergy intake (see box 3.7).

Dose response
A term derived from pharmacology that
describes the degree to which an effectchanges with the level of an exposure, forinstance the intake of a drug or food (see box
3.2).

Energy balance
The state in which the total energy absorbed
from foods and drinks equals total energy
expended. Also the degree to which intake
exceeds expenditure (positive energy balance)or expenditure exceeds intake (negative
energy balance).

Double bondA covalent bond between two carbon atoms
each with one hydrogen atom, for instance infatty acids.

EnzymeA protein that acts as a catalyst in livingorganisms, promoting chemical reactions andregulating the rate at which they proceed.

Dual energy X-ray absorptiometry (DEXA)
A means of measuring the density of different
body tissues such as bone or fat, using two Xray beams with differing energy levels.

Epidemic
A widespread or rapidly spreading disease that
affects many individuals in a population at thesame time, markedly in excess of the number
normally expected.

Dyslipidaemia
Any disorder of lipoprotein metabolism
resulting in abnormal plasma concentrations
or forms of lipoprotein, such as high total or
low-density lipoprotein (LDL) cholesterol
or triglyceride, and low high-density
lipoprotein (HDL) cholesterol concentrations.
Dysplasia
Abnormal development of the cells of a tissue.
Ecological study
A study in which differences in patterns of
exposure, for instance in consumption of aparticular nutrient or food, are compared ataggregate level, with populations (rather than
individuals) as the unit of analysis (see box 3.4).
Egger’s test
A statistical test for small study effects such as
publication bias.
Eicosapentaenoic acid (EPA)
A long-chain n-3 polyunsaturated fatty acid
(C20:5 n3).
Effect modifier/effect modification
Effect modification (or effect-measuremodification) occurs when a measure of effectfor an exposure changes over levels of
another variable (the modifier) (see box 3.6).
Emulsifier
A substance that promotes the formation of astable mixture, or emulsion, of two substancesthat do not normally mix well (for example oil
and water).

DNA (see deoxyribonucleic acid)
Endocrine
Referring to organs or glands that secrete
hormones into the blood.

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EnergyEnergy, measured as calories or joules, isrequired for all metabolic processes. Fats,carbohydrates, proteins, and alcohol fromfoods and drinks release energy when they aremetabolised in the body.

Epigenetic
Relating to the control of gene expression
through mechanisms that do not depend onchanges in the nucleotide sequence of DNA,for example through methylation of DNA oracetylation of histone.
Epithelial (see epithelium)
Epithelial-mesenchymal transition (EMT)
A disorder of cell differentiation where cells
assume a mesenchymal rather than anepithelial phenotype. Cancer cells may havephenotypic similarities to EMT.
Epithelium
The layer of cells covering internal andexternal surfaces of the body, including theskin and mucous membranes lining body
cavities such as the lung, gut, and urinary tract.
Essential amino acidAn amino acid that is required for normal
cellular structure and metabolic function but
which humans cannot synthesise and so mustobtain from food.
Evidence
Information that helps to determine whether
a proposal or belief is true or valid, or false orinvalid.
ExerciseA type of physical activity, often deliberatesuch as sport, which improves fitness or health.

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Exposure
A factor to which an individual may be
exposed to varying degrees, such as intake ofa food, level or type of physical activity, or
aspect of body composition.
Extracellular fluid
All body fluid not contained within cells.
Includes the fluid in blood vessels (plasma) andbetween cells (interstitial fluid).
Factor analysis
A statistical technique used to examine thestructure underlying the interactions between
several variables.
Fat-free mass
The mass of all body tissue excluding the lipid
components.
Fatty acid
A carboxylic acid with a carbon chain ofvarying length, which may be either saturated(no double bonds) or unsaturated (one ormore double bonds). Three fatty acids
attached to a glycerol backbone make up a
triglyceride, the usual form of fat in foods andadipose tissue.
Fermentation
The anaerobic metabolic breakdown ofmolecules such as glucose. Fermentation yields
energy in the form of lactate, acetate,ethanol, or other simple product.
Fetal programming (see programming)
Food systems
The interconnected agricultural, ecological,
economic, social, cultural, and technologicalsystems involved in food production,
distribution, and consumption.
Forest plot
A simple visual representation of the amountof variation between the results of theindividual studies in a meta-analysis. Their
construction begins with plotting theobserved exposure effect of each individual
study, which is represented as the centre of asquare. Horizontal lines run through this toshow the 95% confidence interval. Different
sized squares may be plotted for each of theindividual studies, the size of the box
increasing with the size of the study and theweight that it takes in the analysis. The overallsummary estimate of effect and its confidence
interval can also be added to the bottom of
this plot, if appropriate, and this isrepresented as a diamond. The centre of the
diamond is the pooled summary estimate andthe horizontal tips are the confidence intervals(see box 3.3).
Fortification
The deliberate addition of nutrients to foods
or drinks as a means of increasing the level ofintake in a population (see box 4.10.1).

Functional foodAny food, similar in appearance toconventional food, claiming to have specificphysiological effects that benefit healthand/or reduce the risk of disease. Products are
sometimes sold in medicinal forms (see box
4.10.2).
Gene expression
The active production of the RNA and proteinthat are coded for by a particular gene. In any
cell, not all genes are expressed (seeepigenetic).
Genetic modification
The manipulation of a living organism’s
genetic material by eliminating, modifying, or
adding copies of specific genes, often fromother organisms. Also known as ‘genetic
engineering’.
Germ cell (see germ line)
Germ line
Eggs and sperm and the cells that develop into
them, through which genetic information ispassed from generation to generation.
Genotype
The genetic makeup of a cell or organism.
GH (see growth hormone)
Gleason score
A quantitative measure of the degree ofdifferentiation of prostate cancers. High
Gleason scores, representing aggressive
disease, are associated with poor prognoses.
Whitemore and Jewett scales are used toassess prostate cancer stage.
Glycaemic index
A system for ranking foods containing
carbohydrates according to the effect of astandard amount on blood glucose levels.
Foods that raise the blood sugar the mosthave the highest glycaemic index (see box
4.1.3).
Glycaemic load
The glycaemic index of a food multiplied by
the number of grams of carbohydrate in theserving of food (see box 4.1.3).
GlycerolA three-carbon molecule that forms the
backbone of triglyceride in fats (see fattyacid).
GoitreEnlargement of the thyroid gland, seen as aswelling in the neck; may be hypothyroid, withlow production of thyroid hormone,
euthyroid (normal levels), or hyperthyroid(excessive production). Deficiency of iodine is
one cause.
Gross domestic product
The total market value of all the goods andservices produced within a nation in a given
year.

Growth hormone (GH)
Also known as somatotropin, a hormone
secreted by the pituitary gland that stimulates
secretion of growth factors from the liver andso also protein synthesis and growth of thelong bones in the legs and arms. It also
promotes the breakdown and use of fatty
acids, rather than glucose, as an energy
source.
Haem
The part of the organic molecule haemoglobin
in red blood cells containing iron to which
oxygen binds for transport around the body.
HerbicideA pesticide used to kill or control the growthof unwanted plants. Selective herbicides killcertain targets while leaving a desired crop
relatively unharmed. Non-selective herbicides
kill every plant with which they come into
contact.
Heterocyclic amines
A family of compounds formed from protein
and sugars in meat, chicken, and fish cookedat very high temperatures by grilling (broiling)or frying that have potential carcinogenic
effects (see box 4.3.4).
Heterogeneity
A measure of difference between the resultsof different studies addressing a similar
question. In meta-analysis, the degree ofheterogeneity may be calculated statisticallyusing the I2 test.
High fructose corn syrup (HFCS)A form of corn syrup that has undergone
enzymatic processing in order to increase its
fructose content. Used to sweeten soft drinks,
juices, ice cream, and many other processed
foods, especially in the USA (see box 4.6.1).
High-income countries
Countries with a gross average annual
national product of more than an agreed
figure per head (in 2006 this was more than
$US 10 726). This term is less judgemental andmore descriptive than ‘economicallydeveloped’ countries.
Homeostasis
The maintenance of biological conditions in astable state.
HormoneA substance secreted by specialised cells that
affects the structure and/or function of othercells or tissues in another part of the body.
Hydrogenation
The process by which unsaturated fatty acids
in vegetable oils are made more saturated by
the addition of hydrogen. This makes liquidoils more solid at room temperature and moreresistant to oxidation, for instance in the
manufacture of margarines. Incompletehydrogenation can lead to the formation oftrans-fatty acids (see box 4.5.1).

