Thirteen years ago, in 1986, my predecessor, Surgeon General 

C. Everett Koop, released a comprehensive analysis of the health dangers of

environmental tobacco smoke (ETS)*. This landmark Surgeon General’s

Report, entitled The Health Consequences of Involuntary Smoking (U.S. DHHS,

1986), concluded that ETS causes lung cancer in adults and respiratory

problems in children, and that simply separating smokers and nonsmokers

within the same airspace reduced, but did not eliminate, ETS exposure.

Around the same time, the National Academy of Sciences released an independent report that drew similar conclusions (NRC, 1986). Six years later,

in 1992, the U.S. Environmental Protection Agency (EPA) released its own

risk assessment of the health effects of ETS with respect to lung cancer and

respiratory function (U.S. EPA, 1992); the EPA report reaffirmed the conclusions of both earlier reports. In addition, the EPA identified ETS as a Group

A carcinogen, estimating that it causes 3,000 lung cancer deaths a year

among American nonsmokers. The EPA also estimated that every year, ETS

is responsible for up to 26,000 new asthma cases in children; up to

1,000,000 asthma exacerbations; and up to 300,000 cases of bronchitis and

pneumonia in toddlers—15,000 of which require hospitalization.

In the 7 years since the EPA report was published, the evidence that

ETS causes lung cancer and other serious diseases has continued to accumulate. Lung cancer was the first fatal disease linked to ETS, but in recent

years, evidence that ETS exposure causes other major diseases—particularly

heart disease—has emerged. In response to rapidly accumulating evidence

that ETS causes disease beyond lung cancer and respiratory effects in children, the California Environmental Protection Agency (Cal/EPA) undertook

a comprehensive assessment of the total range of health effects correlated

with exposure to ETS. 

Using the most up-to-date evidence available, Cal/EPA concluded

that ETS causes not only lung cancer in adults and respiratory problems in

children, but also low birth weight, sudden infant death syndrome, middle

ear infections, nasal sinus cancer, and heart disease morbidity and mortality

(Cal/EPA, 1997). Significantly, ETS was estimated to account for up to

62,000 heart disease deaths annually—20 times the number of ETS-related

lung cancer deaths.

i

Preface

* Various terms have been used in the scientific literature to describe a nonsmoker’s exposure

to ambient tobacco smoke. Passive smoking, involuntary smoking, secondhand smoke,

and environmental tobacco smoke are the most prevalent and are often used interchangeably by researchers and the public.
Cal/EPA also found evidence that suggests a link between ETS exposure and spontaneous abortion, adverse effects on cognition and behavior,

exacerbation of cystic fibrosis, decreased pulmonary function in adults (as

well as that previously described for children), and cervical cancer.

The above-mentioned major public health burden caused by ETS

more than justifies public policies creating smoke-free workplaces and public areas. They have also motivated many individuals and families to make

their homes smoke-free in order to protect children and other loved ones

from the toxic chemicals in ETS.

Since the Cal/EPA report was completed, evidence that ETS causes

disease has continued to accumulate. Additional studies have been published, including several major reviews confirming the association between

ETS exposure and increased risk for both lung cancer and heart disease in

nonsmokers. The International Agency for Research on Cancer (IARC) published a large study (Boffetta et al., 1998) demonstrating that nonsmokers

exposed to ETS experience a 16 percent elevation in the risk of developing

lung cancer—a level consistent with other estimates. While the results in

this individual study did not reach statistical significance, the consistency

of their estimates with those of other studies increases the confidence we

can have in the results of earlier studies. Taken together, all the existing

published studies demonstrate a significant and important elevation in lung

cancer risk associated with ETS exposure. 

British investigators (Law et al., 1997) conducted an analysis of 19

epidemiological studies on ETS and heart disease that convincingly demonstrated that the elevation in heart disease risk seen in ETS-exposed nonsmokers is unlikely to be due to the effects of other risk factors. Their finding of a 23 percent increased risk for heart disease is almost identical to that

recently published in the New England Journal of Medicine by a team of U.S.

investigators (He et al., 1999). Furthermore, a study from San Francisco

showed that respiratory symptoms in bartenders improved significantly just

6 weeks after their ETS exposure was eliminated by a new California law

requiring smoke-free bars (Eisner et al., 1998). California restaurants

became smoke-free on January 1, 1995, followed by bars on January 1, 1998

(Macdonald et al., 1997; Glantz and Balbach, 1999 in press). The rapid resolution of the effects of the ETS exposure after the smoke-free law went into

effect both demonstrates that ETS causes respiratory problems and illustrates that simple control measures can protect nonsmokers. The California

legislation was made possible by community action in support of smokefree environments (Glantz, 1997). Hundreds of communities across

America are now following California’s lead.

The California Environmental Protection Agency spent 5 years

preparing this document, and it solicited input from all interested parties—

including the tobacco industry and its consultants. Cal/EPA held several

public workshops to solicit input and made drafts available for public comment and criticisms. The final draft was peer reviewed by California's

Scientific Review Panel, a body created under California law to provide

independent peer review of many scientific aspects of the state's toxic air

contaminants and air pollution programs. 

ii

Smoking and Tobacco Control Monograph No. 10
The National Cancer Institute (NCI), acting on behalf of the U.S.

Public Health Service, recognized the importance of the Cal/EPA report and

saw the need to disseminate it broadly as part of their Smoking and

Tobacco Control Monograph series. I hope that this broad dissemination

will accelerate public recognition that ETS causes lung cancer, heart disease,

sudden infant death, and a wide variety of other serious diseases. I also

hope that awareness of this evidence will continue to stimulate public policies to protect nonsmokers from ETS exposure.

In a speech to the American Lung Association in 1984, Dr. C.

Everett Koop called for a smoke-free society by the year 2000. While we

will not accomplish Dr. Koop's goal, we have made major progress. Just 3

percent of the American workforce was employed in a smoke-free environment in 1986 (Gerlach et al, 1997). By 1996, nearly two-thirds (64 percent)

of the American indoor workforce was covered by a smoke-free workplace

policy (NCI, 1999 in press). Additionally, fully 75 percent of all homes

have adopted rules that restrict smoking, with more than half completely

banning smoking in the home (NCI, 1999 in press). Even among smokers

this trend is evident, with 50 percent of current smokers restricting smoking

in their home to some degree and nearly one in five reporting that they do

not permit smoking anywhere in the home. I can only hope that the information contained in this report will renew the effort to meet the goal of a

smoke-free society in which no one would be involuntarily exposed to ETS.

I call on everyone committed to public health to join with me in a

renewed effort to complete the creation of a smoke-free society by:

• Encouraging communities to enact clean indoor air ordinances requiring 100 percent smoke-free environments in all public areas and

workplaces, including all restaurants and bars.

• Encourage smokers as well as nonsmokers to make their homes

smoke-free to protect their children and families from ETS exposure.

With these simple steps, we can all breathe a little easier.

David Satcher, M.D., Ph.D.

U.S. Surgeon General and 

Assistant Secretary for Health

iii

Preface
Smoking and Tobacco Control Monograph No. 10

iv

Boffetta P., Agudo A., Ahrens W., Benhamou E.,

Benhamou S., Darby S.C., Ferro G., Fortes C.,

Gonzalez C.A., Jöckel K.H., Krauss M.,

Kreienbrock L., Kreuzer M., Mendes A., Merletti

F., Nyberg F., Pershagen G., Pohlabeln H., Riboli

E., Schmid G., Simonato L., Trédaniel J., Whitley

E., Wichmann H.E., Saracci R., et al. Multicenter

case-control study of exposure to environmental

tobacco smoke and lung cancer in Europe [see

comments]. Journal of the National Cancer

Institute 90:1440-1450, 1998.

California Environmental Protection Agency. Health

Effects of Exposure to Environmental Tobacco

Smoke—Final Report and Appendices. Cal/EPA,

Office of Environmental Health Hazard

Assessment, September 1997.

Eisner M.D., Smith A.K., Blanc P.D. Bartenders' respiratory health after establishment of smoke-free

bars and taverns [see comments]. Journal of the

American Medical Association 280:1909-1914,

1998.

Gerlach K.K., Shopland D.R., Hartman A.M., Gibson

J.T., Pechacek T.F. Worplace smoking policies in

the United States: results from a national survey

of more than 100,000 workers. Tobaco Control

6(3):199-206, 1997.

Glantz S. Back to basics: Getting smoke free workplaces back on track (editorial). Tobacco Control

6:164-166, 1997.

Glantz S., Balbach E. California Tobacco Wars

Berkeley, CA: University of California Press (in

press), 1999.

He J., Vupputuri S., Allen K., Prerost, M.R., Hughes

J., Whelton P.K. Passive smoking and the risk of

coronary heart disease – a meta analysis of epidemiological studies. New England Journal of

Medicine 340:920-926, 1999.

Law M., Morris J., Wald N. Environmental tobacco

smoke exposure and ischaemic heart disease: An

evaluation of the evidence. British Medical

Journal 315:973-980, 1997.

Macdonald H.R., Glantz S.A. The political realities

of statewide smoking legislation. Tobacco Control

6:41-54, 1997.

National Cancer Institute. State and Local Legislative

Action to Reduce Tobacco Use. Smoking and

Tobacco Control Monograph 11. Burns, D.,

Shopland, D.R. (Editors). U.S. Department of

Health and Human Services, Public Health

Service, National Institutes of Health, National

Cancer Institute, 1999 in press.

National Research Council Committee on Passive

Smoking. Environmental Tobacco Smoke:

Measuring Exposures and Assessing Health Effects.

Washington, D.C.: National Academy Press,

1986.

U.S. Department of Health and Human Services. The

Health Consequences of Involuntary Smoking. A

Report of the Surgeon General. U.S. DHHS, Public

Health Service, Centers for Disease Control.

DHHS Publication No. (CDC) 87-8398, 1986.

U.S. Environmental Protection Agency. Respiratory

health effects of passive smoking: Lung cancer and

other disorders. U.S. EPA Document No.

EPA/600/6-90/006F, 1992.

REFERENCES
v

Acknowledgements

The Smoking and Tobacco Control Monographs are developed

under the editorial direction of Donald R. Shopland, Coordinator,

Smoking and Tobacco Control Program (STCP), National Cancer Institute,

Bethesda, Maryland. This volume, Heath Effects of Exposure to Environmental

Tobacco Smoke, was originally conceived and developed under the editorial

direction of Lauren Zeise, Ph.D., Chief, Reproductive and Cancer Hazard

Assessment Section (RCHAS), Office of Environmental Health Hazard

Assessment (OEHHA), California Environmental Protection Agency

(Cal/EPA). Amy Dunn, M.P.H., Research Scientist, and Lauren Zeise were

the editors of the original Cal/EPA report. The topic is of such critical public

health importance that NCI, in cooperation with Cal/EPA, is publishing and

disseminating the report as part of NCI’s continuing Smoking and Tobacco

Control Monograph series.

The body of the original Cal/EPA report is presented in this monograph in its entirety, with only minor editorial revision. Due to space considerations, Appendices A and B, which were published alongside the original report, have not been reproduced in this volume. For those readers

interested in obtaining copies of the appendices as they appeared in the

Cal/EPA report, single copies are available, upon written request, from the

California Environmental Protection Agency. Or they may be downloaded

as PDF files through the OEHHA web site at http://www.oehha.ca.gov.

Unlike the original Cal/EPA report, this monograph contains a preface by David Satcher, M.D., Ph.D., U.S. Surgeon General and Assistant

Secretary for Health, Department of Health and Human Services.

The editors and STCP staff members would like to express their sincere appreciation to Stanton Glantz, Ph.D., Professor of Medicine,

University of California, San Francisco for his tireless assistance in the

preparation of this monograph. The STCP staff would also like to acknowledge the dedication and perseverence of Lauren Zeise and Amy Dunn in

developing this comprehensive report.

The original report was prepared by the Reproductive and Cancer

Hazard Assessment Section (RCHAS) and the Air Toxicology and

Epidemiology Section (ATES) within the Office of Environmental Health

Hazard Assessment (OEHHA) of the California Environmental Protection

Agency (Cal/EPA). Lauren Zeise was the project officer with overall responsibility for the contents of this report. Amy Dunn coordinated the development of the draft chapters and their revisions, the public workshops, and

the finalization of the full report. James Donald played a key role in the

Authors and

Acknowledgements

AUTHORS
planning and development of Chapters 3, 4, and 5. Michael Lipsett, M.D.,

OEHHA, gave invaluable editorial assistance in the preparation of the

Executive Summary and Chapter 1.

While OEHHA staff provided technical editing and incorporated

reviewers’ comments into each chapter to develop a comprehensive and

consistent document, the following people were the primary authors: 

Executive Summary Lauren Zeise, Ph.D.

Chief

Reproductive and Cancer 

Hazard Assessment Section

Office of Environmental 

Health Hazard Assessment

Oakland, CA

Amy J. Dunn, M.P.H.

Research Scientist

Reproductive and Cancer 

Hazard Assessment Section

Office of Environmental 

Health Hazard Assessment

Oakland, CA

Chapter 1. Introduction Lauren Zeise, Ph.D.

Chief

Reproductive and Cancer 

Hazard Assessment Section

Office of Environmental 

Health Hazard Assessment

Oakland, CA

Amy J. Dunn, M.P.H.

Research Scientist

Reproductive and Cancer 

Hazard Assessment Section

Office of Environmental 

Health Hazard Assessment

Oakland, CA

Chapter 2. Exposure Measure- Lynne Haroun, M.P.H.

ment and Prevalence Risk Analyst

Tetra-Tech Environmental

Management, Inc.

San Francisco, CA

Amy J. Dunn, M.P.H.

Research Scientist

Reproductive and Cancer 

Hazard Assessment Section

Office of Environmental 

Health Hazard Assessment

Oakland, CA

vi

Smoking and Tobacco Control Monograph No. 10
David Ting, Ph.D., M.P.H.

Staff Toxicologist

Pesticide and Environmental

Toxicology Section

Office of Environmental

Hazard Assessment

Oakland, CA

Chapter 3. Developmental Gayle Windham, Ph.D.

Toxicity I: Perinatal Acting Chief

Manifestations Reproductive Epidemiology Section

Environmental Health 

Investigations Branch

California Department of

Health Services

Oakland, CA

Mari Golub, Ph.D., D.A.B.T.

Adjunct Professor of 

Internal Medicine

University of California

Davis, CA

and Staff Toxicologist

Reproductive and Cancer 

Hazard Assessment Section

Office of Environmental 

Health Hazard Assessment

Sacramento, CA

Chapter 4. Developmental Kirsten Waller, M.D., M.P.H.

Toxicity II: Postnatal Medical Epidemiologist

Manifestations Reproductive Epidemiology Section

California Department of

Health Services

Oakland, CA 

Chapter 5. Reproductive Effects Gayle Windham, Ph.D.

Acting Chief

Reproductive Epidemiology Section

Environmental Health 

Investigations Branch

California Department of

Health Services

Oakland, CA

vii

Acknowledgements
Mari Golub, Ph.D., D.A.B.T.

Adjunct Professor of 

Internal Medicine

University of California

Davis, CA

and Staff Toxicologist

Reproductive and Cancer 

Hazard Assessment Section

Office of Environmental 

Health Hazard Assessment

Sacremento, CA

Chapter 6. Respiratory Michael Lipsett, M.D.

Health Effects Department of Epidemiology

and Biostatistics

University of California

San Francisco, CA

and Public Medical Health Officer

Air Toxicology and Epidemiology

Section

Office of Environmental Health 

Hazard Assessment

Oakland, CA

Dennis Shusterman, M.D., M.P.H.

Associate Clinical Professor

of Medicine

Division of Occupational and

Environmental Medicine

University of California

San Francisco, CA

Jennifer Mann, M.P.H.

Environmental Epidemiology 

Group

Community Health Epidemiology

and Disease Control

San Francisco Department of

Public Health

San Francisco, CA

Chapter 7. Carcinogenic Anna Wu, Ph.D.

Effects Professor in Preventive Medicine

Department of Preventive Medicine

University of Southern California

Los Angeles, CA

Chapter 8. Cardiovascular Anna Wu, Ph.D.

Effects Professor in Preventive Medicine

Department of Preventive Medicine

University of Southern California

Los Angeles, CA

viii

Smoking and Tobacco Control Monograph No. 10
The authors are grateful to the following people for help

in the development of this report: Peggy Jenkins, Susan

Lum and other staff of the Indoor Exposure Assessment Section, Research

Division, Air Resources Board; staff of OEHHA and of the Division of

Epidemiologic and Occupational Disease Control of California Department

of Health Services, for review of preliminary drafts; Mary Ann Mahoney of

the Occupational and Environmental Health Library; William Lockett, Peter

Mathews and Bruce Oulrey in the Ombudsman’s Office, and Robert Krieger

and other staff in the Toxic Air Contaminants Section of the Air Resources

Board for guidance and assistance throughout the many phases of report

development. In addition to the editors and primary authors, the following

OEHHA staff contributed text to the document: Marlissa Campbell, Gerald

Chernoff (now with the Department of Toxic Substances Control), James

Donald, and James Morgan.

The final Cal/EPA document was preceded by a final draft and by

earlier external review drafts of each topic area which were released for public review and comment. The authors wish to thank those who sought to

improve the quality of this report with their comments, and are particularly

grateful to the members of the Scientific Review Panel, especially the leads

on ETS, Craig Byus, Gary Friedman and Stanton Glantz, as well as former

panel member Charles Becker, all of whom provided guidance and detailed

suggestions. Special thanks to Jennifer Jinot and Steven Bayard of U.S. EPA,

and Ira Tager, Kathy Hammond, Neil Benowitz, John Balmes, and John

Pierce. Thanks also go to James Collins, John Faust, Jeff Fowles, Andrew

Salmon, Martha Sandy, and David Ting for assistance with the response to

public comments. 

The authors and editors would like to acknowledge the

assistance of several people: Maria Patricia Aguilar, Julie

Christiansen, Susan Davis, Eydie Duggan, Kathy Elliott, Michael MacIntosh,

Laurie Monserrat, Susan Royo, and Joyce Smylie.

Finally, the editors and STCP staff members would also like to

acknowledge the contribution of the following individuals who provided

technical and editorial assistance in the preparation of this monograph. 

KBM Group, Inc., Silver Spring, MD

Richard H. Amacher, Project Director

Brian E. Steyskal, Editor/Graphic Designer

Cynthia M. DeLano, Copy Editor/Proofreader

Shelia Russel McCullers, Copy Editor/Proofreader

ix

Acknowledgements

CONTRIBUTORS AND

REVIEWERS

FURTHER

ACKNOWLEDGEMENTS

Preface . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .i

Authors and Acknowledgements . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .v

Executive Summary . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .ES-1

Attachment I: Scientific Review Panel Findings . . . . . . . . . . . . . . . . . . . .ES-10

1.0 Impact of ETS on the Health of Californians . . . . . . . . . . . . . . . .1

1.1 Organization of the Report . . . . . . . . . . . . . . . . . . . . . . . . . . . . .3

1.2 Definition of ETS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .3

1.3 Methodology . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .3

1.4 Weight-of-Evidence Evaluations . . . . . . . . . . . . . . . . . . . . . . . . .7

References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .9

2.1 Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .11

2.2 Properties of ETS and Its Constituents . . . . . . . . . . . . . . . . . . . .12

2.3 Exposure Measurement: ETS Concentrations 

in Indoor Environments . . . . . . . . . . . . . . . . . . . . . . . . . . . .18

2.4 Exposure Measurement: Biological Markers . . . . . . . . . . . . . . . . .25

2.5 Exposure Measurement: Use of Questionnaires . . . . . . . . . . . . . .41

2.6 Exposure Prevalence and Determinants . . . . . . . . . . . . . . . . . . .45

2.7 Chapter Summary and Conclusions . . . . . . . . . . . . . . . . . . . . . .66

References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .68

3.1 Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .75

3.2 Fetal Growth . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .75

3.3 Spontaneous Abortion and Perinatal Mortality . . . . . . . . . . . . . .106

3.4 Congenital Malformations . . . . . . . . . . . . . . . . . . . . . . . . . . . . .112

3.5 Chapter Summary and Conclusions . . . . . . . . . . . . . . . . . . . . . .119

References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .130

xi

3 Developmental Toxicity I: Perinatal Manifestations

2 Exposure Measurement and Prevalence

1 Introduction

Contents
4.1 Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .125

4.2 Sudden Infant Death Syndrome . . . . . . . . . . . . . . . . . . . . . . . . .126

4.3 Cognition and Behavior in Children . . . . . . . . . . . . . . . . . . . . . .140

4.4 Postnatal Physical Development . . . . . . . . . . . . . . . . . . . . . . . . .155

4.5 Respiratory Development and Function . . . . . . . . . . . . . . . . . . .162

4.6 Chapter Summary and Conclusions . . . . . . . . . . . . . . . . . . . . . .162

References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .163

5.1 Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .169

5.2 Female Fertility and Fecundability . . . . . . . . . . . . . . . . . . . . . . .169

5.3 Other Female Reproductive Effects . . . . . . . . . . . . . . . . . . . . . . .178

5.4 Male Reproductive Toxicity . . . . . . . . . . . . . . . . . . . . . . . . . . . . .179

5.5 Chapter Summary and Conclusions . . . . . . . . . . . . . . . . . . . . . .181

References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .181

6.0 Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .185

6.1 Acute Health Effects . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .185

6.2 Chronic Health Effects . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .219

6.3 Susceptible Populations . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .246

6.4 Chapter Summary and Conclusions . . . . . . . . . . . . . . . . . . . . . .253

References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .255

7.0 Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .265

7.1 All Cancers (combined) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .267

7.2 ETS and Lung Cancer . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .282

7.3 ETS and Cancer Sites Other Than Lung

that are Associated with Active Smoking: 

Nasal Sinus, Cervical and Bladder . . . . . . . . . . . . . . . . . . . . .309

7.4 ETS and Cancer Sites Where Evidence 

for the Role of Active Smoking is Equivocal . . . . . . . . . . . . . .323

7.5 Chapter Summary and Conclusions . . . . . . . . . . . . . . . . . . . . . .346

References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .348

xii

Smoking and Tobacco Control Monograph No. 10

5 Reproductive Effects

6 Respiratory Health Effects

7 Carcinogenic Effects

4 Developmental Toxicity II: Postnatal Manifestations
8.0 Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 359

8.1 Description of Epidemiologic Studies . . . . . . . . . . . . . . . . . . . . . 362

8.2 Discussion of Epidemiologic Studies . . . . . . . . . . . . . . . . . . . . . . 398

8.3 Other Supportive Evidence . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 403

8.4 Chapter Summary and Conclusions . . . . . . . . . . . . . . . . . . . . . . 425

References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 426

Executive Summary

Table ES.1 Health Effects Associated with Exposure to

Environmental Tobacco Smoke

Table ES.2 Estimated Annual Morbidity and Mortality in Nonsmokers 

Associated with ETS Exposure 

1 Introduction

Table 1.1 Estimated Annual Morbidity and Mortality in Nonsmokers

Associated with ETS Exposure

2 Exposure Measurement and Prevalence

List of Figures:

Figure 2.1 Plasma Cotinine Concentrations in Self-Reported Smokers

and Nonsmokers

Figure 2.2 Urinary Cotinine of Breast-Fed Infants in Relation to

Maternal Cigarette Smoking

Figure 2.3 Percent of Nonsmokers in California Reporting ETS Exposure

Figure 2.4 Reported Average Daily ETS Exposure Duration in California

Figure 2.5 Relative Person-Minutes of ETS Exposure in Different

Environments

Figure 2.6 Adult Smoking Prevalence: California and the United States

(1965-1995) 

Figure 2.7 Linear Trend in Per Capita Consumption of Cigarettes in

California Before and After Proposition 99 and Taxation

Program

xiii

8 Cardiovascular Effects

List of Tables and Figures by Chapter
List of Tables:

Table 2.1 Influence of Puff Volume and Filter Ventilation on Deliveries

of Particulate Matter and Carbon Monoxide in Mainstream

and Sidestream Smoke

Table 2.2 Chemical Constituents of Tobacco Smoke that Have Been

Classified or Identified as to Their Carcinogenicity,

Reproductive Toxicity or Other Health Hazard

Table 2.3 Mean Concentrations of Nicotine and Cotinine in the

Saliva, Plasma, and Urine of ETS-Exposed Volunteers

Table 2.4 Comparison of Biomarkers in Unexposed and ETS-Exposed

Nonsmokers, and Active Smokers

Table 2.5 Cut-Off, Sensitivity, and Specificity of Biomarkers for

Discriminating True Smoking Status

Table 2.6 Studies of Cotinine Measurements in Self-Reported

Nonsmokers and Criteria Used to Distinguish Smokers From

Nonsmokers

Table 2.7 Concentrations of Nicotine and Cotinine in Mothers’ Milk

Table 2.8 Studies with Information on ETS Exposure Prevalence in

California and the U.S.: Adults and Adolescents

Table 2.9 Studies with Information on ETS Exposure Prevalence in

California and the U.S.: Infants and Children

3 Developmental Toxicity I: Perinatal Manifestations

List of Figures:

Figure 3.1 Summary of Differences in Mean Birthweight and 95% 

Confidence Intervals Between ETS Exposed and Unexposed 

Pregnancies, by Definition of ETS and Study Size

Figure 3.2 Odds Ratio (Log Scale) and 95% Confidence Interval for the 

Association of Low Birthweight and ETS, by Definition of 

ETS and Study Size 

List of Tables:

Table 3.1 Studies of Birthweight and ETS Exposure Defined by 

Paternal Smoking Status 

Table 3.2 Studies of Fetal Growth and ETS Exposure at Home Defined 

by Paternal Smoking Status

xiv

Smoking and Tobacco Control Monograph No. 10
Table 3.3 Studies of Fetal Growth and ETS Exposure of Maternal NonSmokers from Multiple ETS Sources

Table 3.4 Studies of Fetal Growth and ETS Exposure Determined by 

Biomarkers

Table 3.5 ETS Exposure in Relation to Spontaneous Abortion and 

Perinatal Death

Table 3.6 ETS Exposure and Congenital Malformations

Table 3.7 Animal Studies of Tobacco Smoke Exposure and Fetal 

Growth

4 Developmental Toxicity II: Postnatal Manifestations

Table 4.1 Sudden Infant Death Syndrome (SIDS): Studies that Assessed

Some Source of Postnatal ETS Exposure

Table 4.2 Cognition in Children: Studies that Assessed Some Source of

Postnatal ETS Exposure

Table 4.3 Behavior in Children: Studies that Assessed Some Source of 

Postnatal ETS Exposure

Table 4.4 Height Growth in Children: Studies that Assessed Some 

Source of Postnatal ETS Exposure

5 Reproductive Effects

Table 5.1 ETS Exposure and Infertility or Fecundability: Adult 

Exposure

Table 5.2 ETS Exposure and Infertility or Fecundability: Childhood 

Exposure

6 Respiratory Health Effects

List of Figures:

Figure 6.1 Reported risk ratios and 95% confidence intervals for studies

that used clinically recognized asthma as an outcome

Figure 6.2 Reported risk ratios and 95% confidence intervals for studies

that used “wheezing bronchitis” or “chronic wheezing/ 

whistling in the chest” as an outcome

xv
List of Tables:

Table 6.1 Studies Cited by U.S. EPA (1993) as Evidence Supporting a 

Causal Relation Between ETS Exposure and Increased 

Episodes and Severity of Asthma in Children

Table 6.2 Controlled Exposures of Asthmatic Subjects to ETS

Table 6.3 Studies of Middle Ear Effusion (MEE) and Otitis Media (OM) 

vs. ETS Exposure Reviewed by the Surgeon General (1986), 

NRC (1986), or U.S. EPA (1992).

Table 6.4 Studies of Middle Ear Effusion (MEE) or Otitis Media (OM) 

vs. ETS Exposure Not Reviewed by the Surgeon General 

(1986), NRC (1986), or U.S. EPA (1992).

Table 6.5 Studies Excluded from Meta-Analysis of ETS and Childhood 

Asthma Induction

Table 6.6 ETS Exposure Relationship with Pulmonary Function, 

Hospitalizations and Disease Severity in Children with 

Cystic Fibrosis

7 Carcinogenic Effects

List of Tables:

Table 7.1 Exposure to Spouse’s Smoking and Relative Risk (RR) of All 

Cancers in Adults

Table 7.2A Hair Concentrations of Nicotine and Cotinine in Women 

and Their Newborn Infants

Table 7.2B 4-Aminobiphenyl Hemoglobin Adduct Concentrations in 

Pregnant Women and Fetuses by Exposure to Tobacco 

Smoke

Table 7.2C Cotinine and PAH-Albumin Levels in Mothers and Their 

Preschool Children

Table 7.3 Maternal Smoking During Index Pregnancy and Risk of All 

Childhood Cancers Combined

Table 7.4 Study Characteristics of the Four U.S. Case-Control Studies 

of Lung Cancer and ETS Published Since 1991

Table 7.5 Association Between Risk of Lung Cancer in Lifetime 

Nonsmoking Females and Exposure to Spousal Smoking

xvi

Smoking and Tobacco Control Monograph No. 10
Table 7.5B Risk of Lung Cancer in Nonsmoking Women and Men: A

Cohort Analysis

Table 7.6 Association Between Risk of Lung Cancer and ETS Exposures

From Parentsand Other Household Members

Table 7.7 Studies on ETS Exposure at the Workplace and Lung Cancer 

Among Lifetime Nonsmoking Subjects

Table 7.8 Association Between Passive Smoke Exposure and Risk of 

Nasal Sinus Cancer in Nonsmokers

Table 7.9 Relationship Between Active and Passive Smoke Exposure 

and Risk of Cervical Cancer

Table 7.10 Nicotine and Cotinine Measured in the Cervical Mucus of 

Smokers, Passive Smokers, and Nonsmokers

Table 7.11 Passive Smoking and Bladder Cancer Among Nonsmokers

Table 7.12 Mean Levels of Hemoglobin Adducts of 4- and 3-

Aminobiphenyls in Nonsmokers

Table 7.13 Mean Levels of 4-ABP Hemoglobin Adducts (PG/G of 

Hemoglobin) Among Smokers and Nonsmokers by 

Acetylator Phenotype

Table 7.14 Brain Tumors in Children and Exposure to Parent’s Smoking

Table 7.15 Maternal or Parental Smoking During Pregnancy and 

Childhood Leukemia

Table 7.16 Association Between Exposure to Passive Smoking and Risk 

of Non-Hodgkins Lymphoma and Lymphoma in Children

8 Cardiovascular Effects

List of Tables:

Table 8.1 Cohort Studies on ETS Exposure and Heart Disease

Table 8.2 Case-control Studies on ETS Exposure and Heart Disease

Table 8.3 Risks of Heart Disease and Active Smoking in Women

Table 8.4 Risks of Heart Disease and Active Smoking in Women By 

Age

xvii
Table 8.5 Effect of Exposure to ETS on Exercise Tolerance

Table 8.6 Effect of Exposure to ETS on Lipid Profile in Children

Table 8.7 Platelet Sensitivity to Antiaggregatory Prostaglandins

Before and After Exposure to ETS

Table 8.8 Measures of Platelet Function in Relation to Exposure

to Active Smoking and Passive Smoking

Table 8.9 Carotid Artery Intimal-Medial Thickness (IMT) as Measured 

by B-mode Ultrasound in Current Smokers, Ex-smokers, 

and Never-Smokers

Table 8.10 Endothelium-Dependent Arterial Dilatation in Active 

Smokers, Never-Smokers exposed to ETS, and Never-Smokers

Not Exposed

xviii

Smoking and Tobacco Control Monograph No. 10
ES-1

Exposure to environmental tobacco smoke (ETS) has been linked to

a variety of adverse health outcomes. Many Californians are exposed at

home, at work, and in public places. In the comprehensive reviews published as Reports of the Surgeon General and by the U.S. Environmental

Protection Agency (U.S. EPA) and the National Research Council (NRC), ETS

exposure has been found to be causally associated with respiratory illnesses—including lung cancer, childhood asthma, and lower respiratory tract

infections. Scientific knowledge about ETS-related effects has expanded

considerably since the release of the above-mentioned reviews. The state of

California has therefore undertaken a broad review of ETS covering the

major health endpoints potentially associated with ETS exposure: perinatal

and postnatal manifestations of developmental toxicity, adverse impacts on

male and female reproduction, respiratory disease, cancer, and cardiovascular disease. A “weight of evidence” approach has been used, in which the

body of evidence is examined to determine whether or not it can be concluded that ETS exposure is causally associated with a particular effect.

Because the epidemiological data are extensive, they serve as the primary

basis for assessment of ETS-related effects in humans. The report also presents an overview on measurements of ETS exposure (particularly as they

relate to characterizations of exposure in epidemiological investigations)

and on the prevalence of ETS exposure in California and nationally.

ETS, or “secondhand smoke,” is the complex mixture formed from

the escaping smoke of a burning tobacco product and smoke exhaled by

the smoker. The characteristics of ETS change as it ages and combines with

other constituents in the ambient air. Exposure to ETS is also frequently

referred to as “passive smoking,” or “involuntary tobacco smoke” exposure.

Although all exposures of the fetus are “passive” and “involuntary,” for the

purposes of this review, in utero exposure resulting from maternal smoking

during pregnancy is not considered to be ETS exposure.

ETS is an important source of exposure to toxic air contaminants

indoors. There is also some exposure outdoors in the vicinity of

smokers. Despite an increasing number of restrictions on smoking and

increased awareness of health impacts, exposures in the home, especially of

infants and children, continue to be a public health concern. ETS exposure

is causally associated with a number of health effects. Listed in Table ES.1

are the developmental, respiratory, carcinogenic, and cardiovascular effects

for which there is sufficient evidence of a causal relationship—including

fatal outcomes such as sudden infant death syndrome and heart disease

GENERAL 

FINDINGS

Executive Summary
ES-2

Smoking and Tobacco Control Monograph No. 10

Table ES.1

Health Effects Associated with Exposure to Environmental 

Tobacco Smoke

Effects Causally Associated with ETS Exposure 

Developmental Effects

Fetal Growth: Low birthweight or small for gestational age

Sudden Infant Death Syndrome (SIDS)

Respiratory Effects

Acute lower respiratory tract infections in children

(e.g., bronchitis and pneumonia)

Asthma induction and exacerbation in children 

Chronic respiratory symptoms in children

Eye and nasal irritation in adults

Middle ear infections in children

Carcinogenic Effects

Lung Cancer

Nasal Sinus Cancer

Cardiovascular Effects

Heart disease mortality

Acute and chronic coronary heart disease morbidity

Effects with Suggestive Evidence of a Causal Association with ETS Exposure 

Developmental Effects

Spontaneous abortion

Adverse impact on cognition and behavior

Respiratory Effects

Exacerbation of cystic fibrosis

Decreased pulmonary function

Carcinogenic Effects

Cervical cancer

mortality, as well as serious chronic diseases such as childhood asthma.

There are, in addition, effects for which evidence is suggestive of an association, but further research is needed for confirmation. These include spontaneous abortion, cervical cancer, and exacerbation of asthma in adults (Table

ES.1). Finally, it is not possible to judge on the basis of the current evidence the impact of ETS on a number of endpoints including congenital

malformations, changes in female fertility and fecundability, male reproductive effects, rare childhood cancers, and cancers of the bladder, breast,

stomach, brain, hematopoietic system, and lymphatic system. 
ES-3

Executive Summary

Many Californians are exposed to ETS, and the number of people

adversely affected may be correspondingly large. Table ES.2 presents morbidity and mortality estimates for health effects causally associated with ETS

exposure. For cancer, cardiovascular, and some respiratory endpoints, estimates are derived from figures published for the U.S. population, assuming

that the number affected in California would be 12 percent of the total.

The estimates for middle ear infection, sudden infant death syndrome, and

low birthweight were derived using information on prevalence of ETS exposure in California and the U.S.

Relative risk estimates (RR) associated with some of these endpoints

are small, but because the diseases are common, the overall impact can be

quite large. A relative risk estimate of 1.3 for heart disease mortality in

nonsmokers is supported by the collective evidence; this estimate corresponds to a lifetime risk of death of roughly 1 to 3 percent for exposed nonsmokers and approximately 4,000 deaths annually in California. The relative risk estimate of 1.2 to 1.4 associated with low birthweight implies that

ETS may impact fetal growth of 1,200 to 2,200 newborns in California,

roughly 1 to 2 percent of newborns of nonsmokers exposed at home or at

work. ETS may exacerbate asthma (RR Å 1.6 to 2) in 48,000 to 120,000 children in California. Large impacts are associated with relative risks for respiratory effects in children such as middle ear infection (RR Å 1.62) and lower

respiratory disease in young children (RR Å 1.5 to 2). Asthma induction

(RR Å 1.75 to 2.25) may occur in as many as 0.5 to 2 percent of ETSexposed children. ETS exposure may be implicated in 120 SIDS deaths per

year in California (RR Å 3.5), with a risk of death approaching 0.1 percent

for infants exposed to ETS in their homes. Lifetime risk of lung cancer

death related to ETS-exposed nonsmokers may be about 0.7 percent (RR Å

1.2). For nasal sinus cancers, observed relative risks have ranged from 1.7

to 3.0, but future studies are needed to confirm the magnitude of ETS-related risks.

ETS is a complex mixture of chemicals generated during

the burning and smoking of tobacco products. Chemicals

present in ETS include irritants and systemic toxicants

such as hydrogen cyanide and sulfur dioxide; mutagens

and carcinogens such as benzo[a]pyrene, formaldehyde,

and 4-aminobiphenyl; and the reproductive toxicants

nicotine, cadmium, and carbon monoxide. Many ETS constituents have

been identified as hazardous by state, federal, and international agencies.

To date, over 50 compounds in tobacco smoke have been identified as carcinogens and six identified as developmental or reproductive toxicants

under California’s Proposition 65 (California Health and Safety Code

25249.5 et seq.).

Exposure assessment is critical in epidemiological investigations of

the health impacts of ETS, and in evaluating the effectiveness of strategies

to reduce exposure. Exposure can be assessed through the measurement of

indoor air concentrations of ETS constituents, through surveys and quesSPECIFIC FINDINGS

AND CONCLUSIONS

Exposure Measurement

and Prevalence
ES-4

Smoking and Tobacco Control Monograph No. 10

Table ES.2

Estimated Annual Morbidity and Mortality in Nonsmokers

Associated with ETS Exposure 

Number of People or Casesa

a The numbers in the table are based on maximum likelihood estimates of the relative risk. As discussed in the body of the report, there are uncertainties in these estimates, so actual impacts could be

somewhat higher or lower than indicated in the table. The endpoints listed are those for which there is

a causal association with ETS exposure based on observations of effects in exposed human populations.

b California estimates for low birthweight, SIDS, and middle ear infection (otitis media) are provided in

Chapters 3, 4, and 6, respectively. U.S. estimates are obtained by dividing by 12 percent, the fraction

of the U.S. population residing in California.

c Estimates of mortality in the U.S. for lung cancer and respiratory effects, with the exception of middle

ear infection (otitis media), come from U.S. EPA (1992). U.S. range for heart disease mortality reflects

estimates reported in Wells (1988 and 1994), Glantz and Parmley (1991), Steenland (1992).

California predictions are made by multiplying the U.S. estimate by 12 percent, the fraction of the U.S.

population residing in the State. Because of decreases in smoking prevalence in California in recent

years, the number of cases for some endpoints may be somewhat overestimated, depending on the

relative impacts of current versus past ETS exposures on the health endpoint.

d Estimates of the impact of ETS exposure on the occurrence of nasal sinus cancers are not

available at this time. 

Condition

Developmental Effects

Low birthweight

Sudden Infant Death

Syndrome (SIDS)

Respiratory Effects in

Children

Middle ear infection

Asthma induction

Asthma exacerbation

Bronchitis or pneumonia

in infants and toddlers 

(18 months and under)

Cancer

Lung 

Nasal sinus

Cardiovascular Effects

Ischemic heart disease

in the U.S. 

9,700 - 18,600 casesb

1,900 - 2,700 deathsb 

0.7 to 1.6 million 

physician office visitsb

8,000 to 26,000 new casesc

400,000 to 1,000,000 childrenc

150,000 to 300,000 casesc

7,500 to 15,000 

hospitalizationsc

136 - 212 deathsc

3,000 deathsc

N/Ad

35,000 - 62,000 deathsc

in California

1,200 - 2,200 casesb

120 deathsb

78,600 to 188,700 

physician office visitsb

960 to 3,120 new casesc

48,000 to 120,000 childrenc

18,000 to 36,000 casesc

900 to 1,800 hospitalizationsc

16 - 25 deathsc

360 deathsc

N/Ad

4,200 - 7,440 deathsc
ES-5

Executive Summary

tionnaires, or more directly through the use of personal monitors and the

measurement of biomarkers in saliva, urine, and blood. There are advantages and disadvantages associated with the various techniques, which must

be weighed in interpreting study results. One important consideration in

epidemiologic studies is misclassification of exposure. Studies on the reliability of questionnaire responses indicate that qualitative information

obtained is generally reliable, but that quantitative information may not be.

Also, individuals are often unaware of their ETS exposure, particularly outside the home. In studies using both self-reporting and biological markers,

the exposure prevalence was higher when determined using biological

markers.

Available data suggest that the prevalence of ETS exposure in

California is lower than elsewhere in the U.S. Among adults in California,

the workplace, home, and other indoor locations all contribute significantly

to ETS exposure. For children, the most important single location is the

home. Over the past decade, ETS exposures in California have decreased

significantly in the home, workplace, and in public places. Over the same

period, restrictions on smoking in enclosed worksites and public places

have increased (e.g., Gov. Code, Section 19994.30 and California Labor

Code, Section 6404.5), and the percentage of the adults who smoke has

declined. Decreases in tobacco smoke exposure may not be experienced for

some population subgroups, as patterns of smoking shift with age, race, sex,

and socioeconomic status. For example, from 1975 to 1988, the overall

smoking prevalence among 16 to 18 year olds declined, but after 1988 the

trend reversed. 

ETS exposure adversely affects fetal growth, with elevated risks of low birth weight or “small for gestational

age” observed in numerous epidemiological studies.

The primary effect observed, reduction in mean birthweight, is small in

magnitude. But if the distribution of birthweight is shifted lower with ETS

exposure, as it appears to be with active smoking, infants who are already

compromised may be pushed into even higher risk categories. Low birthweight is associated with many well-recognized problems for infants and is

strongly associated with perinatal mortality.

The impact of ETS on perinatal manifestations of development

other than fetal growth is less clear. The few studies examining the association between ETS and perinatal death are relatively non-informative, with

only two early studies showing increased risk associated with parental

smoking, and with the sparse data on stillbirth not indicative of an effect.

Studies on spontaneous abortion are suggestive of a role for ETS, but further

work is needed, particularly as a recent report did not confirm the findings

of four earlier studies. Although epidemiological studies suggest a moderate

association of severe congenital malformations with paternal smoking, the

findings are complicated by the use of paternal smoking status as a surrogate for ETS exposure, since a direct effect of active smoking on sperm cannot be ruled out. In general, the defects implicated differed across the studPerinatal Manifestations

of Developmental

Toxicity
ES-6

Smoking and Tobacco Control Monograph No. 10

ies, with the most consistent association seen for neural tube defects. At

this time, it is not possible to determine whether there is a causal association between ETS exposure and this or other birth defects.

Numerous studies have demonstrated an increased risk

of sudden infant death syndrome, or “SIDS,” in infants

of mothers who smoke. Until recently it has not been

possible to separate the effects of postnatal ETS exposure from those of prenatal exposure to maternal active smoking. Recent epidemiological studies

now have demonstrated that postnatal ETS exposure is an independent risk

factor for SIDS. 

Although definitive conclusions regarding causality cannot yet be

made on the basis of available epidemiological studies of cognition and

behavior, there is suggestive evidence that ETS exposure may pose a hazard

for neuropsychological development. With respect to physical development, while small but consistent effects of active maternal smoking during

pregnancy have been observed on height growth, there is no evidence that

postnatal ETS exposure has a significant impact in otherwise healthy children. As discussed in greater detail below, developmental effects of ETS

exposure on the respiratory system include lung growth and development,

childhood asthma exacerbation, and, in children, acute lower respiratory

tract illness, middle ear infection, and chronic respiratory symptoms.

Though active smoking by women has been found to be

associated with decreased fertility in a number of studies,

and tobacco smoke appears to be anti-estrogenic, the epidemiological data

on ETS exposure and fertility are not extensive and show mixed results, and

it is not possible to determine whether ETS affects fecundability or fertility.

Regarding other female reproductive effects, while studies indicate a possible association of ETS exposure with early menopause, the analytic methods

of these studies could not be thoroughly evaluated, and therefore at present, there is not firm evidence that ETS exposure affects age at menopause.

Although associations have been seen epidemiologically between active

smoking and sperm parameters, conclusions cannot be made regarding ETS

exposure and male reproduction, as there is very limited information available on this topic.

ETS exposure produces a variety of acute effects involving the

upper and lower respiratory tract. In children, ETS exposure can exacerbate

asthma, and increases the risk of lower respiratory tract illness and acute

and chronic middle ear infection. Eye and nasal irritation are the most

commonly reported symptoms among adult nonsmokers exposed to ETS.

Odor annoyance has been demonstrated in several studies.

Regarding chronic health effects, there is compelling evidence that

ETS is a risk factor for induction of new cases of asthma as well as for

increasing the severity of disease among children with established asthma.

In addition, chronic respiratory symptoms in children—such as cough,

Female and Male

Reproductive Toxicity

Respiratory Effects

Postnatal Manifestations

of Developmental

Toxicity
ES-7

Executive Summary

phlegm, and wheezing—are associated with parental smoking. While the

results from all studies are not wholly consistent, there is evidence that

childhood exposure to ETS affects lung growth and development, as measured by small but statistically significant decrements in pulmonary function

tests; associated reductions may persist into adulthood. The effect of

chronic ETS exposure on pulmonary function in otherwise healthy adults is

likely to be small and is unlikely by itself to result in clinically significant

chronic disease. However, in combination with other insults (e.g., prior

smoking history, exposure to occupational irritants or ambient air pollutants), ETS exposure could contribute to chronic respiratory impairment in

adults. In addition, regular ETS exposure in adults has been reported to

increase the risk of occurrence of a variety of lower respiratory symptoms. 

Children are especially sensitive to the respiratory effects of ETS

exposure. Children with cystic fibrosis are likely to be more sensitive than

healthy individuals. Several studies of patients with cystic fibrosis, a disease

characterized by recurrent and chronic pulmonary infections, suggest that

ETS can exacerbate the condition. Several studies have shown an increased

risk of atopy (a predisposition to develop IgE antibodies against common

allergens, which can then be manifested as a variety of allergic conditions)

in children of smoking mothers, though the evidence regarding this issue is

mixed. 

The role of ETS in the etiology of cancers in nonsmokers

was explored, as smoking is an established cause of a number of cancers

(lung, larynx, oral cavity, esophagus, and bladder), and a probable cause of

several others (cervical, kidney, pancreas, and stomach). Also, ETS contains

a number of constituents which have been identified as carcinogens. 

Reviews published in the 1986 Report of the Surgeon General, by

the National Research Council in 1986, and by the U.S. EPA in 1992 concluded that ETS exposure causes lung cancer. Three large U.S. populationbased studies and a smaller hospital-based, case-control study have been

published since the completion of the U.S. EPA review. The populationbased studies were designed to, and have successfully, addressed many of

the weaknesses for which the previous studies on ETS and lung cancer have

been criticized. Results from these studies are compatible with the causal

association between ETS exposure and lung cancer already reported by the

U.S. EPA, Surgeon General, and National Research Council. Of the studies

examining the effect of ETS exposure on nasal sinus cancers, all three show

consistent associations, presenting strong evidence that ETS exposure

increases the risk of nasal sinus cancers in nonsmoking adults. Further

study is needed to characterize the magnitude of the risk of nasal sinus cancer from ETS exposure. 

The epidemiological and biochemical evidence suggests that exposure to ETS may increase the risk of cervical cancer. Positive associations

were observed in two of three case-control studies, and a statistically nonsignificant positive association was observed in the only cohort study conCarcinogenic Effects
ES-8

Smoking and Tobacco Control Monograph No. 10

ducted. Findings of DNA adducts in the cervical epithelium as well as nicotine and cotinine in the cervical mucus of ETS-exposed nonsmokers provides biological plausibility. 

For other cancer sites in adults, there has been limited ETS-related

epidemiological research in general; there is currently insufficient evidence

to draw any conclusion regarding the relationship between ETS exposure

and the risk of occurrence. A review of the available literature clearly indicates the need for more research. For example, although compounds established as important in the etiology of stomach cancer are present in tobacco

smoke, only a single cohort study has been performed for this site.

Precursors of endogenously formed N-nitroso compounds suspected of causing brain tumors are present in high concentrations in ETS, and the one

cohort and two case-control studies available suggest a positive association,

but the results are based on small numbers and may be confounded by

active smoking. In biochemical studies of nonsmokers, higher levels of

hemoglobin adducts of the established bladder carcinogen, 4-aminobiphenyl, have been found in those exposed to ETS. However, no significant increases in bladder cancer were seen in the two epidemiological studies (case-control) conducted to date, although both studies were limited in

their ability to detect an effect. Several compounds in tobacco smoke are

associated with increased risk of leukemia, but only one small case-control

study in adults, reporting an increased risk with ETS exposure during childhood, has been performed. Finally, all four studies on ETS exposure and

breast cancer suggest an association, but in two of the studies the associations were present only in select groups, and in three studies there is either

no association between active smoking and the risk of breast cancer, or the

association for active smoking is weaker than for passive smoking.

Moreover, there is no indication of increasing risk with increasing intensity

of ETS exposure. Still, results from a recent study suggest that tobacco

smoke may influence the risk of breast cancer in certain susceptible groups

of women, an association which requires further investigation.

Regarding childhood cancers, it is unclear whether parental smoking increases risk, either overall or for specific cancers such as acute lymphoblastic leukemia or brain tumors, the two most common cancers in

children. The lack of clarity is due to the conflicting results reported and

the limitations of studies finding no association. The epidemiological data

on ETS exposure and rare childhood cancers also provide an inadequate

foundation for making conclusions regarding causality. Some studies in

children found small increased risks in relation to parental smoking for

neuroblastoma, Wilm’s tumor, bone and soft-tissue sarcomas, but not for

germ cell tumors. Studies to date on these rare cancers have been limited

in their power to detect effects. The impact of ETS exposure on childhood

cancer would benefit from far greater attention than it has received to date.

The epidemiological data from prospective and case-control studies conducted in diverse populations, in males and females and in

western and eastern countries, are supportive of a causal association

Cardiovascular Effects
ES-9

Executive Summary

between ETS exposure from spousal smoking and coronary heart disease

(CHD) mortality in nonsmokers. To the extent possible, estimates of risk

were determined with adjustment for demographic factors and often for

other factors related to heart disease—factors such as blood pressure, serum

cholesterol level, and obesity index. Risks associated with ETS exposure

were almost always strengthened by adjustment for other cofactors. For

nonsmokers exposed to spousal ETS compared to nonsmokers not exposed,

the risk of CHD mortality is increased by a factor of 1.3. The association

between CHD and risk is stronger for mortality than for non-fatal outcomes, including angina.

Data from clinical studies suggest various mechanisms by which ETS

causes heart disease. In a number of studies wherein nonsmokers were

exposed to ETS, carotid wall thickening and compromise of endothelial

function were similar to, but less extensive than those experienced by

active smokers. Other effects observed include impaired exercise performance, altered lipoprotein profiles, enhanced platelet aggregation, and

increased endothelial cell counts. These findings may account for both the

short- and long-term effects of ETS exposure on the heart.
ES-10

Smoking and Tobacco Control Monograph No. 10

Interest in the health effects of second-hand tobacco smoke on

the part of members of the Scientific Review Panel (SRP) on

Toxic Air Contaminants led to a request by the SRP for a health

assessment of environmental tobacco smoke and a collaborative agreement between the Office of Environmental Health

Hazard Assessment (OEHHA) and the Air Resources Board (ARB)

to initiate such an assessment. SRP members reviewed the

drafts as they were developed and participated in each of the

workshops held as the document underwent public review.

The final draft reflected the input of SRP members, as well as that of other

reviewers. 

Specific changes made at the request of the SRP following its review of the

final draft include the addition of new studies (e.g., the results of Kawachi

et al.’s analysis of cardiovascular disease risk in the Nurse’s Health study,

published after the release of the final draft, in which it was reported as an

abstract), a discussion of issues related to misclassification of smoking status

and cancer risk, and clarifying language in the presentation of attributable

risk estimates; minor editorial changes were also requested and made. The

SRP discussed the assessment and made findings on the health effects of

exposure to environmental tobacco smoke as a result of its review; these

findings are included in this attachment. 

ATTACHMENT I 

Review of the

OEHHA Assessment

of Environmental

Tobacco Smoke 

by the Scientific

Review Panel (SRP)
ES-11

Executive Summary
ES-12

Smoking and Tobacco Control Monograph No. 10
ES-13

Executive Summary
ES-14

Smoking and Tobacco Control Monograph No. 10
ES-15

Executive Summary

Disease risks due to inhalation of tobacco smoke are not

limited to smokers, but extend to nonsmokers who inhale

environmental tobacco smoke (ETS) at home, at work, or in

public places. Authoritative reviews over the past 2 decades have presented

scientific evidence linking ETS exposures to a number of adverse health outcomes. Smoking and Health: A Report of the Surgeon General (U.S.

DHEW, 1979) noted several adverse respiratory outcomes in children and

adults, as well as some acute cardiovascular effects associated with involuntary exposure to tobacco smoke. The 1982 A Report of the Surgeon

General (U.S. DHHS, 1982), which focused on the carcinogenic effects of

active smoking, raised the concern that involuntary smoking may cause

lung cancer. The large series of epidemiological investigations following

the publication of that report provided compelling evidence of a causal

relationship, and subsequently the 1986 Report of the Surgeon General

(U.S. DHHS, 1986), as well as reviews by the National Research Council

(NRC, 1986) and the U.S. Environmental Protection Agency (U.S. EPA,

1992), concluded that ETS exposure causes lung cancer. The NRC (1986)

and U.S. EPA (1992) also found ETS exposure to be associated with lower

respiratory tract illnesses in young children, as well as with other adverse

respiratory outcomes.

Many people are exposed to ETS. Table 1.1 presents estimates of

impacts for some of the health effects associated with ETS exposure and

predictions of the numbers of people potentially affected in California,

mainly based on extrapolations from national estimates. Recent state and

local restrictions on smoking at work and in public places in California, in

addition to the California Department of Health Services’ (CDHS) advertisement campaign by the Tobacco Control Program, have significantly

reduced ETS exposures of nonsmokers in California. Thus the predictions

in Table 1.1 may overstate the number of Californians adversely impacted

by ETS. Results of the California Adult Tobacco Survey (CDHS, 1995) suggest, however, that it is doubtful that the risks are overstated by more than

two-fold. Exposure to ETS therefore remains a significant public health

concern in California.

Evidence on ETS-related effects has expanded considerably since the

major comprehensive reviews contained in the Reports of the Surgeon

General and published by the U.S. EPA and NRC. The State of California

has therefore undertaken a broad review of ETS covering the major health

endpoints potentially associated with ETS exposure.

1

Introduction

1.0 IMPACT OF ETS

ON THE HEALTH OF

CALIFORNIANS
2

Smoking and Tobacco Control Monograph No. 10

Condition

Developmental

Effects

Low birthweight

Sudden Infant Death

Syndrome (SIDS)

Respiratory Effects

in Children

Otitis media

New asthma cases

Asthma exacerbation

Acute lower respiratory illness (LRI) in

children up to 18

months 

Lung Cancer 

Cardiovascular

Effects

Ischemic heart 

disease

Source

Windham 

et al., 1995

Klonoff-Cohen 

et al., 1995

Etzel, 1992

U.S. EPA, 1992

U.S. EPA, 1992

U.S. EPA, 1992

DiFranza and 

Lew, 1996

U.S. EPA, 1992

NRC, 1986

Wells, 1994; Glantz

and Parmley, 1991;

Steenland, 1992;

Wells, 1988

United States

9,700-18,600b

1,900-2,700 deathsb

0.7 to 1.6 million 

physician office visitsb

8,000- 26,000c

400,000- 1,000,000c

150,000-300,000 

cases of bronchitis 

and pneumoniac

7,500 to 15,000 

hospitalizationsc

136-212 deathsc

3,000 deathsc

2,590-4,040 

deaths in 1985

35,000-62,000 deathsc

California

1,200-2,200b

120 deathsb

78,600-188,700

physician office 

visitsb

960-3,120c

48,000-120,000c

18,000-36,000 

cases of bronchitis 

and pneumoniac

900 to 1,800 

hospitalizationsc

16-25 deathsc

360 deathsc

310-485 deaths

4,200-7,440 deathsc

a The numbers in the table are based on maximum likelihood estimates of the relative risk. As discussed in the body of the report, there are uncertainties in these estimates, so actual impacts could be

somewhat higher or lower than indicated in the table. The endpoints listed are those for which there is

a causal association with ETS exposure based on observations of effects in exposed human populations.

b California estimates for low birthweight, SIDS, and middle ear infection (otitis media) are provided in

Chapters 3, 4, and 6 respectively. U.S. estimates are obtained by dividing by 12 percent, the fraction

of the U.S. population residing in California.

c Estimates of mortality in the U.S. for lung cancer and respiratory effects, with the exception of middle

ear infection (otitis media), come from U.S. EPA (1992). U.S. range for heart disease mortality reflects

estimates reported in Wells (1988 and 1994), Glantz and Parmley (1991), Steenland (1992).

California predictions are made by multiplying the U.S. estimate by 12 percent, the fraction of the U.S.

population residing in the state. Because of decreases in smoking prevalence in California in recent

years, the number of cases for some endpoints may be somewhat overestimated, depending on the

relative impacts of current versus past ETS exposures on the health endpoint.

Table 1.1 

Estimated Annual Morbidity and Mortality in Nonsmokers 

Associated with ETS Exposure

Number of Cases Annuallya
The review begins with introductory material on definitions

and the methodology of the review. In Chapter 2, an

overview is presented on measurements of ETS exposure, particularly as

they relate to characterizations of exposure in epidemiological investigations, and on prevalence of ETS exposure found in studies conducted in

California and nationally. Chapters 3 through 5 address the developmental

and reproductive effects of ETS exposure. Perinatal manifestations of developmental toxicity are addressed in Chapter 3, postnatal manifestations in

Chapter 4, and male and female reproductive effects in Chapter 5. In

Chapter 6, acute and chronic respiratory health effects are described,

including some that, under standard definitions (U.S. EPA, 1991; CDHS,

1991), are considered to be developmental effects, such as pulmonary development and childhood asthma induction. Chapter 7 describes the evidence for carcinogenic effects of ETS exposure; beginning with a discussion

of all sites combined for children and adults, the chapter then describes the

evidence for specific sites: lung, nasal sinus, cervical and bladder cancer

(sites for which active smoking has been causally linked to cancer induction), and breast, stomach, brain, leukemia, lymphomas, non-Hodgkin’s

lymphomas, and other rare childhood cancers (sites for which there is

equivocal evidence for an etiologic role for active smoking). Chapter 8

reviews the evidence for the impact of ETS exposure on coronary heart disease.

ETS is also called “second-hand smoke,” and ETS exposure is frequently used interchangeably with “involuntary smoking” and

“passive smoking.” ETS is formed from the smoldering of a cigarette or

other tobacco product and from smoke exhaled by the smoker (NRC, 1986).

There are other minor contributors, such as the smoke that escapes while

the smoker inhales and some vapor-phase components that diffuse into the

environment. Once released into the environment of the smoker, components are diluted by the ambient air, diffusing in and being transported

through it. These smoke constituents may also aggregate with other components in the air and further age and change in character. This complex

mixture is defined as ETS, and inhalation of it, as ETS exposure. In some

ways this definition may be overly restrictive when it comes to assessing

effects from prenatal smoke exposures. Because the fetus cannot actively

smoke, all of its exposure to tobacco smoke constituents is “passive” or

“involuntary.” Nonetheless, exposure of the fetus due to maternal smoking

during pregnancy is not considered to be ETS exposure in this report.

This review is based on exhaustive searches of the literature,

including electronic searches (e.g., Medline, Toxline), formal requests for

information through an initial “data call-in” through mailed notices, and a

California Regulatory Notice Register announcement and less formal

requests at a number of public workshops, as well as through the public

review process. While published, peer-reviewed literature serves as the primary source of data, additional sources, for example abstracts of meeting

presentations or doctoral dissertations, may be included, particularly if they

provide information in an area where data are lacking. 

3

Chapter 1

1.1 ORGANIZATION

OF THE REPORT

1.2 DEFINITION OF ETS

1.3 METHODOLOGY
Methodological issues that were considered in the review of the epidemiologic literature include: 1) the sample size of the study, which affects

the power to detect an effect; 2) the extent to which the analysis or design

takes into account potential confounders or other risk factors; 3) selection

bias, or whether the study groups were comparable; and 4) the potential for

bias in ascertaining exposure. These factors were considered when identifying those studies of highest quality.

An important consideration in exploring the effects of ETS exposure

is the biological plausibility of an effect. This issue is addressed by comparing findings from studies of ETS exposure to those of active smoking, and

by examining the results of animal studies, short term tests, and biomarker

investigations.

Characterization of ETS exposure in most epidemiological studies is limited to broad categories (e.g.,

yes/no, number of hours per week). Accurate categorization is difficult

given the large variation in exposures individuals experience. Exposure has

generally been determined in three ways: ascertainment of spousal smoking

status; estimation of the number of hours a person is exposed (at home, at

work, or elsewhere); or measurement of biomarkers. Interviews or questionnaires are often used to collect the first two types of information. Some of

the limitations of assessing ETS exposure are briefly discussed below, while

Chapter 2 provides more detail on exposure measurement using biomarkers

and examines issues regarding the use of questionnaires.

Misclassification is an important consideration when reviewing epidemiologic studies. Misclassification of exposure status occurs when individuals are categorized as having been more or less exposed than they actually were. If the likelihood of misclassification does not depend on whether

the study subjects are diseased or not (that is, misclassification is “nondifferential”), then an association between ETS and the disease will be more

difficult to detect. Misclassification is a concern in studies which rely on

the ascertainment of spousal smoking status because ETS exposures also

occur outside the home. In addition, the amount smoked by the spouse

outside and inside the home, as well as the time spent in the home by the

nonsmoking spouse, varies from couple to couple. Other considerations

include size and ventilation of the subjects’ residences. Misclassification

can occur when exposures observed at one point in time are assumed to

apply to other time periods. Misclassification can also be an issue when

exposure is determined by asking subjects about the number of hours they

are exposed, for example, at home or at work. While questions on number

of hours exposed provide more information about multiple exposure

sources, respondents may vary in their awareness of and ability to quantify

their exposure (Coultas et al., 1989). The tendency is toward underestimation of hours exposed (Emmons et al., 1992). Few studies of this type

attempt to verify self-reported exposures.

4

Smoking and Tobacco Control Monograph No. 10

1.3.1 Measures of Exposure

in Epidemiological Studies
To minimize misclassification errors, the occurrence and duration of

exposure to all sources of ETS should be ascertained as completely as possible. More recent studies have used measurement of biomarkers of exposure

to improve assessment of ETS exposure. The biomarker cotinine, a metabolite of nicotine with relatively short half-life (20-30 hours in blood plasma),

is useful in categorizing and verifying recent exposure. However, because it

only reflects exposures of the past day or two, it is less useful in evaluating

chronic exposure. Measurement of cotinine can also be useful for identifying active smokers, as levels generally differ between smokers and nonsmokers exposed to ETS by one to two orders of magnitude.

Characterization of ETS exposure in studies of developmental effects

which manifest perinatally or in the first year of life can be particularly

challenging. Because of the pronounced effects of maternal smoking during pregnancy on some of the outcomes of interest, studies that can distinguish pre- and postnatal ETS exposure from in utero exposure due to maternal active smoking are given more weight. Some studies have attempted to

control for maternal active smoking during pregnancy through statistical

analyses. However, as spousal smoking habits are correlated, it is difficult

to control for the effect of only one partner’s smoking. In addition, almost

all women who smoke throughout pregnancy continue to smoke after their

babies are born (Fingerhut et al., 1990) and thus expose their children both

to mainstream tobacco smoke components prenatally and to ETS after

birth. 

Assessment of current ETS exposure of children is somewhat less

problematic. Although concerns similar to those discussed above regarding

misclassification remain, children, especially infants and young children,

are likely to be exposed to tobacco smoke in fewer circumstances than

adults. Cotinine concentrations in children are well correlated with smoking by the mother (Greenberg et al., 1989; U.S. DHHS, 1986); thus, information on cigarette consumption by the mother is likely to provide a reasonable proxy for a young child’s ETS exposure. This may not be the case if

the mother is not the primary caregiver. The use of paternal smoking alone

as a proxy for ETS exposure of infants and children can be problematic, as

fathers are generally less likely to be the primary caregiver.

Two main exposure issues arise in examining animal studies of tobacco smoke effects. First, there are no direct analogues of active smoking in animals; in all cases the smoke is dispersed in

the air rather than pulled from a cigarette into the lungs. Secondly, in

many study reports, not enough methodological detail is provided to determine whether the smoke generated can be classified as “mainstream” or

“sidestream” smoke, and thus its relevance to ETS exposure is unclear. The

majority of the studies available have attempted to simulate active smoking

by using mainstream smoke, and some delivered the smoke in bursts or

“puffs.” A few recent studies have used exposures characterized as “sidestream smoke,” which is considered more relevant to the assessment of the

effects of ETS exposure.

5

Chapter 1

1.3.2 ETS Exposure in

Animal Studies
Animal models have not been prominent in providing evidence

concerning the toxicity of active smoking. In contrast to humans, rodents,

the most commonly used animals in laboratory experiments, are obligatory

nose breathers and cannot inhale through the mouth. In addition, lung

and nasal cavity morphometry (e.g., shape) differ significantly between laboratory rodents and humans, leading to differences in distribution and

absorption of particulates (Harkema, 1991; Snipes et al., 1989). Also, methods of exposing animals to tobacco smoke comparable to human active

smoking have not been available. To address this issue, “smoking

machines” were developed that provided “puffs” of smoke drawn through

lit cigarettes (Guerin et al., 1979). This smoke could be dispersed in a

chamber or delivered via “nose only” exposure in which the animal’s head

was confined in a separate area to which the smoke was delivered. “Nose

only” exposures are considered superior to chamber exposures. In chambers, smoke constituents could condense on fur and subsequently be ingested during grooming, although this has not been demonstrated.

Animal models for ETS exposure have been recently developed and

studies using such models are being released (Witschi et al., 1997a & b).

Typically, “sidestream” smoke is smoke produced from the lit end of a cigarette, while “mainstream” smoke is that produced when air is drawn

through a lit cigarette. Aging and dilution are provided prior to exposure

to simulate constituent profiles similar to those described for human ETS

exposure (Coggins et al., 1992). Few studies using exposures specifically

designed to simulate human ETS exposure have as yet been published, however.

The association of ETS exposure and a specific outcome

in an epidemiologic study is usually reported as an odds ratio or a rate ratio

with a confidence interval, if available from reported studies. Odds and

rate ratios adjusted for potential confounders in the original studies are

included when available. If not presented in the published report and sufficient data were provided for doing so, crude rate ratios or odds ratios and

confidence intervals were calculated. An important consideration in examining causality is whether a dose-response effect was found, so when available those findings are included.

In general, when evaluating the findings of a study, the statistical

significance of single comparisons, as indicated by the p-value, is considered. However, when evaluating a body of epidemiologic literature, basing

interpretation only on the tallying of statistically significant findings can be

misleading (Greenland, 1987; Frieman et al., 1978). One problem is that

epidemiologic data seldom satisfy the criteria of randomized experimental

trials, for which the statistical testing methods were designed. Furthermore,

statistical significance is influenced by sample size; not all studies may be

large enough to detect a significant association of a given magnitude. This

is especially the case if the effect is expected to be of relatively small magnitude, as is anticipated for several of the potential ETS endpoints. Finally,

comparisons simply on the basis of p-values do not take into account possi6

Smoking and Tobacco Control Monograph No. 10

1.3.3 Measures of Effect
ble sources of bias in the studies. Therefore, in evaluating causality for a

particular endpoint, the overall body of evidence is carefully considered.

To provide a context for judging the importance of effects

caused by ETS exposure, estimates of ETS-related morbidity and mortality

are provided. The estimates are derived from data on prevalence and relative risk through assessing the attributable fraction, also called the attributable risk (Breslow and Day, 1980; Kelsey et al., 1996). The attributable fraction is the proportion of disease occurrence potentially eliminated if exposure was prevented. U.S. EPA (1992) used an attributable fraction approach

in estimating national figures for ETS-related respiratory health effects. In

fact, the national figures derived by U.S. EPA (1992) are used as the basis for

deriving California-specific values for childhood asthma induction and

exacerbation, bronchitis or pneumonia in young children, and lung cancer—the U.S. estimate is multiplied by 12 percent, the fraction of the U.S.

population residing in the state. U.S. statistics reported in the published literature for ETS-related heart disease mortality (Wells, 1988 and 1994;

Steenland, 1992; Glantz and Parmley, 1991) are similarly used to estimate

California-specific impacts. In this report, California-specific values are calculated for SIDS, low birth weight, and otitis media using California prevalence data and relative risk values to first estimate the attributable fraction.

To the extent that smoking prevalence and ETS exposure have been

declining in recent years and that California differs from the rest of the

country, the California-specific values derived from U.S. estimates may be

slightly elevated, depending on the relative impacts of current versus past

ETS exposures on the health endpoint. Cases of lung cancer occurring

today are a consequence of ETS exposures over past decades, and since

smoking prevalence in California was near national levels until the mid1980s, the differences noted should not significantly impact the accuracy of

the California estimate. For heart disease mortality this issue is more difficult to judge, since the importance of current versus past exposures is not

clearly understood. Other sources of uncertainty in estimates based on the

attributable fraction method include limited information on prevalence of

current and past smokers and relative risks of disease associated with smoking status. Methods to describe the sensitivity of these factors to morbidity

and mortality estimates derived using an attributable risk formulation have

recently been discussed (Taylor and Tweedie, 1997).

A “weight-of-evidence” approach has been used to

describe the body of evidence and to determine

whether or not ETS exposure causes a particular effect. Under this

approach, the number and quality of epidemiological studies, as well as

other sources of data on biological plausibility, are considered in making a

scientific judgment. Associations that are replicated in several studies,

either of the same design or using different epidemiological approaches or

considering different sources of exposure, are more likely to represent a

7

Chapter 1

1.3.4 Attributable Risk

1.4 WEIGHT-OFEVIDENCE EVALUATIONS
causal relationship than are isolated observations from single studies (IARC,

1996). If there are inconsistent results among investigations, possible reasons are sought (such as adequacy of sample size or control group, methods

used to assess ETS exposure, range in levels of exposure), and results of

studies judged to be of high quality are given more weight than those of

studies judged to be methodologically less sound. General considerations

made in evaluating individual studies include study design, appropriateness

of the study population, methods used to ascertain ETS exposure, and analytic methods such as the ability to account for other variables that may

potentially confound the ETS effect (see for example: IARC, 1996).

Increased risk with increasing levels of exposure to ETS is considered to be a

strong indication of causality, although absence of a graded response is not

necessarily evidence against a causal relationship (IARC, 1996).

An effect is judged to be causally associated with ETS exposure

when a positive relationship between ETS exposure and the effect has been

observed in studies in which chance, bias, and confounding could be ruled

out with reasonable confidence. Effects considered to have suggestive evidence of a causal association with ETS exposure are those for which a causal

interpretation can be considered to be credible, but chance, bias, or confounding could not be ruled out with reasonable confidence. For several

effects, it is not possible to judge whether or not ETS exposure affects the

severity or prevalence of their occurrence. Either too few studies are available to evaluate the impact, or the available studies are of insufficient quality, consistency, or statistical power to permit a conclusion.

Unlike those of most of environmental contaminants, ETS-related

health impacts are directly observable through studies of people in exposure situations similar to those experienced by the general population. Still,

the relative risks observed can be small, requiring a number of studies or

large studies to confirm the effect. Some endpoints have not been sufficiently studied epidemiologically, in which case the finding of inadequate

evidence should be seen as preliminary. Because the epidemiologic data are

extensive, they serve as the primary basis on which findings of ETS effects

are made. Experimental data are reviewed to determine the extent to

which they support or conflict with the human data. With regard to

addressing biological plausibility, analyses based on particular biomarkers

should be considered with caution. Presumption of a linear dose-response

relationship between ETS exposure as indicated by biomarker measurements

and effect can be problematic. The ratio of constituents in mainstream

smoke differs from that in ETS, and the constituents themselves differ in

their pharmacokinetic properties and in their dose-effect relationships. 

8

Smoking and Tobacco Control Monograph No. 10
Chapter 1

9

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and/or reproductive toxicity. Health and Welfare

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California Department of Health Services. Are

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smoke? A summary of the findings on work site and

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Coggins, C.R., Ayres, P.H., Mosberg, A.T., Ogden,

M.W., Sagartz, J.W., Hayes, A.W. Fourteen-day

inhalation study in rats, using aged and diluted

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Coultas, D.B., Peake, G.T., Samet, J.M.

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exposure to environmental tobacco smoke.

American Journal of Epidemiology 130(2):338-347,

1989.

DiFranza, J.R., Lew, R.A. Morbidity and mortality in

children associated with the use of tobacco products by other people. Pediatrics 97:560-568,

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Emmons, K.M., Abrams, D.B., Marshall, R.J., Etzel,

R.A., Novotny, T.E., Marcus, B.H., Kane, M.E.

Exposure to environmental tobacco smoke in

naturalistic settings. American Journal of Public

Health 82:24-27, 1992.

Etzel, R.A., Pattishall, E.N., Haley, N.J., Fletcher, R.H.,

Henderson, F.W. Passive smoking and middle

ear effusion among children in daycare.

Pediatrics 90:228-232, 1992.

Fingerhut, L.A., Kleinman, J.C., Kendrick, J.S.

Smoking before, during, and after pregnancy.

American Journal of Public Health 80:541-544,

1990.

Frieman, J., Chalmers, T.C., Smith, H. Jr., Kuebler,

R.R. The importance of beta, the type II error

and sample size in the design and interpretation

of the randomized control trial: Survey of 71

“negative” trials. New England Journal of Medicine

299:690-694, 1978.

Glantz, S.A., Parmley, W.W. Passive smoking and

heart disease: Epidemiology, physiology, and biochemistry. Circulation 83:1-12, 1991.

Greenberg, R.A., Bauman, K.E., Glover, L.H.,

Strecher, V.J., Kleinbaum, D.G., Haley, N.J.,

Stedman, H.C., Fowler, M.G., Loda, F.A. Ecology

of passive smoking by young infants. Journal of

Pediatrics 114:774-780, 1989.

Greenland, S. Quantitative methods in the review of

epidemiologic literature. Epidemiologic Reviews

9:1-30, 1987.

Guerin, M.R., Stokely, J.R., Higgins, C.E., Moneyhun,

H.H., Holmberg, R.W. Inhalation bioassay

chemistry—Walton Horizontal Smoking Machine

for inhalation exposure of rodents to cigarette

smoke. Journal of the National Cancer Institute

63:441-448, 1979.

Harkema, J.R. Comparative aspects of nasal airway

anatomy: Relevance to inhalation toxicology.

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monographs on the evaluation of the carcinogenic

risk of chemicals to humans: Printing processes and

printing inks, carbon black and some nitro compounds. IARC Monographs Volume 65. Lyon,

France: World Health Organization, 1996.

Kelsey, J.L., Whittemore, A.S., Evans, A.S.,

Thompson, W.D., Methods in Observational

Epidemiology, Second Edition. Oxford University

Press: 1996

Klonoff-Cohen, H.S., Edelstein, S.L., Lefkowitz, E.S.,

Srinivasan, I.P., Kaegi, D., Chang, J.C., Wiley, K.J.

The effect of passive smoking and tobacco exposure through breast milk on sudden infant death

syndrome. Journal of the American Medical

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smoke: Measuring exposures and assessing health

effects. Committee on Passive Smoking, Board

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Snipes, M.B., McClellan, R.O., Mauderly, J.L., Wolff,

R.K. Retention patterns for inhaled particles in

the lung: Comparisons between laboratory animals and humans for chronic exposures. Health

Physics 57 (Suppl 1):69-78, 1989.

Steenland, K. Passive smoking and risk of heart disease. Journal of the American Medical Association

267:94-99, 1992.

Taylor, S., Tweedie, R. Assessing sensitivity to multiple factors in calculating attributable risks.

Environmetrics, 1997.

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Health Consequences of Smoking: Cancer: A Report

of the Surgeon General. U.S. DHHS, Public Health

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Publication No. (PHS) 82-50179, 1982.

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U.S. Department of Health, Education and Welfare.

Smoking and Health: A Report of the Surgeon

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Publication No. (PHS) 79-50066, 1979.

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for Developmental Toxicity Risk Assessment.

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Wells, A.J. Passive smoking as a cause of heart disease. Journal of the American College of Cardiology

24:546-554, 1994.

Wells, A.J. An estimate of adult mortality in the

United States from passive smoking. Environment

International 14:249-265, 1988.

Windham, G.C., Eaton, A., Waller, K. Is environmental tobacco smoke exposure related to low

birthweight? (abstract) Epidemiology (suppl)

6:S41, 1995.

Witschi, H. Espiritu, I., Peake, J.L., Wu, K.,

Maronpot, R.R., Pinkerton, K.E. The carcinogenicity of environmental tobacco smoke.

Carcinogenesis 18(3):575-586, 1997a.

Witschi, H., Joad, J.P., Pinkerton, K.E. The toxicology of environmental tobacco smoke. Annual

Review of Pharmacology and Toxicology 37:29-52,

1997b.
This chapter provides background information on the prevalence and measurement of exposure to ETS and emphasizes investigation

and monitoring methods used in epidemiological evaluations of health

effects. Section 2.2 briefly reviews the physical and chemical properties of

ETS and identifies some of the important biologically active constituents

present in ETS. Section 2.3 discusses various techniques that have been

used to measure ETS concentrations in indoor environments.

Determination of ETS contamination is a challenge, as ETS is a complex

mixture of over 4,000 compounds, and it is neither feasible nor practical to

characterize every individual constituent of ETS. Given the complex nature

of ETS, markers and tracers of ETS are measured to assess ETS exposures.

The role and limitations of some ETS markers, such as nicotine, particulate

matter in air, and polycyclic aromatic hydrocarbons, are discussed in this

section. Section 2.4 addresses the use of biomarkers to measure ETS exposure. In addition to being dependant on ETS concentration in air, the

measured level of biomarker varies with an individual’s uptake, distribution,

metabolism, and excretion of the chemical of interest. This section

describes the use and limitations of some of the biomarkers, such as nicotine and cotinine in physiological fluids, in determining ETS exposure.

One problem with ETS markers and biomarkers is that most of them

are only capable of estimating ETS exposure over a relatively short period of

time, from a few hours to several weeks, whereas many health effects of ETS

are believed to be associated with long-term exposures that are measured in

months, if not years. In order to address this difficulty, most epidemiological studies cited in this report used questionnaires or interviews to determine the status of the subjects regarding long-term exposure to ETS. Some

studies also used measurements of ETS markers and biomarkers as supplemental information. And just like any epidemiological study that relies on

questionnaires or interviews for exposure information, these studies are

subjected to the problem of misclassification. Section 2.5 of this chapter

describes some of the difficulties associated with classifying subjects into

exposure categories based on the smoking status of other household members. As of today, no perfect method for quantifying ETS exposure has been

found. Yet, as demonstrated by many studies cited in other chapters of the

report, epidemiologists are able to use the information obtained from questionnaires or interviews in classifying the subjects into categorical groups of

ETS exposure (e.g., none, low, medium, or high). The categorical exposure

information is then used to evaluate health risks associated with ETS exposure. However, one drawback of this approach is that it decreases the sensi11

Exposure Measurement and

Prevalence

2.1 INTRODUCTION
tivity or power of a study—i.e., it will not show a positive association when

a health effect is only moderately related to ETS exposure.

Though many ETS monitoring methods (e.g., nicotine and respirable suspended particulates in air, cotinine in body fluids) are discussed

in this chapter, risk assessment of ETS exposure is seldom performed based

on monitoring results. Some of the reasons include short sampling duration in most studies, large uncertainty in extrapolating the ETS levels measured at a specific location to the general population, and large uncertainty

in estimating the frequency and duration of ETS exposure of the general

population. Consistent with the approach used by the National Research

Council (NRC, 1986), U.S. EPA (1992), DiFranza and Lew (1996), and Wells

(1994), this report uses prevalence assessment for the estimation of health

risks that are associated with past or recent ETS exposure. Epidemiologists

often use prevalence assessment, which makes use of semi-quantitative

exposure information, such as job classification or duration of exposure, for

the estimation of health risks associated with occupational and environmental hazards.

Section 2.6 discusses the prevalence of ETS exposures and factors

affecting prevalence, especially in California. In support of the assessment

of reproductive and developmental effects presented in the chapters

addressing these effects, information on both measurement and prevalence

of ETS exposures of the developing child (in utero, during infancy, and during childhood) is described when available. 

ETS is a complex mixture of chemicals generated

during the burning of tobacco products. The principal contributor to ETS is “sidestream smoke,” the

material emitted from the smoldering tobacco product between puffs. Other components of ETS

include exhaled mainstream smoke, mainstream smoke emitted at the

mouthpiece during puff drawing, and compounds diffused through the

wrapper. “Mainstream smoke” is the complex mixture that exits from the

mouthpiece of a burning cigarette when a puff is inhaled by the smoker. 

When a cigarette is smoked, approximately one-half or more of the

smoke generated (by weight) is sidestream smoke emitted from the smoldering cigarette. The chemical composition of mainstream smoke has been

more extensively characterized than that of sidestream smoke, but they are

produced by the same fundamental processes, such that many chemical

constituents are present in both. Over 4,000 individual constituents have

been identified in mainstream smoke, and approximately 400 compounds

have been measured quantitatively in both mainstream and sidestream

smoke. 

12

Smoking and Tobacco Control Monograph No. 10

1 The U.S. EPA (1992) report is the primary source of information presented in this section;

unless a specific reference is provided, the information in this section has been taken

from that report.

2.2 PROPERTIES OF ETS AND

ITS CONSTITUENTS

2.2.1 Physical and Chemical

Properties of ETS1
The large number of constituents results from the chemical composition of tobacco and the variety of chemical and physical processes that

occur as a cigarette is smoked. The majority of the compounds present in

mainstream smoke are formed during combustion, in a pyrolysis-distillation

zone just behind the heat-generating combustion zone (Baker, 1981).

Estimates have been made that the total number of constituents in mainstream smoke actually may be 10 to 20 times the number identified to date;

that is, mainstream smoke may comprise over 100,000 constituents.

However, these unidentified components comprise less than 5 percent of

the mass of mainstream smoke and would be present only at very low concentrations (Guerin et al., 1992). 

Although many constituents present in mainstream and sidestream

smoke are the same, there are important differences in their rates of emission into the air due to physical and chemical differences in the burning

conditions present during their generation. As discussed in Respiratory

Health Effects of Passive Smoking: Lung Cancer and Other Disorders (U.S. EPA,

1992: pages 3-2 to 3-10), some constituents have a higher rate of release

into sidestream than mainstream smoke, while for others the reverse is true.

Once emitted into the air, sidestream smoke may undergo various physical

and chemical changes. Dilution, chemical reactions, deposition, and other

removal processes may decrease the concentration of the airborne constituents of ETS, alter the size distribution of suspended particles, and

chemically modify some of the more reactive constituents of ETS. 

The delivery of selected agents in the mainstream smoke of nonfilter cigarettes and the ratios of the relative distribution of these agents in

sidestream to mainstream smoke are given in U.S. EPA (1992: Table 3-1). As

discussed by U.S. EPA (1992: pages 3-4 to 3-6), sidestream to mainstream

ratios are highly variable and can be misleading, as a number of factors

affecting cigarette design (e.g., presence of a filter and filter ventilation) and

smoking patterns (e.g., puff volume) have a substantial impact on the emissions of mainstream smoke. In contrast, sidestream smoke emissions show

relatively little variability as a function of most of these same factors. A

study of the influence of puff volume and filter ventilation on sidestream

and mainstream deliveries illustrates this point (Browne et al., 1980). The

mainstream delivery of particulate matter and carbon monoxide increases

with puff volume, but decreases with increasing filter ventilation. Because

the sidestream delivery of these constituents remains relatively constant,

the corresponding sidestream to mainstream ratios will decrease or increase

as a function of the specific condition and constituent examined (Table

2.1). 

Data on sidestream emission rates from filtered and commercial cigarettes for many compounds of public health interest are tabulated in U.S.

EPA (1992: Table 3-2). While the data are limited, they suggest that sidestream deliveries are relatively constant across a number of products, with

differences ranging two- to three-fold when measured under standard smoking conditions. These results are consistent with the finding that side13

Chapter 2
stream deliveries are primarily related to the weight of the tobacco and

paper consumed during smoldering, rather than to cigarette design (Guerin

et al., 1992). 

A number of chemicals known or suspected to contribute to adverse health effects are present in tobacco

smoke (mainstream and sidestream smoke), including eye and respiratory

irritants, systemic toxicants, mutagens, carcinogens, and reproductive toxicants. It is outside the scope of this review to assess exposure to each of the

numerous individual constituents of ETS or their specific contribution to

the health effects associated with ETS. This section provides a brief discussion of some of the more toxicologically significant compounds identified

in tobacco smoke. 

Irritants and toxicants with other acute health effects have

been identified in ETS, including ammonia, acrolein, carbon monoxide, formaldehyde, hydrogen cyanide, nicotine, nitrogen oxides,

phenol, and sulfur dioxide. Ammonia, formaldehyde, and sulfur dioxide

are respiratory irritants and may exacerbate the condition of people with

breathing difficulties. Several components, including acrolein, crotonaldehyde, formaldehyde, and hydrogen cyanide, affect mucociliary function,

and at a sufficiently high concentration can inhibit clearance of smoke par14

Smoking and Tobacco Control Monograph No. 10

Milligrams per Cigarette and SS/MS ratio

# of Particulate Matter Carbon Monoxide

Variablea Puffs MS SS SS/MS MS SS SS/MS

Puff Volume 

None, 

Free burn 0 -- 23 -- -- 58 --

17.5 cc 9.6 29 23 0.8 9 63 7

35 cc 8.7 46 20 0.4 19 50 2.6

50 cc 7.4 55 21 0.4 20 56 2.8

Filter Ventilationb

0% 8.7 46 20 0.4 19 50 2.6

33% 8.8 32 21 0.6 13 49 3.8

48% 9.8 21 21 1.0 7 58 8.3

83% 10.6 12 21 1.8 2 56 2.8

Browne et al. (1980)

a USA blend cigarette, FTC smoking conditions unless otherwise noted.

b Percentage of mainstream puff air entering through periphery of filter.