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Excessive thickening of the outer horny layerof the skin, affecting the palms and soles.
Hyperplasia
An increase in the number of cells in a tissue.
Hypertension
High blood pressure; a risk factor for
cardiovascular and kidney disease.
Hypoxia
Abnormally low levels of oxygen in blood ortissues.
IARC
International Agency for Research on Cancer(www.iarc.fr).
IGF binding proteinsProteins that bind to insulin-like growth
factors (which are implicated in the cancer
process, see Chapter 2) in the bloodstream.
Immune response
The production of antibodies or specialised
cells in response to foreign proteins or othersubstances.
Incidence rates
The number of new cases of a condition
appearing during a specified period of time
expressed relative to the size of the
population, for example 60 new cases ofbreast cancer per 100 000 women per year.
Inflammation
The immunologic response of tissues to injury
or infection. Inflammation is characterised byaccumulation of white blood cells that
produce several bioactive chemicals, causing
redness, pain, and swelling.
Inflammatory bowel disease
A term used to describe Crohn’s disease andulcerative colitis: both are characterised bychronic inflammation of the gut.
InsulinA protein hormone secreted by the pancreasthat promotes the uptake and utilisation of
glucose, particularly in the liver and muscles.
Inadequate secretion of, or tissue response to,insulin leads to diabetes mellitus.
Intrinsic sugars
Sugars naturally integrated into the cellular
structure of foods, for example those present
in unprocessed fruits and vegetables.
Intra-abdominal fat
Also known as visceral fat. Fat stored within
the abdomen surrounding the internal organs(see adipose tissue).
In uteroIn the uterus; refers to events that occur
before birth.
Invasive cancer
Tumours that spread into surrounding healthy
tissue.

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Iron-deficiency anaemia
A low blood concentration of haemoglobin
due to a deficiency of iron, due either tounusually high demands or low intake or
impaired absorption.
Irradiation
Exposure to ionising radiation. Foodirradiation is used to disinfest, sterilise, orpreserve food.
Jewett scale (see Whitemore and Jewettscales)K-ras
One of a class of genes (proto-oncogenes)
which when mutated can malfunction to
become an oncogene, promoting thetransformation of normal cells into cancer cells(see box 2.2).
Lactation
The production and secretion of milk by the
mammary glands.
Lacto-ovo-vegetarian diet
A vegetarian diet characterised by the
inclusion of eggs and dairy products, but noother animal products.
Latency
The period of time between the onset of adisease process and its detection or clinicalappearance.

Lymphocyte
Several types of white blood cell, part of theimmune system, found in the blood and lymph
glands.
Macronutrient
Those nutrient components of the diet thatprovide energy: carbohydrate, fat, andprotein; ethanol also provides energy but is
not a nutrient.
Magnetic resonance imaging (MRI)
A technique that produces images of parts ofthe body using analysis of the behaviour ofwater molecules within body tissues whenplaced in a strong magnetic field.
MalignantA tumour with the capacity to spread tosurrounding tissue or to other sites in thebody.
Melanoma
Malignant tumour of the skin derived fromthe pigment-producing cells (melanocytes).
Membrane potential
The difference in electrical charge across thecell membrane.
Menarche
The beginning of menstruation (see boxes 6.1
and 6.2).
MET (see metabolic equivalent)

Lean body mass
The mass of those parts of the body that are
not adipose tissue. Lean body mass includes
some lipid and is not synonymous with fatfree mass.
LesionA general term for any abnormality of cells or
tissues, including those due to cancerouschange.
Linoleic acidAn essential n-6 polyunsaturated fatty acid
(C18:2 n6).
LipidsNaturally occurring organic molecules that are
insoluble in water, including triglycerides;
fatty acids; phospholipids; lipoproteins;
carotenoids; cholesterol, which is aprecursor of steroid hormones and vitamin
D; and the other fat-soluble vitamins A, E, and
K. Lipids are an essential component of cell
membranes and many metabolic processes.
Low-density lipoprotein (LDL) cholesterol
A class of lipoproteins that is the major carrierof cholesterol in the blood in humans. A highblood LDL cholesterol concentration is a causeof coronary artery disease.
Low-income countries
Countries with a gross average annual
national product of less than an agreed
figure per head (in 2006 this was $US 875).
This term is less judgemental and more
descriptive than ‘economically developing’countries.

Meta-analysis
The process of using statistical methods tocombine the results of different studies.
Metabolic equivalent (MET)One MET equals the resting metabolic rate,measured as the rate of oxygen consumption,
which is approximately 3.5 millilitres of oxygen
per kilogram body weight per minute.
Equivalent to physical activity ratio (see box
5.1).
Metabolic syndrome
A common cluster of a variety of several risk
factors for cardiovascular disease including
insulin resistance, abdominal obesity, highblood pressure, and abnormal blood lipids.
Metastasis
The spread of malignant cancer cells to
distant locations around the body from theoriginal site.
Micronutrients
Vitamins and minerals present in foods andrequired in the diet for normal body function
in small quantities, conventionally of less than
1 g/day (see box 4.2.3).
Migrant study
A study of people who migrate from one
country to other countries with different
environments and cultural backgrounds. The
experience, such as mortality or disease
incidence, of the migrant group is comparedwith that of people in their current country ofresidence and in their country of origin.

G L O S S A R Y

MineralAn inorganic compound in food required by
the body for normal function, such as calcium,magnesium, and iron.
Monosaccharide
Simple sugar consisting of a single sugar
molecule, such as glucose, fructose, andgalactose. They form the basis of
disaccharides such as sucrose, and ofoligosaccharides, starch, and non-starchpolysaccharides.
MRI (see magnetic resonance imaging)
MucosalRelating to mucous membranes.
Mutagens
Chemical compounds or physical agents
capable of inducing genetic mutations.
Mycotoxins
Toxins produced by fungi (moulds), especiallyAspergillus flavus under tropical conditions
and Penicillium and Fusarium species undertemperate conditions (see box 4.1.4).
Neoplasm
A benign or malignant tumour.
Nested case-control study
A case-control study in which cases andcontrols are drawn from the population of acohort study; often used for studies ofprospectively collected information or
biological samples.
Neurotransmitter
A chemical secreted by one nerve cell that
stimulates a response in a neighbouring nerve
cell.
Night blindness
A condition in which a person has impaired
vision in the dark, characteristic of vitamin A
deficiency.
NitrateA salt containing the nitrate ion, whichcontains nitrogen and oxygen in proportion
1:3 (NO3). Derived from decomposing organic
material such as manure, plants, and humanwaste, and a component of chemical fertilisers(see box 4.3.2).
NitriteA salt containing the nitrite ion, whichcontains nitrogen and oxygen in proportion
1:2 (NO2). Sodium nitrite is added to many
processed meats. Nitrites are also formed in
the body from nitrates in plant foods that areeaten. When consumed, nitrites can lead tothe generation of N-nitroso compounds,
some of which are known carcinogens (seebox 4.3.2).
Nitrosamines
A group of chemicals formed by the reactionof nitrites with amines; some nitrosamines
are carcinogens (see box 4.3.2).

Non-caloric sweetener
A food additive that replicates the sweetnessof sugar but with negligible food energy (seebox 4.6.2).

Organic farming
Agricultural production system without orwith only limited use of pesticides, synthetic
fertilisers, growth regulators, and livestock
feed additives (see box 4.9.2).

Non-exercise activity thermogenesis(NEAT)The energy used in non-conscious orspontaneous physical activity, such as
fidgeting and posture maintenance.

Osteomalacia
A disease due to vitamin D deficiency
characterised by inadequate bonemineralisation, pain, and increased bone
fragility.

Non-milk extrinsic sugars
Sugars not present within the cellular
structure of foods, apart from those in milk or
milk products. For example those added tofoods or in juices, syrups, or honey.

Osteoporosis
Loss of the tissues of bone (bone cells, mineral,and protein) to an extent that increases therisk of fracture.

Non-starch polysaccharide
A carbohydrate comprising at least 10 simple
sugar molecules; a major component of plant
cell walls and the principal analytic fraction
characterising dietary fibre (see box 4.1.2).
Nucleic acid
The four building blocks of DNA – guanine,
thymine, cytosine, and adenine.
Nutrient
A substance present in food and required by
the body for maintenance of normal structureand function, and for growth anddevelopment. Nutrients include
macronutrients (fat, protein, andcarbohydrate), which provide energy as wellas performing metabolic and structuralfunctions, and micronutrients (vitamins andminerals), which do not provide energy but
are necessary for normal metabolic function.
Obesity
Excess body fat to a degree that increases therisk of various diseases. Conventionallydefined as a BMI of 30 kg/m2 or more.
Different cut-off points have been proposed
for specific populations.
Odds ratio
A measure of the risk of an outcome such as
cancer, associated with an exposure ofinterest, used in case-control studies;approximately equivalent to the relative risk.
Oligosaccharide
A compound comprising between 2 and 10
simple sugar molecules (monosaccharides).
Oncogene
A gene whose protein product contributes tothe transformation of normal cells into cancer
cells. Oncogenes result from the mutation of
normal genes called proto-oncogenes (see box
2.2).
Organic compounds
Any member of a large class of chemicalcompounds whose molecules contain carbon(and other elements), with exception ofcarbides, carbonates, and carbon oxides. Most
occur naturally only in the bodies andproducts of living organisms.

Oxidative damage
Damage to cells or structures in cells caused byoxidation, either by chemicals or by radiation.
Some oxidants are generated in the normal
course of metabolism. Oxidation of DNA isone cause of mutation.
p53
A protein central to regulation of cell growth.
Mutations of the p53 gene are importantcauses of cancer (see oncogene and box 2.2).
Pasteurisation
Partial sterilisation of foods at atemperature that destroys microorganisms
such as bacteria, viruses, moulds, yeast, andprotozoa without major changes in thechemistry of the food.
Pathogenesis
The origin and development of disease. The
mechanisms by which causal factors increase
the risk of disease.
Pedometer
An instrument that records the number ofsteps taken.
Peer review
The scrutiny of scientific papers by one ormore suitably qualified scientists.
PentosanA polysaccharide composed of pentose
sugars (with a ring comprising 5 carbon
atoms), for example arabans or xylans.
Phenotype
The characteristics displayed by an organism;
this depends on both the genotype andenvironmental factors.
Phosphorylation
Addition of phosphate groups to hydroxyl
groups on proteins, catalysed by a protein
kinase with ATP as phosphate donor. A key
process in cell signalling and energy
transfer.
Physical activity
Any movement using skeletal muscles.
Physical activity level (PAL)
Energy expenditure per day as a multiple ofbasal metabolic rate (BMR) (see box 5.2).

N-nitroso compound (see nitrosamines)407

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Physical activity ratio (PAR)The energy cost of an activity per minutedivided by the energy cost of basal
metabolic rate per minute. Thus, the energy
cost of sitting at rest is about 1.2; for walking
at a normal pace, 4; and for jogging, 7.

Processed meat
Meat (usually red meat) preserved bysmoking, curing, or salting, or by theaddition of preservatives. Definitions vary
between countries and studies as to what
precisely is included (see box 4.3.1).

Phytochemicals
Compounds found in plants not required fornormal structure or function, which may
modify physiological functions and influence
health (see box 4.2.1).

Programming
The process whereby events happening during
fetal life (fetal programming), such as growth
restriction, or in infancy can permanently
affect the structure and function of particularorgans, and so also metabolic processes.
Combined with other factors, this can in turn
alter the response to environmental
exposures and so susceptibility to disease.

Point estimate
An estimate that is reported as a single value.
The precision of a point estimate is indicatedby the width of the confidence interval thatsurrounds it.
Point mutation
Mutation of a single DNA base in a gene often
leading to a single peptide change in a
protein, which can influence its function.
Polycyclic aromatic hydrocarbons
A family of chemical compounds, including
several known carcinogens, formed byincomplete combustion of organic substancessuch as wood, coal, diesel, fat, or tobacco (seebox 4.3.4).
Polymorphisms
Common variations (more than 1 per cent of
the population) in the DNA sequence of agene.
Polyphenol
Any of a group of chemical substances foundin plants that have more than one phenolgroup per molecule; includes tannins, lignins,and flavonoids.

Promoter region
The region of DNA in a gene which initiates
the transcription of DNA to RNA when the
enzyme RNA polymerase binds to it.
Prostaglandins
A range of hormones derived from essential
fatty acids. Among many other processes,
they influence blood pressure andinflammation.
Publication bias
A bias in the overall balance of evidence inthe published literature due to selective
publication. Not all studies carried out are
published, and those that are may differ fromthose that are not. Publication bias can betested for with either Begg’s or Egger’s
tests.

Polyunsaturated fatty acids
Fatty acids containing two or more double
bonds.

Randomised controlled trial (RCT)
A study in which a comparison is madebetween one intervention (often a treatment
or prevention strategy) and another (control).
Sometimes the control group receives aninactive agent (a placebo). Groups are
randomised to one intervention or the other,so that any difference in outcome between thetwo groups can be ascribed with confidence tothe intervention. Neither investigators nor
subjects usually know to which condition they
have been randomised; this is called ‘doubleblinding’ (see box 3.4).

Pooled analysis (see pooling)

RCT (see randomised controlled trial)

Pooling
In epidemiology, a type of study where
original individual-level data from two or
more original studies are obtained, combined,
and re-analysed.

Reactive oxygen species
Oxygen-containing radical or reactive ion thatoxidises DNA (removes electrons); can behydroxyl radical (OH-), hydrogen peroxide(H2O2) or superoxide radical (O2-).

Positive energy balance (see energybalance)

Red meat
Meat from domesticated cattle, pigs, sheep,and goats; not poultry and fish or meat fromwild animals.

Polysaccharide
A polymer composed of multiple subunits ofmonosaccharides (simple sugars) linked
together.

Prebiotic
Dietary carbohydrate that reaches the colon,
where it promotes growth of beneficial
bacterial flora (see box 4.10.2).
Precursor
A chemical compound from which anothercompound is formed.

408

Refined sugars
Sugars obtained by purification from plants
which contain it, principally sugar cane or
beet.

Relative risk (RR)
The ratio of the rate of disease or deathamong people exposed to a factor, comparedto the rate among the unexposed, usually usedin cohort studies (see odds ratio).
Resting metabolic rate
Metabolic rate in a fasting subject sitting
quietly (also see basal metabolic rate).
Reverse causation
The situation when an abnormal level of an
exposure is caused by the cancer or its
treatment, rather than the other way round.
For example if cancer causes weight loss, thenthe finding that low BMI is associated withincreased risk may reflect weight loss due tocancer rather than low weight causing cancer.
Ribonucleic acid (RNA)The molecule created by RNA polymerase from
DNA (transcription) which carries the genetic
message to ribosomes (translation), where
proteins are made.
Rickets
Malformation of the bones in growing
children due to deficiency of vitamin D. In
adults the equivalent is osteomalacia.
RNA (see ribonucleic acid)
Salt iodisation
The practice of fortifying salt with iodide as ameans of ensuring adequate iodine intake.
Satiation
The development of fullness during eatingthat limits the size of a meal consumed (seesatiety).
Satiety
The suppression of appetite after eating that
inhibits the starting of eating (see satiation).
Saturated fatty acids
Fatty acids that do not contain any double
bonds.
Selection bias
Bias arising from the procedures used to selectstudy participants and from factors influencing
participation.
Single bondA covalent bond between two carbon atoms,
each with two hydrogen atoms, for instance insaturated fatty acids.
Single nucleotide polymorphism (SNP)
DNA sequence variation where a single
nucleotide in the DNA is altered. SNPs accountfor 90% of all human genetic variation (seepolymorphism and point mutation).
SLR (see systematic literature review)

G L O S S A R Y

Smoking (foods)
Smoking is the process of curing, cooking, orseasoning food by exposing it for long periodsof time to the smoke from a wood fire. ‘Hot
smoking’ is a process that can be used to fully
cook raw meats or fish, while ‘cold smoking’ isan hours- or days-long process that is generally
used to preserve or flavour foods (usuallymeats or fish, but sometimes cheeses,
vegetables, fruits).

Thermodynamics
The branch of physics concerned with thestudy of energy and its conversion between
different forms.

Weight cycling
Repeated abnormal losses and regains ofweight, often the result of repeated dietregimes.

Thermogenesis
The process of heat production. In adults,
arising from the metabolic processes during
the digestion and assimilation of food andduring shivering.

Whitemore and Jewett scales
A scale used to describe the stage of prostatecancer.

SNP (see single nucleotide polymorphism)

Tocotrienol
A form of vitamin E.

Socioeconomic status
A combined product of social and economic
status reflecting education level, personal
wealth, class, and associated factors.
Solvent
Substances (usually liquid) capable ofdissolving or dispersing one or more othersubstances.
Spontaneous physical activity (see nonexercise activity thermogenesis)
Squamous cell carcinoma
A malignant cancer derived from squamous
epithelial cells.
Stabiliser
One of a number of food additives, such asagar or pectin (used in jam, for example), thatgive foods a firmer texture. While they are nottrue emulsifiers, they help to stabilise
emulsions.
Statistical significanceThe probability that any observed result might
not have occurred by chance. In mostepidemiologic work, a study result whose
probability is less than 5% (p < 0.05) is
considered sufficiently unlikely to haveoccurred by chance to justify the designation‘statistically significant’ (see confidence
interval).
Stem cell
A cell that can self-renew or give rise to alineage of more differentiated cells.
Sterilisation
The destruction of bacteria or othermicroorganisms by heat, radiation, or
chemical means.
Steroid hormone
One of several hormones derived fromcholesterol and having a central effect on
growth and metabolism.
Supplement (see dietary supplement)
Systematic literature review (SLR)
A means of compiling and assessing publishedevidence that addresses a scientific question
with a predefined protocol and transparent
methods (see box 3.5).
Testosterone
An androgenic steroid hormone and theprincipal male sex hormone.