Table 2.1

Influence of Puff Volume and Filter Ventilation on Deliveries of Particulate Matter and

Carbon Monoxide in Mainstream and Sidestream Smoke

2.2.2 Biologically Active

Constituents of ETS

2.2.2.1 Toxicants with

Acute Effects
Chapter 2

15

COMPOUND IARC U.S. EPA CAL/EPA

Classificationa Classificationb Prop 65c

//TACd

Organic Compounds

Acetaldehyde 2B B2 yes//yes

Acetamide 2B yes//yes

Acrolein 3 C --- //yes

Acrylonitrile 2A B1 yes//yes

4-Aminobiphenyl 1 yes//yes

Aniline 3 B2 yes//yes

o-Anisidine 2B yes//yes

Benz[a]anthracene 2A B2 yes//yes

Benzene 1 A yes//yes

Benzo[b]fluoranthene 2B B2 yes//yes

Benzo[j]fluoranthene 2B yes//yes

Benzo[k]fluoranthene 2B B2 yes//yes

Benzo[a]pyrene 2A B2 yes//yes

1,3-Butadiene B2 yes//yes

Captan 3 yes//yes

Carbon disulfidee yes//yes

Carbon monoxidee yes//---

Chrysene 3 B2 yes//yes

DDT 2B yes//---

Dibenz[a,h]acridine 2B yes//yes

Dibenz[a,j]acridine 2B yes//yes

Dibenz[a,h]anthracene 2A B2 yes//yes

7H-Dibenzo[c,g]carbazole 2B yes//yes

Dibenzo[a,e]pyrene 2B yes//yes

Dibenzo[a,h]pyrene 2B yes//yes

Dibenzo[a,i]pyrene 2B yes//yes

Dibenzo[a,l]pyrene 2B yes//yes

1,1-Dimethylhydrazine 2B yes//yes

1-Naphthylamine 3 yes//---

2-Naphthylamine 1 yes//---

Nicotinee yes//---

2-Nitropropane 2B yes//yes

N-Nitrosodi-n-butylamine 2B B2 yes//---

N-Nitrosodiethanolamine 2B B2 yes//---

N-Nitrosodiethylamine 2A B2 yes//---

N-Nitroso-n-methylethylamine 2B B2 yes//---

N’-Nitrosonornicotine 2B yes//---

N-Nitrosopiperidine 2B yes//---

N-Nitrosopyrrolidine 2B ---//yes

Styrene 2B ---//yes

Toluenee yes//yes

2-Toluidine 2B yes//yes

Urethane 2B yes//---

Vinyl chloride 1 yes//yes

Table 2.2

Chemical Constituents of Tobacco Smoke That Have Been Classified or Identified as to

their Carcinogenicity, Reproductive Toxicity, or Other Health Hazard
ticles from the lung (Battista, 1976). Nicotine, which is the principal alkaloid in tobacco, is a major contributor to the addictive properties of tobacco. Nicotine has diverse pharmacologic and toxicological actions, ranging

from acute poisoning to chronic effects, some of which may be responsible

for some of the adverse health effects associated with smoking. 

Over 50 compounds have been identified in tobacco smoke

that are recognized as known or probable human carcinogens.

These compounds, which may occur naturally in tobacco or which are

formed during combustion, reside mainly in the particulate phase (IARC,

1986). Most of the major classes of carcinogens, including both organic

and inorganic constituents, are represented. Table 2.2 lists those compounds detected in tobacco smoke for which there is evidence of animal or

human carcinogenicity, as evaluated by the U.S. EPA or the IARC. Also in

Table 2.2 are compounds listed as carcinogens under California’s Safe

Drinking Water and Toxic Enforcement Act of 1986 (Proposition 65,

California Code of Regulations, Title 22, Section 12000) and a number of

tobacco smoke constituents that have been identified as toxic air contaminants by the California Air Resources Board (ARB, 1993). Tobacco smoke

itself is listed as a carcinogen under Proposition 65.

16

Smoking and Tobacco Control Monograph No. 10

COMPOUND IARC U.S. EPA CAL/EPA

Classificationa Classificationb Prop 65c

//TACd

Inorganic Compounds

Arsenic 1 A yes//yes

Cadmium 2A B1 yes//yes

Chromium V1 1 A yes//yes

Leade 2B B2 yes//yes

Nickel 1 A yes//yes

Table 2.2 (Continued )

Sources: ARB (1993); IARC (1985, 1986, 1987, 1992); California Code of Regulations

(1994); U.S. EPA (1994)

a International Agency for Research on Cancer (IARC) Classification: 1, carcinogenic to

humans; 2A, probably carcinogenic to humans; 2B, possibly carcinogenic to humans; 3, not

classifiable as to its carcinogenicity to humans.

b U.S. EPA Classification: A, human carcinogen; B1, probable human carcinogen (primarily

on the basis of epidemiological data); B2, probable human carcinogen (primarily on the basis

of animal data); C, possible human carcinogen.

c Chemicals listed under Proposition 65 are known to the State to cause cancer or reproductive toxicity (California Health and Safety Code Section 25249.5 et seq.).

d Substances identified as Toxic Air Contaminants by the Air Resources Board (ARB), pursuant to the provisions of AB 1807 and AB 2728 (includes all Hazardous Air Pollutants listed in

the Federal Clean Air Act Amendments of 1990).

e Reproductive toxicant

2.2.2.2 Toxicants with

Carcinogenic Effects
Conditions in the burning cone of a cigarette are favorable for the

formation of polycyclic aromatic hydrocarbons (PAHs). Over 35 different

PAHs have been identified in tobacco smoke (IARC, 1986), several of which

are carcinogenic (e.g., benz[a]anthracene, benzo[a]pyrene, and

dibenz[a,h]anthracene). N-Nitrosamines are formed during the curing (drying) of the tobacco leaf and in large part during combustion while smoking.

N-Nitrosamines identified in tobacco smoke include volatile (e.g., N-nitrosodimethylamine), nonvolatile (e.g., N-nitrosodiethanolamine), and tobaccospecific compounds (e.g., N-nitrosonornicotine), formed by N-nitrosation of

nicotine and other pyridine alkaloids. Most of the identified nitrosamines

are carcinogens in experimental animals and some (e.g., N-nitrosodimethylamine) are present in sidestream smoke in amounts 10 to 200 times greater

than in mainstream smoke (U.S. DHHS, 1986; Löfroth, 1989). By weight,

the tobacco-specific nitrosamines are the most prominent of the suspected

carcinogens identified thus far (IARC, 1986). In addition, the inhalation of

nitrogen oxides and amines in tobacco smoke may contribute to the

endogenous formation of carcinogenic N-nitrosamines (Hoffmann and

Brunneman, 1983; Ladd et al., 1984). Other well-established organic carcinogens identified in tobacco smoke are aromatic amines (e.g., 4-aminobiphenyl, 2-naphthylamine and o-toluidine), benzene, hydrazine, and vinyl

chloride. 

Like other plant tissues, tobacco contains minerals and other inorganic constituents derived from soil, fertilizers, agricultural sprays, and polluted rainfall. Upon combustion, most metals remain in the ash; however,

some are vaporized or carried in fragments of ash and thus are also found

in tobacco smoke. Several of these metals, including arsenic, cadmium, and

chromium, are known to be carcinogenic to humans following inhalation. 

Tobacco contains a number of naturally occurring radionuclides, of

which the most important is the alpha-emitter polonium-210 (Cohen et al.,

1980). Polonium-210 and lead-210 in tobacco originate from phosphate

fertilizers (Tso, 1966) and/or from airborne particles containing lead-210

that are trapped by the trichomes of tobacco leaves (Martell, 1974).

Although not a direct source of radon, ETS in indoor environments is associated with an increase in the airborne concentrations of radon decay products, presumably because newly formed decay products are more likely to

attach to smoke particles than to other surfaces in a room (Bergman et al.,

1986). All radioactive chemicals can cause cancer in humans and animals.

Though not all mutagens are carcinogens, mutagenicity tests have

proven to be useful in identifying chemicals that can alter the integrity of

genetic materials and may thus have carcinogenic potentials. Several studies have shown that the semivolatile and particle-bound organic fractions

of sidestream smoke are mutagenic in bacterial systems (Löfroth et al., 1983;

Ong et al., 1984; Löfroth and Lazaridis, 1986; Ling et al., 1987; Claxton et

al., 1989). The results from a variety of short-term tests for genetic endpoints on mainstream smoke and tobacco smoke condensate have been

reviewed by DeMarini (1983), Obe et al., (1984), and IARC (1986). In addi17

Chapter 2
tion, many of the individual constituents of ETS are positive in one or more

short-term tests for genetic activity (Claxton et al., 1989). 

Several compounds listed as developmental or reproductive

toxicants under California’s Proposition 65 have been

detected in tobacco smoke (Table 2.2). ETS constituents

identified as developmental toxicants under Proposition 65 are carbon

disulfide, carbon monoxide, lead, nicotine, cadmium, and toluene. Lead

and carbon disulfide have also been identified as agents causing male and

female reproductive toxicity. Additional ETS constituents investigated as

possible mediators of the developmental or reproductive toxicity of tobacco

smoke include PAHs, which have been found to cause developmental and

reproductive effects in experimental animals. Exposure to tobacco smoke

due to active smoking has been listed as a developmental toxicant as well as

a female and male reproductive toxicant under Proposition 65 (listed as

“tobacco smoke (primary)”); however, ETS has not been listed.

This section summarizes a number of different techniques used by researchers for estimating the degree of

ETS exposure of their subjects. In order to investigate

the health effects of ETS exposure, epidemiologists

characterize the exposure level of their subjects to

determine the extent to which exposure is correlated

with an adverse health effect. Given the extreme spatial and temporal variation of ETS concentration in indoor and outdoor

environments, it is not technically or economically feasible to accurately

determine the long-term ETS exposure history of an individual. Yet often

times it is the long-term exposure to ETS that is of interest in examining

health effects such as developmental effects and cancers. Epidemiologists

circumvent this difficulty by using questionnaires or interviews to determine the status of the subjects with respect to long-term exposure to ETS

and then classifying the subjects into categorical groups of ETS exposure

(e.g., none, low, medium, or high). In this way, they make the best use of

the semi-quantitative exposure information available without compromising the validity of the study results. One drawback of this approach is that

it decreases the sensitivity or power of the study—i.e., a study will not show

a positive association when ETS exposure and an adverse health effect are

only moderately related. Some of the indirect and direct methods used by

researchers in the study of ETS exposure are discussed in the following sections.

Indirect methods for assessing exposure include measurements of

indoor air concentrations of ETS constituents (discussed in this section),

and population surveys and questionnaires used to assess the characteristics, patterns, and extent of exposure (Section 2.5). Direct methods for

assessing ETS exposure include the use of personal monitors (discussed in

this section and in Section 2.4) and measurement of biomarkers of exposure. Personal monitors measure concentrations of ETS constituents at or

near the breathing zone and can be worn by individuals to assess exposures

18

Smoking and Tobacco Control Monograph No. 10

2.2.2.3 Toxicants with

Effects on Development

and Reproduction

2.3 EXPOSURE

MEASUREMENT: ETS

CONCENTRATIONS IN

INDOOR ENVIRONMENTS

2.3.1 Introduction to

Exposure Measurement
occurring in a specific location or accumulated throughout the day, thus

providing an integrated measure of short-term exposure. They are often

used in conjunction with other methods to compare or validate assessment

of exposure. Measurement of biomarkers, ETS constituents or their metabolites in physiological fluids (such as urine, serum, and saliva), is the most

direct assessment of ETS exposure available (Section 2.4). Biomarkers are

often used to study exposure prevalence and to evaluate the degree of misclassification in epidemiologic studies.

Modeling exposure on the basis of measured or modeled air concentrations, and the time an individual spends in a specific environment, is

another indirect method for assessing ETS exposure. Recently, some

researchers have developed and successfully applied models for predicting

airborne ETS constituent concentrations (Ott et al., 1992). For example,

using an estimated cigarette source strength, air exchange rate and volume

of the room, Klepeis et al. (1996) were able to predict minute-by-minute

indoor time series and time-averaged respirable suspended particle concentrations from ETS. However, airborne ETS constituent concentrations

derived from this type of model are location- and situation-specific, and

cannot be easily applied to the general population. Such air models are not

discussed further in this document.

Given the complex chemical composition of ETS2, air concentrations are typically assessed by measuring individual ETS

constituents referred to as tracers, markers, or proxy compounds. Nicotine

and respirable suspended particulates (RSP)3 are the most widely used markers for the presence and concentration of ETS in indoor environments.

Recently, some researchers have used 3-ethenylpyridine, solanesol, and

ultraviolet particulate matter as markers of ETS and suggested that they may

be better correlated with other constituents of ETS than nicotine and RSP

(Hodgson et al., 1996; Jenkins et al., 1996). 

Airborne nicotine is specific to tobacco combustion and is emitted

in large quantities in ETS. Although not specific to tobacco combustion,

large quantities of RSP are emitted during cigarette smoking, resulting in

measurable increases over background levels even under conditions of high

ventilation and low smoking rates. There are other common combustionrelated sources of indoor RSP, such as wood-burning fireplaces, gas stoves,

and kerosene space heaters, but the levels of RSP produced by these sources

are much lower than that produced by tobacco smoke. Other ETS constituents have been measured in field studies assessing the contribution of

19

Chapter 2

2 The information presented refers primarily to ETS derived from cigarettes because few data

are available for cigars and pipes.

3 The term respirable suspended particulates (RSP) has been inconsistently applied in the literature. Typically, it is used to refer to PM2.5 or PM10, i.e., particles for which the mean

aerodynamic diameter is 2.5 or 10 microns, respectively. Particles associated with ETS are

typically smaller than 1 micron, and are included in both PM2.5 and PM10.

2.3.2 Indoor Air

Measurements of ETS
smoking to indoor air quality. Typically, these constituents are not unique

to ETS, but studies indicate that concentrations of some constituents are

higher in environments where smoking takes place as compared to those

where it does not. 

While fixed location measurements of air concentrations of ETS

constituents indicate the presence of ETS and allow an estimation of the

contribution of ETS to indoor air contaminant levels, such measurements

do not constitute a direct measure of an individual’s total ETS exposure.

During the course of a single day, an individual spends varying amounts of

time in a number of different environments; for that individual, the total

exposure is the sum of the concentration at each location multiplied by the

time spent at that location. Further, for different individuals exposed to the

same concentration levels of ETS constituents in the same room, the actual

dose will vary as a function of a number of factors, including gender, age,

specific activity level, and breathing rate at the time of exposure.

The data presented in the following sections on individual ETS constituents have been summarized from a large number of studies of different

microenvironments, primarily within the United States. The measured concentrations of individual constituents in homes and other indoor environments show marked spatial and temporal variation as a result of the complex interaction of factors related to the introduction, removal, and dispersion of ETS constituents. These factors include the rate of tobacco consumption, room size, the location at which smoking occurs, the placement

of air monitors, the ventilation or infiltration rate, air mixing, and removal

of contaminants by air filters or deposition. With few exceptions, studies

were not designed to determine representative ETS concentrations within a

particular environment or area of the country. However, it is expected that

the ranges reported are typical of similar environments within California.

Measurements from the few studies specific to California are reported separately. 

Over 25 separate studies have measured concentrations of nicotine in well over 100 different indoor microenvironments. The

results of these studies are summarized in U.S. EPA (1992:

Section 3.3.1 and Figures 3-4 and 3-7). An extensive compilation of measured nicotine concentrations in various indoor environments is also given

in Guerin et al. (1992). Because airborne nicotine is generally specific to

the combustion of tobacco, any detectable concentrations can be attributed

to ETS (the few exceptions include areas such as work environments in

which tobacco is processed). Both chamber studies (Baker and Proctor,

1990; Eatough et al., 1990; Nelson et al., 1992) and indoor air measurements (Löfroth, 1993) suggest that nicotine disappears from air faster than

other ETS constituents, and hence, its use as a marker may underestimate

the relative concentrations of other constituents. 

Measurements taken in a wide variety of indoor environments in

the U.S. indicate that most average concentrations of nicotine range about

20

Smoking and Tobacco Control Monograph No. 10

2.3.3 Indoor Air

Concentrations of

Nicotine
100-fold, from 0.3 to 30 μg/m3. The average concentration in residences

with one or more smokers typically ranges from 2 to 10 μg/m3, with high

values of up to approximately 14 μg/m3. Measured concentrations are typically higher in the winter than in summer months. In data collected from

the mid-1970’s through 1991, concentrations of nicotine in the workplace

were similar to those measured in residences, with the range of average concentrations showing considerable overlap for the two locations. However,

the maximum values for workplaces were considerably higher than in residences. In a recent paper, Hammond et al. (1995) showed that ETS exposures in workplaces that allow smoking are comparable with, and often

greater than, ETS exposures in smokers’ homes. The highest nicotine concentrations in indoor environments were measured in bars and in the

smoking sections of airplanes, with levels reaching as high as 50 to 75

μg/m3 (U.S. EPA, 1992). (Note: for several years, smoking has been prohibited on domestic flights of commercial airplanes). In a comprehensive survey of indoor measurements, the maximum nicotine concentrations were

30 μg/m3 or less in over 50 percent of the studies examined, and less than

100 μg/m3 in 90 percent of the studies (Guerin et al., 1992). The highest

reported level in the survey was 1010 μg/m3, measured in a passenger car

with the ventilation system shut off. In selected studies using controlled

and field conditions, the concentrations of nicotine were found to increase

as a function of the number of smokers present and the number of cigarettes consumed (U.S. EPA, 1992: Section 3.3.1.2 and pages 3-32 to 3-33). 

Results of four studies (three in the U.S.) using personal monitors to

assess exposure of nonsmokers to nicotine are presented in U.S. EPA (1992:

page 3-37). The average personal exposures associated with the specific

microenvironments in the U.S. for which measurements were taken ranged

from 4.7 to 20.4 μg/m3. In comparing the levels determined from stationary and personal samples, Guerin et al. (1992) reported that in one study,

concentrations determined by the stationary sampler were higher than

those from the personal monitor. In a second study, the reverse was found

to be true. In a more recent study (Jenkins et al., 1996), breathing zone air

samples were taken of approximately 100 nonsmoking individuals in each

of 16 metropolitan areas of the U.S. The mean 24-hour time-weighted average nicotine concentration for those who were exposed to ETS at work and

away from work (3.27 μg/m3) was higher than those who were only

exposed to ETS away from work (1.41 μg/m3) or those who were only

exposed at work (0.69 μg/m3). The mean nicotine concentration measured

by personal monitoring for those who were not exposed to ETS was 0.05

μg/m3.

Nicotine measurements in California residences were included in a

large-scale field study of particle exposure in Riverside in 1990, in which

178 nonsmokers over the age of 10 wore personal particle monitors for two

consecutive 12-hour periods (Ozkaynak et al., 1994). Particle samples were

taken concurrently in indoor and outdoor air. Due to budget constraints,

only a portion of the samples from nonsmoking homes was analyzed for

nicotine, while all samples from smoking homes were analyzed.

21

Chapter 2
Approximately 30 percent of all personal and indoor samples analyzed were

above the detection limit (about 0.05 μg/m3), with 76 percent of the personal samples from individuals reporting one or more minutes of exposure

to ETS above the limit of detection. For those samples exceeding the detection limit, the mean personal 12-hour nicotine concentration for individuals reporting exposure to ETS was 0.96 μg/m3, and 0.11 μg/m3 for individuals with no reported exposure. The mean indoor concentration of nicotine

in homes in which at least one cigarette was smoked (1.07 μg/m3) was significantly higher than in homes with no reported smoking (0.10 μg/m3). 

A large number of studies have measured concentrations of

ETS-associated RSP in indoor microenvironments. These studies are summarized in U.S. EPA (1992: Figures 3-5, 3-8, and 3-

10). An extensive compilation of RSP measurements is also given in Guerin

et al. (1992). In contrast to nicotine, RSP is not specific to ETS and thus RSP

measurements in environments where smoking occurs must be compared

to concentrations in comparable environments where smoking does not

occur. Similar to nicotine, measured concentrations of ETS-associated RSP

range about 100-fold, from 5 to 500 μg/m3 over a wide variety of indoor

environments. In residences with one or more smokers, average daily or

weekly concentrations of ETS-associated RSP are increased about 20 to 100

μg/m3 over concentrations in similar nonsmoking environments.

Somewhat lower levels are reported in the workplace (offices), with average

concentrations ranging from approximately 2 to 60 μg/m3 over concentrations in similar nonsmoking environments. Both the maximum reported

concentration (1,370 μg/m3) measured in any environment and the highest

range of average concentrations (approximately 35 to 986 μg/m3) were for

restaurants (U.S. EPA, 1992: Figure 3-8). 

Studies comparing RSP concentrations in similar locations in which

smoking does and does not take place consistently show higher RSP concentrations in environments where smoking occurs. Typically, the differences range from less than 10 percent to approximately three-fold higher,

although larger differences have been reported (Guerin et al., 1992). Under

selected and controlled field conditions, the concentration of ETS-associated RSP has been found to increase with increased smoking (U.S. EPA, 1992:

page 3-34). 

Recently, Ott et al. (1996) measured RSP in a large sports tavern in

Northern California on 26 dates between 1992 and 1994 during which

smoking was allowed, and subsequently made additional measurements

during the year after smoking was prohibited. Though the degree of active

smoking in the tavern was characterized as low by the authors, they reported that the average RSP concentration indoors was 56.8 μg/m3 above the

outdoor concentration. After smoking was prohibited, another set of 26

follow-up visits (matched to the earlier smoking visits by time of day, day of

the week, and season), yielded an average RSP concentration that was 77

percent of the average concentration during the smoking period. No

decrease in tavern attendance was evident after smoking was prohibited.

22

Smoking and Tobacco Control Monograph No. 10

2.3.4 Indoor Air

Concentrations of

Particulate Matter
Results of five studies using personal monitors to assess exposure of

nonsmokers to RSP are presented in U.S. EPA (1992: page 3-38). Only three

studies reported exposures integrated over several different environments,

with exposure to ETS-associated RSP resulting in increased concentrations

of 18 to 64 μg/m3. Those individuals reporting exposure to ETS had substantially increased exposure to RSP as compared to individuals reporting

no ETS exposure. In a more recent study, Jenkins et al. (1996) took breathing zone air samples of approximately 100 nonsmoking individuals in each

of 16 metropolitan areas of the U.S. The mean 24-hour time-weighted average RSP concentration for those who were exposed to ETS at work and away

from work (47 μg/m3) was higher than for those who were only exposed to

ETS away from work (33 μg/m3) or those who were only exposed at work

(28.7 μg/m3). The mean RSP concentration measured by personal monitoring of those who were not exposed to ETS was 18.1 μg/m3.

Data specific to California are available from one field study conducted in 178 randomly selected homes in the city of Riverside (Pellizzari et

al., 1992). Indoor air concentrations of particles 10 micrometers or less in

aerodynamic diameter (PM10) were significantly higher in homes in which

smoking occurred (n = 28 homes for daytime measurement, 30 for nighttime), as compared to the homes without smoking (n = 139 homes for daytime measurement, 131 for nighttime)—samples from a few homes were

lost due to pump or power failure, or quality control concerns. Mean PM10

levels in the homes with smoking were elevated (125.6 μg/m3 for the 12-

hour daytime measurement, 92.9 μg/m3 nighttime) above those in homes

without smoking (87.8 μg/m3 daytime, 54.6 μg/m3 nighttime) by a consistent amount (approximately 38 μg/m3; Pellizzari et al., 1992). Average personal exposures to PM10 were significantly higher for those persons (n =

29) reporting exposure to ETS during the nighttime period as compared to

persons (n = 139) reporting no ETS exposure during the nightime (104.2

versus 71.4 μg/m3). However, no significant difference in average personal

exposures to PM10 was found for the daytime period (n = 61 ETS-exposed,

110 unexposed; 155.2 μg/m3 versus 146.8 μg/m3). 

Numerous field studies have been conducted to assess the

contribution of smoking to indoor air pollution. Data for

select constituents of public health concern, including Nnitrosamines, benzene, benzo[a]pyrene and total PAHs, carbon monoxide,

formaldehyde, and toluene are presented in U.S. EPA (1992: Table 3-3 and

Figure 3-3), as are references to the literature (U.S. EPA, 1992: Section 3.3.1).

An extensive compilation of data from measurements of a variety of ETSderived constituents is also given in Guerin et al. (1992). 

Because sources other than ETS exist for many of these constituents,

it has been difficult for studies to consistently demonstrate elevated concentrations in smoking environments. For example, formaldehyde, which

is present in a number of consumer products and building materials, is

emitted from these sources at rates usually exceeding those from smoldering cigarettes. Carbon monoxide (CO) is also released from other sources,

23

Chapter 2

2.3.5 Indoor Air

Concentrations of

Other ETS Constituents
including gas stoves and heaters, and may be found indoors from air

exchange with outdoor air contaminanted by vehicle exhaust; thus, it is

often difficult to ascertain the contribution to indoor CO levels due to cigarette smoke (Guerin et al., 1992). However, for many constituents, concentrations in environments where smoking occurs are elevated above levels in

comparable environments where smoking does not occur, particularly for

those environments in which heavy smoking occurs. Concentrations of

ETS-associated constituents measured in different indoor environments are

highly variable, depending on factors such as extent of smoking, air

exchange rates, and room size. 

Concentrations of a variety of toxic air pollutants have been

measured in California homes. Indoor concentrations of 13

PAHs measured in the homes in the Riverside field study (Pellizzari et al.,

1992) described in Section 2.3.4 were reported by Sheldon et al. (1992b).

The oncentrations of most of the PAHs analyzed were significantly higher

(approximately 1.5- to 2-times higher) in homes in which smoking

occurred, as compared to the concentrations in homes without smoking

(number of samples in homes with smoking/homes without: daytime,

17/93; nighttime, 21/85). Included in the analyses were five PAHs

(benzo[a]anthracene, benzo[a]pyrene, benzo[k]fluoranthene, chrysene, and

indeno[1,2,3-cd]pyrene) which are listed as carcinogens under Proposition

65 and detected in ETS. As an example of the magnitude of the concentrations measured, the average 12-hour daytime indoor concentration of

benzo[a]pyrene was 0.51 ng/m3 in homes in which smoking occurred and

0.20 ng/m3 in homes without smoking (Sheldon et al., 1992b). 

A second field study in California (Sheldon et al., 1993) examined

the relationship between indoor concentrations of 14 PAHs and different

combustion sources (tobacco smoking, fireplaces, woodstoves, and gas

heaters); measurements were taken in 280 homes in Placerville and

Roseville. Indoor PAH concentrations in the 64 homes in which tobacco

smoking occurred were significantly higher (approximately 1.5 to 4 times

higher) than in the 39 homes with no specified indoor combustion source.

Of the indoor combustion sources examined, tobacco smoking appeared to

have the strongest effect on indoor levels of PAHs. As an example of the

magnitude of the measured concentrations, the average 24-hour concentrations of benzo[a]pyrene associated with indoor combustion sources were as

follows: tobacco smoking, 2.2 ng/m3; woodstove use, 1.2 ng/m3; fireplace

use, 1.0 ng/m3; gas heat use, 0.41 ng/m3; and no specified indoor combustion source, 0.83 ng/m3 (Sheldon et al., 1993). 

Other toxic air pollutants (30 volatile and semivolatile organic

compounds) were measured in a study of 128 homes in the city

of Woodland. Indoor samples were collected in all homes and personal

monitoring samples for volatile organic compounds were collected for

93 individuals. About 61 percent of the homes were nonsmoking homes,

and smoking occurred in about 39 percent of the homes during the monitoring period. Homes (n = 15) in which heavy smoking (>20 cigarettes

24

Smoking and Tobacco Control Monograph No. 10

2.3.5.1 Polycyclic

Aromatic Hydrocarbons

2.3.5.2 Other

Organic Compounds
smoked/24-hour period) occurred had elevated concentrations of benzene,

para-dichlorobenzene4, tetrachloroethylene, trichlorethylene4, and xylene

(ortho and meta/para) as compared to homes with no smoking. Personal

monitoring air concentration samples of benzene and para-dichlorobenzene

were also higher for persons in homes with “any smoking” and those with

“heavy smoking” compared to homes with no smoking. However, for both

the indoor and personal air measurements, these differences were not statistically significant at the p = 0.05 level, as determined using pairwise t tests

(Sheldon et al., 1992a). Hodgson et al. (1996), using 3-ethenylpyridine as a

tracer, investigated the contribution of ETS to the measured volatile organic

compounds concentrations in several environments in California where

smoking was allowed. In their report, ETS was estimated to contribute 57-

84 percent of the formaldehyde concentrations, 43-69 percent of the 2-

butanone concentrations, 37-58 percent of the benzene concentrations, and

20-70 percent of the styrene concentrations. The fractional contributions

of ETS to the concentrations of acetone, toluene, ethylbenzene, xylene isomers, and d-limonene were all less than 50 percent (Hodgson et al., 1996).

This section addresses use of biomarkers to measure ETS

exposure, with a focus on nicotine and cotinine. Topics

covered include: measured concentrations in physiological fluids of adults; comparisons of levels in smokers, ETS-exposed nonsmokers, and unexposed nonsmokers; and concentrations in physiological

fluids of infants and children, and in breast milk and amniotic fluid. The

use of levels of exhaled carbon monoxide and blood levels of carboxyhemoglobin, as well as thiocyanate levels in blood, urine, and saliva as biomarkers of ETS exposure are also addressed. Measurement of DNA and protein

adducts, and other approaches to assessing tobacco smoke exposure, are discussed briefly. Other sections of this chapter summarize studies of exposure

prevalence as determined by the presence of nicotine or cotinine in body

fluids (Section 2.6) and studies using biomarkers to ascertain smoking status

and estimate the degree of misclassification in epidemiological studies

(Section 2.5).

Exposure to ETS can be assessed directly by the analysis of

physiological fluids (urine, saliva, and serum) for tobacco

smoke constituents or their metabolites, referred to as “biomarkers.” Nicotine, cotinine, thiocyanate, carboxyhemoglobin, hydroxyproline, N-nitrosoproline, aromatic amines, and certain protein or DNA

adducts have been used as indicators of exposure to tobacco smoke. These

biomarkers do not indicate the presence of disease, however, or of an individual’s susceptibility to disease due to exposure to tobacco smoke. The

appropriateness of a given biomarker depends on the nature of the study

and the type of exposure being assessed (e.g., recent or long-term). Ideally,

the biomarker should be specific to tobacco smoke, although few markers

fully meet this criterion.

25

Chapter 2

4 Although measured at elevated concentrations in homes with heavy smoking, paradichlorobenzene and trichloroethylene are not expected to be associated with ETS

(Guerin et al., 1992)

2.4 EXPOSURE

MEASUREMENT:

BIOLOGICAL MARKERS

2.4.1 Introduction to

Biological Markers of

ETS Exposure 
The relationship between a biomarker and exposure is complex, and

varies as a function of both environmental and physiological factors. As

previously discussed (Section 2.3), the degree of exposure is a function of

the time an individual spends in each setting and the air concentration of

tobacco-related constituents in that environment. Factors affecting air concentrations include smoking intensity, room size, and room ventilation.

For a given air concentration, several factors will affect an individual’s

intake, such as gender, age, weight, and activity level (and corresponding

inhalation rate) at the time of exposure. In addition, individual differences

in uptake, distribution, and metabolism will affect the biomarker concentration in physiological fluids. Although the presence of a biomarker indicates that tobacco smoke exposure has occurred, the level of biomarker

measured may not be directly related to the intake level of the tobacco

smoke constituent(s) potentially implicated in the effect of interest (e.g.,

using cotinine as a biomarker of ETS exposure in a study of cancer incidence).

Nicotine and cotinine, a major metabolite of nicotine, are

the most widely used biomarkers of ETS exposure. In

general, the presence of nicotine or its metabolites in

physiological fluids can be attributed to exposure to

tobacco smoke. The few exceptions include occupational

exposure to tobacco leaves (Gehlbach et al., 1975) and

nicotine products, use of smokeless tobacco products, chewing of nicotine

gum, and use of nicotine patches or other aids for smoking cessation. Low

levels of nicotine have been found in tea and in edible solanaceous plants

including eggplant, green pepper, and tomato (Castro and Monji, 1986;

Sheen,1988; Davis et al., 1991; Domino et al., 1993a & b). While some

authors have claimed that dietary intake of nicotine may be of practical

importance in the use of nicotine and cotinine as biomarkers of ETS exposure (Domino et al., 1993a,b), others dispute this assertion (Henningfield,

1993; Jarvis, 1994; Repace, 1994; Benowitz, 1996; Pirkle et al., 1996). In

general, the levels of nicotine and nicotine metabolites in physiological fluids resulting from the ingestion of foods have not been found to significantly impact the levels resulting from exposure to nicotine from tobacco

sources. 

As biomarkers of exposure, nicotine and/or cotinine are typically

measured in blood, saliva, or urine. For studies requiring a quantitative

assessment of exposure, blood has been recommended as the fluid of

choice, although saliva and urine are also considered acceptable (Watts et

al., 1990). Cotinine levels in saliva and plasma tend to be similar, whereas

the ratio of urinary to plasma levels is generally a factor of 5 to 6 (Repace

and Lowrey, 1993; Benowitz, 1996). 

Urinary cotinine excretion is variable across and within individuals,

depending on renal function, urinary flow rate, and urinary pH (Benowitz,

1983). Urinary results may be expressed as nanograms of cotinine per milligram of creatinine in order to correct, in part, for differences in dilution

26

Smoking and Tobacco Control Monograph No. 10

2.4.2 Biomarkers:

Nicotine and Cotinine

2.4.2.1 Nicotine and

Cotinine: General methodological issues
effects. Because the amount of endogenous creatinine produced is a function of muscle mass, and hence, age and sex, individual excretion rates of

creatinine are also variable. In particular, cotinine to creatinine ratios may

not be appropriate for comparisons between males and females. In addition, low levels of creatinine in infants relative to adults may result in cotinine to creatinine ratios for infants that fall into the range reported for

active smokers (Watts et al., 1990). In general, it is preferable to collect

urine over 24 hours, although is impracticable for most studies.

The average half-life of cotinine in different body fluids (plasma,

saliva, and urine) is about the same, approximately 15 to 19 hours (Jarvis et

al., 1988; Benowitz and Jacob, 1994), making it a good indicator of the integrated ETS exposure over the previous 2 to 3 days. The half-life is typically

longer in infants and children, averaging approximately 65 hours in

neonates, 60 hours in infants under 18 months, and 40 hours in children

over 18 months (U.S. EPA, 1992: page 3-41). Nicotine, with its shorter halflife of approximately 2 hours, is a good indicator of exposures occurring

within the previous few hours. 

An interlaboratory study of data from 11 laboratories in six countries was conducted to compare analytical results for nicotine and cotinine

in serum and urine (Biber et al., 1987). The results of the study indicate

that both gas chromatography (GC) and radioimmunoassay (RIA) techniques reliably quantitate nicotine and cotinine in urine and serum samples

and that both techniques are capable of discriminating between smokers

and nonsmokers. However, interlaboratory variability was high. While the

coefficient of variation for spiked samples was low (9-13 percent), the coefficient of variation for samples from smokers was fairly large, ranging from

18 to 45 percent for serum and from 21 to 59 percent for urine. In addition, cotinine levels reported for urine, as determined by RIA, were about

60 percent higher than the levels determined by GC. Besides cotinine,

some less specific immunoassays can also react with other metabolites of

nicotine. Cotinine levels reported for nonsmokers were extremely variable,

and a number of laboratories could not detect cotinine in serum from

exposed nonsmokers. Because of these various factors, caution should be

used in making quantitative comparisons across studies. However, limitations in the design of this study have been noted (Watts et al., 1990); additional studies are required to assess the comparability of these two assay

methods and the results from different laboratories, as well as the performance of other methods (e.g., high pressure liquid chromatography (HPLC)).

A large number of studies are available which report

concentrations of cotinine in physiological fluids of

smokers and nonsmokers. The levels of ETS encountered by exposed nonsmokers during their daily activities are sufficiently

high that nicotine and cotinine are detected in their urine, blood, and saliva. The physiological concentrations of cotinine detected in saliva and

plasma of nonsmokers typically range from 0.5 ng/ml to 10 or 15 ng/ml

(Guerin et al., 1992; U.S. EPA, 1992), and urinary concentrations range to

27

Chapter 2

2.4.2.2 Nicotine and Cotinine:

Measured Concentrations in

Physiological Fluids of Adults
50 or more ng/ml. For example, Cummings et al. (1990) reported that a

population of 663 self-reported nonsmokers attending a cancer-screening

clinic in New York had a mean urinary cotinine concentration of 8.84

ng/ml (range: 0 to 85 ng/ml)—in the Cummings et al. study, a cutoff level

of 90 ng/ml was used to distinguish between smokers and nonsmokers. In

a population-based study of Hispanics in New Mexico, mean salivary concentrations of cotinine in various age groups ranged from 0 (not detected)

to 6.0 ng/ml (Coultas et al., 1987). The studies by Coultas et al. (1987) and

Cummings et al. (1990) are described in Section 2.6.3. However, it is important to realize that some of the differences in cotinine levels reported here

could be explained by the different analytical methods used. For example,

cross-reactivity of cotinine immunoassays with trans-hydroxycotinine

and/or cotinine glucuronide is probably an important contributor to the

often significantly higher levels of urinary cotinine measured by this

method compared to those measured by GC. Thus, in comparing cotinine

levels reported in various studies, it is important to consider the analytical

method employed and the specific analytes that are being measured. 

Studies of individuals exposed in locations of exceptionally high

concentrations of ETS provide some indication of the maximum concentrations of nicotine and cotinine reported in nonsmokers. Jarvis et al. (1992)

reported a median salivary cotinine concentration of 7.95 ng/ml in 42 nonsmoking bar staff in England, with a maximum concentration of

31.3 ng/ml. In a study of individuals exposed on commercial airline flights,

the highest average urinary cotinine concentrations among those who were

measured was approximately 30 ng/mg creatinine (Mattson et al., 1989). 

In one of the few controlled studies in which both ambient air and

biomarker concentrations were measured, uptake of nicotine and cotinine

was determined in 10 nonsmoking volunteers. The subjects were exposed

for 80 minutes in a 16 m3 bare room into which sidestream smoke (generated by the machine smoking of 2 to 4 cigarettes) was continuously injected

(mainstream smoke was released outside the room.) The ventilation rate

was six air exchanges per hour, reported to correspond to the average ventilation conditions in offices in the U.S. Concentrations of measured ETS

constituents attained stable levels within approximately 10 to 15 minutes,

at which time the air concentration of nicotine from the continuous smoking of four cigarettes was 280 μg/m3. The levels of nicotine and cotinine in

urine, saliva, and serum for individuals exposed to the continuous smoking

of four cigarettes are shown in Table 2.3. The average concentrations of

nicotine in saliva increased significantly, reaching a maximum concentration of 880 ng/ml after 60 minutes of exposure. Following cessation of

exposure, nicotine concentrations decreased rapidly, reaching pre-exposure

levels in 2 to 3 hours. Cotinine concentrations continued to increase

throughout the duration of the experiment, reaching concentrations of 3.4

ng/ml and 55 ng/mg creatinine in serum and urine, respectively, 6 hours

and 20 minutes after exposure began (Hoffmann et al., 1984). 

28

Smoking and Tobacco Control Monograph No. 10
Chapter 2

Limited information on cotinine concentrations in California subjects is available from a large multinational study which included a center

located in Los Angeles (Riboli et al., 1990). Study subjects were 100 nonsmoking women with the following marital and employment status: 13 percent married to a smoker and employed; 39 percent married to a smoker

and unemployed; 16 percent not married to a smoker and employed; and

32 percent not married to a smoker and unemployed. The mean urinary

cotinine to creatinine concentration was approximately 8.5 ng/mg for the

entire population and 10.5 ng/mg for those with detectable urinary concentrations. The differences in cotinine levels were found to be large and statistically significant between the 13 centers, and the concentrations at the

Los Angeles center was one of the three highest of the centers in the study. 

Studies comparing ETS-exposed and unexposed nonsmokers and active smokers (Matsukura et al., 1979;

Wilcox et al., 1979; Williams et al., 1979; Haley et al.,

1983; Hill et al., 1983; Jarvis and Russell, 1984; Wall et

al., 1988) have consistently found that measurement of cotinine in the

urine, saliva, or serum can distinguish active smokers from unexposed and

ETS-exposed nonsmokers. Findings have been less consistent with regard to

the use of such assays to distinguish between self-reported unexposed and

29

Saliva (ng/ml) Plasma (ng/ml) Urine (ng/mg creatinine)

Time Nicotine Cotinine Nicotine Cotinine Nicotine Cotinine

Minutes of exposure

0 (baseline) 3 1.0 0.2 0.9 17 14

40 830 1.1 0.3 0.9 --a ---

60 880 2.1 0.3 1.2 --- ---

80 730 1.4 0.5 1.3 84 28

Minutes post exposure

30 148 1.7 0.4 1.8 --- ---

150 17 3.1 0.7 2.9 100 46

240 3 2.0 1.1 3.3 --- ---

300 7 3.5 0.6 3.4 48 55

Table 2.3

Mean Concentrations of Nicotine and Cotinine in the Saliva, Plasma, and Urine of

ETS-Exposed Volunteersa

Source: Hoffmann et al. (1984)

a Individuals were exposed to ETS generated from continuous smoking of 4 cigarettes by

machine. The air concentration of nicotine stabilized at approximately 280 μg/m3 within 10 to 15

minutes.

b Samples not taken for this exposure interval.

2.4.2.3 Nicotine and Cotinine:

Comparison of Levels in

Smokers, and ETS-exposed and

Unexposed Nonsmokers
ETS-exposed nonsmokers. As discussed by Wall et al. (1988), potential reasons for this include intersubject variability in nicotine metabolism

(Benowitz et al., 1982); time of day of sample collection (Jarvis and Russell,

1984); misreporting of smoking status (Jarvis and Russell, 1984; Jarvis et al.,

1987); misreporting of nonsmoking status; adjustment of cigarette consumption for nicotine content (Benowitz et al., 1983); and over- or underreporting of ETS exposure. Another reason is that in the past some of the

methods used for cotinine analysis were simply not sensitive enough to

detect the very low concentration of cotinine in saliva or serum resulting

from ETS exposure.

The levels of nicotine, cotinine and other ETS biomarkers measured

in a study by Jarvis and Russell (1984) are shown in Table 2.4. Study subjects were 100 outpatients, mostly elderly, attending cardiology and vascular clinics at a London hospital. Individuals reported their degree of exposure to ETS over the 3-day period preceding sample collection. In general,

concentrations of nicotine and cotinine in ETS-exposed nonsmokers were

higher than those in nonsmokers reporting no exposure to ETS. The levels

of cotinine in all fluids were significantly higher in smokers than in ETSexposed and unexposed nonsmokers, with cotinine levels in ETS-exposed

nonsmokers approximately 1 percent of the levels found in active smokers.

In this study, concentrations of plasma nicotine were not related to reported exposure. 

Recently, an increasing number of epidemiological studies have

used biomarkers in assessing tobacco smoke exposure. Biomarkers can be

used to categorize individuals as exposed or unexposed, identify deceivers

(individuals misreporting their smoking status), or estimate relative degree

of exposure. In a comparison of tests to distinguish smokers from nonsmokers, Jarvis et al. (1987) analyzed questionnaire responses and biochemical measures of exposure to cigarette smoke in 211 hospital outpatients.

The optimal cutoff levels (in plasma, saliva, and urine) for distinguishing

smokers and nonsmokers as reported in that study are shown in Table 2.5.

Examples of typical cutoff levels for distinguishing smokers from nonsmokers reported in studies using cotinine as the marker of exposure are shown

in Table 2.6 (the use of biomarkers to ascertain smoking status and estimate

the degree of misclassification in epidemiological studies is discussed in

Section 2.5).

For all body fluids, the concentration distributions for smokers and

exposed nonsmokers have been found to overlap; cotinine concentrations

in the occasional smoker are similar to those of the heavily exposed nonsmoker. This is shown in Figure 2.1, in which the distributions of plasma

cotinine concentrations for self-reported smokers and nonsmokers are

shown to overlap. The distribution of values for self-reported nonsmokers

is bimodal, suggesting some denial of active smoking (i.e., deceivers) among

the study subjects. For nicotine and other biomarkers of ETS exposure, the

concentration distributions similarly overlap and are bimodal, presumably

30

Smoking and Tobacco Control Monograph No. 10
Chapter 2

31

Unexposed % of ETS-Exposed % of Active

Nonsmokers Active- Nonsmokers Active- Smokers

Biochemical (n = 46) Smokers’ (n = 54) Smokers’ (n = 94)

Parameter Mean Value Value Mean Value Value Mean Value

CO in expired air 5.7 [6.5] 27 5.5 [6.3] 26 20.8 [24]

(ppm [mg/m3])

COHb (%) 0.9 23 0.8 21 3.9

Nicotine (ng/ml)

in plasma 1.0 7 0.8 5.4 14.8

in saliva 3.8 0.6 5.6 0.8 672.5

in urine 3.9 0.2 12.1* 0.7 1749.9

Cotinine (ng/ml)

in plasma 0.8 0.3 2.0* 0.7 275.2

in saliva 0.7 0.2 2.5** 0.8 309.9

in urine 1.6 0.1 7.7** 0.6 1391.0

Thiocyanate (μmol/l)

in plasma 48 39 53 43 123

in saliva 1270 52 1327 54 2450

in urine 73 47 77 50 155

Table 2.4

Compairison of Biomarkers in Unexposed and ETS-Exposed Nonsmokers and 

Active Smokersa

a From IARC (1986) using data from Jarvis and Russell (1984).

* Indicates p < 0.01 between exposed and unexposed nonsmokers

** Indicates p < 0.001 between exposed and unexposed nonsmokers

reflecting a certain degree of misreporting by the active smoker (Jarvis et al.,

1987).

ETS exposure of infants and children has been examined in a number of studies in which nicotine and

cotinine were used as biomarkers of exposure. Infants

can be exposed prenatally to tobacco smoke constituents if the mother

smokes or if the mother is exposed to ETS during pregnancy. Postnatal ETS

exposure may occur directly, via inhalation, and indirectly, from ingestion

of breast milk. 

Henderson et al. (1989) examined the relationship between levels of

nicotine in home air and the urinary cotinine concentrations in 27 children, 11 months to 5 years of age, attending a day care center at which

2.4.2.4 Nicotine and Cotinine:

Concentrations in Physiological

Fluids of Infants and Children
Smoking and Tobacco Control Monograph No. 10

they were not exposed to ETS. Fifteen children resided in homes with

smokers and 12 did not. The average concentration of air nicotine in the

homes of children who did and did not live with smokers was 3.74 μg/m3

and 0.34 μg/m3, respectively. Urinary cotinine concentrations were greater

than 30ng/mg creatinine in 12 of the 15 children who lived with smokers,

whereas concentrations were consistently less than 30 ng/mg creatinine in

the 12 children without home exposure to ETS; three of the exposed children had urinary cotinine concentrations consistently in the upper range of

values observed in unexposed children. The average home air nicotine concentrations were related to the average log urinary cotinine to creatinine

concentration (r = 0.68, p = 0.006). 

Greenberg et al. (1984) measured the concentrations of nicotine and

cotinine in the urine and saliva of 32 ETS-exposed and 19 unexposed

infants less than 10 months of age visiting a primary care clinic in North

Carolina. An infant was categorized as exposed if the caregiver reported at

least two exposure episodes during the previous 24 hours and unexposed if

32

Cut-of % Smokers % Nonsmokers 95% CI for

Biomarkers Value Detected Detected % Accuracyb

Carbon Monoxide

ECO (ppm) 8.0 90 89 86.2-91.7

COHb (%) 1.6 86 92 83.0-89.2

Nicotine (ng/ml)

Plasma 2.3 88 99 89.4-93.8

Saliva 21.8 90 99 91.6-95.2

Urine 58.6 89 97 93.3-96.3

Cotinine (ng/ml)

Plasma 13.7 96 100 98.3-99.1

Saliva 14.2 96 99 98.5-99.3

Urine 49.7 97 99 98.4-99.2

Thiocyanate

Plasma (μmol/l 78.0 84 91 81.1-87.9

Saliva (μmol/l) 1.64 81 71 66.0-76.0

Urine (μmo/l) 118.0 59 89 67.0-77.0

Table 2.5

Cut-off, Sensitivity, and Specificity of Biomarkers for Discriminating 

True Smoking Statusa

Jarvis et al. (1987), with permission

a True smokers were those who reported smoking cigarettes, pipes, or cigars (n = 90) and 21

"deceivers." Nonsmokers were the self-reported nonsmokers minus the deceivers (n = 100).

b Accuracy defined as overall % correct classification, and estimated for a population with equal

proportions of smokers and nonsmokers.
no exposure had occurred during the previous week. Breast-fed infants

were excluded from this study in order to examine inhalation exposure

only. The concentrations of both nicotine and cotinine were significantly

higher in the saliva and urine of the exposed group as compared to the

unexposed group, with the best indicator of exposure reported to be the

ratio of urinary cotinine to creatinine. The median ratio in the exposed

group was 350 ng/mg as compared to 4 ng/mg in the unexposed group (p <

0.0001). The mother’s self-reported smoking behavior (number of cigarettes

smoked during the previous 24 hours) was related to infant urinary concentration (r = 0.67, p = 0.0001). In a later study from the same group

(Greenberg et al. (1989), described in Section 2.6.3), cotinine was detected

in 60 percent of the 433 infants examined; the median concentration was

121 ng/mg creatinine (range: 6 to 2,273 ng/mg). 

In a large population-based study of infants receiving routine wellchild care in private physicians’ offices in the greater Portland, Maine area,

Chilmonczyk et al. (1990) collected urine samples from 518 infants, six to

eight weeks of age, and obtained information on household smoking habits

(this study is also discussed in Section 2.6.3). In the 305 households where

no smoking was reported, 8 percent of the urinary cotinine values were

33

Chapter 2

Self-Reported Nonsmokers

Sample Percent Criteria

Study Marker Assaya Size Misclassifiedb (ng/ml)

Wald et al. (1986) Urinary cotinine RIA 221 0.9 --c

Cummings et al. (1990) Urinary cotinine HPLC 669 0.9 90

Pojer et al. (1984) Plasma cotinine GC 181 3.3 42

Jarvis and Russell (1984) Plasma cotinine GC 215 9.8 20

Lee (1987) Saliva cotinine GC 808 2.5 30

Pierce et al. (1987) Saliva cotinine GC 622 7.4 25

Coultas et al. (1988) Saliva cotinine RIA 683 6.0 20

Haddow et al. (1988) Serum cotinine RIA 1,508 1.9 10

Riboli et al. (1990) Urinary cotinine RIA 1,369 3.4 50d

Wagenknecht et al. (1991) Serum cotinine RIA 3,445 4.2 14

Perez-Stable et al. (1992) Serum cotinine GC 189 6.3 14

Table 2.6

Studies of Cotinine Measurements in Self-Reported Nonsmokers and Criteria

Used to Distinguish Smokers from Nonsmokers

Modified from Perez-Stable et al. (1992)

a Abbreviations: GC, gas chromatography; RIA, radioimmunoassay; HPLC, high pressure liquid

chromatography

b percentage of self-reported nonsmokers with cotinine levels above criteria listed

c >10% smokers’ median

d ng/mg creatinine
0

5

10

15

20

25

30

35

0

10

20

30

40

50

Smoking and Tobacco Control Monograph No. 10

34

Figure 2.1

Plasma Cotinine Concentrations in Self-Reported Smokers and Nonsmokers

Self-Reported Smokers

Number of Subjects

Plasma Cotinine (ng/ml)

Self-Reported Nonsmokers

Number of Subjects

Plasma Cotinine (ng/ml)

From Jarvis et al. (1987), with permission

50

40

30

20

10

0

1 10 100 1000

35

30

25

20

15

10

5

0

1 10 100 1000
equal to or greater than 10 ng/ml (the concentration of 10 ng/ml is defined

by the authors on the basis of data in this study as a cutoff indicating significant ETS absorption). Median urinary cotinine concentrations in

infants were 1.6 ng/ml in the 305 nonsmoking households, 8.9 ng/ml in

the 96 households where a member other than the mother smoked, 28

ng/ml in the 43 households where only the mother smoked, and 43 ng/ml

in the 74 households where both the mother and another household member smoked. In households where the mother smoked, breast feeding was

associated with significantly higher infant urinary cotinine levels. These

higher levels were seen both in the presence of other smokers in the household (median urinary cotinine: 213 ng/ml with breast feeding and 39 ng/ml

without breast feeding) and in the absence of other smokers in the household (median urinary cotinine: 87 and 25 ng/ml, respectively.) 

35

Chapter 2

Figure 2.2

Urinary Cotinine of Breast-Fed Infants in Relation to Maternal Cigarette Smoking

Source: Schulte-Hobein et al., 1992 Median urinary cotinine-to-creatinine ratio (ng/mg)
Several other studies have examined the relative contribution of

inhalation versus ingestion of mother’s milk to an infant’s intake of nicotine and cotinine (Luck and Nau, 1985; Woodward et al., 1986; Labrecque et

al., 1989; Schulte-Hobein et al., 1992). In general, breast-fed infants whose

mothers smoke were reported to have median urinary cotinine to creatinine

ratios 2- to 10-fold higher than bottle-fed infants exposed only through

inhalation, with the urinary cotinine levels in the infant related to the

number of cigarettes smoked by the mother. Concentrations of urinary

cotinine in breast-fed and bottle-fed babies as a function of the number of

cigarettes smoked by the mother are shown in Figure 2.2. 

The observation that ingestion of breast milk is a significant contributor to infant exposure to ETS constituents (discussed above) is consistent with the findings of numerous studies in which nicotine and cotinine have been measured in milk of mothers who smoke (Ferguson et al., 1976; Hardee et al.,

1983; Luck and Nau, 1984; Woodward et al., 1986; Luck and Nau, 1987;

Labrecque et al., 1989; Schulte-Hobein et al., 1992) and in milk of mothers

exposed to ETS (Hardee et al., 1983; Schulte-Hobein et al., 1992). Results

from these studies are summarized in Table 2.7. For smokers, mean nicotine concentrations in breast milk ranged from 5.16 to 91 ng/ml (range: 0.9

to 512 ng/ml) and mean cotinine concentrations, from 5.6 to 439 ng/ml

(range: not detected to 738 ng/ml). The concentrations of nicotine measured in the breast milk of nonsmokers exposed to ETS were much lower

than those reported for smokers. Nicotine and cotinine were often not

detected in the milk of nonsmoking women; for samples in which these

compounds were detected, nicotine concentrations ranged from 1 to 7

ng/ml (Hardee et al., 1983) and cotinine concentrations from 2 to 277

ng/ml (Hardee et al., 1983; Schulte-Hobein et al., 1992). 

The transfer of nicotine from blood into breast milk is very rapid,

with milk concentrations approximately three times higher than in serum

(Luck and Nau, 1984; Dahlström et al., 1990). The half-life of nicotine in

milk is approximately the same as that in blood (Luck and Nau, 1987). For

cotinine, the reported milk/serum ratio ranges from 0.78 to 1 (Luck and

Nau, 1984; Dahlström et al., 1990). In general, the concentration of cotinine in milk has been found to increase with increasing nicotine consumption (Woodward et al., 1986; Labrecque et al., 1989; Schulte-Hobein et al.,

1992). 

The exposure of a nursed infant to nicotine depends on the daily

intake of breast milk as well as the smoking pattern of the mother, including the number of cigarettes she consumes daily, the extent to which she

inhales, her smoking frequency prior to nursing, and the time interval

between nursing and the last cigarette smoked (Luck and Nau, 1987).

Because of the relatively short half-life of nicotine, diurnal milk concentrations are highly variable; 5- to 10-fold increases in the concentration of

nicotine were observed in milk samples collected during the day, as compared to samples collected in the early morning after night time smoking

36

Smoking and Tobacco Control Monograph No. 10

2.4.2.5 Nicotine and Cotinine:

Concentrations in Breast Milk

and Amniotic Fluid
37

NonsmokersHardee et al.(1983)Schulte-Hobein et al. (1992)SmokersFerguson et al.

(1976)Hardee et al.

(1983)Luck and Nau(1984)Woodward et al.

(1986)

NicotineCotinineCotinineNicotineNicotineCotinineNicotineCotinineNicotineCotinineNicotineCotinine

----

0

91

--------

8.3 (±13.0)

84.4 (±93.3)32.6 (±26.6)

234 (±110.8)

1-7

0-277

20-512 20-15050-300

2-62

12-222

--------

Samples from 10 nonsmokingwomen.Samples from 69 nonsmokingwomen.28 samples from 9 women were collected. Most subjects smoked 0.5-1.5 packs/day.Samples from 3 women44 samples from 23 women werecollected. The number of cigarettessmoked per day ranged from 5-40.The time between the last cigarettesmoked and the collection of samples ranged from 0.25 to 4.0 hours.Samples from 20 women smoking1-20 cigarettes 48 hours prior tosample collection.Samples from 7 women smoking≥21 cigarettes 48 hours prior tosample collection.

Detecplace DetecpartneConcely in staken 

Table 2.7Concentrations of Nicotine and Cotinine in Mothers’ Milk

Concentration (ng/ml)

Study Constituent Mean (SD) Range Study Population 
38

Luck and Nau (1987) Labrecque et al. (1989)

Schulte-Hobein 

et al. (1992)

Dahlstrom et al.

(1990)SchwartzBickenbach 

et al. (1987)

NicotineCotinineNicotineCotinineNicotineCotinineCotinineCotinineNicotineCotinineNicotineCotinineCotinineCotinine

8.3 (± 16)

76 (± 33)28 (± 21)

125 (± 60)

48 (± 25)

230 (± 62)

195 (± 122)

264

5.16

112

55

136

91-322

305-439

------------

28-256

0-738

0.9-17.3

18-38810-14031-46741-580

0-635

Samples from all nursing periods within24 hours. Samples from 10 women smoking 1-10cigarettes/day.Samples from 11 women smoking 11-20cigarettes/day.Samples from 13 women smoking 21-40cigarettes/day.Samples from 33 mothers smoking onaverage 9.8 cigarettes in the previous24 hours.Samples from 69 mothers who smokedmore than 5 cigarettes per day duringpregnancy and continued smoking afterchildbirth. Samples (total = 238) werecollected at monthly intervals for 1 year.Samples from 22 mothers abstainingfrom cigarettes for 12 hoursSamples from 21 mothers 30 minutesafter smoking at least 1 cigaretteSamples from 6 mothers smoking <20cigarettes/day.Samples from 15 mothers smoking >20cigarettes/day.

Determthe numing the ing and cigaretCotininto the nthe mo

0.69, p 

Cotininon nicomother

Range ured 1 Range ured 1 

Table 2.7 (Continued)Study Constituent Mean (SD) Range Study Population 
abstinence (Luck and Nau, 1987; Dahlström et al., 1990). Because of the

longer half-life of cotinine, its concentrations in milk are relatively constant. 

No information was available on the levels of other ETS constituents in breast milk, although it is possible that other compounds would

also be transferred to breast milk. Their relative concentrations in milk

would depend on a number of factors, including their concentrations in

mainstream (or sidestream) smoke, biological half-life, and lipid solubility. 

Cotinine has also been detected in the amniotic fluid of ETSexposed pregnant women and in the urine of their neonates (Jordanov,

1990). Mean concentrations of cotinine in amniotic fluid collected at parturition were 15 μmol/l in unexposed nonsmokers (women not living with

a smoker), 25 μmol/l in exposed nonsmokers (smoker resided in household), and 111 μmol/l in active smokers. Cotinine was also detected in the

urine, collected on the first day of life, of their neonates. Neonates of nonsmokers exposed to ETS had significantly higher concentrations of urinary

cotinine than neonates of unexposed nonsmokers (p < 0.01). 

Carbon monoxide, both in exhaled alveolar air and as

carboxyhemoglobin in blood, originates from endogenous processes as well as from environmental sources. In

addition to cigarette smoke, common environmental sources include vehicle exhaust, gas stoves and furnaces, and kerosene space heaters. Although

carbon monoxide and carboxyhemoglobin have been used to distinguish

smokers from nonsmokers (Ohlin et al., 1976; Sillett et al., 1978; Jarvis et al.,

1983 and 1987), they are generally not good indicators of ETS exposure

because of their lack of sensitivity and specificity. In nonsmokers exposed

to environments heavily polluted with ETS, elevated levels of exhaled carbon monoxide and carboxyhemoglobin in blood have been detected when

measured within 30 minutes following cessation of exposure. However,

several studies of more typical exposure situations did not find significant

differences in the carboxyhemoglobin levels in subjects reporting no, low,

or high levels of ETS exposure (Jarvis et al., 1983; Jarvis and Russell, 1984;

see Table 2.4). 

Present in the vapor phase of tobacco smoke, hydrogen cyanide

is metabolized in the liver, yielding thiocyanate (SCN-

).

Thiocyanate levels in blood, urine, and saliva have been used to distinguish

smokers from nonsmokers, or in combination with assays for nicotine or

cotinine, to distinguish smokers from individuals using smokeless tobacco

or other nicotine-containing products (Haley et al., 1983; Hauth et al., 1984;

U.S. DHHS, 1986; Jarvis et al., 1987). Sources of thiocyanate are also present in the diet, particularly cruciferous vegetables (Haley et al., 1983); thus,

levels of thiocyanate in body fluids are not specific to exposure to tobacco

smoke. In studies examining the use of thiocyanate as a biomarker of ETS

exposure, it was not possible to distinguish between ETS-exposed and unexposed nonsmokers (Hauth et al., 1984; Jarvis and Russell, 1984; See Table

39

Chapter 2

2.4.3 Biomarkers:

Carbon Monoxide and

Carboxyhemoglobin

2.4.4 Biomarkers:

Thiocyanate
2.4). For this reason, thiocyanate is not very useful as a biomarker of ETS

and has not been widely used for monitoring ETS exposure.

Protein and DNA adducts represent both markers of exposure

and measures of a biochemical effect. One of the more common protein adducts measured is the hemoglobin adduct of 4-

aminobiphenyl. Tobacco smoke is the primary source of environmental 4-

aminobiphenyl. Because of the relatively long half-life of these adducts,

their levels reflect exposures occurring over the previous four months.

Levels of 4-aminobiphenyl in ETS-exposed nonsmokers compared to those

of active smokers present an interesting contrast to cotinine levels measured in these two groups. The levels of 4-aminobiphenyl adducts in nonsmokers are approximately 10 percent to 20 percent of the levels measured

in smokers. Although this finding appears to be inconsistent with the

results for urinary cotinine, for which levels in ETS-exposed nonsmokers are

about 1 percent of those in smokers, the results may be explained by the

available information on the relative levels of emission of nicotine and 4-

aminobiphenyl into mainstream and sidestream smoke (see U.S. EPA, 1992:

Table 3-1). Approximately twice as much nicotine is emitted in sidestream

as in mainstream smoke, whereas about 31 times as much 4-aminobiphenyl

is emitted in sidestream as in mainstream smoke, and as a result, the smoker/nonsmoker ratio for 4-aminobiphenyl is about 15 times higher than that

for cotinine.

Another group of protein adducts which have been measured are

the albumin adducts of polycyclic aromatic hydrocarbons (PAHs). Multiple

PAHs are present in tobacco smoke. Crawford et al. (1994) analyzed PAHalbumin levels in peripheral blood of 87 mothers and their preschool children (2-5 years of age; discussed in more detail in Chapter 7, Carcinogenic

Effects, Section 7.1.2.1). They found PAH-albumin levels were significantly

higher in the children whose mothers smoked than in the children of nonsmoking mothers (p < 0.05). Among the nonsmoking mothers, regression

of PAH-albumin against total ETS exposure also showed a significant association with cotinine (r2 = 0.25; p = 0.04).

DNA adducts of tobacco smoke constituents can also be measured.

The distribution of DNA adducts of benzo[a]pyrene diol epoxide, the ultimate carcinogenic metabolite of benzo[a]pyrene, a PAH present in tobacco

smoke, has been analyzed by Denissenko et al. (1996) in the P53 tumor suppressor gene. These authors reported that exposure of human bronchial

epithelial cells to benzo[a]pyrene diol epoxide resulted in strong and selective DNA adduct formation within the P53 gene at mutational hotspots

identified in non-radon associated human lung cancer tissues obtained

from smokers. This mapping of DNA adduct formation to mutational

hotspots provides a direct etiological link between a specific tobacco smoke

carcinogen and human cancer.

40

Smoking and Tobacco Control Monograph No. 10

2.4.5 Biomarkers:

Protein and DNA

Adducts
Testing for other compounds in body fluids and for the mutagenicity of those fluids has been conducted to identify other

approaches to assessing tobacco smoke exposure which are potentially more

relevant to health endpoints of concern (e.g., cancer). In a recent study by

Hecht et al. (1993), five male nonsmokers were exposed to sidestream cigarette smoke generated by machine smoking for 180 minutes on each of two

days, six months apart. The air concentrations of nicotine to which the

men were exposed were reported to be comparable to levels found in a

heavily smoke-filled bar. The mean concentrations of 4-(methylnitrosoamino)-1-(3-pyridyl)-1-butanol (NNAL) and its glucuronide were significantly higher after exposure than at baseline (33.9 versus 8.4 ng per 24-

hour urine sample). The compound NNAL and its glucuronide are metabolites of 4-(methylnitrosoamino)-1-(3-pyridyl)-1-butanone (NNK), a potent

lung carcinogen in rodents (IARC, 1985). NNAL is also a lung carcinogen

in rodents (Castonguay et al., 1983; Rivenson et al., 1988). NNK is formed

by the oxidation and nitrosation of nicotine during the curing (drying) and

smoking of tobacco (IARC, 1985). 

Body fluids from active smokers and ETS-exposed nonsmokers have

been assayed for genotoxic activity in a number of studies, primarily using

the Ames Salmonella test. While the mutagenicity of the urine of cigarette

smokers has been confirmed in a number of studies (IARC, 1986), the

results using the urine from ETS-exposed nonsmokers have been less conclusive. Bos et al. (1983) reported that mutagenic activity of the urine of

nonsmokers was significantly higher (p < 0.02) in samples collected following exposure to ETS than in samples collected prior to exposure, when tested in the Salmonella assay. In other studies, however, no increases or

insignificant increases in mutagenic activity were reported (Sorsa et al.,

1985; Husgafvel-Pursiainen et al., 1987; Mohtashamipur et al., 1987; Scherer

et al, 1987). Limitations of some of these studies include small numbers of

subjects tested and lack of consideration of dietary factors, which have been

shown to influence urinary mutagenicity (Sasson et al., 1985). 

Epidemiologic studies typically evaluate exposure to ETS

using questionnaires in which the subject reports his or her

own exposure history and smoking status. In studies using

questionnaires alone to assess ETS exposure, misclassification of true exposure status can result from a number of factors, including: limited questions

(e.g., spousal smoking status only); possible deception in reporting spousal

smoking status; or inadequate recall of exposure (e.g., parental smoking status; lack of awareness of contemporary exposure). Many studies cited in

this report recognized the possibility of misclassification bias and took

appropriate steps to minimize its impact or adjusted the analysis to account

for this source of error. This section summarizes the results of a number of

studies that have examined the reliability and validity of information collected using questionnaires regarding ETS exposure and smoking status.

41

Chapter 2

2.4.6 Biomarkers:

Other Approaches

2.5 EXPOSURE

MEASUREMENT: USE

OF QUESTIONNAIRES
Studies employing a “test-retest” design have been used

to assess the reliability of information obtained in questionnaires on past exposures to ETS. Coultas et al.

(1989) interviewed a sample of 149 adult nonsmokers

on two occasions, 6 months apart, with regard to

whether their parents had smoked during their childhood. Concordance was 94 percent for mothers’ smoking, 93 percent for

fathers’ smoking, and 85.9 percent for maternal smoking during pregnancy.

However, information provided by the subjects on the amounts smoked

(i.e., number of cigarettes or hours of smoking per day) was found to be less

reliable. 

In a study of similar design, Pron et al. (1988) interviewed 117 subjects (controls in a case-control study of lung cancer) on two occasions separated by an average of 6 months. Agreement of responses with regard to

the subjects’ residential exposure (i.e., if the subject ever resided in the same

household as a regular smoker) was generally good (kappa = 0.66 for all

subjects combined). Smoking by spouses was reported with high reliability

(kappa = 0.89 for both husband and wife). Response agreement for exposure at work (kappa = 0.46 for both sexes) was lower than for residential

exposure. Similar to the findings of the preceding study by Coultas et al.

(1989), quantitative measures of exposure (i.e., number of cigarettes smoked

and duration of exposure) were less reliably reported. 

A number of studies have examined the quality of

information provided by surrogate respondents. Use of

surrogate respondents occurs frequently in studies of ETS exposure. Studies

examining the effects of exposure to spousal or household smoking often

ask subjects to report on the smoking habits of members of their households. In retrospective studies of adult health risks from exposures occurring early in life, subjects who are now adults are questioned concerning

parental smoking habits. 

The quality of parental smoking histories was evaluated in a North

Carolina study of cancer risk from childhood exposure to ETS (Sandler and

Shore, 1986). A total of 1,036 subjects (cases and controls, aged 15 to 59

years) were asked about parental smoking habits during the subject’s childhood and prior to the subject’s birth. Parents or siblings of 70 percent of

the study subjects were also interviewed to obtain the same information.

Interviews were conducted with 355 mothers, 33 fathers, and 261 siblings.

Concordance of subjects and their mothers was greater than 93 percent on

questions concerning mothers’ smoking and 85 percent regarding fathers’

smoking. The study found that the responses were less accurate for information provided about dates or the number of cigarettes smoked. When

extent of smoking was categorized as none, less than one pack, one pack, or

greater than one pack, agreement between mothers and subjects was 82 percent with respect to mothers’ smoking. 

42

Smoking and Tobacco Control Monograph No. 10

2.5.1 Reliability of

Questionnaire Responses

on ETS Exposure

2.5.1.1 Reliability: Test-retest

of the Same Subject

2.5.1.2 Reliability: Self 

Versus Surrogate Respondents
Similar findings were reported by McLaughlin et al. (1987) in a

study of the reliability of surrogate information. The responses of children

about smoking by their deceased parents agreed closely with information

given 10 years previously by the parents themselves, with the level of agreement ranging from 80 to 96 percent. 

Of the study populations examining the quality of information on

smoking habits provided by surrogate respondents, most consisted of husband-wife pairs, although other family members were included in some

studies (Rogot and Reid, 1975; Kolonel et al., 1977; Pershagen, 1984;

Lerchen and Samet, 1986; McLaughlin et al., 1987). Information was

obtained directly from interviews with both members of the pair or from an

interview with one individual and the medical history of the other. These

studies consistently found good agreement in responses concerning spousal

smoking status, ranging from 90 to 100 percent. However, similar to the

findings of studies on parental histories, quantitative information on the

number of years or cigarettes smoked was less accurate. 

In summary, the results of these studies indicate that information

on childhood exposure to ETS provided by individuals who are now adults

is of good quality, particularly with regard to qualitative information.

Similarly, qualitative information on spousal smoking is of good quality.

However, in both cases, quantitative information on the number of years of

smoking, dates of smoking, or number of cigarettes smoked per day is

sometimes less reliably provided. 

A number of the early epidemiologic studies classified an individual’s exposure to ETS solely on

the basis of spousal smoking. Information presented in Sections 2.6.2 and 2.6.3 indicates that

in California and nationwide, locations outside

the home are also important sources of ETS

exposure. The validity of ETS exposure status based on spousal or household smoking has been examined in a number of studies (Friedman et al.,

1983; Coultas et al., 1987; Coghlin et al., 1989; Cummings et al., 1990).

Methods used to validate exposure status include: gathering information on

the extent to which nonsmokers report exposure outside the home; comparison of ETS biomarker levels of those with smoking and nonsmoking

spouses; and comparison of indoor air levels of nicotine in houses with

members who do and do not smoke. Results from these studies indicate

that misclassification may occur when smoking by a spouse or other household member is the basis for determining ETS exposure. 

In a study by Friedman et al. (1983), married couples were asked

about their smoking habits and weekly exposure to ETS. Over 90 percent of

nonsmokers married to nonsmokers reported no weekly exposure to ETS in

the home; however, 40 percent of the nonsmoking females and 49 percent

of the nonsmoking males reported ETS exposures outside the home.

Conversely, substantial percentages of nonsmokers married to smokers (47

43

Chapter 2

2.5.2 Validity of Questionnaire

Responses on ETS Exposure

2.5.2.1 Validity of ETS Exposure

Status Based on Spousal / Household

Smoking
percent of women, 39 percent of men) reported no weekly exposure to ETS

in the home. These studies indicate that classifying an individual’s exposure to ETS on the basis of spousal smoking habits may result in misclassification. 

Biomarker studies have shown that a proportion of subjects reporting no exposure to ETS have measurable biomarker concentrations, indicating that the subject either forgot or was not aware of his ETS exposure. In a

study of 663 nonsmokers attending a cancer-screening clinic, Cummings et

al. (1990) reported that 84 percent of subjects not living with a smoker had

detectable urinary cotinine levels. In an unpublished analysis of only those

subjects who were currently employed nonsmokers in this study, 76 percent

of those reporting no exposure to ETS at home reported exposure at work

(Cummings, 1994). Coultas et al. (1987) reported that in 727 households,

approximately 35 percent of adults and children not living with a smoker

had detectable levels of salivary cotinine (these studies are described in

Section 2.6.3). 

Comparison of reported exposures and questionnaire responses has

also been examined using results from air monitoring of nicotine. Coghlin

et al. (1989) questioned 37 nonsmokers with nonsmoking spouses and 15

nonsmokers with smoking spouses about their weekly exposure to ETS at

home, work, in public places, and in vehicles. Personal nicotine monitors

were worn by study participants to obtain measurements of actual exposure. Of the nonsmokers with nonsmoking spouses, 22 percent had personal nicotine levels similar to those measured for smokers, while 13 percent of

nonsmokers with smoking spouses had low nicotine levels. In addition, 88

percent of nonsmoking women with nonsmoking spouses reported workrelated exposure and 80 percent reported social exposure. 

In a study by Leaderer and Hammond (1991), measurable concentrations of nicotine were detected in 13 percent of residences reporting no

smoking in the home, while nicotine was not detected in 28 percent of the

households with occupants who smoked. For the latter, smoking could

have occurred in rooms other than the primary activity room in which

samples were taken. 

In summary, studies have consistently shown that subjects are misclassified with regard to their ETS exposure status when the sole basis for

classification is the smoking status of other household members. The overall impact of misclassification would be an underestimation of the health

impacts of ETS exposure. 

Biomarkers have been used to examine the quantitative

relationships between the degree of ETS exposure selfreported on questionnaires and concentrations of nicotine

in ambient air (Coultas et al., 1989; Haley et al., 1989; Cummings et al.,

1990; Riboli et al. 1990). Depending on the study design and the endpoints

examined, the reported correlations among the various exposure indices

44

Smoking and Tobacco Control Monograph No. 10

2.5.2.2 Validity of SelfReported ETS Exposure:

Biomarker Concentrations
ranged from moderate to high. Because of the many limitations of these

studies, inconsistencies among studies is not unexpected.

Significant differences in uptake, distribution, metabolism, and

excretion of nicotine are found among individuals (Benowitz et al., 1982),

and thus cotinine levels in biological fluids vary among individuals exposed

under identical conditions. In those studies in which urinary cotinine is

used as the measure of exposure, cotinine concentrations are often assessed

from a single urine sample, which may not adequately represent the exposure period in question. For studies in which ambient air concentrations of

nicotine serve as the exposure measure, it has been shown that air concentrations vary within the same room; intake will depend on the location of

the individual relative to the smoker, the exposure duration, and the physical characteristics of the exposed individuals (e.g., activity level and corresponding breathing rate).

In a test-retest study of the reliability of subjects’ reports

of their own smoking habits, Lee (1987) found that

responses from 93 percent of 166 subjects regarding current or past smoking status were consistent with responses to the same

questions asked five years earlier. 

A number of studies have used biomarkers to validate self-reported

smoking status (Coultas et al., 1989; Haley et al., 1989; Cummings et al.,

1990; Riboli et al. 1990; Perez-Stable et al., 1992). Self-reported nonsmokers

who appear to be smokers on the basis of biochemical measurements are

generally considered “deceivers” of their true smoking status. In a summary of 11 studies in which questionnaire responses regarding smoking status

were compared with cotinine or nicotine measurements (Perez-Stable et al.,

1992), the estimated misclassification rates (self-reported nonsmokers with

elevated cotinine or nicotine levels indicative of active smoking) ranged

from zero in a small study to nearly 10 percent in a sample of nonsmokers

from a clinical setting. These studies are summarized in Table 2.6.

Misclassification of an individual who is a smoker as a nonsmoker may

increase the apparent relative risk of smoking-related diseases in nonsmokers. However, Perez-Stable et al. (1992) suggest that most smokers misclassified as nonsmokers are very light smokers or occasional smokers who binge.

Because the various health endpoints reviewed in

other chapters of the overall ETS assessment may be

the result of either acute or chronic exposures, both

present and past patterns of exposure are of interest, and information on both is included here. Studies of the prevalence of

ETS exposure and its demographic and social determinants summarized

below (Sections 2.6.2 and 2.6.3) should be considered representative only of

the general time periods covered by the study. Smoking prevalence, smoking behaviors, and other factors contributing to exposure to ETS have continued to change as smoking customs have changed in the U.S., with a

number of important changes occurring within the past few years. Thus, it

45

Chapter 2

2.5.3 Reliability and

Validity of Self-Reported

Smoking Status

2.6 EXPOSURE PREVALENCE

AND DETERMINANTS

2.6.1 Introduction
is expected that the number of individuals exposed to ETS and the patterns

of exposure have also changed over time (see Section 2.6.4).

For California, information is available from population-based surveys in which self-reported exposure to ETS was assessed (Friedman et al.,

1983; Phillips et al., 1991; Wiley et al., 1991a & b; Burns and Pierce, 1992;

Jenkins et al., 1992; Pierce et al., 1994). With one exception (Friedman et

al., 1983), these studies relied solely on self-reported exposure and did not

validate questionnaire responses using biomarker data. A certain amount of

misreporting occurs in studies relying on self-reported exposure; several

studies have been conducted to evaluate the relationship among self-reported exposure and other exposure indices (e.g., ambient air concentrations of

ETS constituents and cotinine levels in biological fluids), and these studies

are discussed in Section 2.5. 

For areas outside of California, information on exposure prevalence

is available from a variety of studies, using either self-reported exposure or

the presence of biological markers as the measure of exposure (Coultas et

al., 1987; Greenberg et al., 1989; Chilmonczyk et al., 1990; Cummings et al.,

1990; Overpeck and Moss, 1991; CDC, 1993b; Pirkle et al., 1996). In general, only limited comparisons can be made between the findings on exposure prevalence for California and those available for other areas, primarily

because of important differences in study objectives and study design.

However, indirect indicators of ETS exposure suggest that the prevalence of

ETS exposure in California is less than that of the rest of the U.S. population. A discussion of these indicators and other factors in California

expected to affect trends in exposure prevalence are discussed in Section

2.6.4. The studies presented in the following sections are summarized in

Tables 2.8 and 2.9. 

Taken as a whole, the various studies discussed below indicate that,

within California and the United States, exposure to ETS was widespread

during the time period of the studies (1979 through 1992). Analyses of ETS

exposure within California indicated that the workplace, home, and other

indoor locations contributed significantly to the exposure of adults; for

children, the home was the most important single location contributing to

ETS exposure. In all studies using both self-reporting and a biological marker (cotinine level) as measures of exposure, prevalence was higher when

determined using the biological marker.

In one early study, the prevalence and extent of weekly

exposure to ETS was assessed from questionnaire

responses of 37,881 nonsmokers and ex-smokers receiving multiphasic health checkups in 1979 and 1980

(Friedman et al., 1983). The population consisted of members of the KaiserPermanente Medical Care Program in Oakland and San Francisco.

Altogether, 63.3 percent of the respondents reported some exposure to ETS,

with 28.8 percent reporting exposure durations of between 1 and 9 hours

per week, 18.6 percent reporting exposure durations of between 10 and

46

Smoking and Tobacco Control Monograph No. 10

2.6.2 Prevalence of ETS

Exposure in California

Friedman et al. (1983)
39 hours per week, and 15.9 percent reporting exposure durations of 40 or

more hours per week. The reported locations of exposure were the home

(23.8 percent), other small areas (40.4 percent, defined in the study as “such

as airplane, office, or car, etc.”) or a large indoor area (46.5 percent, defined

in the study as “such as restaurant, hotel lobby, lecture hall, etc.”). 

Exposure was strongly related to age, with 78.2 percent of those in

their twenties reporting exposure, decreasing to 13.9 percent of those aged

80 and over. Serum thiocyanate and expired-air concentrations of carbon

monoxide were determined for 267 persons who completed the questionnaire. The correlations between self-reported ETS exposure and the biomarkers were all positive, but small. While the correlations of thiocyanate

levels with non-home small area, large area, and total exposure were at, or

close to, the p < 0.05 level of statistical significance, for CO, no correlation

approached statistical significance. These findings are not surprising given

that sources of thiocyanate and carbon monoxide in addition to tobacco

smoke are present in the environment. More recent studies indicate that, in

general, they are not suitable as markers of ETS exposure (see Sections 2.4.2

and 2.4.3).

In the late 1980s, the California Air Resources Board (ARB)

funded a statewide survey to obtain information on activity

patterns of Californians and on their use of and proximity

to air pollutant sources, including ETS (Wiley et al., 1991a; Jenkins et al.,

1992). The study consisted of telephone interviews with 1,579 Englishspeaking adults and 183 adolescents (12 to 17 years of age) who were members of households with telephones in California. The interviews were conducted over four seasons—from October 1987 through September 1988.

The participants completed a verbal recall diary of their activities and locations of the previous day, and for each activity and location, were asked

whether anyone smoking a cigarette was present. 

In a second study of similar design (i.e., telephone interviews with

English-speaking individuals) conducted from April 1989 through February

1990, information was obtained on the activity patterns of 1,200 children

(Phillips et al., 1991; Wiley et al., 1991b). In this study, children from 9 to

11 years old were interviewed directly. For children 6 to 8 years of age, the

interview was conducted with a parent or guardian who was encouraged to

consult with the child, and for younger children, the interview was conducted with the adult household member having spent the most time with

the child on the diary day. Because exposure to ETS was not the primary

focus of either the adult or childhood study, the ETS responses had not

been fully analyzed. At the request of the Office of Environmental Health

Hazard Assessment, additional unpublished analyses of the responses on

ETS exposures were conducted by the ARB for inclusion in this report

(Jenkins, 1992 & 1994, personal communication; Lum, 1994a & b, 1994,

personal communication). 

47

Chapter 2

Wiley et al. (1991a & b)

Phillips et al. (1991)

Jenkins et al. (1992)
48

Year/ Measure of Exposure Study Location Description Exposure Prevalence (Age) Com

California Friedman et al. 1979-1980 37,881 nonsmoking Self-report 63.3% (≥18yrs) Expo

(1983) Oakland and adults from the defin

San Francisco, Kaiser-Permanente repoCalifornia Medical Care Program. expo

or m

Wiley et al. 1987-1988 1,579 English-speaking Self-report 43% (≥18 yrs) Activ

(1991a) California adult members of house- (interview) studJenkins et al. (statewide) holds with telephones. 64% (12-17 yrs) indiv

(1992) thos

to ETprecPrevnons

Burns and 1990-1991 Telephone interviews Interview 36.5% (12-17 yrs) ExpoPierce (1992) California with 32,135 English- defin

(statewide) and Spanish-speaking in a 

households least 

Table 2.8Studies with Information on ETS Exposure Prevalence in California and the United States:Adults and Adolescents
49

Year/ Measure of Exposure

Study Location Description Exposure Prevalence (Age) ComOther U.S. areasCoultas et al. 1984-1985 698 nonsmoking adults Salivary 39% (≥18 yrs) Exp

(1987) Albuquerque, from 727 randomly cotinine defin

New Mexico selected Hispanic 48% (13-17 yrs) saliv

households. cent

0.78

Cummings 1986 663 nonsmoking adults Self-report 76% (≥18 yrs) Exp

et al. (1990) Buffalo, attending a cancer- (interview) defin

New York screening clinic repo

to Eperiointer

Urinary 91% (>18 yrs) Expcotinine defin

deteof colimit 

Centers for 1988-1992 800 nonsmoking indivi- Serum 100% (----)a Exp

Disease United States duals, ages 4-91 years, cotinine definControl (1993b) from 81 U.S. counties. dete

of cothe the repometcotin

Table 2.8 (Continued)

a Exposure prevalence reported for entire study population
50

Year/ Measure of Exposure Study Location Description Exposure Prevalence (Age) Com

California Phillips et al. 1989-1990 1,200 children Surrogate 40% (6-11yrs) Expo(1991) California (0 to 11 years old) Report definWiley et al. (statewide) from households with 36% (0-5 yrs) expo

(1991b) telephones and an on th

English-speaking adult inter

Burns and 1990-1991 Telephone interviews Surrogate 32.2%(6-11 yrs) ExpoPierce (1992) California with 32,135 English- Report defin

(statewide) or Spanish-speaking 32.2% (0-5 yrs) in a 

households or m

Other U.S. areasCoultas et al. 1984-1985 Hispanic children Salivary 45% (6-12 yrs) Expo

(1987) New Mexico participating in a cotinine defin

population-based 54% (0-5 yrs) salivsurvey of respiratory centdisease 0.78 

Greenberg 1986-1987 433 healthy infants Surrogate 42% (8-51 days) Expoet al. (1989) Central North Report defin

Carolina to ET

prec

Surrogate 55% (8-51 days) ExpoReport defin

in a or m

Table 2.9Studies with Information on ETS Exposure Prevalence in California and the U.S.:Infants and Children
51

Year/ Measure of Exposure

Study Location Description Exposure Prevalence (Age) ComGreenberg 1986-1987 433 healthy Urinary 60% (8-51 days) Expoet al. (1989) Central North infants cotinine defin

(continued) Carolina dete

of ur

Chilmonczyk 1988 518 infants Surrogate 41% (6-8 wks) Expo

et al. (1990) Portland, Report defin

Maine in a 

or m

Urinary 80% (6-8 wks) Expocotinine defin

deteof ur

Overpeck 1988 5,356 children Surrogate 48.8% (0-5 yrs) Expoand Moss United States from a cross- Report defin(1991) sectional survey in a 

of household one populations regu

since 

Surrogate 42% (0-5 yrs) ExpoReport defin

living one 

Table 2.9 (Continued)
Smoking and Tobacco Control Monograph No. 10

52

Figure 2.3

Percent of Nonsmokers in California Reporting ETS Exposure* Percent Reporting Exposure

70

60

50

40

30

20

10

0

All M F All M F All M F All M F

Adults Adolescents 6 to 11 years 0 to 5 years

Source: Jenkins et al., 1992; Lum, 1994b

* Smoking status of 6 to 11 year olds not determined in the study. Data from 1989 to 1990.

Figure 2.4

Reported Average Daily ETS Exposure Duration* in California

300

250

200

150

100

50

0

Minutes of Exposure

All M F All M F All M F All M F

Adults Adolescents 6 to 11 years 0 to 5 years

Source: Lum, 1994a,b

* Exposure duration is the average value for individuals reporting ETS exposure. For adults, values

are for nonsmokers only. For adolescents, values are for both smokers and nonsmokers. The smoking

status of 6 to 11 year olds was not determined. Data from 1989 to 1990.
Chapter 2

53

Figures 2.3 and 2.4 show the percentage of nonsmokers in

California reporting exposure to ETS and the average daily duration as

determined in this study. Of adult nonsmokers, 43 percent reported exposure to ETS, as did 64 percent of nonsmoking adolescents (Jenkins et al.,

1992). For smokers and nonsmokers combined, approximately 61 percent

of adults and 70 percent of adolescents (age 12 through 17) reported exposure to ETS at some time during the day (at the time of the survey, 22.5 percent of the population reported active smoking on a given day). The

groups with the lowest percentage reporting exposure were children, and

infants and preschoolers, ranging from 35 percent to 45 percent, as a function of age and sex. About 38 percent of children under age 12, statewide,

were exposed to ETS at some time during a typical day. Among those

infants and preschoolers who were exposed to ETS, the average duration of

their exposure was as long as that of adults (about four hours); children

aged 6-11 years who were exposed had an average exposure duration of

three hours (Lum, 1994a & b, 1994, personal communication).