Total energy expenditure
The energy expended in a 24-hour period byan individual or a group of individuals. It
reflects the average amount of energy spentin a typical day, but may not be the exact
amount of energy spent each and every day.
Transcription
Synthesis of RNA from DNA by the enzyme
RNA polymerase.

WHO
World Health Organization (www.who.int).
Wholegrain
Cereal grain that retains the bran and germ as
well as the endosperm, in contrast to refined
grains that retain only the endosperm. Allcomponents of the grain are retained in theirusual proportions, though the term‘wholegrain’ may apply to products that
include other constituents, so that thecomplete product comprises less than 100%wholegrain (see box 4.1.1).
WHR (see waist to hip circumference ratio)

Transition cultures
Countries in the process of changing from one
predominant social/cultural structure toanother, for instance moving from lowerincome to higher-income status with theaccompanying changes that this implies.
Translation
The process by which RNA carries the genetic
message from DNA to generate proteins in
the ribosome.
Tumour suppressor geneA gene whose protein product inhibits tumour
formation (see also oncogene and box 2.2).
UICC
International Union Against Cancer(www.uicc.org).
Ulcerative colitis
A disease causing chronic inflammation of
the large intestine (colon). Together withanother disease of inflammation of theintestines called Crohn’s disease, referred to as
inflammatory bowel disease.
Underwater weighing
A method for estimating the proportions ofbody fat and lean mass. By comparing weightunderwater with weight on land, and taking
account of the different densities of fat andlean tissue, the proportions of fat and lean canbe calculated.
UVA/UVB
Ultraviolet light of different wavelengths.
UVA has relatively long wave lengths, UVB
relatively short.
Visceral fat (see intra-abdominal fat)
Waist to hip circumference ratio (WHR)
A measure of body shape indicating fat
distribution.

409

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IndexA
Abdominal fatness, 213–14, 225–7
breast cancer, 294
colorectal cancer, 225–6, 287–8
endometrial cancer, 227, 301
pancreatic cancer, 226, 273–4
Adaptation, weight gain, 324–5
Adaptive immunity, 38
Additives, 175–6, 385
Adipose tissue-derived oestrogen, 221
Adiposity rebound, early childhood, 232
Adrenal sex hormones, 232
Adult attained height, 231, 232–7
birth weight, 374
body fatness, 39
breast cancer, 233–5, 293–4
colorectal cancer, 232–3, 288
endometrial cancer, 237, 301–2
obesity, 39
ovarian cancer, 236–7, 297–8
pancreatic cancer, 235–6, 274
thyroid cancer, 318–19
Aflatoxins, 70, 279
dietary fibre, 72–3
liver cancer, 73
AIDS, 351–2
Alcohol, 39, 157–71
breast cancer, 165–8, 291
chronic disease, 354
colorectal cancer, 164–5, 286
composition, 158
consumption patterns, 159
definition, 158
evidence and judgements, 159–71
evidence interpretation, 159
kidney cancer, 170–1, 311
laryngeal cancer, 160–2
liver cancer, 168–70, 279
lymphoid and haemopoietic cancers, 320
mouth cancer, 160–2, 248
oesophageal cancer, 162–4, 257
pharyngeal cancer, 160–2
psychological effects, 157
public health goals, 383–4
recommendations, 383–4, 391
report comparisons, 171, 358
sources, 158
types, 159
Alkenylbenzenes, 175–6
Allium vegetables, 92–3, 267–8
colorectal cancer, 93–4
oesophageal cancer, 86
stomach cancer, 92–3
Alpha-carotene, 101
Alpha-linolenic acid, 136
Alpha-tocopherol, 187
prostate cancer, 109, 308–9
Amenorrhea, 240
Animal fatscolorectal cancer, 286
weight gain determinants, 338–9

506

Animal products
consumption trends, 11–12
goals and recommendations, 382–3
see also Meat
Antigrowth signal insensitivity, 42
Antioxidants, 38
Apoptosis evasion, 44–6
Appetite, 329
Arsenic, 150, 152–4, 392
bladder cancer, 153, 314
kidney cancer, 153, 311
lung cancer, 152, 262, 316
skin cancer, 152–3, 316–17
Ascorbic acid (vitamin C), 78, 107–8, 256
Asian diets, 191, 194
Asian populations, body mass index, 213
Aspergillus flavus, 70
Aspergillus parasiticus, 70
Australia, 27

B
Bacteria, 40
Baking, 176
Barbecuing, 177
Barrett’s oesophagus, 38, 254
Beerscomposition, 158
consumption patterns, 159
liver cancer, 169
mouth, pharynx, and larynx cancer, 161oesophageal cancer, 163
sources, 158
Beta-carotene, 185–7
lung cancer, 185, 263
oesophageal cancer, 103, 256
oral cancers, 101
prostate cancer, 105, 308–9
skin cancer, 105, 186–7, 317
Beta-cryptoxanthin, lung cancer, 102
Betel quid, oral cancers, 246
Binge drinking, 159
Biological pathways, 54–5
Biomarkers, 56, 363
Birth weight, 230
Black tea, consumption trends, 149
Bladder cancer, 153, 312–14
dairy products, 133
Egypt, 7evidence and judgements, 314
evidence interpretation, 313
milk and dairy products, 133previous report comparisons, 314
supplements, 346
trends, incidence, and survival, 312–13
Body composition, 210–42
Body fatness, 211–28
adult attained height, 39
assessment, 212
body mass index, 212, 325
breast cancer, 218–19, 292–3

I N D E X

classification, 214colorectal cancer, 216–18, 287
definitions, 212–14
distribution, 213
endometrial cancer, 221–3, 301
evidence and judgements, 214–28
evidence interpretation, 214
gallbladder cancer, 223–4, 276
kidney cancer, 223, 311–12
liver cancer, 224–5, 279–80
lung cancer, 224–5, 264
lymphoid and haemopoietic cancers, 320
measurement, 214
oesophageal cancer, 257–8
pancreatic cancer, 215–16, 273
patterns, 212–14
previous report comparisons, 228public health goals, 374–9
recommendations, 374–9
regulation, 327–9
reporting bias, 214
thyroid cancer, 318
Body mass index (BMI), 324, 375
body fatness, 212, 325
cancer survivors, 347
chronic diseases, 330
international trends, 13
principle cut-off points, 212–13
risk of death, 329
Boiling, 176, 385
Bottling, 175, 385
Brain growth, 230
Brain tumours, 321
Brazil, 28
Breakfast cereals, 68
Breast cancer, 289–95
abdominal fatness, 294
adult attained height, 233–5, 293–4
alcohol, 165–8, 291
birth weight, 294
body fatness, 218–19, 292–3
evidence and judgements, 291–5
evidence interpretation, 291
fat intake, 138, 294
inherited mutations, 290
international trends, 21
lactation, 240–1, 292
life events, 290
menarche, age of, 232
menopause status unspecified, physical activity, 204
pathogenesis, 290–1
physical activity, 204, 292
postmenopausal see Postmenopausal breast cancer
premenopausal see Premenopausal breast cancer
previous report comparisons, 295
radiation, 291
trends, incidence, and survival, 290
weight gain, 294
Western diets, 194
Breastfeeding, 193, 239–42, 331, 335–6
chronic disease, 354

dietary patterns in adulthood, 195–6
growth, 231
infectious diseases, 352
nutritional deficiencies, 351
public health goals, 388
recommendations, 388
urban-industrial food systems, 8
Broiling, 177
Butter, 139
colorectal cancer, 139
lung cancer, 139, 262
Butyrate, 43CCaffeine, sources, 151
Calcium, 43, 134, 187–8
colorectal cancer, 132–3, 286–7
foods containing, 131
prostate cancer, 134, 307
Cancercommon diagnoses, global, 17
hallmarks, 44
incidence measurement, 18–19
international trends, 17
other report findings, 355–8
outcomes, 56–7
principles of, 31
processes linked to, 33, 45
projected increase, 17
Cancer process, 30–46
carcinogen metabolism, 36–7
causes, 37–41
endogenous, 38–40
exogenous, 40–1
cellular, 32–6
nutritional influence, 41–6
principles of, 31–2
Cancer survivors, 342–7
definitions, 343–4
evidence interpretation, 344–5
judgements, 345–7
occurrence, 344
previous report comparisons, 347
public health goals, 389–90
recommendations, 389–90
supplement use, 346
Canning, 175, 385
Cantonese-style salted fish, 120, 392
nasopharyngeal cancer, 125–6, 252
Carbohydrates, 180
Carcinogenesis, 41–2
Carcinogens
cigarette smoke, 40
food, 41
metabolism, 36–7
Carotenoids, 78, 100–6
laryngeal cancer, 100–1
lung cancer, 101–2, 261
oesophageal cancer, 103oral cancers, 100–1, 248

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pharyngeal cancer, 100–1
prostate cancer, 103–5
skin cancer, 105–6
Carrots
cervical cancer, 94, 304
endometrial cancer, 92
oral cancers, 83–4
stomach cancer, 91
Case-control studies, 50–1
Catch up growth, 231
Cell cycle, 43
Cell proliferation, 42–4
Cell signalling, 33
Cellular cancer prevention, 41
Cellular cancer processes, 32–6
Cereals (grains), 67–74, 180
chronic disease, 353
composition, 69
consumption patterns, 11, 70–1
definitions, 68
dominant indigenous crops, 6
evidence and judgements, 71–3
interpretation, 71
infectious diseases, 351
recommendations, 385
report comparisons, 73, 358
sources, 68
wholegrain, 68, 336–7
Cervical cancer, 302–4
carrots, 94, 304
evidence and judgements, 304
human papilloma viruses, 303
international trends, 21
life events, 304
pathogenesis, 303
previous report comparisons, 304
tobacco use, 304
trends, incidence, and survival, 302–3
Cheese, 133–4, 286, 382
Chemical preservation, 175
Chewing tobacco, 246
Childhood obesity, 10, 326
Children, 335
Chilli, 113, 268
China, 10–11
Cholesterol, 136
Chronic disease, 352–5
Chronic inflammatory conditions, 38
Cigarette smoke, 40
Citrus fruits, 95, 96–7
Coffee, 148, 149, 152
decaffeinated, 149
kidney cancer, 155, 311
pancreatic cancer, 153–4, 273
previous report comparisons, 156
sources, 149
Cohort studies, 51
Colon anatomy, 281
Colorectal cancer, 280–8
abdominal fatness, 225–6, 287–8
adult attained height, 232–3, 288
alcohol, 164–5, 286
animal fats, 286
animal products, 284–5
body fatness, 216–18, 287
butter, 139
calcium, 187–8, 286
cheese, 133–4, 286
dietary fibre, 71–2, 282–3
evidence and judgements, 282–8
evidence interpretation, 282
fish, 125, 285

508

folate, 107, 284
fruits, 100, 283–3
international trends, 20
iron, 127
meat, 120–1
Mediterranean diets, 193–4
milk and dairy products, 132–4, 285
nitrates, 284
pathogenesis, 282
physical activity, 202–3, 287
previous report comparisons, 288
processed meat, 123, 284–5
selenium, 111–12, 189, 284, 287
sugars, 144–5, 286
tobacco use, 286
trends, incidence, and survival, 282
vegetables, 91, 93–4, 283
vitamin D, 125–6, 285
waist circumference, 225
waist to hip ratio, 225
Western diets, 194
Colours, added, 176‘Concentration’ biomarkers, 56
Contaminants, 175, 385
Conventional therapies, 345
Coronary heart disease (CHD), 352
CpG islands, 34
Crop availability differences, 11
Cruciferous vegetables, 37
endometrial cancer, 92
oesophageal cancer, 86
oral cancers, 83
Cultural dietary patterns, 192–3
Cyclin dependent kinases (CDKs), 42
CYP2EI, 37
Cytochrome P450, 36

D
Dairy products
bladder cancer, 133
chronic disease, 354
colorectal cancer, 132–3, 285
composition, 130
consumption patterns, 130–1
definition, 130
evidence and judgements, 131–4
evidence interpretation, 131
infectious diseases, 129–34, 352
lymphoid and haemopoietic cancers, 320
previous report comparisons, 134
prostate cancer, 307
recommendations, 382
sources, 130
testicular cancer, 319
see also Milk
Dansinger trial, 336, 337
Decaffeinated coffee, 149
Descriptive studies, 49
Development see Growth and development
Diallyl disulphide, 43
Dietary assessment methods, 55–6
Dietary constituents, 179–89
evidence and judgements, 183–9
interpretation, 183previous report comparisons, 189
Dietary fibre, 71–2
aflatoxins, 72–3
colorectal cancer, 71–2, 282–3
foods containing, 69, 80
liver cancer, 73
oesophageal cancer, 72, 255

I N D E X

weight gain determinants, 337–8
Dietary guidelines, 349
Dietary patterns, 190–6
characterisation, 190
cultural, 192–3
evidence and judgements, 193–6
previous report comparisons, 196traditional, 191–2
Dietary Patterns and Cancer (DIETSCAN), 195
Dietary recommendations, 180
Dietetics, 190
Diethylstilboestrol, 304
Diet interventions, adult, 333
Diets, 5–10
Differentiation, 35
Disaccharides, 142
DNA, 31–2, 33
damage, 35–6
methylation, 34
repair, 35–6
Dose response, 52‘Double blind’ RCT, 51
Dried milk, 130
Drink trends, 11–13
Drying, 174, 385E
Ebbeling trial, 336, 337
Ecological studies, 22–5, 49–50
Effect modification, 56
Eggs, 382
composition, 119consumption patterns, 120
definition, 117
infectious disease, 351
report comparisons, 358
sources, 117
Egypt, 6–7
Endometrial cancer, 299–302
abdominal fatness, 227, 301
adult attained height, 237, 301–2
body fatness, 221–3, 301
evidence and judgements, 300–2
meat, 122, 300–1
pathogenesis, 300
physical activity, 301
previous report comparisons, 302
trends, incidence, and survival, 299
vegetables, 92, 300
waist circumference, 227
waist to hip ratio, 227
Energycosts, 200–1
density, 324
intake, 328
output, obesity, 328
requirement, 328
Energy adjustment, 57
Energy balance, 328
body composition and, 330–1
Energy-dense foods
public health goals, 379
recommendations, 379
weight gain determinants, 338
Energy restriction, 46, 328
Environmental factors, 4
Epigenetic regulation, 34
Epstein-Barr virus, 251, 319
Ethanolbreast cancer, 167–8
colorectal cancer, 164–5

definition, 158
kidney cancer, 170liver cancer, 168–9
European Prospective Investigation into Cancer
and Nutrition (EPIC), 194
Evidence evaluation, 48–62
assessment methods, 55–7
causation and risk, 57–8
epidemiological, 49–52
experimental, 52–5
interpretation issues, 50
judgement, coming to, 58–62
Evidence grading criteria, 60–1, 62
Extrinsic sugars, 141–2

F
Familial adenomatous polyposis (FAP), 38, 282
Famines, 325
Fast food, 325, 339–40, 379
Fats and oils, 135–40, 180–1
breast cancer, 138, 294
composition, 136–7
consumption, 135, 137
definitions, 136
evidence and judgements, 138–9
evidence interpretation, 137–8
lung cancer, 138, 262
lymphoid and haemopoietic cancers, 320
production, 135
purpose, 136
quality, 136
report comparisons, 139, 358
sources, 136
Fat stores, peripheral, 213
Fatty acids, 136
Fermenting, 174–5, 385
Fibre see Dietary fibre
Fish, 125, 382
chronic disease, 353
colorectal cancer, 125, 285
composition, 118–19
consumption patterns, 12, 119
definition, 117
lymphoid and haemopoietic cancers, 320
report comparisons, 128, 358
sources, 117
thyroid cancer, 318
Fish oil supplements, 43
Flavonoids, 37
Flavours, added, 175–6
Flemming trial, 336, 337
Flores trial, 334, 337
Folate, 36, 43, 78, 106–7
colorectal cancer, 107, 284
metabolism, 37
oesophageal cancer, 106–7, 256
pancreatic cancer, 272–3
Food balance sheets, 13
Food-based approach, 60–1
Food consumption measurement, 13
Food diary, 55
Food frequency questionnaires, 55
Food preparation, 176–7, 384–6
Food preservation methods, 174–5, 384–6
Food processing, 175–7, 384–6
Food production methods, 172–4
chronic disease, 354
evidence and judgements, 177
evidence interpretation, 177
infectious diseases, 352
report comparisons, 177, 358

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Food-related disease prevention, 356–7
Food supply measurement, 13
Food systems, 5–10, 173, 190
Food trends, 11–13
Forest plots, 53
Fortification, 182
Foster trial, 336, 337
Fruit(s)chronic disease, 353
classification, 82
colorectal cancer, 100, 283–4
composition, 79
consumption patterns, 80–1
global consumption, 73
infectious diseases, 351
laryngeal cancer, 94–5
liver cancer, 100, 278–9
lung cancer, 97–9, 261
lymphoid and haemopoietic cancers, 320
nasopharyngeal cancer, 99, 251–2
nutritional deficiencies, 351
oesophageal cancer, 95–7, 255
oral cancers, 94–5, 247–8
pancreatic cancer, 99–100, 272
pharyngeal cancer, 94–5
recommended minimum daily amounts, 12
report comparisons, 114, 358
sources, 77
stomach cancer, 90, 98–9, 268
Fruit juices, 148–56
chronic disease, 354
composition, 151
consumption patterns, 151
definition, 149evidence and judgements, 152–6
evidence interpretation, 151–2
sources, 149
Frying, 177
Functional foods, 182