A separate analysis of the survey data was conducted to determine

the relative proportion of the population’s ETS exposure duration (measured in person-minutes) occurring in different locations (Lum, 1994a & b,

1994, personal communication). The various locations identified in the

study were grouped into three or four mutually exclusive categories for each

population subgroup and the mean duration of reported exposure to ETS

while in those locations was determined. For adults, the categories were

home, work, other indoor, and outdoor; for adolescents and children,

home, school, other indoor, and outdoor; and for infants and preschoolers,

home, other indoor, and outdoor. The relative person-minutes of reported

exposure at each location (i.e., the product of the number of individuals

reporting ETS exposure and the average reported exposure duration, divided

by the total number of person-minutes of reported ETS exposure at all locations) was then calculated to provide a crude index of the relative importance of each exposure location. 

Although the concentration of ETS at each location is also an

important parameter in estimating exposure, measurements of ETS concentrations were not obtained in this study, which focused primarily on timeactivity patterns. In other studies (see Section 2.3.3), home and workplace

concentrations of nicotine (as an indicator of ETS) fall within the same general range. Thus, this location/duration index provides a rough estimate of

the relative extent of the population’s exposure at these locations.

However, ETS concentrations at locations grouped as other indoor (e.g.,

bars, restaurants, banks, or hospitals) are highly variable, and little information is available on concentrations in outdoor environments (e.g., at parks

or bus stops). Overall, the index provides an indication of the locations at

which exposure occurs, but not of the relative dose incurred at each location.

The results of the analysis are shown in Figure 2.5. For adult male

nonsmokers, the highest exposure index was estimated for the workplace
(46 percent), with the index at other locations (i.e., the home, other indoor,

and outdoor) ranging from 15 to 23 percent. For female nonsmokers, the

highest indexes were for the workplace (35 percent) and other indoor locations (31 percent), followed by the home (20 percent) and outdoor locations (13 percent). Somewhat different patterns were found for adult smokers reporting exposures to ETS from someone else’s smoking. For male

smokers, the exposure index was similar at all locations, ranging from 21 to

29 percent. For female smokers, the highest index was for the home (53

percent), ranging from 12 to 22 percent at other locations. Different patterns were observed for adolescents and children. For adolescents, the

exposure index was approximately the same for home and other indoor

locations (41 to 42 percent), followed by outdoor locations (13 percent) and

school (4.5 percent). (It should be noted that the values for adolescents are

based on a small sample size of 183.) Not unexpectedly, for children (6 to

11 years old) and infants and preschoolers (0 to 5 years old) the highest

exposure index (54 percent and 62 percent, respectively) was for the home.

Workplace exposures to ETS were also examined (Jenkins, 1994, personal communication). Approximately 40 percent of nonsmokers working

outside the home reported exposure to ETS in the workplace. While fewer

nonsmoking working females (30 percent) reported exposure than nonsmoking working males (47 percent), their average exposure duration at

work was somewhat longer (females, 5.8 hours; males, 5.2 hours). The proportion of the total daily reported exposure duration occurring in the workplace for these nonsmoking workers was 51 percent for males, and 38 percent for females.

Limited information on exposure to ETS is also available from

a survey on tobacco use in California, conducted between

June 1990 and July 1991 (Burns and Pierce, 1992). Using a stratified random-digit dialing technique, the head of household in 32,135 homes was

surveyed briefly (in either English or Spanish) to enumerate household

members and determine the smoking status of each household member.

From this information, all adult household members who were reported as

having smoked within the past five years were scheduled for an in-depth

interview, as were 28 percent of nonsmokers. The prevalence of active

smoking, as reported in this study, was 22.2 percent, with males (25.5 percent) smoking more than females (19.1 percent). Information was obtained

on household ETS exposure of children up to 18 years of age. The study

found that 32.2 percent of children under 5 years of age live in homes with

one or more smokers. Similar values were reported for children 6 to 11

years old (32.2 percent) and 12 to 17 years old (36.5 percent).

Using data collected in the California tobacco-use survey (Burns and

Pierce, 1992) described above, Borland et al. (1992) examined the extent of

exposure of nonsmoking workers to ETS according to type of work-site

smoking policy, work area, workplace size, and demographic characteristics.

The analysis reported by Borland et al. is for weighted population estimates

and differs slightly from that in the original report of Burns and Pierce

54

Smoking and Tobacco Control Monograph No. 10

Burns and Pierce (1992)

Borland et al. (1992)
(1992). The sample consisted of 7,301 nonsmokers from the larger study

who reported that they worked primarily indoors. Workplace ETS exposure

of these individuals was assessed by asking the question, “During the past

two weeks has anyone smoked in the area in which you work?” Additional

questions were not asked to define the frequency and extent of exposure.

Overall, 31.3 percent of the nonsmoking workers reported workplace ETS

exposure at least once in the preceding two weeks. Examined as a function

of work-site smoking policy, workplace exposure of nonsmokers was 9.3

percent for those working in a smoke-free worksite, 23.2 percent for those

working where there was a work-area smoking restriction, 46.7 percent for

those working where the smoking policy did not include the work area, and

51.4 percent for those working where there was no work-site smoking policy. The study also found that a greater percentage of male workers reported

exposure than did female workers (35.8 percent versus 22.9 percent); that

more workers under 25 reported exposure than did older workers (41.9 per55

Chapter 2

Figure 2.5 (Figure continues on next page)

Relative Person-Minutes of ETS Exposure* in Different Environments

Source: Lum, 1994a,b

* Percentages may not add to 100 due to rounding errors. Data from 1989 to 1990.

Work

46%

Home

15%

Outdoor

16%

Other indoor

23%

Adult Male Nonsmokers

Adult Male Smokers

Adult Female Nonsmokers

Adult Female Smokers

Work

35%

Home

20%

Outdoor

13%

Other indoor

31%

Work

12%

Home

53%

Outdoor

12%

Other indoor

22%

Work

26%

Home

29%

Outdoor

24%

Other indoor

21%
cent versus 26.4 percent); and that the number of workers reporting exposure decreased with increasing level of education, from 43.1 percent of

those with less than 12 years of education to 18.6 percent of those with a

college education. 

The California Department of Health Services (CDHS)

conducts annual telephone surveys of a representative

sample of Californians–the California Adult Tobacco

Survey (CATS). The 1995 survey interviewed over

4,000 adults about their smoking behavior. According to 1995 data from

the California Adult Tobacco Survey and an additional survey (Behavioral

Risk Factors Survey), CDHS estimated that 16.7 percent of the adult population in California smokes.

Survey results from 1994 and 1995 indicate increasing percentages

of nonsmoking and smoking California adults reporting that smoking is

prohibited at their work sites (1994: 84 percent (nonsmokers) and 75 per56

Smoking and Tobacco Control Monograph No. 10

Figure 2.5 (Continued)

Source: Lum, 1994a,b

* Percentages may not add to 100 due to rounding errors. Data from 1989 to 1990.

Infants and Preschoolers

(0 - 5 years)

Children

(6 - 11 years)

Adolescents

(12 - 17 years)

Outdoor

17%

Home

62% Other

Indoor

21%

Home

54%

School

0.5%

Outdoor

27%

Other

Indoor

19%

Home

41%

School

4.5%

Outdoor

13%

Other Indoor

42%

California Department of Health

Services (1995 and 1996) 

Pierce et al. (1994 and 1996, 

personal communication)
cent (smokers); 1995: 89 percent (nonsmokers) and 78 percent (smokers)).

Similarly, the percentages of nonsmoking and smoking adults in California

reporting that smoking is prohibited in public areas of their work has also

increased (1994: 74 percent (nonsmokers) and 63 percent (smokers); 1995:

82 percent (nonsmokers) and 85 percent (smokers)). The percentages of

adults reporting a complete ban of smoking in their own homes has also

increased (1994: 64 percent (nonsmokers) and 24 percent (smokers); 1995:

80 percent (nonsmokers) and 34 percent (smokers)).

The California Adult Tobacco Surveys in 1990, 1992, and 1993 were

conducted for CDHS by Pierce et al. (1994) at the University of California,

San Diego, who sampled relatively large numbers of Californians: 8,224 to

30,716 adults (18 years and older) and 1,789 to 5,040 teenagers (12-17 years

of age, CDHS, 1996). From the results of those surveys, prevalence of active

smoking and ETS exposure for various subpopulations can be estimated.

For example, of the 2,047 women interviewed in 1992 who were pregnant

over the previous 5 years, 15.1 percent smoked prior to pregnancy, and of

these, 37.5 percent quit during the pregnancy; thus, a prevalence estimate

of 9.4 percent for California women smoking throughout pregnancy can be

obtained. Regarding ETS exposure of women of child-bearing age, Pierce et

al. (1996, personal communication) estimated that in 1993 of the 6,513,891

women aged 18-44 in California, 634,028 were nonsmokers exposed to ETS

at home, 564,411 were nonsmokers exposed indoors through their work,

and 46,083 were exposed at both work and home. From this, the proportion of nonsmoking women in California of child-bearing age who are ETSexposed is estimated to be 22.1 percent. Regarding childhood exposures,

the 1993 survey suggests 19.6 percent of those age 17 and under and 17.7

percent of those under age 5 may be exposed to ETS in their homes (Pierce

et al., 1994).

Historically, the main focus of large population-based studies of tobacco smoke exposure has been on active smoking,

with little or no information obtained on exposure to ETS.

More recently, several studies in the U.S. have addressed various aspects of

ETS exposure, including exposure prevalence in various population subgroups. The measures of exposure used in these studies include both questionnaire responses and measured levels of biological markers (primarily

cotinine). As previously noted, self-reporting can result in some degree of

misclassification. The use of biomarkers can also result in some misclassification, however, in that it is not always possible to distinguish between a

nonsmoker heavily exposed to ETS and a very light smoker; another concern is that, in some studies, the timing of sample collection relative to

exposure may not have been appropriate. In addition, most biomarkers

reflect exposures occurring within the past few days, whereas the exposure

period of interest for many studies extends over a time period of many

years. These factors are discussed in Section 2.4.1. For those studies summarized below in which prevalence was assessed using biomarkers, the biomarker levels detected in biological fluids are mentioned. The use of biomarkers as an exposure measure is discussed in detail in Section 2.4.

57

Chapter 2

2.6.3 Prevalence of

ETS Exposure in the

United States
As part of the Third National Health and Nutrition

Examination Survey (NHANES III), the National Centers for

Environmental Health and the National Center for Health

Statistics of the Centers for Disease Control (CDC) measured serum levels of cotinine to assess exposure to tobacco

of persons in the United States aged 4 years and older. The

study was conducted from 1988 through 1994; preliminary information

was available in 1993 (CDC, 1993b), and final results of the 1988 to 1991

survey were recently published (Pirkle et al., 1996). In the 1988 to 1991

survey, 14,269 persons aged 4 years and older were interviewed; of those,

12,678 were examined, and of those examined, 10,642 had serum cotinine

measurements taken. Reported data on ETS exposure in the home were

available for 3,185 children aged 2 months to 3 years, 3,011 aged 4 to 11

years, and 878 aged 12 to 16 years. Serum cotinine levels were available on

737 adolescents and 7,740 adults with complete information on tobacco

use and ETS exposure. 

Of US children 11 years and younger, 43 percent lived in homes of

at least one smoker, as did 37 percent of adult non-tobacco users. Serum

cotinine levels, however, indicated more widespread exposure to nicotine,

with 87.9 percent of non-tobacco users with detectable levels of serum cotinine. Both the number of smokers in the home and the hours exposed at

work were significantly and independently associated with increased serum

cotinine levels (p < 0.001, multiple regression t test). Identified groups with

higher exposure to ETS were children, non-Hispanic blacks, and males.

Dietary variables showed no consistent association with serum cotinine levels, and dietary contributions, if any, appeared to be extremely small.

Cummings et al. (1990) assessed the prevalence of ETS

exposure of 663 nonsmokers and ex-smokers who attended the Roswell

Park Memorial Institute cancer-screening clinic in Buffalo, NY in 1986.

Both self-reported exposure and measured urinary cotinine were used as

measures of exposure. An interviewer questioned subjects about their exposure over the 4-day period preceding the interview and a single urine sample was collected on the day of the interview. A total of 76 percent of the

subjects reported some exposure to ETS during the 4 days preceding the

interview. The average number of exposures over the 4-day period was 3.3

(range: 0 to 21), and for those exposed, the average daily reported exposure

was 2 hours (range: <1 to 13.25 hours/day). The reported exposure locations were work (28 percent), home (27 percent), restaurants (16 percent),

private social gatherings (11 percent), car or airplane (10 percent), and public buildings (8 percent). Cotinine was detected in the urine of 91 percent

of samples (detection limit not given), suggesting that individuals are not

always able to recall exposures or are not aware that exposure has occurred.

It is also possible that for some subjects, cotinine was detected as a result of

exposures that preceded the 4 days reported in the interview. The measured cotinine levels for self-reported nonsmokers ranged from 0 to 85

ng/ml (average, 8.84 ng/ml), with 92 percent of the values less than 20

ng/ml. 

58

Smoking and Tobacco Control Monograph No. 10

2.6.3.1 General

Population Studies

Centers for Disease Control

(CDC, 1993b; 

Pirkle et al., 1996)

Cummings et al. (1990)
In a recent additional (unpublished) analysis of this study,

Cummings (1994) examined ETS exposure at work among currently

employed nonsmoking subjects (n = 339) who did and did not report exposure to tobacco smoke in the home. Of currently employed nonsmokers,

substantial percentages (81 percent and 76 percent, respectively) reported

ETS exposure at work, both among those who were exposed at home (n =

122) and those who were not (n = 217). Overall, exposure to ETS at home

was not predictive of being exposed to ETS at work. Mean urinary cotinine

values for employed nonsmoking subjects in the study were analyzed by

self-reported exposure to tobacco smoke at work and at home. Subjects

exposed both at work and at home had mean urinary cotinine (12.8 ng/ml)

very similar to those exposed at home but not at work (11.0 ng/ml), with

those exposed at work and not at home showing lower mean cotinine (7.5

ng/ml). As noted by the author, many of the subjects took time off work to

attend the clinic where the study was conducted, and thus a stronger influence of home exposure on mean urinary cotinine is not surprising.

Subjects reporting no exposure at work or at home had a mean urinary cotinine level (8.7 ng/ml), which is indicative of exposure to ETS.

Coultas et al. (1987) conducted a population-based household

survey of respiratory disease in 2,029 Hispanic children and adults in New

Mexico, in which salivary cotinine was measured for 1,360 nonsmokers and

ex-smokers. Nonsmoking status was ascertained on the basis of self-reported smoking status and a salivary cotinine concentration of less than 20

ng/ml; the reported detection limit in this study was 0.78 ng/ml saliva.

Exposure prevalence, estimated using data presented in the report, was: 39

percent for adults (18 years and older), 48 percent for adolescents (13-17

years), 45 percent for children (6-12 years), and 54 percent for infants and

preschoolers (5 years of age and under). The mean salivary concentrations

in the various age groups ranged from 0 (not detected) to 6.0 ng/ml.

The prevalence of a detectable level of cotinine was about 35 percent for those living in a nonsmoking household and increased with the

number of cigarettes smoked by household members. In a multiple logistic

regression model, the major determinants of a detectable level of cotinine

in children were mother’s smoking (odds ratio (OR) = 3.2), father’s smoking

(OR = 2.1), and the smoking of other household members (OR = 4.0); the

other household smokers were primarily grandparents (41 percent), siblings

(26 percent), or aunts and uncles (15 percent). Among adults, the effects of

spouse’s smoking were smaller, with ORs of 1.3 and 1.4 for husband’s and

wife’s smoking, respectively.

Infants and young children are particularly susceptible to the

adverse effects of ETS (See chapters on Developmental and

Reproductive Effects of Exposure to ETS, and Respiratory Health Effects of

Exposure to ETS). A number of studies have examined exposures of this population group (Greenberg et al., 1989; Chilmonczyk et al., 1990; Overpeck

and Moss, 1991).

59

Chapter 2

Coultas et al. (1987)

2.6.3.2 Studies of

Infants and Children
In 1988 the National Center for Health Statistics collected

information on household exposure to ETS for a sample of 5,356 children 5

years of age and under (Overpeck and Moss, 1991). The information was

obtained as part of the National Health Interview Survey, a continuous

cross-sectional survey representing the household population of the United

States (the authors report that the sample is representative of 86 percent of

U.S. children in this age group). Overall, the survey found that about onehalf of all U.S. children 5 years of age and under are exposed to tobacco

smoke constituents due to prenatal maternal smoking and/or are exposed

to ETS from household members after birth. Of the total sample, 28 percent had both prenatal and postnatal exposure, 21 percent were exposed

only after birth, with 1.2 percent exposed prenatally only. 

Forty-two percent of the children were currently living in a household with a smoker. Of these children, a disproportionately high number

lived in homes comprising the lower income and educational categories.

Children in families at the lowest income level category were almost twice

as likely to live in a home with a current smoker (58 percent) compared to

children in families at the highest income level (30 percent). More than

twice as many children whose mothers had not completed high school (61

percent) were currently exposed to household smoke as compared to children whose mother had completed one year or more of college (28 percent).

In a study of infant exposure to ETS, Greenberg et al. (1989)

obtained detailed information on household smoking habits from mothers

of 433 infants from a representative population of healthy neonates in central North Carolina during 1986 and 1987; infant urine samples were also

collected. Approximately 55 percent (239) of the study infants lived in a

household with at least one smoker. As determined from the questionnaire

responses, 42 percent of the infants were exposed to ETS during the week

preceding data collection, where exposure was defined as the production of

smoke in the same room or vehicle as the infant. As in other studies,

prevalence was higher when the metric of exposure was cotinine. Of the

433 infants, cotinine was detected in 60 percent of the urine samples.

Measured concentrations ranged from 6 to 2,273 ng/mg creatinine, with a

median concentration of 121 ng/mg creatinine (see Section 2.4.2.1 for a discussion of cotinine to creatinine ratios).

In a large population-based study of infants receiving routine well-child care in private physicians’ offices in the greater Portland,

Maine area, Chilmonczyk et al. (1990) collected urine samples from 518

infants, 6- to 8-weeks of age, and obtained information on household

smoking habits. Forty-one percent of the study population lived in households in which at least one household member smoked. Of the total sample, 80 percent had detectable urinary cotinine concentrations (concentrations less than 1 μg/L were reported as not detected), with concentrations

greater than 2 μg/L in 64 percent of the samples. In the 305 households

where no smoking was reported, 8 percent of the infants’ urinary cotinine

60

Smoking and Tobacco Control Monograph No. 10

Overpeck and Moss (1991)

Greenberg et al. (1989)

Chilmonczyk et al. (1990)
values were equal to or greater than 10 μg/L (on the basis of data in the

study, the authors defined the concentration of 10 μg/L as a reasonable estimate of significant ETS absorption). Corresponding rates of urinary cotinine >10 μg/L were 44 percent in infants living in the 96 households where

a member other than the mother smoked, 91 percent for those in the 43

households where only the mother smoked, and 96 percent for those in the

74 households where both the mother and another household member

smoked. 

Because data are not available to quantify trends in

ETS exposure in California, this section examines

trends in the prevalence of smoking, the results of legislative efforts to limit

smoking, and other factors contributing to ETS exposure of the nonsmoker.

Indirect evidence (e.g., smoking prevalence trends) suggests that exposure to

ETS in California is declining and that ETS exposure prevalence in

California may be lower than elsewhere in the U.S. 

Data from 1965 to 1985 show that there has been a

continual decline in smoking prevalence among U.S.

adults, with an annual rate of decline of 0.5 percent over that time period

and a 1.1 percent annual decrease between 1987 and 1990 (U.S. DHHS,

1989; CDC, 1992). In a 1991 survey of a representative sample of the U.S.

civilian population (18 years and older), 49.8 percent of the population

were ever-smokers and 25.7 percent were current smokers (CDC, 1993a).

Comparative data for the U.S. and California indicate that both smoking

prevalence and cigarette consumption are lower in California than in the

rest of the U.S., and that the annual rate of decline in California has been

somewhat more rapid over the last decade (Figures 2.6 and 2.7; Burns and

Pierce, 1992; Pierce et al., 1994; CDHS, 1996). Limited information is available to determine whether there have been corresponding decreases in ETS

exposures of nonsmokers, either nationwide or in California. Although

smoking prevalence is clearly related to ETS exposures, other factors associated with smoking behavior that contribute to exposure of nonsmokers

(e.g., location of smoking) must also be considered. 

Although overall trends in smoking prevalence and

other factors suggest that ETS exposure is decreasing,

this may not be true for all population subgroups, in addition, the rate of

decline may differ among different groups. Patterns of cigarette smoking in

the U.S. have shifted over the years among sex, race, educational, and

socioeconomic groups (Fiore et al., 1989; Pierce et al., 1989; U.S. DHHS,

1989; Overpeck and Moss, 1991), with differential impacts on ETS exposure

of the nonsmoker. As one example, although the overall prevalence rates

of smoking have declined among men and women during the last decade,

smoking has decreased at a slower rate among women. In 1991, it was

reported that the onset of smoking for females is occurring at younger ages

and until recently, smoking initiation was increasing for the least educated

females. As a result, the differential risk of ETS exposure of infants and

children may have changed because of the smoking patterns among

61

Chapter 2

2.6.4 Factors Influencing

Exposure to ETS

2.6.4.1 Smoking Prevalence

Trends: California versus U.S.

2.6.4.2 Smoking Prevalence

Trends in Subpopulations
women with higher than average birth rates and those who spend more

time with the developing child (Overpeck and Moss, 1991). 

Teenagers are another important example of a population subgroup

with smoking prevalence trends that differ from overall trends. Smoking

prevalence among 16- to 18-year-olds declined fairly steadily from 1975

through 1981, and again from 1984 through 1988. After 1988, this trend

was reversed and smoking prevalence among California adolescents began

to increase; however, data for 1992 and 1993 indicate that the rising trend

may not be continuing (Pierce et al., 1994). This trend is significant

because the teen years are the time when most people who become smokers

start smoking. The age of smoking initiation in the U.S. has been declining

and now peaks among 16- to 18-year-olds (Pierce et al., 1994).

Hammond et al. (1995) measured occupational exposures to ETS in

25 diverse settings in Massachusetts, including offices and production areas,

to evaluate the effectiveness of smoking restrictions in the workplace.

Average weekly concentrations of nicotine, measured by 15 to 25 passive

samplers in each worksite, were used to indicate ETS exposure. The

researchers found that worksite smoking policies had a major effect on the

ETS exposure, with median nicotine concentrations lowered by a factor of 6

by smoking restrictions and by a factor of 30 by smoking bans in open

offices at worksites. Non-office worksites were similarly affected, with

restrictions lowering exposure by a factor of 3 and bans by a factor of 10.

Within the last several years, there has been a major

public health effort in California to reduce smoking

prevalence and ETS exposure of the nonsmoker. These

efforts are due, in part, to the Tobacco Tax and Health Protection Act

(Proposition 99) passed in 1988 by voters in California. The measure raised

the tax on cigarettes by 25 cents per pack, providing funding for a statewide

health education program to reduce tobacco use. Funds from this measure

have also supported the collection of data on smoking behavior; telephone

surveys of California households have been conducted using both cross-sectional and longitudinal designs. These California Tobacco Surveys (CTS) as

analyzed by Pierce et al. (1994) were the main sources used to estimate the

prevalence trends described below.

Analyses of CTS data to evaluate the effectiveness of programs

implemented as a result of the passage of Proposition 99 suggest that these

programs have been effective in reducing smoking prevalence (Burns and

Pierce, 1992; Pierce et al., 1994). Among adults, smoking prevalence in

California for the year before the tax increase (i.e., 1987) was 26.8 percent;

the 1990 estimate was 22.2 percent, a 17 percent decline in 3 years (Burns

and Pierce, 1992); the 1995 estimate is 16.7 percent (CDHS, 1996; Figure

2.6). More recent information indicates that the prevalence of smoking

among adults 20 years and older has dropped even further, to an estimated

19.1 percent in 1993, while for adolescents 16 to 18 years old, prevalence is

estimated to be 7.75 percent (based on 1990 data; Pierce et al., 1994). If the

62

Smoking and Tobacco Control Monograph No. 10

2.6.4.3 Factors Affecting ETS

Exposure in California:

Proposition 99 Efforts
Chapter 2

63

Tax increase,

California Tobacco Control

Program begins

United States

California

1965196619671968196919701971197219731974197519761977197819791980198119821983198419851986198719881989199019911992199319941995

Figure 2.6

Adult Smoking Prevelance: California and the United States, 1965 to 1995 Percent Prevalence

50

40

30

20

10

0

Pre-program trend

Projected trend

Program Trend

Packs per Month

Figure 2.7

Linear Trend in Per Capita Consumption of Cigarettes in California Before and After

Proposition 99 and Taxation Program

Source: Pierce et al., 1994

Source: California Department of Health Services, 1996

1984 1985 1986 1987 1988 1989 1990 1991 1992 1993

12

10

8

6

4
decline in smoking prevalence observed in California between 1988 and

1993 continues through the 1990s, smoking prevalence among Californian

adults will be 10.2 percent by the year 1999. This rate of decline in smoking prevalence will not achieve the California Department of Health

Services (CDHS) Tobacco Control Program’s legislatively set goal of a 75 percent reduction in smoking prevalence (to 6.5 percent) by the year 1999

(Pierce et al., 1994). Although the decline in smoking may fall short of the

set goal, the program has been successful in reducing smoking prevalence

among adults; the 1993 prevalence level was 16 percent lower than it

would have been had the 1984 through 1988 pre-program trend continued. 

A decline in per capita consumption of cigarettes in California has

also been observed from 1980 through 1993 (Figure 2.7). Similar to the

observations with respect to smoking prevalence, a sharp acceleration in

the rate of decline in tobacco consumption was observed at the time of the

Proposition 99 tax increase. As shown in Figure 2.7, the rate of change of

per capita consumption appears to have leveled off following an initial

rapid decline (Burns and Pierce, 1992). More recent information on cigarette consumption indicates that per capita consumption in 1992 was 5.34

packs per month, 13.82 percent lower than the 6.23 packs per month predicted if consumption trends before the passage of Proposition 99 had continued through 1992 (Glasscock et al., 1992-93). Per capita cigarette consumption dropped even lower in 1993 to 4.84 packs per month (Pierce et

al., 1994). These declines have been attributed to the 1988 tax increase and

subsequent tobacco education efforts. 

Children have been a priority of the CDHS Tobacco Control

Program’s efforts to reduce ETS exposure and its associated health costs.

The home is the primary location of exposure of young children and efforts

have been made to reduce exposure at this location. Data available for the

last 2 years suggest that exposure of children is decreasing—in 1992, 75.5

percent of children 18 years of age and younger lived in a smoke-free

household; in 1993, this proportion had increased significantly to 80.4 percent (p < 0.05; Pierce et al., 1994).

As indicated in Section 2.6.2, the workplace represents an important ETS

exposure location in California. Over the last several

years, an increasing number of workplaces have adopted policies restricting smoking, and studies have

shown that reported nonsmoker exposure to ETS decreases with increasing

degree of worksite restriction on smoking (Borland et al., 1992; Pierce et al.,

1994). More specifically, it is estimated that the percentage of indoor workers with smoke-free workplaces (i.e., smoking is prohibited in all areas) nearly doubled in California, from 35 percent in 1990 to 65 percent in 1993; in

1993, the proportion of workers covered by at least a work-area ban on

smoking (i.e., smoking is prohibited in the work area) was 87.3 percent

(Pierce et al., 1994). Recent legislation (discussed below) can be expected to

further lower these numbers. Thus, the relative importance of the workplace as an exposure location is expected to decline in California as more

64

Smoking and Tobacco Control Monograph No. 10

2.6.4.4 Factors Affecting ETS

Exposure in California:

Smoking Laws and Ordinances
workplace restrictions are imposed through the enactment of new laws or

implementation of smoking policies by the private sector. 

Data available for California and the United States suggest that

workplace exposure in California is less than in the country as a whole,

although the different time periods for which the data are available and the

rapid change in workplace smoking policies limit the conclusions that can

be made. Approximately 36 percent of workers (smokers and nonsmokers)

in California worked in a smoke-free worksite (data for 1990), as compared

to only 3 percent of workers in the U.S. population as a whole (data for

1986). Further, 71.3 percent of indoor workers in California reported some

type of work-site smoking policy in 1990, compared with only 45 percent

nationally in 1986 (Pierce and Hatziandreu, 1986). 

In California, smoking in state-owned buildings and leased space,

state prisons and hospitals, and state-owned passenger vehicles was banned

in 1993 by Executive Order (W-42-93), with full compliance required by

December 31, 1993 (Gov. Code, Section 19994.30). Restrictions on smoking in a wide range of workplaces in California went into effect on January

1, 1995, as the result of legislation (AB13 - Friedman) passed in 1994 and

signed by Governor Pete Wilson. This addition to the California Labor

Code (Section 6404.5) provides that “no employer shall knowingly or

intentionally permit, and no person shall engage in, the smoking of tobacco products in an enclosed space at a place of employment.” All restaurants are included under the statute. Private residences are not included

under the statute, except for those licensed as family day care homes, in

which case, the statute applies during the hours of operation and in those

areas where children are present. The law specifies other “places of employment” which are not covered, including (for example): portions of hotels

(designated lobby areas, guest rooms, and meeting rooms); bars and taverns; cabs of trucks; warehouses; and certain places of employment where

fewer than five persons work. This workplace smoking prohibition could

have substantial impact on ETS exposures in California.

In addition to limitations on smoking in the workplace, an increasing number of cities and counties in California have placed various types of

restrictions on smoking. These include restrictions on smoking in city- and

county-owned facilities, restaurants, workplaces, and other public locations;

also included are restrictions on the sale or promotion of tobacco products,

typically by restricting the location of vending machines, advertising, or

sampling activities. As of July 1994, 77 cities and 16 counties in California

have local ordinances which require all workplaces and all restaurants to be

100 percent smoke-free (Americans for Nonsmokers’ Rights, 1994). An

additional 72 California cities have ordinances requiring 100 percent

smoke-free workplaces, and 91 have ordinances requiring 100 percent

smoke-free restaurants (California Smoke-free Cities, 1994). 

Smoking has also been prohibited in all day care centers and in pri65

Chapter 2
vate residences licensed as family day care homes during hours of operation

(ARB 615, 1993). A similar law, called the Pro-Children Act of 1994, was

passed on the national level which prohibits smoking in any health care,

day care, or early development services facility, and in facilities providing

kindergarten, elementary or secondary education, or library services to children (HR 1804, Section 1041, 1994).

Finally, other less quantifiable changes in smoking

behavior may also be contributing to changing patterns of ETS exposure of the nonsmoker. For example, increased awareness of the potential health effects of ETS exposure and

increased willingness of nonsmokers to object to smoking in their presence

may result in changes in smoking behavior; for example, smokers may

refrain from smoking in the presence of children, or may confine smoking

to outdoor areas, even at home. Recent data indicate that half of all

Californians surveyed voluntarily made their homes smoke-free by 1993,

and 20 percent had some household smoking restrictions, where smoking

was permitted only in certain rooms or at certain times. The number of

smokers reporting a smoke-free home increased from 18.8 percent of those

surveyed in 1992 to 27.1 percent of those surveyed in 1993 (Pierce et al.,

1994). Smokers who had young children living in the home were more

likely than smokers living without children to report a smoke-free home. 

ETS can be a major source of indoor air contaminants

in environments where smoking occurs. Composed of

both sidestream and mainstream smoke, ETS contains

over 50 compounds identified as carcinogens and five identified as developmental and reproductive toxicants (under Proposition 65). Although

changes in cigarette design (e.g., filters) have had substantial impact on the

composition of mainstream smoke, these changes have had little impact on

the composition of sidestream smoke, the principal contributor to ETS.

In many indoor environments that have been monitored, ETS has

been detected, and studies consistently show that concentrations of a number of toxic and carcinogenic constituents (e.g., PAHs, nitrosamines) are elevated in environments where smoking is allowed as compared to those

where it is not. Levels of ETS encountered by exposed nonsmokers, including infants and children, during their daily activities are sufficiently high

that ETS constituents have been detected in their urine, blood, and saliva. 

Although the presence of cotinine (and other biomarkers) in the fluids of nonsmokers provides evidence of the degree of exposure to ETS, the

ratio of cotinine levels in ETS-exposed nonsmokers to those in smokers may

not be indicative of the exposure ratio for other ETS constituents. The ratio

of sidestream to mainstream emissions is not constant for all constituents,

and indoor air measurements suggest that different constituents are

removed from air at differing rates. In addition, differences exist in the

uptake and metabolism of individual constituents. 

66

Smoking and Tobacco Control Monograph No. 10

2.6.4.5 Other Factors Affecting

ETS Exposure in California

2.7 CHAPTER SUMMARY

AND CONCLUSIONS
Although nicotine and cotinine are typically used as markers of

exposure to ETS, a limited number of studies have examined other biomarkers more directly related to a biological effect. For example, hemoglobin

adducts of 4-aminobiphenyl (a human carcinogen) have been used as biomarkers of exposure in some epidemiologic studies. More work is needed to

expand the use of biomarkers such as hemoglobin adducts of 4-aminobiphenyl, which have relevance to the health effects under study.

Questionnaires, widely used in assessing ETS exposure, provide

accurate qualitative information on self-reported exposure to spousal,

parental, or other household smoking, although quantitative information is

less reliable. Because of the importance of the workplace and other indoor

locations for adult exposures, misclassification may occur when exposure

status is based solely on exposure at home. In addition, biomarker studies

have shown that a proportion of subjects reporting no exposure to ETS (at

work or at home) have measurable biomarker concentrations, indicating

that the subject either forgot or was not aware of actual exposure. Thus,

biomarker measurements may be useful in validating the questionnairebased exposure status of ETS-exposed subjects.

Californians spend a major portion of their time indoors, where

most exposure to ETS occurs. Estimates from surveys conducted in the late

1980s indicated that 43 percent of the nonsmoking adult population was

exposed to ETS on any given day. In these surveys, ETS exposure was

reported for approximately 40 percent of all children under the age of 12,

and for approximately 64 percent of nonsmoking adolescents. The most

significant location of exposure for adult nonsmokers was the workplace,

although other locations (home, other indoor, and outdoors) were also

important. For infants and children, the home was the most significant

exposure location. Thus, at the time of these surveys, a significant proportion of the California population was exposed to ETS.

Overall trends in smoking prevalence and other factors, including

an increasing number of restrictions on smoking in the workplace and public locations, suggest that exposure to ETS is decreasing in California. These

decreases can be attributed, in part, to programs implemented under

California’s Proposition 99, passed in 1988; further decreases are expected

due to the passage of AB 13, effective in January 1995, which restricts

smoking in most workplaces. Lower rates of smoking and per capita consumption of cigarettes in California as compared to the entire U.S. suggest

that exposure to ETS is lower in California than nationwide. However, certain subpopulations (e.g., low income women, teenagers) may be experiencing different smoking trends that may affect ETS exposure rates of others

(e.g., infants). Because the teen years are the time when most people who

become smokers start smoking, continued surveillance of this subspopulation is needed to identify public health efforts which will further reduce

ETS exposures in California.

67

Chapter 2
Despite the decreasing prevalence of ETS exposure of California

nonsmokers due to increasing restrictions on smoking in the workplace and

public locations, exposure of young Californians, especially infants and

young children, is of continuing public health concern. The timing and

routes of infants’ exposure to tobacco smoke constituents are unique in

that infants can be exposed prenatally if the mother smokes or is exposed

to ETS during pregnancy; postnatal exposure may occur directly through

inhalation and indirectly from ingestion of breast milk. Studies of nursing

infants indicate that mother’s milk contributes significantly to urinary cotinine levels in nursing infants. It is possible that other ETS constituents are

also present in breast milk and ingested by the infant. Persons exposed as

infants to potentially large doses (relative to their small bodyweight) of the

carcinogenic constituents in ETS may face a relatively higher risk due to

this early exposure. Those exposed in utero and in early life to the developmental toxicants found in ETS may be at higher risk for a number of negative health outcomes. With the home as the most significant ETS exposure

location for these age groups, educational efforts for women who are pregnant (or plan to become pregnant) and their partners about reducing their

children’s ETS exposure are warranted.

The potential adverse health effects resulting from these exposures

are addressed in the other chapters of this assessment.

68

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This chapter reviews the evidence on the impact of ETS exposure during pregnancy on: 1) fetal growth, including decreased birthweight,

growth retardation, or prematurity; 2) fetal loss, including spontaneous

abortion and perinatal mortality; and 3) congenital malformations. The

review of each of these three categories of outcome begins with a brief discussion of studies which assessed the effect of active smoking by the mother during pregnancy. Although the impact of active smoking on development is not the topic of this document, it provides a context within which

to consider the possible effects of ETS exposure. The brief discussion of

active smoking effects is followed by detailed descriptions of epidemiologic

studies relating ETS exposure to the specific outcome. Pertinent animal

studies are then described. Each review concludes with a discussion of the

overall evidence from animal and epidemiological studies for adverse

impacts of ETS.

By far the majority of epidemiologic studies on perinatal

effects of ETS exposure have investigated fetal growth, and most of these

studies have focused on birthweight. Technically, fetal growth should be

measured by comparing size at a number of time intervals. However, measures at birth are commonly used as surrogates. Those measures include

mean birthweight, low birthweight (LBW, <2500 grams), and intra-uterine

growth retardation (IUGR), which is defined as less than the tenth percentile of weight for gestational age. The LBW category includes infants

that are growth retarded or small for their gestational age, as well as infants

who are not growth retarded but were born prematurely. These outcomes

may result from different etiologies, therefore some investigators examine

LBW (or IUGR) in term births only; pre-term births are also examined as a

separate category. Examining IUGR over the range of gestational ages (22-

42 weeks) provides more power than examining only LBW at term. Because

a portion of the “normal” population will fall into the IUGR category, however, there is some question as to what extent this categorization measures

“abnormality” (Stein and Susser, 1984).

Smoking by the mother during pregnancy has long

been considered an important independent risk factor for decreased infant birthweight. The association

was first reported in 1957, and the weight of evidence indicates a causal

effect (Stillman et al., 1986; U.S. DHHS, 1980). Infants of active smokers

typically have a mean birthweight 150-200 grams less than those of non75

Developmental Toxicity I:

Perinatal Manifestations

3.1 INTRODUCTION

3.2 FETAL GROWTH

3.2.1 Overview of Fetal

Growth and Maternal

Smoking During Pregnancy
76

Smoking and Tobacco Control Monograph No. 10

smokers and are twice as likely to be of low birthweight. The reduction in

birthweight does not appear to be due to more pre-term births; rather,

infants are growth retarded at all gestational ages. There is evidence that

other growth measures, such as length and head circumference, are also

reduced in infants of smokers.

The effect of smoking may result primarily from exposure to carbon

monoxide and nicotine. Carbon monoxide can cause fetal hypoxia, for

which the fetus is physiologically unable to adequately compensate

(Stillman et al., 1986; U.S. DHHS, 1980). Nicotine leads to decreased uteroplacental perfusion and also crosses the placenta to affect the fetal cardiovascular system as well as the gastrointestinal and central nervous systems

(Stillman et al., 1986). Other constituents of cigarette smoke (e.g., toluene,

cadmium) have been shown to produce fetal growth deficits (Donald et al.,

1991; OEHHA, 1996). All of these compounds are also present in ETS. 

Many of the early epidemiological studies of ETS exposure

and fetal growth did not adjust for confounders. When

examining fetal growth, a number of co-variables should be

considered initially, including: maternal age, race, parity or prior reproductive history, maternal smoking, socioeconomic status, and/or access to prenatal care. Few studies have information on maternal stature or weight

gain, but these are also important determinants of fetal weight, as are certain illnesses, complications of pregnancy, and gender of the infant.

Gestational age at delivery is the strongest predictor of birthweight.

Multiple births are much more likely to result in lower birthweights, so

study populations are often limited to singleton births. Although many

factors may be related to birthweight, their distribution by ETS exposure

status must vary in order for them to confound an association of ETS and

birthweight. A confounder in one study population is not necessarily a

confounder in another.

The descriptions of the epidemiological evidence on fetal growth

are presented by exposure measure (i.e., home exposure, home and work

exposure, biomarkers). The numerous studies on exposure to ETS in the

home are presented in two different subsections, one on mean birthweight,

the other on growth retardation or prematurity.

All but one of the studies of the impact of ETS exposure

in the home on mean birthweight found a decrement

in mean birthweight, although in about half, the decrement was small

(Table 3.1; Figure 3.1, top). A few early studies found little effect, but none

of them controlled for confounders or performed much statistical analysis.

Of the studies conducted in the last decade, seven found decrements ranging from 30 to 200 grams while four found very little association with

paternal smoking, and weight decrements of less than 20 grams. Two of

the four which found little association were based on selected populations

(e.g., offspring of twins); this may have introduced some bias and affected

the generalizability of the results (Magnus et al. 1984; MacArthur and Knox,

3.2.2 Human Studies

of Fetal Growth and

ETS Exposure

3.2.2.1 Home ETS Exposure

and Mean Birthweight
77

Chapter 3

Authors (year)

Country

MacMahon et al. (1966)

U.S. (Massachusetts)

Comstock & Lundin (1967)

U.S. (Maryland)

Underwood et al. (1967)

Worldwide

Borlee et al. (1978)

Belgium

Magnus et al. (1984)

Norway

Rubin et al. (1986)

Denmark

MacArthur & Knox (1987)

England

Study Design

Retrospective mail 

questionnaire 

(12,192 white singletons)

(5,935 maternal nonsmokers)

Special census linked to vital

records (448 births)

Naval records of labor and

delivery; cross-sectional

(48,505 singletons with 

24,674 maternal nonsmokers)

Retrospective interview (175

normal live births, 

202 malformed)

Retrospective interview of 

twins (parents of offspring studied)

(3,130 families; 5,188 births)

Interview at delivery

(500 term live births >2,000g)

Unknown

(180 mothers who quit smoking

in pregnancy)

Difference in Mean Birthweight

by Exposure1

-22g (-57-13) females

-20g (-55-15) males

-28g for pipe/cigar (ns)

no consistent effect by amount

-42g (no statistics provided)

-7 to -3g, by amount smoked

-228g (-429.0 to -26.7) crude

(p = 0.06 for paternal smoking

impact analysis that controlled for

maternal smokers)2

Regression for categories of

about 10 cigs/day:

crude: -48g (-65 to -31)

adjusted for maternal

smoking2: -5g (-23-13)

Adjusted for maternal smoking: 

-6.1g/cig (-12 to -0.2)2

-120g/pack

-14g crude

not significant in an analysis for

the effect of paternal smoking

1 All effect measures assessed in nonsmoking mothers unless otherwise specified (e.g., "smoking

adjusted"). All 95 percent confidence intervals calculated by reviewers from available data. ns =

not statistically significant (p > 0.05).

2 Control for at least some confounders (see text discussion of studies).

3 Based on living with a household smoker, not only the spouse.

Table 3.1

Studies of Birthweight and ETS Exposure Defined by Paternal Smoking Status
78

Smoking and Tobacco Control Monograph No. 10

Authors (year)

Country

Schwartz-Bickenbach et al.

(1987)

Germany

Campbell et al. (1988)

England

Brooke et al. (1989)3

England (London)

Chen et al. (1989)3

China (Shangai)

Saito (1991)

Japan

Mathai et al. (1990)2

England (Liverpool)

Mathai et al. (1992)

India (Vellore)

Zhang & Ratcliffe (1993)

China (Shangai)

Martinez et al. (1994)

U.S. (Arizona)

Study Design

Interview at delivery 

(54 pairs-smoke and not,

followed while breast-feeding)

Interview 1 month post-delivery

(518 white singles)

Prospective interview

(1,513 white births with

1,018 nonsmokers) 

Retrospective mail

questionnaire (1,058 births)

Interview at infant care visit

(3,000 couples)

Prospective interview

(285 white singles)

Interview 

(994 singletons)

Interview post-delivery

(1,785 singleton term births)

Interview at delivery

(1,219 births, 907 nonsmokers)

Difference in Mean Birthweight

by Exposure1

-205g (-440-30.1), crude

-113g (-216 to -8)2

(from regression after adjusting

for maternal smoking)

-18g or 0.5% reduction

(p = 0.56)

-11g (-81.9-64.1)

paternal smoking ≤10/day

-15g (-94.5-64.5)

any other smokers ≥10/day

adj made no difference2

no dose effect

Smoke any: -33.4g (-66.3 to -0.5) 

For 40 cigs/day:

-111g (-191.0 to -31.7), crude

-66g (-213.0-81.1), crude

-63g (-114g to -12)2

-30g (-66-7)2

-62g for 15-19 cigs/day

but +32 for ≥20/day

-34g (-63 to -5)2 per 10 cigarettes

1 All effect measures assessed in nonsmoking mothers unless otherwise specified (e.g., "smoking

adjusted"). All 95 percent confidence intervals calculated by reviewers from available data. ns =

not statistically significant (p > 0.05).

2 Control for at least some confounders (see text discussion of studies).

3 Based on living with a household smoker, not only the spouse.

Table 3.1 (Continued)

1987). Similarly, one which found the greatest weight decrement also studied a select population (Schwartz-Bickenbach et al., 1987). The studies are

described in chronological order below.

MacMahon et al. (1966) studied a large sample of live births

by sending their mothers a questionnaire to ascertain parental smoking

habits during the calendar year in which the pregnancy started. Overall,

the study found an 86.8-gram decrement associated with any paternal

smoking for female infants, with a slightly lower decrement for male

MacMahon et al. (1966)
79

Chapter 3

-500 -400 -300 -200 -100 0 100

Difference in Mean Birthweight (grams)

a Schwartz-Bickenbach et al. (1987)

Borlee et al. (1978)

Mathai et al. (1990)

***Rubin et al. (1986, per 10 cigs/day)

***Campbell et al. (1988)

Chen et al. (1989, >10 cigs/day)

**Mathai et al. (1992)

**Martinez et al. (1994, per 10 cigs/day)

Zhang and Ratcliff (1993)

Saito (1991)

Saito (1991, >40 cigs/day)

MacMahon et al. (1966, males)

***Magnus et al. (1984, per 10 cigs/day)

Roquer et al. (1995)

**Lazzaroni et al. (1990)

**Haddow et al. (1988, cotinine 1-10 ng/ml)

**Eskanazi et al. (1995, cotinine >2 ng/ml)

Mainous and Hueston (1994, high exp)

**Ahlborg and Bodin (1991, home exp only)

**Martin and Bracken (1986)

**Rebagliato et al. (1995, >42 hrs/wk)

**Rebagliato et al. (1995, 

cotinine >1.7 ng/ml)

Ogawa et al. (1991)

Figure 3.1

Summary of Differences in Mean Birthweight and 95% Confidence Intervals Between

ETS-Exposed and Unexposed Pregnancies by ETS Definition and Study Size*

* Smallest studies at top of each section

** Adjusted

*** All women (includes smokers), adjusted

ETS exposure defined by paternal smoking status ETS exposure from multiple sources

-205

-228

-66

-61

-113

-11

-63

-34

-30

-33

-111

-20

-5

-192

-38

-104

-45

-84

-34

-24

-41.3

-87.3

-24
infants (-78 grams). Limiting the analysis to nonsmoking mothers, a crude

22-gram decrement for female infants was associated with paternal smoking

and a 20-gram decrement for males (Table 3.1). There was no evidence of a

dose-response effect. Paternal pipe or cigar smoking was associated with

similar decrements, on the order of 20-30 grams.

In a study of Maryland vital records, Comstock and

Lundin (1967) noted that the mean birthweight of infants with smoking

fathers and nonsmoking mothers was 42 grams less than that of infants

whose parents both did not smoke. In addition to a lack of statistical

analysis, this study ascertained smoking status from a special census and

thus was not specific to the pregnancy.

Underwood et al. (1967) published a large study of newborns

delivered in naval installations worldwide. The greatest limitation of this

study is the unusual ascertainment of smoking status; it was obtained from

the physician attending the birth in the various labor and delivery rooms.

Examining infants whose mothers did not smoke, the authors found that

mean birthweight was decreased only 3-7 grams depending on the amount

smoked by the father. However, from a figure in the report it appeared that

heavy (>30 cigarettes/day) paternal smoking had a greater effect on birthweight in infants born before 35 weeks (about a 100-gram decrement),

although the authors did not comment on this. No confounders were considered in this analysis.

Borlee et al. (1978) examined birthweight and body measurements

of infants from a hospital-based, case-control study of congenital malformations conducted in Belgium. The authors appear to include the malformed

children in most of the analyses, which may make the results less generalizable. Mean birthweight of infants born to nonsmoking mothers was

decreased by 228 grams if the father smoked before conception. Among

infants of smoking mothers, those with smoking fathers were heavier than

those with nonsmoking fathers, but this finding is based on only 14 infants

with nonsmoking fathers and smoking mothers, so is not reliable. Length

and head circumference varied little by paternal smoking status. Using the

entire study group for an analysis of variance with a few co-variables (malformation, prematurity, maternal tobacco use), there was an association

between paternal smoking and birthweight (p < 0.06), but the adjusted difference was not presented. Other important potential confounders identified by the authors were not taken into account. The magnitude of effect of

ETS exposure seems implausibly large, but the decrement in mean birthweight associated with active maternal smoking, among infants of nonsmoking fathers, was much greater still (e.g., -561 grams, crude difference).

Magnus et al. (1984) studied causes of variations in birthweight

in offspring of adult twins in Norway. This is a select population (offspring

of parents who are twins), and the generalizability of the results is unclear.

The authors assumed that smoking status at interview reflected habits during childbearing years. There are few data on this topic, for fathers in par80

Smoking and Tobacco Control Monograph No. 10

Comstock and Lundin (1967)

Underwood et al. (1967)

Borlee et al. (1978)

Magnus et al. (1984)
ticular. However, some decrease in smoking during the 10-15 years since

some of the study births would be expected. Fathers who smoked during

the target pregnancy but not at the later interview, would be included as

nonsmokers, diluting any effect. In a bivariate regression, paternal smoking

was associated with a 48-gram decrement in birthweight (p < 0.01). In a

multiple regression analysis that included maternal smoking and some

other covariates, paternal smoking was only associated with a 5-gram decrement (Table 3.1). Maternal smoking remained significantly associated with

birthweight decrements.

In a study conducted in Bulgaria, Karakostov (1985) reported an

84-gram weight decrement in infants of women exposed to ETS during

pregnancy compared to infants whose parents were both nonsmokers. The

measure of variability in birthweight is unclear; it is presented as the standard deviation, but because it is so small (i.e., 60 to 80 grams) it appears to

be the standard error. Assuming the latter, the confidence interval is wide

(95% CI = -280 to 111). Mean length was decreased by about one-half centimeter. No confounders were controlled.

In 1986, Rubin et al. reported a positive association between birthweight and paternal smoking which spurred many of the subsequent studies. Five hundred Danish women were interviewed shortly after delivery

regarding smoking by fathers and other household members. Births were

all greater than 2,000 grams and 35 weeks gestation, so they represent a relatively healthy group a priori. Maternal and paternal smoking were highly

correlated; both variables were examined together in regression models.

Adjusting for many co-variables (but not maternal height or weight), the

independent decrement in birthweight per cigarette (or cigar or pipe bowl)

smoked daily by the father was 6.1 grams (p < 0.03). This yields about a

120-gram decrement for smoking a pack of cigarettes each day. The association appeared to be greatest in the lower social classes, although no interaction terms were included in the regression models. The decrement seen

with maternal smoking was 9.2 grams per cigarette per day (adjusted for

paternal smoking and other variables).

A second study with a highly selected sample was reported in a letter to Lancet. MacArthur and Knox (1987) focused on 180

women who reported that they stopped smoking during pregnancy, a group

unlikely to be representative of nonsmokers. Some data related to paternal

smoking were provided, but not information about the study from which

the data were derived or the statistical methods used. As maternal and

paternal smoking are usually correlated, it was somewhat surprising that

there was no reported difference in the mean amount smoked before pregnancy by women whose partners smoked compared to women whose partners did not. The authors found only a 14-gram decrement in mean birthweight if the father smoked. They indirectly standardized the birthweight

distributions of each paternal smoking group for maternal height and parity, and for sex and gestational age of the infant, and noted a 123-gram

excess if the father smoked. However, both groups had an “excess” birth81

Chapter 3

Karakostov (1985)

Rubin et al. (1986)

MacArthur and Knox (1987)
weight (100 grams among infants of nonsmoking fathers and 223 grams

among those of smoking fathers) relative to an unspecified comparison

group. The excess in both groups may indicate that women who stop

smoking adopt other healthy behaviors that contribute to a healthier outcome, or that this group of women is not comparable to the general population.

Schwartz-Bickenbach et al. (1987) reported on a

small study in Berlin of mothers who intended to breast feed their infants;

they compared infant development in pairs where one mother smoked during pregnancy and the other did not. Among the nonsmoking women (n =

54), about half had a spouse who smoked. Those infants with smoking

fathers and nonsmoking mothers weighed on average 205 grams less than

infants whose parents did not smoke (Table 3.1). This is a large decrement

in weight, but the decrement associated with maternal smoking was on the

order of 400 grams. There was no statistical comparison of these weight

differences. Assuming that the variability index in the published table is

the standard deviation, the p-value for a t test of the weight decrement

associated with exposure to ETS would be 0.095. There was no difference in

head circumference by parental smoking habits but there were slight differences in body length. The magnitude of effect of paternal smoking was

about half that of maternal smoking at 1.1 cm (95% CI = -2.3-0.1). This

population was highly selected, and no confounding variables were controlled.

Campbell et al. (1988) examined the effect of ETS exposure in

a population-based sample of births that occurred in Southampton,

England. The mothers were interviewed one month after delivery. In

infants of maternal nonsmokers, the authors found a crude weight difference of -73 grams associated with paternal smoking. In a multiple regression analysis adjusting for maternal smoking, age, alcohol consumption,

and social class, current paternal smoking status was associated with a 113-

gram decrement in birthweight, about one-half the effect of maternal smoking (-253 grams) in all births (Table 3.1). The greatest decrement in weight

was seen when both parents smoked. This appears to be a well-conducted

study, but the inclusion of maternal smokers in the regression analysis complicates its interpretation.

Brooke et al. (1989) reported a thorough prospective study of factors influencing birthweight, which was conducted in London. Smoking

habits were ascertained at registration for prenatal care and at 28 and 36

weeks gestation. The ETS exposure variable was defined as any smokers

(other than the mother) in the household. Birthweight was expressed as a

ratio of observed birthweight to expected mean birthweight for gestational

age. That ratio was then adjusted for parity, maternal height, and infant

sex. In infants of nonsmoking mothers, those with ETS exposure had a 0.5

percent reduction in the birthweight ratio; among infants of smoking

mothers with ETS exposure, there was a one percent reduction. This corre82

Smoking and Tobacco Control Monograph No. 10

Schwartz-Bickenbach et al. (1987)

Campbell et al. (1988)

Brooke et al. (1989)
sponded to a difference in mean birthweight (adjusted to 40 weeks) associated with ETS exposure of 18 grams in nonsmokers and 39 grams in smokers.

Chen et al. (1989) reported a retrospective study of all births

occurring during a 6-month period in 1981 in an area of Shanghai, China.

One advantage of this study is that none of the interviewed mothers were

smokers; disentangling the correlation of spousal smoking habits is therefore not an issue. ETS exposure estimates were based on the daily cigarette

consumption by the spouse and other family members. The proportion of

mothers exposed to ETS (72 percent) was higher in this study than in most

other studies. Mean birthweight was decreased only 9-11 grams, depending

on the amount smoked by the spouse (1-9 or ≥10 cigarettes/day; F = 0.3, p =

0.74) and was decreased 4-15 grams, depending on the amount smoked by

all family members (F = 0.7, p = 0.92). The authors stated that adjusting for

multiple confounders (gender, parity, education, maternal age, and income)

did not change the results. Two potential confounders not available were

maternal height and weight, which may not be as variable in China as in

the U.S.

A study from Japan (Saito, 1991) examined the smoking habits of

about 3,000 couples who brought their infants into a large Tokyo medical

center for care during 1987. The majority of women did not smoke during

their pregnancy and about half the fathers smoked. Among infants whose

father smoked but whose mother did not smoke during pregnancy, there

was a decrement in mean birthweight of 33.4 grams (p < 0.05) compared to

infants of nonsmoking parents (Table 3.1). Among infants whose parents

both smoked, the mean birthweight was further decreased 66 grams (or

about 100 grams total). The author found a dose-response effect by amount

the father smoked, with a weight decrement of 111 grams (p < 0.01) among

infants of fathers who smoked 40 or more cigarettes per day. In this later

analysis, the author appears to include couples in which the mothers also

smoked. Such couples do not comprise a large portion of the sample (perhaps 8 percent), but nevertheless, a direct effect of maternal active smoking

may have influenced the dose-response results. The author further found

that the weight decrement was slightly greater among female (126.5 grams)

than among male infants (94.3 grams) of heavily smoking fathers. This

gender differential was even more striking for weight decrements seen with

active maternal smoking. In addition to including smoking mothers in

some analyses, this study is limited because it did not control for any confounders, despite reporting that smoking levels varied by age, education,

and paternal occupation.

Mathai et al. (1990 and 1992) conducted two studies

in different populations and obtained similar results (Table 3.1). The first

study was conducted prospectively among 285 white women attending a

prenatal clinic in Liverpool, England in 1987 (Mathai et al., 1990). Fiftyfour women (19 percent) were nonsmokers who lived with a smoker and

were thus considered exposed to ETS. Their infants had a mean weight

83

Chapter 3

Chen et al. (1989)

Saito (1991)

Mathai et al. (1990 and 1992)
decrement of 66 grams compared to non-exposed nonsmokers; this difference was not statistically significant, but it was based on small numbers.

No confounders were controlled in the analysis. A subsequent, improved

study (Mathai et al., 1992), designed specifically to examine ETS exposure in

a population with few women smokers, included 994 mothers of singletons

born in 1990 in Vellore, India. The timing of interview was not specified,

but appears to be after delivery. None of the women used tobacco, but 52

percent lived with smokers and were considered to be exposed to ETS. ETS

exposure was crudely associated with a 55-gram decrement in mean birthweight. Adjusting for multiple confounders (maternal age, height, parity,

social class, gestation, and infant sex), the mean decrement was 63 grams (p

= 0.015). No information on a dose-response relationship was available.

Zhang and Ratcliffe (1993) examined the effects of paternal smoking on live births who had served as controls in a study of birth

defects. Among singleton term births of nonsmoking women in Shanghai,

there was a crude weight decrement of 26 grams associated with paternal

smoking. Adjustment for parity, maternal age, gestational age, and mother’s occupation by multiple linear regression yielded a decrement of 30

grams (95% CI = -66-7). There was a nonlinear trend by amount smoked,

with greater adjusted weight decrements seen up to 19 cigarettes/day, but

an increase in weight at higher levels (20 or more cigarettes/day, Table 3.1).

The confidence interval at the higher level of paternal cigarette consumption overlapped with the decrements estimated at lower smoking levels.

The non-monotonic trend in dose-response may be due to chance, inaccuracy in reporting of paternal amount by their spouses, or a confounding

variable not taken into account. The paternal smoking ascertained appeared

to reflect usual smoking status, not necessarily that during pregnancy.

Martinez et al. (1994) studied enrollees of the Tucson

Children’s Respiratory Study, conducted in a large health maintenance

organization in Tucson, Arizona. Information (including birthweight) was

obtained by nurses while the mothers were in the hospital following the

births. Each parent was given a questionnaire to answer about his or her

own smoking habits, and the person’s current smoking habit was used to

estimate the amount smoked during pregnancy; this was possible because

the current status was obtained so soon after delivery. Among the 992 nonsmoking mothers, infant birthweight significantly decreased with increasing paternal smoking; infants whose fathers smoked more than 20 cigarettes per day had a mean weight decrement of 88 grams. Maternal smoking of more than 20 cigarettes per day was associated with an average 273-

gram decrement. In a multiple regression analysis adjusting for gestational

age, gender, race, parity, education, and maternal age, paternal smoking was

associated with a 34-gram decrement for each additional 10 cigarettes

smoked per day (coded as an ordinal variable: 0 = none, 1 = one to ten, 2 =

11 to 20, 3 = greater than 20 cigarettes per day; Table 3.1). Duration of

pregnancy was not affected by the smoking habits of either parent.

Cotinine measured in cord blood for a subsample indicated that perhaps

1.5 percent of the women were smokers misclassified as nonsmokers. The

84

Smoking and Tobacco Control Monograph No. 10

Zhang and Ratcliffe (1993)

Martinez et al. (1994)
two women thus misclassified had nonsmoking spouses, so it is not clear

that such misclassification would necessarily lead to finding a greater

weight decrement with ETS exposure, which is a common criticism of studies of ETS. Detection of cord blood cotinine was reported to be strongly

correlated with the number of cigarettes smoked by the father. Minor limitations of this study are the lack of information on other potential confounders such as alcohol consumption, and the use of smoking habits

reported after delivery to represent smoking during pregnancy; however, it

is unlikely that women who smoked during pregnancy would quit after

delivery.

Several of the studies mentioned above, as well as some

additional ones, examined the impact of spousal smoking

status on low birthweight, growth retardation, or prematurity (Table 3.2; Figure 3.2, top). These studies are

described below. Low birthweight was defined as less than 2,500 grams in

all but one study. For the most part, odds ratios or similar measures indicating ETS impacts were of a magnitude of 1.5 or less; some studies found

evidence of dose-response trends.

In a large study of births in naval institutions (discussed

above), information on parental smoking status was obtained from the

attending physician (Underwood et al., 1967). The authors reported little

difference in rates of LBW or prematurity (<36 weeks) by amount smoked

by the father, among births of nonsmoking mothers (Table 3.2). Based on

the data provided, odds ratios were calculated as 0.9 for any paternal smoking and 1.05 for smoking over 30 cigarettes per day for either LBW or prematurity (Table 3.2). The reliability of the smoking information is unclear,

particularly given the means of ascertainment of smoking status and the

number of institutions involved. However, the finding of a dose-response

relationship for maternal smoking and LBW, as expected, provides some

confidence in the classification of smoking status. No confounders were

controlled.

A study (Terris and Gold, 1969) sometimes cited in the literature has not been included in the tables or figures. It was a case-control

study of LBW among black births, with controls matched by infant sex and

birth order as well as by maternal age and marital status. The main problem with the study is that no separation or control of maternal smoking

was attempted in considering paternal smoking. Smoking was more frequent among mothers of LBW cases, but paternal smoking status varied little between cases and controls.

Using data from the large, prospective Child Health and

Development Studies conducted among members of the Kaiser Foundation

Health Plan, Yerulshalmy (1971) examined the effect of parental smoking

on fetal growth. He found that the proportion of LBW infants from pregnancies in which the husband smoked was increased significantly compared to those in which the husband did not smoke. When stratified by

85

Chapter 3

3.2.2.2 Home ETS Exposure

and Low Birthweight,

Growth Retardation or

Prematurity

Underwood et al. (1967)

Terris and Gold (1969)

Yerulshalmy (1971)
86

Study Design Naval records of labor and delivery (24,674 nonsmoking mothers) Prospective study of Kaiser members (9,793) Prospective interview (5,183; 3,696 nonsmokers) Prospective interview (2,371 nonsmokers)Retrospective, self-administered(1,163)Retrospective interview(3,000 couples)Interview, but timing unclear(994) Interview post-delivery (1,785 term births of nonsmokers)

Low Birth Weight (LBW)0.9 (0.8-1.0) any1.05 (0.82-1.3) >30 cigs0.9 (n.s.) mother nonsmoker1.4 (p < 0.05) mother smoker1.4 (1.0-1.9)>10 cigs/day1.4 (0.9-2.2)3----------------------------------In non-working women:1.7 (1.0-2.9)31.5 (0.75-3.2)

--

1.0 (0.4-2.3)

(LBW defined as <2,000g)

--

IUGR/SGA

----

1.2 (0.9-1.>10 cigs/d1.2 (0.8-2.--------------1.4 (0.8-2.

--

1.3 (1.1-1.

--

1.1 (0.83-1

Authors (year)LocationUnderwood et al. (1967)1WorldwideYerulshalmy (1971)1US (N. California)Mau & Netter (1974)1GermanyNakamura et al. (1988)

Japan (Osaka)Chen et al. (1989)1,2

China (Shanghai)Saito (1991)1Japan (Osaka)Mathai et al. (1992)1,2IndiaZhang & Ratcliffe (1993)China (Shanghai)

Table 3.2Studies of Fetal Growth and Exposure at Home, Defined by Paternal Smoking Status

1 Odds ratio and/or confidence intervals estimated from published data, not published by original authors.2 Based on any household smoker, instead of only paternal smoker.3 Controlled for confounders.4 “n.s.” indicates lack of statistical significance at p = 0.05

IUGR—Intrauterine Growth Retardation; SGA—Small for Gestational Age; LBW measured at term.

Study Odds Ratios (with 9
87

Chapter 3

1.0

1.5

1.4

1.7

1.1

1.3

1.4

1.1

1.9

0.5

1.1

0.7

1.35

2.2

1.6

0.98

1.2

1.0

0.1 1.0 10.0

Odds Ratios (log scale)

Figure 3.2

Odds Ratios and 95% Confidence Intervals for the Association of Low Birthweight 

(or IUGR) and ETS, by ETS Definition and Study Size*

* Smallest studies at top of each section

** Adjusted

*** OR and CI calculated from data, sometimes estimated

ETS exposure defined as living with a smoker

(usually a spouse)

ETS exposure from other sources

***Mathai et al. (1992)

***Chen et al. (1989)

**Nakamura et al. (1988)

**Nakamura et al. 

(1988, non-working)

Zhang and Ratcliff (1993)

***Saito (1991)

***Mau and Netter (1974, >10 cigs)

***Underwood et al. 

(1967, >30 cigs)

Roquer et al. (1995, Å20 cigs/day)

**Chen and Pettiti 

(1995, 330 hrs/wk)

**Ahlborg and Bodin (1991, work)

**Ahlborg and Bodin (1991, home)

Eskanazi et al. 

(1995, cotinine 3 2 ng/ml)

**Martin and Bracken

(1986, 32 hrs/day)

**Mainous and Hueston

(1994, high exposure)

**Fortier et al. (1994, home)

**Fortier et al. (1994, work)

**Ogawa et al. (1991, 32 hrs/day)
maternal smoking status, this association was apparent only among pregnancies in which the mother also smoked; the highest rates of LBW

occurred where both parents smoked during pregnancy. Calculating a rate

ratio for LBW and paternal smoking yielded 1.4 among smoking mothers

(reported p < 0.05) and around 1.0 among nonsmoking mothers. The raw

data were not presented in this paper, nor was there any control for confounding.

Mau and Netter (1974) reported data on parental smoking

and a number of fetal growth parameters from a large, prospective study

conducted in Germany. They examined rates of IUGR, prematurity, and

LBW by amount smoked by the father among 3,696 pregnancies of nonsmoking mothers. About 44 percent of these pregnancies were exposed to

paternal smoking. The investigators found slight increases in each outcome

among infants of fathers who smoked more than 10 cigarettes per day, but

none of the chi-square tests for the distribution of amount of paternal

smoking by each pregnancy outcome was statistically significant. The

authors standardized the “value of expectation” for paternal age, so it is not

clear whether the rates and numbers in the tables represent raw data and

can be used for confidence interval calculations (as we did in Table 3.2).

Nevertheless, focusing on the fathers who smoked more heavily, the rate

ratios were 1.2 for IUGR and prematurity and 1.4 for LBW (Table 3.2). No

confounders other than paternal age were controlled in these analyses.

Nakamura et al. (1988) conducted a prospective study of

pregnancies during 1984-1986 in Osaka, Japan. The authors noted that the

percentage of males who smoked (67 percent) was one of the highest in the

developed world, whereas few females smoked (13 percent), so the rate and

intensity of ETS exposure may be greater than elsewhere. They examined

the rates of LBW, LBW at term (also referred to as small for gestational age,

or SGA), and prematurity. Focusing on nonsmoking mothers only, the

crude rates for positive paternal smoking status were increased for LBW (OR

= 1.5), and slightly for pre-term and SGA births (OR = 1.2). The investigators adjusted for a variety of potential confounders in a logistic regression

model. The adjusted relative risk for LBW was 1.4 (95% CI = 0.9-2.2; Table

3.2). Because they had no information on ETS exposure at work, the investigators also performed an analysis in non-working women so that exposure

would be less likely to be misclassified. The adjusted relative risk for home

exposure and LBW in this group was significantly elevated: 1.7 (95% CI =

1.0-2.9). The authors noted that residence size was small in this area,

which may have resulted in ETS exposures of relatively high intensity.

The retrospective study reported by Chen et al. (1989) discussed

above, which was conducted in Shanghai, also reported a high prevalence

of male smokers (58 percent) and no female smokers. The authors found

no evidence of a dose-response relationship of amount smoked by the

father or by all household members to rates of LBW, nor did consideration

of a few confounders change the results (adjusted data not presented).

Combining results across all categories of paternal smokers, a crude odds

ratio of 1.5 (95% CI = 0.75-3.2) was calculated for LBW.

88

Smoking and Tobacco Control Monograph No. 10

Mau and Netter (1974)

Nakamura et al. (1988)

Chen et al. (1989)
In the study of Japanese couples discussed above, Saito (1991) examined the rate of “small for dates” (SFD), which was defined as a weight less

than 1.5 standard deviations below an established population mean. The

rates of SFD were slightly increased among infants of smoking fathers and

nonsmoking mothers (calculated OR = 1.3; p ≤ 0.05; Table 3.2). The only

stratified analysis conducted was by paternal education, which appeared to

confound slightly the relationship of SFD and paternal smoking. Paternal

smoking of 20 or more cigarettes per day increased the rate of SFD within

both categories of paternal education, by about 40 percent (p < 0.05), compared to infants of fathers who smoked less or not at all. The rate of prematurity did not vary by paternal smoking status.

The Mathai et al. (1992) study of 994 East Indian births in

Vellore discussed above also examined prematurity and LBW by whether

the mother lived with a smoker. The authors reported that 52 percent of

births were thus exposed to ETS. The outcome variable was limited to

lighter (<2,000 grams) babies than the usual definition for LBW, and the

authors found no difference in these rates of LBW by mother’s ETS exposure (Table 3.2). The rate of prematurity was increased somewhat with ETS

exposure (OR = 1.6, 95% CI = 0.82-2.9). No confounders were considered

in the analysis of these outcomes.

In the Zhang and Ratcliffe study (1993) of infants of nonsmoking Chinese women discussed previously, the rates of LBW at term

and IUGR were similar whether the father was a smoker or a nonsmoker

(crude RRs = 1.07 and 1.11, respectively; Table 3.2). No consistent doseresponse trend was seen with amount smoked. No confounders were considered in this analysis.

Fewer studies have examined fetal growth in relation to ETS

exposures defined by something other than paternal smoking status, so all outcomes are grouped together in this subsection. All of these are recent and thus tend to reflect today’s higher

methodologic standards. Four studies published in 1995 are reviewed as an

addendum at the end of this section. Generally, these studies found associations between ETS exposure and fetal size of smaller but more consistent

magnitudes than the paternal smoking studies (Table 3.3). 

In 1986, Martin and Bracken published results from a

widely cited prospective study of 3,891 pregnancies ending in livebirths

between 1980-82 in Connecticut (Table 3.3). Passive smoking (ETS exposure) was defined as being exposed to someone else’s cigarette smoke for at

least 2 hours per day, either at home or at work. However, it is not clear

whether this was asked as a “yes/no” question or whether data were pooled

from a few questions. Among all infants of nonsmokers, ETS exposure was

crudely associated with a 61-gram decrement in mean birthweight (p =

0.005) and a slightly increased rate of LBW (RR = 1.3). These associations

with ETS exposure were not seen in infants of active maternal smokers.

There was no association of prematurity with ETS exposure. Stratifying by

89

Chapter 3

Saito (1991)

Mathai et al. (1992)

Zhang and Ratcliffe (1993)

3.2.2.3 Home and Work

ETS Exposure and Fetal

Growth

Martin and Bracken (1986)
gestational age, there was a significant association in nonsmokers who had

term pregnancies (OR for LBW: 2.7, weight decrement: 85 grams), which

the authors interpreted as indicating an effect on growth retardation.

Adjustment for confounders by multiple regression yielded a mean weight

decrement of 24 grams (p = 0.20) and an odds ratio for LBW of 2.2 (95% CI

= 1.1-4.5) among term births. 

One criticism of this paper has been that the authors included only

confounders that were significant at the p = 0.1 significance level in a stepwise regression model. This approach is now considered inappropriate

because confounding should not be assessed by a significant association

with the outcome variable, but by the magnitude of change in the odds

ratio if that co-variate is not taken into account (Rothman, 1986).

Nevertheless, the variables usually considered important were included (i.e.,

maternal age, parity, and ethnicity). The authors also included gestational

age in the models, even though they were only examining term births. The

authors stated that maternal weight gain was not included because it was

missing for about 25 percent of respondents. In an analysis of those for

whom the information was available, this variable did not appear to confound the relationship with ETS exposure. Therefore, there is little evidence that important confounders were excluded. No association was seen

with ETS exposure and prematurity in the regression analyses. The authors’

interpretation that their data is indicative of an effect of ETS exposure during pregnancy leading to growth retardation rather than to preterm delivery appears justified. 

Ogawa et al. (1991) examined ETS exposure in a study of almost

7,000 women who delivered a singleton in 1987 in Aichi Prefecture, Japan.

Women were interviewed by medical staff before or soon after delivery.

Each woman was asked about her smoking habits and those of her husband

before and during pregnancy, as well as about the average length of ETS

exposure per day during pregnancy at home, at work, or elsewhere.

Overall, about 15 percent of women smoked before pregnancy, but only 6

percent of women continued to smoke during pregnancy. Among all

women, 62 percent reported some ETS exposure and 65 percent had husbands who smoked. Among women who had never smoked, there was a

24-gram decrement in mean weight of term births with exposure to ETS for

2 or more hours per day. Adjusting for a number of confounders yielded a

weight decrement of 10.8 grams, which was noted as non-significant. The

crude and adjusted odds ratio for LBW at term did not indicate any

increased risk with ETS exposure (Table 3.3). Interestingly, the adjusted

weight reduction associated with active smoking of 10 cigarettes per day

was only 56 grams, compared to the 200 grams found in many other studies. The data on husband-only smoking status in association with pregnancy outcome were not presented.

Lazzaroni et al. (1990) examined data from a multi-center, hospital-based study of about 1,000 pregnant women in Italy. The analysis is

based on questionnaires administered to women within 5 days of delivery

90

Smoking and Tobacco Control Monograph No. 10

Ogawa et al. (1991)

Lazzaroni et al. (1990)
of a newborn during 1989. Newborns born before 36 weeks and weighing

less than 2,000 grams were excluded, so prematurity and LBW could not be

examined. ETS exposure was ascertained by asking the number of hours of

exposure at home and work; anyone reporting a minimum of 1 hour per

day was considered exposed (about 25 percent of the respondents fell into

this category). Nonsmokers with ETS exposure were compared to those

without, but both categories could include women that quit smoking during pregnancy. Almost 30 percent of women were considered active smokers during pregnancy. Mean birthweight of infants of women exposed to

ETS was reduced 51 grams, which was not statistically significant.

Adjusting for a number of important potential confounders by multiple

regression indicated a weight decrement of 16.9 grams per hour of ETS

exposure (p = 0.07), or about 38 grams for any (versus no) exposure among

nonsmoking women with term births (Table 3.3). Excluding women only

exposed one hour per day yielded a greater decrement in weight of 61

grams (95% CI = -149.3-26.8), indicating that highly exposed women are at

greater risk. The authors further noted that the mean birthweight of

infants of women heavily exposed to ETS (≥5 hours/day) was less than that

of infants of light active smokers. The adjusted overall decrease in infant

length was not significant (0.26 cm, 95% CI = -0.56-0.03).

Ahlborg and Bodin (1991) conducted a prospective study

of 4,701 Swedish women reporting for prenatal care in 1980-1983. They

examined prematurity and LBW at term among nonsmoking women

exposed to ETS, which was defined as living with a smoker during pregnancy or spending most of the time at work in rooms where other people were

smoking. In an attempt to separate the effects of home and work exposure,

the authors further limited the sample to working women. The adjusted

odds ratio for term LBW and ETS exposure only in the home was 0.7 (95%

CI = 0.21-2.3) and for prematurity was 0.5 (95% CI = 0.23-1.1). These figures are based on very small numbers of affected births in the exposed

group (n = 3 and 7, respectively). 

The manner in which the question to ascertain work exposure was

asked would tend to identify a fairly heavily exposed group. The adjusted

relative risk for workplace ETS exposure and prematurity was 1.3 (95% CI =

0.7-2.3) and for LBW at term was 1.1 (95% CI = 0.33-3.6; Table 3.3). The

women could also be exposed to ETS at home; further limiting the analysis

to those with a nonsmoking partner increased the ORs (1.8 for prematurity

and 1.2 for term LBW). The authors stratified the association (with any

workplace exposure) by whether the work was full-time or part-time, in an

attempt to examine a dose-response relationship. The adjusted relative

risks among infants of full-time workers were increased somewhat for prematurity (RR = 1.5, 95% CI = 0.87-3.0) and for term LBW (RR = 1.4, 95% CI

= 0.33-5.9). The authors also examined mean birth weight. Among these

working women, home exposure was associated with a 34-gram decrement

in mean birthweight, but workplace exposure was not associated with a

birthweight reduction (Table 3.3). As noted earlier, these analyses must

have been based on extremely small numbers. 

91

Chapter 3

Ahlborg and Bodin (1991)
92

Smoking and Tobacco Control Monograph No. 10

Authors (year)

Country (study size1)

Martin & Bracken (1986) 

U.S.—Connecticut

(n = 2,473)

Prospective interview

Ogawa et al. (1991)

Japan (n = 5,336) 

Interview around delivery

Lazzaroni et al. (1990)

Italy (n = 648; examined

births >2,000g, 

>37wks gestation)

Interview postpartum

Ahlborg & Bodin (1991)

Sweden (n = 2,461

employed) 

Interviewed during month

2 or 3 of pregnancy

Fortier et al. (1994)3

Canada—Quebec 

(n = 4,644 nonsmokers)

Interview within few

months post partum

ETS Level

(% Exposed)

≥2 hr/day at home 

or work (34%)

≥2 hr/day at home, 

work or elsewhere (35%)

≥1 hr/day at home

or work (25%)

Home exposure 

only (16%)

----------------------------

Most time at work in

rooms with smokers

(11%)

Home only

(13%)

----------------------------

Work only

(28%)

----------------------------

Home and Work

(8%)

Difference in Mean

Weight 

-24g adjusted (-60-13)

-85g (p < 0.002) crude 

-10.8g (n.s.)

-24g (-47 to -2) crude

-38g (-106.9-30.7)

-17g/hr (-35-1.3)

-34g (-82-15) 

-------------------------------

20g (-37-77)

-------------------------------

-------------------------------

IUGR/LBW3

OR (95% CI)

2.2 (1.1-4.5) LBW

1.0 (0.7-1.5) LBW

--

0.7 (0.21-2.3) LBW

(based on 3 affected 

infants)

------------------------

1.1 (0.33-3.6) LBW 

1.4 (0.33-5.9) LBW 

if worked full-time

0.98 (0.67-1.44) IUGR 

------------------------

1.18 (0.90-1.56) IUGR

------------------------

0.94 (0.60-1.49) IUGR

Study Results2

Table 3.3

Studies of Fetal Growth and ETS Exposure of Maternal Nonsmokers

from Multiple ETS Sources

This study offers a lot of data, but there are some difficulties with its

analysis of fetal growth. First, the number of pregnancies included in each

analysis was unclear. There were 4,701 pregnancies that were not excluded

or lost to follow-up, but information was only available about the father’s

smoking for 4,075 (87 percent) of these. Further reductions were made to

examine only nonsmoking women and working women, although the

numbers presented in the tables do not appear consistent. In addition, it is

not known if mean birthweight was determined in all livebirths or only in

term births, as was the case for LBW. Secondly, the proportion of nonsmoking women living with a smoker seems low at about 15 percent, par-
93

Chapter 3

Authors (year)

Country (study size1)

Mainous and

Hueston (1994)

U.S.—nationwide 

(n = 3,253)

Retrospective survey

Chen and Petitti (1995)

U.S. – California

(n = 111 cases,

124 controls, whites)

Retrospective interview

Roquer et al. (1995)

Spain (n = 129)

Interview at delivery

Rebagliato et al. (1995a)

Spain (n = 710)

Interview in 3rd trimester

ETS Level

(% Exposed)

Categorized as:

never (23%)

occasional (46%)

often (17%)

always (13%)

Assessed in 4 locations 

and as average hours 

per week

Any exposure (54%)

≥30 hours/wk (7%)

"Significant" defined 

as exposed to

≥20 cigarettes/day

Assessed hours per

week from 4 sources

Any exposure (88%)

≥42 hours/week (22%)

Difference in Mean

Weight 

-84g (-150 to -18) for 

highest exposure, crude

No decrement at lower 

levels

--

-192 (-365 to -19), crude

Any: -85g, crude

Any ≥42 hours/wk: -41g 

(-144-61)

Spouse ≥42hrs/wk: 31g 

(-103-165)

IUGR/LBW3

OR (95% CI)

1.6 (0.92-2.7) LBW

with high exposure

(p ≤ 0.01 doseresponse trend)

≥30 hrs/week: 

0.5 (0.14-1.7) IUGR

Work only:

1.0 (0.39-2.6) IUGR

Home only:

0.5 (0.13-1.8) IUGR

1.9 (0.57-6.1)

1.10 IUGR

1.11 crude

--

Study Results2

Table 3.3 (Continued)

1 The study size (n) presented is for term births to nonsmokers, not the total study size.

2 Effect measure adjusted for a number of confounders, unless otherwise indicated as "crude."

Abbreviations: LBW - low birth weight; IUGR - intrauterine growth retardation.

3 The analysis adjusted for LBW in previous births. This may result in substantial underestimation of effect.

ticularly because 37 percent of women overall reported smoking in the first

trimester, calling into question the validity of the reporting of paternal

smoking habits. With respect to the results, a weight reduction with ETS

exposure at home, but not in the workplace seems inconsistent. On the

other hand, ETS exposure among full-time workers may be slightly associated with term LBW. When the authors attempted to look at possible confounders to explain this (lifting, stress, etc.), they found little change in the

association. The true association may be diluted in this study by the focus

on only women highly exposed at work, so that those less exposed may fall

into the comparison group. The authors did note an increased risk of prematurity and term LBW with maternal smoking.

A large study from Quebec, Canada also ascertained exposure at

home and work (Fortier et al., 1994). Women who had singleton livebirths

in 1989 were interviewed by phone, on average, 6 weeks after delivery.

Fortier et al. (1994)
Questions about ETS exposure included whether the subject resided with

smokers and how much they smoked in her presence, as well as hours and

intensity of exposure at work. Of the over 7,000 respondents, 4,644 nonsmokers were available for analysis, of which nearly half (49 percent) were

exposed to ETS at home and/or work. The crude OR for any ETS exposure

and IUGR was 1.3, but decreased to 1.1 (95% CI = 0.85-1.4) with adjustment for maternal weight, parity, previous LBW, and caffeine intake (Table

3.3). ETS exposure at home only was not associated with IUGR (adjusted

OR = 0.98), nor was there a dose-response trend. The risk of IUGR associated with workplace-only exposure was slightly greater (adjusted OR = 1.2)

and showed evidence of a slight dose-response trend with heavier exposure,

even when controlled for potential confounding by job characteristics.

However, women exposed both at home and at work had IUGR rates more

similar to the home-only exposed women (adjusted OR = 0.94).

Adjustment for previous LBW may be over-controlling, as such LBW may

have been associated with ETS exposure as well. ETS exposure at any location was not associated with pre-term birth. The authors noted that the

odds ratios of IUGR in the nonsmokers most heavily exposed to ETS at

work (1.30-1.36) were similar to those found in light smokers (1-5 cigarettes/day) in their study population.

Mainous and Hueston (1994) analyzed data from the

1988 National Health Interview Survey (NHIS), a household interview conducted on a nationwide sample, examining pregnancies occurring in the

past 6 years (mean was 2 years). ETS exposure was determined by asking

respondents to categorize their contact with smokers (friends, coworkers or

family members) as “occasional, often, always, or never” during pregnancy.

There was little difference in the frequency of LBW infants among ETS

exposed versus unexposed women. However, when examined by categories

of increasing exposure, there was a trend towards increasing rates of LBW (p

< 0.01). Controlling for race, parity, income, and maternal age, the adjusted odds ratio was about 1.6 for the highest exposure category (Table 3.3)

and was greater among non-whites (OR = 2.3, 95% CI = 1.1-5.0).

Comparing mean birthweight, women in the highest exposure category had

infants that weighed on average 84 grams less than infants in the very low

exposure category (Table 3.3). No dose-response trend in mean birthweight

was noted for lower levels, which the authors interpreted as evidence for a

threshold effect. The weight decrements were unadjusted, and information was not included about other potential confounders of the relationship

with LBW. Further, this study may be subject to some recall error, as pregnancies could have occurred up to six years earlier and the measure of outcome (as well as exposure) was obtained from the women themselves. The

qualitative measure of exposure used may be less subject to recall error than

a more quantitative measure would have been. The main advantage of the

study is its large, population-based sample.

Chen and Pettiti conducted a case-control study of IUGR

among singleton, term infants born in 1991 in Contra Costa County,

California. Controls were non-growth-retarded, non-malformed infants

94

Smoking and Tobacco Control Monograph No. 10

Mainous and Hueston (1994)

Chen and Pettiti (1995)
identified from birth certificates. ETS exposure was ascertained by first asking about location (work, home, car, other) and then the total number of

hours per week exposed to ETS for each trimester. The small sample of

nonsmokers is a major limitation of the study, as well as the fairly low completion rate (50-55 percent). By quintiles of average hours of exposure over

all trimesters, there was no indication of an increased risk of term IUGR

with greater exposure. Most women reported exposure in “other” places,

but none of the locations considered showed evidence of increased risk of

term IUGR. Adjusting for a variety of variables showed a decreased risk

with exposure but very wide confidence intervals with home exposure or

home and elsewhere (ORs about 0.5); work and car exposure had odds

ratios around one. In addition to low power and a fairly high refusal rate,

this study may be hampered by recall error, although subjects were interviewed fairly soon after delivery (mean was 8 months).