G
G1 phase, cell cycle, 42
G2 phase, cell cycle, 42
Gallbladder cancer, 223–4, 275–6
Gallstones, 275
Gamma-tocopherol, 109
Garlic, 93–4, 267, 283
Gatherer–hunter food systems, 5–6, 68
Gene expression, 33–4
Gene–nutrient interactions, 362
Genetic material, 31–2
Genetic modification, 174
Genetic polymorphisms, 362
Glucose, 142
Glucosinolates, 37, 43, 92
Glutathione-S-transferases (GSTs), 36, 73
Glycaemic index, 69, 180
Glycaemic load, 69
Grains see Cereals (grains)
Green tea, 150
Grilling, 177, 269, 385
Growth and development, 210–42
definitions, 230–1
evidence and judgements, 231–8
evidence interpretation, 231
patterns, 230–1
prepubertal, 230–1
previous report comparisons, 238
Growth factors, 39, 306
Growth hormones, 231
Growth phases, 230

510

Growth signal autonomy, 42
GSTM1, 37

H
Haemopoietic cancers, 318–20
Harvey Berino trial, 336, 337
Health Professionals Follow-Up Study, 194
Healthy diets, 193
trials, 345–6
Height, adult attained see Adult attained height
Helicobacter pylori, 40
in drinking water, 150
salt, 145–6
stomach cancer, 20, 266
Hepatitis virus, 73, 278
liver cancer, 278
Herbicides, 173
Herbs, 78, 113
Hereditary nonpolypopsis colorectal cancer (HNPCC), 282
Heterocyclic amines, 41, 119High birth weight, 230, 237–8
adult attained height, 374
breast cancer, 294
High fructose corn syrup, 141–2
High temperature food and drink, 155–6, 257
Histone structures, 33
HIV, 351–2
Hodgkin’s lymphoma, 319
Hormone replacement therapy (HRT), 219, 291
Hormones, 39–40, 290
Hot drinks, 148–56
chronic disease, 354
composition, 151
consumption patterns, 151
definition, 149–50
evidence and judgements, 152–6
evidence interpretation, 151–2
sources, 149–50
Household income surveys, 13
Human evolution, 324–5
Human feeding studies, 52–3
Human papilloma viruses, 303
cervical cancer, 303
Hydrogenation, 8, 136–7

I
Immune surveillance hypothesis, 38
India, 14–15
Indole-3-carbinol, 37
Industrial chemicals, 40–1
bladder cancer, 313
lung cancer, 260
stomach cancer, 266–7
Industrial cooking, 176
Industrial dietary patterns, 191–2
Industrial revolution, 7
Infant growth, 230–1
Infectious agents, 40, 351–2
bladder cancer, 313
stomach cancer, 266
Inferring causation, 57
Inflammation, 38–9
chronic conditions, 38
Inherited germ line mutations, 38
Inherited susceptibility, 244
Initiation, 41
Innate immunity, 38
Insulin, 43
Insulin-like growth factor 1 (IGF-1), 39
Insulin-like growth factors (IGF), 306

I N D E XInterleukin 6 (IL-6), 39
International Agency for Research on Cancer (IARC), 49
International Classification of Disease (ICD) codes, 57
International variations and trends, 4–29
foods and drinks, activity, and body composition, 11–22
food systems and diets, 5–10
Intestinal bacteria, 165
In vitro studies, 53–4
Ionising radiation, 40
Iron, 118, 127, 285
colorectal cancer, 127
Irradiation, 175
Irritant drinks, 150
Isothiocyanates (ITCs), 37

J
Japan, 17–18
Judgement, 58–62
levels and types, 59
robust, basis for, 61–2

K
Kidney cancer, 310–12
alcohol, 170–1, 311
arsenic, 153, 311
body fatness, 223, 311–12
coffee, 155, 311
evidence and judgements, 311–12
evidence interpretation, 311
pathogenesis, 310–11, 313
previous report comparisons, 312
tobacco use, 311
trends, incidence, and survival, 310
Western diets, 195

L
Lactation, 239–42
breast cancer, 240–1, 292
definition, 239–40
evidence and judgements, 240–2
evidence interpretation, 240
ovarian cancer, 242, 298
patterns, 239–40
previous report comparisons, 242
total duration, 241–2
Lactose, 130
Landmark reports, 349
Laryngeal cancer, 245–9
alcohol, 160–2
carotenoids, 100–1
evidence and judgements, 247–9
fruits, 94–5
maté, 155
pathogenesis, 246previous report comparisons, 249
trends, incidence and survival, 245–6
vegetables, 82–4
Leermarker’s trial, 332
Legumes see Pulses (legumes)
Leukaemia, 319
Life events
breast cancer, 290
cervical cancer, 304
ovarian cancer, 297
Life expectancy, by country, 9Linoleic acid, 136
Liquors see Spirits/liquors
Literature reviews, systematic, 54
Live animal models, 5Liver cancer, 277–80
aflatoxins, 73
alcohol, 168–70, 279
body fatness, 224–5, 279–80
dietary fibre, 73
evidence and judgements, 278–80
evidence interpretation, 278
fruits, 100, 278–9
hepatitis virus, 278
international trends, 20
pathogenesis, 278
previous report comparisons, 280
trends, incidence, and survival, 277–8
Low birth weight, 230
Low energy-dense food, 336
Lung cancer, 259–64
animal products, 262
arsenic, 152, 262, 316
beta-carotene, 185, 263
beta-cryptoxanthin, 102
body fatness, 224–5, 264butter, 139, 262
carotenoids, 101–2, 261
China, 10–11
evidence interpretation, 260
fats and oils, 138, 262
fruits, 97–9, 261
industrial chemicals, 260
international trends, 19meat, 121–2
pathogenesis, 260
physical activity, 206–7, 263–4
previous report comparisons, 264
processed meat, 124, 262
quercetin, 112, 262
retinol supplements, 184, 263
selenium, 109, 188, 261–3
tobacco use, 260
trends, incidence, and survival, 260
vegetables, 90–1, 261
Western diets, 195
Lycopene, 101, 103–4, 308
Lymphoid cancer, 318–20

M
Macronutrients, 180–1
Maltose, 142
Maté, 148, 392
laryngeal cancer, 155
oesophageal cancer, 155–6, 257
oral cancers, 155, 248
pharyngeal cancer, 155
sources, 150
Matvienko trial, 336, 337
Matrix approach, 58–9
Matrix metalloproteases (MMPs), 46
Meal frequency, 193, 195–6
Meatchronic disease, 353
colorectal cancer, 120–1
composition, 118
consumption patterns, 119
definition, 117
endometrial cancer, 122lung cancer, 121–2
lymphoid and haemopoietic cancers, 320
oesophageal cancer, 121
pancreatic cancer, 122processed see Processed meat
red see Red meat
report comparisons, 128, 358

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sources, 117
Medications, carcinogenic, 41
Mediterranean diets, 191, 193–4
Melanoma skin cancer, beta-carotene supplementation, 187
Menarche, age of, breast cancer, 232
Meningiomas, 321
Meta-analysis, 51–2
Metabolic equivalents (METs), 200
Metastasis, 46
Methodology Task Force, 54, 55
Methylation of DNA, 34
Methylenetetrahydrofolate reductase (MTHFR) gene, 37
Mexico, 26
Micronutrients, 78, 181–3
Micro RNAs (miRNAs), 33–4
Microwaving, 177
Migrant studies, 22–5, 50
Milk, 129–34
bladder cancer, 133, 314
colorectal cancer, 285
composition, 130
consumption patterns, 130–1
definition, 130
evidence and judgements, 131–4
evidence interpretation, 131
lymphoid and haemopoietic cancers, 320
previous report comparisons, 134
products made from, 129
prostate cancer, 307
recommendations, 382
sources, 130
testicular cancer, 319
Minerals, 182
MONICA project, 13
Monosaccharides, 142
Monounsaturated fatty acids, 136
Morbid obesity, gradings, 212–13
Mortality measurement, 18–19
Mo-Suwan trial, 334
Moulds, 41
Mouth cancer, 245–9
alcohol, 160–2
carotenoids, 100–1
evidence and judgements, 247–9
evidence interpretation, 247
fruits, 94–5
maté, 155
pathogenesis, 246previous report comparisons, 249
trends, incidence, and survival, 245–6
vegetables, 82–4
Western diets, 195
mRNA, 31
Multicentre Growth Reference Study (MGRS), 230
Multiple myeloma, 319
Musculoskeletal system cancers, 320–1
Mycotoxins, 70

N
n-3 fatty acids, 46
Nails, selenium
colorectal cancer, 111
lung cancer, 109
prostate cancer, 110–11
stomach cancer, 111
Nasopharyngeal cancer, 125–6, 250–2
Epstein-Barr virus, 251
evidence and judgements, 251–2
evidence interpretation, 251
fruits, 99, 251–2
pathogenesis, 251

512

previous report comparisons, 252
trends, incidence, and survival, 250
variants, 250
vegetables, 90
Nervous system cancers, 321
Nested case-control studies, 51
Nitrates, 118
colorectal cancer, 284
stomach cancer, 269
Nitrosamines
nasopharyngeal cancer, 252
stomach cancer, 266
N-nitroso compounds, 37, 41, 118
Non-Hodgkin’s lymphoma, 319
Non-melanoma skin cancer, 315–16
beta-carotene supplementation, 186–7, 317
Nucleotide excision repair, 36
Nurses Health Study, Western diets, 194
Nutrigenomics, 32
Nutritional deficiencies, other report findings, 350–1
Nutritional patterns, 392
Nutrition interventions, 337
Nutrition over life course, 34
Nutrition status, 56
Nuts and seeds
composition, 80
definition, 77–8
sources, 77–8

O
Obesityadult attained height, 39
characteristics, 39
childhood, 10, 326
genetically determined, 329
global pandemic, 326–7
hormones and growth factors, 39
physical health problems, relative risk, 326
projected increases, 14
public health issue, 325–6
report findings, 355
see also Overweight
Obesity determinants see Weight gain determinants
Oesophageal cancer, 253–8
alcohol, 162–4, 257
animal products, 256–7
beta-carotene, 103body fatness, 214–15, 257–8
carotenoids, 103, 256classification, 254–5
dietary fibre, 72, 255
evidence and judgements, 255–8
evidence interpretation, 254–5
folate, 106–7, 256
fruits, 95–7, 255
high temperature food and drink, 155–6
international trends, 17–19
maté, 155–6, 257
meat, 121, 256
pathogenesis, 254
previous report comparisons, 258
processed meat, 123, 2573
pyridoxine (vitamin B6), 107, 256
tobacco use, 254
trends, incidence and survival, 254
vegetables, 84–6, 255
vitamin C, 107–8, 256
vitamin E, 108, 256
Western diets, 194
Oestradiol, fats and, 139
Oestrogen, 39, 139

I N D E X

adipose tissue-derived, 221
Oils see Fats and oils
Oncogenes, 35
Oral combined contraceptive pill, 39
Organic farming, 174
Ovarian cancer, 296–8
adult attained height, 236–7, 297–8
evidence and judgements, 297–8
evidence interpretation, 297
lactation, 242
pathogenesis, 296–7
trends, incidence, and survival, 296
vegetables, 91–2
Overweightchildren, 10, 326
determinants see Weight gain determinants
gradings, 212–13
increase estimates, 327
international trends, 13–14
prevalence estimates, 327
principal cut-off points, 212
rates, 323
risks, 329–30
Oxidative stress, 38P
p53 gene, 44
Packaging, 176
Palm oil, 137
Pancreatic cancer, 271–4
abdominal fatness, 226, 273–4
adult attained height, 235–6, 274
body fatness, 215–16, 273
coffee, 153–4, 273
evidence and judgements, 272–4
evidence interpretation, 272
folate, 106
fruits, 99–100
meat, 122
pathogenesis, 272
physical activity, 207–8
previous report comparisons, 274
trends, incidence, and survival, 271–2
Western diets, 195
Pasteurisation, 175
Patient-centred Assessment and Counselling
for Exercise (PACE) Trial, 332
Patterns, 391–3
integrated approach, 391–2
national recommendations, integration with, 392
regional and special circumstances, 392
Peasant-agricultural food systems, 6–7
Peripheral fat stores, 213
Personal recommendations, 373–90
alcohol, 384
animal foods, 383
body fatness, 375
breastfeeding, 388
cancer survivors, 390
food processing and preservation, 385
physical activity, 377
plant foods, 381
supplementation, 387
weight gain, 379
Pesticides, 173
Pharyngeal cancer, 245–9
alcohol, 160–2
carotenoids, 100–1
evidence and judgements, 247–9
evidence interpretation, 247
fruits, 94–5

maté, 155
pathogenesis, 246previous report comparisons, 249
vegetables, 82–4
Western diets, 195
Phase I metabolising enzymes, 36
Phase II metabolising enzymes, 36
Phenacetin, 311
Phenolic compounds, 43
Physical activity, 198–209
achieving healthy levels, 377
breast cancer, 204, 292
cancer survivors, 347
colorectal cancer, 202–3, 287
definition, 15, 199–200
endometrial cancer, 205–6, 301
evidence and judgements, 201–8
evidence interpretation, 201
interventions
adult, 333
children, 334
lung cancer, 206–7, 263–4
measurements, 56
pancreatic cancer, 273
public health goals, 376–8
recommendations, 376–8
report comparisons, 208, 354
types and levels, 200–1
weight gain determinants, 332–5
Physical activity levels (PALs), 200–1
future influences, 16international trends, 14–17
projected levels of inactivity, 15urban-industrial food systems, 10
Phytochemicals, 79, 182–3
Phytoestrogens, 43, 46
Pituitary hormones, lactation, 240
Plantains see Roots, tubers, and plantains
Plant-based diets, 191–2
Plant foods, goals and recommendations, 380
Poland, 20–1
Polychlorinated biphenyls (PCBs), 40–1
Polycyclic hydrocarbons, 36, 41, 119
Polyunsaturated fatty acids, 130, 136‘Portfolio’ approach, 58
Postmenopausal breast cancer, 292
abdominal fatness, 226
adult attained height, 234, 293
body fatness, 219–20
fats and oils, 138–9
physical activity, 205
waist circumference, 226
waist to hip ratio, 226
weight gain, 227–8
Western diets, 195
Poultry, 382
composition, 118
consumption patterns, 119
definition, 117
sources, 117
Pound of Prevention trial, 332
Premenopausal breast cancer, 292
adult attained height, 235, 293
body fatness, 220–1
fats and oils, 138
high birth weight, 237–8
physical activity, 204–5
Prepubertal growth, 230–1
Processed meat, 117, 123–4
colorectal cancer, 123, 284–5
lung cancer, 124, 262
oesophageal cancer, 123, 257

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prostate cancer, 307
stomach cancer, 124, 268–9
Progesterone, 221
Projections, 244
Promotion, 41–2
Prostate cancer, 305–9
alpha-tocopherol, 109, 187
beta-carotene, 105, 185, 308–9
calcium, 134, 307
carotenoids, 103–5
evidence and judgements, 306–9
evidence interpretation, 306
gamma-tocopherol, 109international trends, 21–2
lycopene, 103–4
milk and diary products, 131–2
pathogenesis, 306
physical activity, 208
processed meat, 124pulses, 113
report comparisons, 309
selenium, 109–10, 188soya, 113
tomatoes, 103
trends, incidence, and survival, 305–6
vitamin E, 108–9
Western diets, 194
Prostate specific antigen (PSA), 305
Proteins, 180–1, 183
Pro-vitamin A carotenoids, 101, 103
Public health goals, 373–90
alcohol, 384
animal foods, 382
body fatness, 375
breastfeeding, 388
food processing/preservation, 385
physical activity, 377
plant foods, 380–1
principles ofbroad based, 369
cancer, 370
challenging, need to be, 372
global, 369
gradual changes, 372
impact, 370
integrated, 369
other disease prevention, 371
quantification, 371
supplementation, 387
weight gain, 379
Pulses (legumes), 112–13
composition, 80
consumption patterns, 81
definition, 77
prostate cancer, 113, 306
sources, 77
stomach cancer, 112–13, 268
Pyridoxine (vitamin B6), 78, 107, 256

Q
Quantification of risk, 58
Quercetin, 78
lung cancer, 112, 262

R
Radiation, 40, 291, 316
Randomised controlled trials (RCT), 51, 345–7
Rapeseed oil, 137
Raw vegetables
oesophageal cancer, 85514

oral cancers, 83
stomach cancer, 89
Reactive oxygen species, 38, 44‘Recovery’ biomarkers, 56
Rectal cancer, 20, 22, 217
Red meatcolorectal cancer, 284
endometrial cancer, 300–1
lung cancer, 262
lymphoid and haemopoietic cancers, 320
oesophageal cancer, 256
pancreatic cancer, 273
Red wine, composition, 158
Refrigeration, 144, 385
Religious diets, 192
Renal cancer see Kidney cancer
Replicative potential, limitless, 42–4
Report findings, other, 348–58
cancer, 355–8
chronic disease (non-cancer), 352–5
comparisons, 355
data interpretation, 350
diseases and exposures, 349
infectious diseases, 351–2
method, 349–50
nutritional deficiencies, 350–1
obesity, 355
physical activity, 354
reports reviewed, 349–50
weight gain, 355
Research issues, 360–3
cancer survivors, 363
environmental and genetic factors, 362
evidence updating, 361
food production methods, 363
geographic variations, 363
growth and development, 362–3
measurement improvement, 363
nutrition linkage mechanisms, 362
principles, 361
weight loss, 362
Retinoic acid, 42
Retinol, 184–5
lung cancer, 184, 263
skin cancer, 184, 317
Risk quantification, 58
Roasting, 176
Roots, tubers, and plantains, 67–74
composition, 69
consumption patterns, 70–1
definitions, 68–9
evidence and judgements, 71–3
evidence interpretation, 71
oesophageal cancer, 86
previous report comparisons, 114
stomach cancer, 91
Ruminant animals, 130