Roquer et al. (1995) conducted a small study of Spanish women

presenting for labor and interviewed them after delivery. ETS exposure was

defined as “significant” if the woman was exposed to the smoke of 20 or

more cigarettes per day at work or home; that is, exposure to one smoker

who smoked a pack or more per day or two smokers who each smoked a

half-pack per day. A major problem with the design is that the interviewer

measured the infant within four hours after birth, so outcome determination was not blinded with respect to exposure. The mean birthweight of

infants whose mothers were exposed was 192 grams less than that of

infants whose mothers were unexposed, and was comparable to the weight

decrement in infants of women who smoked 1 to 9 cigarettes per day.

Infants of mothers who smoked heavily had weight decrements of over 450

grams. No confounders were considered, but parity and employment status

were similar in ETS-exposed and unexposed women. The rate of IUGR was

about doubled with ETS exposure, again similar to that seen in infants of

light smokers, but was not statistically significant (Table 3.3). ETS exposure

was associated with a reduction of one centimeter in length (calculated 95%

CI = -1.8 to -0.2). This study is limited by its small size and lack of adjustment for confounders, as well as by the possible measurement bias

(although weight is subject to less measurement error than length).

In the best of the new studies, Rebagliato et al. (1995a)

conducted a prospective cohort study (also in Spain) of nonsmoking pregnant women. Subjects were interviewed in their third trimester of pregnancy, and a saliva sample was collected for cotinine analysis. The investigators asked extensive questions about exposure from four sources and on different days of the week to calculate an average weekly exposure during

pregnancy. Of the 710 nonsmoking women, 88 percent reported some

exposure; their infants were on average 85 grams lighter than those of

unexposed nonsmokers. However, no dose-response trend was evident and

results were not consistent by source, with exposure at home not resulting

in a birthweight decrement. In a multiple regression model which adjusted

for a number of covariates including gestational age (but not alcohol use),

the highest exposure category was associated with a 41-gram decrement in

95

Chapter 3

Roquer et al. (1995)

Rebagliato et al. (1995a)
birthweight (Table 3.3), while other categories had decrements ranging from

26 to 77 grams. Because of the small numbers of subjects in these categories, none of the weight decrements were statistically significant. More

women were exposed at home, and for longer periods of time, so the inconsistent results are difficult to explain. However, exposures at work may be

more intense, with more smokers present. 

There has been an effort in the past 10-15 years to validate tobacco smoke exposures using biomarkers, and a

few studies have examined biomarkers in relation to pregnancy outcome in

that time, with two additional studies published in 1995 (Table 3.4).

Cotinine is the preferred biomarker because of its specificity to tobacco

smoke exposure and longer half-life (20-30 hours in plasma) than nicotine

(see chapter on Exposure Measurements and Prevalence). Nevertheless, cotinine only reflects relatively recent exposures, and there is much inter-individual variation in its metabolism. Thiocyanate, a detoxification product of

cyanide, has a longer half-life than cotinine (3-14 days) but is not as specific to tobacco smoke.

Hauth et al. (1984) looked at thiocyanate concentrations as a

biomarker of ETS exposure in 163 women who had had a term pregnancy,

by drawing maternal serum at the time of admission to labor and delivery.

Thiocyanate (SCN) levels were compared among three groups, defined as

smokers (10-40 cigarettes/day), passive smokers (live or work with a smoker), and nonsmokers. Umbilical cord blood was obtained immediately after

birth. Maternal and cord blood SCN levels were significantly greater in

smokers than in the other two groups, but the levels in passive smokers

were only slightly greater than those in nonsmokers. There was a significant inverse relationship between umbilical cord SCN level and birthweight

in infants born to smokers (published r = 0.74, p < 0.001), but not in

infants of passive or nonsmokers. The authors reported that infants of passive smokers had similar birthweights to those of nonsmokers, but the data

were not presented. No confounders were assessed in this analysis.

Another problem is that blood obtained at the time of labor may not accurately reflect exposure earlier in pregnancy, particularly if a woman exposed

to ETS at work has left her job near the end of pregnancy.

In the largest biomarker study to date, Haddow et al. (1988)

analyzed blood sampled during the second trimester of 1,231 pregnancies

of nonsmoking white women in Maine. The authors defined ETS exposure

as a cotinine level between 1.1 and 9.9 ng/ml, with lower levels split into

two groups: those 0.5-1.0 ng/ml and those less than 0.5 ng/ml, which was

the lower limit of detection. Women who had levels of 10 ng/ml or greater

(n = 29) were excluded. The authors found a crude decrement of weight

between the highest and lowest groups of 107 grams, or 108 grams after

adjustment for a number of important confounders (p < 0.001). Compared

to the group with cotinine levels of 0.5-1.0 ng/ml, the ETS-exposed group

had an adjusted weight decrement of 104 grams (95% CI = -173 to -35;

Table 3.4). The authors also examined cotinine level as a continuous vari96

Smoking and Tobacco Control Monograph No. 10

3.2.2.4 Fetal Growth and

Biomarkers of ETS

Hauth et al. (1984)

Haddow et al. (1988)
able and found a weight decrement of 28 grams per ng/ml of cotinine (p =

0.04). The mean level of cotinine was 2.14 ng/ml in the ETS-exposed

group, which would predict about a 60-gram deficit overall. This, combined with data on active smoking, led the authors to suggest that the relationship of cotinine to birthweight may not be linear. However, the discrepancy may also be due to inter-individual variations in cotinine metabolism. The authors also mentioned that LBW was increased 29 percent in

the ETS-exposed group, but no further data were provided.

Overall, this appears to be a well-conducted study. While the

authors reported that in their previous work cotinine levels correlated well

with self-reported exposure, data on self-reported ETS exposures unfortunately were not available for comparison to the cotinine levels. Because

data were obtained from birth certificates, one variable not included in the

analysis was alcohol consumption. However, nonsmokers are unlikely to be

heavy drinkers, or at least not heavy enough to explain the observed

results. Another variable not mentioned was gestational age—a strong predictor of weight—so it is not possible to determine whether the weight

decrement seen is due to prematurity or growth retardation.

A study from Japan (Ueda et al., 1989) reported finding an association of ETS exposure (as well as active smoking) with lowered birthweight,

based on an analysis of cotinine levels. Women attending prenatal clinics

(n = 257) were interviewed, and samples of blood and urine were obtained.

The authors classified women into seven categories of exposure based on

their self-reported active smoking and exposure to ETS at home and elsewhere. Of the nonsmokers, most (84 percent) reported some ETS exposure.

Cotinine levels in maternal urine appeared to differentiate those exposed to

ETS from those not exposed. Mean cotinine levels were lowest in women

who reported no exposure (3.98 ± 3.2 ng/ml), intermediate in women who

reported exposure only at home (10.9 ± 39 ng/ml) or only outside the

home (11.1 ± 20 ng/ml), and highest among those exposed in both places

(55.5 ± 135 ng/ml). For comparison, the mean in active smokers was 228.4

± 214.6 ng/ml. Cotinine levels in maternal serum were not well correlated

with self-reported exposure. 

Despite the relatively high urinary cotinine levels in exposed nonsmokers, relative birthweight did not appear to vary by self-reported ETS

exposure category. Relative birthweight (RBW) was calculated by comparing the true birthweight to a national standard, by gestational age. The

investigators plotted cotinine levels by RBW and found a “correlation/relation” that was significant by the chi-square test (p < 0.01). However, this is

an unconventional statistical method for examining a correlation, and neither the magnitude of the correlation nor the slope of a regression line was

provided. The authors compared the RBW in two groups of women defined

by whether their urinary cotinine levels were above or below 9 ng/ml,

which represented the mean ±1.5 standard deviations of the unexposed

group’s level. The RBW of infants of women with higher cotinine levels (n

= 46) was lower (96.2 ± 12.9 percent) than that of infants of women with

97

Chapter 3

Ueda et al. (1989)
98

Smoking and Tobacco Control Monograph No. 10

Authors (year)

Location

Hauth et al.

(1984)

U.S.—Texas

Haddow et al.

(1988)

U.S.—Maine

Mathai et al. 

(1990)

England

Eskenazi et al.

(1995)

U.S.—California

Rebagliato et al.

(1995a)

Spain

Design

(size)

Maternal serum

at labor

Cord blood

at delivery

(163; 134 

nonsmokers)

Serum drawn early

in 2nd trimester

(1,231 nonsmokers)

Urine at 16 weeks

(285; 184 nonsmokers)

Serum in 2nd

trimester, stored

for 25 years

(3,578; 2,292 nonsmokers)

Saliva in 3rd

trimester

(n = 710 nonsmokers)

Biomarker

Levels

Mean in ETS = 

26 ±2.5 μmol/L

SCN vs. 23 ±1.5 in

nonsmokers’ cord

blood (ns)

1-10 ng/ml cotinine

vs. <0.5 in 

nonsmokers

Mean in ETS = 

0.85 ±2.8 vs. 

0.29 ±1.4 μg 

cotinine/mg creatinine in nonsmokers

2-10 ng/ml cotinine

versus <2 ng/ml

continuous cotinine

level

≤0.5 = unexposed

Quintiles of cotinine

(Mean in ETS 

exposed = 1.2 

ng/ml)

Weight 

Difference

Correlation of wt. and

SCN = -0.74 in smokers (p < 0.001) vs. 

r = 0.02 in 

ETS exposed,

r = 0.15 in 

nonsmokers

-104 g (adj.)

(-173 to -35)

-28 g/ng/ml

cotinine

(CI = -55 to -2,)

-25 g/μg cotinine/mg

creatinine (p < 0.001)

(includes smokers)

-45g (adj.) (-126, 36)

inclding smokers: 

1g per ng/ml cotinine 

(adj.) (-1.14 to -0.79) 

Any: -35g, crude.

Highest quintile

(>1.7ng/ml): 

-87g, (adj.)

(-174 to -1)

Low Birth 

Weight

--

"rate +29%"

(e.g., OR : 1.29)

no statistics 

or numbers 

provided

--

1.35 (0.60, 3.0)

crude

--

Study Results

Table 3.4

Studies of Fetal Growth and ETS Exposure Determined by Biomarkers

Abbreviations: SCN—Thiocyanate; CI—Confidence Interval; OR—Odds Ratio;

r—Correlation Coefficient; ns—not statistically significant
lower cotinine levels (n = 127, 102.4 ± 10.1 percent; p < 0.001). However,

it is not clear whether active smokers were excluded. Although active

smokers represent only a small proportion (6.6 percent) of the total group,

they may account for a fairly large proportion of those with elevated cotinine levels. The results of this study are difficult to evaluate due to insufficient information and unusual methods. The lack of consistency between

cotinine levels in maternal urine versus serum is difficult to explain.

In one of the studies of Mathai et al. (1990) previously mentioned, the investigators obtained maternal urine to measure cotinine levels

at 16 and 32 weeks of pregnancy, and at delivery. Data from 285 women

were included, of which about 47 percent were nonsmokers, 19 percent

were nonsmokers who lived with a smoker, and 34 percent were active

smokers at study entry. Cotinine levels increased across the exposure

groups, as well as slightly with increasing gestational age, although whether

these differences were statistically significant was not specified. Infant

birthweight was regressed against a number of co-covariates, with exposure

in one model included as both the number of cigarettes smoked actively

and exposed to passively at 16 weeks, as well as a separate model with cotinine levels replacing self-reported exposure. Alcohol was not included as

one of the variables. There was a 25-gram decrease in birthweight with

every μg cotinine/mg creatinine (creatinine is used as a measure of the concentration of the urine). The mean cotinine level of passive smokers was

0.85 μg/mg creatinine; hence only a very small weight decrement would be

predicted, rather than the 66-gram decrement observed. This measure also

underestimated the decrement seen with active smoking, again indicating a

non-linear effect. Cotinine levels explained slightly more of the variation

in birthweight than did self-reported tobacco exposure. This study would

have been more valuable for assessing an association of ETS exposure (as

measured by cotinine) and birthweight if smokers were excluded, particularly if there is a non-linear relationship. The fact that cotinine was detected

in the urine of some of the nonsmokers who did not report living with a

smoker (mean = 0.29 μg/mg creatinine) indicates that some of them are

probably exposed to ETS. This confirms the problem inherent in studies

that base ETS exposure status only on reported household exposure. If this

misclassification of exposure is nondifferential, it tends to bias effect estimates toward the null.

Eskenazi et al. (1995) used data from the Child Health and

Development Studies in California (as did Yerulshalmy, 1971) to look at

birthweight in relation to cotinine measured in stored serum samples.

Interviews were conducted and sera were collected around the 27-28th

week of pregnancies that occurred between 1964 and 1967. The infants of

women who had never smoked during pregnancy experienced an average

weight decrement of 45 grams (Table 3.4). This figure was similar both

unadjusted and in a multiple-regression model that included women who

were active smokers, as well as a number of co-variates including gestational age. The authors reported that alcohol and caffeine consumption were

considered, but did not improve the model. The crude mean birthweight

99

Chapter 3

Mathai et al. (1990)

Eskenazi et al. (1995)
of ETS-exposed infants was similar to that of infants of light smokers, but

there was a 30-gram difference after adjustment. The highest cotinine level

(>165 ng/ml, e.g. active smoking) was associated with a 230-gram weight

decrement. Examining cotinine as a continuous variable (including smokers), there was a 1-gram weight decrement for each nanogram per milliliter

increase in cotinine. This is based on a linear model, which may not be

appropriate. The authors also found a slight increase in LBW associated

with ETS exposure (Table 3.4), but found no effect on gestational age or prematurity (unadjusted). 

The definition of ETS exposure in this population may be problematic, as the reported exposure rate of only 5 percent is so low, especially for

the 1960’s. Of those considered unexposed based on cotinine level, 50 percent reported having a spouse who smoked, so the reference group may

have included exposed women who were not identified by the relatively

high detection limit (2 ng/ml). Of reported nonsmokers with detectable

cotinine levels, one-third had levels greater than 10, and were excluded.

These may in fact have been nonsmokers who were more highly exposed,

as there would have been fewer reasons to misreport smoking status in that

time period (as the authors themselves suggest). Use of current cotinine

levels to define ETS exposure (versus active smoking) may not be appropriate for these older samples and an assay that was apparently less sensitive.

Another problem with exposure assessment in this study may have been

the age (25 years old) of the samples. 

As noted in Section 3.2.2.2, Rebagliato et al. (1995a) studied

ETS exposure in 710 nonsmoking women using a questionnaire and sampling saliva for cotinine. The investigators examined birthweight by quintiles of cotinine levels less than 14 ng/ml, with subjects having cotinine levels of 0 to 0.5 ng/ml serving as the reference group. In the highest quintile

(>1.7 ng/ml), there was a crude weight decrement of 98 grams, which was

reduced slightly to 87 grams after adjustment for co-variates (Table 3.4).

There was little evidence for a dose-response trend as subjects in the fourth

quintile had a slight weight increment, but the highest category examined

does not represent a particularly high ETS exposure level. For comparison

to Haddow et al. (1988), the weight decrement associated with any cotinine

level greater than 0.5 ng/ml was 35 grams. The adjusted weight decrement

found with high cotinine level was greater than that found with high selfreported exposure. However, in a separate analysis of exposure measures

(Rebagliato et al., 1995b), the authors reported that duration of recent exposure to each source of ETS (as self-reported) and the summary measure at all

locations were significantly correlated with cotinine levels (Spearman’s r =

0.52 for all locations). The apparent inconsistency may be due to differences in the way women report their own exposure, so that some misclassification results.

A number of studies of the effects of tobacco smoke

on intrauterine growth in rodents have been reported

in the literature. The majority of available studies

attempted to simulate active smoking by using mainstream smoke (MS),

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Smoking and Tobacco Control Monograph No. 10

Rebagliato et al. (1995a)

3.2.3 Animal Studies of

Fetal Growth and Tobacco

Smoke Exposure
and some delivered the smoke in bursts or “puffs.” Of 10 such studies

reviewed (see Table 3.7, page 118), five reported significant group differences in intrauterine growth retardation ranging from 4 to 31 percent relative to controls. In two other studies, pup weights were lower (6-16 percent) in the groups exposed to tobacco smoke, but group differences were

not significant. Pup weights were determined at the end of gestation after

removal of pups by hysterotomy or after spontaneous birth. The phrase

“fetal weight at term” rather than “birth weight” is used to describe the

results of the animal studies. Premature delivery is rare in laboratory

rodents, so that weight for gestational age is not an issue. 

In addition to these studies of mainstream smoke, three recent studies in rats (see Table 3.7, page 118) which used exposures characterized as

“sidestream smoke” (SS) are described below. 

Leichter (1989) used a 2-hour daily exposure throughout pregnancy

and found a statistically significant 9 percent reduction in mean fetal

weight at term relative to controls. Fetal weights in the SS-exposed group

were also significantly smaller than in a pair-fed group which was included

to control for effects of sidestream smoke on food intake. The smoke was

not characterized chemically in this study. 

Witschi et al. (1994) used a 6-hour exposure on days 3-10 of gestation and found identical fetal weights at term in the SS-exposed group

and in controls. However, litter size was significantly lower in the sidestream smoke group. Reduced litter size can sometimes be viewed as offsetting an effect on intrauterine growth, due to a greater availability of nutrients for each fetus when there are fewer fetuses per litter (Romero et al.,

1992). Also, exposures in this study did not extend into the fetal period of

gestation when weight gain is most rapid. 

Rajini et al. (1994), from the same research group as Witschi et al.

(1994), used exposures on days 3, 6-10, and 13-17 of gestation and found a

statistically significant 7 percent reduction in mean fetal weight at term in

the SS-exposed group relative to controls. In this study there was no sidestream smoke effect on litter size; further, the exposure period extended

into the fetal period of gestation. There were no group differences in

maternal weight gain during pregnancy in this study.

More than 25 epidemiologic studies of the relationship

between fetal growth and ETS exposure have been reviewed.

All but one of the studies that examined mean birthweight have shown a

decrement with ETS exposure, although some of the weight differences

were small (Figure 3.1). Only a few studies examined fetal length, and

though results were in the direction of a small decrement with ETS exposure (0.25-1.1 cm), two were unadjusted, so conclusions cannot be reached.

Fifteen studies have examined low birthweight or “small for gestational

age” as shown in Figure 3.2. The figure indicates that the majority of studies which have examined these outcomes have shown a slightly elevated

101

Chapter 3

Leichter (1989)

Witschi et al. (1994)

Rajini et al. (1994)

3.2.4 Discussion

and Conclusions
risk with ETS exposure. The area of overlap of the confidence intervals is

consistent with up to a 1.4- or 1.5-fold increased risk of small fetal size;

however, it is also consistent with there being no association. Only a few of

the findings were statistically significant on their own. Taken together,

however, they support a slight increase in LBW or IUGR in association with

ETS exposure. There was little evidence found for an association with preterm birth. 

The biomarker studies, in particular Haddow et al. (1988), provide

the most convincing evidence of an effect on growth (or weight). The

Haddow et al. study is based on measurement of biomarkers, addressing

exposure assessment issues; it has adequate control of confounders, and it

has a large study population. As such, the findings of a 100-gram weight

deficit must be considered strong evidence, but in need of replication. The

biomarker data of Ueda et al. (1989) and Mathai et al. (1990) add some supportive evidence, but are not comparable to the Haddow study because

analyses were not limited to nonsmokers. The weight decrement found by

Haddow et al. is about half the magnitude of that seen with active smoking

and is thus greater than might be expected based on cotinine levels measured in those exposed to ETS compared to active smokers. Nevertheless,

this magnitude of effect relative to that of active smoking was reported in a

number of other studies based on self-reported ETS exposure (Borlee et al.,

1978; Rubin et al., 1986; Schwartz-Bickenbach et al., 1987; Campbell et al.,

1988; Martin and Bracken, 1986; Lazzaroni et al., 1990). Furthermore, the

Haddow et al. (1988) data suggest that the association with birthweight is

not linear with “dose” as measured by cotinine level. The two newer biomarker studies confirm Haddow et al.’s results but found lower weight differences. In Eskenazi et al.’s (1995) study, only a small proportion of the

study subjects were found to be exposed, as defined by cotinine level, and

this lack of exposure did not correspond with self-reporting; these results

raise the possibility of misclassification and the dilution of an effect.

Rebagliato et al. (1995), like Haddow et al. (1988), found a statistically significant effect for any ETS exposure and a similar magnitude (88-105g) of

birthweight decrements with higher exposures (defined by cotinine level). 

The second strongest evidence comes from studies that attempted to

ascertain total ETS exposure from multiple sources, with adequate control

of confounding. The four such studies published before 1994 (Table 3.3)

showed small decrements in mean birthweight after adjustment (20-40

grams). Three (and perhaps four) of these studies examined term births

only; weight differences in this group would be less variable than in all

births and are thus not comparable to the majority of studies. In addition,

the studies were not comparable in their definition of exposure, and some

of the risk measures may be diluted by inclusion of less-exposed pregnancies in the reference groups, particularly in Ogawa et al. (1991), and

Ahlborg and Bodin (1991). The studies published in 1994 and 1995 (Table

3.3) found more variable weight differences, but some of the measures presented were unadjusted or were in the highest exposure subgroup only, and

thus are not entirely comparable to the earlier studies’ results. Two of the

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Smoking and Tobacco Control Monograph No. 10
studies indicated that more highly exposed women may be more greatly

affected (Lazzaroni et al., 1990; Mainous and Hueston, 1994). However,

Rebagliato et al. (1995) did not find a consistent dose-response trend with

self-reported exposure; this was due in part to a finding of no effect with

home exposure, only with exposure outside the home. Based on these

studies, an average weight decrement of 25-50 grams appears plausible, and

is closer to what might be expected based on relative cotinine levels in

those exposed to ETS versus active smokers.

Among the studies which ascertained ETS exposure from multiple

sources, only one found a strong association with growth retardation

(Martin and Bracken, 1986). The Martin and Bracken study has been criticized (Hood, 1990) because of its low rate (2 percent) of LBW. However, the

rate of LBW at term is expected to be much less than overall rates of LBW:

Ogawa et al. (1991) found a rate of 3 percent and Ahlborg and Bodin (1991)

observed a rate of only 1.5 percent. Two of the newer studies also found

similarly elevated risks, although one was unadjusted and based on small

numbers (Roquer et al., 1995), and the other found an increased risk only

with high exposure (Mainous and Hueston, 1994,Table 3.3). Two studies

(Ahborg and Bodin, 1991; Fortier et al., 1994) found greater associations

with workplace than with home exposures; associations with work exposure

increased with increasing number of hours worked. The case-control study

by Chen and Pettiti (1995) also found some differences between work and

home exposure, with no effect at work but a slightly protective effect at

home. However, in each of these three studies which examined home and

work exposure separately, the confidence intervals were wide and overlapped, so the effects of exposure at home and at work may not be truly different. Some studies have found that subjects were more likely to be

exposed at work than at home (Fortier et al., 1994) or that they were

exposed longer at work than at home (Lazzaroni et al. 1990); however, this

may vary by culture, as Ogawa et al.(1991) found more women were

exposed at home. Workplace exposure may also differ from that at home

due to the number of smokers contributing to ETS and to the influence of

environmental conditions (e.g., air exchange rates, temperature).

Overall, the weight differences observed in the studies based on

exposure to spousal or household smokers vary greatly, from a decrement of

3 to over 200 grams (Table 3.1 and Figure 3.1). The studies are difficult to

compare because of their many differences, including: when they were conducted (over a 25-year timespan); the location and nationality of study populations; the range of sample size and sample selection; the extent to which

confounders were controlled; and the analytic methods used. Furthermore,

the crude assessment of exposure in most studies allows for a great variation in the actual “amount” of exposure being compared. The two studies

with the highest birthweight decrements provided only crude estimates,

unadjusted for potential confounders, and neither included populationbased samples.

103

Chapter 3
Of these studies of mean birthweight and exposure to household

smokers, the highest quality studies—based on study design, sample size,

and control of confounders (Brooke et al., 1989; Chen et al., 1989; Rubin et

al., 1986; Campbell et al., 1988; Mathai et al., 1992; Zhang and Ratcliffe,

1993)—found weight decrements ranging from 15 to 100 grams. Martinez

et al. (1994), the only one of the new studies in this category, found a statistically significant adjusted weight difference in the same range. Two of

these studies (Campbell et al., 1988; Rubin et al., 1986) did not exclude

active maternal smokers, but rather adjusted for them. Four of these studies

reported examining the data for a dose-response relationship; such a relationship was observed by Rubin et al. (1986) and Martinez et al. (1994),

while the two studies from Shanghai reported no or an inconsistent trend

(Chen et al. 1989; Zhang and Ratcliffe, 1993). In addition to these studies,

the Saito (1991) study, which was the largest but did not control for confounders, also found a mean weight decrement in the same range and

demonstrated a dose-response relationship. These studies provide further

evidence for a decrement in birthweight associated with ETS exposure.

The studies based on paternal or household ETS exposure tended to

show slight (or no) increases in the risk of LBW or IUGR. The best, and the

most recent studies (conducted in the past decade, see Table 3.2), were all

from Asia and reported ORs ranging from 1.1 to 1.7. Two of these showed

no indication of a dose-response trend (Chen et al., 1989; Zhang and

Ratcliff, 1993), whereas two others showed some evidence of a trend

(Nakamura et al., 1988; Saito, 1991).

In general, the results of animal studies support an effect of sidestream smoke exposure during pregnancy on intrauterine growth. In particular, the recent study by Rajini et al. (1994) demonstrated an effect on

intrauterine growth in the absence of an effect on maternal weight gain in

a situation using well-characterized sidestream smoke exposures. The

extent of growth retardation in the animals studied was greater than that

reported in infants of ETS-exposed women, but the exposure levels were

also higher (e.g., concentrations of total suspended particulates were about

10 times higher than the average exposure caused by indoor cigarette smoking).

Although it is difficult to separate out the possibility of uncontrolled confounding or misclassification in an individual study with a relative risk of 1.2-1.4, the consistency of the association found in these studies

from different countries strengthens the evidence for causality, as do the

corresponding effects seen in animal studies. Furthermore, there is some

evidence that higher exposures may have effects approaching those expected in light smokers. Additional studies might help clarify any differences

between chronic, low-level exposure and shorter, higher exposures.

Lending further support in terms of a biological basis for these findings from epidemiologic and animal studies are the well-established relationships, first, between active smoking and fetal growth retardation in

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Smoking and Tobacco Control Monograph No. 10
humans, and second, between constituents of tobacco smoke (e.g., nicotine,

carbon monoxide, toluene, cadmium) and fetal growth retardation in animals. There appears to be sufficient evidence that ETS is associated with a

decrement in birthweight (and fetal growth retardation), based on all

sources of data with primary emphasis on the high quality epidemiologic

studies. The effect is of a small magnitude (perhaps 25-50 grams) that may

not be clinically significant for an individual infant at low risk. Yet, if the

entire birthweight distribution is shifted lower with ETS exposure, as it

appears to be with active smoking, infants who are already compromised

may be pushed into even higher risk categories. Low birthweight is associated with many well-recognized problems for infants and with perinatal

mortality. A meta-analysis of studies conducted up to mid-1994 was

reported (Windham et al., 1995a), which pooled results of the studies into a

summary estimate based on a weighted average (with the weight equal to

the square of the inverse of the standard error of the estimate of each study,

as in Greenland, 1987). Studies which did not provide an error measurement (or confidence interval) could not be included in the summary. If

study results appeared heterogeneous (p-value for homogeneity chi-square

>0.10), an influence analysis was conducted by removing studies individually to see which had the greatest effect on the results. The weighted average for difference in mean birthweight was -28 grams (95% CI = -40 to -16)

among studies limited to nonsmoking women (e.g., with and without ETS

exposure, n = 12). The summary odds ratio for low birthweight at term or

IUGR studies was 1.2 (95% CI = 1.1-1.3, n = 8) and for LBW was 1.4 (95%

CI = 1.1-1.8, n = 4). The latter excludes the Underwood et al. (1967) study,

which appeared to be an outlier but had a large influence due to its high

sample size, and had numerous methodological limitations as described earlier.

Low birthweight affects 6-7 percent of the births in the

United States (U.S. DHHS, 1996), and thus, of the 551,226

births in California in 1995 (California Department of Finance, 1996)

approximately 36,000 may have been of low birthweight. Both active

smoking and ETS exposure are risk factors for low birthweight, and estimates of attributable cases due to ETS exposure are more accurate when

active smoking prevalence is taken into account. From the equations used

by U.S. EPA (1992) for estimating attributable lung cancer risks, attributable

risk (a) for low birthweight due to ETS exposure can be estimated by using

the following formula:

a = (1 - PS

)PE(RE - 1) / [(1 - PS)PE(RE - 1) + PS(RS(PERE + 1 - PE)) + 1]

where PS is the prevalence of smokers in the population, PE the prevalence

of ETS-exposed nonsmokers, RS the relative risk of low birthweight in smokers relative to nonsmokers, and RE the relative risk of low birthweight in

ETS-exposed nonsmokers relative to non-ETS-exposed nonsmokers. The

above expression assumes that there is no tobacco-related impact on birthweight among those characterized as nonexposed. In the event that this is

incorrect, the expression above is biased in the direction of underestimating

ETS-related attributable risk.

105

Chapter 3

3.2.4.1 Risk Attributable

to ETS Exposure
The prevalence of exposure can be estimated from the results of the

1993 California Tobacco Survey reported by Pierce et al. (1994, 1996, personal communication): 9.4 percent of women who are pregnant are active

smokers; 21.2 percent of pregnant nonsmokers are exposed to ETS, based

on the proportion of 18-44 year-old nonsmoking women exposed at home

or work. This estimate may understate the prevalence of ETS exposure of

pregnant women because those exposed in other indoor locations have not

been included. To estimate the relative risk of low birthweight due to

active smoking and ETS exposure, we use ORs (which we take to be approximations of the relative risk) of 2 and 1.2 to 1.4, respectively. Applying

these values to the equation given above, the proportion of all low birthweight newborns in California that may be associated with ETS exposure is

estimated to be 3.3 to 6.2 percent, which corresponds to 1,200 to 2,200

newborns in California in 1995 with low birthweight associated with ETS

exposure. 

In this section, studies evaluating the effect of ETS on

spontaneous abortion and perinatal mortality are

described. For the purposes of this discussion, perinatal mortality is defined as death in the period from 20 weeks gestation to 28

days post-delivery. Perinatal mortality includes stillbirths (fetal death from

20 weeks to term) and neonatal deaths (death between birth and 28 days of

life). Relatively few studies have assessed the effect of ETS exposure on perinatal mortality. Spontaneous abortion or miscarriage is currently defined as

pregnancy loss in the first 20 weeks of gestation, but was defined as loss up

to 28 weeks in older reports. Some authors have combined spontaneous

abortions with stillbirths to look at prenatal and perinatal deaths.

Perinatal death encompasses a wide variety of causes or diagnoses

(e.g., abruptio placenta, premature rupture of membranes (PROM), severe

malformation) that may result from different etiologic factors.

Identification of confounders is particularly complex. As prematurity and

LBW are risk factors for neonatal death, birthweight and gestational age

should be considered when studying perinatal mortality. When examining

spontaneous abortion, maternal age, prior history of pregnancy loss, and

socioeconomic status indicators at a minimum should be considered as

potential confounders.

The literature on the association of active maternal

smoking during pregnancy and fetal loss is not as definitive as it is for birthweight. Many studies have found an

association with perinatal mortality (Stillman et al.,

1986; Kleinman et al., 1988). The 1980 report of the

Surgeon General states that the risk of mortality

“increases directly with increasing levels of smoking during pregnancy,”

and that the effect is greater in women with other risk factors (U.S. DHHS,

1980). Furthermore, the increased risk appears to be related to problems of

pregnancy and prematurity rather than to abnormalities of the neonate.

Some of the perinatal mortality has been found to have resulted from pla106

Smoking and Tobacco Control Monograph No. 10

3.3 SPONTANEOUS

ABORTION AND

PERINATAL MORTALITY

3.3.1 Overview of

Human Studies of

Spontaneous Abortion

and Perinatal Mortality

and Maternal Smoking

During Pregnancy
centa praevia, in which the placenta separates from the uterine wall. This is

consistent with the changes associated with exposure to carbon monoxide

and nicotine described earlier in Section 3.2.1.

Active maternal smoking is often cited as a risk factor for spontaneous abortion in descriptive overviews (Stillman et al., 1986; Pirani, 1978;

Kline and Stein, 1984), but the data are not consistent. Studies which

reported an association found odds or rate ratios of 1.5-2.0, particularly

with heavier smoking (Kline et al., 1977). Not all of these studies adjusted

for confounders such as alcohol consumption. Several studies, including

some discussed below (Windham et al., 1992; Hemminki et al., 1983), did

not find substantial associations. Inconsistencies may be due to the fact

that the study populations were from different backgrounds in different

time periods, in which the pattern of active smoking during pregnancy may

have varied. As smoking during pregnancy becomes less prevalent, fewer

women are exposed and an association becomes more difficult to detect. If

there is an association of perinatal mortality with active smoking, it appears

more likely to occur with later fetal losses (U.S. DHHS, 1980; Kallen, 1988). 

Eight studies were reviewed. Two recent studies

suggest a link between ETS and spontaneous abortion, but a third does not. Several earlier studies

also suggested an increased risk of neonatal death

associated with paternal smoking. Studies of stillbirth did not suggest

increased risk.

In an early study (Table 3.5), Comstock and Lundin

(1967) examined stillbirth and neonatal death rates in relation to parental

smoking. The sample consisted of 376 live births in Maryland between

1953 and 1963, and 476 stillbirths or neonatal deaths in the same time

period. Smoking status was determined from a special population census

conducted in the study area and could not be specifically related to the

pregnancy under study. The authors reported “no significant differences”

in the rates of stillbirth by paternal smoking status, but no data were

shown. Neonatal death rates, adjusted for infant gender and paternal education, were elevated in infants with nonsmoking mothers and smoking

fathers (17.2 per 1,000) compared to infants with no parental smokers (11.9

per 1,000). Neonatal death rates were highest when both parents smoked

(26.5 per 1,000). There was no statistical testing of the differences in the

adjusted rates. Because the adjusted rates were very similar to the crude

rates, we calculated a crude odds ratio and 95 percent confidence interval

for the association of neonatal death and paternal smoking (OR = 1.45, 95%

CI = 0.9-2.4). The authors noted that neonatal mortality rates were also

increased among a small group of infants whose mothers did not start

smoking until after pregnancy. This could reflect ETS exposure of the

infant. Only a few confounding factors were addressed in this study, and

the possibility that birthweight could be the mediating factor in neonatal

mortality was not considered.

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Chapter 3

3.3.2 Human Studies of

Spontaneous Abortion and

Perinatal Mortality and ETS

Exposure 

Comstock and Lundin (1967)
Tokuhata (1968) used data from a case-control study of reproductive cancers in Tennessee to examine infertility and fetal losses in relation

to the smoking experience of couples. The results showed that husbands’

smoking status was unrelated to fetal loss (RR = 1.1). This study is limited

in several ways. First, information about miscarriage and stillbirth was

obtained from a next of kin long after the events in question had occurred.

This delay makes the ascertainment of miscarriage particularly unreliable.

Second, the entire reproductive period was included: some subjects had had

multiple pregnancies, and the observed events were not independent.

Third, lifetime smoking history was used, which may not pertain to specific

pregnancies. Information on amount smoked or potential confounders was

not addressed.

Yerushalmy’s (1971) analysis of data from the comprehensive

Child Health and Development Studies conducted in 1960-1967 included

an examination of neonatal mortality rates among low birthweight infants

only, a select group. He found higher mortality rates among LBW births to

couples in which the father was a smoker, particularly among blacks. The

data presented in a figure in the study report indicate about a 10 percent

increase in the rates among whites and a 35 percent increase among blacks.

This pattern was seen whether the mother was a smoker or not. No raw

data were presented for estimating an effect measure or confidence interval,

nor were confounding variables considered.

In their report of a large prospective study in Germany (see

Section 3.2.2.1), Mau and Netter (1974) examined the association of paternal smoking with perinatal mortality (the definition of which was not stated). The authors found an increased rate of perinatal mortality among

pregnancies where the father smoked 10 or more cigarettes per day, both

for all women and for nonsmoking women (p < 0.01). There was not a

monotonic dose-response relationship with the amount the husband

smoked (there was a slightly lower mortality rate for infants of lighter

paternal smokers (1-10 cigarettes per day) than for infants of nonsmokers).

Calculating a crude rate ratio for the heavier smoking category yields an

approximate measure of 1.5 (p < 0.05), (Table 3.5). Stillbirth rates were

identified separately and were also included in the perinatal mortality rates.

Stillbirth rates increased only slightly with heavier paternal smoking among

infants of all women (RR = 1.2), with no further information provided on

nonsmoking women. Mau and Netter (1974) noted that the rate of miscarriage in women whose husbands smoked more than 10 cigarettes per day

was slightly higher than among those whose husbands did not smoke (9.3

percent versus 8.2 percent). This difference was not statistically significant

and no further data were presented.

The small (or lack of ) association of paternal smoking with either

stillbirth or miscarriage indicates that the association with perinatal mortality may be due to increased neonatal mortality. The authors examined various confounding factors and judged that they had little effect on the association of paternal smoking with perinatal mortality, but the factors were not

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Smoking and Tobacco Control Monograph No. 10

Tokuhata (1968)

Yerushalmy (1971)

Mau and Netter (1974)
adjusted for simultaneously. The authors apparently did not adjust for

birthweight, because they did not find a significant association of low birthweight with paternal smoking in their study. They did exclude births with

congenital malformations and found that the increase in perinatal mortality persisted.

In a small study of nonsmoking female controls (n = 136) from a

lung cancer study in Hong Kong, Koo et al. (1988) compared life-history

variables by the husband’s smoking status. The authors reported that

women whose husbands had ever smoked were 40 percent more likely to

have had a miscarriage or abortion and twice as likely to have had a dilation and curettage (D & C) than wives of nonsmokers. The results were statistically significant (p < 0.03) for D & C only, and the authors claimed that

most of those pregnancy losses would have been spontaneous rather than

induced abortions, but that claim was not substantiated. Wives of smokers

also tended to have more pregnancies, which was not accounted for in

comparing the percentage of women (versus pregnancies) with one or more

pregnancy losses, nor were potential confounding factors considered. 

A case-control study from Finland, designed to examine the

effect of paternal lead exposure on spontaneous abortion, also reported

paternal smoking habits (Lindbohm et al., 1991). The crude odds ratio for

spontaneous abortion associated with any paternal smoking was 1.3 (95%

CI = 0.9-1.9) (Table 3.5). Maternal smoking had an OR of 1.5 (95% CI =

0.9-2.4), but was not taken into account in the association with paternal

smoking. This study may not be generalizable because it targeted men who

had been identified through a blood lead monitoring service.

The previously described study of Ahlborg and Bodin

(1991) had information about ETS exposure at home as well as in the workplace, ascertained in a prospective study of about 4,700 pregnancies in

Sweden. ETS exposure (any versus none) was not found to be associated

with excess risk for hospital-ascertained intrauterine deaths (spontaneous

abortions plus stillbirths) among nonsmoking mothers. However, there was

an excess risk among working women with workplace exposure, with an

adjusted rate ratio of 1.5 (95% CI = 0.98-2.4; Table 3.5). This risk did not

vary much by whether the woman worked full- or part-time, or by whether

or not her partner smoked. When a distinction was made on the basis of

whether the loss was early (≤12 weeks) or later in pregnancy, the association

with workplace exposure appeared limited to early losses (RR = 2.2, 95% CI

= 1.2-3.8) rather than later losses (RR = 1.1). Among working women, exposure only in the home was not associated with intrauterine death. 

This study has several strengths, including its ascertainment of multiple sources of exposure, its use of adequate numbers of pregnancies for

assessing fetal loss and its thorough control of known confounders.

However, the fetal loss rate was low and first trimester losses before prenatal

care began were probably under-ascertained. Several of the findings were

somewhat inconsistent, such as an association only with workplace expo109

Chapter 3

Koo et al. (1988)

Lindbohm et al. (1991)

Ahlborg and Bodin (1991)
110

Design (study size) Sample from special cen- sus, vital records (n = 234 still births, 158 neonatal) Interview in early pregnancy (n = 5,183) Case-control study of SABs in lead-monitored men and wives (n = 213

SABs, 300 controls)Prospective questionnaire(n = 4,687 pregnancies)

Case-control (n = 626

SABs, 1,300 births)

Exposure DefinitionPaternal smoking (nonsmoking mother)Paternal smoking by 

amount (>10 cigs/day)

Paternal smoking status“Live with smoker." Most time at work with 

smokers

(nonsmoking mother)≥1 hr/day (yes/no) in first20 weeks.Paternal smoking (nonsmoking mother)

Authors (year)LocationComstock & Lundin 1967)2U.S.—MarylandMau & Netter (1974)2GermanyLindbohm et al. (1991)

FinlandAhlborg and Bodin (1991)SwedenWindham et al. (1992)

U.S.—California

ResultsRR = 1.45 (0.9-2.4) for NM.No effect on SB. (notedincreased NM in smallgroup where mom startedsmoking after pregnancy).RR of perinatal death = 

1.5 (CI = 1.1-2.3)

RR for SB = 1.2 (ns)RR for SAB = 1.1 (ns)OR for SAB = 1.3 (0.9-1.9)RR for SAB + SB and ETS 

at home = 1.0at work = 1.5 (0.98-2.4)

RR = 2.2 (1.2-3.8) forearly SAB and work ETS. OR for SAB = 1.6 (1.2-2.1)

late SAB (>12 wks)OR = 1.9 (1.4-2.7)

Table 3.5ETS Exposure in Relation to Spontaneous Abortion and Perinatal Death11 Includes stillbirth or fetal death and neonatal mortality.2 Odds ratios and confidence intervals calculated from data, not by original authors.

Abbreviations: SAB—Spontaneous Abortion; SB—Stillbirth; NM—Neonatal Mortality; FD—Fetal Death; RR—R

ns—not statistically significant.
sure and not with home exposure. The question format, however, would

tend to yield a more highly exposed group at work than at home (e.g. “Do

you spend most of your time at work in rooms where other people are

smoking?” versus “Do you live with a person who smokes inside your

home?”). It might have been helpful if the authors had examined the

hours of exposure at home or the amount smoked by the household smoker. Secondly, the association of ETS exposure at work with intrauterine

deaths in this study is on the same order or greater than the association

found for active smoking and intrauterine death. Lastly, in contrast to the

ETS findings, the association with active smoking is more striking in later

rather than early pregnancy losses.

Windham et al. (1992) examined ETS exposure in a large

case-control study of spontaneous abortion conducted in California. Cases,

which were confirmed by medical records, were compared to live-born controls frequency matched (to cases) by hospital and date of mother’s last

menstrual period. The ascertainment of exposure included a question on

the amount smoked by the “father of the pregnancy,” as well as a separate

question on whether the subject was regularly exposed to cigarette smoke

for an hour or more per day during the first 20 weeks of her pregnancy.

The adjusted odds ratio for self-reported ETS exposure of one hour or more

per day among nonsmokers was 1.6 (95% CI = 1.2-2.1), with a somewhat

greater association among second trimester than first trimester losses (Table

3.5). The association varied little with the woman’s employment status. For

amount smoked by the father, the adjusted odds ratios were all close to

unity. However, among women reporting ETS exposure, the association

was slightly greater if her partner smoked (OR = 2.0) than if he did not (OR

= 1.5), potentially indicating heavier ETS exposure. 

This study lends some support to the findings of Ahlborg and Bodin

(1991) of an increased risk of fetal death associated with ETS exposure. Of

further note is that the Windham et al. (1992) study also found a lower

association of spontaneous abortion with active smoking than with ETS

exposure, even when active smokers were compared to nonsmokers with no

ETS exposure (OR = 1.3). An inconsistency is that Windham et al. (1992)

found a slightly greater association with later abortions, while Ahlborg and

Bodin (1991) found a greater association with earlier spontaneous abortions. However, in the Swedish study, the late pregnancy losses also

included stillbirths. Recall bias may be a concern with a retrospective

study, although the questions about ETS exposure were embedded in a

series of questions about other exposures and were not the main hypothesis

of the Windham et al. study.

In a recently reported prospective study (Windham et al.

(1995b), unpublished symposium presentation), the finding of an association between ETS exposure and spontaneous abortion was not confirmed.

In that study, pregnant women were interviewed in the first trimester

regarding the number of hours per day of ETS exposure at home or work,

from which a daily total for each woman was calculated. Among the more

111

Chapter 3

Windham et al. (1992)

Windham et al. (1995b)
than 4,000 nonsmokers in the study, there was no association with any

measure of ETS exposure, including paternal smoking, nor was there any

dose-response relationship (adjusted OR for any ETS = 1.0, 95% CI = 0.80-

1.3). However, among women who consumed moderate amounts of alcohol (greater than or equal to three drinks per week) or caffeine (greater than

300 mg/day), there was evidence of an association with ETS (adjusted OR

around 3), indicating the possibility of interaction or a more susceptible

subgroup.

Information on perinatal mortality in animals is provided by endpoints such as: numbers of resorptions,

number of live and dead fetuses at term (in studies

with term hysterotomy), and litter size (in studies with spontaneous birth).

Studies using mainstream smoke (see Table 3.7, page 120) were not generally supportive of effects on these parameters. 

In the three available studies using sidestream smoke (Table 3.7),

one study (Witschi et al., 1994) found statistically significant effects of SS

exposure on both the number of implantation sites per litter and the number of live pups per litter; this suggests that the primary effect was on

implantation. The other two studies (Leichter, 1989; Rajini et al., 1994) did

not find effects of SS exposure on variables related to perinatal mortality.

Relatively few studies have examined the association of ETS

exposure and perinatal death. Two early studies (Comstock

and Lundin, 1967; Mau and Netter, 1974) that examined neonatal mortality

rates by paternal smoking status suggested an increased risk on the order of

50 percent. A third study (Yerulshalmy, 1971) did not present enough data

for satisfactory interpretation, but suggested a possible effect of paternal

smoking on neonatal death rates in LBW infants. The data with respect to

stillbirth are even more sparse, but are not indicative of an association. 

Two more recent studies of spontaneous abortion and ETS exposure

(Windham et al. 1992; Ahlborg and Bodin, 1991) offer better data, although

the exposure assessments were still somewhat crude and were based only on

questionnaire responses. Both studies reported an association of spontaneous abortion with ETS exposure, also on the order of 50 percent,

although in one study the association was observed only with workplace,

not home, exposure. One consideration in examining the relationship of

fetal loss to paternal smoking is that it could reflect a direct effect of smoking on the sperm (if losses are due to fetal abnormalities), rather than an

effect of ETS exposure to the mother and fetus. The two more recent studies of spontaneous abortion were based not only on paternal exposure, but

also included other sources of ETS exposure. The finding in these two studies of a similar association of spontaneous abortion with ETS exposure as

with active smoking may be difficult to reconcile with a causal association,

given the lower levels of biomarkers measured in nonsmokers exposed to

ETS and the fact that active smokers are also exposed to ETS. However,

Remmer (1987) has suggested that enzyme induction of mono-oxygenase

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Smoking and Tobacco Control Monograph No. 10

3.3.3 Animal Studies of

Perinatal Mortality and

Tobacco Smoke Exposure

3.3.4 Discussion

and Conclusions
systems among active smokers leads to detoxification of toxic compounds;

because such enzyme induction would probably not occur with the lower

exposures of those exposed only to ETS, their fetuses are less protected.

In the three animal studies of the effects of sidestream smoke on

variables related to perinatal mortality, results are indicative of an effect in

only one (Witschi et al. 1994); studies using mainstream smoke were not

generally supportive of an effect on these variables. Based on this limited

information, it appears that measures reflecting perinatal mortality in animals are not particularly sensitive to gestational tobacco smoke exposure. 

In conclusion, there is some epidemiologic evidence that ETS exposure may play a role in the etiology of spontaneous abortion, which is consistent with some but not all studies of active smoking. More work is needed because of the few studies available and the inconsistent findings.

Congenital malformations include a wide variety of diagnoses,

such as neural tube defects (e.g., anencephaly, spina bifida),

cleft palate, and defects of the genitourinary and the cardiovascular systems, among others. About 2 to 3 percent of births are generally considered

affected. However, this may vary across studies, because some defects are

not detectable at birth and thus would not be included in studies that did

not ascertain defects later in infancy. Some studies limit cases to major

malformations, whereas others use a broader definition of anomaly. There

is some controversy about how to categorize diagnoses, e.g., by organ system or embryologic origin. Potential confounding variables are not well

defined, but maternal age, prior reproductive history, and socio-economic

status should be considered.

The literature on the relationship of active maternal smoking to congenital malformations is inconsistent. Some studies have found associations with defects (Kelsey et al., 1978;

Himmelberger et al., 1978), including tube defects (Little

and Elwood, 1990) and oral clefts (Saxen, 1974; Khoury et

al., 1987), but others have not (Werler et al., 1990; Kallen,

1989; Seidman et al., 1990). The 1980 Surgeon General’s report found there

was insufficient data to support a judgment about whether parental smoking increases the risk of malformations (U.S. DHHS, 1980). A number of

the papers cited above (and below) were published subsequent to that

report, but do not present a stronger case, except perhaps for oral clefts.

A half dozen studies have examined the potential

association of prenatal ETS exposure and congenital

malformations (Table 3.6); all published studies were

based on paternal smoking status only. Thus, any association seen may be

due to a direct effect of smoking on sperm, rather than due to ETS exposure

of the mother. Some studies have suggested that active smoking might

cause genetic damage to the sperm as reflected by alterations in sperm

parameters (Evans et al., 1981; Marshburn et al., 1989). Although little

113

Chapter 3

3.4 CONGENITAL

MALFORMATIONS

3.4.1 Overview of

Human Studies of

Congenital

Malformations and

Maternal Smoking

During Pregnancy

3.4.2 Human Studies of

Congenital Malformations

and ETS Exposure
work has been done associating sperm parameters with pregnancy outcome,

genetic damage could theoretically lead to a birth defect. Given the controversial nature of the data on the association of maternal active smoking and

congenital malformations, we also present those results with the studies

reviewed that looked at both maternal and paternal smoking.

Mau and Netter (1974) looked at the incidence of malformations in their prospective study of pregnancy and child development (see

Section 3.3.2). The rates of severe malformations among all newborns

increased with amount smoked by the father: rates were 0.8 percent among

those whose fathers did not smoke, 1.4 percent among those whose fathers

smoked 1-10 cigarettes per day, and 2.1 percent among those whose fathers

smoked more than 10 cigarettes per day (p < 0.01). A crude odds ratio of 2.6

(95% CI = 1.5-4.7) was calculated for infants of fathers smoking more than

10 cigarettes per day (Table 3.6). The authors stated that the increase in risk

was similar in surviving children and independent of maternal or paternal

age, socioeconomic status, and the participating clinic. No association was

found with maternal smoking; deleting maternal smokers from the analysis

did not change the results for paternal smoking. The increased risk was

observed for specific categories of defects, namely, facial clefts (RR = 7.0),

neural tube defects (RR = 1.7), and cardiac defects (RR = 1.9). These categories included very small numbers, and only the elevated risk of clefts was

statistically significant. An increased risk was also observed for multiple

malformations (RR = 3.3).

A case-control study of central nervous system

defects designed to examine occupational factors (Holmberg and

Nurminen, 1980) also reported on parental smoking. Cases were identified

from the Finnish Register of Congenital Malformations for the years 1976-

1978, and controls comprised the live birth immediately preceding the case

born in the same district. A questionnaire was administered to mothers of

cases and controls within a few months of delivery. Based on a matched

analysis, an odds ratio of 1.3 (95% CI = 0.74-2.5) was calculated for paternal

smoking, restricted in the interview to “the time when the woman became

pregnant.” Maternal smoking showed a greater association (OR = 2.1, 95%

CI = 1.0-4.4), but the authors reported that this association was diminished

when adjusted for solvent exposure. No confounders were considered in

the analysis of paternal smoking, including maternal smoking.

In a very small case-control study of neural tube defects initiated

to investigate an identified cluster, Hearey et al. (1984) examined a wide

variety of possible risk factors. Both mothers (n = 36) and fathers (n = 25)

were interviewed. Paternal smoking was the only variable found significantly associated with the defects. The odds ratio for paternal smoking during the 6 months before conception or the first trimester was 16.0 (95% CI

= 1.1-230.7). No adjustment for other factors, including maternal smoking,

was made. The authors noted that the association was not significant in

the matched analysis, nor in the time period restricted to only the 6

months before conception. The latter observation may actually make a

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Smoking and Tobacco Control Monograph No. 10

Mau and Netter (1974)

Holmberg and Nurminen (1980)

Hearey et al. (1984)
115

Authors (year)LocationMau & Netter (1974)2GermanyHolmberg &Nurminen (1980)FinlandHearey et al. (1984)

CaliforniaSeidman et al.

(1990)2IsraelSavitz et al. (1991)

CaliforniaZhang et al. (1992)2

China

Design(study size)Interview in early

pregnancy (n = 5,183)

Case-control, registrybased (n = 120 CNS

anomalies & 120 cntrls)NTD cluster, case-cntrl(n = fathers of 8 cases

and 17 controls)Retrospective interview

Interview post-partum

(n = 17,152 infants)Prospective in HMOmembers (Child Health& Development Study)(n = 14,685 births)Case-control interviewin hospital(n = 1,012 cases,1,012 controls)

ExposureDefinition1Paternal smokingby amount(>10/day)Paternal smokingat conceptionFather smokepericonceptional(father interviewed)Paternal smoking(amount)Paternal smokingat prenatal interviewPaternal smoking

ResultsRR for severe BD = 2.6 (1.5-4.7)RR for facial clefts = 7.0 (p < 0.05)

Cardiac defects = 1.9 (ns)NTDs = 1.7 (ns)OR = 1.3 (0.74-2.5)OR = 16.0 (p < 0.05) unmatchedRR = 1.45 (0.73-2.8)for >30 cigs/day2 and major BDs.

RR = 1.1 (0.85, 1.5) for minor BDs.OR = 2.4 (ns) for hydrocephalus OR = 2.0 for VSD and urethralstenosis (ns)OR = 1.7 for CLP (ns)OR = 0.6 for NTDs (ns)RR = 1.2 (1.0-1.5) for all BD.Numerous types elevated, but nsRR = 1.6 for CPRR <1.5 for hydrocephalusRR <1.0 for VSDRR = 2.0 (1.1, 3.7)2 for NTDs

CommeLooked adjustedods. (ApsmokersNot adjuIncludes Not adju(Includes 

n.s. in mSmall n

Multivarishown). Multivarismoking Multiple responseNot adjuGreater single deMultiple 

Table 3.6ETS Exposure and Congenital Malformations

1 Among nonsmoking women unless otherwise specified. Exposure ascertained from mother unless otherwise s2 Confidence interval calculated by reviewer.

Abbreviations: BD = birth defects, NTD = neural tube defects, CNS = central nervous system, VSD = ventricul

CLP = cleft lip and/or cleft palate, CP = cleft palate, ns = not significant or p > 0.05.
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Smoking and Tobacco Control Monograph No. 10

stronger case for an ETS effect, because if the excess is associated with paternal smoking during pregnancy (rather than prior to conception), the possibility of an effect on sperm is precluded.

Seidman et al. (1990) examined parental smoking and congenital malformations using data from the Jerusalem Study of Oral

Contraceptive Use. Over 15,000 women who delivered between 1974 and

1976 were interviewed within a few days postpartum. Focusing on only the

results for nonsmoking mothers, the authors noted nonsignificant increases

in rates of minor and major malformations associated with heavy paternal

smoking. The odds ratio we calculated for paternal smoking of greater than

30 cigarettes per day shows only a very slight elevation in the rates of

minor malformations and a moderately elevated association with major

malformations (Table 3.6). The authors reported that a multiple regression

analysis revealed no significant associations with paternal smoking, but did

not publish the results. In the regression analysis, maternal smoking was

not associated with the incidence of either major or minor malformations.

However, among older women (35 years) the malformation rates were elevated two-fold in smokers. The rates of some specific defect categories

(spina bifida and genitourinary system defects) were non-significantly elevated among infants of maternal smokers, but data were not presented by

defect category for paternal smoking.

Savitz et al. (1991) analyzed data from the large Child Health

and Development Studies of Kaiser Births from 1959-1966 with respect to

the influence of paternal variables on the incidence of congenital anomalies. Congenital anomalies were broadly defined and were ascertained up

to 5 years after birth. The association with paternal smoking was examined

for over 30 categories of defects, so some were based on small numbers.

Prevalence odds ratios (POR) adjusted for maternal variables were greater

than 1.5 for four diagnoses: cleft lip with or without cleft palate; hydrocephalus, a nervous system defect; ventricular septal defect, a cardiovascular

system defect; and urethral stenosis (Table 3.6). All of the confidence intervals were wide and included unity. A dose-response relationship for smoking one pack or more per day was suggested only for the clefts and urethral

stenosis. A number of diagnoses had associations with a POR less than 0.7,

including neural tube defects and patent ductus arteriosus, a cardiovascular

defect. In these analyses, maternal smokers were not excluded, but this

variable was controlled in the logistic regression model. Unfortunately, the

number of unaffected births by exposure status was not provided, thus

defects could not be grouped into broader diagnostic categories or by organ

system for comparison to other studies.

Zhang et al. (1992) examined data on paternal smoking from a

case-control study of birth defects conducted in Shanghai from 1986-1987.

Birth defects were ascertained within the first week of life or from pathology exams of perinatal deaths; controls were normal live births. Only two

mothers reported smoking; they were excluded. Other confounders (e.g.,

age, paternal drinking, and chemical exposures) were not adjusted because

Seidman et al. (1990)

Savitz et al. (1991)

Zhang et al. (1992)
117

Chapter 3

their occurrence was rare (<5 percent). The overall odds ratio of birth

defects and paternal smoking was slightly elevated with little evidence of a

dose-response effect (Table 3.6). Among 25 defect categories, elevated odds

ratios were seen for pigmentary anomalies of the skin (3.3, 95% CI = 0.9-

1.8), diaphragmatic hernia (2.3, 95% CI = 0.7-8.4), anencephaly (2.1, 95%

CI = 0.9-4.9), spina bifida (1.9, 95% CI = 0.7-5.4), and varus or valgus deformities of feet (1.8, 95% CI = 0.97-3.3). As can be seen, some confidence

intervals were rather wide. The odds ratios for most other categories were

greater than one. Exceptions were ventricular septal defect and other heart

anomalies, polydactyly or syndactyly, hypoplasia of lung, or hypospadias;

none of these were significantly below unity. For neural tube defect diagnoses (e.g., anencephaly and spina bifida) alone, and in combination with

other central nervous system defects (e.g., hydrocephalus and microcephalus), we calculated ORs of 2.0 (95% CI = 1.1-3.7) and 1.6 (95% CI =

1.0-2.6), respectively. For some of the defects with elevated rates there was

an indication of a dose-response relationship (e.g., spina bifida, diaphragmatic hernia, and the pigmentary anomalies). Classifying defects as isolated or multiple (in the affected individual) revealed a slightly greater association with multiple malformations, but no dose-response effect. The authors

felt that confounding or reporting bias were unlikely to explain the

observed results.

A study recently reported at a scientific meeting (Shaw et

al., 1993) provided some data on parental smoking as

well as other sources of ETS exposure. This case-control study of oral clefts

found a dose-response association with amount of maternal smoking.

Paternal smoking also appeared to show such an association, but not when

maternal smokers were excluded. Thus, paternal smoking appeared to

interact with maternal smoking. Exposure to others’ smoke at work, or at

places other than home, led to slightly increased risks among infants of

maternal nonsmokers (OR = 1.5, 95% CI = 0.95-2.2, and OR = 1.3, 95% CI =

0.88-1.8, respectively), as well as among smokers. These data are preliminary and are not adjusted for co-covariates (and thus are not included in

the tables). The findings for home (e.g., paternal smoking) and workplace

exposure are inconsistent, but the latter are indicative of a slight association

with ETS.

A more recent presentation from the same investigators (Wasserman

et al., 1994) provided data on parental smoking and neural tube and

conotruncal heart defects. An increase in the ORs for the heart defects was

seen when both parents smoked (crude ORs ranged from 1.4 to 2.0 by

amount smoked), but not when only one parent smoked. Little consistent

pattern of risk with parental smoking was noted with neural tube defects, in

contrast to the published studies discussed above. Information on workplace exposure was not presented. 

Malformations in animals are detected in term

fetuses by gross examination, soft tissue examination via dissection, and skeletal examination after

staining; a complete teratology study includes all three exams. Of seven

Shaw and Wasserman (1993)

Wasserman et al. (1994)

3.4.3 Animal Studies of

Congenital Malformations

and Tobacco Smoke Exposure
studies of mainstream smoke using one or more of these techniques, four

did not find any effects (Wagner and Chouroulinkov, 1972; Reznik and

Marquard, 1980; Peterson, 1981; Bassi et al., 1984) and three mentioned

limited findings (Schoeneck, 1941; Tachi and Aoyama, 1983; Amankwah et

al., 1985) but did not provide enough information for evaluation or for

characterization of defects.

Of the three available sidestream smoke studies, one (Witschi et al.,

1994) did not examine malformations. Using gross examination only,

Leichter (1989) reported no effects. Rajini et al. (1994) reported finding no

effects using gross and skeletal examinations, but did no soft tissue examination. Thus, no complete teratology study has been conducted with sidestream smoke.

Although the epidemiologic studies reviewed suggest a moderate association of severe congenital malformations with paternal smoking (with odds ratios from 1.2-2.6 for all malformations combined,

or for major malformations), none presented compelling evidence that ETS

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Smoking and Tobacco Control Monograph No. 10

Mainstream or Unidentified Type of Smoke

Authors (year) Species Exposure Period Fetal Weight at Term

Essenberg et al. (1940) rats mating through "2/3rds under weight" 

lactation (no statistics)

Younoszai et al. (1969) rats day 3-22 gestation -16% 

Wagner et al. (1972) mice day 11-16 days -16% (not significant)

gestation

Haworth & Ford (1972) rats day 3-20 gestation -19%

Reckzeh et al. (1975) rats day 1-18 gestation -6% (not significant)

Reznik & Marquard (1980) rats day 0-21 gestation -31%

Peterson et al. (1981) mice day 6-17 gestation -4% (not significant)

Bertolini et al. (1982) rats day 1-20 gestation -9% (not significant)

Tachi & Aoyama (1983) rats day 0-21 gestation -30%

Bassi et al. (1984) rats day 5-20 gestation -21%

Amankwah et al. (1985) mice day 0-birth -4%

Rogers & Kuehl (1988) baboons "throughout -17% (no statistics)

pregnancy"

Sidestream Smoke

Leichter (1989) rats day 1-20 gestation -9%

Witschi et al. (1994) rats day 3-10 gestation 0% (not significant)

Rajini et al. (1994) rats day 3, 6-10 and -7%

13-17 gestation

Mohtashamipur et al. (1987) rats "1st, 2nd and 3rd "significant losses"

(abstract) week of pregnancy" no statistics

Table 3.7

Animal Studies of Tobacco Smoke Exposure and Fetal Growth

3.4.4 Discussion

and Conclusions
exposure causes congenital malformations. The use of paternal smoking status as a surrogate for ETS exposure means that a direct effect of active

smoking on the sperm cannot be ruled out. Several studies found greater

associations with specific defects, but the defects implicated differed in different studies. The most consistent association appears to be with central

nervous system or neural tube defects; this association was observed in all

but one study (Savitz et al., 1991) of the five that provided sufficient data.

Due to the limitations in assessing exposure in the existing studies, it is not

possible to determine whether there is an association of ETS exposure with

birth defects.

None of the studies currently published had information on ETS

exposure from multiple sources (e.g., home and work), nor did any include

measurement of a biomarker. Thus, an association will be more difficult to

detect if there is misclassified exposure such that the comparison group

includes pregnancies exposed to ETS from sources other than the spouse.

Given that the results of studies of active smoking have been inconsistent, a

teratogenic effect of ETS is unlikely to be strong; it would be very difficult

to detect a significant association of a weak teratogen which occurs at such

low levels with outcomes as rare as specific birth defects. Furthermore,

because of the relative dearth of information on causes of malformations, it

is difficult to determine whether confounding variables have been adequately controlled. Several of the studies did not exclude maternal smokers, and only one of those adjusted for maternal smoking (Savitz et al.,

1991).

In animals, the three available sidestream smoke studies found no

effects; however, no complete teratology study has been conducted. Results

of only three of seven studies of mainstream smoke suggest an association

(Shoeneck, 1941; Tachi and Aoyama, 1983; Amankwah et al., 1985). Based

on this limited information, measures of congenital malformations in animals do not appear to be sensitive to tobacco smoke exposure.

In conclusion, it is not possible at this time to determine whether

there is an association of ETS exposure with birth defects. 

More than 25 epidemiologic studies of the relationship between fetal growth and ETS exposure were

reviewed. All but one of the studies that examined mean birthweight

found a decrement with ETS exposure, although some of the weight differences were small. A few early studies found little effect, but none of them

controlled for confounders or performed rigorous statistical analyses. The

majority of studies which examined the endpoints “low birth weight” or

“small for gestational age” have shown a slightly elevated risk (20-40 percent) with ETS exposure. Current epidemiologic studies, with support from

animal studies and the known association with active smoking, provide sufficient evidence that ETS exposure adversely affects fetal growth. The primary effect is a reduction in birthweight that is of a small magnitude (25-50

grams) and may not be clinically significant for an individual infant at low

119

Chapter 3

3.5 CHAPTER SUMMARY

AND CONCLUSIONS
Ahlborg, G. Jr., Bodin, L. Tobacco smoke exposure

and pregnancy outcome among working

women. A prospective study at prenatal care

centers in Orebro County, Sweden. American

Journal of Epidemiology 133(4):338-347, 1991.

Amankwah, K.S., Kaufmann, R.C., Weberg, A.D.

Ultrastructural changes in neonatal sciatic nerve

tissue: Effects of passive maternal smoking.

Gynecologic and Obstetric Investigation 20:186-193,

1985.

Bassi, J.A., Rosso, P., Moessinger, A.C., Blanc, W.A.,

James, L.S. Fetal growth retardation due to

maternal tobacco smoke exposure in the rat.

Pediatric Research 18:127-130, 1984.

Bertolini, A., Bernardi, M., Genedani, S. Effects of

prenatal exposure to cigarette smoke and nicotine on pregnancy, offspring development and

avoidance behavior in rats. Neurobehav Toxicol

Teratol 4:545-548, 1982.

risk. Yet, if the entire birthweight distribution is shifted lower with ETS

exposure, as it appears to be with active smoking, infants who are already

compromised may be pushed into even higher risk categories. Low birthweight is associated with many well-recognized problems for infants and is

strongly associated with perinatal mortality.

Of the relatively few studies that have examined the association of

ETS exposure and perinatal death, early studies suggest an increased risk of

neonatal mortality rates associated with paternal smoking. The data with

respect to stillbirth are more sparse, but are not indicative of an association.

Two modern studies reported an association of spontaneous abortion and

ETS exposure from multiple sources, although in one study the association

was observed only with workplace, not home, exposure. These, as well as

two weaker studies, provide some epidemiologic evidence that ETS exposure

may play a role in the etiology of spontaneous abortion, but further work is

needed, particularly as a recent report did not confirm these findings.

Although the epidemiologic studies reviewed suggest a moderate

association of severe congenital malformations (birth defects) with paternal

smoking, none presented compelling evidence that ETS exposure causes

congenital malformations. The use of paternal smoking status as a surrogate for ETS exposure means that a direct effect of active smoking on the

sperm cannot be ruled out. Several studies found associations with specific

defects, but the defects implicated differed in different studies. The most

consistent association appears to be with central nervous system or neural

tube defects; this association was observed in all but one of the five studies

that provided sufficient data. Due to the limitations in assessing exposure

in the existing studies, it is not possible to determine whether there is an

association of ETS exposure with birth defects. 

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In this section we examine associations between ETS exposure and three outcomes occurring after the neonatal period: Sudden Infant

Death Syndrome (SIDS), neuropsychological development, and physical

growth. 

The discussion of each outcome begins with a brief review of studies

that assessed the effect of active smoking by the mother during pregnancy.

Although reviewing active smoking effects is not the purpose of this document, the review of these studies provides a context within which to consider the results of the studies of ETS exposure.

The brief review of active smoking effects is followed by detailed

descriptions of epidemiologic studies of ETS exposure and their outcomes.

Pertinent animal studies are then described. The section concludes with a

discussion of overall evidence on the impact of ETS exposure and the endpoint. 

The issue of adequate control of confounding is

central in attempting to identify causal factors in

child development. Smokers as a group appear to differ from nonsmokers

in many ways that may influence child development (Broman et al., 1987).

For example, smokers are more likely to be of lower socioeconomic status,

to be less educated (Fiore et al., 1989; Pierce et al., 1989; Escobedo et al.,

1990), to drink alcohol (Kuzma and Kissinger, 1981), and are less likely to

breast-feed their infants (Goodine and Fried, 1984) than are nonsmokers.

Differences between smokers and nonsmokers with respect to personality

and emotional tone have also been observed (Waal-Manning and de

Hammel, 1978; Haines et al., 1980; Frerichs et al., 1981). Fried and

Watkinson (1988) have reported that the home environments of smokers

are on average less conducive to optimal child development. These associations may confound the relationship between ETS exposure and child

development. 

Adjustment for potential confounders must be done carefully or

incomplete control may result. For example, Rantakallio (1983) discovered

that within each social class stratum used in her analysis, mothers who

smoked were more disadvantaged in terms of employment, family intactness, and health status than were nonsmoking mothers. Conversely, a

smoking effect may be concealed through adjustment for intervening variables. For example, adjusting for birthweight could obscure an effect attributable to smoking, if smoking exerts the effect through lowered birthweight. 

125

Developmental Toxicity II:

Postnatal Manifestations

4.1 INTRODUCTION

4.1.1 Confounding in Studies

of Child Development
The above-mentioned factors make it very difficult to examine the

association between ETS exposure and developmental outcomes in children.

Nevertheless, postnatal ETS exposure of the child may be an important or

even the most relevant route of exposure to tobacco smoke components for

some outcomes. Identifying an adverse outcome associated with exposure

to ETS could have significant implications for public health. Using data

from the 1988 National Health Interview Study, Overpeck and Moss (1991)

estimated that 49 percent of all U.S. children under 5 years of age are regularly exposed to tobacco smoke after birth by their mother or another member of their household. It is important to distinguish the effects of prenatal

and postnatal exposure to tobacco smoke components because approximately two-thirds of women who quit smoking while they are pregnant

restart after the birth of the child (Gillies et al., 1988). Identification of any

adverse developmental effects due solely to postnatal ETS exposure may

help motivate women who quit smoking during pregnancy to remain nonsmokers after their babies are born.

Sudden Infant Death Syndrome (SIDS) is generally defined

as the sudden death of any infant which is unexpected by

history and in which a thorough postmortem examination fails to demonstrate an adequate cause of death (Beckwith, 1970). The diagnosis of SIDS

is usually restricted to infants aged 1 month to 1 year, but investigators

sometimes expand the age-at-death criterion. In the United States and

other developed countries, SIDS is the most common cause of post-neonatal

death. Maternal risk factors that have been identified include young age,

high parity, low socioeconomic status, cigarette smoking, and illicit drug

use; risk factors in the infant include male sex, black or American Indian

race, prematurity, low birthweight, a history of recent illness, having a

“near-miss SIDS episode,” having a sibling who died of SIDS, not breast

feeding, and sleeping in the prone position; other risk factors include the

winter season (Kraus and Bulterys, 1991; Guntheroth and Spiers, 1992). 

Active maternal smoking during pregnancy has been

consistently found to be a significant risk factor for SIDS

with odds ratios (for any versus no maternal smoking)

ranging from 1.6 to 4.4. Many studies, particularly the

earlier ones, did not adequately control for potential confounders (Steele

and Langworth, 1966; Schrauzer et al., 1975; Naeye et al., 1976; Bergman

and Wiesner, 1976; Lewak et al., 1979); others had problems with potential

selection bias (Bergman and Wiesner, 1976) or incomplete assessment of

maternal smoking status (Rintahaka and Hirvonen, 1986). However, there

have been two case-control studies (Hoffman et al., 1987 and 1988; Mitchell

et al., 1991 and 1992) and two population-based cohort studies (Malloy et

al., 1988; Haglund and Cnattingius, 1990) that have been large and reasonably well controlled, adjusting for at least maternal age, parity, race, and

socioeconomic status or maternal educational level. In these studies, maternal smoking during pregnancy remained a significant independent risk factor for SIDS with adjusted ORs ranging from 1.8 to 2.5. The effect of maternal smoking on risk of SIDS is independent of birthweight, as demonstrated

by Hoffman et al. (1987), Malloy et al. (1988), Kraus et al. (1989), Wierenga

126

Smoking and Tobacco Control Monograph No. 10

4.2 SUDDEN INFANT

DEATH SYNDROME

4.2.1 Overview of

Human Studies of SIDS

and Maternal Smoking

During Pregnancy
127

Chapter 4

et al. (1990), and Li and Daling (1991). Some investigators have suggested

that the residual effect of maternal smoking during pregnancy after adjusting for birthweight could represent an effect of postnatal ETS exposure to

the child (Kraus et al., 1989; Dwyer and Ponsonby, 1992). 

Several investigators (Steele and Langworth, 1966; Naeye et al.,

1976; Kraus et al., 1989; Bulterys et al., 1990; Haglund and Cnattingius,

1990; Malloy et al., 1992) have noted an increase in SIDS risk with increasing levels of maternal smoking during pregnancy. The exception (a reanalysis of the Hoffman case-control study described in Malloy et al. (1992))

had used maternal smoking during the first trimester as its measure of

exposure. It may be that the risk of SIDS associated with maternal active

smoking varies depending on the timing and duration of exposure. 

No studies were found that specifically examined the

relationship of ETS exposure of the mother during pregnancy to the subsequent risk of SIDS in the infant. 

Ten studies were found that examined the relationship

between SIDS and postnatal ETS exposure (Table 4.1).

Some of these studies were reviewed by the U.S.

Environmental Protection Agency (1992).

Bergman and Wiesner (1976) Bergman and Wiesner (1976) conducted a small casecontrol study of SIDS in King County, Washington. Cases and controls

were matched on date of birth, sex, and race; there was no adjustment for

other co-variates. Exposure was ascertained retrospectively by a mailed

questionnaire. The study’s case participation rate was poor (56 of 100 identified cases versus 86 of 100 identified controls) with non-responding mothers more likely to be young and to live in poor neighborhoods. This probably led to an underestimation of the proportion of smokers among the

cases. The authors ascertained the level of maternal smoking both during

and after pregnancy and the level of paternal smoking (timing unspecified). They found an overall crude OR for any maternal smoking during

pregnancy of 2.2 (95% CI = 1.0-4.5), and for any maternal smoking after

pregnancy of 2.4 (95% CI = 1.2-4.8). There was a large degree of overlap

between the “smoking during” and “smoking after” groups: of the smoking

mothers, the mothers of only one case and four controls did not smoke

both during and after pregnancy. The effect of maternal smoking after

pregnancy was independent of level of maternal education, but was present

only among mothers <25 years old. Among the infants of these young

mothers, there was evidence of a dose-response effect, with ORs of 3.8 (95%

CI = 1.2-11.8) and 7.7 (95% CI = 1.4-52.4) for <20 cigarettes and >20 cigarettes per day, respectively. Paternal smoking had an OR of 1.5 (95% CI =

0.7-3.2). Maternal smoking was not controlled for in the analysis of paternal smoking. 

McGlashan (1989) McGlashan (1989) conducted a case-control study of virtually all

unexplained infant deaths in Tasmania from 1980 to 1986. Parents of the

167 cases were interviewed as part of routine grief counseling by public

health nurses. Two controls were matched to each case by date of birth and

4.2.2 Human Studies of

SIDS and ETS Exposure

4.2.2.1 ETS Exposure of the

Mother During Pregnancy

4.2.2.2 Postnatal ETS

Exposure
128

Comments Matched on ticipation. Vsmoked in pafterwards. Matched on ORs were capresented rethat were difwho smoked afterwards. Controlled fosocial factorand sleeping response noVirtually all mpregnancy aMatched for Controlled foEffect of PS increased. 

Odds Ratio(95% CI)2.2 (1.0-4.5)2.4 (1.2-4.8)1.5 (0.7-3.2)1.9 (1.2-2.9)1.9 (1.2-2.9)"significantly 

increased"

2.7 (crude)3.0 (crude)1.8 (1.0-3.3; adj)2.1 (1.5-3.1)1.6 (1.1-2.4)

Exposure Group1• Any vs. no MS 

during pregnancy

* Any vs. no MS after

pregnancy

* Any vs. no PS• Any vs. no MS 

during pregnancy

* Any vs. no MS in 

child's first year

* Any vs. no PS• Any vs. no MS 

during pregnancy (from medical records)

* Any vs. no recent MS 

(from interview)

• Any vs. no MS 

during pregnancy 

* Any vs. no PS 

Study Size56 cases,86 controls167 cases,334 controls128 cases,503 controls (subset of Mitchellet al. (1993))

242 cases,251 controls

Authors (year)LocationBergman & Wiesner(1976)United States (King County,Washington)McGlashan (1989)TasmaniaMitchell et al. (1991)New ZealandNicholl & O'Cathain(1992) United Kingdom 

Table 4.1Sudden Infant Death Syndrome (SIDS) Studies that Assessed some Source of Postnatal ETS 

Exposure Group Comparison
129

CommentsRestricted to ≥2,500 g. Ceducation, ain "during anheavier smo"after only" cThe first 3 Oseason, breing; mother’and smoking age, sex, biing position; smoking by other house

Odds Ratio(95% CI)

White Black

3.1 3.1

(2.3-4.2) (2.2-4.3)

1.8 2.3

(1.0-3.0) (1.5-3.7)

1.4 0.9

(1.0-1.9) (0.7-1.3)

1.7 (1.2-2.3)1.4 (1.0-1.8)1.2 (0.8-1.6)

No PS PS

1.0 1.0

(ref) (0.6-1.6)

2.6 4.4

(1.7-3.8) (3.3-6.0)

3.4 7.4

(2.0-5.8) (4.9-11.1)

Exposure Group1• Any vs. no MS during

and after pregnancy

* Any vs. no MS after

pregnancy only

* Other household 

smokers (vs. no otherhousehold smokers)

* Any vs. no recent

MS 

* Any vs. no PS* Any vs. no other

household smokers

* MS cigs/day:

0

1-19

≥20

Study Size435 cases,6,000 controls485 cases,1,800 controls

Authors (year)LocationSchoendorf & Kiely(1992)United States(U.S. National Maternaland Infant HealthSurvey)Mitchell et al. (1993)New Zealand 1 Abbreviations: MS-maternal smoking; PS-paternal smoking; asterisk (*) denotes proxy measurement for ET

bullet (•) denotes non-ETS exposure.

Table 4.1 (Continued)

Exposure Group Comparison
130

Odds Ratio (95% CI) Unadjusted Adjusted 3.1 (1.8-5.6) 2.3 (1.0-5.0) 6.2 (2.6-14.6) 4.6 (1.8-11.8) 3.5 (2.0-6.3) 3.5 (2.0-6.3) 9.2 (3.7-23.2) 8.5 (3.3-21.6) 3.8 (2.3-6.4) 3.5 (1.8-6.8) 6.2 (3.3-11.7) 5.0 (2.4-11.0) 3.1 (1.8-5.5) 3.0 (1.5-6.0)5.2 (2.5-10.7) 5.3 (1.9-14.5)8.1 (1.5-44.5) 5.1 (0.7-36.6)2.3 (1.1-4.7) 2.4 (1.1-5.4)3.5 (1.7-7.1) 3.6 (1.5-8.8)12.6 (4.3-37.1) 22.7 (4.8-107.2)

Exposure Group1,2* Any MS* Any same-room MS* Any PS* Any same-room PS* Any household smoking* Any same-room 

household smoking

Total number of household smokers:

123

Total cig exposure/day:

1-10

11-20

≥21

Study Size200 cases,200 controls

Authors (year)LocationKlonoff-Cohen et al. 

(1995)United States(Southern California)

Table 4.1 (Continued)

Exposure Group Comparison
131

CommentMatching bis adjusted status, SEand alcohoing positio

Odds Ratio(95% CI)2.5 (1.5-4.2)3.4 (2.0-5.9)1.02.5 (1.3-4.7)4.0 (2.4-6.6)7.6 (4.0-14.3)

Exposure Group1* Any vs. no PS * PS/no MS vs. 

no PS or MS 

* Household cigs/day:

0

1-19

20-39

≥40

Study Size195 cases,780 controls

Authors (year)LocationBlair et al. (1996)

United Kingdom 

1 Abbreviations: MS-maternal smoking; PS-paternal smoking; asterisk (*) denotes proxy measurement for 

bullet (•) denotes non-ETS exposure.

2 All odds ratios are for postnatal exposure and are relative to infants with no smoke exposure.

Table 4.1 (Continued)

Exposure Group Comparison
sex. Parents of controls were interviewed much later after pregnancy than

were parents of cases, introducing a potential source of recall bias. The levels of maternal smoking during pregnancy and throughout the baby’s first

year of life, as well as levels of paternal smoking, were ascertained. As in

the Bergman and Wiesner (1976) study, there was virtually complete overlap between the women who smoked during pregnancy and who smoked

during the infants’ first year of life, with ORs for both forms of maternal

smoking of 1.9 (95% CI = 1.2-2.9). No clear dose-response relationship was

seen. The author also stated that cases were significantly more likely than

controls to have a father who smoked, or to have either a mother or father

who smoked, but the actual data were not presented. There was no adjustment for co-variates. 

Mitchell et al. (1991) Results from the first year of a 3-year case-control study of SIDS

in New Zealand were reported in Mitchell et al. (1991). The interim report

included 128 SIDS cases and 503 controls. Cases were well-defined and

study participation was over 80 percent. Information regarding all major

risk factors for SIDS except for maternal illicit drug use was either obtained

through an interview with the parents (conducted on average one month

after the death of the case infant) or abstracted from medical records.

Maternal smoking status was assessed two ways: as a yes/no variable

abstracted from the obstetric record and as the average number of cigarettes

smoked per day in the two weeks prior to interview. Neither of these

approaches are ideal—the first method would underestimate exposure if a

smoking history was not consistently obtained, and the second method

might overestimate smoking among mothers of cases if they were smoking

more due to the stress of recently losing a baby. Nevertheless, both methods resulted in very similar crude ORs of 2.7 and 3.0, respectively. In a

multivariate analysis incorporating most known risk factors for SIDS except

maternal smoking during pregnancy, any maternal smoking in the 2 weeks

prior to interview had an OR of 1.8 (95% CI = 1.0-3.3). There was no data

presented regarding smoking by the father or other family members. 

Nicholl and O’Cathain (1992) Nicholl and O’Cathain (1992) conducted a study of 242

SIDS cases and 251 controls drawn from a larger study of post-neonatal

mortality in the United Kingdom. The authors calculated independent

risks of SIDS for maternal smoking during pregnancy and for smoking by

the mother’s partner. Smoking by the partner was associated with an OR of

1.6 (95% CI = 1.1-2.4) whereas smoking (during pregnancy) by the mother

was 2.1 (95% CI = 1.5-3.1). This analysis controlled for spousal smoking

but did not control for any other potential confounders. In the subset of

infants whose fathers smoked and whose mothers were nonsmokers, the

OR for paternal smoking was 1.4 (95% CI = 0.8-2.4). The researchers did

not ascertain maternal smoking status after pregnancy, nor did they distinguish partner’s smoking level during and after the pregnancy. In a secondary analysis, the infants were divided into four subgroups by age at death of

the case-infant. As the infants’ ages increased, the independent ORs associated with partners’ smoking increased, from 1.5 at <8 weeks to 2.6 at >24

weeks. Conversely, the ORs associated with maternal smoking decreased

(from 4.0 to 1.4) as infants’ ages increased (confidence intervals were not

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Smoking and Tobacco Control Monograph No. 10
given). The authors suggested that this pattern implies that prenatal exposure to maternal active smoking components may be more important for

younger infants, and postnatal ETS exposure more important for older

infants. Their finding that maternal smoking was less important than partner’s smoking in infants >24 weeks of age is problematic, since most mothers who smoked during pregnancy presumably also exposed their infants to

ETS by continuing to smoke after delivery. However, the numbers in each

age category were small and the point estimates are probably imprecise. 

Schoendorf and Kiely (1992) The first study to independently examine maternal

smoking during and after pregnancy was published by Schoendorf and

Kiely (1992). They performed a case-control analysis of data from the 1988

National Maternal and Infant Health Survey. Within this dataset, 201 black

and 234 white autopsied SIDS cases were identified from death certificates;

approximately 3,000 controls for each race were used. The analysis was

restricted to infants weighing >2,500 grams at birth. Mothers were questioned regarding their level of cigarette consumption during pregnancy and

at the time of interview, and from their responses categorized as nonsmokers, smokers after pregnancy only, or smokers during and after pregnancy.

After adjustment for maternal age, education, and marital status, maternal

smoking only after pregnancy had an OR of 1.8 (95% CI = 1.0-3.0) for

whites and 2.3 (95% CI = 1.5-3.7) for blacks. The risk of SIDS among

infants of women who smoked both during and after pregnancy was 3.1

(95% CI = 2.3-4.2) and 3.1 (95% CI = 2.2-4.3) for whites and blacks respectively. The ORs for “passive” (postnatal) and “combined” (pre- and postnatal) exposure were not directly comparable, as mothers who smoked during

and after pregnancy tended to smoke more cigarettes per day than mothers

who smoked only after pregnancy. The authors also examined the risk of

SIDS in relation to the presence of other smokers in the household. In

whites, household smoking was significantly associated with SIDS (OR =

1.4, 95% CI = 1.0-1.9), but no relationship was seen in blacks (OR = 0.9,

95% CI = 0.7-1.3). This latter analysis controlled for mother’s smoking status only. 

Mitchell et al. (1993) Final results from the New Zealand case-control study were published in Mitchell et al. (1993). The study’s catchment area covered 78 percent of all live births in New Zealand during the 3-year study period. Four

hundred eighty-five SIDS cases were compared to 1,800 controls. Case

infants were much more likely than were control infants to have mothers

who had smoked in the 2 weeks prior to interview (OR = 4.1, 95% CI = 3.3-

5.1). The OR decreased to 1.7 (95% CI = 1.2-2.3) but was still significant at

the p = 0.05 level after adjusting for region, season, breastfeeding, and bed

sharing; mother’s marital status, socioeconomic status, age, and smoking

during pregnancy; infant’s age, sex, birthweight, race, and sleeping position; and smoking by the father and other household members. Although

results were adjusted for maternal smoking during pregnancy, less than 10

percent of the mothers changed their smoking behavior through pregnancy

and the first year of the infant’s life. There was a strong dose-response relationship observed between amount smoked by the mother and risk of SIDS

(these ORs were not adjusted for any co-variates). The researchers also

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Chapter 4
found a significant relationship between recent paternal smoking and SIDS,

with a crude OR of 2.4 (95% CI = 1.9-3.0) and an adjusted OR of 1.4 (95%

CI = 1.0-1.8; adjusted for maternal smoking as well as the other co-variates

listed previously). They did not see a dose-response relationship for paternal smoking. Among infants whose mothers did not smoke (131 cases and

1,081 controls), there appeared to be no difference in SIDS risk between

infants whose fathers smoked and those with non-smoking fathers (OR =

1.0, 95% CI = 0.6-1.6). However, having a smoking father appeared to substantially increase the risk of SIDS among infants whose mothers smoked.

The authors speculated that non-smoking mothers may be more likely than

smoking mothers to insist that fathers smoke away from the child. 