S
Salt, 141–7
chronic disease, 353–4
composition, 143
consumption patterns, 143
definition, 142
evidence and judgements, 144–7
evidence interpretation, 143–4
report comparisons, 147, 358
sources, 142
stomach cancer, 269
Salted foods, 143
recommendations, 385

I N D E X

stomach cancer, 146, 269–70
Saturated fats, 136
Schistosomiasis, 150, 313
Schmidtz trial, 332
Sedentary activity, 16, 201, 335
Seeds see Nuts and seeds
Selenium, 36, 78, 188–9
cancer survivors, 346
colorectal cancer, 111–12, 189, 284, 287
foods containing, 109
lung cancer, 109, 261–3
prostate cancer, 109–10, 307–8
skin cancer, 188–9, 317
stomach cancer, 111, 268
Seventh-day Adventist diets, 195
Sex hormones, 39, 232
Sexual maturity, 232
Shah trial, 336, 337
Sheppard trial, 336, 337
Silverman trial, 336
Skin cancer, 315–17
arsenic, 152–3, 316–17
beta-carotene, 105, 317
supplementation, 186–7
carotenoids, 105–6
evidence and judgements, 316–17
evidence interpretation, 316
pathogenesis, 316
previous report comparisons, 317
retinol supplements, 184, 317
selenium, 188–9, 317
trends, incidence, and survival, 315–16
Smoked foods, 127, 269
Sodium, 143, 145
Soft drinks, 148–56
chronic disease, 354
consumption patterns, 151, 152
definition, 149evidence and judgements, 152–6
evidence interpretation, 151–2
sources, 149
Soft juices, composition, 151
Solvents, 176
South Africa, 8–9
Soya
prostate cancer, 113, 306
stomach cancer, 112–13
Soya bean oil, 137
Spain, 22–3
Spices, 78, 113
Spirits/liquors
composition, 158
laryngeal cancer, 161–2
liver cancer, 170
mouth cancer, 161–2
oesophageal cancer, 164pharyngeal cancer, 161–2
sources, 158
Starchy foods, 69, 381
Steaming, 176, 385
Stem cells, 35
Steroid hormones, fats and oils, 139
Stewing, 176
Stomach cancer, 265–70
animal products, 268–9
chilli, 113, 268
China, 10evidence and judgements, 267–70
evidence interpretation, 267
fruits, 90, 98–9, 268
grilled/barbecued meat, 127–8
Helicobacter pylori, 20, 266

industrial chemicals, 266–7
infectious agents, 266
international trends, 19–20
migrant mortality, 22
nitrates, 269
nitrosamines, 266
pathogenesis, 266
previous report comparisons, 270
processed meat, 124, 268–9
pulses (legumes), 112–13, 268
salt, 145–6
salted foods, 146, 269–70
selenium, 111, 268
smoked foods, 127
soya, 112–13
trends, incidence, and survival, 265–6
vegetables, 86–93, 267
Western diets, 194
Study design options, 361
Sucrose, 142
Sugars, 8, 141–7
chronic disease, 353–4
colorectal cancer, 144–5, 286
composition, 142–3
consumption patterns, 143
definition, 142
dietary requirement, 142–3
evidence and judgements, 144–7
evidence interpretation, 143–4
extrinsic, 141–2
manufactured foods, 142previous report comparisons, 147
public health goals, 381
recommendations, 381
report comparisons, 358
sources, 142
Sugary drinks
public health goals and recommendations, 379
recommendations, 379
weight gain determinants, 339
Sunflower seed oil, 137
Sunlight, 40
Supplementation, 179–89
bladder cancer, 346
cancer survivors, 346
chronic disease, 354
evidence and judgements, 183–9
evidence interpretation, 183
infectious diseases, 352
levels, 183
nutritional deficiencies, 351
phytochemicals, 182–3
public health goals, 386–7
recommendations, 386–7
report comparisons, 189, 358
Surveillance, Epidemiology and End Results (SEER) programme, 57
Sustained angiogenesis, 46
Sweeteners, chemical, 143
Swinburn trial, 336, 337
Systematic literature reviews, 54

T
Tap water quality, 149
Tea, 148
consumption trends, 149, 152previous report comparisons, 156
sources, 149–50
Television viewing, 331, 340
Telomeres, 42
Testicular cancer, 319
Theophylline, 151

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Therapies
conventional, 345
unconventional, 345
Thermodynamics, 327–8
Thyroid cancer, 318–19
adult attained height, 318–19
body fatness, 318
Western diets, 195
Tissue invasion, 46
Tobacco use, 40, 393
bladder cancer, 313
cervical cancer, 304
chewing, 246
colorectal cancer, 286
kidney cancer, 311
lung cancer, 260
oesophageal cancer, 254oral cancers, 246–7, 248
Tomatoesoesophageal cancer, 86
oral cancers, 84
prostate cancer, 103
stomach cancer, 88–9
Toubro trial, 336, 337
Trace elements, 182
Traditional dietary patterns, 191–2
Transcription factors, 33, 35
Trans-fatty acids, 136–7
Transport-related physical activity, 15
Trends see International variations and trends
Triglycerides, 136
Tubers see Roots, tubers, and plantains
Tumour suppressor genes, 35, 38
Tylosis A, 254

U
Undernutrition, 39, 232
United Kingdom, 18–19
United States of America, 24–5
Unsaturated fats, 136
Urban industrial food systems, 7–10
dietary patterns, 190
ill-effects, 9
UV-damaged cells, 316
UV radiation, 40

VVegan diets, 192
Vegetables
allium see Allium vegetables
chronic disease, 353
classification, 82
composition, 79
consumption patterns, 80–1
cruciferous see Cruciferous vegetables
definition, 77
endometrial cancer, 92
global consumption, 73
green leafy
oesophageal cancer, 86
oral cancers, 83
ovarian cancer, 92
stomach cancer, 88, 91
infectious diseases, 351
laryngeal cancer, 82–4
lymphoid and haemopoietic cancers, 320
mouth cancer, 82–4
nasopharyngeal cancer, 90
non-starchycolorectal cancer, 283

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endometrial cancer, 300
lung cancer, 90–1, 261
mouth cancer, 82–4, 247
nasopharyngeal cancer, 251
oesophageal cancer, 84–5, 255
ovarian cancer, 91–2, 297
stomach cancer, 86–7, 267
weight gain determinants, 338
nutrient bioavailability, 79
nutritional deficiencies, 351
ovarian cancer, 91–2
pharyngeal cancer, 82–4
preparation, 79
previous report comparisons, 114
raw see Raw vegetables
recommended minimum daily amounts, 12
report comparisons, 358
sources, 77
thyroid cancer, 318
Vegetarian diets, 192, 195
Veterinary drugs, 173–4
Viruses, 40
Vitamin(s), 130, 181–2, 183
Vitamin A, 42, 184–5
Vitamin C, 78, 107–8, 256
Vitamin D, 40
colorectal cancer, 125–6, 285
meat, 118
Vitamin E, 78
oesophageal cancer, 108, 256
prostate cancer, 108–9, 308

W
Waist circumferencecolorectal cancer, 225
endometrial cancer, 227
pancreatic cancer, 226
postmenopausal breast cancer, 226
Waist to hip ratio
colorectal cancer, 225
endometrial cancer, 227
pancreatic cancer, 226
postmenopausal breast cancer, 226
Water, 148–56
chronic disease, 354
composition, 150
consumption trends, 149, 151
contamination, 150
definition, 149evidence and judgements, 152–6
evidence interpretation, 151–2
fluoridation, 176
sources, 149
Weight control, 329
Weight gain
adult, 213–14, 227–8
breast cancer, 294
fast food, 339–40
pancreatic cancer, 226public health goals, 378–9
recommendations, 378–9
report findings, 355
Weight gain determinants, 322–41
animal fats, 338–9
definitions, 323–4
evidence and judgements, 331–40
evidence interpretation, 330–1
incidence, 324–7
method, 330
physical activity, 332–5
previous report comparisons, 341

I N D E X

trends, 324–7
Western diets, 192, 194–5
colorectal cancer, 194
kidney cancer, 195
lung cancer, 195
oesophageal cancer, 194
pharyngeal cancer, 195
stomach cancer, 194
White vegetables, stomach cancer, 88–9
Wholegrain cereals, 68, 336–7
Whole milk, composition, 130
Winescomposition, 158
consumption patterns, 159
laryngeal cancer, 161liver cancer, 169
mouth cancer, 161oesophageal cancer, 163–4
pharyngeal cancer, 161
sources, 158
Women’s Healthy Lifestyle Project, 332
World Bank Living Standards Measurement Study, 13YYoghurt, 130517