Mitchell et al. also looked at the relationship between the number

of smokers in the household and the risk of SIDS. Having any other smokers in the household—excluding the parents—resulted in a crude OR of 1.5

(95% CI = 1.2-2.0) and an adjusted OR of 1.2 (95% CI = 0.8-1.6). When

parents were included, there was a strong dose-response relationship

between the number of household smokers and the risk of SIDS.

Milerad et al. (1994) Milerad et al. (1994) published a small case-report study of

autopsied SIDS cases. Sixteen consecutive cases with no other positive histological or other findings at post-mortem had pericardial fluid tested for

cotinine, a nicotine metabolite often used to quantify exposure to tobacco

smoke. Nine of the 16 (56.3 percent) cases had pericardial cotinine levels

indicative of moderate to heavy ETS exposure (cotinine 2.2-156.9 ng/ml).

Swedish national surveys report that 18 percent of Swedish women smoke

after having a baby, thus more of the autopsied SIDS cases were exposed

than would be expected using national data. This small descriptive study

has a number of limitations, including the lack of information on the actual smoking practices of the SIDS cases’ family members, and the lack of

controls. However, to date this is the only study to look at a biomarker of

tobacco exposure in SIDS. 

Mitchell et al. (1995) Mitchell et al. (1995) describes a follow-up study to the New

Zealand case-control SIDS study (Mitchell et al., 1991) designed to examine

the risk of maternal smoking by considering where the smoking took place.

As location of smoking had not been determined in the original interview,

a questionnaire was mailed to all participants. Mothers who smoked were

asked whether they had usually, sometimes, or never smoked in various

parts of their home. Non-Europeans had a poor response rate and were

excluded. Of the European participants, 60.3 percent of the case parents

and 76.9 percent of the control parents responded. Non-respondents were

more likely than respondents to be smokers, younger, and of a lower occupational group. There was no discernible pattern in risk between locations

or between smoking frequency, with ORs associated with maternal smoking

ranging from 1.7 to 3.0. Mothers who smoked but claimed they never did

so in the house had a higher risk of SIDS (OR = 5.1; 95% CI = 1.5-15.4) than

did mothers who smoked in the house (OR = 2.2; 95% CI = 1.4-3.5), but the

number of women in the group who never smoked in the house was very

small (n = 18). There was no control for potential confounders. The

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Smoking and Tobacco Control Monograph No. 10
authors felt that the increased risk even among women who did not smoke

in the home suggested that risk was primarily from in utero exposure.

However, this conclusion was driven by a very small group of women, and

there was no accounting for the smoking habits of other family members.

The authors themselves cautioned that there may be societal pressures for

smokers to report not smoking in the home; also, in previous analyses of

their own data, they saw an effect of paternal smoking. Thus, they stated

that their results should not be interpreted to mean that ETS exposure after

birth is not important. 

Haglund et al. (1995) Although the study by Haglund et al. (1995) did not measure

postnatal ETS exposure, it is included here because the authors felt it had

implications for the issue of pre- versus postnatal exposure. The authors

linked the Swedish death register to the Medical Birth Register to create a

cohort of over 800,000 infants, of whom 749 died of SIDS. Maternal smoking (yes/no) at the first prenatal visit was included in the birth registry. The

authors found that the winter season and maternal smoking were both

independent risk factors for SIDS, but that the excess risk due to smoking

did not vary by season (i.e., risks for the winter season and smoking were

simply additive). The excess relative risk of smoking was approximately 3.5

for early SIDS deaths (7-90 days) and 2.5 for late SIDS deaths (91-364 days).

They speculated that exposure to ETS would be likely to vary by season,

and thus stated that “possibly the effect of smoking is prenatal rather than

the result of passive smoking after birth.” They did not have any direct

information about the infants’ exposure to tobacco smoke after birth, nor

did they present any evidence that ETS exposure would vary significantly

by season. 

Klonoff-Cohen et al. (1995) Klonoff-Cohen et al. (1995) conducted a large case-control

study (200 SIDS cases and 200 controls) that had the most extensive assessment of exposure to tobacco smoke of any SIDS study to date. The investigators assessed quantitatively the amount smoked by the mother during

each trimester of pregnancy and after birth, by the father during and after

pregnancy, and by other live-in adults and day-care providers;they also

assessed the proximity of these individuals to the infant as they smoked.

They also inquired about smoking and breastfeeding practices. Results were

adjusted for several potential confounders including maternal smoking during pregnancy, birthweight, sleep position, breastfeeding, and medical conditions. Every measure of ETS exposure was associated with increased SIDS

risk. The adjusted OR for postnatal maternal smoking was 2.3 (95% CI =

1.0-5.0). Paternal smoking had an adjusted OR of 3.5 (95% CI = 1.9-6.3).

Although the OR for paternal smoking was higher than the OR for maternal

smoking, the high correlation between maternal smoking during and after

pregnancy probably resulted in an underestimate of the effect of maternal

smoking after pregnancy when adjusting for smoking during pregnancy.

Increased risk was also seen with increasing number of household smokers

and with total cigarette exposure per day (see Table 4.1). Furthermore, the

risk associated with smoking increased when the comparison was restricted

to smoking in the same room as the infant. For example, the adjusted OR

for postnatal maternal smoking increased from 2.3 to 4.6 (95% CI = 1.8-

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Chapter 4
11.8) when restricted to same-room exposure. Similarly, the adjusted OR

for any household smoking increased from 3.5 (95% CI = 1.8-6.8) to 5.0

(95% CI = 2.4-11.0). The authors concluded, “These data suggest that exposure to tobacco smoke after birth, after adjusting for prior fetal exposure, is

associated with an increased risk of SIDS.” 

Klonoff-Cohen et al. also examined the interaction between breastfeeding and maternal smoking. As expected, breastfeeding was protective

for SIDS among nonsmokers (adjusted OR = 0.4, 95% CI = 0.2-0.8). No protective effect of breastfeeding was seen among the smokers, although there

were only 22 women who both smoked and breastfed their infants (adjusted OR = 1.4, 95% CI = 0.2-12.0). 

Blair et al. (1996) A recently published case-control study by Blair et al. (1996) corroborated the findings of Klonoff-Cohen et al. The study documented significant, dose-related increases in SIDS risk for the three main measures of

household smoke that were examined: the number of smokers in the

household, the hours of smoke exposure to the infant daily, and the number of cigarettes smoked daily in the household. The latter variable yielded

results quite similar to those of Klonoff-Cohen et al., with ORs for 1-19, 20-

39, and ≥40 cigarettes per day of 2.5, 4.0, and 7.6, respectively. They also

demonstrated elevated risk in families where the mother was a nonsmoker

and either the father (OR = 3.4, 95% CI = 2.0-5.9) or another family member (OR not given but p = 0.007) smoked. These analyses were unadjusted

for potential confounders. In a multivariate analysis that controlled for

sleep position, breast feeding, socioeconomic status indicators, maternal

smoking, and other factors, paternal smoking remained an independent risk

factor (OR = 2.5, 95% CI = 1.5-4.2). The authors calculated that the population-attributable risk for SIDS associated with smoking by at least one parent was 61 percent (this included the effect of smoking by the mother during pregnancy). An interesting feature of this study was that it was conducted in England after the 1991 “Back to Sleep” campaign. This campaign, which sought to reduce the prevalence of risk factors for SIDS, particularly putting infants to sleep in the prone position, had been associated

with a fall in the incidence of SIDS in the United Kingdom (Wigfield and

Fleming, 1995).

There is no established animal model for SIDS. However,

Slotkin et al. (1995) proposed a rat model for SIDS based

upon changes in neurochemical function and increased

hypoxia-induced mortality of rat pups prenatally exposed to nicotine.

According to the model, prenatal exposure to nicotine causes lasting neurochemical changes, which in turn place an infant at greater risk for cardiorespiratory failure during neonatal apneic episodes. A direct link between

specific nicotine-induced neurochemical changes and the observed increase

in hypoxia-induced mortality has not yet been established. However, in

other studies (Milerad et al., 1995), nicotine was found to attenuate the

ventilatory response to hypoxia in neonatal lambs, suggesting that neurochemical effects of nicotine could alter either the sensitivity of the carotid

body to carbon dioxide or the central processing of chemo-receptor input

in the brain.

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4.2.3 Animal Studies

of SIDS and Tobacco

Smoke Exposure
Existing data indicate a causal relationship between maternal

smoking in general and risk of SIDS. Numerous studies have

consistently found maternal smoking to be a significant predictor of SIDS,

with ORs from well-controlled studies ranging from 1.8 to 3.1. A metaanalysis performed by DiFranza and Lew (1995) on studies of SIDS among

offspring of women who smoked and who did not smoke during pregnancy

(regardless of smoking status after pregnancy) found a pooled OR of 2.98

(95% CI = 2.51-3.54). Several investigators (but not all) have found clear

dose-response relationships between the number of cigarettes smoked per

day during pregnancy and SIDS risk. Although the etiology of SIDS is not

fully understood, a favored current hypothesis is that chronic fetal hypoxia

impairs development of the fetal central nervous system, leading to abnormal control of cardio-respiratory activity (Harper and Frysinger, 1988).

Maternal smoking during pregnancy promotes fetal hypoxia through placental insufficiency or by increasing the concentrations of carbon monoxide and carboxyhemoglobin in the fetus (U.S. DHHS, 1980). In support of

this hypothesis is the finding by Bulterys et al. (1990) that low hematocrit

during pregnancy becomes an important predictor of SIDS as the level of

maternal smoking increases. Exposure to nicotine may also alter an infant’s

catecholamine metabolism and response to hypoxia (Milerad and Sundell,

1993), an effect recently demonstrated in rats (Slotkin et al., 1995).

Ten epidemiologic studies have attempted to specifically examine

the relationship between ETS exposure and SIDS. These studies have looked

at smoking by the mother after pregnancy, paternal smoking, household

smoking, and smoking during different seasons. In three studies that

looked at maternal postnatal smoking (Bergman and Wiesner, 1976;

McGlashan, 1989; Mitchell et al., 1991), extensive overlapping between

women smoking during and after pregnancy precluded any attempt to

identify an independent relationship to ETS exposure. Haglund et al.

(1995) speculated that because the risk associated with maternal smoking

did not rise in the winter, when indoor ventilation might be poorer, prenatal tobacco exposure might be more important than postnatal exposure.

They did not, however, measure postnatal maternal smoking, nor did they

provide evidence that ETS exposure is greater in the winter. In Mitchell et

al. (1993), a significant association between postnatal maternal smoking

and SIDS remained after adjustment for smoking during pregnancy and

other co-variates. However, the number of smokers who had not smoked

during pregnancy was very small. Mitchell et al. later attempted to refine

their assessment of maternal smoking by reinterviewing their subjects about

location of smoking (Mitchell et al. 1995). Although the authors interpreted their finding that never smoking inside the home did not reduce the risk

of SIDS as implying that prenatal exposure is more important than postnatal exposure, the numbers in this group were very small. In addition, they

did not link location of smoking to the location of the infant. Schoendorf

and Kiely (1992) took advantage of the recent trend for women who are

smokers to quit smoking during pregnancy by comparing infants of women

who smoked primarily only after pregnancy with infants of non-smoking

mothers. Their adjusted OR (1.8) was quite similar to the adjusted OR (1.7)

calculated by Mitchell et al. (1993). Bulterys (1993) pointed out that most

137

Chapter 4

4.2.4 Discussion

and Conclusions
of the women who smoked “after pregnancy only” also smoked during the

first few weeks of pregnancy; thus, it was possible, though not likely, that

the increased risk was due to ETS exposure or to maternal active smoking

early in pregnancy. Klonoff-Cohen et al. (1995), in a fairly large study with

detailed exposure assessment and good control of potential confounding,

reported an adjusted OR for postnatal maternal smoking of 2.3. This value

is also consistent with the ORs seen in Mitchell et al. (1993) and Schoendorf

and Kiely (1992). In addition, Klonoff-Cohen et al. (1995) found that the

risk associated with maternal smoking increased when the exposed group

was restricted to those women who smoked in the same room as their

infant, implying that more concentrated exposure increased risk.

Six papers examined the association between paternal smoking and

SIDS. Two (Bergman and Wiesner, 1976; McGlashan, 1989) found that

crude ORs for paternal smoking were slightly elevated, but no adjustment

for maternal smoking had been made. The third paper to examine paternal

smoking (Nicholl and O’Cathain, 1992) found a significantly elevated risk

of SIDS independent of maternal smoking. The risk associated with paternal smoking increased with the age of the infant, suggesting that passive

exposure of the infant was important. They also found an increased risk of

SIDS in families where the father but not the mother smoked, although the

confidence interval included unity (OR = 1.4, 95% CI = 0.8-2.4). Lack of

control for potential confounders somewhat reduces confidence in their

findings. Mitchell et al. (1993) looked extensively at smoking among

fathers. Overall, paternal smoking remained associated with SIDS even after

controlling for maternal smoking and a number of other co-variates.

However, the risk did not vary with the amount smoked by the father, and

in families where the mother did not smoke, the presence of a smoking

father did not appear to increase SIDS risk. The authors presented a plausible explanation for this pattern of results, namely that in families where the

mother does not smoke, the father may be less likely to smoke near the

infant; however, this speculation remains to be confirmed. Klonoff-Cohen

et al. (1995) found an increased risk of SIDS associated with paternal smoking independent of maternal smoking. Their OR (3.5) was somewhat higher than Nicholl and O’Cathain and Mitchell et al. (1.6 and 1.4 respectively),

but this difference could have been due to differences in the time fathers

spent with their children. Klonoff-Cohen et al. found some evidence of a

dose-response in that the risk increased substantially when the analysis was

restricted to those fathers who smoked in the same room as their infant.

Blair et al. (1996) was able to demonstrate significantly increased SIDS risk

in families where the father smoked but the mother was a nonsmoker (OR

= 3.4, compared to families were neither parent smoked). In a fully adjusted model, any paternal smoking conferred an OR of 2.5, which was

between the ORs reported by Mitchell et al. and Klonoff-Cohen et al.

Four studies looked at household smoke exposure and SIDS.

Schoendorf and Kiely (1992) found that among white infants there was an

increased risk of SIDS associated with the presence of smokers other than

the mother in the household; no such association was seen among black

infants. With the information available to them, Schoendorf and Kiely

(1992) were not able to explain why no association was seen among blacks.

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Smoking and Tobacco Control Monograph No. 10
Mitchell et al. (1993) found a dose-response relationship (unadjusted)

between the number of smokers in a household and the risk of SIDS. The

adjusted OR for the presence of any smokers other than the parents in the

household was small (1.2) and the confidence interval included unity.

These non-parental smokers might have spent less time with the infant,

however. Klonoff-Cohen et al. (1995) looked extensively at household

smoke exposure, measuring it as total number of household smokers, and

as total cigarette exposure per day. A dose-response relationship between

ETS and SIDS was seen with both these measures: adjusted ORs for 1-10, 11-

20, and >21 cigarettes/day were 2.4, 3.6, and 22.7, respectively. Blair et al.

(1996) found very similar dose-related risks for household cigarette exposure, although their results were unadjusted for possible confounding.

One study in Sweden, Milerad et al. (1994), examined cotinine levels in the pericardial fluid of a small number of consecutively autopsied

SIDS cases. They found cotinine levels indicating ETS exposure in over half

of the cases, a proportion approximately three times higher than would be

expected given the percentage of Swedish women who report smoking postnatally. Although limited, this study provides further corroboration of the

association between ETS and SIDS seen in other studies. 

There is some evidence that suggests a relationship between ETS and

SIDS is biologically plausible. Hoppenbrouwers et al. (1981) found an association between air pollution levels and incidence of SIDS, suggesting that

airborne contaminants may play a role in the etiology of SIDS. Since tobacco smoke is a major contributor to indoor air pollution, ETS could influence

SIDS risk through mechanisms similar to those of other air pollutants. ETS

may impair respiratory control through chronic carbon monoxide (Watkins

and Strope, 1986) and nicotine exposure (Milerad and Sundell, 1993), and

ETS can directly affect lung function (U.S. DHHS, 1986). Finally, exposure

to ETS increases the likelihood of respiratory tract infections in infants (as

discussed in the chapter Respiratory Health Effects) which in turn may

increase the risk of SIDS. These hypotheses remain to be confirmed.

In conclusion, the strength of the Klonoff-Cohen et al. and Blair et

al. studies, their consistency with two earlier well-conducted studies

(Mitchell et al., 1993; and Schoendorf and Kiely, 1992), and the identification of dose-response relationships provide sufficient evidence that postnatal ETS exposure of the child is an independent risk factor for SIDS. 

In a large epidemiological study that addressed several

potential confounders (Klonoff-Cohen et al., 1995), an OR

of 3.5 (1.8-6.8) was found for ETS exposure resulting from any household

smoking. Pierce et al. (1994) estimated that, in 1993, 17.3 percent of children under the age of five were exposed to ETS in California households.

Following DiFranza and Lew (1996), from the proportion exposed to ETS (p)

and relative risk (R, which is approximated by the OR), the proportion of

cases attributable (a) to ETS exposure can be estimated:

a = p(R - 1) / (p(R - 1) + 1)

139

Chapter 4

4.2.4.1 Risk Attributable

to ETS Exposure
Thus, of the 398 cases of SIDS in California occurring in 1995, 30

percent—or 120 cases—may be attributed to ETS exposure. Nationally, 40-

55 percent of children may live in households with ETS exposure (Pirkle et

al., 1996; Overpeck and Moss, 1991; Greenberg et al., 1989), and 4,669 cases

of SIDS occurred in 1993 (U.S. Bureau of the Census, 1996). Thus, 50-58

percent of SIDS cases nationally (1,868-2,708 deaths in 1993) may be attributed to ETS exposure.

The determinants of cognitive ability and behavior in

children are extremely complex. A wide array of genetic, social, and environmental factors are thought to influence neuropsychological development, including parental intellectual and emotional makeup, socioeconomic status, nutritional status, quality of the home environment, number and spacing of siblings, birth order, sex, and maternal intake

of alcohol during pregnancy. Many of these factors do not act independently of each other, but instead create a web of influence that can be very

difficult to untangle. 

A number of epidemiological studies have examined the association between active maternal

smoking during pregnancy and cognition and

behavior in children. These have been reviewed

in Rush and Callahan (1989), Rush (1992), and

Tong and McMichael (1992). In the following

summary of the literature, studies of cognition in infants, pre-schoolers,

and older children are discussed, followed by a review of behavioral studies. 

Infant neuropsychological development is often assessed using the

Bayley Scales of Infant Development, an administered test that includes

mental, psychomotor, and behavioral components (Bayley, 1969). Garn et

al. (1980) examined the Bayley scores of over 43,500 infants enrolled in the

National Collaborative Perinatal Project and found that the proportion with

low mental and motor scores increased as maternal cigarette consumption

increased. The association was very small until maternal consumption

exceeded 20 cigarettes per day; there was no control for potential confounders. Streissguth et al. (1980) failed to find significant relationships

between maternal smoking (converted to a nicotine score) and Bayley

scores after adjusting for gestational age and maternal education, parity,

alcohol and caffeine intake. Whether non-significant relationships existed

could not be determined from the data presented. Gusella and Fried (1984)

found modest negative correlations between nicotine consumption and

psychomotor, verbal comprehension, and fine motor indices (the range of

Pearson correlation coefficients (r) was -0.11 to -0.22), controlling only for

father’s education. Only the relationship with verbal comprehension was

significant (exact p-values were not calculable from data presented). 

Fried and Watkinson (1988) studied a larger sample from the same

cohort studied by Gusella and Fried (1984), weighted so that children with

heavier exposure to prenatal tobacco and alcohol would be over-represented. They found that after adjustment for the quality of the home environment (assessed by the Home Observation for Measurement of the

140

Smoking and Tobacco Control Monograph No. 10

4.3 COGNITION AND

BEHAVIOR IN CHILDREN

4.3.1 Cognition and Behavior

in Children whose Mothers

Smoked During Pregnancy

4.3.1.1 Studies of Children whose

Mothers Smoked During Pregnancy
Environment (HOME) test), maternal alcohol use, and various demographic

factors, differences between 2-year-old children of smokers and nonsmokers

diminished to nearly nil (the HOME test measures a variety of characteristics of the home environment and maternal-child interaction and is strongly correlated with many measures of child development (Siegel, 1982)).

Thus, this study suggests that most, if not all, of the negative association

between maternal smoking during pregnancy and scores on the Bayley

exam can be explained by confounding by other variables. 

Two studies have evaluated pre-school children using the McCarthy

Scales of Children’s Abilities. The McCarthy is an administered test with

verbal, perceptual, quantitative, general cognitive, memory, and motor subscales, and is a good predictor of school performance (Kaufman and

Kaufman, 1977). Fried and Watkinson (1990) found negative correlations

between nicotine consumption during pregnancy and all subscales, particularly the verbal subscale (approximate 10 percent decrement among children of heavy smokers). These differences were adjusted for HOME score

only. The investigators also found comparable decreases in Peabody Picture

Vocabulary Test scores (a test of receptive vocabulary) and the expressive

language component of the Reynell Developmental Language Scales.

Sexton et al. (1990) compared children born to women who quit smoking

during pregnancy with children of persistent smokers. One-third of the

mothers were “quitters” and two-thirds of the mothers had smoked

throughout pregnancy. Children of persistent smokers had adjusted scores

that were 2 to 4 percent lower than scores of children of quitters; the effect

was most pronounced in the verbal and general cognitive indices. Control

variables included a variety of demographic factors, family characteristics,

maternal use of alcohol during pregnancy, maternal smoking after pregnancy, and the child’s birthweight, gestational age, and health status. Similar

results were seen using the Minnesota Child Development Inventory. Thus,

in both studies of pre-schoolers there was a pattern of decreased McCarthy

scores, especially in the verbal subscale. 

Conversely, two studies that used data from the Kaiser Permanente

Child Health and Development Studies, Bauman et al. (1991) and Eskenazi

and Trupin (1995), failed to find an association between smoking during

pregnancy and lowered scores on the Peabody Picture Vocabulary Test and

the Raven Colored Progressive Matrices Test. Bauman et al. defined smoking status using interview data, whereas Eskenazi and Trupin used serum

cotinine levels measured in mid-pregnancy. These studies were large (over

1,500 subjects) and well-controlled, including adjustment for postnatal

smoke exposure. 

The association between maternal smoking during pregnancy and

impairments of cognition and school achievement in older children are

generally consistent, although the decrements are small and not always statistically significant. A longitudinal study of 17,000 British children found

modest but statistically significant dose-related delays in reading, math, and

general ability at 7, 11, and 16 years, and a lower level of educational

attainment at age 23 (Davie et al., 1972; Butler and Goldstein, 1973;

Fogelman, 1980; Fogelman and Manor, 1988). The decrements were

141

Chapter 4
approximately halved after adjusting for a variety of demographic factors

and birthweight. In studies derived from the National Collaborative

Perinatal Project, Hardy and Mellits (1972) and Naeye and Peters (1984)

found adjusted decrements of two to four percent among children of smokers on the spelling and reading sections of the Wide Ranging Achievement

Test; Naeye and Peters (1984) also found an increasing effect with number

of cigarettes smoked. Nichols and Chen (1981) found a 25 percent

increased risk (unadjusted) of learning difficulties among children of heavy

smokers (>20 cigarettes per day). In their crude analysis, risk varied with

dose; however, the association between maternal smoking and learning difficulties diminished to non-significance in the final multivariate model. In

an uncontrolled analysis, Dunn et al. (1977) found that children of mothers

who smoked during pregnancy scored approximately 3 percent lower on

the Wechsler Intelligence Scale than did children of nonsmokers. 

None of these studies of older children controlled for maternal alcohol intake during pregnancy, parental intelligence, quality of the home

environment, or current smoking status of the child or family members. In

an attempt to control for unassessed genetic and environmental factors,

Naeye and Peters (1984) also conducted a sibling pair comparison, balanced

for birth order, in which the mother smoked during one pregnancy and not

the other. This study again found achievement test scores 2-5 percent

lower among children of smoking mothers. Changes in marital status or

outside employment did not explain the association. 

Behavioral problems such as hyperactivity have been inconsistently

reported in studies of children with prenatal exposure to maternal active

smoking. Dunn et al. (1977) found that male children of mothers who

smoked during pregnancy were judged by their teachers to have more problems with behavior, social development, and temperament (uncontrolled

analysis; proportions were not given). In their work with the large National

Collaborative Perinatal Project, Nichols and Chen (1981) found that schoolaged children of women who smoked more than 20 cigarettes per day during pregnancy had a 28 percent increased risk of hyperkinetic-impulsive

behavior. Naeye and Peters (1984) found that children’s attention span

decreased and level of activity increased as the number of cigarettes smoked

per day by the mother during pregnancy increased, even after adjustment

for demographic factors, gestational age, and breast feeding. Similar results

were found in the sibling pair comparison. 

The findings of Landesman-Dwyer et al. (1981) did not support an

association between maternal active smoking during pregnancy and hyperactive behavior. They scored 4-year-olds on a large number of behaviors

during a 3-hour observation period in the children’s homes. There were no

differences noted between children of smokers and children of nonsmokers

after adjustment for sex, birth order, maternal alcohol use, and HOME

score. However, smoking mothers rated their children as “intense”, “persistent”, and “willing to approach strangers” more often than did nonsmoking mothers. Similarly, in a large, well-controlled study, Eskenazi and

Trupin (1995) failed to find an association between smoking during pregnancy and “active” behavior as reported by the mother. Unlike the other

142

Smoking and Tobacco Control Monograph No. 10
studies, this study also adjusted for the child’s exposure to tobacco smoke

after birth. Thus, of all the studies described in this section, their results are

the only ones likely to represent the effect of prenatal exposure alone.

Three groups of investigators have used computer-controlled “vigilance tasks” to evaluate attention, impulsivity, and reaction time in children. Poor vigilance performance is related to childhood hyperactivity

(Porrino et al., 1983). Streissguth et al. (1984), controlling for birth order

and maternal education, nutrition, and caffeine and alcohol intake, found

that maternal nicotine consumption in pregnancy was significantly associated in a dose-related manner with poorer attention span. Kristjansson et

al. (1989) found that increased activity levels were more common in children of mothers who smoked during pregnancy, even after adjustment for

age, sex, income, maternal education, alcohol and marijuana use, and postnatal smoke exposure. In a larger sample drawn from the same cohort as

Kristjansson et al. (1989), Fried et al. (1992) found that vigilance parameters

reflecting impulsiveness and attention, as well as the McCarthy memory

subscale, significantly discriminated between children whose mothers were

non-, light, and heavy smokers in a discriminant function analysis.

Smoking mothers were also more likely to report impulsive and hyperactive

behavior in their children, but the difference was not significant (p > 0.10).

No adjustments for co-variates were made, as the authors stated that no

potentially confounding variables were associated with both smoking and

the outcome variables. 

Most studies of cognitive development demonstrated

small decrements, especially in language skills, in children whose mothers smoked during pregnancy. Where

data were presented to make the calculation possible,

differences associated with maternal smoking ranged from about 2 to 5 percent (Sexton et al., 1990; Hardy and Mellits, 1972; Naeye and Peters, 1984;

Rantakallio, 1983). In most studies that found an association, doseresponse relationships were also noted. Studies of infants tended not to

show effects after adjustment for co-variates, whereas studies of older children tended to show significant effects. The relative lack of association

seen in studies of infants may reflect the fact that studies of infants tended

to be better controlled than studies of older children. This hypothesis is

supported by the results of Baghurst et al. (1992), Bauman et al. (1991), and

Eskenazi and Trupin (1995), all well-controlled negative studies of older

children. Alternatively, effects of active maternal smoking during pregnancy may become more “measurable” as children mature, and their intellectual functions become more complex. 

Eight of ten studies of behavior and active maternal smoking during

pregnancy have shown increased activity level and decreased attention span

in children of smokers. Of the four studies with good control of potential

confounders (Landesman-Dwyer et al., 1981; Weitzman et al., 1992; Naeye

and Peters, 1984; Eskenazi and Trupin, 1995), Weitzman et al. (1992) and

Naeye and Peters (1984) found significant behavioral impairments in children of smokers. However, Weitzman’s outcome measure was based on

mothers’ reports, making it possible that the effect of smoking was due to

143

Chapter 4

4.3.1.2 Discussion of

Evidence from Studies in

Children whose Mothers

Smoked During Pregnancy
differences in mothers’ interpretations of their children’s behavior, rather

than differences in the actual behavior of the children. This possibility is

supported by Landesman-Dwyer et al. (1981) who reported no differences in

objective measures of children’s behavior related to maternal smoking during pregnancy, but found smoking-related differences in mothers’ assessments of their children’s behavior. 

It is biologically plausible that smoking during pregnancy could

eventually lead to neuropsychological deficits. One hypothesis is that

chronic hypoxia impairs fetal brain development. There are several mechanisms by which maternal smoking can make the fetus hypoxic. Maternal

smoking exposes the fetus to both nicotine and carbon monoxide.

Nicotine reduces uteroplacental blood flow and carbon monoxide produces

carboxyhemoglobin, both of which reduce oxygen delivery to fetal tissues

(Lehtovirta and Forss, 1978; Cole et al., 1972). Supporting this hypothesis

is the finding by Naeye and Peters (1984) that among children of smoking

mothers, those with behavioral abnormalities had had significantly higher

neonatal hemoglobin levels (a sign of chronic fetal hypoxia) than had children with normal behavior. Furthermore, nicotine has been shown to have

direct adverse effects on the developing brain (Lichtensteiger et al., 1988).

Although the few animal studies of exposure to mainstream or sidestream

smoke that have been reported do not provide supportive data, the large literature on the effects on animals of prenatal exposure to carbon monoxide

and nicotine do suggest that adverse impacts of these agents on postnatal

neurobehavior is biologically plausible.

In summary, there is some evidence from reasonably well-controlled

studies that maternal smoking during pregnancy is adversely associated

with measures of cognition and behavior in children. Dose-response relationships were demonstrated in several studies, and an adverse effect is biologically plausible. However, most of the studies that found significant relationships failed to control for smoke exposure after birth, thus it is difficult

to determine if the findings are truly related to smoking during pregnancy,

or are in fact related to smoking after pregnancy. Studies that did control

for postnatal smoke exposure tended to find no association between prenatal smoke exposure and cognition or behavior. Furthermore, smoking is

also known to be strongly associated with many social and environmental

characteristics that adversely influence neuropsychological development

(Overpeck and Moss, 1991; Fried and Watkinson, 1988). That fact, along

with the small size of the associations seen between maternal smoking and

neuropsychological outcomes, makes it particularly difficult to rule out the

possibility of a spurious effect due to undercontrolled confounding.

Two papers that addressed ETS exposure of the mother during pregnancy were identified.

Makin et al. (1991) administered an extensive neuropsychological test battery to children of women

who were active smokers, exposed to ETS, and not

exposed to ETS during pregnancy. Assessment of

exposure to ETS was prospective but imprecise, as it was ascertained by ask144

Smoking and Tobacco Control Monograph No. 10

4.3.2 Cognition and

Behavior in Children whose

Mothers were Exposed to

ETS During Pregnancy

Makin et al. (1991)
ing subjects during pregnancy “Are you regularly exposed to a smoke-filled

environment?” There were less than 35 children in each exposure group.

Measures of language, intelligence, and attention were outcomes that significantly distinguished non-exposed, ETS-exposed, and active-smoking mothers in a discriminant function analysis. Scores of children of ETS-exposed

mothers tended to fall between scores of children of non-exposed and

active-smoking mothers. No adjustment was made for potential confounders, as the authors stated that none were related to both tobacco

smoke exposure and outcome. 

Eskenazi and Trupin (1995) The Child Health and Development Studies were conducted from 1959 to 1967 among women and children who received their

health care at the Kaiser Permanente Medical Center of Oakland, California.

Pregnant women were interviewed and gave serum samples, which were

stored. The children of these pregnancies were administered various neurobehavioral tests at ages 5, 9-11, and 15-17 years. Eskenazi and Trupin

(1995) measured cotinine, a nicotine metabolite, in the stored serum samples and examined the results in relation to the 5-year neurobehavioral

scores. There were a total of 2,124 mother/child pairs included in this

analysis, of whom 1,348 were considered to have no tobacco exposure during pregnancy (nonsmokers with cotinine levels <2 ng/ml) and 68 were

classified as having ETS exposure during pregnancy (nonsmokers with cotinine levels from 2-10 ng/ml). The remainder were classified as either active

smoking during pregnancy only, active smoking after pregnancy only, or

active smoking during and after pregnancy. Forty-three women were

excluded because of cotinine levels that did not correspond to their selfreported smoking status. There have been some questions raised about the

validity of the definition of ETS exposure used in this study (see discussion

of Eskenazi et al., 1995 in Section 3.2.2.4). The neurobehavioral tests examined in this study included the Peabody Picture Vocabulary Test (PPVT), the

Raven Colored Progressive Matrices Test (tests of vocabulary and nonverbal

reasoning, respectively), and the child’s activity level as rated by the mother. Children whose mothers were exposed to ETS during pregnancy did not

have Raven or PPVT scores that differed significantly from the scores of

children with no smoking exposure, even after adjustment for race, birth

order, preschool attendance, parents’ education, socioeconomic status, and

other factors. The OR for “active” behavior among children whose mothers

were exposed to ETS during pregnancy was somewhat elevated (adjusted OR

= 1.5), but the confidence interval included unity (95% CI = 0.7-3.1). 

Of seven studies of neuropsychological development

that have assessed effects of some measure of postnatal ETS exposure, four focused on cognitive ability

and two focused on behavioral outcomes. One examined both. These

seven studies are reviewed below and summarized in Table 4-2.

Rantakallio (1983) conducted a nested exposure-control study within the Finnish Cohort Study. Women

who had smoked through the second month of pregnancy (n = 1,819) were matched on age, parity, marital

status, and residence to nonsmoking pregnant women. When their off145

Chapter 4

4.3.3 Cognition and

Behavior in Children

Exposed to ETS Postnatally

4.3.3.1 Studies of Cognition

and Postnatal ETS Exposure

Rantakallio (1983)
146

Smoking and Tobacco Control Monograph No. 10

spring were 14 years of age, information regarding the children’s health and

school performance and the fathers’ smoking status was obtained by a

mailed questionnaire. As an outcome measure Rantakallio devised a sixpoint score based on school performance in “theoretical subjects.” The

method by which this score was derived was not explained. The magnitude

of the association seen with maternal smoking during pregnancy was comparable to other studies of prenatal exposure, with an adjusted difference in

mean performance score between children of heavy smokers and nonsmokers of approximately 2.5 percent (this is an estimate from a figure, data were

not presented). In a regression analysis that included social class, family

size, maternal age and education, and sex of the child as co-variates, both

maternal and paternal smoking were significant predictors of the school

performance score. Paternal smoking was a slightly stronger predictor of

score (standardized coefficient = -0.068) than maternal smoking during

pregnancy (standardized coefficient = -0.049). It was unclear if paternal

smoking represented current smoking status or smoking at the time of the

pregnancy. The smoking status of the mother after the second month of

pregnancy, and the current smoking status of the child or other family

members were not ascertained. 

Bauman et al. (1989) Bauman and coworkers conducted two studies that looked at

current smoking by the parents and other family members. The first study

(Bauman et al., 1989) was a re-analysis of data collected in 1980 to investigate social and psychological determinants of smoking among eighthgraders in one North Carolina school district. The students had been interviewed regarding their own smoking behavior, and their mothers had been

given a questionnaire which ascertained the total number of cigarettes

smoked per day by all family members. Smoking status of the students and

mothers was validated by analysis of breath samples for carbon monoxide.

For this study, the analysis was restricted to the 973 students who denied

being smokers themselves and who had alveolar carbon monoxide levels of

<9 ppm. The students were later routinely administered the California

Achievement Test (CAT) by their school. In the crude analysis, scores for

the total battery and each of the four subtest scores (math, language, reading, and spelling) decreased as family smoking increased over four categories (zero, 1-19, 20-39, and >40 cigarettes per day). The differences by

smoking level were all statistically significant (p < 0.001). After adjustment

for eight co-variates, including age, sex, race, and parents’ educational level,

generally consistent inverse relationships between family smoking and test

scores remained. However, the associations between the math and reading

subscores were no longer significant at the p = 0.05 level. The magnitude of

difference in scores was not large. For example, the mean adjusted total

CAT score was 618.8 for children of nonsmoking families and 602.9 for

children in the heaviest family smoking category—a difference of about 3

percent of the range for these test scores. The language subscores also differed by approximately 3 percent, whereas the spelling subscores differed by

about 6 percent. There was no adjustment for maternal smoking status during pregnancy. 

Bauman et al. (1991) The second study (Bauman et al., 1991) was done using data

from the examinations of children at ages 5, 9-11, and 15-17 years (referred
147

Chapter 4

to as the 5, 10, and 16-year examinations) enrolled in the Kaiser

Permanente Child Health and Development Studies. This dataset allowed

the authors to control for maternal smoking during pregnancy, as well as a

number of other pertinent co-variates. Sample sizes for each of the examinations ranged from 2,020 (the 16-year exam) to 4,939 (the 5-year exam).

Parental smoking status was obtained by periodic interviews with the mothers, but fathers’ smoking had to be interpolated for the 5- and 16-year

examinations. Twelve to thirty percent of the children had missing parental

smoking information and were excluded from the analysis. Cognitive tests

performed at the 5-year exam included the Peabody Picture Vocabulary Test

(PPVT), the Raven Colored Progressive Matrices Test (a test of reasoning

ability), the Quick Test (another test of receptive vocabulary), and the

Goodenough-Harris Draw-A-Man test of intellectual maturity. Ten-year-olds

were administered the PPVT and Raven test, and the 16-year-olds were

administered the PPVT only. 

The authors first examined mean test scores by mother’s prenatal

smoking (yes/no) and current smoking (yes/no). For all Raven and PPVT

exams, mean scores were 3-10 percent lower in children of current smokers,

independent of maternal smoking status during pregnancy (p < 0.001).

Conversely, there was little difference in mean scores by prenatal smoking

status after stratification by current parental smoking (No difference by

smoking status was seen in the Quick Test or Draw-A-Man, and the authors

did not consider these tests further). The investigators then examined the

effect of current parental smoking after adjustment for multiple confounders, including mothers’ smoking during pregnancy, age, sex, race, low

birthweight, and parents’ education, occupation, and income. For the 16-

year exam, active smoking by the child was also included in the regression.

Again, current parental smoking had a negative effect on PPVT and Raven

scores whereas the mother’s smoking during pregnancy had a negligible

effect. 

The results were significant only at the 10-year examination, where

a 3-5 percent decrement in test scores was seen. The authors speculated

that the loss of significance at the 5- and 16-year exams may have been

related to their method of interpolating smoking status, which would have

biased results toward the null. The adjusted scores for the 10-year PPVT

and Raven examinations displayed a dose-response relationship over four

categories of parental smoking (p < 0.01 for linear trend).

Baghurst et al. (1992) Baghurst et al. (1992) conducted a longitudinal study that

examined maternal smoking during and after pregnancy. Their study

cohort had been assembled for the primary purpose of assessing the effect

of lead exposure upon cognition. Of the 723 infants enrolled in the study

at birth, 548 were still enrolled at the age of 4 years. Each child was administered the Bayley exam at age 2 and the McCarthy exam at age 4. One

hundred and sixty children had been exposed to prenatal maternal smoking, and 232 were exposed postnatally to ETS (most of these were also

exposed prenatally). In the crude analysis, both prenatal and postnatal

maternal smoking were associated with lower scores on all Bayley and

McCarthy subscales. The decrements in scores seen with postnatal smoking
148

CoMS pasizexNofirmagsoNo exUp paing Adweed(in Dosc

ResultsChange in score:-1.8%-2.5% ^^^ Inverse associationMean total score:618.8610.0606.8602.9 ^Score difference:

PPVT RAVEN-0.06 -0.14-1.55^^^ -0.89^-0.92

Exposure Group• MS during 

pregnancy:<10 cig/day vs. 0≥10 cig/day vs. 0

* Any vs. no PS* Cig/day smoked

by family:

0

1-19

20-39

>40

* Any vs. no parental

smoking at age:

5

1016

Outcome AssessmentSchool ability intheoretical subjectsCaliforniaAchievementTestPPVTRAVEN

Authors (year)LocationRantakallio (1983)FinlandBauman et al.

(1989)United States (North Carolina)Bauman 

et al. (1991)

United States(California)

Design (n)

Age at Follow-upProspective(1,763 prenatallyexposed, 1,781controls)14 year oldsProspective(973)8th gradersProspective(1,500-2,800)5,10,16 year olds

Tobacco Exposure Comparison1,2

Table 4.2Cognition in Children: Studies that Assessed some Source of Postnatal ETS Exposure
149

CoAdanpreca65caAdsoordothAdas 

ResultsScore difference:Bayley MDI -0.55McCarthy

GCI -0.45verbal -0.17perceptual -0.67quantitative -0.21

Mean score:PPVT RAVEN50.7 10.751.9 10.852.5^ 11.3^49.9 10.450.8 10.6Score difference fromchildren of nonsmokingmothersPPVT RAVEN-1.5^ -0.5^-1.3 -0.3-1.3 -0.6^

Exposure Group* Any vs. no maternal

postnatal smoking

• No smoke exposure* Maternal ETS during 

pregnancy

• MS during pregnancy* MS after pregnancy * MS both during and

after pregnancy

* Current cig/day 

smoked by mother:

1-9

10-19

≥20

Outcome AssessmentBayley(at 2 years)McCarthy(at 4 years)PPVTRAVEN

Authors (year)LocationBaghurst et al.

(1992)Port Pirie, AustraliaEskenazi andTrupin (1995)California

Design (n)

Age at Follow-upProspective (548)2 and 4 year oldsProspective(2,124)5 year olds

Tobacco Exposure Comparison1,2

Table 4.2 (Continued)

1 Abbreviations: MS-maternal smoking; PS-paternal smoking; asterisk (*) denotes proxy measurement for ETS 

on-ETS exposure; PPVT-Peabody Picture Vocabulary Test; RAVEN-Raven Colored Progressive Matrices Test,

Index of the Bayley Scales of Infant Development; GCI-General Cognitive Index of the McCarthy Scales of Ch

Observation for Measurement of the Environment. 

2 ns = not significant (p>0.05), ^p<0.05, ^^p<0.01, ^^^p<0.001, n = study size.
were consistent with other studies (ranging from 2.4-4.1 percent) and were

generally statistically significant. In contrast, differences associated with

prenatal maternal smoking were smaller and not statistically significant. A

dose-response relationship was seen between level of maternal smoking

after pregnancy and the Mental Development Index of the Bayley exam.

There was no attempt to calculate the effect of postnatal maternal smoking

independent of prenatal maternal smoking. When the analysis of postnatal

smoking was adjusted for socioeconomic status, HOME score, and the

mother’s intelligence quotient, test score differences dropped by 65-90 percent to near nil and lost statistical significance. In the final regression

model (which also included sex, birthweight, number of siblings, and

breast- versus bottle-feeding), neither maternal nor paternal smoking was

associated with any subscale score.

Eskenazi and Trupin (1995) Similar to Bauman et al. (1991), Eskenazi and Trupin

(1995) also conducted a re-analysis of data from the Child Health and

Development Studies to examine the relationship between cognition and

postnatal ETS exposure. Although Eskenazi and Trupin used serum cotinine

levels during pregnancy to determine ETS exposure of the mother (see section 4.3.2), interview information was used to classify smoking status at the

child’s 5-year examination. In addition to categorizing children as being

exposed to active maternal smoking during pregnancy only (prenatal exposure), after pregnancy only (postnatal exposure), or during and after pregnancy, the number of cigarettes smoked by the mother per day at the time

of the 5-year examination was evaluated. Unlike Bauman et al., paternal

smoking was not considered, and results from the 10- and 16-year examinations were not included. Raven and PPVT scores for children with prenatal

or postnatal exposure only were not significantly lower than scores for children with no smoking exposure. In contrast, Raven and PPVT scores for

children with both pre- and postnatal exposure were lower (p < 0.05) than

those for children with no exposure; however, the differences in mean

scores disappeared after adjustment for parent’s education, socioeconomic

status, race, birth order, preschool attendance, and other factors. When the

number of maternal cigarettes smoked per day was examined, mean scores

on both the Raven and the PPVT among children of smoking mothers were

generally lower than the mean scores among children of nonsmoking

mothers; this was true whether the model was unadjusted, adjusted for prenatal exposure only, or adjusted for prenatal exposure and a variety of other

co-variates. However, no clear dose-response relationship was seen in any

of the models (see Table 4.2). Because of the lack of a dose-response relationship, the authors felt that the effect seen in children of smoking mothers could potentially be explained by uncontrolled social and environmental factors. 

Denson et al. (1975) conducted a small case-control

study comparing 20 hyperkinetic children with dyslexic

and normal controls, matched for sex, age, and social

class (Table 4.3). Parental cigarette consumption at the

time of interview and during pregnancy was ascertained by interview with

the mother. The mean number of cigarettes smoked per day during pregnancy was greater in mothers of cases than in mothers of normal controls

150

Smoking and Tobacco Control Monograph No. 10

4.3.3.2 Studies of Behavior

and Postnatal ETS Exposure

Denson et al. (1975)
151

Chapter 4

(14.3 vs. 6.3 cigarettes/day, p < 0.05). The difference was more pronounced

when consumption at the time of interview was compared (23.3 vs. 8.2 cigarettes/day, p < 0.001). Sixteen of the twenty case mothers smoked during

pregnancy (80 percent), but the number of control mothers who smoked

was not given (thus ORs cannot be calculated). The fathers of cases smoked

slightly more than fathers of controls, both during pregnancy (22.2 vs. 18.5

cigarettes/day) and at interview (21.3 vs. 20.7 cigarettes/day), but the differences were not significant. There was no control for confounding other

than matching, and there was no attempt to separate pre- and postnatal

exposure. 

Weitzman et al. (1992) Weitzman et al. (1992) attempted to examine the separate

contributions of pre- and postnatal exposure. The investigators examined

children of women who had been enrolled in the National Longitudinal

Survey of Youth in 1979. A total of 2,256 children aged 4 to 11 years were

studied. Maternal smoking was categorized as none, only during pregnancy

(there were only 132 children in this group), only after pregnancy, and during and after pregnancy. Since the smoking categories were derived from

the mother’s smoking status during pregnancy and in 1984, exposure misclassification among the smokers probably occurred. Thus, some mothers

in the “only during pregnancy” group may have smoked in pregnancy and

for several years afterwards as long as they quit before 1984. Mothers completed a Behavior Problem Index (BPI) survey regarding their children’s

activities and social relationships. A large number of potential confounders

were included in the analysis, including demographic factors, birthweight,

current health status of mother and child, HOME score, and maternal education, intelligence, use of alcohol during pregnancy, self-esteem, and

employment. Paternal or family smoking was not assessed. 

The investigators found that smoking was associated with BPI score

in a dose-related manner in two groups of children with mothers who

smoked: children whose mothers smoked after pregnancy only, and children whose mothers smoked both during and after pregnancy. In the small

group of children whose mothers smoked during pregnancy only, smoking

1-20 cigarettes per day was also associated with higher BPI scores, but not

significantly so (p = 0.13). The adjusted differences in BPI score were fairly

comparable across the three categories of exposure. A similar pattern of

results was seen when odds ratios for extreme scores on the BPI were calculated. Since the outcome measure was assessed by the mother, differences

in BPI may have reflected different perceptions of behavior by smoking

mothers rather than altered behavior of the child. 

Eskenazi and Trupin (1995) In addition to examining the effects of tobacco smoke

during and after pregnancy on cognition, Eskenazi and Trupin (1995) used

data from the Child Health and Development Studies to examine the relationship between behavior and postnatal ETS exposure. Their measure for

“active” behavior was based on three questions from a 42-item behavioral

inventory completed by the mother at her child’s 5-year examination. If

the mother felt that her child had more energy than most, hated to sit still,

and disliked playing quietly, the child was rated as “active.” Overall, 17.3

percent of the children were rated as active by their mothers. Analyses
152

Design (n) Age at Follow-up Retrospective (20 cases, 40 controls) 5-15 year olds Prospective (2,256)

4-11 year olds

Outcome AssessmentHyperactivityBehavior ProblemIndex >14 (ratingby mother)

Authors (year)LocationDenson et al. (1975)

SaskatchewanWeitzman et al.

(1992)US NationalLongitudinal Survey of Youth

Tobacco Exposure Comparison1• MS during pregnancy* PS during pregnancy* Current MS* Current PSMS in cig/day:• Pregnancy only:

<20 vs. 0

≥20 vs. 0

* Post-preg only:

<20 vs. 0

≥20 vs. 0

* Both:

<20 vs. 0

≥20 vs. 0

Results Parents of casessmoked more cig/dathan parents of conp < 0.05 only for MS

OR (95% CI):1.6 (1.0-2.5)0.4 (0.1-1.6)1.2 (0.9-1.7)2.0 (1.3-3.1)1.4 (1.1-1.8)1.5 (1.1-2.2)

Table 4.3Behavior in Children: Studies that Assessed some Source of Potential ETS Exposure
153

Design (n)

Age at Follow-upProspective(2,124)Five year olds

Outcome AssessmentRated "active"by mother

Authors (year)LocationEskenazi andTrupin (1995)California

Tobacco Exposure Comparison1• No smoke exposure* Maternal ETS 

during pregnancy

• MS during 

pregnancy only

* MS after 

pregnancy only

* MS during and 

after pregnancy

* Current cig/day 

smoked by mother:

1-9

10-19

≥20

Results OR (95% CI)Unadjusted Adjusted1.0 1.01.6 (0.7-3.3) 1.5 (0.7-3.1)1.1 (0.6-2.0) 1.0 (0.5-1.9)1.4 (0.8-2.7) 1.2 (0.6-2.2)1.6 (1.2-2.1) 1.2 (0.9-1.7)Unadjusted Adjusted1.2 (0.7-1.9) 1.0 (0.6-1.7)1.5 (0.9-2.3) 1.1 (0.8-2.0)1.8 (1.2-2.6) 1.6 (0.9-2.8) 

Table 4.3 (Continued)

1 Abbreviations: MS-maternal smoking; PS-paternal smoking; asterisk (*) denotes proxy measurement for ETS 

bullet (•) denotes non-ETS exposure; HOME-Home Observation for Measurement of the Environment-Short F
analogous to those described in the previous section on cognition were performed. The OR for active behavior was somewhat elevated among children with postnatal exposure only, and with prenatal and postnatal exposure, although the effect diminished with adjustment for co-variates (unadjusted OR for pre- and postnatal exposure = 1.6, 95% CI = 1.2-2.1; adjusted

OR = 1.2, 95% CI = 0.9-1.7). When maternal cigarettes/day were examined,

the ORs for active behavior increased with increasing exposure. This doseresponse relationship was seen whether the model was unadjusted, adjusted

for prenatal exposure only, or adjusted for prenatal exposure and a variety

of other co-variates. However, the effect diminished and lost statistical significance in the full model (see Table 4.3). Despite the presence of a modest dose-response relationship, the authors felt they could not rule out

uncontrolled confounding as an explanation for their findings. 

Behavioral teratology studies in animals examine postnatal behavioral function after developmental exposures

to toxicants. Bertolini et al. (1982) reported an enhanced

rate of learning of an active avoidance task in offspring

of rats exposed to mainstream tobacco smoke daily during gestation.

Studies using sidestream smoke have been reported only in abstract form

(Lindsay et al., 1985; Mactutus et al., 1993) and do not present enough

information for evaluation. There is a large literature concerning the effects

of prenatal exposure to nicotine and carbon monoxide on postnatal behavior; these data are discussed in a recent review (Mactutus, 1989).

The evidence that ETS exposure of a nonsmoking pregnant

woman can result in neuropsychologic deficits in the child,

though very limited, is inconclusive. One small study (Makin et al., 1991)

found an association between ETS exposure of nonsmoking mothers during

pregnancy and decrements in their offspring’s test scores. However, a much

larger study that used a biomarker to ascertain ETS exposure (Eskenazi and

Trupin, 1995) failed to find any associations between ETS exposure during

pregnancy and three measures of cognition and behavior.

The five studies that have looked at postnatal ETS exposure and cognitive endpoints in children have shown inconsistent results. Four of the

studies (Rantakallio, 1983; Bauman et al., 1989 and 1991; Eskenazi and

Trupin, 1995) found modest decrements in performance by ETS-exposed

children, even after adjustment for a variety of other factors. Dose-response

relationships were reported in the two Bauman et al. studies, but were not

seen in Eskenazi and Trupin. The findings of Bauman et al. (1991) were

internally inconsistent in that associations were not seen at all ages, and

results differed for two tests of receptive language (the PPVT and the Quick

Test). None of these studies adjusted for parental intelligence or characteristics of the home environment. In the fourth study, Baghurst et al. (1992),

in their crude analysis, also found decrements in test scores associated with

maternal smoking after pregnancy. However, these decrements disappeared

after adjustment for several powerful confounders, including socioeconomic

status, HOME score, and maternal IQ. 

Of the three studies that examined postnatal ETS exposure and children’s behavior, Denson et al. (1975) was too small and poorly conducted to

154

Smoking and Tobacco Control Monograph No. 10

4.3.4 Animal Studies of

Cognition and Behavior

and Tobacco Smoke

Exposure

4.3.5 Discussion and

Conclusions
allow any conclusions to be drawn. On the other hand, Weitzman et al.

(1992) conducted a large, well-controlled study that enabled prenatal exposure to maternal active smoking and postnatal ETS exposure to be examined independently. They found significant, dose-related associations

between most categories of postnatal maternal smoking and a behavior

problem index. Eskenazi and Trupin (1995) also found modest, dose-related

asociations between postnatal ETS exposure and “active” behavior. Both

studies used a mother-reported outcome; thus, they were unable to determine if maternal smoking was associated with differences in the children’s

behavior or in the mothers’ perceptions. 

Proposed mechanisms through which ETS could affect a child’s neuropsychological development include a direct effect of nicotine (a stimulant) upon the central nervous system, and adverse impacts of chronic

exposure to carbon monoxide. Exposure to ETS increases concentrations of

carboxyhemoglobin in the blood (Huch et al., 1980; Jarvis et al., 1983), and

increased ambient carbon monoxide levels adversely affect mental functioning in humans (National Research Council, 1977; World Health

Organization, 1979). As noted above, the large literature on the effects on

animals of prenatal exposure to carbon monoxide and nicotine suggest that

adverse impacts of these agents on postnatal neurobehavior is biologically

plausible.

In conclusion, there are very few studies that have examined the

relationship of neuropsychological development to postnatal ETS exposure

of the child, independent of prenatal exposure to maternal active smoking.

Two studies of behavior (Weitzman et al., 1992; Eskenazi and Trupin, 1995)

did a reasonably good job of separating postnatal from in utero exposure

and also controlled for other pertinent co-variates. These studies found

adverse relationships associated with childhood ETS exposure. With respect

to cognitive development, one well-controlled study showed no association

with ETS, but four other fairly well controlled studies showed modest decrements associated with ETS. No conclusions regarding causality can be

made on the basis of these studies, but they do provide suggestive evidence

that ETS exposure may pose a neuropsychological developmental hazard.

When evaluating studies of postnatal physical development, it should be kept in mind that growth

varies not only with genetic influences (e.g., sex and parental height) and

nutrition, but also with social factors such as socioeconomic status, birth

order, and family size (Goldstein, 1971).

Active maternal smoking during pregnancy can cause

significant decreases in birthweight (U.S. DHHS, 1980).

There is also evidence that body length at birth is

affected by smoking during pregnancy (Persson et al.,

1978). Birthweight, which is also a significant predictor

of physical development, may be an intervening variable between prenatal exposure to tobacco smoke and

growth. There may also be an effect of prenatal exposure to tobacco smoke independent of birthweight. A review of the topic is

contained in Rush and Callahan (1989). 

155

Chapter 4

4.4 POSTNATAL PHYSICAL

DEVELOPMENT

4.4.1 Postnatal Physical

Development of Children

whose Mothers Smoked

During Pregnancy

4.4.1.1 Studies of Children

whose Mothers Smoked

During Pregnancy
Several studies, some involving thousands of children, have examined the relationship between maternal smoking during pregnancy and

height, and have found that children of smokers are slightly shorter than

children of nonsmokers. The largest height decrements were seen in studies by Dunn et al. (1976) and Naeye (1981). Dunn et al. (1976), in an

uncontrolled study, reported differences of 1.6-2.0 cm for normal birthweight children aged 4-6.5 years. Naeye (1981), in a sibling pair comparison, found the offspring of smoke-exposed pregnancies were 1.7 cm shorter

than their non-exposed siblings. Among studies of pre-pubertal children

that controlled for a variety of social factors, height decrements for offspring of maternal heavy smokers (at least 10 cigarettes per day) ranged

from 0.7-1.0 cm (Hardy and Mellits, 1972; Goldstein, 1971; Butler and

Goldstein, 1973; Wingerd and Schoen, 1974; Eskenazi and Bergmann,

1995). The last four papers reported mean heights of children whose mothers were moderate smokers to be intermediate between those of children

whose mothers were heavy smokers and nonsmokers. 

Fox et al. (1990) compared 3-year-old children of women who

smoked throughout pregnancy with children of women who had quit and

also found an adjusted height difference of 1.0 cm. Studies of the British

National Child Development Study cohort at 16 and 23 years of age have

shown that the effect of maternal smoking during pregnancy appears to

persist beyond puberty, although the size of the effect is not consistent

(Fogelman, 1980; Fogelman and Manor, 1988). The sole exception to this

pattern was reported by Fried and O’Connell (1987), who failed to find a

significant negative correlation between children’s height and mothers’

smoking status during pregnancy. The point estimate was not presented, so

the direction of the association is not known. However, a subsequent larger

study taken from the same cohort found children of heavy smokers to be

significantly shorter than children of nonsmokers (Fried and Watkinson,

1988). The presentation of data did not allow a specific height difference to

be identified. 

The effect of adjusting height differences for birthweight has been

explored in four study populations. Goldstein (1971), and Fogelman and

Manor (1988), using data from the National Child Development Study,

found that adjusting for birthweight reduced height differences by 30-60

percent. Fox et al. (1990) corroborated this finding, calculating a 50 percent

reduction of effect. The studies by Hardy and Mellits (1972) and Eskenazi

and Bergmann (1995) reported that differences in height were virtually

eliminated when birthweight was taken into account. 

Hardy and Mellits (1972), Dunn et al. (1976), Naeye (1981), Fried

and Watkinson (1988) and Fox et al. (1990) also examined prenatal exposure to maternal smoking and children’s weight. All five studies found

small negative associations with maternal smoking, but the effect was significant only in Naeye’s sibling pair comparison. Both Fox et al. (1990) and

Hardy and Mellits (1972) reported that the effect disappeared when birthweight was controlled. 

156

Smoking and Tobacco Control Monograph No. 10
Investigators have consistently observed a height

decrement of 0.7-1.0 cm among children of

women who smoked at least 10 cigarettes per day

during pregnancy. Fox et al. (1990) demonstrated

a similar effect when comparing children of quitters and persistent smokers.

Dose-response relationships have also been consistently observed.

Although very small, the effect appears to be independent of sex, parental

height, socioeconomic status, birth order, and family size. One study

(Eskenazi and Bergmann, 1995) also controlled for postnatal exposure to

ETS. This, together with the lack of evidence associating ETS exposure with

height growth (see below) and Berkey et al.’s (1984) finding that ETS exposure was not related to rate of growth, suggests that the effect is specifically

associated with in utero exposure to maternal active smoking. 

Half or more of the effect on height appears to be related to reductions in birthweight among offspring of smokers. As maternal smoking is

known to cause reductions in birthweight, and as birthweight is a predictor

of height (Goldstein, 1971), it is plausible that in utero exposure to maternal

active smoking could result in small reductions in height growth. 

Five poorly controlled studies have found small inverse relationships between maternal smoking during pregnancy and children’s postnatal

weight growth. More work is required before any conclusions can be drawn

regarding the effect of active smoking during pregnancy and children’s

weight. 

In summary, the evidence suggests that the relationship between

active maternal smoking during pregnancy and impaired height growth of

approximately one centimeter in the pre-adolescent child may be causal.

Dose-response relationships have been repeatedly demonstrated, and there

are plausible mechanisms to explain the association. 

One study was found that examined the relationship

of ETS exposure of the mother to the height of the

child at 5 years of age.

Eskenazi and Bergmann (1995) reanalyzed data from

the Kaiser Permanente Child Health and Development

Studies that were conducted in Oakland, California

from 1959 to 1966. The authors measured cotinine, a

nicotine metabolite, in stored serum samples taken

from women in mid-pregnancy. Of the 2,622 women included in this

study, 1,610 were considered to have no tobacco exposure during pregnancy (nonsmokers with cotinine levels <2 ng/ml) and 77 were classified as

having ETS exposure during pregnancy (nonsmokers with cotinine levels

from 2-10 ng/ml). The children’s heights were measured within 6 months

of their fifth birthday; the measurements were then extrapolated using linear regression to their height at exactly 5 years. Children of ETS-exposed

pregnancies were on average 0.4 cm higher than non-smoke-exposed children (95% CI = -0.5-1.4) after adjustment for birth weight, gestational age,

race, sex, birth order, and maternal height, body mass index, education,

and age. 

157

Chapter 4

4.4.1.2 Discussion of Evidence

from Studies on Physical

Development in Children whose

Mothers Smoked During Pregnancy

4.4.2 Postnatal Physical

Development of Children

Exposed to ETS

4.4.2.1 ETS Exposure of the

Mother During Pregnancy

Eskenazi and Bergmann (1995)
Six studies have evaluated the association between some indicator of postnatal ETS exposure and height (Table 4.4). No

studies were found of ETS exposure and children’s postnatal weight growth. 

Three studies have been conducted by Rona and colleagues using cross-sectional data from the ongoing

British National Study of Health and Growth. In their initial study of 4,961

primary school children in England and Scotland, Rona et al. (1981) found

an inverse association between the number of people smoking more than

five cigarettes per day at home and the standardized height of the child.

Height differences could not be calculated from the data presented. Results

remained significant after adjustment for birthweight, age, sex, social class,

and parental height. Prenatal exposure to tobacco smoke was not assessed. 

Rona et al. (1985) refined their exposure assessment by ascertaining

the total number of cigarettes per day smoked at home by both parents.

Forty-three percent of fathers, and 34 percent of mothers smoked in this

sample. After adjusting for prenatal exposure to maternal smoking,

parental height, infant birthweight, age, sex, degree of overcrowding, and

number of siblings, children of smokers were still slightly but significantly

shorter than non-exposed children (p < 0.01). The adjusted height decrement was small—approximately 0.2 cm for every 10 cigarettes smoked at

home. Father’s smoking, mother’s current smoking, and smoking during

pregnancy were all independently associated with height. 

In Chinn and Rona (1991), the study was varied by using an even

larger cohort of over 11,000 school children and including more co-variates

in the analysis, including social class, ethnicity, and receiving school meals.

No association was seen between number of cigarettes smoked at home and

height. The investigators then repeated the analysis using their 1985 database and found that the height difference, although still negative, diminished by a third and was no longer statistically significant. They concluded

that postnatal ETS exposure has no effect on children’s height. 

Rantakallio (1983) Rantakallio (1983) studied over 2,800 Finnish 14-year-olds, evenly

divided as to prenatal exposure status. The adjusted height decrement associated with maternal smoking during pregnancy was approximately -0.9 cm

(estimated from a figure), consistent with estimates calculated by other

investigators. In a regression analysis that included demographic and

socioeconomic factors, prenatal exposure status, and maternal height, paternal smoking status was negatively related to children’s height (p = 0.07).

The size of the standardized coefficients for maternal smoking during pregnancy and paternal smoking were roughly equivalent. There was no adjustment for birthweight. 

Berkey et al. (1984) Berkey et al. (1984) examined height and height growth rate in a

longitudinal study of 9,273 children aged 6-11 years (the same study is also

described in Ferris et al., 1985). The study’s main intent was to examine the

health effects of air pollution. The authors found a very significant doserelated decrease in height with increasing current maternal cigarette consumption. Children of mothers who smoked >10 cigarettes per day were

0.7 cm shorter than children of nonsmokers, after adjusting for age, sex,

158

Smoking and Tobacco Control Monograph No. 10

4.4.2.2 Postnatal ETS

Exposure 

Rona et al. (1981 and 1985)

Chinn and Rona (1991)
159

Chapter 4

parent’s education, and use of gas for cooking in the home. There was no

adjustment for prenatal exposure to maternal smoking or birthweight, thus

it is likely that the effect associated with current maternal smoking actually

reflected the effect of smoking during pregnancy. The similarity of the

height decrement to decrements seen in studies of maternal smoking during pregnancy supports this interpretation. A nonsignificant association

was seen with paternal smoking, with an adjusted height decrement of 0.1

cm among children of fathers smoking >10 cigarettes per day. Over an

average of 4 years of observation per child, there was no association of

either mother’s or father’s smoking with the child’s rate of growth, which

led the authors to suggest that the height differences were due to in utero or

early life exposure. 

Eskenazi and Bergmann (1995) As described in the previous section, Eskenazi and

Bergmann (1995) used data from the Child Health and Development

Studies to examine the relationship between maternal smoking and height

of the child at age 5 years. They used information from interviews with the

mothers during pregnancy and at their child’s 5-year examination to categorize smoke exposure as prenatal only, postnatal only, and pre- and postnatal. Children with prenatal exposure only, and those with pre- and postnatal exposure were 0.3 cm and 0.5 cm shorter than children of nonsmokers, respectively (prenatal exposure, 95% CI = -1.1-0.5; pre- and postnatal

exposure, 95% CI = -0.9 to -0.1; adjusted for race, sex, birth order, and

maternal education, age, height, and body mass index). These differences

diminished to -0.01 and -0.02 cm after also controlling for birthweight and

gestational age. In contrast, children with postnatal exposure only were on

average 0.5 cm taller than children of nonsmokers, though this difference

was not statistically significant (95% CI = -0.3-1.3). The authors concluded

that any height decrements seen in children of smokers were probably

related to in utero exposure rather than postnatal exposure. 

No studies on this topic that used mainstream smoke

were located. One study (Tachi and Aoyama, 1988b)

purports to deal with the effects of “sidestream” tobacco

smoke on postnatal growth in rats. Exposures began at

weaning (21 days postnatal) and continued through adulthood (54 days of

age). Rats mature sexually at 35-45 days of age. Reduced growth rates in

smoke-exposed animals were reported within a few days of initiation of the

exposure. Growth was determined by daily weighing during the study and

determination of organ weights at the conclusion of the study. A control

group was exposed to carbon monoxide levels comparable to those experienced by the group exposed to tobacco smoke. However, no pair-fed controls were included. Pair-fed controls are important in establishing that the

exposure protocols did not lead to reduced food intake due to disruption of

normal feeding routines or general malaise. 

Using paternal smoking as a proxy for postnatal ETS exposure,

Rantakallio (1983) and Berkey et al. (1984) found very small,

nonsignificant negative correlations with height after adjusting for maternal smoking. Berkey et al. (1984) found no association between current

maternal or paternal smoking and the rate of growth, suggesting that

4.4.3 Animal Studies of

Postnatal Physical

Development and

Tobacco Smoke Exposure

4.4.4 Discussion

and Conclusions
160

CommentAdjusted foheights, # No control Adjusted foparental heexposure, Adjusted foabove, plumeals. MS adjusteparental hesize. PS aexposure aAdjusted foparental edNo control prenatal ex

Height Differencein cm

Inverse association (p < 0.05)

-0.2 (p < 0.01)

No significant 

association

-0.6-0.9 (p < 0.05)Inverse association (ns)-0.5 -0.7 (p < 0.001)-0.04-0.1 (ns)No association betweenMS or PS and rate ofgrowth

Source/Amount ofTobacco Exposure1*Number of people 

smoking >5 cig/day at home

*Every 10 cig/day 

smoked at home by parents

*Total cig/day smoked 

at home by parents

•MS during pregnancy:

<10 cig/day vs. 0≥10 cig/day vs. 0

*Any vs. no PSCurrent cig/day:•MS <10 vs. 0

≥10 vs. 0

•PS ≥10 vs. 0

≥10 vs. 0

Authors (year)LocationRona et al. (1981)

United KingdomRona et al. (1985)

United KingdomChinn & Rona(1991)United KingdomRantakallio (1983)FinlandBerkey et al.(1984);

Ferris et al. (1985)

United States

Design (n)

Ages at Follow-upCross-section(4,961)5-11 year oldsCross-section(5,903)5-11 year oldsCross-section(11,224)5-11 year olds(1,763 prenatally exposed, 1,781 controls)14 year oldsLongitudinal cohort(9,273)6-11 year olds

Table 4.4Height Growth in Children: Studies that Assessed some Source of Postnatal ETS Exposure
161

CommModel birth orcation, mass iModel factors gestati

Height Differencein cm

Model I Model II

0.5 (-0.5-1.4) 0.4 (-0.5-1.3) 

-0.3 (-1.1-0.5) -0.01 (-0.8-0.8)

0.5 (-0.3-1.3) 0.5 (-0.3-1.3)

-0.5 -0.02 (-0.4-0.4)

(-0.9 to -0.1)

Source/Amount ofTobacco Exposure1*Maternal ETS during 

pregnancy

•MS during pregnancy

only

*MS after pregnancy 

only

*MS during and after

pregnancy

Authors (year)LocationEskenazi and Trupin (1995)California

Design (n)

Ages at Follow-upProspective(2,622)5 year olds

Table 4.4 (Continued)

1 Abbreviations: MS-maternal smoking; PS-paternal smoking; asterisk (*) denotes proxy measurement for ET

bullet (•) denotes non-ETS exposure; n-study size.
height decrements seen in children of smokers reflect differences that exist

at birth. In corroboration of this interpretation, Eskenazi and Bergmann

(1995) found no height decrement among children with postnatal ETS

exposure only; they also found that the height decrement seen among children whose mothers smoked during and after pregnancy disappeared after

controlling for birth weight and gestational age. 

In Rona et al. (1985) and Chinn and Rona (1991), a reasonably good

measure of ETS exposure was obtained (number of cigarettes smoked at

home by parents), and analyses were controlled for prenatal exposure to

maternal active smoking. These studies found an extremely small ETS

effect (-0.2 cm) and no effect, respectively. When the 1985 data were reanalyzed using the same methods employed for the 1991 data, the height

decrement diminished by a third and lost statistical significance. These

results imply that if any effect of ETS exposure on height exists, it is vanishingly small. 

Although there are plausible mechanisms through which ETS exposure could impact postnatal height growth (e.g., impairment of appetite,

increased frequency of illness), there is little to no epidemiological evidence

that ETS exposure has a significant effect on height growth of children. A

single animal study of postnatal sidestream smoke exposure did find

reduced growth rates in exposed animals; however, the lack of pair-fed controls in this study limits the conclusions which can be drawn from its

results. 

The impact of ETS exposure on the respiratory tract has been

reviewed by a number of authoritative bodies (U.S. DHHS,

1986; NRC, 1986; U.S. EPA, 1992). Several acute and chronic

non-cancer respiratory health effects of ETS have been observed, including

exacerbation of childhood asthma, acute lower respiratory tract illness, middle ear infection, and chronic respiratory symptoms in children. Also,

while the results from all studies are not wholly consistent, there is substantial evidence that childhood exposure to ETS affects lung growth and development, as measured by small but statistically significant decrements in

pulmonary function tests. Drawing on the above-mentioned reviews, as

well as more recent literature, these impacts are discussed at length in the

Chapter entitled Respiratory Health Effects of Exposure to Environmental

Tobacco Smoke.

Interest in Sudden Infant Death Syndrome (SIDS) stems from

numerous studies demonstrating that infants of smoking mothers

have an increased risk of SIDS. There is adequate epidemiological

evidence of a causal relationship between maternal smoking in general and

risk of SIDS. In most of the studies examining the relationship between

ETS exposure and SIDS, it was not possible to separate the effects of postnatal ETS exposure from those of prenatal exposure to maternal active smoking. Recent findings of elevated risk of SIDS associated with postnatal ETS

exposure independent of maternal smoking in reasonably well controlled

epidemiological studies provide compelling evidence that postnatal ETS

exposure of the child is an independent risk factor for SIDS. 

162

Smoking and Tobacco Control Monograph No. 10

4.5 RESPIRATORY

DEVELOPMENT

AND FUNCTION

4.6 CHAPTER

SUMMARY AND

CONCLUSIONS
Although studies have shown fairly consistently that maternal

smoking during pregnancy is adversely associated with measures of cognition and behavior in children, very few studies have examined these effects

in relation to children’s postnatal ETS exposure. One study of behavior

which did a reasonably good job of separating postnatal from in utero exposure and controlled for other pertinent co-variates found significant adverse

relationships associated with childhood ETS exposure. With respect to cognitive development, the best controlled study showed no association with

postnatal ETS exposure, but three other fairly well-controlled studies

showed modest decrements associated with postnatal ETS exposure. A single small study of nonsmoking pregnant women found an association of

ETS exposure during pregnancy with decrements in their offspring’s test

scores. While conclusions regarding causality cannot be made on the basis

of these studies, they do suggest that ETS exposure may pose a neuropsychological developmental hazard.

While small but consistent effects of active maternal smoking during pregnancy on physical growth of offspring have been demonstrated in a

number of studies, there is no epidemiological evidence that postnatal ETS

exposure has a significant effect on the height growth of children after controlling for prenatal exposure to maternal active smoking. Although a relatively small number of studies have addressed this issue, to date there is no

evidence that postnatal ETS exposure is an independent and significant

hazard to height growth in humans.

Further evidence of developmental toxicity of ETS exposure on respiratory outcomes is provided in Chapter 6, which presents substantial evidence that childhood exposure to ETS affects lung growth and development, exacerbates childhood asthma, and causes acute lower respiratory

tract illness, middle ear infection and chronic respiratory symptoms in children.

163

Chapter 4

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Bauman, K.E., Flewelling, R.L., LaPrelle, J. Parental

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Bauman, K.E., Koch, G.G., Fisher, L.A. Family cigarette smoking and test performance by adolescents. Health Psychology 8:97-105, 1989.

Bayley, N. Bayley Scales of Infant Development.

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Beckwith, J.B. Discussion of terminology and definition of the sudden infant death syndrome. In:

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Berkey, C.S., Ware, J.H., Speizer, F.E., Ferris, B.G.

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The study of reproductive toxicity includes measures of

female fertility and fecundability; other female reproductive effects, such as

lowered age at menopause and menstrual disorders; and male reproductive

effects, including altered sperm parameters, which may influence a couple’s

fertility and/or fecundability. Very few studies have investigated the effects

of ETS exposure on male and female reproductive function (Tables 5.1 and

5.2). Of these, most have examined delay to conception in women who

eventually achieve pregnancy, as an indication of subfecundability. Many of

these studies were designed to look at the woman’s active smoking, not ETS

exposure, but they also reported the husband’s smoking status, a surrogate

for ETS exposure used in studies of other outcomes. Three of the studies

reviewed examined the possibility of an effect on women’s fertility occurring earlier in development by trying to ascertain childhood and in utero

exposure to ETS.

The discussion below of the potential impact of ETS on each outcome begins with a brief review of epidemiological studies that assessed the

effect of active smoking. Although reviewing active smoking effects is not

the purpose of this document, the review of these studies will provide a

context within which to consider the results of the studies of ETS exposure.

Epidemiologic studies of ETS exposure are discussed in more detail, followed by a description of pertinent animal studies. Studies are then discussed as a group, and conclusions are presented.

In epidemiological studies, measurement of female fertility (ability to reproduce) and fecundability (the

probability of conceiving in a given menstrual cycle) generally relies on

reported failure to conceive or delay to conception following a time period

of unprotected sexual intercourse. Infertility is commonly defined as not

becoming pregnant within a year of unprotected intercourse; of course,

some couples may go on to conceive later. Fecundability may be measured

by determining the number of cycles needed to conceive and calculating

the conception rate in each cycle. The probabilities (or rates) of conception

can then be compared between two groups—exposed and unexposed—in

the form of a ratio. When such a “fecundability ratio” (FR) is less than one,

it indicates that the exposed group has lower or “sub”-fecundability than

the comparison group. When examining fertility and fecundability, covariates related to sexual practices are important to consider, including frequency of coitus, contraceptive use, and history of sexually transmitted diseases, as well as maternal age, socioeconomic status, and reproductive history. In animal studies, measures of female fertility derived from the standard

169

Reproductive Effects

5.1 INTRODUCTION

5.2 FEMALE FERTILITY

AND FECUNDABILITY
170

CommeNot adjuinfertilityThorougNot a reSES). No data ceptionNo data smoking (vs. befNot adjuIncludes 

Results1Had lowest risk of neverhaving been pregnant.OR = 0.67 (0.46-0.98)No association with delayto conception after adjustment for active smokingand confounders.Adjusted OR of delayedconception (6-12 mo):= 1.3 (1.2-1.4), potentiated by age.OR = 1.3 (1.0-1.8) for ≥20cig/day and delay of >6mos. In maternal nonsmokers. OR in smokers = 1.6 (1.3-2.1) FR: = 2.1 (1.2-3.5) 

for 1-10 cig/day

FR: = 1.0 (0.7-1.6) 

for >10 cig/day

Exposure DefinitionHusband smokedHusband smokingHusband smokingHusband smokingPartner smoking

Authors (yr)LocationTokuhata (1968)United States(Memphis)Baird & Wilcox(1985)United States(Minnesota)Suonio et al. (1990)

FinlandOlsen (1991)DenmarkFlorack et al. (1994)

The Netherlands

Design(study size)Questionnaire to nextof-kin. Case-controlstudy of cancer (n = 2,016)

Retrospective interviewof pregnant volunteers(n = 678)Retrospective interviewat prenatal care clinics,population-based (n = 2,198)Retrospective questionnaire to pregnantwomen (n = 10,886)

Interview of womenplanning pregnancy, follow 12 months (n = 259) Prospective

Table 5.1ETS Exposure and Infertility or Fecundability: Adult Exposure

1 OR = odds ratio; SES = socioeconomic status; FR = fecundability ratio; Fecundability ratio (FR) indicates 

at each cycle. FR > 1 indicates improved fecundability, whereas FR < 1 indicates sub-fecundability, when c
multigeneration study in rodents are the fertility index, the fecundity

index, the mating index, and the parturition index; however, multigeneration studies have not been conducted with tobacco smoke. Reproductive

organ weights and histology, ovulation, estrus cycles, mating behavior,

implantation and resorption may be directly determined from other study

designs, and effects on these parameters are considered relevant to female

fertility.

Active smoking by women has been found to be associated with decreased fertility in a number of studies

(reviewed in Stillman et al., 1986; Westhoff, 1990; and

Spira et al., 1987). Associations have been found

between smoking and both delay to conception and infertility, particularly

related to tubal factors. Delay to conception has been measured in different

time intervals, but studies have found increased risks of 40-80 percent

among smokers (e.g., odds ratios of 1.4-1.8; Howe et al., 1985). The studies

that found an association with tubal infertility reported odds ratios of 1.6-

3.3 (Daling et al., 1986; Stillman et al., 1986). Many of the studies have

found a dose-response effect. The 1980 Surgeon General’s report (U.S.

171

Chapter 5

Design

(study size)

Re-interview

women who had

pregnancy 

(n = 631)

Prospective study

after stopping birth

control (n = 230)

Prospective exposure (of mother)

and cross-sectional

(n = 318)

Authors (yr)

Location

Wilcox et al.

(1989)

Minnesota

Weinberg et al.

(1989)

North Carolina

Schwingl

(1992)

California

Exposure

Definition

Parental smoking

(childhood ETS

and in utero

exposure)2

Childhood exposure to smokers.

In utero

exposure2

Childhood exposure

In utero

exposure2

Comments

Biologic plausibility?

In utero exposure 

FR = 0.9. Other characteristics of moms

not ascertained.

Selected group. In

utero exposure FR =

0.5 (0.4-0.8).

Exposure prior to

attempt to conceive.

Exposure from mother

herself. Adjusted.

No association of FR

with active smoking.

Results

FR1 = 1.3 (1.1-1.6) 

for 1 or 2 household 

smokers, 

1.6 (1.1-2.2) for more

FR = 1.0 crude

FR = 1.6 (1.0-2.4)

if exposed to 2 

smokers, adjusted 

for in utero exposure 

and other variables.

FR = 1.1 for 

1 smoker

FR = 1.2 for 

2 smokers (p > 0.2)

FR = 1.2 (0.9-1.4), 

no dose-response.

Table 5.2

ETS Exposure and Infertility or Fecundability: Childhood Exposure

1 Fecundability ratio (FR) indicates probability of conception at each cycle. FR > 1 indicates improved

fecundability, whereas FR < 1 indicates sub-fecundability, when comparing 2 groups.

2 In utero exposure indicates that the mother of the target participant smoked during her pregnancy.

5.2.1 Overview of Human

Studies of Female Fertility

and Fecundability and

Active Smoking
DHHS, 1980) stated that “cigarette smoking appears to exert an adverse

effect on fertility,” and many of the important studies were conducted since

that report was published. In the ETS studies reviewed below, associations

reported for active smoking and fertility are presented along with the ETS

findings.

The human studies are presented below in two groups,

based on when exposure to ETS occurred: first, studies

are described in which exposure occurred during adulthood, usually from a smoking spouse (Table 5.1); second, studies are described in which exposure occurred during childhood

from smoking parents (as well as in utero, or exposure as a fetus, due to

maternal active smoking; Table 5.2).

In the single study of infertility conducted to date,

Tokuhata (1968) obtained information from the next-of-kin

of 1,095 cancer cases and 921 controls about the lifetime

reproductive history and smoking history of the subjects

and their spouses. Infertility was defined as never having been pregnant.

The crude odds ratio for fertility among couples in which the wife did not

smoke and the husband did smoke was calculated as 0.67 (Table 5.1). There

did appear to be an association with the wife’s active smoking (OR = 1.5)

which was diminished when only couples with nonsmoking husbands were

examined (OR = 1.3). 

This study has a number of problems. Many of the couples (about

400) were excluded because of lack of data on husband’s smoking status.

The reporting by next-of-kin about pregnancies that ended in fetal loss is

probably not accurate, so some women may be misclassified as infertile.

There was no information available on any confounders, nor on contraceptive practices. Neither was there any detailed information on exposure to

tobacco smoke during specific reproductive periods.

Baird and Wilcox (1985) Baird and Wilcox (1985) conducted a study in Minnesota to

investigate the effect of smoking on fertility. Reduced fertility was determined retrospectively as time to conception in 678 pregnant women who

had stopped using birth control in order to become pregnant, and who had

subsequently conceived within two years. A strength of the study is that

the authors made some attempt to exclude cycles “not at risk” for conception, e.g., those during which women reported being sexually abstinent or

using birth control. The authors found that women who were smokers had

reduced fertility, with a dose-response effect. They stated that husband’s

smoking status did not affect fertility after adjusting for the woman’s smoking status and other potential risk factors (p = 0.95). However, no data were

presented. These results may not be generalizable because the study was

conducted in a population of volunteers from a group with high socioeconomic status who had planned their pregnancies.

Suonio et al. (1990) A study in Finland (Suonio et al., 1990) examined data from

interviews conducted with 2,198 women during their 20th week of pregnancy. Fecundability—or specifically, delay to conception—was analyzed by

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Smoking and Tobacco Control Monograph No. 10

5.2.2 Human Studies of

Female Fertility and

Fecundability and ETS

Exposure

5.2.2.1 Exposure During

Adulthood

Tokuhata (1968)
husband’s smoking status. Limiting the analysis to women who conceived

within 12 months, the risk of not conceiving by 6 months was 1.3 (95% CI

= 1.2-1.4) if the husband smoked and 1.5 (95% CI = 1.3-1.8) if the pregnant

woman herself smoked. Both effects were potentiated by increasing age.

This effect was not seen when the entire dataset was analyzed (i.e., not

truncated at 12 months). The odds ratios were adjusted for some factors,

but many that are related to time to conception were not available, including contraceptive practices and coital frequency. This study also did not

appear to have data for determining cycles at risk of pregnancy and may

thus have some misclassification bias. Furthermore, the association was

examined in all pregnancies, including those of women who were active

smokers as well as those of nonsmokers, and it is not clear whether maternal and paternal smoking were entered in the regression models simultaneously. If not, the results are not adjusted for smoking by the partner.

Olsen (1991) Olsen (1991) examined fecundability in a large study of almost

11,000 Danish women who completed a questionnaire in their last month

of pregnancy. The question about time to conception was pre-coded with

broad categories of 0-6 months, 7-12 months, and greater than 12 months.

Women treated for infertility were excluded. Current smoking by the

woman’s partner was associated with a delay to conception in the pregnancies of both smoking and nonsmoking women; a dose-response effect was

more apparent in pregnancies of women who were smokers. Among nonsmoking women, the adjusted risk of not conceiving within 6 months was

1.1 if their partner smoked 1-9 cigarettes per day and 1.3 for those whose

partner smoked ten or more per day (10-19 cigarettes/day, 95% CI = 1.1-1.6;

20 cigarettes/day, 95% CI = 0.96-1.8). The risk for not conceiving within 12

months for these nonsmoking women with spouses who smoked was also

elevated, but did not show any dose-response effect. Contraceptive practices and coital frequency were not assessed. This analysis included women

who became pregnant while using contraception, but Olsen stated that

excluding these women did not change the results. The measurement of

time to conception was rather crude in this study.

Florack et al. (1994) A recent study examined cigarette smoking, alcohol consumption, and caffeine intake of both partners in relation to time to conception

in Dutch non-medical hospital workers. Current habits were recorded and

rates of conception were followed for the next twelve months to estimate

fecundability ratios. A major problem with the approach used by these

investigators is that more than half the study population had been trying to

conceive for greater than one year prior to the beginning of the study. Not

taking this attempt time into account can bias results, particularly if those

having difficulty conceiving had changed habits such as smoking. The univariate analysis by proportionate hazard models showed slightly increased

fecundability if either partner smoked moderately (Table 5.1). Heavier

smoking by spouses made no difference in time to conception, while heavier smoking by females was associated with a slight decrement in fecundability. No data on per-cycle conception rates were reported. Adjusted

odds ratios were not presented, although they were reported to change little. No data on confounders such as frequency or timing of intercourse

173

Chapter 5
were available. The association of fecundability with spousal smoking was

not examined separately for female nonsmokers, so the possible effects of

ETS exposure cannot be estimated.

In the Wilcox et al. (1989) study, women who participated

in the Minnesota study described above (Baird and Wilcox,

1985) were re-interviewed about the smoking status of their

mother when she was pregnant with them, as well as about

household smokers during their childhood. The authors found that women

exposed to ETS as children became pregnant faster than unexposed women.

In other words, their probability of conceiving in a given menstrual cycle

(fecundability) was higher than in the unexposed women. This association

was present irrespective of who the household smoker was, and was slightly

stronger with more smokers in the household. The adjusted fecundability

ratio (FR) was 1.3 for one or two household smokers and 1.4 for more

smokers. Controlling for exposure due to the woman’s mother smoking

during pregnancy (in utero exposure) in the regression model made these

associations slightly stronger, with an FR of 1.6 (95% CI = 1.1-2.2) for three

or more household smokers. In utero exposure to maternal smoking showed

a weak association with reduced fecundability (FR = 0.9, 95% CI = 0.7-1.1).

Women who were exposed to tobacco smoke during childhood but not in

utero had an FR of 2.0 (95% CI = 1.3-2.9) compared to unexposed women.

Age at menarche was not altered by ETS exposure in childhood. Several covariates that may confound the association were not controlled, particularly

socioeconomic variables relating to the women’s parents. The authors speculated on possible biological mechanisms to explain this unexpected finding, including earlier maturation and accelerated growth of oocytes in

exposed females, or induction of liver enzymes in ways that change adult

patterns of hormone metabolism.

Weinberg et al. (1989) The second study with data on the issue of fecundability and

childhood ETS exposure was conducted in North Carolina to examine rates

of very early fetal loss (Weinberg et al., 1989). The study participants (n =

230), who were enrolled at the time they discontinued contraception, collected urine for 6 months and were then re-contacted at 12 and 24 months

if they had not yet conceived. Time to conception was truncated at 13

months so that treatment for infertility would not effect the analysis. 

According to the authors, when adjustment was made for in utero

tobacco smoke exposure and other variables (e.g., age, frequency of intercourse, age at menarche, and current smoking status) in a proportional hazards model, there was an association of childhood exposure with increased

fecundability; without adjustment, there was no association. The adjusted

FR was 1.3 (95% CI = 0.9-1.8) for one household smoker and 1.6 (95% CI =

1.0-2.4) for two smokers. The authors also reported that in utero exposure

reduced fecundability (adjusted FR = 0.5, 95% CI = 0.4-0.8). This study did

not consider the spouse’s smoking status or other sources of ETS exposure

in adulthood. These results support the findings of the Minnesota study

with respect to childhood exposure, but indicate a much stronger association of reduced fecundability with in utero exposure. The authors concen174

Smoking and Tobacco Control Monograph No. 10

5.2.2.2 Exposure In Utero

or During Childhood

Wilcox et al. (1989)
trated their discussion on this reduced fecundability and did not comment

on the childhood ETS findings. No other information about the mothers of

these women was available for analysis.

Schwingl (1992) A recent study available as a dissertation (Schwingl, 1992) was conducted in association with researchers Baird and Weinberg, who conducted

studies described above. In this study, daughters of women who had participated in the Child Health and Human Development studies of the 1960’s

were followed into adolescence and recontacted when they were of reproductive age. Thus, prospectively collected data were available on prenatal

(or in utero) exposure of women who were now approximately 30 years old.

These women completed questionnaires about their most recent non-contracepting interval (NCI) of sexual activity to determine “attempt” times or

time to conception. Women never at risk of pregnancy were excluded, but

unlike the two previous studies, not all NCIs ended in pregnancy. The

crude FR for in utero smoke exposure varied only slightly with adjustment

for various confounders, and the final model yielded an FR of 1.2 (95% CI =

0.9-1.4). Adding childhood exposure to the model reduced the in utero FR

slightly to 1.1. Childhood ETS exposure (one or two parents smoking) was

associated with FRs of 1.1-1.2. Current smoking by the daughters was also

not associated with fecundability (FR = 1.0-1.1 by amount smoked).

These findings do not support the findings of the two earlier studies

with respect to increased fecundability among women exposed to ETS as

children. The finding of little association with in utero smoke exposure is

similar to the Wilcox et al. (1989) study, but not that of Weinberg et al.

(1989). The finding of no association of reduced fecundability with active

smoking is inconsistent with most of the studies discussed above and in the

literature. The sample for this study was highly selected, as it included only

women who had remained in a longitudinal study during their childhoods

and who were still traceable; these women tended to come from families of

higher socioeconomic status than the original study population and were

mostly white. However, the mothers of the sample women had smoking

habits very similar to those of the original study population.

The standard study design for evaluating male and

female reproductive toxicity, the multi-generation breeding study, has apparently not been conducted with

tobacco smoke. One abstract using such a design was

located (Mays et al., 1987), but a report of the full study was not found in

the literature.

Two studies of ovarian cyclicity in female rats using mainstream

smoke have been reported. Tachi and Aoyama (1983, 1988) found disrupted estrus cycles but no effect on ovulation (number of corpora lutea produced once estrus occurred) or mating behavior (once estrus occurred) with

inhalation exposure to mainstream smoke. McLean et al. (1977) found that

mainstream smoke exposure in rats delayed the luteinizing hormone surge

associated with ovulation. In this study, the incidence of ovulation was

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Chapter 5

5.2.3 Animal Studies of

Female Fertility and

Fecundability and

Tobacco Smoke Exposure
reduced in rats exposed to smoke from a high (but not a low) nicotine cigarette. No studies of ovarian cyclicity using sidestream smoke have been

reported. 

An early study described ovarian atrophy in young mice after 2-3

months of exposure to mainstream smoke (Essenberg et al., 1951). A study

demonstrating oocyte destruction after exposure to cigarette condensates

has also been conducted (Mattison et al., 1989), but a full report of these

data was not located in the literature. No studies of ovarian pathology

using sidestream smoke were located. 

Studies using sidestream smoke exposure during pregnancy (discussed in Section 3.2.3) also contain information on female reproductive

toxicity, such as implantation and resorption rates and litter size. Of the

three studies using sidestream smoke, one (Witschi et al., 1994) reported a

reduced number of uterine implantation sites and a smaller number of live

pups at the end of gestation in rats, while the other two (Leichter, 1989;

Rajini et al., 1994) did not. The discrepancy between the Witschi et al.

study and the Rajini et al. studies, which used identical sidestream smoke

exposure methodology, may be due to the timing of the exposures. In the

Rajini et al. study, rats were not exposed on gestation days 4 and 5, the days

immediately preceding implantation (on day 6), while Witschi et al.

exposed their animals continuously from days 3 through 10 gestation.

By its association with various adverse reproductive outcomes

as well as certain chronic diseases, cigarette smoking appears to

be anti-estrogenic (Baron et al., 1990). Several studies have reported finding

altered levels of hormones or their metabolites in smokers as compared to

nonsmokers. Both the steroids estrogen and progesterone, as well as homeostatic hormones (from the adrenal or pituitary glands) may be affected

(MacMahon et al., 1982; Michnovicz et al., 1986; Seyler et al., 1986; BarrettConnor, 1990; Canick and Barbieri 1990; Stillman et al., 1986). Nicotine

has been suggested as the primary constituent in tobacco smoke that produces these effects (Stillman et al., 1986).

The study of infertility (and fecundability) is complicated by the

fact that it includes a number of components that may have different causes. Successful reproduction is a multi-step process that includes gametogenesis, ovulation, fertilization, tubal transport, implantation, and early placentation, any of which might be affected by tobacco smoke exposure. The

entire process is mediated by hormones, so an alteration in their production or metabolism caused by constituents of tobacco smoke could impair

fertility. The processes most affected by such alterations would likely be

ovulation and perhaps implantation.

Other mechanisms have been suggested to explain an association

between smoking and reduced fertility (Stillman et al., 1986). Some human

and animal studies have suggested an effect of tobacco smoke or nicotine

on tubal physiologic features leading to altered tubal transport, which supports the findings of an association of smoking with tubal infertility.

Animal data suggest that exposure to tobacco smoke, or its nicotine and

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Smoking and Tobacco Control Monograph No. 10

5.2.4 Discussion

and Conclusions
PAH constituents, results in oocyte/follicle destruction, which could lead to

reduced fertility.

In summary, the mechanism by which smoking may affect fertility

has not been definitively identified, but such an effect appears plausible;

the epidemiologic literature on active smoking and fertility is supportive of

an effect. If active smoking leads to reduced fertility, ETS exposure might

also be associated with reduced fertility. The epidemiologic data on this

topic are not extensive and show mixed results. Three studies examined

conception delays (in women who ultimately became pregnant) with

respect to spousal smoking habits. Two of the studies (Suonio et al., 1990;

Olsen 1991), both conducted in Scandinavia, found slightly (about 30 percent) but significantly increased risks of conception delays (of 6 to 12

months). This is only slightly lower than the magnitude of association

seen with active smoking. A study in the United States did not find such

an association (Baird and Wilcox, 1985), nor did a study of time to conception in Dutch women (Florack et al., 1994). With the data provided, it is

not possible to compare the different studies in terms of smoking rates or

proportions of conceptions delayed, but exposures may well be more

intense in Scandinavia where smoking is generally more accepted and

prevalent. On the other hand, the U.S. study had more information about

sexual practices and evaluated delay to conception in a more rigorous fashion than did either of the “positive” Scandinavian studies. In addition,

because ETS exposure is defined as spousal smoking in these studies, the

association seen may be due to direct effects on male reproductive parameters. Thus, it is not possible to determine from the studies conducted to

date whether ETS exposure as an adult is associated with female fertility.

Three studies examined childhood ETS exposure and fecundability

(Wilcox et al., 1989; Weinberg et al., 1989; Schwingl, 1992). Two of them,

conducted by the same investigators but in different populations, found

that childhood exposure tended to increase the fecundability ratio, or likelihood of conceiving; the third study did not confirm this finding. Potential

problems with the studies of childhood exposure include the reliability of

exposures reported with a longer period of recall and the lack of ascertainment of other covariates associated with childhood exposure. No mechanism to explain this increased fecundability has been suggested by the data

collected to date. An inconsistency in these data is that in utero exposure to

tobacco smoke (from maternal active smoking) was not associated with a

similar pattern of increased fecundability. Such exposure occurs at another

time in development (and is not considered to be ETS exposure for the purpose of examining reproductive and developmental effects in this document).

Animal studies have demonstrated effects of tobacco smoke exposure on ovarian cycles and implantation that are compatible with reduced

fertility. However, multigeneration studies that would provide a more complete evaluation of effects of chronic exposure on production of offspring

have not been conducted.

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Chapter 5
In conclusion, the data are inadequate to determine whether there

is an association of ETS exposure with effects on fertility or fecundability.

In addition to studies of fertility and fecundability,

investigators have examined the role of exposure to

tobacco smoke on earlier age at menopause and on rates of menstrual disorders.

Substantial data exist to document that smokers have

earlier age at menopause (U.S. DHHS, 1980; Midgette

and Baron, 1990; Tajtakova et al., 1990). The mean

age at menopause in smokers is on average 2 years less

than that of nonsmokers. Some studies have also suggested increases in

menstrual disorders associated with cigarette smoking (Brown et al., 1988;

Sloss and Frerichs, 1983). Furthermore, as discussed above (Section 5.2.4),

cigarette smoke appears to be anti-estrogenic and may affect homeostatic

hormones as well.

Everson et al. (1986) reported an association of ETS

exposure and lower age at menopause. Data were

obtained from 261 women who had been controls in

a case-control study of cancer in North Carolina. The

mean age at menopause was reduced by 2 years

among nonsmoking women whose spouses smoked, compared to those

whose spouses did not smoke. The risk of early menopause was elevated in

nonsmokers exposed to ETS (“passive smokers”) compared to those not

exposed (OR = 1.9, 95% CI = 1.0-3.9). Adjustment for some confounders

(age, race, education, and alcohol intake) increased the odds ratio to 2.1

(95% CI = 1.0-4.5). Both these measures were similar to the association

observed for active smoking and earlier age at menopause in this study.

The authors found that childhood exposure to paternal smoking was not

associated with early menopause. Only four subjects had mothers who

smoked and these subjects’ age at menopause was reduced about 2 years.

These findings were reported in a brief format, so details of the study design

and analysis were not available. For example, the definition of early

menopause was not specified, nor was it clear if the term “passive smokers”

included those exposed to a parent or only to a spouse who smoked.

Whether the decrease of 2 years in the age at menopause of passive smokers

was statistically significant is not discussed. The finding of an association

with maternal, but not paternal, smoking during the subject’s childhood

appears inconsistent. However, the estimate (OR) of the maternal association is based on very small numbers and is probably imprecise. On the

other hand, children may be more exposed to their mothers’ smoking

habits than to their fathers’, and children of mothers who smoke may also

have been exposed in utero.

Tajtakova et al. (1990) One additional study (Tajtakova et al., 1990) provided data on

age at menopause and exposure to ETS, but it was published in Slovak and

therefore could not be thoroughly evaluated. According to the English

abstract, women who were smokers had a mean age at menopause 1.7 years

younger than that of nonsmokers; the dose-response relationship was such

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Smoking and Tobacco Control Monograph No. 10

5.3 OTHER FEMALE

REPRODUCTIVE EFFECTS

5.3.1 Overview of Human

Studies of Other Female

Reproductive Effects and

Active Smoking

5.3.2 Human Studies of

Other Female Reproductive

Effects and ETS Exposure

Everson et al. (1986)
that the mean age at menopause was up to 2.4 years earlier in heavier

smokers, consistent with other studies. Those exposed to ETS had a mean

age at menopause that was slightly younger than nonexposed nonsmokers,

but the difference was not statistically significant. We calculated a difference of -0.7 years (95% CI = -1.9-0.51) from data presented in a table.

These differences are unadjusted for confounders.

No material was located which used an animal model

for menopause.

Two studies found indications of early menopause associated with ETS exposure, which is consistent with

findings of early menopause among active smokers.

The possible mechanisms described in relation to infertility (Section 5.2.4), such as hormone perturbations or

oocyte destruction, might also influence age at menopause. The magnitude

of the effect of ETS exposure on age at menopause, because it is similar to

that of active smoking, seems large in one of the studies. However, studies

of the effect in active smokers generally compare smokers to all nonsmokers, including those exposed to ETS. If there is an association with ETS

exposure as well, studies of active smokers should exclude ETS-exposed

women from the comparison group, which should then strengthen the

association seen with active smoking. Everson et al. (1986) demonstrated

such a phenomenon in their data. More studies are needed to confirm this

finding of decreased age at menopause with exposure to ETS. While

human studies have examined the effects of active smoking on menstrual

disturbances and hormonal status, none were found that examined these in

relation to ETS exposure.

In conclusion, there is a paucity of data on the association of ETS

exposure and lowered age at menopause or other measures of menstrual

cycle dysfunction, and conclusions regarding causal associations cannot be

reached.

Male reproductive toxicity includes altered sperm

parameters, such as lower density, decreased motility

or abnormal morphology, and effects on fertility. 

Several studies have shown an association between

active smoking and altered sperm parameters,

including abnormally shaped sperm (Evans et al.,

1981), decreased seminal fluid and decreased sperm motility (Marshburn et

al., 1989). Authors of a recent meta-analysis of the literature on sperm density and smoking (Vine et al., 1994) concluded that smokers’ sperm density

is on average 13-17 percent lower than that of nonsmokers. The 1980

Surgeon General’s Report (U.S. DHHS, 1980) states that “spermatogenesis,

sperm morphology, sperm motility and androgen secretion appear to be

altered in men who smoke.” These outcomes could result from some of the

same mechanisms proposed to explain the effects of smoking on female

179

Chapter 5

5.3.3 Animal Studies of

Other Female

Reproductive Effects and

Tobacco Smoke Exposure

5.3.4 Discussion and

Conclusions

5.4 MALE REPRODUCTIVE

TOXICITY

5.4.1 Overview of Human

Studies of Male Reproductive

Toxicity and Active Smoking
reproductive functions, namely alterations in hormone regulation and

gamete production.

No published studies were found that were designed

to examine the association between ETS exposure of

males and altered sperm parameters or fertility. The

report by Wilcox et al. (1989) of their Minnesota study (described above in

Section 5.2.2.2) briefly states that childhood ETS or in utero exposure of the

husband was not related to the couple’s fecundability (i.e., time to pregnancy). Another study (Ratcliffe et al., 1992) examined the effects of early

exposure to maternal smoking on fertility in adult males using data from

clinical trials of diethylstilbesterol treatment (DES). This study could not

separate in utero exposures (due to maternal active smoking) from postnatal

ETS exposure. The authors reported no significant effects on sperm quality,

hormone levels or perceived infertility in the sample of 229 men in the follow-up study. However, among the subgroup of men not exposed to DES,

there was a significant decrease in sperm motility and a significant increase

in oligospermia (deficiency in the number of spermatozoa in the semen);

this subgroup is probably more representative of the general population

than those who were exposed to DES. Confounders other than adult smoking status of the subjects were not assessed. Compared to nonsmokers,

men who smoked as adults had a significantly lower percentage of sperm

with normal morphology, after adjustment for maternal smoking and DES

exposure.

No animal studies specifically examining male fertility and exposure to mainstream or sidestream

smoke were located. There are some limited data

on testicular pathology from chronic toxicity studies using mainstream

smoke. Viczian (1968) reported disruption of the sperm cycle in male rats

exposed for 15 minutes 8 times daily for 6 weeks. Dontenwill et al. (1973a

& b) reported a higher incidence of testicular atrophy in hamsters exposed

for 6 to 80 months. This effect occurred only with certain cigarettes and

particular daily exposure durations. The functional implications of these

results are unclear. No studies of testicular pathology using sidestream

smoke were located.

No epidemiologic or animal studies were found which investigated the association of ETS exposure and male reproductive

parameters. A study that examined the effects of early exposure to maternal smoking (both in utero and postnatal ETS exposure) found significant

differences in sperm motility and oligosperma in the subgroup of subjects

not exposed to DES. Associations have been seen in human studies of

active smoking and sperm parameters. Therefore, the findings of subfecundability in women exposed to ETS sby husbands who smoke may in

fact be due to direct effects of active smoking on male reproductive capacity

rather than to the effects of ETS exposure of the women.

In conclusion, due to the paucity of data it is not possible to determine whether there is a causal association between ETS exposure and male

reproductive dysfunction.

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Smoking and Tobacco Control Monograph No. 10

5.4.2 Human Studies of

Male Reproductive Toxicity

and Exposure to ETS

5.4.3 Animal Studies of Male

Reproductive Toxicity and

Exposure to Tobacco Smoke

5.4.4 Discussion

and Conclusions
Though active smoking by women has been found to

be associated with decreased fertility in a number of

studies, and tobacco smoke appears to be anti-estrogenic, the epidemiologic

data on ETS exposure and fertility are not extensive and show mixed

results. A well-controlled study in the U.S. found no association of conception delays with spousal smoking habits, contrary to the results of two

Scandinavian studies which found slight increases in conception delays but

were potentially more biased studies. A recent Dutch study also did not

find an association, but included maternal smokers. When ETS exposure is

defined as spousal smoking (as in all these studies), any association seen

may be due to direct effects of active paternal smoking on male reproductive parameters. Two studies have found an association between ETS exposure during childhood and increased fecundability (in adulthood); a third

study did not confirm these findings. All three studies are constrained by

lack of information on potential confounders related to childhood ETS

exposure. Thus, it is not possible to determine from the conflicting epidemiologic studies conducted to date whether or not ETS exposure is associated with changes in female fertility or fecundability.

One study found a strong association of early menopause with ETS

exposure, which is consistent with findings of early menopause among

active smokers. Another study reported a slight, non-significant decrease in

age at menopause. Because the analytic methods of these two studies could

not be thoroughly evaluated, more studies are needed to confirm this finding. While the effect is biologically plausible, at present there is not firm

evidence that ETS exposure lowers the age at menopause or affects other

measures of female reproductive dysfunction.

No epidemiologic or animal studies were found which investigated

the association of ETS exposure and male reproductive parameters.

Associations have been seen in human studies of active smoking and sperm

parameters. At present, there is inadequate evidence to draw conclusions

regarding the effect of ETS exposure on male reproductive dysfunction. 

181

Chapter 5

5.5 CHAPTER SUMMARY

AND CONCLUSIONS

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The relationship between ETS exposure and a variety of

nonmalignant respiratory tract health endpoints has been examined extensively in the epidemiologic and experimental literature. Among children,

the most common outcomes studied include asthma induction and exacerbation, alterations in lung development, and otitis media and chronic middle ear effusions in children. Among adults, endpoints of interest have

included lower respiratory tract symptoms, reduced lung function, and

acute irritative symptoms of the upper respiratory tract. Each of the lower

respiratory tract endpoints, as well as otitis media, were reviewed in reports

by the Surgeon General’s Office (U.S. DHHS, 1986), the National Research

Council (NRC, 1986), and most recently by the U.S. Environmental

Protection Agency (U.S. EPA, 1992); upper respiratory tract irritation and

sensory annoyance were reviewed in the Surgeon General’s and NRC

reports only. This chapter synthesizes the data considered in these prior literature reviews with results from more recent studies in order to assess the

possible relationship between ETS exposure and each of the above-mentioned health endpoints.

Asthma is a chronic respiratory condition characterized by airway inflammation and episodic airflow limitation. Depending on the clinical definition used, about 2-3 percent of adults and up to 10 percent of children

may be affected (Evans et al., 1987b; Schwartz et al., 1990; Gergen and

Weiss, 1990; Gerstman et al., 1989). Asthma is the most common chronic

condition of childhood and in 1990 accounted for approximately $6.2 billion in health care expenditures nationally (CDC, 1992). No similar cost

estimate is available for California; however, in the state in 1993, there were

approximately 43,000 admissions to hospitals with a primary diagnosis of

asthma, about 18,600 of which were for children under age 18 (personal

communication: Dr. Marvin Bohnstedt, California Department of Health

Services). Typical symptoms of asthma include cough, chest tightness, difficulty breathing, and wheezing. One of the hallmarks of asthma is airway

hyperresponsiveness, an exaggerated tendency of the airways to constrict in

response to chemical agents, such as methacholine or histamine, or to

physical stimuli, such as cold, dry air.

In its recent review, the U.S. EPA (1992) concluded that, “There is

now sufficient evidence to conclude that passive smoking is causally associated with additional episodes and increased severity of asthma in children

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6.0 INTRODUCTION

6.1 ACUTE HEALTH EFFECTS

6.1.1 Asthma (exacerbation)
186

Results3.1± 0.4 vs. 1.8 ± 0.3* (p = 0.008) emergenc

room visits per year inchildren of smoking anonsmoking parents

*mean ± standard e

Significantly increasedresponse in asthmaticsubjects whose mothesmokedHigher scores (p < 0.0

in children of smokingmothersNo effectHigher levels of cotiniin asthmatic children OR = 1.9 (95% CI = 1.0-3.4)

Outcome VariableEmergency room visitsand hospitalizations forasthma (from medicalrecords)Bronchial response tocold airAsthma symptom scorefor severity of asthmaChanges in lung functionEmergency room andasthma clinic visits

ETS ExposureAssessmentParental questionnaireParental questionnaireParental questionnaireDirect exposure toETS for 1 hourCotinine levels inurine of children;smoking by maternal caregiver

Population Studied191 children, aged 4to 17 yrs. in New York,New York292 subjects aged 6to 21 yrs. in Boston,Massachusetts415 children aged 1 to17 yrs. with asthma inVancouver, Canada11 asthmatic children228 children: 72 withacute asthma, 35 withnonacute asthma, and121 controls

AuthorsEvans et al.

(1987b)O’Connor et al.

(1987)Murray and Morrison (1989)Oldigs et al. 

(1991)Ehrlich et al. 

(1992)

Table 6.1Studies Cited by U.S. EPA (1993) as Evidence Supporting a Causal Relation Between ETS ExpIncreased Episodes and Severity of Asthma in ChildrenSource: Adapted from U.S. EPA (1993), Table 7-7
who already have the disease” (p. 248). This conclusion appears to have

been based on a review of several studies summarized in Table 6.1. These

and additional relevant studies are described in the following pages.

Evans et al. (1987b) analyzed data on 276 children from

low-income families receiving care for asthma at outpatient

clinics of several New York City hospitals. Information on ETS exposure

was obtained during interviews of the parent or guardian and the child.

Data on emergency room (ER) visits and hospitalizations were obtained by

reviewing records for a 1-year period; data on lung function were obtained

during a random clinic visit occurring within 1 year after the interviews.

Eight children who admitted to active smoking were excluded from the

analysis, as were 77 other children with incomplete data. The relationships

between the child’s ETS exposure (as reported by the parent or guardian)

and the outcome variables were analyzed by multiple-regression techniques

in which the influence of up to 34 potential confounders and effect modifiers were considered, including age, gender, ethnicity, several indicators of

socioeconomic status, indices of medical management, and an index of residential allergen and irritant exposure, among others. Evans et al. reported

that ER visits were positively associated with reported ETS exposure (p <

0.01). The mean annual frequency of ER visits among the children exposed

to ETS in the home was 3.09 ± 0.40, while that for children not exposed

was 1.83 ± 0.29. Thirty-nine percent of children from nonsmoking homes

made no ER visits, compared with 29 percent of children from households

with smokers. In addition, 13 percent of children from nonsmoking homes

made four or more ER visits, compared with 32 percent of children from

smoking households. 

Evans et al. also reported, however, that ETS exposure was not associated with either hospitalizations or with percentage of predicted lung

function. While ostensibly inconsistent with the ER results, there were relatively few hospitalizations during the period of observation (191 children x

0.20 (mean) hospitalizations/child/yr Å 38), resulting in a low power to

detect an effect. Furthermore, to the extent that nondifferential misclassification of exposure occurred (or that some smokers may have reported that

they were nonsmokers), the analysis could be biased against finding an

effect. Either of these types of misclassification of exposure would also tend

to diminish the reported relationship between ETS exposure and ER visits.

The report does not provide enough information to evaluate the lack of

association of ETS exposure and lung function. The protocol for pulmonary function test (PFT) administration is not well described; for example, it is not clear whether any children were experiencing an asthma flare

when tested. Here also, misclassification of exposure status could also create a bias against finding an association. 

More recently, Chilmonczyk et al. (1993) undertook a study of similar design to that of Evans et al.(1987b), using more sensitive indicators of

asthma exacerbations (review of medical records at a large allergy/asthma

clinic) and of ETS exposure (measurement of urinary cotinine at enrollment

in addition to parental questionnaire). Cotinine is the major metabolite of

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6.1.1.1 Epidemiologic

Evidence
nicotine and is a good integrated indicator of recent ETS exposure (1-2

days; see chapter on Exposure Measurements and Prevalence). Review of medical records was done by observers blinded to the children’s ETS exposure

status. Of the 199 children (aged 8 months to 13 years, mean Å 7.5 years)

enrolled in the study, 145 were old enough to undergo pulmonary function

testing. Whether assessed by urinary cotinine or by parental reporting, ETS

exposure was found to be associated with increased frequency of asthma

exacerbations in a dose-dependent manner. Using multiple-regression techniques that adjusted for the child’s age, gender, daycare attendance, and the

mother’s age and educational level, the investigators reported relative risks

for the highest versus the lowest exposure categories of 1.7 (95% CI = 1.4-

2.1) for exposure assessed by cotinine and 1.8 (95% CI = 1.4-2.2) for parentreported exposure. Pulmonary function tests reported as percent predicted

FEV1 (forced expiratory volume in 1 second—a measure of lung volume and

central airway caliber) and FEF25-75 (expiratory flow during the middle half

of a forced vital capacity (FVC) maneuver—an indicator of the caliber of the

more peripheral, mid-sized to smaller airways) were decreased with

increased ETS exposure in a dose-dependent manner, with urinary cotinine

as the exposure indicator.

In this investigation, parental reports of no ETS exposure were consistent with the cotinine results 86 percent of the time, while the concordance of reported exposure and cotinine measurements was 77 percent.

Henderson et al. (1989) have previously shown that cotinine levels in preschool children tend to be stable over at least a 4-week period, presumably

due to regular daily patterns of ETS exposure. Ogborn et al. (1994) reported

similar findings in children aged 3 to 11 (see below). To the extent that the

single urinary cotinine measurement in the study by Chilmonczyk et al.

was an accurate reflection of longer-term exposure, this study suggests an

exposure-related chronic effect on exacerbations of pediatric asthma and on

indices of lung function.

Murray and Morrison (1989) examined 419 children aged 1 to 17

attending an allergy clinic in Vancouver, British Columbia. At the initial

visit, a trained interviewer administered a standardized questionnaire to the

parent and the patient containing questions regarding the child’s asthma

history, symptoms and medication use, other respiratory illnesses, and a

variety of potential residential exposures (ETS from one or both parents,

whether a woodstove was used for home heating or a gas stove for cooking,

the presence of cats or dogs). The children were asked privately if they

were themselves active smokers: the four that admitted to this were excluded from the analysis. The investigators created an asthma severity score

based on questionnaire responses. In addition, the patients had allergy

testing (by skin prick), spirometry (for those 3 6 years old), and an examination of bronchial reactivity to histamine (in children 3 7 years old).

Children of smoking mothers (n = 92) had more severe asthma than children of nonsmoking mothers (n = 322), as evidenced by an increased asthma score, and greater airway reactivity, as well as decreased FEV1 and FEF25-

75 (for all these differences, p < 0.01). These results were driven by the

effects observed in boys; for girls, only the asthma severity score was significantly increased with smoking versus nonsmoking mothers.

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Murray and Morrison found that differences between asthmatic

children of smoking versus nonsmoking mothers became more pronounced

with increasing age (or duration of exposure). In multivariate regressions of

these indices of severity on several independent variables (recent respiratory

infection, recent bronchodilator use, positive skin prick test, presence of gas

stove or wood stove, and the number of cigarettes smoked at home by

either parent), stratified on age and/or gender, maternal smoking repeatedly

emerged as one of the two strongest predictors of asthma severity. Paternal

smoking was generally without effect.

The results of this study were consistent with earlier publications by

the same investigators using subsets of this study population (Murray and

Morrison, 1986 and 1988). In an analysis of 240 subjects for whom data

were collected as described above (for the 1989 publication), Murray and

Morrison found a highly significant association between indices of

increased asthma severity (here limited to airway reactivity, FEV1, and FEF25-

75) and maternal smoking, with no such associations observed for paternal

smoking. Hypothesizing that the children’s asthma would be exacerbated

during the colder, wetter months (when homes would be kept more tightly

closed and children would spend more time indoors, thereby increasing the

intensity of ETS exposure), they stratified the analysis by season (October

through May versus June through September). They observed no differences in any of the above indices between children of smoking and nonsmoking mothers during the dry season, but found highly significant differences in FEV1, FEV25-75, and airway reactivity during the wetter months.

Moreover, during the wet, but not the dry, season there was evidence of an

exposure-response relationship between the number of cigarettes smoked

by the mother in the home with each of these indices. These relationships

were corroborated by multiple regressions of FEV1, FEF25-75, and airway reactivity on age, duration of asthma, gender, recent respiratory infection,

recent medication use, positive skin allergy test, family history of asthma,

presence of pets, heating type, presence of a gas range, number of siblings,

and parental smoking.

More recently, Murray and Morrison (1993) expanded their analysis

to include 807 nonsmoking asthmatic children and adolescents meeting

the same eligibility requirements and for whom similar data were collected

as in these authors’ prior reports. In this analysis, they compared indices of

asthma severity in children first attending the asthma clinic before July

1986 with those attending afterward. They reported that, among children

with at least one smoking parent, reported daily exposures to cigarettes

smoked in the same room were markedly lower after 1986 (3.4 after versus

6.6 before for smoking mothers (p = 0.005) and 2.0 after versus 4.6 before

for fathers (p = 0.001)). Concomitant with this apparent decline in exposure, children of smoking parents entering the study after July 1986 had

asthma that was less severe than those entering earlier, as manifested by significant improvements in the asthma score, FEV1 and FEF25-75. Among children of nonsmoking parents who enrolled after July 1986, the asthma

severity score was not significantly different, but both FEV1 and FEF25-75

were increased, though less so than among the children of smoking par189

Chapter 6
ents. Improvements in pulmonary function test values occurred regardless

of the smoking status of either parent; however, a significant difference in

the asthma severity score was observed only among the children of smoking mothers. Modeling the spirometric indices as a function of numbers of

cigarettes smoked in the same rooms as the child(ren), controlling for several relevant covariates (age, gender, age of asthma onset), Murray and

Morrison found that the differences among smokers’ children across the

time periods decreased, which would be expected if exposure to parents’

smoking is one of the etiologic factors underlying the difference. Airway

reactivity showed no marked differences in before/after comparisons within

either group of children. In light of the significant improvement in the

other indicators of asthma severity, the lack of a significant change in airway reactivity was unexpected; the authors had no ready explanation for

this anomaly other than that the persistent hyperresponsiveness of these

asthmatics’ airways might not have been affected by recent decreases in

exposure to parental ETS.

O’Connor et al. (1987) examined the relationship between parental

smoking and airway reactivity in 286 children, aged 6 to 21years (mean Å

13), in East Boston. Airway responsiveness was assessed by measuring FEV1

before and after challenge with subfreezing air. Of the 21 asthmatic study

subjects, those with smoking mothers showed a greater reduction in FEV1 in

response to cold air challenge than did those with nonsmoking mothers (24

± 3.3 percent versus 11.9 ± 4.8 percent, respectively; p = 0.07). In multiple

linear regression models examining cold air-induced change in FEV1 as the

dependent variable in relation to nine putative independent variables,

maternal smoking emerged as a significant (p = 0.02) predictor of ÆFEV1,

after adjusting for predicted FEV1. In a stepwise multiple linear regression,

maternal smoking and predicted FEV1 were the only two variables to enter

the model. Paternal smoking was unrelated to bronchial responsiveness in

any analysis. The small sample size of the asthmatic children and adolescents in this study limits both the statistical significance and the generalizability of the findings. Nevertheless, the trend observed in this investigation is consistent with the results reported by Murray and Morrison (1989).

Strachan and Carey (1995) reported the results of a case-control

study of residential environmental determinants of severe asthma among

763 children, aged 11-16, in Sheffield, England. To be eligible, the child

must have had 12 or more episodes of wheezing or at least one speech-limiting attack of wheezing (during which the child could say only one or two

words between breaths). Controls who had no history of asthma or wheeze

at any age were frequency matched on age and school class. ETS exposure

was assessed by parental questionnaire. The analysis focused on factors in

the home environment that contributed to status as a case, which was

defined as having had at least 12 episodes of wheezing, one or more

speech-limiting attacks, or both. The only ETS-related data pertained to

three current parental smoking categories: none, 1-10, or >10 cigarettes/day.

While paternal smoking was unrelated to the outcomes examined, maternal

smoking of >10 cigarettes/day was significantly related to the combined category of frequent wheezing plus speech-limiting attacks (crude odds ratio

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Smoking and Tobacco Control Monograph No. 10
2.28, p < 0.05). However, in models adjusting for numerous other household factors (e.g., current and past pet ownership, type of pillow and bedding used, age of mattress, and so forth), the odds ratio for maternal current smoking was still elevated (1.49) but no longer significant. It is not

clear from this report whether the investigators examined the “healthy passive smoker effect,”—i.e., whether the parents of children most severely

affected stopped smoking because of the children’s asthma. This study

examines risk factors for having severe asthma versus not having asthma at

all; it does not address whether exposure to ETS or other factors influence

the severity of asthma among children who already have the disease.

Household ETS exposure may affect severity of asthma in adults as

well as children. Jindal et al. (1994) investigated several measures of respiratory morbidity in 200 never-smoking adult asthmatics, aged 15 to 50,

attending an outpatient chest clinic in India. Information on ETS exposure

and on various indices of asthma control during the preceding year were

obtained by questionnaire during a clinic visit. ETS-exposed participants (n

= 100) were defined as those who reported a minimum of 1 hour exposure/day, or 7 hours/week, for at least 1 year. Indices of asthma control

included lung function measurements, the use and number of maintenance

bronchodilator medications, requirement for corticosteroids (presumably

orally administered, though this is not clear from the article), number of

visits to the emergency department, admissions to the hospital, number of

acute episodes, and number of times that the patients used parenterally

administered (i.e., via injection) asthma medications at home (reportedly a

common practice in the study area). Pulmonary function testing was done

within 24 hours of the clinic visit at which the questionnaire was administered. In comparison with a nonexposed group of 100 patients, the ETSexposed group showed significantly lower forced expiratory lung function

indices (FEV1, FEV1/FVC, and FEF25-75). In addition, though the numbers of

patients in the two groups did not differ with respect to most of the morbidity measures, the ETS-exposed group included significantly more

patients on maintenance bronchodilator therapy and corticosteroids

required to control symptoms. When expressed on a per-patient-per-year

basis, however, all the indices in the ETS-exposed group were significantly

higher, except for the numbers of hospital admissions and weeks of bronchodilator use per patient. Although not conducted or analyzed as meticulously as the investigation by Chilmonczyk et al. (1993, above), this report

suggests that regular ETS exposure may affect control and severity of asthma in adults as well as children.

Bailey et al. (1990) report a primarily descriptive examination of

patients served by the Comprehensive Asthma Program of the University of

Alabama at Birmingham. Though the investigators apparently examined

the prevalence of passive smoking among the 263 of 479 patients served by

this clinic program, there were no data on ETS exposure assessment or

prevalence or on the relationship of ETS exposure to asthma severity provided in the report, other than that the investigators “found no relationship between asthma severity and ... passive smoking,” and that “exposure

at work was more common (for those who worked) than exposure at

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Chapter 6
home.” This report analyzed numerous asthma co-morbidities and potential determinants of severity and asthma management, but, unlike the

Jindal study, provides no information about ETS exposure assessment, and

hence is difficult to evaluate.

Hong et al. (1994) examined the influence of numerous lifestyle and

behavioral influences on indices of asthma morbidity in 787 of 1,352 eligible adult patients, aged 21-54, attending government-run asthma outpatient clinics in Singapore. Asthma morbidity was assessed by questionnaire

and the dichotomous outcome variable of “increased morbidity” was designated to include, during the year preceding administration of the questionnaire, 31 “attack”/week (in the day or at night), 34 urgent care visits for

asthma, 31 hospital admission, or 37 days of sick leave. Unlike the Jindal

study, which undertook a quantitative assessment of the relationship

between ETS exposure and a variety of indices of asthma severity, Hong et

al. apparently collapsed their indices of severity into a single dichotomous

variable, thereby decreasing substantially the likelihood of detecting any

effect of ETS exposure. In addition, this study provides no detail about

exposure assessment, other than that it was ascertained by questionnaire

and that it was treated as a dichotomous variable. Dichotomizing ETS

exposure as well would tend to bias the analysis towards the null hypothesis of no effect. These limitations, in addition to potential selection bias

(fewer than 65 percent of eligible patients were included in the analysis) all

limit the interpretability and generalizability of this study.

The above reports support the existence of an association of chronic

or repeated ETS exposure with severity of asthma measured by a variety of

indices. In several epidemiologic studies, ETS has been implicated as a risk

factor for exacerbation of asthma, measured as an increase in symptoms,

medication use, and clinic or emergency room visits (Evans et al., 1987a;

Chilmoncyzk et al., 1993; Jindal et al., 1994; Ostro et al., 1994 (see below)).

Airway responsiveness, one indicator of asthma severity, tends to be

increased in asthmatic children whose mothers smoked in comparison with

those with nonsmoking mothers (O’Connor et al., 1987; Murray and

Morrison, 1989). The results of one controlled-chamber investigation suggest that even single exposures of adult asthmatics to ETS can elicit prolonged airway hyperresponsiveness (AHR), which could provide experimental support for the epidemiological observations (Menon et al., 1992).

Increased airway responsiveness facilitates bronchoconstriction (and the

concomitant symptoms of chest tightness, wheeze, and difficulty breathing)

in response to respiratory irritants, such as ETS (NRC, 1986). The above

findings support the assessment articulated by the U.S. EPA that there is sufficient evidence to support the inference of a causal relationship between

ETS exposure and “additional episodes and increased severity of asthma in

children who already have the disease.” 

Whether acute ETS exposure can precipitate a specific asthma flare

is not so clear-cut, however. Ehrlich et al. (1992) undertook a case-control

study of 72 children visiting the emergency room (ER) for their asthma, 35

children attending an asthma clinic who were not acutely ill, and 121

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Smoking and Tobacco Control Monograph No. 10
nonasthmatic control children. ETS exposure was assessed by questionnaire

and by urinary cotinine/creatinine ratios (CCR). Using a cut-point of 30 ng

cotinine/mg creatinine to distinguish exposed versus unexposed children,

they found no difference in recent ETS exposure between asthmatics

recruited from the ER and those from the clinic. In contrast, the ETS exposure odds ratio for all asthmatics versus controls was 1.9 (95% CI = 1.04-

3.35). The mean CCR in the acute asthmatics (46.2 ± 98.3) was greater

than that in the nonacute asthmatics (38.5 ± 74.1), but this difference was

not statistically significant. From the questionnaire responses, there was no

significant difference between acute and nonacute asthmatics in relation to

maternal smoking, whereas the exposure odds ratio for asthmatics versus

controls was 2.0 (95% CI = 1.1-3.4). This investigation suggests that ETS

exposure is a risk factor for clinical asthma but, in this study population,

may not have been a significant precipitant of asthma flares serious enough

to warrant a visit to the ER. However, the investigation by Ehrlich et al.

cannot adequately address the latter issue because of limited statistical

power (<50 percent probability of detecting a two-fold exposure difference

between acute and nonacute asthma), coupled with the likelihood that the

children recruited from the clinic had more severe asthma (with 80 percent

on daily asthma medication versus 36 percent of the ER patients).

Ogborn et al. (1994) also investigated whether there was an association between exacerbations of asthma and acute exposure to ETS. Data

consisted of parental responses to detailed ETS exposure questionnaires and

measurements of urinary cotinine obtained from children, aged 3 to 11,

who were seen during a visit to the ER or primary-care clinic during an

acute asthma flare and at a follow-up clinic visit after the flare had subsided. The investigators found no significant difference between mean urinary cotinine values (± standard deviation) at the acute versus the well visit

(81 ± 62 ng/ml and 77 ± 57 ng/ml, respectively). Similarly, the mean CCRs

at the acute versus the well visits were 93 ± 109 ng/ml and 97 ± 87 ng/ml,

respectively. (Note that the mean CCR values in this study are at least

twice as great as those reported in the Ehrlich et al. (1992) study, suggesting

heavy ETS exposure.) In this population, the prevalence of household

smoking was remarkably high (77 percent overall, and 63 percent among

the children’s mothers). However, this investigation is also limited by low

power—the sample size of 56 had a power of 0.80 (a = 0.05) to detect the

change in CCR expected to result from a 20-cigarette per day change in ETS

exposure. In other words, this study would have the power to detect a difference equivalent to household smokers’ (or other sources of ETS exposure)

reducing their consumption of cigarettes by one pack a day, over a severalweek interval, with no concerted smoking cessation intervention. Thus,

this underpowered study cannot address the issue of whether acute ETS

exposure can provoke an exacerbation of asthma.

However, the study by Ogborn et al. does provide additional interesting information about the stability of CCRs over time. The acute and

well visits of these children were separated by approximately 3 to 4 weeks

(detailed information on the timing of the visits is not provided in the

report). Among the children reported to be “exposed” to ETS, the mean

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Chapter 6
CCR was 105 ± 119 ng/ml at the ER visit and 105 ± 85 ng/ml at the followup visit, which is consistent with regular ongoing exposures. In addition,

this study provides evidence that parents may under-report ETS exposure.

Using a urinary CCR of 30 ng/mg as a cut-point for recent ETS exposure,

the mean CCR levels in the children reported not to have been exposed at

the acute and well visits were 41 ± 30 ng/ml and 83 ± 100, respectively.

There is suggestive recent evidence that ETS exposure may elicit

acute symptoms in adults. Ostro et al. (1994) investigated the relationships

between exposures to indoor combustion products and daily symptoms in a

population of adult asthmatics residing in Denver, Colorado. This study

included 164 subjects, many of whom had moderate to severe asthma, and

some of whom experienced respiratory infections and asthma flares during

the period of observation. This investigation also had more than 10,000

observations, which afforded substantial statistical power to detect associations with indoor exposures, including ETS. Both symptom and exposure

data were recorded by the study participants in an intake questionnaire and

in daily diaries over a three-month period. In multiple logistic regression

models corrected for serial correlation and repeated measures, these investigators reported an odds ratios of 1.61 (95% CI = 1.06-2.46) for restricted

activity days in relation to ETS exposure. They also reported significantly

increased odds ratios for the occurrence of moderate to severe cough and

shortness of breath, which were still elevated but no longer significant after

correction for autocorrelation. However, having a smoker in the home during the course of the study corresponded to an odds ratio of 2.05 (95% CI =

1.78-2.40) for increased daily moderate to severe shortness of breath, suggesting a relationship of chronic exposure to acute symptoms as well.

The studies reviewed in this section support the previous finding by

the U.S. EPA (1992) that there is “sufficient evidence...that passive smoking

is causally associated with additional episodes and increased severity of

asthma in children who already have the disease.” There is suggestive evidence that ETS exposure may exacerbate adult asthma. The U.S. EPA (1992)

estimated that ETS exposure potentially could exacerbate pre-existing asthma in approximately 20 percent of 2 to 5 million children, i.e., in 0.4 to 1

million children. Assuming that 12 percent of those children reside in

California would result in estimates of 48,000 to 120,000 asthmatic children who could experience a worsening of their condition due to exposure

to ETS.

Several chamber studies have investigated potential relationships between controlled exposure to ETS and lung

function and airway reactivity in asthmatic subjects. The results of these

investigations are summarized in Table 6.2. Experimental exposure of

human volunteers to various pollutants under controlled laboratory conditions can provide useful pathophysiological information. The principal

advantages of this methodology over epidemiological studies is that exposure to the pollutant(s) of interest can, in theory, be precisely measured,

and thus exposure-response relationships determined. While exposure conditions can also be controlled in animal experiments, the obvious strength

194

Smoking and Tobacco Control Monograph No. 10

6.1.1.2 Evidence from

Chamber Studies
195

Symptoms3/14 SOB;5/14 wheeze;6/14 chest tig5/14 cough.Symptoms repranged from tmoderate sev3/6- chest tigness; 2/6-whe

AirwayResponsivenessNot measured.

with histamine

on exposure vs.control days.

Lung FunctionSl. TLC and sl.

FVC for ETS vs.

sham exposures.4 "sensitive" subjects did not differfrom others’responses, exceptfor sl. FEV1.

Mean decline frombaseline of 11% onETS exposure vs.an increase of 4%on control day.

Exposure2-hr. mechanicalsmoke generationin a small room.Estimated TSPrange = 2-4mg/m3; CO average estimated to

be 24 ppm.1 hr. Mechanicalcigarette smokegeneration.

Subjects14 mild to moderate asthmatics(aged 19-65;9M/5F).6 patients with"mild to moderateasthma."

StudyShephard et al.(1979b)Knight andBreslin (1985)Table 6.2Controlled Exposures of Asthmatic Subjects to ETS
196

SymptoRespiratsymptomreportedboth asthand nonamatics resevere onasal anirritation.Not repo

AirwayResponsivenessNot tested.

with methacholine at 6 hr.

(32% vs. 18%) and24 hr. (29% vs.10%), for asthmatics vs. controls.

Lung Function5/6 "reactors" showed>20% FEV1 after 1-2

hr. exposure. Noneshowed 320% FEV1

after sham exposure.The 6th "reactor"showed >20% FEV1after 6 hr. exposure.No "nonreactors" orcontrols experiencedsignificant declines inFEV1 in either 2-hr. or

6-hr. ETS exposures.Pretreatment withdrugs blocked FEV1(p = 0.06 for single

drug; 

p = 0.03 for

combination)5/31 asthmaticsshowed 320% 

FEV1 vs. 0/39 controls.

Exposure2- or 6-hr. chamberexposure, with meanTSP = 1145 ±325μg/m3, mean nicotine= 205 ±54 μg/m3.

"Reactors" also subject to "sham" exposure in chamberwithout ETS."Reactors" subsequently retested afterpretreatment with abronchodilator(albuterol), an antiinflammatory medication (cromolyn sodium), or both.4 hr. chamber exposure, with mean TSP= 1266 ±283 μg/m3,

mean nicotine = 226±49 μg/m3.

Subjects15 self-reported"smoke-sensitive"asthmatics, including 6 "reactors" and9 "nonreactors" toprior ETS challenge(aged 25-51,3M/12F); 15 selfreported "smokesensitive" controlswith upper respiratory symptoms onexposure to ETS(aged 21-48;5M/10F). All subjects were atopic.31 "smoke-sensitive" asthmatics(11M /20F); 39"smoke-sensitive"controls with upperrespiratory symptoms (17M /22F). Allsubjects aged 12-50; atopic.

StudyMenon et al.

(1991)Menon et al.(1992)

Table 6.2 (Continued)
197

Sympto3/9-mild eye and pharyngeirritation.Only eye tion signdifferent ETS vs. exposureAll subjesimilar dof eye annasal irri

AirwayResponsivenessSl. with methacholine immediately post-exposure.No significant differences with histamine challengebefore and afterETS exposure.Not tested.

Lung FunctionSl. (2%)

FVC (p = 0.01). No

change in FEV1

No significant difference before and afterETS exposure inFEV1 or SRaw.

FVC 20%, FEV1

21.4%, FEF25-7519.2% in asthmatics; vs. no change to

SC. in these indicesamong controls. Progressive linear decrease in asthmatics’PFTs with increasingduration of exposure.

Exposure1 hr. chamber exposure, with mean CO = 40-50 ppm.Subjects allowed towear goggles.1 hr. chamber exposure, with mean TSP= 2,743 ±348 μg/m3,

mean nicotine = 397±78 μg/m3, mean CO

= 20.5 ±0.5ppm.During control exposure, mean TSP = 17±57 μg/m3, mean CO= 0.1 ±0.3 ppm.1-hour chamberexposure, CO estimated at 15-20 ppmbased on in subjects’ carboxyhemoglobin

Subjects9 mild, asymptomatic asthmatics(aged 19-30;5M/4F). Not selected on basis ofsmoke sensitivity.11 mild asthmaticchildren (aged 8-13,10M/1F); not selected on basis ofsmoke sensitivity.10 asthmatics(aged 18-26), 5 ofwhom were smokesensitive, 10healthy controls(aged 24-53)

StudyWiedemann (1986)Oldigs et al.

(1991)Dahms et al.

(1981)

Table 6.2 (Continued)
198

SymptomCough, dyand/or cheness in all with FEV

Eye irritatisubjects; ngestion anache in se

Airway Responsiveness Not tested. Lung Function 7/21 showed FEV1 exceeding 20%, maximum decrement Å50%. Exposure 2 hr. "low-level" exposure (mean par- ticle concentration = 852 ±52 μg/m3, mean CO = 8.7 ±1.7 ppm, mean nicotine = 180 ±44 μg/m3) for 2 sub- jects. All others had 2 additional hr. "high- level" ETS exposure (mean particle concentration = 1,421

±300 μg/m3, mean

CO = 13.3 ±3.2 ppm,mean nicotine = 439±121 μg/m3).

Subjects21 smoke-sensitiveasthmatics (aged21-50; 5M/16F);19/21 atopic.

StudyStankus et al. (1988a)

Table 6.2 (Continued)
199

SymptomNo signifsymptom ence betETS and air exposWeak symatic resthough dcough antightness creased ETS contions.

AirwayResponsivenessETS exposure didnot affect exerciseinduced bronchoconstriction.Not tested.

Lung FunctionTransient FEV1(7.2% ETS vs. 3.2%in ambient air).No effect in healthysubjects. 9/10 withAHR had FEV1,

5/10 had FEV1>

10%. Mean FEV1

= -6.5% at 2 ppm COand -8.7% at 32 ppmCO. ANOVA showedhighly significant (p <

0.0001) effect of ETSon FEV1, FVC and

MEF50.

Exposure1 hr. (54 min. at restand 6 min. bicycleexercise) mean particle concentration =3,197±665 μg/m3,

mean CO concentration = 20.2±0.7 ppm).Goggles worn to prevent eye irritation.Serially increasing 2-min. exposures toETS delivered viamouthpiece. COconcentrations =0,2,4,8,16 and 32ppm±5%. Subjectswore nose-clips during exposures.

Subjects13 atopic childrenwith asthma (aged8-13, 8M/5F)10 healthy and 10subjects withhyper-reactive airways (aged 24-51;8M/12F), 5 of lattergroup had asthma,3 additional subjects had symptoms suggestive of asthma.

StudyMagnussenet al. (1993)

Danuser 

et al. (1993)

Table 6.2 (Continued)

Sl. = slight, TSP = total suspended particulates, CO = carbon monoxide, TLC = total lung capacity, FVC = force

FEV1 = forced expiratory volume in one second, SOB = shortness of breath, AHR = airway hyperresponsivenes

airway resistance, FEF25-75 = forced expiratory flow during middle half of expiration, ANOVA = analysis of varian
of human chamber studies is that no cross-species extrapolation is required.

On the other hand, microscopic or biochemical examination of pollutantinduced tissue damage is more limited in humans by both ethical and practical considerations. However, controlled human exposures are also subject

to the following structural limitations: (1) only short-term responses to relatively brief exposures (i.e., minutes to hours) can be evaluated; (2) there is

often limited statistical power to detect effects, due to the typically small

number of subjects; (3) controlling the experimental conditions may result

in failure to capture effects found in complex real-world exposures; (4) multiple selection biases in recruiting volunteers reduce the generalizability of

such studies (e.g., systematic exclusion of people with a history of recent

respiratory infection; relatively few studies of children, adolescents, or other

potentially susceptible subgroups). It should be emphasized, however, that

these limitations all tend to underestimate pollutant effects. In contrast, the

use of ETS concentrations that exceed those likely to occur in most common exposure situations would tend to have the opposite effect (see Table

6-2). Given the potential shortcomings of such investigations, negative

findings may in some cases reflect the constraints of study design more

than biological reality.

In controlled exposure studies, volunteer subjects are exposed to

one or more pollutants through a mouthpiece (oral breathing only) or in a

chamber (oronasal breathing). ETS-related studies of asthmatics have mainly been conducted in exposure chambers with resting subjects. Data collected usually have included graded respiratory symptoms and a variety of

indices of pulmonary function, such as the amount of air a subject can

exhale in one second after a deep inspiration (FEV1) or the lung’s resistance

to airflow (airway resistance (Raw) or specific airway resistance (SRaw)).

Several studies of asthmatics involving ETS exposures have also examined

airway responsiveness, also known as bronchial reactivity (described below).

Chronic airway inflammation and episodic, reversible bronchoconstriction are hallmarks of asthma. Inflammation is associated with

bronchial hyperreactivity or hyperresponsiveness, which refers to an exaggerated tendency of the airways to constrict when exposed to respiratory

irritants or other substances. Airway hyperresponsiveness (AHR) is also

observed in many persons with emphysema and bronchitis and in otherwise healthy individuals during and after respiratory tract infections and

after exposure to respiratory irritants such as ozone. In general, however,

such reactivity is markedly greater in asthmatics compared with nonasthmatics. Airway responsiveness to numerous stimuli can be measured in

clinical studies. Methods used to induce and measure nonspecific

bronchial reactivity in asthmatics include exercise or hyperventilation with

cold or dry air, or inhalation of pharmacological agents (e.g., histamine or

methacholine). Although these pharmacological agents also cause bronchoconstriction in healthy individuals, asthmatic airways constrict at much

lower exposure concentrations. AHR creates the potential for a flare or

exacerbation of asthma, with heightened bronchial responses to other nonspecific airborne irritants.

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Smoking and Tobacco Control Monograph No. 10
The series of studies conducted at Tulane University (Stankus et al.

1988a; Menon et al., 1991 and 1992) suggests that a substantial fraction of

asthmatics with self-reported sensitivity to ETS also appear to demonstrate

susceptibility by more objective means of assessment (tests of lung function

and airway responsiveness). While such susceptible individuals have

increased baseline AHR (as measured by methacholine challenge testing),

nonspecific airway reactivity does not fully explain this sensitivity, since

other asthmatics with increased AHR do not show marked reactions to ETS

inhalation challenge. Although the physiologic basis for susceptibility is

not well understood, the effects of exposure on such ETS-reactive and nonreactive individuals appear to be reproducible, suggesting the existence of

intrinsic individual characteristics (Stankus et al., 1988a; Menon et al.,

1991). Though these acute studies cannot replicate exposure conditions

experienced by free-living subjects, the findings of increased AHR support

the epidemiological studies described earlier, which indicate that repeated

household ETS exposures tend to result in worse control of asthma.

Most of the ETS inhalation chamber studies show slight-to-moderate transient effects on lung function in at least some of the study subjects.

In several studies, participants experienced decrements in lung function

exceeding 20 percent, which would be considered clinically significant, particularly in conjunction with the occurrence of lower respiratory symptoms

such as chest tightness, dyspnea, and cough. To the extent that subjective

symptoms of asthma were reported, clinically meaningful respiratory symptoms were identified in some participants in several studies (Knight and

Breslin, 1985; Dahms, 1981; Stankus et al., 1988a; Shephard et al., 1979a);

however, this was clearly not a universal finding (Magnussen et al., 1993;

Oldigs et al., 1991). AHR occurring after ETS exposure was also reported

inconsistently in these studies; nevertheless, the only studies that examined

delayed AHR at times that would be likely to detect the effects of an inflammatory response did find significant ETS-associated increases (Menon et al.,

1991 and 1992).

The controlled exposure studies do not clearly demonstrate a consistent effect of acute ETS exposure on asthmatics as a whole. As noted above,

however, general design constraints in such studies militate against finding

effects, e.g., small sample size, systematic exclusion of potential participants

who have recently been ill or those with brittle asthma, acute exposures

only. Each of these studies has one or more weaknesses in design or analysis; thus, neither individually nor collectively can these investigations

definitively address the issue of whether acute ETS exposure can precipitate

an asthma flare. For instance, in Shephard et al. (1979a), anti-asthma medications were not withheld prior to the exposures in 13 of the 14 participants, a fact which may have dampened any potential effects of ETS.

Several investigations involved fewer than a dozen subjects (Knight and

Breslin, 1985; Wiedemann, 1986; Oldigs et al., 1991); all but two of the

remaining studies had fewer than two dozen subjects. In at least two studies (Oldigs et al., 1991; Magnussen et al., 1993), the participants were also

regularly exposed to ETS at home, which could affect their responses in an

acute experimental setting. Menon et al. (1991) indicated that at least 1

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Chapter 6
hour of exposure was needed to elicit respiratory responses, even among

their ETS-sensitive subjects. Several of the chamber studies (including most

of the “negative” ones) involved exposure to ETS that was limited to only 1

hour (Knight and Breslin, 1985; Wiedemann, 1986; Oldigs et al., 1991;

Dahms, 1981; Magnussen et al., 1993; Danuser et al., 1993). Moreover,

there is considerable variability among asthmatics with respect to susceptibility to airborne irritants, including ETS. For instance, adult asthmatics

vary at least seven-fold in their susceptibility to the bronchoconstrictive

effects of sulfur dioxide, which is probably the most well-studied respiratory

irritant in relation to asthma (Horstman et al., 1986). Thus, even apart

from differences in study design and experimental conditions, investigations of the effects of acute ETS exposure in asthmatics would be expected

to produce variable results.

Finally, one criticism of ETS chamber studies has been that the characteristic odor and mucous membrane irritation make it difficult to blind

the participants to the nature of the exposure (ETS versus clean air). This in

turn is hypothesized to result in psychological suggestion as a cause of

observed symptoms, changes in lung function, and so forth (Witorsch,

1992). Similarly, it has been argued that the physical conditions of participating in an inhalation challenge study create “stress” to which any positive results might be attributed (Witorsch, 1992). As for the latter observation, the use of control exposures, control subjects, or both are intended to

provide a basis for “control” for whatever stresses are associated with the

experimental procedure. Suggestibility related to the lack of blinding may

theoretically augment symptomatic and physiological responses, but experimental evidence suggests that, if present, its influence is weak. In the study

by Danuser et al. (1993), the subjects wore nose clips and had the ETS

administered by mouthpiece, essentially blinding them to the differences in

concentration of ETS delivered. Yet most of the symptomatic responses of

the subjects with AHR, though not clinically severe, appeared to be doserelated, which would be difficult to attribute to suggestion. Urch et al.

(1988) investigated the role of suggestibility in 40 nonsmokers, including

16 asthmatic and 24 nonasthmatic adults. Participants were exposed in an

exposure chamber on separate occasions for 65 minutes to clean air

(“sham”), moderate, or heavy smoke (17 and 31 ppm carbon monoxide,

respectively). Though they viewed a bank of burning cigarettes outside the

chamber on all occasions, the smoke was diverted during the sham experiment. These investigators reported, among other results, the occurrence of

significant dose-related symptoms in asthmatics and nonasthmatics and a

dose-response relationship for several measures of lung function. They also

administered a battery of psychometric tests to assess the subjects’ suggestibility, and found little correlation between physiological changes and

indices of suggestibility. Assuming the subjects were unable to distinguish

between the moderate and heavy smoke concentrations, Urch et al. concluded that the dose-response relationships were more likely of physiological than psychological origin, although the latter may have played a minor

role in the observed responses.

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In summary, although the design constraints of the chamber studies

limit the interpretation of the results, they do suggest that there is likely to

be a subpopulation of asthmatics who are especially susceptible to ETS

exposure. The physiological responses observed in these investigations

appear to be reproducible in both “reactors” and “nonreactors.” It is

unlikely that the physiological and symptomatic responses reported are due

exclusively to either stress or suggestion. 

Infections of the respiratory tract are the most common

acute illness of childhood. Apart from the morbidity (and

occasional mortality) attributable to respiratory infections, they also represent risk factors for asthma (both induction and exacerbation of existing

disease) and possibly other chronic respiratory effects in later life (Burrows

et al., 1977; Gold et al., 1989; Henderson et al., 1992; Schroekenstein and

Busse, 1988). The relationship of parental smoking to the risk of respiratory

infection has been extensively investigated. It has been clearly established

in nearly two dozen reports reviewed by the NRC (1986), the Surgeon

General (U.S. DHHS, 1986), and the U.S. EPA (1992) that ETS exposure

increases the risk of acute lower respiratory disease in young children by 1.5

to 2-fold.

The estimates of the magnitude of the effect of household ETS exposure on respiratory infections are remarkably consistent among the many

studies that have examined this relationship. The effects are most marked

in infants and toddlers, and are often not detectable in school children,

who may be less exposed than younger children or who may have developed immunity against many respiratory pathogens. Several studies noted

the existence of a dose-response relationship, where dose was measured by

the number of cigarettes smoked in the household. In studies conducted

mainly in Europe and North America, maternal smoking has repeatedly

been found to bear a stronger relationship to respiratory illness than paternal smoking. This is likely to be due to the greater amount of time spent

by mothers than by fathers with young children, enhancing the frequency

and intensity of ETS exposure, strengthening the inference of a causal association. However, the series of reports by Chen (1989) and Chen et al.

(1986 and 1988), which involved cohorts of infants with nonsmoking

mothers, also found dose-response relationships with paternal smoking.

The reviews by the U.S. EPA, NRC, and the Surgeon General all noted that

most of these studies, while not free of all sources of bias, had adjusted for

many identifiable confounding variables and found that the ETS effects

were independent of sex, race, maternal age, socioeconomic status (SES),

residential crowding, and number of siblings. In some studies, breast-feeding had a protective effect, as did daycare attendance, the latter presumably

by decreasing exposure to parental ETS. Low birth weight increased susceptibility to ETS effects (U.S. EPA 1992). As a group, these nearly two dozen

investigations are quite consistent and provide convincing evidence of an

increased risk of lower respiratory illness in young children.

The discussion of the relationship between ETS exposure and pediatric respiratory illness has been adequately addressed in the reviews by the

NRC, the Surgeon General, and the U.S. EPA, and therefore a de novo analy203

Chapter 6

6.1.2 Respiratory

Infections (children)
sis of the primary literature has not been undertaken. More recent published investigations support the conclusions articulated in these reviews.

For example, Chen (1994) reported increased risks of hospitalization for respiratory illness during the first 18 months of life in China as follows: ORs =

2.91 (95% CI = 1.41-6.01) and 4.48 (95% CI = 2.07-9.73) among low-birthweight infants exposed to light and heavy household smoking, respectively,

and 1.40 (95% CI = 0.96-2.03) and 1.61 (95% CI = 1.08-2.41) for similar

exposures among children of normal birth weight. Similarly, Robertson

(1994) found an ETS-associated increased risk of hospitalization (for respiratory and other causes) during the first 6 to 10 months of life in a cohort of

1,877 infants in New Zealand (OR = 1.52, 95% CI = 1.08-2.14). In a

prospective study of respiratory illness during the first two years of life in

836 Australian children, Douglas et al. (1994) reported that maternal smoking was associated with a significantly increased frequency of respiratory illness in the second, but not the first year of life. While each of these investigations has one or more methodological limitations, they are generally

consistent with the reports discussed in the above-noted reviews. These and

other recent studies support the conclusions stated in the reports by the

NRC, the Surgeon General, and the U.S. EPA., that ETS exposure clearly

confers an increased risk of acute lower respiratory disease in young children.

As noted above, ETS exposure in early childhood has been estimated

to increase the risk of lower respiratory infection by 1.5 to 2-fold. On a

national level, this magnitude of increased risk would correspond to

150,000 to 200,000 ETS-related cases of lower respiratory illness annually in

children under 18 months of age (U.S. EPA, 1992). Noting that approximately 5 percent of patients with lower respiratory illness require hospitalization, the U.S. EPA estimated that 7,500 to 15,000 admissions to hospitals

are attributable to ETS exposure each year in the U.S. These may be underestimates of effect, since the calculations on which they were based did not

account for either exposure to paternal smoking or the likelihood of occurrence of repeated episodes of illness in regularly exposed children. If 12

percent of the population at risk resides in California, these estimates would

correspond to 18,000 to 36,000 new cases of lower respiratory illness each

year and 900 to 1,800 hospitalizations attributable to ETS exposure.

A number of studies, cited in the preceding subsections, link

passive smoking with lower respiratory tract conditions in

children. The relationship between ETS exposure and childhood upper respiratory tract conditions, particularly acute and chronic otitis media, constitutes a separate area of concern. This topic has been reviewed extensively

by the Surgeon General’s Office (U.S. DHHS, 1986), the NRC (1986), and

the U.S. EPA (1992). This section briefly summarizes the findings of the

above three reports, reviews those studies not included in the reports, and

explores related evidence on pathophysiology.

Otitis media is the most commonly diagnosed

problem in outpatient pediatrics in the United States today (Etzel et al.,

1992). In the context of this discussion, it is useful to consider the anato204

Smoking and Tobacco Control Monograph No. 10

6.1.3 Otitis Media

(children)

6.1.3.1 Background/Definitions
my and physiology of middle ear disease before reviewing the data concerning ETS as a risk factor for otitis media. The middle ear communicates with

the nasopharynx via the eustachian tube. The eustachian tube acts as a

barrier to microorganisms originating in the pharynx, as a pressure equalization channel, and as a conduit of drainage for secretions originating in

the middle ear. Eustachian tube dysfunction of whatever etiology results in

a sustained pressure differential between the middle ear and the surrounding atmosphere, with subsequent effusion of serous fluid into the middle

ear. Alone, this condition is called “serous otitis media,” and produces a

sensation of fullness and temporarily decreased hearing. Should the serous

fluid become infected (usually with bacteria), “acute otitis media” results,

with pain, fever, and the potential for tympanic membrane (TM) perforation. Serious secondary complications (meningitis, mastoiditis) can also

occur, as can a self-perpetuating cycle of acute and serous otitis media

(Goycoolea, 1991). Chronic serous effusions, with or without intervening

infections, may lead to a variety of complications, including mucoid effusion (so-called “glue ear”) and stretching of the tympanic membrane

(“incompetent TM” or “atelectatic TM”), each resulting in more sustained

hearing loss than does simple serous otitis. Tympanic membrane perforation can result, not only in hearing loss, but also in the formation of a

“cholesteatoma”—an ingrowth of squamous cells from the exterior of the

TM—which, in turn, can expand and destroy the ossicles of the middle ear.

Hearing loss, whether from sustained serous otitis media, mucoid effusion,

atelectatic TM, TM perforation, or ossicle destruction due to cholesteatoma,

can result in communication difficulties and educational impairment in

children.

The Surgeon General (U.S. DHHS, 1986) and NRC

(1986) reviewed five and the U.S. EPA (1992) an additional ten studies on

ETS exposure in childhood and upper respiratory tract conditions. Twelve

of these 15 studies examined acute or chronic otitis media and/or middle

ear effusions. These 12 studies included five case-control, four prospective,

and three retrospective or cross-sectional investigations and are summarized

in Table 6.3, as well as in the above three reviews. In all but three of these

12 studies, statistically significant relationships between exposure and outcome were apparent.

The reports of both the Surgeon General and the U.S. EPA expressed

concern regarding potential misclassification of exposures based solely

upon historical measures. Two studies (Strachan et al., 1989; Etzel et al.,

1992) used objective measures of ETS exposure (salivary and serum

cotinines, respectively), and both found a statistically significant relationship between ETS exposure and outcome. Likewise, two studies (Iverson,

1985; Etzel et al., 1992) employed periodic prospective screening for middle

ear disease, thus eliminating differential utilization of medical services by

parents as a possible confounder. Again, both of these studies found statistically significant associations between ETS exposure and middle ear disease.

Table 6.4 summarizes an additional ten epidemiologic studies not

included in the above summary reports (the Surgeon General’s Office, NRC,

or U.S. EPA). Several of these additional studies were problematic with

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Chapter 6

6.1.3.2 Epidemiologic Data
206

Author/Year Study Design Measures of Exposure and Effect/Findings Kraemer et al. case-control 76 children admitted for ear surgery for persistent MEE compared with n(1983) OR for ear surgery and 32 smokers in home = 2.8 (95% CI = 1.1-7.0). Iverson et al. prospective 337 children age 0-7 years followed in day care for 3 months with period(1985) rate for MEE significantly associated with parental smoking, as determin

Black (1985) case-control 150 children referred for ear surgery for "glue ear" (secretory OM) match

ratio for parental smoking = 1.64 (95% CI = 1.03-2.61).

Pukander et al. case-control 264 cases of acute OM were compared with 207 non-OM outpatients ag

(1985) trend in proportion of children with historical ETS exposure as a function 

time OM episodes.

Fleming et al. retrospective Phone interview of 449 households. For children under 5 years old, mat(1987) risk factor for upper respiratory tract infection, but not otitis media, within 

(OR = 1.1; p = 0.82 for OM).

Tainio, et al. prospective 183 infants followed from birth to 2.3 years of age. Parental smoking wa

(1988) OM episodes (RR = 1.7; 95% CI = 1.1-2.7). Also, a significantly higher p

dren with "recurrent" OM (35 episodes) smoked (p < 0.05).

Table 6.3Studies of Middle Ear Effusion (MEE) and Otitis Media (OM) vs. ETS Exposure Reviewed the Surgeon General (1986), NRC (1986), or U.S. EPA (1992)
207

Author/Year Study Design Measures of Exposure and Effect/FindingsReed and Lutz cross-sectional 49 children with a prior history of either acute OM (n = 24) or another ou

(1988) were examined by tympanometry. OR for MEE and reported parental sm

Hinton (1989) case-control 115 children, age 2-11 years, admitted for ear surgery compared with 26 

36 children with non-otologic diagnoses. Borderline significant trend in psurgical to clinic to nonotologic patients (p = 0.06).

Teele et al. prospective 877 children observed from birth to one year of age, 698 to age 3, and 4

(1989) ing was significant risk factor for acute OM in children under age one yeStrachan et al. cross-sectional Tympanometry and salivary cotinine samples obtained on 872 school ch(1989) Significant trend in OR for abnormal tympanogram (MEE) as a function 

level.

Takasaka case-control 67 children with OM were compared with 134 age- and sex-matched co(1990) was reported for ETS exposure and OM, numbers were not shown.Etzel et al. prospective 132 children followed between age 6 months and 3 years with regular e

(1992) serum samples. Children with serum cotinine concentrations greater tha

excess of new-onset otitis media with effusion compared with unexposeratio = 1.38; 95% CI = 1.21-1.56). Peak risk occurred before 24 months 

Table 6.3 (Continued)
208

Author/Year Study Design Measures of Exposure and Effect/Findings Kallail et al. case-control 119 school children with hearing loss on audiometry were compared wit(1987) classmates. There was a nonsignificant excess of ETS exposure amon

problems who were later confirmed by physicians to have "middle ear p

Hinton and case-control 70 children aged 1-11 years referred to ENT clinic (n = 26) or optometry 

Buckley (1988) 100% of the former and 41% of the latter had MEE. Comparison of chil

revealed a nonsignificant excess of cases from smoking homes. Zielhuis et al. case-control 1,439 preschoolers were followed from age two to four with tympanome

(1989) (nested in 3-month intervals. Incident cases of OM with MEE were compared with prospective) controls from same cohort. A nonsignificant excess of smoking was app

parents of cases (OR = 1.11; p = 0.643).

Barr and case-control 115 children aged 1.5-11.5 years who were referred for ear surgery were Coatesworth patients with nonotologic diagnoses. No difference in self-reported pare(1991) observed.Green and case-control 164 children aged 1.5-8 years who were seen in ENT clinic for ear pain Cooper (1991) pared with like number of nonotologic outpatients. OR for ENT clinic att

maternal smoking = 1.92 (95% CI = 1.23-2.99).

Pönka et al. prospective 2,216 children in daycare centers were followed for average of one year 

(1991) of any medical causes of absence, as well as home ETS exposure. "No 

between historically reported OM episodes and ETS exposure (numbers 

Table 6.4Studies of Middle Ear Effusion (MEE) and Otitis Media (OM) vs. ETS Exposure not Reviewthe Surgeon General (1986), NRC (1986), or U.S. EPA (1992)
209

Author/Year Study Design Measures of Exposure and Effect/FindingsRa (1992) cross-sectional 87 10-month-old infants tested for hearing loss. ETS exposure at home 

increase in hearing loss (49% prevalence in ETS-exposed children vs. 1p = 0.001). 

Collet et al. cohort 918 pre-school children followed from birth to age four. ETS exposure d

(1995) History of OM determined by parental questionnaire at age four. Matern

cigarettes/day associated with increased risk of recurrent OM (defined a(CI = 1.1-3.0), but not with single episodes RR = 0.9 (CI = 0.6-1.4). Trerent OM with increasing number of cigarettes smoked. No effect of pate

Ey et al. cohort 1,013 children followed during first year of life. ETS exposure determine

(1995) at one year. Episodes of OM determined by review of medical records. 

rettes/day associated with increased risk of recurrent OM (defined as 33 

episodes in a year): OR = 1.78 (95% CI = 1.01-3.11), but not with single (95% CI = 0.74-2.24). Low birth weight (<3.5 kg) and heavy maternal smfold increased risk of recurrent OM (OR = 3.29, 95% CI = 1.71-6.36). No 

Kitchens case-control History of ETS exposure of 175 children (cases), aged three or younger(1995) adhesive OM requiring tympanostomy tubes compared with 175 age-ma

cantly more likely than controls to have household exposure to ETS (OR 

related to smoking status of primary or secondary caretakers (typically ttively) alone were also elevated, but nonsignificant. Within case group tcome between those exposed and those not exposed to ETS when follo

Table 6.4 (Continued)
respect to their study designs. For example in the Kallail (1987) study, cases

and controls were not subjected to the same screening procedures. In the

Pönka (1991) study, parental reporting, rather than medical records or

objective surveillance, was the index of disease outcome. Nevertheless,

three of the studies reported nonsignificant positive associations between

ETS and middle ear disease, five reported a significant relationship, and

none reported a protective effect. None of these studies utilized biomarkers

of ETS exposure. The one study that used an objective measure applied on

a prospective basis (tympanometry) did report a slight, but nonsignificant

association (Zielhuis, 1989).

The Surgeon General’s report (U.S. DHHS, 1986) summarized the studies as “show[ing] an excess of chronic middle

ear effusions and diseases in children exposed to parental smoke.” The U.S.

EPA (1992) report concluded that there was “good evidence demonstrating

a significant increase in the prevalence of middle ear effusion in children

exposed to ETS,” but only “some evidence [for] acute middle ear infections”

(acute otitis media). While the ten studies in Table 6.4 are collectively

somewhat less supportive of an association between ETS exposure and middle ear disease than those previously reviewed by the Surgeon General’s

Office and the U.S. EPA, the study design of some of these studies was problematic.

Ten of the 12 studies reviewed by the Surgeon General’s Office or

the U.S. EPA reported statistically significant relationships between ETS

exposure in the home and middle ear conditions in children. Of the additional ten studies reviewed here, five showed a statistically significant relationship, three showed excesses that did not reach statistical significance,

and two showed “no relationship” (in one case without numbers being presented). Overall, no studies show a protective effect (such as would be

expected in at least some studies if all findings were a product of random

variation). Two of three studies involving objective prospective surveillance

(tympanometry or insufflation otoscopy) showed statistically significant

associations, and the third a nonsignificant excess of middle ear problems

with ETS exposure. Both studies involving biomarkers of ETS exposure

showed statistically significant relationships between exposure and outcome. Overall, the epidemiologic data strongly support a relationship

between ETS exposure in the home and either acute otitis media with effusion or serous otitis media (middle ear effusion without acute infection),

particularly among children under 2 years of age. Limitations of available

data on the chronicity of physical findings, as well as the differing patterns

of recruitment in the various studies, make it impossible to distinguish separate relationships between ETS exposure and acute serous otitis media,

chronic serous otitis media, and acute infectious otitis media.

Several reports on the relationship between ETS exposure and otitis

media have been published since the earlier draft release of this chapter

(Collet et al., 1995; Ey et al., 1995; Kitchens et al., 1995). The results of

these investigations (summarized in Table 6.4) are consistent with the conclusions articulated above.

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6.1.3.3 Summary of

Epidemiologic Data
6.1.3.4 Biological Plausibility Eustachian tube dysfunction (ETD) plays a central

role in the pathogenesis of middle ear disease. While the U.S. EPA did not

find plausible biological mechanisms for ETS-related acute otitis media,

there are at least four mechanisms whereby ETS might produce eustachian

tube dysfunction. These include:

1) Decreased mucociliary clearance

At least in active smokers, cigarette smoke is well known to interfere

with normal ciliary activity in the tracheobronchial tree (Wanner,

1977). Intact ciliary function is important for the proper barrier function of the eustachian tube against the entrance of microorganisms

(Sismanis, 1991). To our knowledge, however, there is no direct experimental evidence regarding the effects of ETS on ciliary function in the

eustachian tube at this time.

2) Decreased eustachian tube patency due to adenoidal hyperplasia

Said et al. (1978) documented an increased prevalence of ETS exposure among children previously referred for tonsillectomy and/or adenoidectomy, and Corbo et al. (1989) found a similar association among

children with a history of tonsillectomy and adenoidectomy, rhinitis, or

snoring. While many variables may govern whether a given individual

has surgery, the common denominator among these conditions is lymphoid hyperplasia and decreased upper airway patency. Adenoidal

hyperplasia is a recognized risk factor for the development of otitis

media (Sismanis, 1991).

3) Decreased patency due to ETS-induced mucosal swelling

Chronic pathologic changes associated with otitis media with effusion include goblet cell hyperplasia and hypertrophy within the

eustachian tube (Sando et al., 1991). While direct evidence of ETSinduced goblet cell pathology in the eustachian tube has not been

reported to date in the literature, similar goblet cell hypertrophy has

been observed in the lower airways of smokers (Richardson, 1988).

Acute upper respiratory tract mucous membrane swelling due to ETS

exposure is explored in some detail in Section 6.1.4 (sensory irritation).

4) Decreased patency and impaired mucociliary clearance secondary to

increased frequency of viral upper respiratory tract infections (URIs)

An increased frequency of upper respiratory tract infection in ETSexposed children was demonstrated by Fleming et al. (1987), and may

accompany some of the lower respiratory tract illnesses documented in

Section 6.1.2. Viruses are known to immobilize respiratory tract cilia

and to produce vascular, secretory, and interstitial changes that compromise airway patency. URIs frequently precede development of otitis

media, and experimental induction of rhinovirus infection (the “common cold”) decreases upper airway patency and induces eustachian

tube dysfunction (McBride et al., 1989).

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Etzel et al. (1992) estimated that, with the relative risk of otitis media with effusion (OME) as a function of ETS exposure

peaking at 1.62 at age 18 months—and with an estimated

exposure prevalence of 38 percent (North Carolina)—some 8 percent of otitis media episodes occurring between ages 6 and 24 months are attributable

to ETS exposure. Iverson et al. (1985) calculated that for Danish children

attending daycare (estimated ETS exposure prevalence, 60 percent), 15 percent of middle ear effusions (MEE) may be smoking related, with the ETSattributable fraction actually greater in the 6-to 7-year-old group than in

younger children. Strachan et al. (1989) computed the odds ratio for MEE

in 6.5 to 7.5-year-old children as a function of a doubling of salivary cotinine as 1.14 (crude) or 1.13 (adjusted for gender and housing type). As

median cotinine levels in that study varied by a factor of 25 (or 4.5 doublings) between the unexposed children and those living with at least two

smokers, odds ratios as high as 1.69 were observed in the more highlyexposed children. 

An estimate of yearly physician office visits for early childhood otitis media episodes attributable to ETS exposure in California can be derived

as follows:

1) According to an activity study sponsored by the California Air Resources

Board, 38 percent of children under age 12 years, statewide, are exposed

to ETS at some time during a typical day, with an average exposure time

of 202 minutes (Wiley et al., 1991). Broken down by age and sex, 38

percent of boys and 28 percent of girls under age 3 years are exposed to

ETS, yielding a pooled exposure prevalence of 33 percent in this age

group.

2) Etzel et al. (1992) applied observed incidence densities among ETS- versus

non-ETS-exposed children and an estimated exposure prevalence rate of

38 percent to obtain an ETS-attributable fraction of 8.2 percent for OM

cases among children between ages 6 months and 2 years in North

Carolina. These calculations were repeated using Etzel’s data for children 23 years, applying California’s estimated ETS exposure prevalence

(p) of 33 percent for this age group. These figures yielded an ETS-attributable otitis media fraction of 11.2 percent for California children under

age 3 years. Using the equation below, a standard approach to calculating attributable risk (Lillienfeld and Lillienfeld, 1980) where R is an estimate of the relative risk, we obtained an ETS-attributable risk fraction

(a) of 11.1 percent, with a 95 percent confidence interval of 6.5-15.6

percent.

a = p(R - 1) / (p(R - 1) + 1)

3) Data from the National Ambulatory Medical Care Survey (NAMCS) indicates that otitis media is the most common outpatient pediatric diagnosis nationwide (accounting for approximately 18 percent of all office

visits for children under age 5 years). As of the most recent survey, OM

was cited as the principal diagnosis for 102 office visits per 100 children

(under 2 years of age) per year in 1990; and for 48 office visits per 100

children aged 2-5 years (Schappert, 1992).

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6.1.3.5 Dose-response

and Attributable Risk

Considerations
4) In 1990, California had a population of 1,452,250 children under age 3

years (US Department of Commerce, 1992). Of these children, 424,303

were under age 1 year, 524,558 were 1-2 years, and 503,389 were in

their third year of life.

5) Assuming that ETS-related otitis media episodes generate the same number of total (initial + follow-up) visits as do non-ETS related episodes,

one can combine Etzel’s data (pertaining to incident cases of otitis

media) and the NAMCS data (pertaining to OM-related office visits—

both initial and follow-up). The resulting figure may be an underestimate, since ETS usually constitutes an ongoing insult to normal

eustachian tube function, in contrast to such events as viral upper respiratory tract infections.

Combining the above data, one obtains an estimate of almost

135,000 (95 percent confidence limits, 78,615-188,676) office visits per year

among California children under age 3 years for ETS-attributable otitis

media episodes:

At the national level, this would roughly correspond to 700,000 to 1.6 million physician office visits annually, assuming approximately 88 percent of

U.S. children under age 3 reside outside California.

A substantial body of literature addresses the acute

and reversible irritative effects of ETS on the upper

respiratory tract. Symptoms subsumed in this category include eye, throat,

and nasal irritation, rhinorrhea, nasal congestion, hoarseness, and odor

“annoyance.” ETS-related irritant and annoyance effects were reviewed in

both the Surgeon General’s and NRC reports (U.S. DHHS, 1986; NRC, 1986),

and more recently by Samet et al. (1991). In the period since these reports

were written, additional insight has been gained into the pathophysiology

of upper airway irritant responses, and progress has been made in developing objective methods to validate ETS-related symptom complaints. In this

section we will first review exposure dynamics and pathophysiology before

considering the newer epidemiological and experimental literature. Note,

however that whereas ETS is frequently dealt with as a general cofactor in

the study of indoor air quality, this literature review has been restricted to

studies in which ETS effects are examined directly.

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Chapter 6

Age-specific ETS ETS-AttribPopulation Population Otitis Media OM-Related Attributable utable

Description at Risk  ́ Visit Rate = Office Visits  ́ Fraction = Visits/Year

Age 22 yr. 948,861  ́ 102/100 = 967,838

Age 2-3 yr. 503,389  ́ 48/100 = 241,627

1,209,465  ́ 0.111 = 134,251 

(95% CI: 

78,615-188,676) 

6.1.4 Sensory Irritation

and Annoyance
6.1.4.1 Exposure Dynamics As noted in the chapter on Exposure Measurements and

Prevalence, ETS consists of a complex and dynamic mixture of particulate

and vapor-phase constituents. Both odor and irritation associated with ETS

appear to derive predominantly from the vapor, rather than particulate

phase (Hugod, 1984; Weber, 1984; Samet, 1991). The chemical constituents

of ETS thought to be responsible for sensory irritation include organic acids

(acetic, proprionic), aldehydes (formaldehyde and acrolein), nicotine,

ammonia, pyridine, toluene, sulfur dioxide, and nitrogen oxides, among

others (U.S. DHHS, 1986; Ayer and Yeager, 1982; Triebig and Zober, 1984).

The predominant site of deposition of various respiratory tract irritants is thought to be governed by two factors, particle size (for irritants

adsorbed to particulates) and water solubility (for gaseous organics and

vapor-phase inorganics). In general, the larger the particle or the more

water soluble the compound, the higher the proportion of the inhaled dose

that is likely to be deposited in the upper respiratory tract, particularly during nasal breathing. Of note, many of the gaseous and vapor phase irritants in ETS have sufficient water solubility to be active on the upper respiratory tract—i.e., nasal cavity, nasopharynx, and hypopharynx (U.S. DHHS,

1986).

Selected investigators have examined the human sensory and reflex

respiratory response to specific ETS constituents. Kendal-Reed et al. (1996)

demonstrated reflex changes in respiration (decreased tidal volume) among

human volunteers exposed briefly (15 seconds) to propionic acid vapor at

concentrations of 0.12-85 ppm. Walker et al. (1996) examined the olfactory

and irritant (trigeminal) properties of nicotine in both humans and experimental animals. The investigators pointed out that, on a part-per-million

basis, nicotine was more potent than acetic acid, propionic acid, or amyl

acetate in eliciting olfactory sensation (in subjects with a normal sense of

smell) and subjective nasal irritation (in subjects lacking the sense of smell).

The investigators were able to corroborate their estimates of the relative

stimulatory potencies of these compounds by obtaining electrophysiologic

recordings from the trigeminal nerve in rats, finding a 15 to 60-fold lower

response threshold for nicotine versus the other study compounds.

6.1.4.2 Pathophysiology ETS stimulates the sensory apparatus of the upper respiratory tract through four neurological pathways: the olfactory, trigeminal,

glossopharyngeal, and vagus nerves (cranial nerves I, V, IX, and X). The

olfactory nerve is responsible for the sense of smell and projects to areas of

the primitive forebrain responsible for emotional arousal, including the

amygdala and portions of the frontal and temporal lobes. The nasal and

oral cavities are innervated by the trigeminal nerve, the nasopharynx by

the glossopharyngeal nerve, and the oropharynx and hypopharynx by the

vagus nerve; these nerves project to various areas of the brainstem. The

trigeminal, glossopharyngeal, and vagus nerves are responsible for the perception of touch, temperature, and sensory irritation (or what has been

termed the “common chemical sense”) in all head and neck mucosae. The

two nasal senses—olfaction and irritant chemoreception—as well as the

related sense of taste, functionally interact to produce an integrated impres214

Smoking and Tobacco Control Monograph No. 10
sion of one’s chemical environment (Cain, 1974; Cain and Murphy, 1980;

Frank and Rabin, 1989).

The olfactory epithelium occupies a total area of approximately 5

cm2 bilaterally in the upper reaches of the nasal cavity. The olfactory apparatus is variably stimulated during normal relaxed nasal breathing; “sniffing,” or attentive smelling, creates eddy currents which facilitate the delivery of odorant molecules to the olfactory epithelium. Odorant molecules

diffuse through the nasal mucus layer, probably aided by an odorant binding protein, to make contact with receptor sites on olfactory receptor cells

(Pevsner et al., 1988). The olfactory receptor cells are the only neurons

known to regenerate on a regular basis; this may constitute a functional

response to the fact that olfactory receptor cells are directly exposed to a

variety of environmental insults (Frank and Rabin, 1989).

In contrast to the limited distribution of olfactory receptor cells,

trigeminal nerve endings are located throughout the nasal and oral cavities,

as well as the nasopharynx, oropharynx, and hypopharynx—the vagus

nerve innervates the lower respiratory tract, including the trachea, and tracheobronchial tree. Trigeminal fibers carry sensory information of a variety

of types; of primary interest here is the chemosensory function of irritant

perception. The nerve fiber type thought to be responsible for mediating

airborne chemical irritation (both in the upper and lower respiratory tract)

is the small-diameter, unmyelinated, capsaicin-sensitive C fiber (Lundberg et

al., 1988 and 1991; Silver, 1992), although A2 (delta) fibers have also been

implicated in some studies (Hummell et al., 1992).

Important for purposes of understanding the upper airway response

to ETS is the fact that trigeminal stimulation can activate both long and

short reflex arcs (“neurogenic reflexes”). The long reflex arc involves the

trigeminal nerve for the afferent (perceptual) limb and the facial nerve (cranial nerve VII) for the efferent (effector) limb. Exposure to intense irritants

anywhere within the nasal or oral cavities produces reflex rhinorrhea and

lacrimation via a long reflex arc, autonomic (cholinergic) response. On

provocative irritant testing (e.g., after ingestion of horseradish or inhalation

of ammonia), subjects typically experience subjective nasal stuffiness and

rhinorrhea and have acute increases in nasal airway resistance, dilation of

vessels within the nasal mucosa, and increased content of plasma and glandular proteins in nasal secretions (Raphael et al., 1991; McLean et al., 1979).

This response is mimicked by local instillation of methacholine (an acetylcholine analog), and is blocked by pretreatment with atropine (an acetylcholine antagonist).

For mild to moderately intense irritant stimuli, local reflexes may

predominate over the above-described long-arc autonomic response. The

so-called “axon” reflex is a local reaction in which neuropeptides (vasoactive peptides including substance P, neurokinin A, gastrin-releasing peptide,

and calcitonin gene-related peptide) are released near the mucosal surface.

Interestingly, this reflex involves the sensory limb of the nerve only, and is

analogous to the so-called “wheal and flare” reaction observed upon

mechanical stimulation of the skin. Depending upon the specific peptides

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Chapter 6
involved, these mediators produce some combination of engorgement of

blood vessels, transudation of fluid and plasma proteins into tissues, stimulation of secretions, and migration of inflammatory cells (Baraniuk and

Kaliner, 1990; Lundberg et al., 1991; Silver, 1992; Widdicombe, 1990).

Apparent cross-species differences in both the distribution of mediators and

their physiological effects have posed a challenge to researchers attempting

to understand the axonal response in the human airway (Bascom et al.,

1991). Newer studies of airway responses to ETS should be viewed against a

background of more traditional methods in irritant toxicology. Animals

exposed to highly water soluble upper respiratory tract irritants reveal predictable changes in respiratory pattern, including slowing of respiration,

sneezing, coughing, and increased secretions (Alarie, 1973). In humans, the

analogous respiratory pattern is an involuntary pause during inspiration or

frank breath-holding (Cain et al., 1987a). Exposure levels necessary to produce these responses, however, are generally high, and researchers in the

field of indoor air quality and ETS have searched for more sensitive indices

of respiratory tract irritation. As noted below, evidence of true allergic (IgEmediated) upper airway reactions to ETS is quite limited.

For discussion purposes, “sensory irritation” refers to subjectively reported tingling, stinging, burning, or pain involving

the mucous membranes of the upper respiratory tract

and/or cornea (in humans), or to (unconditioned) aversive

responses to an airborne chemical agent in experimental animals. When

associated reflex physiologic alterations are present (e.g., changes in airway

caliber, respiratory behavior, or blink rate), they are so indicated.

“Pathological irritation” refers to irritant-related changes in tissue structure

and/or biochemical function including necrosis, mucosal desquamation,

vascular congestion, cellular infiltration, and/or release of inflammatory

mediators.

Eye Irritation In several questionnaire studies, subjective eye irritation was the most

commonly reported upper respiratory tract symptom among nonsmokers

exposed to ETS (Bascom et al., 1991; Basu et al., 1978; Shephard, 1979b;

Speer, 1968; White et al., 1991). The cornea is richly innervated with

trigeminal nerve endings that are sensitive to both mechanical and chemical stimuli, and blinking occurs reflexively in response to corneal stimulation. Experimentally, Weber et al. (1976, 1984, 1987) and Muramatsu et al.

(1983) exposed volunteers to progressively increasing concentrations of

ETS; as exposure duration and intensity increased, subjects began to report

subjective eye irritation, and blink rate also increased. In another human

experimental study, researchers measured precorneal (tear) film breakup

time, using fluorescein dye both pre- and post-exposure to ETS. A significant decrease in tear-film breakup time occurred after ETS exposure—i.e.,

the tear film was less stable after ETS exposure (Basu et al., 1978). Both

blinking and lacrimation act as protective responses to airborne irritants by

restoring the protective tear film and diluting any chemical insult. The literature on ETS-induced eye irritation was reviewed in greater detail in the

Surgeon General’s report (U.S. DHHS, 1986, pp. 234-238).

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Smoking and Tobacco Control Monograph No. 10

6.1.4.3 Specific Health

Effects

Definitions
Nasal Irritation Bascom et al. (1991) and Willes et al. (1992) identified a subgroup of

research subjects who reported a variety of nasal symptoms (congestion,

rhinorrhea, sneezing, and postnasal drip) upon prior exposure to ETS. This

group comprised approximately one-third of their study population, and

were labeled the “historically ETS-sensitive” subgroup in the authors’ subsequent provocative testing protocol. Using a climate-controlled exposure

chamber, the investigators conducted sidestream tobacco smoke (STS) challenge testing, examining a variety of endpoints. As a group, historically

ETS sensitive, but not ETS non-sensitive, subjects showed significant

increases in nasal airway resistance (NAR) by rhinomanometry after 15-

minute exposures to STS at levels chosen to simulate a smoking lounge.

These changes in objectively measured NAR paralleled the onset of symptoms of nasal stuffiness and rhinorrhea. Although the symptoms described

above resemble those of allergic rhinitis, the authors noted that only a

small proportion of historically ETS-sensitive subjects have positive skin test

reactivity to tobacco-leaf extract (see review of tobacco allergy in Stankus et

al., 1988b). To investigate the mechanism(s) underlying the responses they

observed, Bascom et al. (1991) performed nasal lavage pre- and post-STS

exposure. Although allergy-like nasal symptoms were provoked acutely, traditional markers of allergic nasal response (including histamine, various

kinins, and albumin) were not found to be increased post-exposure. These

findings were taken as evidence that acute nasal responses to STS/ETS may

occur via non-allergic, irritative mechanisms (see discussion of neurogenic

reflexes, above). Despite a lack of evidence for direct allergic mechanisms,

individuals who display both subjective and objective ETS sensitivity are

more likely than non-responders to have documented non-tobacco allergies, implying a modulatory effect of allergy upon the irritant chemoreceptive system (Bascom, 1991 and 1992; Cummings et al., 1991).

Alteration of Sensory Thresholds Cigarette smoking has the ability to change apparent

chemosensory sensitivity to airborne odorants and irritants; in at least one

case, these observations extend to passive smokers. Ahlstrom et al. (1987)

tested smokers, nonsmokers, and passive smokers for odor acuity to nbutanol and pyridine (the latter being a constituent of tobacco smoke).

Both active and passive smokers reported lower perceived odor intensities

(i.e., were less sensitive) than nonsmokers. Cometto-Muñiz et al. (1982)

and Dunn et al. (1982) examined the endpoint of altered respiration (reflex

transitory inspiratory pause) as a measure of nasal irritant sensitivity. Both

studies reported higher irritation thresholds (i.e., lower sensitivity) among

smokers versus nonsmokers exposed to a non-odorant stimulus (high-level

carbon dioxide). This finding was recently replicated using a CO2-detection

threshold as the endpoint of interest (Shusterman and Balmes, 1997). On

the other hand, Kjaergaard et al. (1990 and 1992) exposed smokers and

nonsmokers to carbon dioxide by mask to determine eye irritation thresholds, and found no appreciable difference in sensitivity between the two

groups. No published studies were identified which examined trigeminal

irritant thresholds among passive smokers.

A number of mechanisms could explain observed sensory shifts in

active and passive smokers. Decreased odor acuity among smoke-exposed

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Chapter 6
individuals could result from increased nasal secretions, which in turn

would pose an increased diffusion barrier to odorant molecules.

Alternatively, habituation (in effect, ignoring the stimulus) may explain the

odor perception findings; Ahlstrom et al. (1987) emphasized the latter possibility because passive smokers did not differ from nonsmokers in the number of “zero intensity” responses given. Shifts in irritant thresholds could

result from depletion of neuropeptides in trigeminal sensory fibers; this

phenomenon has been documented after high-level treatment with capsaicin, the irritant constituent in hot peppers (Lundberg and Saria, 1983).

As noted above, however, irritant thresholds have not been studied among

passive smokers to date.

Odor “Annoyance” “Annoyance” is a subjective state of displeasure resulting from a

defined environmental stimulus. In the context of ambient (outdoor) air

pollution, citizen reactions to unpleasant odors are responsible for the

majority of publicly initiated complaints to air quality management districts in California, and provide the rationale for a significant fraction of socalled “nuisance” abatement actions. ETS contains a number of odorant

compounds (e.g., pyridine) which are typically described as unpleasant. It is

not surprising, then, that even in the absence of eye, nose or throat irritation, nonsmoking citizens often complain of annoyance from the odor of

ETS in indoor settings. This endpoint has been discussed extensively in the

National Research Council report (NRC, 1986, pp. 166-181) and by Samet et

al. (1991, pp. 152-160). In addition to annoyance, indoor air quality

researchers have shown that unpleasant odors detract from the sense of

well-being of building occupants and, at times, interfere with concentration

and productivity (Rotton, 1983; Knasko, 1992)).

Cain et al. (1983) demonstrated that nonsmokers, on the average,

are more likely than smokers to complain of an offensive odor when

exposed to a given dilution of smoke-contaminated indoor air. They also

showed that when smokers and nonsmokers occupy the same air space, air

dilution rates required to render odorant levels acceptable to nonsmokers

may be unrealistically high from an engineering standpoint. The practical

implication of these findings is that apparently a strict no-smoking policy

or segregation of smokers into areas with separate, nonrecirculating air supplies may be necessary in order to protect nonsmoking building occupants

from annoyance and associated effects.

Cain et al. (1987b), using a climate-controlled exposure

chamber, found that 10 percent of nonsmoking subjects

complained of unacceptable air quality (either due to eye irritation or odor

annoyance) when ETS raised carbon monoxide (CO) levels by 2 ppm over

background, and over 20 percent expressed dissatisfaction at 5 ppm over

background. Muramatsu et al. (1983) reported that nearly 30 percent of

experimental subjects had complaints of moderate-to-severe eye irritation

with ETS-derived CO levels 2.5 ppm over background. By comparison, CO

levels can reach up to 10 ppm over background in smoking-permitted

offices (average, 2.5-2.8 ppm), and as high as 29 ppm (average, 4.8-17 ppm)

in taverns (Triebig and Zober, 1984). Although most experimental work on

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6.1.4.4. Dose-Response

Considerations
sensory annoyance has been performed using CO as an index of ETS exposure, some investigators believe that CO is an insensitive and unreliable surrogate measure for irritant and odorant exposure (Chapelle and Parker,

1977).

6.1.4.5. Summary ETS exposure produces a variety of irritative symptoms involving

the upper respiratory tract; increasingly, these endpoints are able to be

objectively documented and quantified. In addition to irritation, odor

annoyance may detract significantly from subjective well-being and productivity among building occupants. Experimental studies conducted by investigators familiar with building ventilation practice suggest that, short of

prohibiting indoor smoking, protection of nonsmokers against both sensory

irritation and odor annoyance can only be achieved through relatively

extreme engineering measures.

There is considerable evidence that continuing exposure to

cigarette smoke results in the induction of asthma in children. Two large cross-sectional studies involving a total of

about 8,000 children and adolescents resulted in odds ratios

of approximately two for the presence of asthma with

parental smoking (Burchfiel et al., 1986) or maternal smoking of greater

than 10 cigarettes a day (Weitzman et al., 1990). In a longitudinal investigation of asthma incidence among 774 children up to 5 years of age at entry,

Martinez et al. (1992) reported a relative risk of 2.5 (95% CI = 1.4-4.6) when

maternal smoking exceeded 10 cigarettes/day and the mother had at most a

high-school education. Another prospective study of 770 school children,

however, found no effect of maternal smoking on asthma prevalence at the

inception of the study or on incidence during 11 years of follow-up (RR =

1.1, 95% CI = 0.7-1.7; Sherman et al., 1990). The U.S. EPA (1992, pp. 7-51)

reviewed these and other studies and stated that, “The consistency of all

the evidence leads to the conclusion that ETS is a risk factor for inducing

new cases of asthma. The evidence is suggestive of a causal association but

is not conclusive.”

To investigate the relationship between ETS exposure and childhood

asthma more thoroughly, a meta-analysis of studies purporting to examine

this issue was undertaken. A MEDLINE search was conducted to identify all

epidemiologic studies published between 1975 and 1995 examining ETS

exposure as a risk factor for the induction of childhood asthma. Sixtyeight studies were identified as potentially relevant. Studies were selected

for inclusion if they met the following four criteria. First, the endpoint

studied must represent the development of asthma in persons <18 years of

age. Because of difficulties related to the diagnosis of asthma, particularly

in young children, studies that examined outcomes of “wheezy bronchitis”

or “constant wheeze/whistling in chest” were also included and analyzed

both separately and jointly with those studies which examined only physician-diagnosed asthma. Second, the exposure studied must represent postnatal household sources of ETS. While studies were not excluded for failure

to evaluate separately the effects of post- and prenatal exposures, they were

excluded if they only examined in utero exposures to ETS. Third, odds

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6.2 CHRONIC

HEALTH EFFECTS

6.2.1 Asthma 

(induction)
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Smoking and Tobacco Control Monograph No. 10

ratios or relative risks must be reported or sufficient data must be presented

to allow for calculation of risk ratios and estimates of their standard errors.

Lastly, studies must be independent. If more than one study reported on

the same cohort of children, then the study that best met the previous

three criteria was selected for inclusion.

Thirty-one studies were excluded for failure to meet one or more of

the inclusion criteria (see Table 6.5). Risk ratios and standard errors were

extracted from each of the remaining 37 studies or were calculated using

formulae given by Greenland (1987).

The random-effects model proposed by DerSimonian and Laird

(1986) was used for this analysis. Under the DerSimonian and Laird model,

a pooled risk ratio (pooled RR) is calculated as a weighted average of the risk

sizes reported by each study. Each study is weighted by a factor equal to

the inverse of the variance of the true underlying effect size (estimated by

the among-study variance (t2) added to its own within-study variance (s2)).

Because significant among-study variance was detected, potential sources of

heterogeneity by subset analysis and linear meta-regressions were evaluated.

Indicator variables were created a priori to characterize study design (casecontrol, cohort, or cross-sectional), exposure metric (level and method of

measurement), outcome metric (wheeze or asthma), method for identifying

cases (parental reporting or medical record extraction), year of publication,

age of study participants (preschool, school-age, or all ages), location (North

America, Europe, or elsewhere), and covariates controlled for in the analysis

(age, sex, socioeconomic status, family history of atopy/asthma, reporting

of parental respiratory symptoms, early childhood respiratory illness, history of breast-feeding, and in studies involving children older than 10 years

of age, the children’s own smoking habits). These indicator variables were

then used in the subset and meta-regression analyses to explore sources of

heterogeneity.

Of the 37 studies included in this analysis, all but three reported a

risk ratio (RR) greater than 1.0, albeit many were not statistically significant

at a = 0.05. The pooled RR for those studies with clinically diagnosed asthma as the outcome was 1.44 (95% CI = 1.27-1.64) and did not significantly

differ from that of studies examining “wheezy bronchitis” or “chronic

wheeze/whistling in chest” (pooled RR = 1.47, 95% CI = 1.34-1.61; See

Figures 6.1 and 6.2). Subset analyses revealed several potentially important

sources of heterogeneity. Significantly higher pooled estimates of risk were

derived from the subset of case-control studies that used population-based

controls (pooled RR = 2.43, 95% CI = 1.67-3.53) and the subset of studies of

preschool children in North America or Europe (pooled RR = 2.00, 95% CI =

1.58-2.54). There was little evidence of heterogeneity in either of these

groups. Both subsets, however, consisted of relatively few studies.

Stratifying the data on other study characteristics yielded pooled RRs ranging from 1.14 to 1.86. The subset analyses substantially reduced the interstudy heterogeneity, but did not eliminate it. 

Because substantial heterogeneity persisted even after the subset

analyses, linear meta-regressions were fit to evaluate the influence of the
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Chapter 6

Study Author (year)

Chen et al. (1986)

Chen (1989)

Leibowitz & Burrow (1976)

Pedreira et al. (1985)

Kerribijn et al. (1977)

Wittig et al. (1978)

Chilmoncyk et al. (1993)

Evans et al. (1987)

Murray & Morrison (1993)

Ogborn et al. (1994)

Frischer et al. (1992)

Cunningham et al. (1994)

Rona & Chinn (1993)

Tager et al. (1993)

Young et al. (1991)

Anderson et al.(1987)

Holberg et al. (1993)

Leeder et al. (1976)

Peat et al. (1980)

Stanhope et al. (1979)

Wilkie et al. (1995)

Lebowitz et al. (1990)

Shilling et al. (1977)

Jin & MacKay (1993)

Schenker et al. (1983)

Tominaga & Itoh (1985)

Tsimoyianis et al. (1987)

Toyoshima et al. (1987)

Lewis et al. (1985)

Fergusson et al. (1985)

McConnochie & Roghmann (1989)

Reason for Exclusion of Study

Did not specifically analyze asthma or

wheezing as outcome; lumped

asthma/wheeze together with other 

respiratory illnesses of childhood

Examined exacerbations of symptoms

in asthmatic children (rather than 

prevalence or incidence)

Used lung function as the outcome

measure

Did not specifically address household

sources of postnatal ETS exposure

Insufficient presentation of data (i.e.,

odds ratios, relative risks or sufficient

data to allow for calculation of risk ratios

and estimates of their standard errors

were not included)

Redundancy with other studies

Table 6.5

Studies Excluded from Meta-Analysis of ETS and Childhood Asthma Induction

study characteristics simultaneously. This multivariate approach identified

several additional sources of heterogeneity. Studies of preschool children

yielded approximately 50 percent higher risk ratios than those that included older children. Studies that adjusted for gender also tended to yield significantly higher risk estimates than those that did not. Furthermore, while

studies controlling for a family history of atopy did not yield significantly

different estimates of risk than those studies that did not, limiting the study

population to atopic children or to children with a family history of atopy
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Smoking and Tobacco Control Monograph No. 10

Risk Ratio

12 10 8 6 4 2 0

Willers et al. (1991)

Weitzman et al. (1990)

Stern et al. (1989)

Soyseth et al. (1995)

Somerville et al. (1988)

Sherman et al. (1990)

Palmieri et al. (1990)****

O’Connell et al. (1974)

Neuspeil et al. (1989)

Murray et al.***

McConnochie et al. (1989)

Martinez et al. (1992)

Kershaw (1987)

Kay et al. (1995)

Infante-Rivard (1993)

Horwood et al. (1985)

Gortmaker et al. (1982)

Forastiere et al. (1992)

Ehrlich et al. (1992)

Dodge (1982)

Dekker et al. (1991)

Clark et al. (1993)

Chinn & Rona (1991)

Chen et al.

Burchfiel et al. (1986)**

Bener et al. (1991)

Andrae et al. (1988)*

Figure 6.1

Reported Risk Ratios and 95% Confidence Intervals for Studies that Used Clinically

Recognized Asthma as an Outcome

* In presence of household dampness

** In boys

*** In children with a history of atopic dermatitis

**** In non-atopic children 3-6 years of age
yielded approximately 60 percent higher estimates of risk. The overall fit of

the model was reasonably good (p = 0.40), indicating little evidence of

unmodeled heterogeneity.

Though the meta-analysis was not restricted to studies examining

only maternal exposure, OEHHA compared the pooled estimates for asthma

RRs for studies in which there were separate estimates for maternal smoking

versus those for general household smoking. When exposure was related to

maternal smoking the pooled RR was 1.60 (95% CI = 1.29-1.99), while that

for household smoking generally was 1.34 (95% CI = 1.11-1.61). 

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Chapter 6

10 9 8 7 6 5 4 3 2 1 0

Burchfiel et al. (1986)*

Chinn & Rona (1991)

Cogswell et al. (1987)

Cuijpers et al. (1995)*

Dekker et al. (1991)

Dijkstra et al. (1988)

Dodge et al. (1982)

Duff et al. (1993)

Ekwo et al. (1983)

Geller-Bernstein et al. (1987)

McConnochie et al. (1986)

Neuspeil et al. (1989)

Rylander et al. (1993)

Somerville et al. (1988)

Stoddard & Miller (1995)**

Volkmer et al. (1995)

Ware et al. (1984)

* In girls

** Includes children with physician-diagnosed asthma

Figure 6.2

Reported Risk Ratios and 95% Confidence Intervals for Studies that Used “Wheezing

Bronchitis” or “Chronic Wheezing/Whistling in the Chest” as an Outcome

Risk Ratio
The smoking status of the children being studied was a commonly

omitted and potentially important confounder in the studies included in

this analysis. To evaluate the influence of this factor on the pooled RRs,

the analysis was repeated excluding studies involving children who were 10

years of age or older that did not control for the children’s own smoking.

This did not change the results, although the confidence intervals became

slightly wider (pooled RR = 1.48, 95% CI = 1.28-1.71).

OEHHA staff also undertook an influence analysis, in which one

study at a time was dropped, and the pooled RRs were re-estimated. No single study had a significant effect on the pooled estimates.

Most studies relied on crude measures of ETS exposure, i.e., parental

reporting of the presence of household smokers or the estimated number of

cigarettes smoked in the home. Four studies, however, reported risk ratios

in relation to exposures assessed by measurement of salivary or urinary concentrations of cotinine as well as by parental reporting (Clark et al., 1993;

Duff et al., 1993; Ehrlich et al., 1992; Willers et al., 1991). In all four, the

estimated risk ratios associated with exposure to ETS were higher when

exposure classification was based on cotinine levels rather than on parental

reporting and produced a pooled RR of 2.52 (95% CI = 1.61-3.95). Because

this estimate was based on only four studies, it combined the outcome categories of wheeze and clinical asthma.

The results of this meta-analysis indicate a strong and consistent

association between exposure to ETS and development of childhood asthma. This relationship persisted throughout various influence and sensitivity analyses. As anticipated, there was significant heterogeneity of results

across studies. The subset and meta-regression analyses revealed several

important sources of heterogeneity related to elements of study design, particularly with respect to exposure assessment.

The studies reviewed by U.S. EPA (1992) and those published subsequently indicate that ETS is clearly a risk factor for induction of asthma,

particularly in young children. To discriminate between causal and noncausal associations, Hill (1965) listed the following considerations: strength

of the association, consistency in results among different studies, the existence of a biological gradient or dose-response, an appropriate temporal

sequence between the effect and its putative cause, “coherence” with existing knowledge of the natural history of the disease, and biological plausibility (which is often closely related to, if not indistinguishable from, “coherence”). Other criteria for causal inference listed by Hill (1965) are either

obsolete (“specificity”) or superfluous in this instance (“analogy” and

“experimental evidence”). As can be seen in Figures 6.1 and 6.2, most of

the estimates of relative risk extracted from the investigations were statistically significant. Of the 37 studies included in the meta-analysis, 14 had

point estimates greater than 2.0, suggesting a strong association between

ETS exposure and the occurrence of childhood asthma (“strength of association”). The effect estimates tend to be higher in those studies involving

pre-school-aged children and in those that used more precise measures of

exposure. Recognizing the heterogeneity indicated during the process of

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creating pooled estimates in the meta-analysis, almost all studies had point

estimates of relative risk significantly greater than one, and most were statistically significant, whether the outcome was clinically diagnosed asthma

or wheezy bronchitis. If there were no relationship between ETS and childhood asthma, one would expect a random distribution of point estimates

above and below the null value. This consistency is apparent despite the

diversity of study designs and populations (“consistency”).

There appears to be a simple biological gradient of effect (or doseresponse) in studies that collected data on levels of smoking, where effects

were detectable only when the mother smoked 10 or more cigarettes per

day (e.g., Martinez et al. 1992). This finding suggests that a threshold of

ETS exposure intensity is required in order to evoke this response. The temporal relation between childhood asthma and parental smoking is not at

issue here, since asthma in children is unlikely to precede active smoking

by their parents. However, it might be argued that, since the association

seems to be strongest between maternal smoking and asthma prevalence in

pre-school children, the key exposures may have taken place in utero.

Several recent studies suggest that prenatal exposures may cause persistent

decrements in lung growth and development (Cunningham et al. 1994 and

1995; Hanrahan et al. 1992). It is possible that prenatal effects may play a

role as well in the etiology of childhood asthma. However, the studies by

Chen (1986, 1988, 1989), showing effects of paternal smoking alone, as

well as studies of ETS exposure linked to increased risks of asthma in nonsmoking adults (Leuenberger et al., 1994), indicate that postnatal exposures

can be sufficient to elicit this outcome. Development of asthma as a result

of ETS exposure is “coherent” with other investigations demonstrating that

both active and passive exposure to cigarette smoke are associated with

increases in airway responsiveness, which (as noted above) is a characteristic feature of asthma. The biological plausibility of this relationship is

strong: 1) ETS exposure predisposes young children to an increased risk of

repeated respiratory infection, a recognized risk factor for the development

of asthma; 2) ETS causes airway hyperresponsiveness; 3) ETS may increase

the risk of childhood atopy and of increased circulating allergy-related antibodies (IgE), enhancing the probability of allergic asthma; and 4) cigarette

smoke causes airway inflammation in active smokers (Niewohner, 1974)

and may have similar (but lower-level) effects in people exposed to sidestream smoke. Taken as a whole, the epidemiologic evidence of causation

is compelling.

Though not typically considered part of the Bradford Hill criteria,

the potential role of confounding should also be considered in causal inference. In epidemiological studies, a confounder is a factor or variable that is

associated with both the disease outcome and with the exposure of interest,

and can produce a distortion of the relationship (or lack thereof) between

the exposure and the disease outcome. The effect of a potential confounding variable can be addressed in the design phase of a study, or if data on

the putative confounder are collected during the study, then the potentially

distorting effects of the confounder can be controlled for, statistically, during the analysis. In any given study, there are likely to be few potentially

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Chapter 6
confounding exposures sufficiently important to control for. For studies

examining the relationship between childhood asthma and ETS exposure,

probably the most important variables to be evaluated as potential confounders, given the current state of knowledge, include the child’s age, history of atopy or allergy, parental history of asthma, allergy, or other respiratory symptoms, and an indicator of family socioeconomic status. Other

variables that ideally should be examined and adjusted for, if necessary,

would include the child’s gender, whether the child was breast-fed in infancy, type of fuel used for heating and cooking, the presence of allergens recognized to be risk factors for induction of asthma (e.g., from household pets

or dust mites), home dampness and/or mold, serious lower respiratory

infection in early childhood, number of siblings, and maternal smoking

during pregnancy (to the extent that it can be segregated from postnatal

exposure). Approximately two-thirds of the studies included in the metaanalysis controlled for three or more potential confounders and effect modifiers, and these studies tended to have greater estimates of relative risk of

asthma than those studies that adjusted for fewer than three covariates.

The association of ETS exposure with asthma was usually found to be independent of these various risk factors. Several studies examined or adjusted

for ten or more potential confounders, and some adjusted for many more;

for example, Infante-Rivarde (1993) apparently adjusted for nearly two

dozen variables, reporting an odds ratio of 2.77 (95% CI = 1.35-5.66) for

maternal smoking of at least one pack of cigarettes/day. Nevertheless, routine adjustment for a long list of putative confounders is methodologically

undesirable, as it may affect the precision and therefore the significance of

the estimate of the relationship between ETS exposure and disease.

The U.S. EPA derived a quantitative estimate of risk of asthma

induction associated with maternal ETS exposure (U.S. EPA, 1992, pp. 8-10

to 8-13). Using a threshold model and assuming relative risks ranging from

1.75 to 2.25 for children of mothers smoking more than ten cigarettes/day,

U.S. EPA estimated that 7 to 9 percent of “all cases of asthma” (presumably

pediatric cases only) could be attributable to maternal ETS exposure. This

translated to an annual incidence of 8,000 to 26,000 cases attributable to

ETS. U.S. EPA also calculated an annual incidence range of 13,000 to

60,000 using a nonthreshold model, noting, however, that a threshold

model is more consistent with current epidemiologic data.

There are no California-specific data on asthma prevalence or incidence. Thus, an admittedly simplistic approach to estimating the attributable risk of ETS-induced pediatric asthma in California would be to multiply

U.S. EPA’s estimates by the percentage of the U.S. population living in this

state, i.e., about 12 percent. This would lead to estimates of 960 to 3,120

new cases of childhood asthma each year using U.S. EPA’s threshold model

or 1,560 to 7,200 cases using the nonthreshold model.

Dozens of epidemiologic studies have linked chronic

domestic ETS exposure with recurrent symptoms of

cough, wheeze, and excess phlegm production in children. The NRC report

(1986) concluded, based on a review of nine such studies involving approximately 25,000 subjects:

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6.2.2 Chronic Respiratory

Symptoms (Children)
“Children of parents who smoke compared with the children of

parents who do not smoke show increased prevalences of respiratory symptoms, usually cough, sputum, and wheezing. The odds

ratios from the larger studies, adjusted for the presence of parental

symptoms, were 1.2 to 1.8, depending on the symptoms.”

This range may underestimate the effects of ETS, since adjustment

for parental symptoms, which is intended to address possible biased

parental reporting of symptoms because of greater somatic awareness, may

actually overcorrect for children’s symptoms in that it also corrects for

parental smoking (Ferris et al., 1985). The Surgeon General’s report (1986),

reviewing ten large epidemiologic studies that examined chronic symptoms

in approximately 31,500 children, came to a similar conclusion: 

“[C]hildren whose parents smoke had a 30 to 80 percent excess

prevalence of chronic cough or phlegm compared with children of

nonsmoking parents. For wheezing, the increase in risk varied

from none to over six-fold among the studies reviewed. Many

studies showed an exposure-related increase in the percentage of

children with reported chronic symptoms as the number of

parental smokers in the home increased” (p. 48).

The U.S. EPA report (1992) reviewed an additional 14 studies published since 1986, which basically confirmed the findings of the previous

major reviews. The U.S. EPA concluded:

“There is sufficient evidence for the conclusion that ETS exposure

at home is causally associated with respiratory symptoms such as

cough, phlegm, or wheezing in children. The evidence is particularly strong for infants and preschool children; in this age range,

most studies have found a significant association between exposure

to ETS...and respiratory symptoms in the children, with odds ratios

generally ranging between 1.2 and 2.4. ...The evidence is significant but less compelling for a relationship between exposure to ETS

and respiratory symptoms in school-age children. Odds ratios for

this age group are usually between 1.1 and 2.0 ...[T]here are significant differences in susceptibility to ETS between individuals.

[S]everal factors may amplify the effects of passive smoking: prematurity, a family history of allergy, a personal history of respiratory

illnesses in early childhood, and being exposed to other environmental pollutants.”

The reports by the Surgeon General (U.S. DHHS, 1986), the National

Research Council (1986), and the U.S. EPA (1992) concluded that a causal

relationship is the most likely explanation of the consistently observed

associations between ETS exposure and respiratory symptoms in children.

Because this issue has been adequately addressed in these reports, a de novo

analysis of the primary literature has not been undertaken. More recent

published investigations tend to support the conclusions articulated in

these reviews. In a study of 343 children, aged 7-12, Henderson et al.

(1995) found odds ratios of 2.9 (95% C.I = 1.2-7.0) for ETS exposure in rela227

Chapter 6
tion to risk of wheeze in nonallergic children and 4.4 (95% C.I = 1.2-16.1)

in allergic girls but not allergic boys. Goren et al. (1995) found significantly

increased prevalences of a variety of respiratory symptoms and conditions

(cough and sputum, wheeze with and without respiratory infection, bronchitis, and others) associated with maternal or paternal smoking among

8,259 elementary school children in Israel. 

Bråbäck et al. (1995) undertook a cross-sectional study of 2,594 children, aged 10-12, in cities in Sweden, Poland, and Estonia, examining a

variety of risk factors for respiratory symptoms and for atopic sensitization.

The relevant odds ratios, derived from multiple logistic regression analysis,

for “coughing attacks” (defined as either nocturnal cough lasting at least 4

weeks or exercise-induced cough) are presented in the following summary: 

There were findings of other significant associations between maternal smoking and respiratory symptom indices in Poland and Estonia, but

not in Sweden. The difference in results between Sweden and the other

two countries may be related to the intensity of smoke exposure related to

dwelling size and crowding, since most families in Poland and Estonia lived

in apartments, while only about one-third of Swedish families did, and the

average number of persons per room was 0.9 in Sweden, 1.7 in Poland, and

1.5 in Estonia. In addition, the authors noted that in Sweden there is widespread public awareness of health hazards associated with ETS exposure,

leading many parents to smoke outdoors.

Cuijpers et al. (1995) undertook a cross-sectional examination of a

variety of potential indoor environmental influences on respiratory symptoms and lung function in 535 Dutch children, aged 6-12. This study

reported significant associations between ETS exposure and cough for 11-20

cigarettes per day in boys, but not for <11 or >20 cigarettes per day, and it

found no significant associations for girls. However, the numbers of symptomatic boys and girls were small (e.g., 33 and 26, respectively). The “significant” result for 11-20 cigarettes per day was based on a significance level

of 0.10 rather than the more conventional level of 0.05. Examining the

symptom of shortness of breath, Cuijpers et al. reported an exposureresponse relationship for boys: the odds ratios for <11, 11-20, and >20 cigarettes per day for maternal smoking were 1.61 (0.58-4.50), 2.80 (1.13-6.95),

and 4.58 (1.19-17.65) (again with the significance level set at 0.10, so these

represent 90 percent confidence intervals, which would be even wider had

the investigators set a = 0.05). While there was no relationship between

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Smoking and Tobacco Control Monograph No. 10

Maternal smoking All Sweden Poland Estonia

1-9 cigarettes/day 1.55 0.67 1.38 1.80 

(1.07-2.24)* (0.25-1.78) (0.52-3.70) (1.15-2.80)**

>9 cigarettes/day 2.60 1.40 2.88 4.27 

(1.69-4.01)*** (0.70-2.80) (1.23-6.74)** (2.04-8.91)***

*p < 0.05, **p < 0.01, ***p < 0.001
paternal smoking and boys’ symptoms, the odds ratio for <11 cigarettes per

day for girls was elevated (2.85) and significant at a = 0.10. In this study, it

appears that boys might be more susceptible to ETS-related effects; however,

because the numbers of children affected were so small, the confidence

intervals are quite wide.

Moyes et al. (1995) conducted a cross-sectional investigation of asthma and allergy in 2,614 primary school and 2,752 secondary school children in six districts bordering the Bay of Plenty in New Zealand. They

reported that parental ETS exposure was related to nocturnal cough, nasal

symptoms, and wheeze in the older (ages 13-14) but not the younger (ages

6-7) children. The odds ratios for nocturnal cough and wheeze were highly

significant (p < 0.01). While this study does not have the same statistical

power issues as that reported by Cuijpers et al. (1995), the analysis of passive smoking was crude (i.e., “Parental smoking”- yes/no, without stratification by maternal versus paternal smoking or quantification of numbers of

cigarettes smoked/day) and the only other variable adjusted for was ethnicity (European versus Maori). 

Forastiere et al. (1992) examined the relationships between a variety

of predictors and respiratory illness in 2,929 Italian children, aged 7-11

years old, in a cross-sectional study in 1987, and found significantly elevated odds ratios in relation to the children’s exposure to passive smoking. For

example, the odds ratios (and 95 percent confidence intervals) for any

smoker in the house were 1.3 (95% CI = 1.03-1.6) for early respiratory infection and 1.8 (95% CI = 1.2-2.7) for night cough. Though the odds ratios

were elevated for either maternal or paternal smoking alone, they were not

statistically significant, probably because of reduced power that accompanied dividing the responses by gender.

Wolf-Ostermann et al. (1995) undertook a prospective cohort investigation of respiratory illness in 8,514 German children, with data collection in 1977, 1979, and 1985. They also found a variety of significantly

increased odds ratios for several adverse respiratory outcomes—e.g., 1.26

(1.07-1.49) for bronchitis, and 1.55 (1.30-1.85) for fall and winter cough.

Mannino et al. (1996) analyzed data from the 1991 National Health

Interview survey to estimate the relationships between parental smoking

and the occurrence of respiratory illness in children aged 1-10 in the 2

weeks preceding the interview. They found that ETS-exposed children had

21 percent more restricted activity days, 31 percent more days of bed confinement, and 39 percent more days of school absence than those not

exposed (all relationships were highly significant p < 0.01). Adjusting for

age, sex, family size, socioeconomic status, season, and region, Mannino et

al. found a higher incidence of acute respiratory illness (RR = 1.10, 95% CI

= 0.95-1.26) and a higher prevalence of chronic respiratory illness (OR =

1.28, 95% CI = 0.99-1.67). Though these latter estimates were not statistically significant, Mannino et al. indicated that, because of the nature of the

survey, the study had a power of 0.30 to detect a 10 percent increase in the

two-week incidence of acute illness and 0.60 to detect a 25 percent increase

in the prevalence of chronic disease. The investigators also pointed out a

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Chapter 6
variety of other considerations that would bias their results towards the null

hypothesis, such as the dichotomous exposure classification (exposed versus

not exposed).

These and other studies support the conclusion, also stated in the

reports by the NRC, the Surgeon General, and the U.S. EPA, that there is

sufficient evidence that ETS exposure at home is causally associated with

chronic respiratory symptoms (cough, phlegm, or wheezing) in children,

particularly infants and young children.

Numerous cross-sectional and cohort studies have

been published since the late 1970s examining the

relationship of ETS exposure to various indices of lung function in children.

A total of 29 studies, involving lung function measurements on approximately 77,000 subjects, were reviewed by the Surgeon General (U.S. DHHS,

1986), the National Research Council (1986), and the U.S. EPA (1992).

While the results from all the studies reviewed were not wholly consistent,

there was sufficient evidence for these three reviews to reach the conclusion

that childhood exposure to ETS affects lung growth and development as

measured by pulmonary function tests (PFTs). Conclusions reported in

these reviews are listed below, followed by a description of clinical implications of these findings, plus brief summaries of several more recent studies.

The three major ETS reviews found that:

1) Some longitudinal (or cohort) studies report a small, but statistically significant, decrease in the rate of lung growth in children (as measured by

multiple indices of lung function) exposed to ETS compared with nonexposed children. The magnitude of this decrement in naturally occurring growth, if projected through adolescence, appeared to be 3 to 5

percent or less (Surgeon General, NRC, U.S. EPA).

2) In a majority of cross-sectional studies, ETS-exposed children had modestly lower PFT values, on average, than nonexposed children. These

effects were greater in at least some susceptible subgroups (e.g., low

birth weight, younger children) or in low SES families (e.g., in which the

mothers had less than 12 years of education; U.S. EPA).

3) Maternal smoking had a more marked impact on children’s PFTs than

paternal smoking, though in a data set from China in which all the

mothers were nonsmokers, there was an effect of paternal smoking, as

well (Chen et al., 1986, Surgeon General, NRC).

4) In several studies, lower PFT values tended to be found with an increasing number of smokers in the child’s household. In other words, in

these investigations there appeared to be an exposure-response relationship (Surgeon General, NRC).

How ETS causes lung function decrements in otherwise healthy

children is not known, but the observed effects may be related (at least in

young children) to increased susceptibility to respiratory infection or to

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6.2.3 Decreased Lung

Development (Children)
delayed developmental effects attributable to in utero exposure to maternal

smoking. Several recent papers suggest that in utero or early childhood

exposures to ETS may result in changes in lung development that may persist through childhood and adolescence (Cunningham et al., 1994 and

1995; Hanrahan, 1992; Brown, 1995). The short-term clinical consequences

of these apparent reductions in children’s PFTs are likely to be of less importance, however, than their potential long-term implications. As was

observed in the Surgeon General’s report (U.S. DHHS, 1986), “The absolute

magnitude of the difference in lung function is small on average. A small

reduction of function, on the order of 1 to 5 percent of predicted value,

would not be expected to have functional consequences.” Nonetheless,

reductions of lung function in childhood may persist into adulthood and

increase the risk of developing chronic obstructive pulmonary disease (U.S.

DHHS, 1986; NRC, 1986; U.S. EPA, 1992).The likelihood of such potential

long-term consequences, however, has not yet been fully evaluated.

Several investigations of the relationship between childhood ETS

exposure and lung function have been published since the U.S. EPA

reviewed the data on this topic. As with previous studies, the evidence

from these investigations is somewhat heterogeneous. The results from several large cross-sectional studies, in particular, tend to support the existence

of a relationship between household ETS exposure and decreased lung function. Lebowitz et al. (1992) reported an analysis of ETS exposure on PFTs

measured at least three times over a 13-year period in 138 Caucasian children (67 boys and 71 girls), aged 5 through 15 upon entrance into the

study. ETS exposure was assessed by parental survey: there was no distinction made between light and heavy smoking. The analysis was stratified by

gender and by level of lung function (normal or low) at the initiation of the

study. This group of investigators had previously reported that, in comparison with children with normal lung function, children with lower initial

PFTs experienced their peak lung growth at an earlier age and at a lower

absolute value. In this report, there was no ETS effect detected in females

who started with either normal or low lung function. Similarly, no effect

was detected in males starting with normal lung function. In contrast, boys

starting with low lung function who were ETS-exposed had a decreased

FEV1 (forced expiratory volume in one second) between ages 13 and 16, relative to unexposed boys with low initial lung function. Interestingly,

growth of the forced vital capacity (FVC, which is a rough indicator of lung

volume), in the ETS-exposed boys exceeded that in the nonexposed group

between the ages of 17.5 and 23.5. Within this age interval, the ratio of

FEV1/FVC (and another similar index of airway obstruction) decreased significantly in the exposed versus the unexposed low-function subjects (and

versus the subjects with normal initial lung function). The clinical implications of these findings are unclear, since the apparent accelerated decline in

the lung function ratios is at least partly attributable to the increase in the

denominator (FVC). Furthermore, though there were a total of 142 lung

function measurements made over the course of this study in the low-function males, there were only 28 in this group, including both smokers and

nonsmokers. Thus, though it appears that the low-function ETS-exposed

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Chapter 6
males began adult life with an accelerated decline from a lower-than-normal baseline, no definite conclusions can be made until this type of analysis is replicated with a larger sample size.

Sherrill et al. (1992) recently reported results from a longitudinal

study of lung function in a cohort of 634 children (327 males, 307 females)

in New Zealand. The children were part of a larger birth cohort whose

health status was assessed by questionnaire every 2 years from 3 to 15 years

of age. Questions regarding parental smoking were asked only at ages 7, 9,

and 11. Spirometric measurements were performed at ages 9, 11, 13, and

15. There were no statistically significant ETS-related effects on FEV1 or

FVC in males, though females whose parents both smoked tended to have a

slower rate of growth in FEV1 and those exposed to maternal smoking tended to have a lower FVC than the nonexposed (p < 0.1 for both findings).

The investigators indicated that because of a potential disjunction between

somatic growth and lung-function growth in adolescence, the ratio of FEV1

to FVC might be a more accurate measure of lung-function growth than

either index alone. Using the FEV1/FVC ratio, detrimental effects of ETS

were identified; males, but not females, showed a nonprogressive decrease

related to parental smoking. Moreover, in children with asthma or a history of wheezing, progressive decrements in FEV1/FVC were observed in children of both sexes, compared with an increase in this ratio observed in

nonexposed children with wheeze. The average reduction in FEV1/FVC by

age 15 was 3.9 percent in ETS-exposed boys with wheeze and 2.3 percent in

girls. As noted by the authors of this report, there does appear to be an ETSrelated effect on the subgroup of children with a history of wheezing, but

the lack of an obvious separate effect on FEV1 or FVC weakens this conclusion somewhat.

Wang et al. (1994) investigated the relationship between several

measures of childhood ETS exposure and annual lung function measurements made in 8,706 nonsmoking white children between the ages of 6

and 18 who were participants in the Harvard Six Cities Study. ETS exposure

metrics included: pre-school exposures (during the first 5 years of life),

cumulative exposure from age 6 to the year before each annual examination, and current maternal and paternal smoking as reported each year. In

this report, the investigators used regression splines to model pulmonary

function growth as a function of ETS exposure, adjusting for age, height,

city of residence, and parental education (a surrogate for socioeconomic status). Both current maternal smoking and pre-school exposure to maternal

smoking were significant predictors of the children’s pulmonary function:

there were no significant differences of effect observed in boys versus girls.

Both of these measures were associated with small, but statistically significant reductions in FEV1/FVC and FEF25-75 (an indicator of flow rates in the

smaller airways) through adolescence. Interestingly, early maternal smoking was also associated with a small increase in FVC, which was statistically

significant only in children aged 11 to 18. In children aged 6 to 10, current

maternal smoking was related to slower growth rates of both FVC and FEV1,

and in older children, with a reduction in the growth rate of FEF25-75. The

findings of an increased FVC and reduced FEV1 and FEF25-75 are similar to

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those of Lebowitz et al. (1992), and suggest that early childhood ETS exposure may induce an exaggerated disjunction in growth rates for airways (as

measured by FEV1 and FEF25-75) and lung parenchyma (lung volume as indicated by FVC), a process referred to as “dysanapsis.” Moreover, after controlling statistically for current ETS exposure, this report suggests that early

childhood exposures appear to exert long-lasting effects on lung maturation

as measured by pulmonary function tests.

Rona and Chinn (1993) studied lung function in relation to reported home ETS exposure in 2,756 children, aged 61⁄2 to 12, who took part in a

cross-sectional national health survey in 1987 and 1988 in Great Britain.

ETS exposure was assessed by parental questionnaire. A large number of

potentially confounding variables were controlled for in the analysis,

including age, height, ethnic group, weight, birth weight, percentage body

fat (as measured by triceps skinfold thickness), reported parental heights,

mother’s age at child’s birth, family size, father’s social class, “overcrowding,” whether the child resided with one or both parents, mother’s educational level, father’s employment status, type of cooking fuel, study area,

type of school meals, and a variety of the child’s respiratory symptoms.

The investigators found significant associations of maternal smoking with

reduced FEF25-75 and FEF75-85 in boys, but not girls. They also found similar

gender-associated reductions of FEV1 with maternal ETS exposure and of

FEF25-75 with total parental smoking, which were of borderline statistical significance. The results of this study are consistent with numerous others in

showing an association between reduced childhood lung function and

maternal but not paternal smoking. However, the differential effects on

boys versus girls remains unexplained and, as the investigators noted,

“illustrate the difficulties in making generalizations about the association

between lung function and passive smoking in childhood.”

Haby and colleagues (1994) assessed the relationship of several variables to spirometric indices (FVC, FEV1, PEFR, and FEF25-75) in a cross-sectional study of Australian children in grades three to five (ages 7-12). ETS

exposure was assessed by parental questionnaire and was included as a continuous variable in stepwise multiple regression analyses of predictors of

lung function in a group of 2,765 children. Other variables entered in the

final models included height, weight, age, gender, current and past asthma,

and the presence of a respiratory infection. The investigators reported a linear, dose-related reduction in FEV1, PEFR, FEF25-75, but not in FVC, where

dose referred to the number of cigarettes smoked daily in the home. The

magnitude of the reduction was small: a 10-year-old child would be expected to have a 2.4 percent reduction of FEF25-75 if more than one pack of cigarettes were smoked in the home every day. The investigators did not report

effects of prenatal or early childhood exposure to ETS, whether there were

gender differences in the relationship of ETS exposure to spirometry, or the

effects of maternal versus paternal smoking. As in several studies described

above, Haby et al. speculated that the differential effects of ETS on FVC versus the flow-related measures of lung function may be due to dysanaptic

growth of the lung.

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Cook et al. (1993) examined the relationships between several lungfunction measures and ETS exposure in a population-based sample of 5.0-

to 7.9-year-old children randomly selected from elementary schools in 10

towns in England and Wales. ETS assessment was conducted by both

parental questionnaire and by measurement of salivary cotinine obtained

from the participants. Multiple regression models relating the spirometric

indices to salivary cotinine were based on data from 2,511 children who

had provided complete, acceptable data. The analysis relating lung function to questionnaire-based ETS assessment contained data from 2,500 children. In analyses adjusted for age, gender, height, body mass index, lung

function technician, and town of residence, several indices of lung function

(FVC, FEV1, FEF25, FEF50, FEF75) were negatively associated with salivary cotinine; all were highly significant statistically. Only the ratio FEV1/FVC was

not correlated with salivary cotinine. Additional adjustment for birth

weight, presence or absence of a gas-burning stove, and the head of household’s social class (an indicator of SES) did not materially change the estimates. FEV1 declined linearly with increasing salivary cotinine. The results

from the questionnaire-based ETS exposure assessment were more ambiguous, reflecting the increased uncertainty and measurement error associated

with such data. Though there was no clear exposure-response relationship

between FEV1 and the numbers of cigarettes reportedly smoked by the

mother or the father, when ETS exposure was categorized by the number of

smokers to which the child was exposed on a regular basis, all of the above

indices except FVC declined with increasing numbers of smokers, though

this negative association was significant only for FEF25, FEF50, FEF75, and

FEV1/FVC. As was true of the cotinine analysis, the strongest association

was with FEF50. For a small subset of the children (n = 111), salivary cotinine was sampled twice (6 months apart), and though the mean levels were

slightly different (1.59 versus 1.37 ng/ml), the difference was not significant, indicating the stability of ongoing exposure patterns. The cotininebased analysis supports the existence of an exposure-response relationship

between ETS and childhood lung function; however, these investigators

could not distinguish between the effects of current versus early childhood

exposures.

Two recent reports by Cunningham et al. (1994 and 1995) suggest

that prenatal or very early postnatal exposures to tobacco smoke components may affect lung development, inducing persistent effects that may be

detected throughout childhood. As part of the Harvard 24-Cities Study,

Cunningham et al. presented results of an analysis of 8,863 nonsmoking

white children, aged 8-12, in which they examined the relationships of a

variety of lung-function measures to maternal smoking during pregnancy as

well as to current maternal smoking. In regression models adjusted for sex,

height, weight, age, parental education, city of residence, and interaction

between sex and height, the investigators found decrements in FEV0.75,

FEV1, FEV1/FVC, PEFR, FEF25-75, and FEF65-75 that were highly significantly

related to both maternal smoking during pregnancy and to maternal ETS

exposure in the year preceding the examination. However, when adjusted

for current maternal smoking, the associations of these measures with

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maternal smoking during pregnancy were slightly reduced, but remained

highly significant statistically. In contrast, when adjusted for maternal

smoking during pregnancy, the effects of current smoking on the children’s

lung function were markedly decreased and were no longer significant.

Boys showed greater ETS-related deficits than girls in all the above measures

of lung function, but this was due to the greater effects in boys with a history of allergy, asthma, parental asthma, or severe respiratory illness.

Among boys and girls with none of these risk factors for decreased lung

function, the estimates of ETS-related effects were of similar magnitude. In

general, mothers who smoked during pregnancy are likely to continue to

smoke afterwards, so these two measures of ETS tend to be highly correlated. However, because of the large size of this study, the investigators were

able to undertake a variety of subgroup analyses that highlighted the

importance of in utero and possibly very early childhood exposure to maternal ETS. Paternal smoking was not a significant predictor of the participants’ lung function.

Cunningham et al. (1995) undertook a similar analysis with a sample of 493 white and 383 black children, aged 9-11, in Philadelphia. ETS

exposure history was obtained through the children’s mothers’ answers to

questionnaires. In the statistical analysis, exposures were modeled as

dichotomous variables for maternal smoking and for current smoking, and

as a continuous variable for the number of cigarettes smoked per day.

Pulmonary function testing was conducted at school. Multiple regression

techniques were employed to model several lung function measurements as

a function of ETS exposure, adjusting for height, weight, age, area of residence, parental education, mother’s primary language, and single-parent

family status. Models that included boys and girls or members of both

races required additional adjustments for gender, race, interaction of gender

and height, race and gender, race and height, race and weight, and race and

age. In regression models for the whole study population, maternal smoking during pregnancy was associated with statistically significant decrements of -8.1 percent FEF25-75 (95% CI = -12.9 to -3.1 percent) and -2.0 percent in FEV1/FVC (95% CI = -3.0 to - 0.9 percent), while a decrease in FEV1

was not significant. No decrease in FVC was observed. Larger deficits were

observed in black than in white children, with the greatest decreases detected in African-American boys (-19.6 percent FEF25-75 (95% CI = -31.1 to -6.1

percent), -5.9 percent in FEV1/FVC (95% CI = -8.7 to -2.9 percent); FEV1 = -

6.0; (95% CI = -10.4 to -1.4 percent)). These differences could not be

explained by potential confounding by SES, prior respiratory illness, or

housing characteristics. Current ETS exposure was not associated with lung

function deficits after adjustment for maternal smoking during pregnancy.

Casale et al. (1991), in a study of 143 Italian children aged 6-11,

found dose-dependent relationships between several measures of lung function (particularly those related to airflow at low lung volumes) and ETS

exposure. In this study, ETS exposure was measured by both urinary cotinine and parental questionnaire. Goren and Hellman (1995), in a cross-sectional study of 8,259 Israeli second- and fifth-graders, found no relationship

of parental smoking with measures of lung volume and central or large air235

Chapter 6
way caliber (FVC, FEV1, PEF, and FEV1/FVC). Guneser et al. (1994), in a

study of 617 Turkish school children (287 boys and 330 girls), aged 9-12,

found that all measures of lung function were lower in boys exposed to ETS

compared with those who were not (with the exception of FEV1 in 12-year

olds), but that these differences were significant only for FVC in 9-year-olds,

FEV1 in 9- and 10-year-olds, peak flow in 10-year-olds, FEF25 in 10-year-olds,

and FEF25-75 in 9-year-olds. No data were presented for girls. Soyseth et al.

(1995), in a study of parental smoking and asthma, bronchial hyperresponsiveness, and atopy in 620 Norwegian children aged 7-13, reported that, of

the 573 children performing spirometry, there was a slight, but not statistically significant decrease in the FEV1/FVC ratio (one measure of airway

obstruction) in relation to maternal smoking (-0.7 percent), that was even

less for paternal smoking (-0.2 percent). This was the only spirometry result

reported in this paper. Cuijpers et al. (1995), in a study of 535 Dutch children aged 6-12, found significant decreases in several indices of lung function (FVC, FEV1, PEF and FEF25-75) in boys related to cumulative lifetime

exposure to ETS, with larger decrements related to exposure during their

entire lives versus part of their lives. As with respiratory symptoms, a lesser

effect was seen in girls, with only one index (FEF25-75) showing a similar

trend that was significant. Finally, Richards et al. (1996), in a cross-sectional study of 395 South African adolescents aged 14-18, found no significant

differences in FEV1 and FEF25-75 between exposed and non-exposed children. 

In their ensemble, these studies, especially the cross-sectional investigations, tend to support the conclusions reached in the earlier reviews by

the NRC, the Surgeon General, and the U.S. EPA regarding the relationships

between ETS exposure and lung function in children. However, as noted

above, the data are not entirely consistent. Some of the differences may be

explicable by the crudeness of questionnaire-based exposure assessment,

which is likely to result in nondifferential misclassification of exposure and

a consequent bias towards the null hypothesis of no relationship. In this

regard, the study by Cook et al. (1993) is instructive. In this investigation

of 2,500 English and Welsh school children, aged 5-7, there were significant, consistent relationships between ETS exposure as measured by salivary

cotinine and several indices of lung function. These associations were

weaker and insignificant when based on questionnaire score, suggesting

that this more commonly used method of exposure assessment may well

result in a bias towards the null hypothesis. Some inter-study discrepancies

may also be attributable to the different age ranges of the study populations, especially since early childhood or in utero exposures appear to exert

long-lasting effects, which may diminish over time. Finally, although the

mean changes observed have generally been of small magnitude and uncertain clinical significance, the potential long-term implications of these lung

function decrements warrant additional investigation.

Several investigators have examined the question of

chronic chest symptoms and/or pulmonary function

changes in adults exposed to ETS. It is well established that active smoking leads to increased age-related decrements in pulmonary function. For example, in a large multi-center longitudinal study,

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6.2.4 Chronic Pulmonary

Disease and Respiratory

Symptoms (Adults)
the yearly decline in FEV1 was 30-40 percent greater in smokers than in

nonsmokers (Xu et al., 1992). Smoking also can lead to chronic obstructive

pulmonary disease (COPD). COPD is characterized by mucus hypersecretion/infection (chronic bronchitis) and loss of elastic recoil and alveolar

integrity (emphysema), resulting in varying degrees of airway obstruction

(particularly during expiration) and sputum production. Mechanisms

underlying these changes include cigarette smoke-induced bronchopulmonary inflammation, induction of airway hyperresponsiveness, inhibition

of mucociliary clearance (and other antimicrobial defenses), goblet cell

hyperplasia, release of proteolytic enzymes from inflammatory cells, and

possibly inhibition of antiproteases (Snider, 1989 and 1991; Wagner, 1992).

This section reviews the epidemiologic evidence bearing on the question of

chronic exposure to ETS, lung function, and chronic respiratory symptoms

in adults.

The Surgeon General’s Office (U.S. DHHS, 1986) and NRC (1986)

reviewed five, and the U.S. EPA (1992) an additional six, studies of chronic

respiratory symptoms and/or pulmonary function among adults exposed to

environmental tobacco smoke in the home or workplace; these are summarized below. Several additional studies were found which were not summarized in any of the above reviews.

White and Froeb (1980) surveyed 2,100 middle-aged subjects who

enrolled in a physical fitness course sponsored by the University of

California, San Diego over a 10-year period. Roughly 87 percent of the registrants were white collar workers. For both sexes, nonsmokers who reported chronic workplace exposure to ETS had, as a group, significantly lower

FEF25-75 (forced expiratory flow during the middle half of the forced vital

capacity maneuver) and FEF75-85 values than did non-ETS exposed nonsmokers; comparable decrements were found in the above parameters among

light smokers and smokers who did not inhale. By comparison, persons

actively smoking at least one pack-per-day for 20 years or more had decrements in the forced expiratory volume in one second (FEV1) and the forced

vital capacity (FVC), which were not seen in passive smokers or light smokers.

Comstock (1981) analyzed cross-sectional data on 1,724 adult participants in two different studies of respiratory symptoms. Non-significant

excesses of subjects with an FEV1 <80 percent of predicted or an FEV1/FVC

of <70 percent were observed among males exposed to ETS; no such excesses were seen among women. Most respiratory tract symptoms were equally

prevalent among those exposed and not exposed.

Kauffman et al. (1983 and 1989) analyzed questionnaire and pulmonary function data in two cross-sectional studies that included 3,855

French women (aged 25 to 59 years) and 2,220 American women (aged 25

to 74). For most lower respiratory symptoms, odds ratios comparing passive

smokers with nonsmokers were elevated, but not to a statistically significant degree. Among French women over age 40, both FEV1 and FVC were

significantly lower among the passive smokers. In the U.S. sample, there

was a significantly elevated rate of self-reported wheezing among passive

smokers compared to the unexposed group.

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Chapter 6
Kentner et al. (1984) conducted a cross-sectional study of 1,351

office workers, including both a questionnaire and pulmonary function

testing. Smokers, ex-smokers, and passive smokers were compared to lifetime nonsmokers. Whereas active and prior smokers had significantly

lower age- and sex-standardized ventilatory parameters, no such changes

were evident among persons whose sole lifetime exposure was passive

smoking.

Brunekreef et al. (1985) followed 97 nonsmoking rural Dutch

females for approximately 15 years with serial measures of pulmonary function. Analyzed cross-sectionally, those women 40 to 60 years of age at the

time of the latest measurement who were passively exposed to cigarette

smoke in the home had significantly lower peak expiratory flow (PEF) than

did the unexposed group. Among those with passive smoke exposure

throughout the period of the study, forced expiratory flow at 75 percent of

total lung volume (FEF75) was also significantly lower. Other lung function

parameters, while generally lower among passive smokers, were not significantly so. Analyzed longitudinally, however, there was no significant difference in yearly age-related pulmonary function loss between the two groups.

Svendsen et al. (1987) analyzed data from the Multiple Risk Factor

Intervention Trial on 1,245 married men aged 35-57 years who had never

smoked, roughly a quarter of whom had wives who smoked. Upon entry

into the study, the latter had FEV1 values, on average, 99 ml (2.8 percent)

lower than those with nonsmoking wives (95% CI = 5-192 ml lower).

However, separating subjects whose wives smoked less than one pack per

day versus greater than one pack per day did not provide evidence of a

dose-response relationship. Passive smoking histories were validated with

serum thiocyanate levels (no difference observed by spousal smoking) and

expired air carbon monoxide (significant trend with increasing spousal

smoking).

Kalandidi et al. (1987 and 1990) conducted a case-control study,

comparing 103 nonsmoking Greek women aged 40-79 who were admitted

to the hospital for an initial diagnosis of COPD with 179 similarly aged

nonsmoking visitors (i.e., friends and family of patients). A significant

trend was observed in the odds ratio for COPD and spousal smoking as the

husband’s estimated (during-marriage) total cigarette consumption

increased, with the OR equaling 1.3 for fewer than 3x105 cigarettes and 1.8

for greater than 3x105—i.e., greater than approximately 40 pack-years of

spousal cigarette smoking (p = 0.01 crude, p = 0.03 adjusted). Factors

adjusted for in the analysis included age, education, rural versus urban residence, and employment status.

Euler et al. (1988) performed a multivariate logistic regression analysis of questionnaire data from 7,445 nonsmoking Seventh Day Adventists in

California. The study, which focused mainly on the effects of air pollution,

looked at passive smoking as a covariate. Among other variables, selfreported ETS exposure, both in the workplace and in the home, was significantly related to self-reported symptoms of COPD (breathlessness, sputum

production, and wheezing).

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Masi et al. (1988) did a cross-sectional analysis of 293 nonsmoking

men and women, 15-35 years of age, who had previously been recruited for

a study of lung function in adolescence and young adulthood. There was a

significant decrement in FEF25-75, FEF50, and residual volume as a function of

cumulative lifetime exposure to ETS at home (but not at work) among

males only. Females showed a significant trend toward lower carbon

monoxide diffusion capacity (DLCO) with increasing cumulative ETS exposure at work (but not at home). The analysis involved a total of 40 test statistics. Of note, the observation of a significantly lower residual volume

(RV) in males exposed to ETS at home runs counter to the hypothesis that

ETS exposure produces clinically significant COPD, since an elevated RV is

normally observed in COPD.

Hole et al. (1989) interviewed and examined 671 lifetime nonsmoking Scottish men and women, 243 of whom lived with one or more smokers. Age-, height-, and sex-adjusted FEV1 values were significantly lower

among those exposed to ETS compared to those not exposed (difference =

3.5 percent). A variety of respiratory symptoms (e.g., shortness of breath,

sputum production) were elevated to a nonsignificant degree among the

ETS-exposed group.

Schwartz and Zeger (1990) re-analyzed data from a diary study of

acute respiratory symptoms among 100 student nurses. Subjects completed

daily entries for as long as 3 years. Variables used in the analysis included

smoking and ETS exposure history, allergy status, and various measures of

outdoor air quality. Controlling for personal smoking, self-reported phlegm

production was significantly more common among students with smoking,

as opposed to nonsmoking, roommates (OR = 1.41; p < 0.001).

The studies described below were not included in the Surgeon

General’s (U.S. DHHS), NRC, or U.S. EPA reports.

Schilling et al. (1977) conducted a cross-sectional analysis of questionnaire and pulmonary function data from 376 families in Connecticut

and South Carolina. They found no significant differences in adult symptom reporting rates or, controlling for prior smoking history, in pulmonary

function measures as a function of spousal smoking habit.

Masjedi et al. (1990) administered a questionnaire to (and performed pulmonary function tests on) 275 lifetime nonsmoking hospital

employees and physicians. Among male subjects (n = 167), significantly

lower spirometric values (FEV1, FVC, and FEF25-75) were observed for those

who reported ETS exposure at work (not home) versus those who did not.

Among females, no systematic differences were found with ETS exposure at

either work or home. A potential confounder in the study was the high

level of ambient air pollution in the area surrounding the recruiting hospital (Teheran, Iran). 

More recently, Jaakkola et al. (1995) reported the results of a longitudinal study of lung function in 117 nonsmoking young adults (aged 15 to

35) in Montreal, Canada who were tested in 1981-1983 and again in 1988-

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Chapter 6
1989. ETS exposures at home and at work during and prior to the study

were assessed by questionnaire. In multiple linear regression analyses controlling for age, gender, height, Quetelet index (wt/ht2), baseline FEV1, baseline FEF25-75, atopic status, and the presence of wheeze at baseline, these

investigators did not find a significant relationship between either current

or past home or work exposure to ETS and the change in FEV1 or in FEF25-75

during the study period. In a subanalysis of the subjects who were 25 years

of age or younger at baseline (n = 62), Jaakkola and colleagues found that

work-related ETS exposure during the study period was associated with a

slight, but significant increase in the rate of decline of FEV1. They also calculated 95 percent confidence intervals on their estimates, indicating that,

given the exposure conditions and baseline health of their study population, the changes in lung function during young adulthood potentially

attributable to ETS would be approximately (1.0 ml/yr per pack-year, which

would be of little clinical importance. It should be noted, however, that 80

percent of the men (total n = 60) in this study had no ETS exposure at

home during the study period, while another 8 percent were exposed to

fewer than 10 cigarettes/day; only one man was exposed to a pack or more

on a daily basis. For women (n = 57), the corresponding numbers were 45

percent with no ETS exposure at home, 33 percent with exposure to less

than half a pack, and six who were exposed to a pack or more. The frequencies of work-related exposures were greater, but still reflected light to

moderate exposure at most. Thus, as the investigators acknowledged, their

findings would not necessarily be representative of what might occur with

more frequent exposure in smaller indoor spaces with poorer ventilation.

Also, the authors of this small study focused only on changes during the

study period and did not report whether baseline lung function was related

to prior ETS exposure. 

Dayal et al. (1994) undertook a case-control study of the relationship between self-reported, previously diagnosed obstructive lung disease

(including asthma, chronic bronchitis, and emphysema), where cases and

controls were selected from a probability sample of 4,200 individuals residing in nine Philadelphia neighborhoods in 1985-1986. In an analysis

restricted to never-smokers, the cases (n = 219) were matched on age, gender, and neighborhood with three randomly selected controls. The matching on neighborhood was intended to control both for SES and local environmental conditions, such as air pollution. In conditional logistic regression analysis that also controlled for type of heating and whether a gas

stove was present (and possibly other variables), Dayal et al. found a significant relationship between reported obstructive lung disease and household

ETS exposure involving one or more packs a day, corresponding to an odds

ratio of 1.86 (95% CI = 1.21-2.86). While this result suggests that household ETS exposure increases the risk of obstructive lung disease, the interpretation of this study is limited by a lack of information about the study

populations (e.g., basic demographics) and about the temporal character of

the disease outcomes in relation to the study date—in other words,

whether the disease(s) reported by the participants were “ever-diagnosed”

or still present (i.e., asthma and chronic bronchitis). 

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Xu and Li (1995) analyzed relationships of household and occupational ETS exposure on pulmonary function in 1,033 adults (including 502

never-smokers), aged 40 to 69, in a residential area of Beijing. Current ETS

exposure was assessed by questionnaire. In stratified multiple regression

analyses controlling for age, income, educational level, personal smoking

status, indoor use of coal stoves for heating or cooking, and occupational

exposures to dusts, gases, or fumes, Xu and Li reported reduced levels of

FEV1 and FVC associated with ETS exposure, which were statistically significant in never-smoking men, but not women. While almost all of the estimates of effect of ETS exposure on lung function in ever-smokers were also

negative, these were significant only for the pooled group (men and

women) exposed both at home and at work. Also, when the exposures

were categorized as low (1-5 cigarettes/day) versus high (>6/day), Xu and Li

found evidence of linear exposure-response relationships, which were statistically significant for FEV1 and FVC in never-smoking men and for eversmoking women. In this study, the magnitudes of the lung function decrements reported to be associated with ETS exposure were substantial (4.2 ±

1.8 ml/cigarette smoked in the household for FEV1 and 5.2 ± 1.9 ml/cigarette for FVC). However, the exposure conditions in Beijing are clearly different from those in California or the U.S., potentially limiting the generalizability of these findings.

Robbins et al. (1993) reported that several measures of childhood

and adult ETS exposure were associated with onset of airway obstructive

disease (AOD, comprised of asthma, chronic bronchitis, and emphysema) in

3,914 nonsmoking Seventh Day Adventist adults in a prospective investigation. Questionnaires about both symptoms and historical ETS exposure

were administered to study participants in California in 1977 and again in

1987. Though all three disease entities constituting AOD were self-reported, the questions about both asthma and emphysema were structured to

require a physician’s diagnosis. Statistical analysis relied on multiple logistic regression modeling of AOD onset over the 10-year period, controlling

for age, education level (an indicator of SES), gender, years of past smoking

(15 percent of the study population), and an indicator of chronic exposure

to particulate air pollution. Robbins et al. reported that several, but not all,

qualitative measures of ETS exposure were associated with an increased relative risk of developing AOD during this interval, including adult plus childhood exposure (RR = 1.72, 95% CI = 1.31-2.23), but not childhood or adult

exposure alone (RR = 1.09, 95% CI = 0.69-1.79 and RR = 1.28, 95% CI =

0.90-1.79, respectively). Similarly, examining the outcomes of chronic

bronchitis and asthma separately, they reported increased RRs for both outcomes in relation to combined adult and childhood ETS exposures: RR =

1.71 (95% CI = 1.27-2.27) for chronic bronchitis and RR = 1.89 (95% CI =

1.13-3.15) for asthma. Several sensitivity analyses indicated that these findings were robust: specifically, the ETS risk estimates changed little when the

analysis was restricted to never-smokers, and when terms were included in

these regressions for childhood respiratory illness and frequency of childhood colds. One unexpected finding in this report, however, was that the

RR for AOD corresponding to having actively smoked for 10 years was

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Chapter 6
lower (RR = 1.27, 95% CI = 1.10-1.47) than those estimated for the combined adult and childhood ETS exposures. The authors explained this

unusual result as a combination of factors: the low prevalence of ever-smoking adults in the study population (15 percent), the long time that had

elapsed since the active smokers had quit (mean = 21.4 years), and the

“short” period of time during which active smoking had taken place (mean

= 14.8 years). 

In a separate analysis of virtually the same data set, Greer et al.

(1993) examined the incidence of new cases of asthma as a function of

adult ETS exposure (“years lived with a smoker” and “years worked with a

smoker”), controlling for years of active smoking, ozone and particulate air

pollution, occupational dust and vapor exposures, childhood history of

AOD, age, gender, and education. In the final models that Greer et al.

reported, the incidence of “definite asthma” by reported symptoms or

reported physician diagnosis during the 10-year interval was significantly

related to occupational ETS exposure, with a relative risk of 1.45 (95% CI =

1.21-1.80). Separate subanalyses for men and women produced similar

results. Greer et al. (1993) also obtained medical records for 49 of the selfreported cases of asthma and validated the diagnosis in 30 (61 percent),

suggesting a reason for caution in interpreting the results of these investigations. Although these investigators indicated that the relative risks for

occupational ETS exposure remained significant when only the validated

asthma cases were used in the regression models, the magnitudes of the

risks were not specified. Based on the results of these two studies, it seems

likely that ETS exposure is significantly related to self-reported symptoms of

AOD, but the extent to which this relationship holds true for each of the

subsets of AOD (i.e., asthma and chronic bronchitis) would require additional research.

In a cross-sectional study of nonsmoking women in Singapore, Ng

et al. (1993) reported increased risks of chronic respiratory symptoms and

reduced FEV1 associated with household ETS exposure. Symptom and ETS

exposure data were collected from 1,438 women, 1,282 of whom were lifelong nonsmokers. Of the latter, 1,008 provided acceptable FEV1 tracings for

analysis. In multiple logistic regressions that adjusted for age, race, employment status, and area and size of residence (indicators of SES)—adjustments

were also made for chronic rhinitis and eczema when examining odds

ratios for wheeze and physician-diagnosed asthma—Ng et al. found elevated

odds ratios for all respiratory symptoms where the women were exposed to

one or more heavy smokers (defined as those who smoked 3 20

cigarettes/day). ORs were significantly elevated for chronic or usual cough

(OR = 3.79, 95% CI = 1.76-8.14), cough at least 3 months out of the year

(OR = 3.01, 95% CI = 1.13-8.03), breathlessness on exertion (OR = 1.83,

95% CI = 1.30-2.58), and wheeze (OR = 2.69, 95% CI = 1.23-5.88). For

women exposed to one or more light smokers (i.e., those consuming < 20

cigarettes/day), the only significantly increased OR was for usual or chronic

cough (OR = 2.84, 95% CI = 1.29-6.24). Restricting the analysis to housewives (n = 548), who would be expected to be exposed to ETS only at home,

resulted in elevated ORs for all symptoms examined except for physician242

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diagnosed asthma, though these increases were statistically significant only

for chronic cough and breathlessness on exertion. Analysis of FEV1 in relation to ETS, controlling for the same potentially confounding factors and

effect modifiers (with the addition of the variable height), indicated that

small, but statistically significant reductions in lung function were associated with the presence of one or more light or heavy smokers in the home,

whether the analysis included all women or only housewives. In this study

population, frequency of gas cooking was not associated with increased

risks of respiratory symptoms (except breathlessness on exertion), but was

associated with small reductions in lung function. The investigators’ conclusions would have been strengthened had they also controlled for this

potential confounder in the ETS analyses.

In a cross-sectional study of 4,197 never-smoking adults, aged 18 to

60, Leuenberger et al. (1994) examined the relationships between ETS exposure and a variety of symptoms. Information on both exposure and symptoms were obtained through structured interviews. Analysis involved multiple logistic regression that controlled for age, gender, body mass index

(weight/height2), area of residence, parental and sibling history of asthma,

and atopy (determined by a serum immunofluorescence assay for specific

IgE against common inhalant allergens). Leuenberger et al. found elevated

odds ratios for all respiratory symptoms examined except allergic rhinitis;

specific ratios were elevated as follows: wheezing apart from colds (OR =

1.94, 95% CI = 1.39-2.70), physician diagnosed asthma (OR = 1.39, 95% CI

= 1.04-1.86), dyspnea on exertion (OR = 1.45, 95% CI = 1.20-1.76), symptoms of bronchitis (OR = 1.59, 95% CI = 1.17-2.15), and symptoms of

chronic bronchitis (OR = 1.65, 95% CI = 1.28-2.16). These estimates of elevated risk did not change significantly when a variety of sensitivity analyses

were undertaken, such as excluding subjects whose mothers had ever

smoked, excluding subjects who were likely to have been active smokers

(determined by measuring the concentration of exhaled carbon monoxide

in their breath) and controlling statistically for low educational level (an

indicator of SES), and for occupational exposures. Moreover, these investigators found evidence of a dose-related increase in risk for all these symptoms where dose was represented as either reported hours per day or years

of passive smoke exposure. This study addressed most concerns usually

raised about potential confounders in epidemiological studies of ETS-related

health effects, notably differential symptom reporting by those whose

mothers smoked during pregnancy or during the subjects’ early childhood,

by active smokers claiming to be nonsmokers, by factors related to SES, and

by occupational exposures. On the basis of the studies reviewed prior to

1987, the Surgeon General’s Office (U.S. DHHS, 1986) concluded, “The

small magnitude of effect implies that a previously healthy individual

would not develop chronic lung disease solely on the basis of involuntary

tobacco smoke exposure in adult life.” On the basis of more recent studies

(particularly Hole et al., 1989 and Svendsen et al., 1987) the U.S. EPA (1992)

estimated a 2.5 percent lower FEV1 and a 30-60 percent increase in respiratory symptoms among passive smokers as compared to unexposed individuals. U.S. EPA further concluded that the “...effects of passive smoking on

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Chapter 6
lung function are approximately comparable to those reported for light

(<10 cigarettes/day), male active smokers.” The report did point out that

several of the studies reviewed were problematic with respect to control for

potential confounding variables.

Prior to the publication of relevant recent studies, it appeared that

the effect of chronic ETS exposure on pulmonary function in otherwise

healthy adults was likely to be small in comparison with active smoking,

and was unlikely, by itself, to result in clinically significant chronic disease,

as concluded by the Surgeon General’s Office and the U.S. EPA. The results

of Leuenberger et al. (1994), Robbins et al. (1993) and other recent papers,

however, suggest that ETS exposure may make a significant contribution to

chronic respiratory symptoms in adults. In conjunction with reports of

acute lower respiratory tract symptoms among individuals with pre-existing

asthma (see Section 6.1.1), the small differences in lung function found in

epidemiological studies are a basis for concern and further study. 

Evidence for effects of mainstream smoke (MS) exposure of pregnant rodents on fetal lung development

has been provided over the past 10 years. More recently, effects of sidestream smoke (SS) on both prenatal and postnatal lung development, function and airway reactivity have been studied in rats. In animal studies, MS

and SS are distinguished by the mode of generating the smoke, but all

exposures have been passive or environmental (i.e., smoke has been

inhaled from ambient air). SS differs from ETS in that it does not contain

exhaled mainstream components.

Studies of lung development were undertaken after data indicated a

proportionally greater growth retardation in fetal lung than in other organs

as a result of MS exposure of pregnant rats (Bassi et al., 1984).

Histopathology and morphometry studies of the growth-retarded lungs

demonstrated increased sizes and reduced numbers of primitive alveoli (saccules) leading to a reduced surface area available for gas exchange in the

term fetus (Collins et al., 1985). When 15-day-old rats were examined after

in utero smoke exposure, gas diffusion capacity of the lung as determined

from histomorphometry was similar to that of controls (Lichtenbeld and

Vidic, 1989). Nonetheless, biochemical measures suggested delayed septal

growth and development of lung interstitial cells (Vidic et al., 1989). Since

septa subdivide existing alveoli to produce new alveoli, these findings are

consistent with the lower number of alveoli seen in fetuses at term (Collins

et al., 1985). However, functional lung parameters (respiratory capacity,

reactivity, immune defense) were not evaluated in these studies.

Developmental studies of lung function and reactivity have recently

been undertaken in rats using methodologies specifically designed for producing SS exposure (Teague et al., 1994).

Joad et al. (1993 and 1995b) studied functional lung parameters

(compliance, resistance, reactivity) in adult rats exposed to SS prenatally

and/or postnatally. The rats were 7-10 weeks of age (sexual maturation in

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6.2.5 Studies on Lung

Development in Animals
rats occurs at 5-6 weeks of age) at the time of the lung function tests. As

measured in isolated perfused lungs, compliance was decreased 24 percent,

and reactivity (to methacholine challenge) was 200 percent greater in rats

exposed to SS both prenatally and postnatally. Furthermore, the number of

neuroendocrine cells, an immature cell type in the lung, was 22-fold greater

after the combined gestation/lactation exposure. Hyperplasia and persistence of neuroendocrine cells, which contain mediators of bronchoconstriction, were considered the basis for reduced compliance and increased reactivity. The SS air concentration in this study was 1 mg/m3, which is at the

top of the range of ETS exposures recorded in any environment (U.S. EPA,

1993).

These effects were not seen when exposures occurred only prenatally or only postnatally (Joad et al., 1993). The postnatal exposures were

given from day 2 through 7-15 weeks of age, or only at 15 weeks of age,

and thus covered the entire period of postnatal lung development. The

lack of effect emphasizes the importance of exposure during fetal as well as

postnatal stages of lung development. In rats exposed only postnatally to

SS, cell division in epithelial cells of terminal but not proximal bronchi was

lower than in controls at 7 and 14 days of age. Since cell division is an

immature property of the bronchiolar epithelium, this indicated stimulation of lung maturation, as also suggested by studies of enzyme induction. 

Induction of metabolic enzymes by SS in the immature lung has

been studied in the postnatal period. The establishment of metabolic competence of the lung is delayed well into the postnatal period in laboratory

animals as well as in humans. Aryl-hydrocarbon hydroxylase (AHH), also

known as cytochrome P450 1A1, was induced in lungs of rat offspring who

were exposed to MS constituents in utero, by nursing, or directly through

inhalation after birth (Bilimoria and Ecobichon, 1989). This enzyme is

known to be induced by polycyclic aromatic hydrocarbons (PAHs) present

in cigarette smoke (Bilimoria and Ecobichon, 1980). Little or no induction

was seen in hamster or guinea pig offspring. The results seen in rats

demonstrate that tobacco smoke components can reach the fetal lung of

rats and produce a biochemical response. Other studies demonstrated that

SS exposure can alter the ontogenetic time course of appearance of lung

enzymes (Ji et al., 1994). In rat pups exposed to SS from birth at a concentration of 1 mg/m3, cytochrome P450 1A1 was seen earlier, and persisted at

high levels longer after the normal developmental peak. Clara cells, an

epithelial cell type that contains P450, also demonstrated reduced cell proliferation in late maturing areas and increased NADPH reductase expression,

two indicators of early maturation. Two other Clara cell enzymes,

cytochrome P450 2B and Clara cell secretory protein, were not affected.

Premature induction of metabolic pathways could be seen to serve a protective function in the immature lung; however, production of reactive intermediates that induce oxidative damage and genotoxicity is also possible.

Postnatal SS exposure has also been studied in connection with lung

responsiveness associated with the C-fiber system. C-fibers in the lung

mediate an airway defense response which includes mucus secretion, bron245

Chapter 6
choconstriction, and coughing in response to irritants. Compliance, resistance, and lung morphology were measured in the isolated, perfused lungs

of 43-day-old guinea pigs that had been exposed to SS at a concentration of

one mg/m3 from 8 days of age (Joad et al., 1995a). Baseline compliance was

increased modestly (17 percent) by SS exposure, but lung morphology and

baseline resistance were not altered. The response of the lung to capsaicin,

a specific C-fiber agonist, was reduced by SS exposure, but the response to

substance P, which is released by the C-fiber, was not affected; this suggests

a down-regulation of C-fiber responsiveness (i.e., the lung is still able to

respond directly to substance P, but doesn’t respond to capsaicin, indicating

that decreased responsiveness to capsaicin involves the C-fibers). Reduced

C-fiber responsiveness indicates a depressed defense response that could

result in greater penetration of toxicants and infectious agents into the lung

and be responsible for higher incidence of respiratory problems. 

Atopy refers to an inherited predisposition to develop IgE

antibodies against common environmental and dietary

allergens. This predisposition is manifested in several

chronic conditions: allergic asthma, atopic dermatitis,

allergic rhinitis, and allergic gastroenteropathy. Allergy

(atopy with or without high serum levels of IgE) can be documented in

most cases of asthma (Burrows et al., 1989, as cited in U.S. EPA, 1992),

although exercise-induced bronchospasm, reactive airways dysfunction syndrome, and many types of occupational asthma can occur in nonatopic

individuals.

The evidence relating ETS exposure to the development of atopy is

mixed. Several studies have shown that exposure to passive smoke is significantly associated with total serum IgE concentration and may therefore

affect the development of allergic disease. Studies that showed a relationship between active smoking and IgE levels, such as those reviewed in U.S.

EPA (1992) (Gerrard et al., 1980; Burrows et al., 1981; Zetterstrom et al.,

1981; Taylor et al., 1985), prompted researchers to investigate the relationship of passive smoke exposure and allergic sensitization in children.

Several studies have shown up to a 2.2-fold increased risk of atopy in children of smoking mothers (Weiss et al., 1985; Martinez et al., 1988).

Ronchetti et al. (1990) analyzed the same population used by Martinez et al.

(1988) and found that total serum IgE levels and eosinophil counts were

significantly greater in children of smoking parents.

In contrast, two studies of maternal active and passive smoking during pregnancy showed no association of in utero ETS exposure and umbilical

cord blood IgE (Oryszczyn et al., 1991; Ownby et al., 1991). High levels of

cord blood IgE are predictive of the development of childhood allergy. A

group of 99 singleton births in a hospital in Paris, France, were used to validate use of cord blood cotinine and maternal urinary cotinine concentrations in a study of in utero exposure to parental smoking (Oryszczyn et al.,

1991). Twenty percent of the mothers smoked at least one cigarette per day

during one of three trimesters. Infants whose mothers smoked or had been

passively exposed to ETS had significantly higher cord blood cotinine levels

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6.3 SUSCEPTIBLE

POPULATIONS

6.3.1 Atopy/Atopic

Dermatitis
than infants whose mothers neither smoked nor been exposed to ETS.

However, no association was observed between cord blood IgE and maternal smoking as assessed by either questionnaire or cord blood cotinine.

This study did not examine postnatal ETS exposure.

Ownby et al. (1991) followed 114 infants born to subscribers of a

health maintenance organization in Michigan. The infants were selected

from a stratified sample chosen to assure nearly equal proportions of

infants from nonsmoking, light, and heavy smoking households, although

the definitions for each category are not stated in the report. As in the previous study, cord cotinine concentrations were measured to assess the validity of self-reported maternal smoking. Neither univariate analyses nor

analyses that adjusted for the children’s gender, birth weight, birth length,

paternal history of allergies, maternal history of allergies or asthma, maternal visit to an allergist, history of skin testing, or immunotherapy were significantly related to cord blood IgE. The authors speculated that if passive

smoking induces atopy only in those with a familial tendency, such a study

design might mask an association if atopics are less likely to smoke.

Therefore, regression models were run both with and without adjustment

for parental history of allergic disease. The association was also nonsignificant for a subgroup of infants whose parents were not atopic. When multiple regression models were used, the authors detected an association of

immunoglobulin D (IgD) and paternal, but not maternal, smoking.

However, the function of IgD and its relationship, if any, to the development of atopy and allergy, have not yet been elucidated.

Recently, Soyseth et al. (1995) investigated the relationship of prenatal and postnatal household smoking to the prevalence of atopy, defined as

at least one positive skin prick test, in a cross-sectional study of 556

Norwegian school children, aged 7 to 13 years. Questionnaire assessment

of ETS exposure addressed smoking by either parent during the mother’s

pregnancy, as well as several indices of parental postnatal smoking. In multivariate analyses that initially included age, gender, reported bronchitis

before 2 years of age, and parental history of asthma or hay fever, Soyseth et

al. reported that prenatal maternal smoking was negatively associated with

atopy (OR = 0.6, 95% CI = 0.4-0.9), while postnatal ETS exposure was not

associated with this condition (OR = 1.2, 95% CI = 0.7-2.1). No index of

paternal smoking was associated with atopy. The authors did not believe

that this negative association of prenatal smoking with atopy was causal,

but hypothesized rather that it may have been due to selective avoidance of

smoking during pregnancy by women whose offspring might have been at

higher risk of developing atopy (e.g., because of a family history of allergy).

Regardless of the validity of this hypothesis, these results do not indicate an

increased risk of allergic sensitization due to parental smoking, either prenatally or postnatally.

Investigators have also examined both the interactive effect of passive smoke exposure in children with atopic dermatitis (AD) and subsequent development of asthma. AD is characterized by a chronic or relapsing pruritic (itchy) rash. Murray and Morrison (1990) studied 240 asthmat247

Chapter 6
ic children aged 6 to 17 years. They found a relationship between AD and

subsequent development of asthma in children with mothers who smoked.

In a reanalysis of the data (Murray and Morrison, 1992), asthmatic children

with smoking mothers were found to have significantly greater asthma

severity than those with nonsmoking mothers. The authors concluded that

passive smoking may cause asthma only in children who have a history of

atopic dermatitis, while exacerbating severity in those who are already

symptomatic.

In summary, whether there is a relationship between the development of atopy and prenatal or postnatal exposure to ETS has not been as

thoroughly researched as have other outcomes discussed in this report.

Published investigations of this issue have produced mixed results.

6.3.2. Cystic Fibrosis Cystic fibrosis (CF) is an autosomal recessive disease characterized by thickened mucus, a nonfunctional mucociliary clearance pathway, and recurrent and chronic pulmonary infections. Among whites in the

United States, it is the most common life-threatening genetic disease, occurring in one in 2,500 live births. Incidence of CF is much lower in U.S.

black populations, affecting only 1 in 17,000 live births. Certain patients

with CF have severe pancreatic insufficiency with intestinal malabsorption

and growth retardation. Life expectancy for patients with CF has improved

dramatically over the past 2 decades. In 1978, only 18 percent of CF

patients were aged 18 and older. By 1991, this had risen to 33 percent.

Patients with CF are now living into the sixth and seventh decades of life

(Boat and Boucher, 1994). Only a few studies have examined potential

effects of ETS on patients with CF: these are summarized in Table 6.6

In a cross-sectional study, Gilljam et al. (1990) studied 32 Swedish

children with CF, aged 1 to 20 years, 22 of whom had at least one parent

who smoked one or more cigarettes per day in the home. A clinical index

was computed for each child using the Shwachman score (the lower the

score, the more severe the disease). The number of severe respiratory infections was assessed by the number of days of antibiotic treatment in a hospital during a 1-year interval. Pulmonary function tests were administered,

and the number of weekly scheduled physical activities per week was counted. Gilljam et al. found that there was no significant association between

passive smoking and clinical score; however, six of seven children with low

scores came from smoking families. There was a significant difference

between days of antibiotic treatment in a hospital if the mother was a

smoker compared to if only the father smoked (p < 0.05). High physical

activity level appeared to dampen the negative effects of ETS. Lung function was not associated with passive smoking.

In another cross-sectional study, Rubin (1990) studied 43 Canadian

children (18 girls and 25 boys) aged 6 to 11 years at a CF summer camp to

assess the relationship of passive smoke exposure to growth, nutritional status, lung function, clinical condition, and number of hospital admissions.

More than half (24) of the children came from homes with smokers—nearly

40 percent from families in which the mother smoked. None of the children smoked. Although statistical analyses were normalized for age, no further adjustments were made.

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Hospital admission rates (defined as the total number of admissions

adjusted for the child’s age) were strongly correlated with number of cigarettes smoked in the home (r = 0.58, p < 0.0001) for the group as a whole

and for the subset of children with smoke exposure in the home. When

analyses were stratified by gender, this relationship was apparent for female

subjects only. A significant correlation of ETS exposure and clinical score

was apparently confounded by nutritional status, attributed largely to the

strong correlation between nutritional subscore and ETS exposure. In addition, those children assessed as having poor nutritional status who were

exposed to passive smoke had higher admission rates than those with poor

nutrition from nonsmoking homes (p = 0.10).

Rubin also found a significant interaction between lung function

and ETS in relation to hospital admission rates (p = 0.05); among children

with lower lung function, smoking in the home was associated with significantly more hospitalizations. There was also a significant association

between percentage of predicted peak expiratory flow rate (PEFR) and

smoke exposure, but no significant associations were found for other pulmonary function measures. For girls, there was a significant inverse correlation between number of cigarettes smoked per day in the home and height

and weight (p < 0.05); for boys, there was a near-significant correlation with

height (p = 0.067). There was no association of coughing, sputum production, or nasal polyps with passive smoke exposure.

This study did not adjust for socioeconomic status (SES). However,

changes in clinical status that could be related to economic barriers to

health access are unlikely to have affected the results because Canada has

national health insurance. Moreover, this CF population was in fairly good

health, with participants scoring an average of 22 points on the 25-point

Shwachman score. Although the camp population might not be representative of all children with CF, the camp was free and open to anyone with the

disease. On the other hand, in epidemiological studies of ETS, SES may be

a confounder, not only because people in lower SES brackets tend to have a

greater prevalence of smoking, but also because their residences tend to be

smaller, increasing the probability of exposure to more concentrated ETS

and other household respiratory irritants that could exacerbate CF.

Campbell et al. (1992) studied 44 CF patients aged 1 to 22 years,

who were homozygous for the F508 deletion (the most prevalent CF mutation) to examine the effect of ETS exposure on clinical status after controlling for age and SES. All patients had pancreatic insufficiency, a condition

associated with more severe disease. Of the 44 patients, 22 lived in homes

with light smoke exposure (1-2 packs per day) and six lived in homes with

heavy exposure (3-4 packs per day). The data were analyzed using a generalized linear model. There were no significant differences between the

light-exposure and no-exposure groups, so these two groups were combined

in later analyses and compared to the heavy smoking group. Heavy exposure was significantly associated with disease severity as measured by the

Shwachman score, FEV1 (p = 0.007), forced vital capacity (p < 0.0001) and a

five-fold increase in the number of pulmonary related hospital admissions

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Chapter 6
(p < 10-6). Models were adjusted for age and SES. Since the heavy-exposure

group contained only six people, other investigators have cautioned that

the results of this study may have been due to a chance clustering of high

ETS exposure and poor nutritional status. The authors did conduct a “sensitivity analysis” in which two of six people were given normal pulmonary

function levels and severity scores; however this did not reduce the results

to nonsignificance.

More recently, Smyth et al. (1994) assessed the relationship of ETS

exposure as measured by questionnaire and urinary cotinine in 57 children

with CF and 51 controls. The age range of both groups was 5 to 16 years.

The investigators examined the relationship of ETS to pulmonary function

(FEV1 and FVC) in the CF patients. Urinary cotinine levels and ETS exposure assessed by questionnaire (“smoking index”) were both significantly

greater in the homes of control children. FEV1 and FVC (both expressed as

a percentage of predicted for height) were regressed on cotinine concentration, smoking index, parental occupations, and patient’s age and sex.

Smoking index was a significant predictor of decreased FEV1 (p = 0.022) and

FVC (p = 0.047)—for each ten-cigarette increment in the smoking index,

the investigators predicted a 4 percent decrement in FEV1 and a 3 percent

decline in FVC. However, urinary cotinine was not predictive of either

measure of lung function, which Smyth et al. speculated might have been

due to the flatness of the cotinine versus lung-function curve in the lowest

three-fifths of the cotinine distribution. The geometric mean urinary cotinine concentration was 5.12 ng/ml, which lends credibility to the investigators’ hypothesis; however, not enough detail is provided in this brief report

to evaluate adequately the discrepancy between the results of the smoking

index and cotinine analyses. Smyth et al. did not examine the relationship

of ETS to either disease severity or hospitalizations in these CF patients.

Kovesi et al. (1993) examined relationships between household ETS

exposure and several clinical parameters in 325 patients attending the

Cystic Fibrosis Clinic at the Hospital for Sick Children in Toronto in 1990

to 1991. Data on household smoking were routinely obtained by clinic

nurses on standardized forms, and included whether anyone in the household (including the patient) smoked cigarettes and, if so, the total number

of cigarettes consumed in the home by all smokers. The age range of 1 to

42 years was considerably larger than in any of the other studies (Kovesi,

personal communication), but separate analyses were done on children

aged 6 to 11 for comparison to the study by Rubin (1990). The percentage

of participants exposed only to maternal smoking was not identified.

Given the reported mean age in both exposed and nonexposed groups,

some of these patients were probably not living with their parents, which

might distinguish this study population from the others described above.

Comparing patients from smoking versus nonsmoking households, there

were no significant differences in Shwachman scores, spirometry (FVC,

FEV1, FEF25-75), height and weight percentiles, colonization by Pseudomonas

species, or other variables. However, patients with ETS exposure were

younger, with a mean age of 14.4 years versus 17.0 years for the unexposed.

Linear regression analysis showed no relationship between the number of

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cigarettes smoked in the household and the children’s weight or weight percentiles, weight for height, Shwachman or Brasfield scores (different measures of clinical status), spirometric indices, number of hospital admissions,

or number of days spent in the hospital. When households with smokers

(n = 97) were analyzed separately, similar results were obtained. When the

subset of children aged 6 to 11 were analyzed, the results were similar to

those obtained for the entire study population, except that there was a significant inverse correlation between the number of cigarettes smoked in the

household and the patients’ height percentile (r = -0.27, p = 0.04). 

The authors also conducted separate longitudinal analyses of

spirometry, weight and height percentiles for 182 patients who had had

smoking and spirometric data collected between 1977 and 1985. ANOVA

was used to compare various clinical parameters among three groups: those

who reported no smoke exposure in either data collection period

(“NEVER”), those reporting ETS exposure both times (“ALWAYS”), and those

reporting such exposure between 1977 and 1985, but not in 1990 or 1991

(“QUIT”). A fourth “STARTED” group was too small and heterogeneous to

be used in analysis. The height percentile increased for the NEVER group,

while the index decreased for the ALWAYS group and decreased even more

for the QUIT group. This same relative order was observed for changes in

weight percentile and weight for height percentile. Though all groups

experienced a decline in their percent predicted spirometric indices (FVC,

FEV1, FEF25-75), the decrease was greatest in the QUIT group and least in the

NEVER group. When the analysis was restricted to the subgroup of CF

patients homozygous for the ÆF508 mutation, similar results were found,

after an “outlying” patient with “extremely heavy smoking exposure” was

excluded from the analysis.

In this large study, Kovesi et al. confirmed the existence of a negative dose-response relationship between household ETS exposure and linear

growth in children with CF aged 6 to 11, reported previously by Rubin

(1990). In the longitudinal component of the investigation, they found

that exposure to household ETS was associated with growth suppression. In

contrast to the findings of Campbell et al. (1992) and Smyth et al. (1994),

but similar to Rubin (1990), those investigators did not find a relation

between ETS exposure and lung function. In the Campbell study, which

examined patients homozygous for the ÆF508 deletion, effects were found

only in six patients with relatively high reported ETS exposure. Moreover,

the distribution of reported smoking levels in the investigation by Kovesi et

al. was such that all patients would have been classified in the “light-exposure” group in the Campbell study, thus the results of these two reports are

not inconsistent. 

In the Kovesi study population, there was considerable inter-child

variability in spirometry, which is characteristic of CF patients, making

small mean lung function differences difficult to detect. Kovesi et al. also

could not confirm the relationship between ETS and hospital admissions

reported by both Rubin and Campbell et al. However, whereas Rubin examined age-adjusted hospitalizations over the children’s lifetimes, Kovesi et al.

appear to have examined only hospitalizations (and days in hospital) over

251

Chapter 6
the year preceding the children’s clinic visit. Furthermore, although the

initial analysis comprised a much larger study population than previous

studies, the subsample of children aged 6 to 11 was not much larger than

that of Rubin. In addition, the study by Kovesi et al. included older

patients than the other five studies, although the investigators were not

able to detect an interaction of age and smoking exposure on any of the

outcomes. As noted above, the reported exposure distribution of ETSexposed children in the Kovesi study was comparable to Campbell et al.’s

“light-exposure” group, for which the latter investigators found no effect of

ETS exposure on hospitalizations. Thus, the results of the Kovesi study

with respect to hospital admissions are not necessarily inconsistent with

those reported by others. In addition, the identities of household smokers

(other than the few actively smoking study participants) were not obtained.

In other settings (e.g., induction of childhood asthma), maternal smoking

appears to be more strongly related to young children’s actual ETS exposure

than paternal smoking. Thus, here, as elsewhere, misclassification of exposure may have produced a bias towards the null hypothesis of no effect.

Finally, in the regression analysis conducted by Kovesi et al., it appears that

they did not adjust for SES, which could also have confounded the results

(see above).

In part because CF is such an uncommon disease, four of these five

studies have small sample sizes and low statistical power. Given this limitation, the finding that ETS is associated with hospitalizations for respiratory

infection in three of four studies is striking. This relationship was observed

in Rubin’s (1990) study, which included relatively healthy children, and

Campbell’s study in which the children presumably had more severe disease. Rubin (1990) also detected interactions of ETS with the number of

hospitalizations in those with lower pulmonary function and poor nutrition. While Gilljam et al. (1989) did not observe a direct effect of ETS on

hospitalizations, they did find effects in those exposed to maternal smoking. In contrast, Kovesi et al. (1993) did not find any relationship between

ETS exposure and hospitalizations. 

The relationship between ETS exposure and pulmonary function in

CF patients is less clear. Campbell et al. (1992) observed an association

between ETS exposure and pulmonary function, whereas Gilljam et al.

(1990), and Kovesi et al. (1993) in a much larger study, did not. Smyth et

al. (1994) observed a relationship between ETS and lung function, as measured by FEV1 and FVC, when questionnaire data were used but not when

ETS was assessed using salivary cotinine levels. Rubin (1990) found an association with PEFR but not with other spirometric measures. People with CF

demonstrate greater variability on pulmonary function tests than healthy

subjects. This variability combined with the rarity of the disease make it

difficult to demonstrate effects on pulmonary function.

Disease severity was investigated in four of the five studies. Only

one study, that of Campbell et al. (1992) found a relationship with ETS

exposure. Gilljam et al. (1989) found a positive but nonsignificant relationship with disease severity, Rubin’s analysis was confounded by nutritional

status, and Kovesi et al. found no effect of ETS on disease severity in their

252

Smoking and Tobacco Control Monograph No. 10
large study population. Finally, in the two studies that looked at effects on

growth, both found effects in the 6- to 11-year-old age group. Rubin

observed age-adjusted relationships with height and weight in girls and

with height in boys. Kovesi et al. also found a significant relationship with

height by household smoking group in their longitudinal analysis.

In reviewing these five studies, it is important to note that the age

ranges of the study populations were different. Two studies included children only (Smyth et al., 1994; Rubin, 1990), two study populations were

comprised of infants, children and young adults (Campbell, 1992; Gilljam

et al., 1989) and one included infants, children, and young and older adults

(Kovesi et al., 1993). Some of the differences in study findings are potentially attributable to this variation in composition. In particular, if young

children with CF are most sensitive to ETS or are likely to experience the

greatest intensity of exposure, the study population of Kovesi et al. would

have had any ETS-related effects diluted by the inclusion of relatively older

participants.

In summary, although several reports suggest that passive smoke

exposure can affect patients with CF, the extent and magnitude of such

effects are still uncertain. The evidence for an effect on hospitalizations is

compelling, while the studies are less conclusive in showing an effect on

pulmonary function or disease severity. The two studies that have looked

at growth have both found an inverse relationship between ETS exposure

and linear growth. Because of the rarity of CF, relatively few children with

CF in California are likely to be affected by ETS exposure. In all five studies, however, the proportion of CF patients with ETS exposure was quite

high, ranging from 42 percent in the study by Kovesi et al. (1993) to 69 percent in the study by Gilljam et al. (1989).

ETS exposure produces a variety of acute effects

involving the upper and lower respiratory tract. ETS

exposure can exacerbate asthma in children, perhaps affecting 48,000 to

120,000 children annually in California; adults may also be affected.

Parental smoking is associated with an increased risk of acute lower respiratory tract illnesses in children, as well as acute and chronic otitis media

with middle ear effusions. In California, ETS-related otitis media cases may

result in an estimated 78,000 to 188,000 office visits per year among children under three years of age. From 18,000 to 36,000 cases of ETS-related

bronchitis or pneumonia can be predicted to occur in children 18 months

of age and under, based on national statistics. Eye and nasal irritation are

the most commonly reported symptoms among adult nonsmokers exposed

to ETS; in addition, odor annoyance from indoor exposure to ETS has been

shown in several studies. Experimental studies conducted by investigators

familiar with building ventilation practice suggest that, short of prohibiting

indoor smoking, protection of nonsmokers against both sensory irritation

and odor annoyance can only be achieved through extensive engineering

measures.

253

Chapter 6

6.4 CHAPTER SUMMARY

AND CONCLUSIONS
254

Cystic FibrSeverityPositive but significantYes, but confounded bynutrition(UnadjustedSignificantNot examinens

Hospitalizations for Cystic FibrosisIn those exposed tomaternal smoking, aneffect of ETS on numberof days of antibiotic treatment in hospitalSignificant, overall and inETS group, but only forgirl-ETS. Interaction withboth poor nutrition andlow pulmonary functionSignificant, RR = 4.7 (95% CI = 1.8-7.6)Not examinedns

Pulmonary FunctionNSSignificant only forPEFR, not for FEV1 or

FVCSignificant for both FEV1

and FVCAssessment of ETS exposure by questionnairebut not cotinine related toboth FEV1 and FVC

NS in cross-sectionalstudy; in longitudinalstudy, QUIT group wassignificantly worse thanNEVER group

ETSExposurePrevalence22/32 (69%)24/53(56%)28/44 (64%)33/57(58%)97/228(43%)

Age ofSubjects (N)1-20(32)6-11(43)1-22(44)5-16(57)1-42(325)

StudyGilljam et al.(1989)Rubin (1990)Campbell et al. (1992)

Smyth et al.

(1994)Kovesi et al.(1993)

Abbreviations: N = study size; PEFR = peak expiratory flow rate; FEV1 = forced expiratory volume in one secondFVC = forced vital capacity; RR = relative risk; ns = nonsignificant

Table 6.6ETS Exposure Relationship with Pulmonary Function, Hospitalizations, and Disease Severity in Cystic Fibrosis
There is consistent and compelling evidence that ETS is a risk factor

for induction of new cases of asthma; in California, between 960 and 3,120

new cases per year may be ETS-related. In addition, chronic respiratory

symptoms in children, such as cough, phlegm, or wheezing, are associated

with parental smoking. While the results from all studies are not wholly

consistent, there is substantial evidence that childhood exposure to ETS

affects lung growth and development, as measured by small, but statistically significant decrements in pulmonary function tests; associated reductions

of lung function may persist into adulthood. The effect of chronic ETS

exposure upon pulmonary function in otherwise healthy adults is likely to

be small, and is unlikely by itself to result in clinically significant chronic

disease. However, in combination with other insults (e.g., prior smoking

history, exposure to occupational irritants, or ambient air pollutants), ETS

exposure could contribute to chronic respiratory impairment in adults. In

addition, regular ETS exposure in adults has been reported to increase the

risk of occurrence of a variety of lower respiratory symptoms.

Children are especially sensitive to the respiratory effects of ETS

exposure. Children with cystic fibrosis are likely to be more sensitive than

healthy individuals. Several studies of patients with cystic fibrosis, a disease

characterized by recurrent and chronic pulmonary infections, suggest that

ETS can exacerbate the condition. Several studies have shown an increased

risk of atopy (a predisposition to develop IgE antibodies against common

allergens, which can then be manifested as a variety of allergic conditions)

in children of smoking mothers, though the evidence regarding this issue is

mixed. 

255

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264
It has been estimated that 22 percent of all cancer deaths

in women and 45 percent of all cancer deaths in men can be attributed to

personal smoking habits (Shopland et al., 1991). Smoking is an established

cause of cancers of the lung, larynx, oral cavity (including pharynx), esophagus, and bladder. It is a probable cause of cancers of the kidney, pancreas,

and stomach in men and women, and of cervical cancer in women (IARC,

1986; U.S. DHHS, 1989). Environmental tobacco smoke (ETS) has been

established as a cause of lung cancer in nonsmokers (U.S. DHHS, 1986;

NRC, 1986; U.S. EPA, 1992). This document explores the role of ETS in the

etiology of cancers, including lung cancer and cancers other than lung, in

nonsmokers.

In the first part of this review, available data is presented on the relationship between ETS and all cancers combined, in adults (Section 7.1.1),

and in children (Section 7.1.2). Second, evidence is discussed regarding the

role of ETS in the etiology of specific cancer sites. Section 7.2 presents the

data on ETS and lung cancer. In Section 7.3, the evidence is discussed on

ETS exposure and cancer sites other than lung which are causally linked to

active smoking. The evidence on ETS and cancer sites where the role of

active smoking is equivocal (e.g., cancers of the breast, stomach, brain, and

hematopoietic system) is discussed in Section 7.4. That section also

includes the evidence on ETS exposure and risk of childhood cancers (specific sites). Individual studies are described briefly, and the results, including the point estimates of relative risks and corresponding 95 percent confidence intervals, are presented. Findings from the studies are evaluated, taking into account the quality of the studies with respect to their study

design, sample size, assessment of exposure, adjustment for potential confounders, and consideration of sources of biases. For cancers that are

causally associated with active smoking, we also compare the magnitude of

the risk associated with ETS exposure versus that of active smoking.

The 1986 National Research Council report (NRC, 1986)

and a subsequent paper, Wald et al. (1986) pointed out

that because smokers tend to marry smokers, if a study contains smokers

who are misclassified as nonsmokers, they are more likely to be classified as

exposed to ETS. Therefore, the estimate of relative risk to ETS exposure will

be exaggerated due to the association of lung cancer with active smoking

for this group of misclassified subjects. Wald et al. (1986) estimated the

proportion of ever-smokers who are misclassified as lifelong nonsmokers to

be about 7 percent. This estimate was based on the percentage of self265

Carcinogenic Effects

7.0 INTRODUCTION

7.0.1 Misclassification

of Smoking Status
reported nonsmokers (2.1 percent) who have levels of nicotine and cotinine

in the range of those of smokers and the percentage of smokers who, on

subsequent re-interview, claimed to have never smoked (4.9 percent). Lee

(1986, 1989, 1992) has argued that the extent of this misclassification bias

is higher—about 12 percent. As discussed in detail below, two recent studies (Riboli et al., 1995; Nyberg et al., 1997) using different methodologies

conclude that, while there is some misclassification of smokers as nonsmokers, the misclassification rate is low and is unlikely to explain the observed

lung cancer risk from ETS exposure.

Riboli et al. (1995) reported the results of a multicenter (13 centers)

international (10 countries) study organized by the International Agency

for Research on Cancer (IARC) to validate self-reported exposure to ETS

from different sources by analysis of urinary cotinine levels. Questionnaire

data and urine samples were collected from 1,369 nonsmoking women who

had not used any tobacco products for at least 2 years. Forty-seven women

had urine cotinine levels above 50 ng/mg creatinine, a level used to discriminate smokers from nonsmokers in some previous studies. Further

investigation of these 47 women showed that 27 had levels between 50-150

ng/mg while 20 had levels exceeding 150 ng/mg. In fact, the majority of

women (16 of 27) with levels between 50-150 ng/mg had reported long

daily exposure to ETS ( >5 hours per day) 4 to 8 days prior to sample collection and were exposed to at least eight cigarettes per day. On the other

hand, a significantly lower percentage of women with cotinine levels

exceeding 150 ng/mg had long daily exposure to ETS or were exposed to at

least eight cigarettes per day. These investigators concluded that most of

the women with levels between 50 to 150 ng/mg were truly heavily

exposed to ETS, while those with levels above 150 ng/mg were more likely

to be deceivers and may have smoked. Thus the percentage of deceivers

(1.5 percent, 20 of 1,369) in this cross-sectional study is quite comparable

to that reported by Fontham et al. (1994) in which 0.6 percent of lung cancer cases (2 of 356) (prescreened for smoking status on the basis of medical

history and other factors) and 2.3 percent of population controls (25 of

1,064) showed cotinine/creatinine concentrations of 100 ng/mg or higher.

Results from this study also illustrate that cotinine levels of 50-150 ng/mg

are quite plausible when nonsmokers are very heavily exposed to ETS.

Nyberg et al. (1997) investigated misclassification rates in two large

Swedish cohorts in which smoking habits were assessed on two separate

occasions some 6 to 10 years apart. Two types of misclassification rates

were presented. The first misclassification rate was calculated based on the

number of ever-smokers misclassified as never-smokers divided by the total

population of ever-smokers. The second misclassification rate was calculated based on the number of reported never-smokers who really were smokers

divided by the total population of never-smokers. In this study, the proportion of ever-smokers misclassified as never-smokers was 4.9 percent among

men and 4.5 percent among women in the first cohort studies; the corresponding figures in the second cohort were 5.0 percent and 7.3 percent.

The misclassification rate expressed as the proportion of never-smokers who

really were smokers was 11.1 percent in men and 1.3 percent in women in

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Smoking and Tobacco Control Monograph No. 10
the first cohort study and 11.5 percent and 2.2 percent, respectively, in the

second cohort study. Nyberg et al. (1997) noted that there is good agreement in most studies in terms of the first misclassification rate irrespective

of geographic area or gender of subjects. On the other hand, the second

misclassification rate is much more variable from study to study, and that

rate can be misleading because it is dependent on the number of nonsmokers in a particular study. Aside from the rate of misclassification, these

investigators also showed that in this, as in other study populations, most

of the ever-smokers who were misclassified as nonsmokers had quit smoking some time earlier and smoked less than the average smokers. Thus, this

study also suggested that there is limited smoker misclassification and that

misclassification bias does not explain the observed lung cancer risk associated with ETS exposure.

Both of these studies suggest that to a large extent, misclassification of

smokers as nonsmokers can be minimized if adequate screening questions

are used to ensure that former smokers are identified and are excluded from

studies of lifetime nonsmokers. Although cotinine is only a marker of

recent tobacco exposure, it is still useful to be able to exclude current smokers from a study. In fact, multiple sources of information and questions

designed to screen out current or former smokers were used in many of the

newer studies of ETS and lung cancer (such as Fontham et al., 1994) so that

this source of misclassification bias has been minimized. Thus, the collective evidence from the newer studies (Riboli et al., 1995; Nyberg et al.,

1997), as well as the studies reviewed by the U.S. EPA (1992), indicates that

misclassification bias does not explain the observed lung cancer risk associated with ETS exposure.

Overall cancer related death rates for smokers are about two

times higher than for nonsmokers (U.S. DHEW, 1979).

Those nonsmokers who are exposed to tobacco smoke are exposed to the

same toxic constituents of tobacco smoke as smokers (U.S. DHHS, 1986),

although active smokers and those exposed to ETS may differ in the relative

amounts of carcinogens to which they are exposed. Furthermore, the phase

distributions of compounds differ between mainstream smoke and ETS.

More of the constituents appear in the vapor phase (versus the particulate

phases) in ETS compared to mainstream smoke, and particle sizes are smaller in ETS. Components also enter the vapor phase from the particulate

phase as ETS ages. Therefore, the relative uptake and deposition of these

components potentially differ between active and passive smokers (Guerin

et al., 1992). Because of these differences, it is not apparent which cancer

sites may be most affected by ETS exposure. This section describes studies

addressing the overall risk of cancer (all sites combined) from ETS exposure,

in adults and in children.

Cancer risk in adult life may be due to an accumulation of

exposures incurred transplacentally, during childhood, and

during adult life. To study the potential role of ETS exposure in the etiology of various cancers in adults, most of the studies have focused on the

association between adult exposure to ETS and subsequent risk (Hirayama,

267

Chapter 7

7.1 ALL CANCERS

(COMBINED)

7.1.1 All Cancers In

Adults
1984; Sandler et al., 1989; Reynolds et al., 1987; Sandler et al., 1985a),

although the role of ETS exposure during childhood as a risk factor for

adult cancers has also been investigated (Sandler et al., 1985b).

7.1.1.1 Cohort Studies Risk of all cancers in nonsmokers exposed to ETS (based on

spousal smoking) was evaluated in three cohort studies.

Hirayama (1984) In the first cohort study, the mortality of 91,540 nonsmoking

wives in relation to the smoking habits of their husbands was investigated

in Japan (Hirayama, 1984). Mortality of the cohort was monitored by

review of death certificates and the annual census of residents. After 16

years of follow-up, there were a total of 2,705 cancer deaths (all sites)

among the nonsmoking women. The relative risks (RRs) were 1.00, 1.12

(95% CI = 1.03-1.21), and 1.23 (95% CI = 1.12-1.35) for women whose husbands were nonsmokers, ex-smokers or smokers of 1-19 cigarettes per day,

and smokers of 20 or more cigarettes per day, respectively, when adjustment was made for husband’s age and occupation. In this population, the

increased risk for all cancers combined was due mainly to the increased risk

observed for cancers of the lung, nasal sinus, and brain. These respectively

accounted for 7 percent, 1 percent, and 1 percent of the tumors in this population. Stomach cancer, representing 31 percent of the cancers in this

population, was not associated with passive smoking (Hirayama, 1984).

There was a small increased risk of cervical cancer in passive smokers (see

Section 7.2.2) (Table 7.1).

Sandler et al. (1989) Using a cohort surveyed in 1963 in Western Maryland, Sandler

et al. (1989) evaluated the all-cancer mortality in nonsmokers who lived

with smokers. A total of 22,973 Caucasian men and 25,369 Caucasian

women were enrolled; 4,162 men and 14,873 women were lifetime nonsmokers. In 1975, death records were reviewed to evaluate the risk of mortality, and specific causes of mortality, in passive smokers compared to nonsmokers not exposed to ETS. In brief, a score ranging from 0-12 was

assigned to each adult in the household based on his/her smoking history.

A total household smoking score was then calculated by summing the

smoking contribution scores of all persons living in that household. Each

individual’s household ETS exposure was calculated by subtracting his or

her own contribution from the total household score. Among nonsmokers,

1,248 men (30.0 percent) and 9,551 women (64.2 percent) were exposed to

household tobacco smoke and were considered to be passive smokers.

Exposure to ETS did not increase the risk for all cancers combined in nonsmoking men (RR = 1.01, 95% CI = 0.66-1.53) and nonsmoking women (RR

= 1.00, 95% CI = 0.82-1.21) after adjusting for age, marital status, education, and housing quality. When the analysis was conducted separately for

tumors related to smoking and tumors not related to smoking, exposure to

ETS was associated with a small increased risk for smoking-related tumors in

women (RR = 1.45, 95% CI = 0.88-2.40), but not in men (RR = 0.96, 95% CI

= 0.66-1.53). In men and women, there was no association between ETS

exposure and risk of non-smoking-related tumors (Table 7.1).

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Smoking and Tobacco Control Monograph No. 10
269

Chapter 7

Exposure to RR (95% CI) for

Cohort Studies # Cases Passive Smoking Spouse’s Smoking

Hirayama, 1984 Husband’s smoking

All cancersa 634 Nonsmoking 1.00

1,341 Ex-/1-19/day 1.12 (1.03-1.21)b

730 20+/day 1.23 (1.12-1.35)

Sandler et al., 1989 Males Household smoking

All cancersa 84 No 1.0

31 Yes 1.01 (0.66-1.53)

Females

211 No 1.00

290 Yes 1.00 (0.82-1.21)

All cancers classified as:

Smoking-related cancers Males

24 No 1.0

8 Yes 0.96 (0.43-2.62)

Females

27 No 1.0

49 Yes 1.45 (0.88-2.40)

Other cancers Males

60 No 1.0

23 Yes 1.03 (0.40-2.62)

Females

184 No 1.0

241 Yes 0.93 (0.76-1.54)

Reynold et al., 1987 Husband’s smoking

All cancersa 71c No 1.00

Yes 1.68 (1.12-1.5)b

Smoking-related cancers 4c No 1.00

Yes 7.01 (1.05-47.0)

Table 7.1

Exposure to Spouse’s Smoking and Relative Risk (RR) of all Cancers in Adults

a There were 200 lung cancers in Hirayama (1984); 2 lung cancers in Sandler et al., 1989; and

an unspecified number in Reynold et al., 1987.

b 90% CI confidence intervals.

c The distribution of the 71 cancers by husband’s smoking was not presented; the specific cancer

sites were not presented.
Reynolds et al. (1987) Reynolds et al. (1987) reported results from a small cohort of

2,413 married women (46 percent had never smoked) who participated in a

population-based survey in Alameda County, California in 1965. Smoking

history was independently ascertained for each spouse. Based on 71 cancers diagnosed among the 1,111 nonsmoking women during the 17 years of

follow-up, nonsmoking women whose husbands smoked showed a RR of

1.68 (90% CI = 1.1-2.5) for all cancers combined compared to women

whose husbands did not smoke. The authors also reported a 7-fold

increased risk (90% CI = 1.1-47.0) of smoking-related cancers in relation to

husband’s smoking (Table 7.1), but this was based on four cases only (smoking-related cancers included cancers of the lung, mouth, esophagus, bladder, pancreas, liver, kidney, and uterine cervix); the specific sites of the four

cases were not presented.

Overall cancer risk in relation to ETS exposure from

spouses and parents was evaluated in a case-control

study conducted by Sandler et al. (1985a). This study

included all cancers (excluding skin cancers) diagnosed between ages 15

and 59, during July 1979 through March 1981, from the hospital-based

tumor registry affiliated with the University of North Carolina. Of the 740

eligible cancer cases, 518 completed a mailed questionnaire which included

information on ETS exposure during childhood and adult life. For 360 of

the 518 cases, a friend/acquaintance of the same race, gender, and within 5

years of age of the case served as a control in the study. The remaining

controls were identified by systematic telephone sampling using the telephone numbers of the cases as a starting point. Passive smoke exposure

during childhood was based on whether their natural parents ever smoked,

smoked before the subject’s birth, smoked in the house for most of the

years before the subject was 10 years old, and whether mothers smoked

while pregnant with the index subject. Passive smoke exposure during

adult life was based on the number of years of marriage during which a

spouse smoked at least one cigarette per day for as long as 6 months. The

average number of cigarettes smoked by spouses was also obtained. Among

the 518 cases and controls, 231 cases and 235 controls were lifetime nonsmokers.

Among lifetime nonsmokers, there was a significant 2-fold increased

risk (95% CI = 1.4-3.0) associated with spouses’ smoking after adjustment

for gender, race, and age. When the effect of ETS exposure was examined

by age group, gender, and race, the effect was more apparent for subjects

aged 40-49 (adjusted RR = 2.0, 95% CI = 1.4-2.9), females (adjusted RR =

2.0, 95% CI = 1.3-2.9), and non-whites (adjusted RR = 2.0, 95% CI = 1.4-

3.0). However, no dose-response relationship was observed between risk

and either the number of years married to a smoker or number of cigarettes

husbands smoked per day (data not presented). The role of ETS exposure

was also investigated by site of tumor. The increased risk was not limited to

lung cancer and other smoking-related tumors, such as cervical cancer.

Increased risks were also observed for breast and endocrine gland cancers—

tumors not causally associated with active smoking. 

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7.1.1.2 Case-Control Studies

Sandler et al. (1985a and b)
In a second report of the same adult study population, Sandler et al.,

(1985b) evaluated the association between ETS exposure from parents and

risk of all cancers. Mothers and father’s smoking habits were available on

438 cases and 470 controls; 197 cases and 223 controls were lifetime nonsmokers. Maternal and paternal smoking were each associated with a nonsignificant 20 percent increased risk for all cancers among nonsmokers.

The effect of maternal and paternal smoking was evaluated for ‘smokingrelated’ and ‘non-smoking related’ cancers. ‘Smoking-related’ cancers

included tumors of the oral cavity and pharynx, esophagus, pancreas, respiratory and intrathoracic organs, urinary tract and cervix, and accounted for

some 25 percent of tumors in nonsmokers. For ‘smoking-related’ tumors,

the RR was 0.76 (95% CI = 0.25-2.30) for maternal smoking and 1.68 (95%

CI = 0.86-3.29) for paternal smoking. For cancers not related to smoking,

the RR was 1.24 (95% CI = 0.65-2.36) for maternal smoking and 1.13 (95%

CI = 0.73-1.75) for paternal smoking.

7.1.1.3 Summary In summary, there is limited evidence from two cohort studies

(Hirayama, 1984; Reynolds et al., 1987) and one case-control study (Sandler

et al., 1985a) that exposure to spouses’ smoking may increase overall risk of

cancer in nonsmoking women. In one study, the increase is explained primarily by an elevated risk observed for lung cancer (Hirayama, 1984).

However, in two studies, elevated risks were observed for sites not typically

related to active smoking, as well as sites related to smoking (Reynolds et

al., 1987; Sandler et al., 1985a). In the study by Reynolds et al. (1987), the

strong association between husbands’ smoking and smoking-related tumors

was based on very few cases, accounting for only 6 percent of all cancers.

In the study by Sandler et al. (1985a), increased risks were observed for both

smoking-related (lung, cervix), and nonsmoking-related sites (breast and

endocrine gland) after adjustment for age and education. Although the

results on nonsmoking-related cancers are intriguing, they are difficult to

interpret given that known risk factors for the specific cancers under study

were not adjusted for (Sandler et al., 1985a). Possible effects of potential

confounders are a concern and should be more carefully researched in further studies. For example, sexual activity is a risk factor for cervical cancer

and exposure to ETS may be associated with sexual activity. Alcohol intake

is a risk factor for breast cancer and exposure to ETS may be positively associated with alcohol use. 

Exposure to ETS has been investigated as a risk factor for

all childhood cancers combined and for specific childhood tumors (see Sections 7.3.3 to 7.3.6). Exposure to ETS may occur during the prenatal or postnatal period. Prenatally, the fetus may be exposed

to tobacco smoke constituents when the mother smokes during pregnancy

(i.e., transplacental effects) or if the mother is exposed to someone else’s

smoking, most likely the father’s smoking. Postnatally, the child may be

exposed to ETS directly by inhalation. The main sources of postnatal ETS

exposure for a child whose parents both smoke are likely to be from the

mother, and to a lesser extent the father. 

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7.1.2 All Cancers In

Children
In this chapter, mothers’ smoking during pregnancy is considered to be

a surrogate measure of mothers’ smoking postnatally (see below). However,

since studies on childhood cancers included subjects who were diagnosed

with cancer up to age 24, it is reasonable that tobacco smoke exposure both

in utero and postnatally would be important. Thus, study findings require

cautious interpretation.

The extent of information on passive smoke exposure varied in the different studies. Two case-control studies conducted in the 1950’s asked

about mothers’ or fathers’ smoking habits at the time of interview or study

enrollment. In one study, this pertained to smoking habits of parents at

the time of interview which was after the death of the subject under study

(Stewart et al., 1958). The other study focused on the mothers’ smoking

habits when study subjects were enrolled (Manning and Carroll, 1957). In

more recent studies, mothers’ smoking habits during pregnancy were available (Neutel and Buck, 1971; Stjernfeldt et al., 1986a & b; Pershagen et al.,

1992; Severson et al., 1993). Several studies offered more detailed information by including mothers’ smoking habits 1-2 years before and during the

pregnancy (Gold et al., 1979; Van Steensel-Moll et al., 1985; John et al.,

1991; Gold et al., 1993). Mothers’ smoking during pregnancy represents

transplacental exposure to tobacco smoke constituents and may also be

used as a proxy variable of postnatal ETS exposure of the child. There are

data to support the assumption that mothers’ smoking habits during pregnancy represent an unbiased estimate of their smoking habits after pregnancy. In a study of childhood cancers and maternal smoking (Stjernfeldt

et al., 1986a & b), comparison of mothers’ smoking habits 5 years before,

during, and after pregnancy showed that a similar percentage (8 percent) of

cases’ and controls’ mothers reported they smoked after pregnancy when

they had not smoked during pregnancy. In a study of childhood brain

tumors (Gold et al., 1993), comparable percentages of mothers of cases (72

percent) and of population controls (73 percent) who had ever smoked

reported they were smoking during the birth year of the child. However,

some women may quit during pregnancy and resume afterwards so there is

potential misclassification when smoking status is based only on smoking

habits during pregnancy. 

Other studies on childhood cancers obtained information on both

mothers’ and fathers’ smoking habits during the index pregnancy (PrestonMartin et al., 1982; McKinney and Stiller, 1986; Buckley et al., 1986; Howe

et al., 1989; John et al., 1991; Gold et al., 1993; Kuijten et al., 1990;

McCredie et al., 1994). Children whose nonsmoking mothers were exposed

to spouses’ smoking were thus considered exposed to ETS prenatally. In

some studies, the effect of fathers’ smoking was evaluated among children

of nonsmoking mothers (John et al., 1991; McCredie et al., 1994; Gold et

al., 1993). None of the studies collected information on fathers’ smoking

postnatally. However, on the basis of the above-mentioned data that

showed mother’s smoking during pregnancy to be an unbiased estimate of

her smoking postnatally (Stjernfeldt et al., 1986a & b) or ever smoking

(Gold et al., 1993), it is assumed that father’s smoking during pregnancy is

also an unbiased proxy for father’s smoking postnatally. 

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Chapter 7

The effects of transplacental exposure to tobacco

smoke constituents due to maternal active smoking

during pregnancy are difficult to distinguish from

those of postnatal ETS exposure. Recent studies investigating the levels of three different biomarkers of tobacco-smoke exposure

in the offspring of mothers who smoke have demonstrated that the fetus

(Coghlin et al., 1991; Hammond et al., 1993), the newborn (Eliopoulos et

al., 1994), and the young child (Crawford et al., 1994) are all exposed to

considerable amounts of tobacco products.

Eliopoulos et al. (1994) In one of the studies (Eliopoulos et al., 1994), mothers were

identified 1 to 3 days after delivery and five to seven hair shafts were

obtained near the skull from both the mothers and their newborns for

determination of nicotine and cotinine levels (Table 7.2a). Although previous studies typically measured cotinine and nicotine levels in saliva, serum,

or urine, levels measured in hair samples provide more long-term assessment of ETS exposure. Nicotine and cotinine levels were highest in mothers who were active smokers, intermediate in nonsmokers who were passive

smokers, and lowest in nonsmokers not exposed to ETS. The respective

mean levels were 19.2, 3.2, and 1.2 for nicotine (ng/mg) and 6.3, 0.9, and

0.3. for cotinine (ng/mg). Newborns of smokers showed significantly higher mean levels of nicotine (2.4 ng/mg) than newborns of passive smokers

(0.28 ng/mg) or nonsmokers (0.4 ng/mg). Nicotine levels in newborns of

passive smokers were not higher than those of nonsmokers but the difference in levels was not statistically significant. On the other hand, mean

levels of cotinine were highest in newborns of smokers (2.8 ng/mg), intermediate in passive smokers (0.6 ng/mg), and lowest in nonsmokers (0.26

ng/mg). The cotinine levels in newborns of passive smokers were significantly higher than levels in newborns of nonsmokers, and were significantly lower than levels in newborns of smokers. The authors explained that

nicotine may be a less sensitive marker than cotinine because of its shorter

half-life (1-3 hours for nicotine compared to 10-14 hours for cotinine). 

In a study conducted by Coghlin et al. (1991), maternal-fetal

exchange of a potent tobacco-related human carcinogen, 4-

aminobiphenyl (4-ABP), was studied in smoking (n = 14) and nonsmoking

(n = 38) pregnant women. N-hydroxy-4-ABP, the active metabolite of 4-

ABP, forms chemical adducts with hemoglobin. Levels of 4-ABP hemoglobin adducts were detected in all maternal-fetal paired blood samples. The

mean levels of such adducts were 183 (pg/g of hemoglobin) in smoking

women, 92 in fetal blood samples from smokers, 22 in nonsmoking

women, and 17 in fetal blood samples from nonsmokers. In a related study

conducted by the same investigators (Hammond et al., 1993), the relationship between levels of 4-ABP-hemoglobin adducts and exposure to ETS in

nonsmoking women (based on nicotine levels measured by passive monitors) was investigated. The median level of 4-ABP adduct was 26 pg/g

among nonsmoking women in the highest ETS exposure category (±2

μg/m3 weekly average nicotine) compared to median levels of 15 pg/g

among those with the lowest ETS exposure (<0.5 μg/m3 weekly average

nicotine). The levels of 4-ABP hemoglobin adducts in nonsmoking women

7.1.2.1 Biomarkers Studies of

Exposure to Tobacco Smoke

Constituents In Utero and

Postnatally

Coghlin et al. (1991)

Hammond et al. (1993)
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Mean (SEM)* Mean (SEM)

Concentration of Concentration of

Nicotine (ng/ml) Cotinine (ng/ml)

Active smoking women (n = 36) 19.2 (4.9) 6.3 (4.0)

Newborn of active smoking women 2.4 (0.9) 2.8 (0.8)

Passive smoking womena (n = 23) 3.2 (0.8) 0.9 (0.3)

Newborn of passive smoking women 0.28 (0.05) 0.6 (0.15)b

Nonsmoking women (n = 35) 1.2 (0.4) 0.3 (0.06)

Newborn of nonsmoking women 0.4 (0.09) 0.26 (0.04)

Reference: Eliopoulos et al. (1994)

* (SEM) = Standard error of the mean.

a Defined as regular and steady gestational exposure to other person’s cigarette smoke, either at

home or in the workplace.

b p < 0.01 when compared to newborns of active smoking women and newborns of nonsmokers.

Table 7.2a

Hair Concentrations of Nicotine and Cotinine in Women and their

Newborn Infants

Table 7.2b

4-Aminobiphenyl Hemoglobin Adduct Concentrations in Pregnant Women and 

Fetuses by Exposure to Tobacco Smoke

Mean Standard

Concentration Deviation

(pg/g of hemoglobin)

Nonsmoking pregnant womena (n = 40) 22 8

Smoking pregnant women (n = 15) 183 108

Nonsmoking women by levels of

exposure to passive smoking based

on nicotine concentrationsb,c

μg/m3

<0.5 (n = 7) 17.6 2.4

0.5-1.9 (n = 20) 20.8 2.0

≥2.0 (n = 9) 27.8 1.4

Fetuses of nonsmoking mothersb (n = 40) 17 13

Fetuses of smoking mothers (n = 16) 92 54

a Reference: Coghlin et al. (1991)

b Reference: Hammond et al. (1993)

c This represented weekly average nicotine concentrations measured during the third trimester

when each subject wore a lightweight monitor. Nonsmoking women in this study were the same

nonsmoking pregnant women reported in Coghlin et al. 1991.
were 12 percent of those in smokers whereas levels in fetuses of nonsmoking women were about 9 percent of those of smoking women. These two

studies provided evidence that 4-ABP crosses the human placenta and binds

to fetal hemoglobin in both nonsmoking and smoking mothers and that

among nonsmoking women, the levels of 4-ABP adducts increased significantly with increasing levels of ETS exposure (Hammond et al., 1993).

Crawford et al. (1994) In the third study, Crawford et al. (1994) evaluated levels of

serum cotinine and polycyclic aromatic hydrocarbon (PAH)-albumin

adducts in Hispanic and African-American preschool children and their

mothers. In this study, mean serum cotinine levels were highest in mothers

who smoked (170 ng/ml), intermediate in nonsmoking mothers exposed to

passive smokers in the household (1.64 ng/ml), and lowest in nonsmoking

mothers not exposed to ETS in the household (0.96 ng/ml). A similar gradient in serum cotinine was observed in preschool children whose mothers

were smokers (4.14 ng/ml), passive smokers (0.87 ng/ml), and nonsmokers

not exposed to household ETS (0.25 ng/ml). Levels of PAH-albumin

adducts (fmol/μg) followed the same pattern in mothers who were smokers,

passive smokers, and nonsmokers; the respective levels were 0.80, 0.49, and

0.31. In preschool children of smokers, passive smokers, and nonsmokers

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Chapter 7

Mean (SE) Mean (SE) PAHCotinine albumin 

Level (ng/ml) Level (fmol/μg)

Active smoking women (n = 31) 170 (21.2) 0.80 (0.15)

Preschool children of 4.14 (0.54) 0.35 (0.07)

active smoking women

Passive smoking womena (n = 32) 1.64 (0.97) 0.49 (0.08)

Preschool children of 0.87 (0.20)b 0.18 (0.04)c

passive smoking women

Nonsmoking women (n = 24) 0.96 (0.79) 0.31 (0.08)

Preschool children of 0.25 (0.12) 0.15 (0.02)

nonsmoking women

Table 7.2c

Cotinine and PAH-Albumin Levels in Mothers and their Preshool Children

Reference: Crawford et al. (1994)

Abbreviations: PAH = polyaromatic hydrocarbon; SE = standard error

a Exposure to ETS at home from other household members and visitors.

b Levels in preschool children in households with ETS exposure were significantly higher

(p <0.01) than those in children in nonsmoking households.

c Levels in preschool children in households with ETS exposure were not significantly higher than

those in children in nonsmoking households.
not exposed to ETS, the corresponding levels of PAH-albumin adducts were

0.35, 0.18, and 0.15. Comparisons between the three groups of mothers

and between the three groups of preschool children show that there were

statistically significant differences in levels of cotinine and PAH-albumin

adducts, with those in smokers (and their children) higher than those in

passive smokers and nonsmokers not exposed to ETS (and their children).

Although levels in passive smokers (and their children) were also higher

than those in nonsmokers not exposed to ETS (and their children), the differences were not statistically significant. Levels of cotinine and PAHadducts in children whose mothers were passive smokers (i.e., exposed to

household ETS) were lower than those of their mothers who were living in

the same ETS-exposed households (levels were about one-third to one-half),

presumably because mothers had more opportunities to be exposed to ETS

outside the home than did their preschool children. 

In this study, young children exposed to ETS via their mothers’ smoking

showed increases in cotinine and PAH-albumin adducts. These results suggest that exposed children can take up and metabolically activate respiratory carcinogens. Children with nonsmoking mothers who were exposed to

ETS from other household members also showed increases in levels of cotinine and PAH-albumin adducts, although the increases were smaller. 

7.1.2.2 Cohort Studies Two prospective studies and a case-cohort study investigated

the effect of maternal smoking during pregnancy and risk of cancer in children (Table 7.3). 

Neutel and Buck (1971) A study by Neutel and Buck (1971) was based on 89,302

births registered in Canada and the United Kingdom. The cohort included

all births registered in ten Canadian hospitals between 1958 and 1961, as

well as those registered in all hospitals in England and Wales during a oneweek period. Smoking habits of mothers during pregnancy were recorded

before or just after the birth of the child. For 74 percent of the cohort (n =

66,456), mothers were classified as nonsmokers, smokers of less than one

pack per day, or smokers of one or more packs per day. In the remainder of

the cohort, nonsmoking mothers and those smoking less than one pack per

day could not be distinguished and thus are excluded from this discussion.

A total of 65 cancer deaths (22 leukemias, 20 nervous system tumors, and

23 other sites) occurred before age 10 among the 66,456 births. There was

a small increased risk for all cancers combined (RR = 1.31, 95% CI = 0.8,

2.2) among children whose mothers smoked compared to children whose

mothers did not smoke. There were few cases in the heavy smoking category, and no consistent dose trend of increasing risk with increasing amounts

smoked by mothers during pregnancy was observed. 

Pershagen et al. (1992) A second cohort study was conducted by Pershagen et al.

(1992) who utilized data from the Swedish Medical Birth Registry and the

Swedish Cancer Registry. Cancer incidence in a cohort of 497,051 children

born between 1982-1987 was determined and compared by maternal smoking at 2-3 months of pregnancy (none, <10 cigarettes/day, or >10 cigarettes/day). Relative risks were adjusted for potential confounders which

included maternal age, birth order, year and county of birth of index sub276

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ject. There were a total of 327 cancers for which maternal smoking habits

were known—198 solid tumors and 129 tumors of the lymphatic and

hematopoietic system. There was no association between maternal smoking and risk of all cancers combined (adjusted RR = 0.99, 95% CI = 0.78-

1.27). The lack of an association persisted when the analysis was conducted

separately for solid tumors combined (adjusted RR = 0.96, 95% CI = 0.70-

1.32), and for lymphatic and hematopoietic tumors combined (adjusted RR

= 1.04, 95% CI = 0.71-1.52). 

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Chapter 7

Smoking

Cohort Studies Habits Odds Ratio (95% CI)

(Age of Subjects) # Cases (cig/day) for Maternal Smoking

Neutel and Buck, 1970 34 No 1.0

(Age ≤ 10) 30 Yes 1.3 (0.8-2.2)

Pershagen et al., 1992 230 No 1.0

(Age ≤ 5) 61 <10 1.04 (0.8-1.4)

36 ≥10 0.92 (0.6-1.3)

Case-Control Smoking

Studies # Cases/ Habits Odds Ratio (95% CI) 

(Age of Subjects) # Controls (cig/day) for Maternal Smoking

Stjernfeldt et al., 1986a 177/220 0 1.0

(Age ≤ 16) 30/35 1-9 1.07 (0.6-1.8)

73/58 10+ 1.56 (1.1-2.3)

McKinney et al., 1986 555/1,100a 0 1.0

(Age ≤ 15) 1-10 1.12 (0.9-1.5)

11+ 0.84 (0.7-1.1)

Buckley et al., 1986 1,814/720a 0 1.0

(Age ≤ 15) 1-9 1.31 (0.9-1.9)

10+ 0.97 (0.8-1.2)

Golding et al., 1990b 13/61 <5 1.0

(Age ≤ 10) 20/38 ≥5 2.47 (1.2-5.1)

John et al., 1991 223/196a 0 1.0

(Age ≤ 14) 1-10 1.4 (0.7-2.7)

11+ 1.5 (0.8-2.7)

Table 7.3

Maternal Smoking During Index Pregnancy and Risk of all Childhood Cancers

Combined

a Numbers represent total cases/controls. Case/control distribution of maternal smoking by

case/control status was not presented.

b Case-cohort study.
The study by Pershagen et al., (1992) has several strengths, but also a

major limitation. The compilation of the cohort of births was nearly complete (99 percent). Of the 422 childhood cancer cases identified in the

Swedish Cancer Registry during this time period, 408 could be linked to a

subject in the birth cohort (we assumed that 81 of 408 cases were excluded

from the analysis because data on maternal smoking habits were missing).

Data on mothers’ smoking habits at 2-3 months of pregnancy were available on over 90 percent of children born between 1983 to 1987 and for

about 50 percent of children born in 1982. The lower figure in 1982 was

due mainly to logistical problems during this first year when the birth registry started to collect information on smoking. Results remained

unchanged when births in 1982 were excluded from the analysis. The percentage of mothers who smoked in this study was also similar to that

reported in other Swedish studies, so that underreporting of smoking during pregnancy cannot explain the lack of an association. The main limitation of this study is that the maximum follow-up was to 5 years of age, and

thus an effect of maternal smoking on cancers occurring at older ages was

not assessed; there were small numbers of cancers diagnosed among the 4-5

year olds.

Golding et al. (1990) A case-cohort study was conducted by Golding et al. (1990),

who collected information prospectively on 16,193 infants delivered over a

one-week period in 1970 in the United Kingdom. These children were followed up at ages 5 and 10; 80 percent and 94 percent respectively were successfully contacted. By 1980, 33 children had developed cancer (9

leukemia, 5 lymphoma, 8 brain, 5 Wilm’s tumor, 6 other). For each cancer

case, three controls were selected and matched to cases on factors including

maternal age at birth of index subject, parity, and social class. Significantly

more mothers of cases had smoked five cigarettes or more per day throughout pregnancy compared to the controls (RR = 2.47, 95% CI = 1.2-5.1).

Maternal smoking remained statistically significant in logistic regression

analysis when other risk factors were controlled for (e.g., social class, X-ray

in pregnancies, use of various medications).

7.1.2.3 Case-control Studies One of the first case-control studies to examine the

role of parental smoking and risk of childhood cancers was a hospital-based

study conducted in the U.S. (Manning and Carroll, 1957). Smoking habits

of mothers (at time of study enrollment) of children with cancers (188

leukemias, 42 lymphomas, and 93 other cancers) were compared to mothers of children with orthopedic diseases (n = 50). There was no difference

in the percentage of mothers of children with cancer who smoked ten or

more cigarettes per day (37.4 percent) compared to mothers of controls

(38.0 percent). A second study was conducted by Stewart et al. (1958) who

included as cases all children in England and Wales who had died of

leukemia or other cancers before their tenth birthday between 1953 and

1955. Controls were individually matched to cases on gender, age (plus or

minus 6 months of the birth date of the cases), and locality of residence. A

total of 1,416 case/control pairs were available for analysis. Fathers and

mothers of the index subjects were classified as heavy, moderate, light, or

nonsmokers. The smoking habits of fathers of children with cancer (82.9

percent smoked at least one cigarette or pipe per day) were similar to those

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of fathers of control children (80.9 percent smoked). There was a small

excess of mothers of cases who smoked (47.8 percent) compared to mothers

of controls (43.8 percent) (OR = 1.09, p = 0.04), but this was not adjusted

for potential confounding factors. The authors cautioned that since parents

were interviewed after the death of the index patients, their smoking habits

may be affected by bereavement. 

Results from five case-control studies conducted since the 1980’s offer

better information on smoking habits of parents during pregnancy (Table

7.3). 

Stjernfeldt et al. (1986a, 1986b, 1992) Stjernfeldt et al. (1986a, 1986b, 1992) conducted a population-based, nationwide case-control study of childhood cancer

in Sweden. A total of 305 children, aged 16 or younger, diagnosed with

cancer during 1978 and 1981 were identified by the Swedish Child

Leukemia Group. Cases were compared to 340 control children with

insulin-dependent diabetes mellitus. Families of cases and controls completed a self-administered questionnaire with an overall participation rate of

about 95 percent in both groups. Controls were not individually- or frequency-matched to cases on age or gender, but these variables were controlled for in the analysis. Information on smoking habits of mothers was

obtained on 92 percent of cases and controls for the 5-year period before

pregnancy, during pregnancy, and postnatally to onset of disease in the

index subject.

There was some suggestion of an increased risk for all cancers combined

in relation to mother’s smoking during pregnancy. Compared to children

whose mothers were nonsmokers, children whose mothers smoked 1-9, and

10+ cigarettes per day showed RRs of 1.07 (95% CI = 0.63-1.80) and 1.56

(95% CI = 1.05-2.33) respectively. The increase in risk was not observed for

solid tumors but was restricted to tumors of the reticuloendothelial system,

primarily acute lymphoblastic leukemias. The authors did not present

results separately for mother’s smoking after birth of the index subject, but

suggested that since mothers who smoked during pregnancy generally

smoked after the child was born, it would be difficult to separate the effect

of in utero exposure to tobacco smoke constituents versus postnatal ETS

exposure.

Despite concerns raised regarding the choice of controls and possible

selective recall bias among cases (McKinney and Stiller, 1986; Buckley et al.,

1986; Dahlquist and Wall, 1986; Li, 1986; Cunningham, 1986), none of

these biases appear to explain the study’s findings. It can be argued that

mothers of diabetic children would recall more similarly to mothers of children with cancer if there is any recall bias associated with having a disease.

Smoking habits of mothers of diabetic children were representative of the

general population since their smoking prevalences were comparable to

those of Swedish women surveyed in studies conducted during the same

time period. Moreover, differences between cases and controls in ages at

diagnosis, geographic location, and socioeconomic status could not explain

the apparent findings (Stjernfeldt et al., 1986b). The increased risk associated with maternal smoking was observed after adjustment for factors including maternal age, birth order of index subject, and parental occupation.

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Chapter 7
McKinney and Stiller (1986) In response to the findings of Stjernfeldt et al. (1986a &

b), McKinney and Stiller (1986) published a letter to the editor and a more

detailed paper (McKinney et al., 1987) presenting data collected for the

Inter-Regional Epidemiology Study of Childhood Cancer (IRESCC), a collaborative study conducted in three health regions in the United Kingdom

(Yorkshire, West Midlands, and North West) between 1980 and 1983. Study

subjects included 555 children (under age 15) diagnosed with childhood

cancer. Two healthy, age- and sex-matched control children were identified

for each case using the general practitioner lists and admissions to hospital

for minor conditions. Parents of cases and controls were asked identical

questions regarding the antenatal period of the index subject—e.g., illness,

use of medications, complications, smoking and drinking habits (McKinney

et al., 1987). Maternal smoking habits during pregnancy were not associated with risk for all cancers combined; the RRs were 1.0, 1.12 (95% CI =

0.85-1.47) and 0.84 (95% CI = 0.65-1.09), respectively for mothers smoking

0, 1-10, and 11+ cigarettes/day. Leukemias and lymphomas, which

accounted for 44 percent of the childhood cancers in this population, were

not associated with maternal smoking. However, maternal smoking was

associated with nonsignificant increased risks for soft-tissue sarcomas and

bone tumors (see Section 7.4.6.4: Bone and Soft-Tissue Sarcomas).

Buckley et al. (1986) Also in response to Stjernfeldt’s findings, Buckley et al. (1986)

investigated the role of maternal smoking during pregnancy and the risk of

childhood cancer using data gathered by the US Children’s Cancer Study

Group. Since 1983, the parents of 1,814 children have completed a questionnaire which included smoking histories of the mother and father before

and during the pregnancy of the index subject. Controls were drawn at

random from approximately the same geographic regions as cases in the US

and Canada. There was no association between maternal smoking during

pregnancy and risk of all cancers combined; the RRs were 1.31, and 0.97

respectively, for mothers smoking 1-9, and 10+ cigarettes/day during pregnancy compared to nonsmokers. Acute lymphoblastic leukemia, representing 41 percent of cancers in this study, was not related to mother’s smoking. Paternal smoking during the index pregnancy was also not associated

with all childhood cancers combined (data were not presented).

Adjustment for potential confounders (e.g., birth year of the child, maternal

age, illnesses during the pregnancy, and socioeconomic factors) did not

alter the results.

John et al. (1991) John et al. (1991) investigated the role of parental smoking before

and during pregnancy and the risk of childhood cancer in a populationbased case-control study conducted in Colorado. The study included incident childhood cancers, diagnosed between 1976 and 1983 among children

14 years old or younger. Controls were selected by random-digit dialing

and were individually matched to cases on age (±3 years), sex, and telephone exchange area. Of the 356 eligible cases, 252 (response rate of 70.8

percent) participated in the study compared to 222 controls (response rate

of 62.8 percent). Structured interviews were administered to parents of

index subjects and included questions on smoking habits of mothers,

fathers, and other household members during the index pregnancy. In

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Smoking and Tobacco Control Monograph No. 10
addition, questions regarding the mother’s cigarette smoking habits at three

months prior to the index’s conception and during each trimester of the

pregnancy were asked. Questions on father’s smoking included use of cigarettes, cigars, and pipes. Information on other smokers in the household

was derived based on questions regarding the number of regular smokers at

each residence from conception to the time of the child’s diagnosis. The

definition of nonexposed in this study is “not exposed to smoking by either

parent or by other household members from the period starting 1 year

before birth through the time of diagnosis.” Data on the number of cases

and controls who were exposed to other household members only (but not

to parents’ smoking) were not presented. 

For all cancers combined, there was a small increased risk associated

with exposure to mothers or fathers’ smoking. The RRs for all cancers were

1.3 (95% CI = 0.8-2.0), 1.5 (95% CI = 1.0-2.5), and 1.4 (95% CI = 0.9-2.4),

respectively, in relation to mothers who smoked during the 3 months prior

to conception, the first trimester, and all three trimesters of the pregnancy.

The OR for all cancers combined was 1.3 (95% CI = 0.9-2.0) in relation to

any tobacco use by the father. The ORs for all cancers combined in association with mothers’ smoking in the absence of father’s smoking, fathers’

smoking in the absence of others’ smoking, and the combined effect of

mothers’ and fathers’ smoking were 1.7 (95% CI = 0.7-4.3), 1.4 (95% CI =

0.9-2.3), and 1.5 (95% CI = 0.9-2.6), respectively. The data suggest an

increasing trend in risk with increasing amounts smoked by mothers, but

not by fathers. The positive association between ETS exposure and risk of

all cancers is largely due to its effect on risk for acute lymphoblastic

leukemia, lymphoma, and brain tumors. Father’s education was a potential

confounder in this study. The OR for all childhood cancers in relation to

fathers’ and mothers’ smoking was 1.5 (95% CI = 0.9-2.6); this OR was

reduced to 1.2 (95% CI = 0.7-2.1) when father’s education was accounted

for in the analysis.

7.1.2.4 Summary While in some studies increased risks overall in childhood cancers

were observed, in others no such increases were seen. There are several limitations in both the studies finding an association and those finding no

association between ETS exposure and risk of childhood cancers. The

cohort study of Pershagen et al. (1992) is limited in that it can only examine the effect of ETS exposure on tumors diagnosed up to 5 years of age,

whereas all the other studies included cancers up to 10 or 16 years of age.

Causes of childhood cancers in very young children may differ from those

of older children. The two large case-control studies which found no association with maternal smoking were collaborative studies of childhood cancers conducted in the United Kingdom (McKinney and Stiller, 1986) and

the U.S. (Buckley et al., 1986). Selection bias of cases cannot be ruled out in

these studies. Childhood cancer patients admitted to academic institutions

were enrolled in these studies and may be unrepresentative of all childhood

cancers in the population (e.g., higher social class). The denominator of

childhood cancers was not presented, and thus participation rates could not

be calculated. Because of the association between social class/education

and smoking habits, selection bias associated with social class/education

281

Chapter 7
cannot be precluded. Prevalence of smoking habits of mothers/fathers was

not presented in these two studies. On the other hand, the strongest positive finding reported in the case-cohort study by Golding et al. (1990) was

based on a small number of cases and classification of mother’s smoking as

less than five versus greater than five cigarettes/day. The choice of the less

than five cigarettes/day as the baseline category was not explained, and it is

unclear whether this cut-off was an a priori decision. Presenting the results

using nonsmoking mothers as the baseline group would have been a useful

comparison to other studies. The results by Stjernfeldt et al. (1986a & b)

have also been questioned because of the choice of controls (children with

diabetes). Finally, there is some suggestion that inadequate adjustment for

paternal education (as a surrogate for social class) may have produced an

association between parental smoking and risk of childhood cancer that is

artificially strengthened (John et al., 1991).

In summary, the evidence for a role of parental smoking and childhood

cancers is inconclusive. One (Neutel and Buck, 1971) of two cohort studies

reported an elevated risk which is not statistically significant (OR = 1.3,

95% CI = 0.8-2.2). Two (Stjernfeldt et al., 1986; Golding et al., 1990) of five

recent case-control studies (conducted in the 1980s) reported significant

associations between mother’s smoking during pregnancy and risk of childhood cancers. A third case-control study (John et al., 1991) which reported

elevated risks that were not statistically significant was the only study in

which fathers’ smoking during pregnancy in the absence of mothers’ smoking was evaluated; the investigators found a statistically nonsignificant

increased risk associated with fathers’ smoking alone (OR = 1.4, 95% CI =

0.9-2.3). The positive findings are due largely to the significant association

between maternal smoking and acute lymphoblastic leukemia in these studies. No other cancer site appeared to be significantly affected by maternal

or paternal smoking.

Active smoking is firmly established as a causal factor for

lung cancer. The Surgeon General (U.S. DHHS, 1986),

National Research Council (NRC, 1986), and U.S. EPA (1992) have reviewed

epidemiologic studies investigating the role of ETS exposure as a cause of

lung cancer in nonsmokers. Our review focuses on studies published since

the latest review—three large U.S. population-based case-control studies

(Stockwell et al., 1992; Brownson et al., 1992; Fontham et al., 1991 and

1994), a fourth, considerably smaller, hospital-based case-control study

(Kabat et al., 1995), and a recent U.S. cohort study (Cardenas et al., 1997).

In 1981, the first epidemiological studies of ETS exposure

and lung cancer were published (Hirayama, 1981;

Trichopoulos et al., 1981). These studies found that nonsmokers married to smokers showed a significantly higher risk of lung cancer than nonsmokers married to nonsmokers. Some 30 epidemiological

studies have since been published. Most of the individual studies found a

small increased risk, and a few found statistically significant results; however, all the studies published in the 1980s had small sample sizes which

lacked statistical power to detect small associations. The Surgeon General

(U.S. DHHS, 1986), NRC (1986), and U.S. EPA (1992) conducted compre282

Smoking and Tobacco Control Monograph No. 10

7.2 ETS AND LUNG

CANCER

7.2.1 Epidemiologic

Studies Published

Prior to 1991
hensive reviews of the epidemiological literature and concluded that ETS

exposure was causally associated with lung cancer. Their conclusions were

based on the total weight of evidence and not on any individual study.

The U.S. EPA (1992) report reviewed a total of 30 epidemiologic studies

(four prospective follow-up and 26 case-control studies) from eight countries. All the studies examined the risk of lung cancer in nonsmokers in

relation to spousal smoking habits. Each study was examined in detail and

then the studies were examined collectively. Because none of the studies

were exactly alike, and the individual studies had different methodologic

strengths and weaknesses, the U.S. EPA report ranked the studies in four

tiers and gave special consideration to the 15 studies in the two highest

tiers. The U.S. EPA report concluded that ETS is responsible for approximately 3,000 lung cancer deaths per year in U.S. nonsmokers.

In order to gain a more accurate estimate of the association between

ETS exposure and lung cancer, a meta-analysis approach has been used to

pool results of comparable studies. Numerous meta-analyses have been

published on this subject (U.S. DHHS, 1986; NRC, 1986; U.S. EPA, 1992;

Fleiss and Gross, 1991; Arundel et al., 1987; Kilpatrick, 1992; Pershagen,

1992; Vainio and Partensen, 1989; Repace and Lowry, 1990; Spizer et al.,

1990; Wells et al., 1991; Wells, 1993). A widely disseminated and reviewed

meta-analysis was conducted by the U.S. EPA (U.S. EPA, 1992; Farland et al.,

1994; Jinot and Bayard, 1994). Despite careful considerations of many

methodologic issues of concern in the meta-analysis of ETS exposure and

lung cancer (e.g., measurement of ETS exposure, misclassification bias of

nonsmoker status and disease status, adjustment for potential confounders),

the U.S. EPA report was criticized (LeVois and Layard, 1994; Gori, 1994a &

b). Some of the concerns centered around issues that were specific to the

study of ETS exposure and lung cancer, including misclassification bias of

smokers as nonsmokers and the extent of such misclassification. On the

other hand, other issues were generic to meta-analysis techniques, and they

include possible publication bias of positive studies and the difficulty in

obtaining adjusted risk estimates (Gori, 1994a & b) for meta-analysis. The

issue of publication bias has been reviewed in detail by Bero et al. (1994),

who concluded that there is no publication bias against statistically nonsignificant results on ETS in the peer-reviewed literature. 

The U.S. EPA’s (1992) reporting of 90 percent confidence intervals has

gained much attention and is worth addressing here. The U.S. EPA report

uses a one-tailed test of statistical significance (with p = 0.05) and reports

the corresponding 90 percent confidence intervals, consistent with the onetailed test. Use of a one-tailed statistical test could be considered to increase

the probability of accepting an association (for an individual study) that

occurs by chance. A one-tailed test is a standard statistical methodology

used when there is prior evidence that the effect of an agent is likely to be

in one specific direction. In this case, the Surgeon General (U.S. DHHS,

1986), NRC (1986), and an International Agency for Research on Cancer

work group (IARC, 1986) all previously concluded that ETS exposure

increased lung cancer risk. The established causal association between

active smoking and lung cancer and the chemical similarity between main283

Chapter 7
stream smoke and ETS were considered by the U.S. EPA (1992) to provide

prior evidence that any effect of ETS on lung cancer would be likely to be

positive (i.e., to increase the risk); thus, the one-tailed significance test was

the appropriate method for evaluating the hypothesis of an effect of ETS on

lung cancer risk (U.S. EPA, 1994). Had the EPA used a two-tailed statistical

significance test (with corresponding 95 percent confidence intervals)

instead of a one-tailed test (with 90 percent confidence intervals), the overall conclusions regarding causality and degree of risk would have been the

same (U.S. EPA, 1994).

Three large U.S. population-based case-control studies

designed specifically to investigate the association between

ETS exposure and lung cancer have been published since

1991; they confirm and extend the results of the pooled U.S. studies presented in the U.S. EPA report. These studies were conducted in Florida

(Stockwell et al., 1992), Missouri (Brownson et al., 1992), and in five geographic areas of the U.S.—New Orleans, Louisiana; Atlanta, Georgia;

Houston, Texas; Los Angeles County, California; and San Francisco Bay

Area, California—referred to as the U.S. multicenter study (Fontham et al.,

1991 and 1994). Preliminary findings from the U.S. multicenter study

(Fontham et al., 1991) were included in the U.S. EPA (1992) report. A

fourth study, which is a considerably smaller, hospital-based case-control

study, was published in 1995 (Kabat et al., 1995). In addition, three other

studies which provide some information on ETS exposure as part of investigations of lung cancer and indoor air pollution in Guangzhou, China (Liu

et al., 1993), familial risk factors in Detroit (Schwartz et al., 1996), and various suspected risk factors in Kaohsiung, Taiwan (Ko et al., 1997) are also

briefly reviewed in this section.

The case-control studies will be reviewed, and their respective study

designs and the main findings will be described. In the evaluation of the

methodologic issues related to the study of ETS exposure, the focus will be

on the sources of cases and controls, the methods used to obtain information on the exposures of interest, the verification of the exposures of interest and of the diagnosis of lung cancer, and the consideration of potential

confounding variables in the analysis of ETS exposure. 

To minimize confusion, the ORs and confidence intervals will be cited

exactly as theywere reported in the original papers. This means that some

numbers are reported to one decimal place whereas others are reported to

two decimal places. Odds ratios that had to be calculated for this review

are labeled as such in the text and tables—e.g., “calculated odds ratio”—and

these estimates are referred to as “crude odds ratios.” In some instances,

the numbers of cases and controls (presented in the tables) by various

intensity of ETS exposure (i.e., pack-years, years of exposure) did not add up

to the total numbers of subjects included in the individual studies, and it is

assumed that these differences in numbers are due to missing information

on specific parameters of intensity of ETS exposure or on the covariates

included in the adjustments (the variables that were adjusted for in the different analyses are described as footnotes in the various tables). The meas284

Smoking and Tobacco Control Monograph No. 10

7.2.2 Case-Control

Studies Published

Since 1991
ures of intensity of exposure were generally in terms of years (or smokeyears) or pack-years of exposure, number of cigarettes (or tobacco products)

smoked per day, or the number of smokers in the household. 

Stockwell et al. (1992) conducted a population-based casecontrol study of women in 28 counties in central Florida

(Table 7.4). Eligible cases included women diagnosed

with a histologically confirmed primary lung cancer

between April 1, 1987, and February 28, 1991, and were

identified through the Florida Statewide Cancer Registry and the tumor registries of area hospitals. Age criteria for the study subjects were not specified. Population controls were selected by random-digit dialing; it is

unclear whether cases and controls were frequency-matched on any criteria.

All cases and control subjects were lifetime nonsmokers, defined as having

smoked for a total of less than 6 months or less than 100 cigarettes in their

lifetime. The nonsmoking status of the study subjects was verified by

checking medical records and checking with physicians’ offices (for cases)

and by inquiry at the time the subjects were contacted to set up the interview as well as at the beginning of the interview (for cases and controls).

The response rate for lung cancer cases was 83 percent; it was not specified

for controls. 

A combination of telephone (51 percent for cases; 46 percent for controls) and in-person (41 percent for cases; 54 percent for controls) interviews and mailed questionnaires (8 percent for cases; 0.3 percent for controls) were used to obtain information from study subjects. Interviews of

surrogate respondents (primarily husbands and children) were necessary for

66.7 percent of the case patients who were too ill to be interviewed or were

deceased. Information was obtained on a total of 210 lung cancer patients

and 301 controls.

Subjects were asked about their exposure to ETS from husbands, mothers, fathers, siblings, and other household members and at the workplace.

Compared to unexposed individuals who had no household ETS exposure,

women who were exposed to husbands’ smoking had ORs of 1.6 (95% CI =

0.8-3.0) for those who had ever been exposed and 2.2 (95% CI = 1.0-4.9) for

those with 40 or more smoke-years of exposure after adjustment for age,

race, and education. Similar odds ratios were observed for exposure to

smoking by husbands and other household members in adult life (Table

7.5). Exposure to ETS from mothers, fathers, and siblings was associated

with an increased risk of lung cancer, although none of the individual

increases in risks were statistically significant. Stockwell et al. (1992) also

considered ETS exposure from different sources during childhood/adolescence in terms of years of exposure. Women who experienced 22 years or

more of ETS exposure from all household members combined during childhood/adolescence showed a significantly elevated OR for lung cancer (2.4,

95% CI = 1.1-5.4) (Table 7.6). When ETS exposures from both

childhood/adolescence and adulthood (i.e., from husbands and other

household members) were considered jointly, women who reported 40 or

more years of exposure experienced an elevated risk of lung cancer (OR =

2.3, 95% CI = 1.1-4.6) compared to women who had fewer than 22 years of

285

Chapter 7

7.2.2.1 Four U.S. CaseControl Studies of ETS 

and Lung Cancer

Stockwell et al. (1992)
exposure (data not shown). These investigators noted that there was no

statistically significant association in this study between ETS exposure at

work or during social activities and risk of lung cancer (actual results were

not presented in Stockwell et al., 1992).

The elevated risks associated with ETS exposure (during childhood/adolescence, adulthood, and all lifetime combined) were observed for all lung

cancer cell types; the risk was stronger for cell types other than adenocarcinoma of the lung. Analysis by respondent type showed that the risk estimates for ETS exposure varied by the source of case information. For example, ETS exposure from husbands was a stronger risk factor for lung cancer

when the respondents were the case patients (OR = 3.1, 95% CI = 0.9-10.6)

or their husbands (OR = 3.1, 95% CI = 0.7-13.7). When the surrogate

respondent was a family member other than the patient’s husband, ETS

exposure was not associated with elevated risk (OR = 0.9, 95% CI = 0.4-1.9). 

It should be noted that the distribution of study subjects by ETS exposure was not presented; only the odds ratios were presented. The “unexposed” reference category was comprised of individuals with no household

ETS; presumably this same reference category was used in all analyses for

cases and controls.

Brownson et al. (1992) Brownson et al. (1992) conducted a population-based casecontrol study of women in Missouri (Table 7.4). Females aged 30 to 84

years who were diagnosed with primary lung cancer between January 1986

and June 1991, and were identified from the Missouri Cancer Registry, were

considered eligible. Population controls were identified from a sample of

the state driver’s license files and Health Care Finance Administration listings. The case group included both lifetime nonsmokers and ex-smokers

who had stopped smoking at least 15 years before diagnosis or who had

smoked less than 1 pack-year. The definition of lifetime nonsmokers was

not specified explicitly. The control group was matched by age group to

case patients at about a two to one ratio. Tissue slides were reviewed to

confirm the histologic classification for 468 (76 percent) of the 618 lung

cancer cases. 

The response rate was 95 percent for cases and 75 percent for controls,

nonsmokers and ex-smokers combined. Information was collected on a

total of 618 lung cancer cases of whom 432 were lifetime nonsmokers and

186 were ex-smokers. Of the lung cancer patients, 402 interviews were conducted with surrogate respondents and 216 interviews were with the lung

cancer patients themselves. A total of 1,400 control subjects were interviewed, all of whom were self-respondents; 1,166 controls were lifetime

nonsmokers. 

All case and control interviews were conducted by telephone at which

time the nonsmoking status was verified. Questions on ETS exposure pertained to exposures in both childhood (17 years and younger) and adult life

(18 years and older). For each time period, respondents were questioned

about the source of exposure (e.g., a parent or spouse) including both

household and workplace exposure. After an individual source was deter286

Smoking and Tobacco Control Monograph No. 10
287

Chapter 7

Stockwell et al. Brownson et al. Fontham et al. Kabat et al.

(1992) (1992) (1994) (1995)

Area Central Florida Missouri 5 U.S. metro- 4 U.S. cities

politan areas

Accrual period 1987-1991 1986-1991 1985-1991 1983-1990

Sample size1

cases 210 (F) 432 (F) 653 (F) 69 (F), 41 (M)

controls 301 (F) 1166 (F) 1253 (F) 187 (F), 117 (M)

Ages NA (% by birth 30-84 20-79 not specified

year groupings 

provided)

Source of cases Florida Cancer Missouri Cancer All hospital/regis- 6 hospitals in 

Registry Registry tries in specific the 4 cities

geographic areas

Source of controls RDD DMV, HCFA RDD, HCFA other hospital

patients

Matching variables NA age age, area, age, race, hospital,

of lifetime non- & race date of interview

smoking controls

Percent of selfrespondents

cases 33 34* 63 100

controls 100 100 100 100

Mode of in-person, tele- telephone in-person in-person

data collection phone, mailed 

questionnaires

% Histologic 100% 76%** 100%** 100%

confirmation

% adenocarcinoma 61% 66% 76% NA

Definition of smoked for a total not described <100 cigarettes, <365 cigarettes

lifetime nonsmoker of <6 months or no use of other over lifetime

<100 cigarettes tobacco for 

in their lifetime >6 mos

Verification of multistep-medical at interview multistep-medical at interview

nonsmoking status record, physician, record, physician,

at initial contact at initial contact

& interview & interview

Biological markers none none urinary cotinine*** none

1 Sample size of lifetime nonsmokers in study

* Presented for nonsmokers and ex-smokers combined

** Confirmed by independent histologic review

*** On 81% of self-respondent cases and 85% of controls

Abbreviations: F-females, M-males, NA-not available, RDD-random digit dialing, DMV-Department of

Motor Vehicle, HCFA-Health Care Financing Administration 

Table 7.4

Study Characteristics of the Four U.S. Case-Control Studies of Lung Cancer and ETS

Published Since 1991
288

Years exposed /Amount smoked by spousSmoke-years in adulthousehold (spouse and othe

<22

23-39

40+

Cigarettepack-years cases co

0 213 50-15 32 115-40 54 240+ 110 2

Adjusted OddsRatio (95% CI)for exposedAORa1.01.6 (0.8-3.0)AORb1.01.0 (0.8-1.2)

Exposure StatusSpouse smokeda

noyes

Spouse smoked Cases* Controls*

never 213 568ever 218 598

StudyStockwell et al.(1992)Brownson et al.(1992)Table 7.5Association Between Risk of Lung Cancer in Lifetime Nonsmoking Females and Exposure to Spousal Smoking
289

Years exposed /Amount smoked by spousBy pack-years of exposureto spouses cases* co

0 267 5<15.0 146 315.1-39.9 92 140.0-79.9 80 180.0+ 24 2

MalesSpouse smoked: cases/co

1-10 cigs/day 5 / 1711+ cigs/day 5 / 2

FemalesSpouse smoked: cases/c

1-10 cigs/day 17 / 5011+ cigs/day 12 / 28

Adjusted OddsRatio (95% CI)for exposedAORc1.29 (1.04-1.60)1.18 (0.96-1.46)1.25 (0.92-1.71)1.19 (0.88-1.60)AORd1.01.60 (0.67-3.82)1.01.08 (0.60-1.94

Exposure StatusSpouse cases exposed/ controls exp/smoked total cases total controlsany type

tobacco 433/651 766/1,253cigarettes 366/648 691/1,253cigars 85/641 138/1,253pipes 86/640 158/1,253

MalesSpouse smoked: cases/controls*

no 28/79yes 11/19

FemalesSpouse smoked: cases/controls*

no 26/ 71yes 41/102

StudyFontham et al.(1994)Kabat et al.(1995)

Table 7.5 (Continued)

a Distribution of cases and controls was not presented; ORs adjusted for age, race, and education; ORs ar

of Stockwell et al. (1992).

b Adjusted for age, previous lung disease; ORs are from Table 2 of Brownson et al. (1992).c Adjusted for age, race, study area, education, fruits & vegetables & supplemental vitamin index, dietary c

family history of lung cancer, and employment in high-risk occupations; ORs are from Table 3 of Fontham e

d Adjusted for age, years of education, and type of hospital; ORs are from Table 4 of Kabat et al. (1995).* The number of cases and controls by intensity of exposure may not add up to the total numbers of subjec

missing values.
290

Smoking and Tobacco Control Monograph No. 10

Study Exposure Status No. of Lung Multivariate

Cancer Deaths RRa CI 

Cardenas et al. Among women

(1997) -- who never smoked 54 --

-- husband ever smoked 96 1.0 0.8-1.6

-- current smoker 44 1.2 0.8-1.8

-- former smoker 52 1.1 0.8-1.6

By cigarettes per day smoked by husbands

never 30 1.0 --

1 to 19 9 1.1 0.5-2.2

20 to 39 22 1.2 0.7-2.2

40+ 13 1.9 1.0-3.6

By years in marriage to smoker

0 30 1.0 --

1-17 13 1.5 0.8-2.9

18-29 14 1.5 0.8-2.8

30+ 17 1.1 0.6-2.1

By pack-years of exposure

0 30 1.0 --

1-16 10 1.0 0.5-2.1

17-35 16 1.5 0.8-2.7

36+ 18 1.5 0.8-2.6

Among men

-- who never smoked 79 1.0

-- wives ever smoked 18 1.1 0.6-1.8

-- current smoker 8 1.0 0.5-2.0

-- former smoker 10 1.1 0.6-2.2

a Adjusted for age, race, education, dietary intake of vegetables and total fat, occupation, and

history of lung disease.

Table 7.5b 

Risk of Lung Cancer in Nonsmoking Women and Men: 

a Cohort Analysis
291

Chapter 7

Study &

Study area

Janerich et al.

(1990)

New York

Stockwell et al.

(1992)

Central Florida

Brownson et al.

(1992)

Missouri

Fontham et al.

(1994)

Five U.S. areas

Sex

M, F

F

F

F

Cases/

Controls

57 68

82 94

52 29

210 301

357 877

74 289

323 802

108 364

304 669

299 556

76 161

548 1,079

148 444

95 291

146 485

Odds Ratio

(95% CI)

for exposed

1.0

1.09 (0.68-1.73)

2.07 (1.16-3.68)

1.6 (0.6-4.3)

1.2 (0.6-2.3)

1.7 (0.8-3.9)

1.6 (0.7-3.6)

1.1 (0.5-2.6)

2.4 (1.1-5.4)

1.0

0.7 (0.5-0.9)

1.0

0.8 (0.6-1.1)

1.00

0.83 (0.67-1.02)

1.00

0.86 (0.62-1.18)

1.00

0.99 (0.73-1.35)

0.88 (0.67-1.16)

ETS exposure

Smoker-years in 

childhood/adolescence

0

1-24

25+

(Distributions by exposure 

not presented)

mother

father

siblings

During childhood/adolescence

from parents and siblings 

(in yrs) <18 

18-21

22+

During childhood from parents

never

ever

During childhood from any

household members

never

ever

During childhood

 father

no

yes

mother

no

yes

Childhood household exposure 

(in yrs.) 0

1-17

18+

STUDIES CONDUCTED IN THE UNITED STATES

Table 7.6

Association Between Risk of Lung Cancer and ETS Exposure from Parents and Other

Household Members
292

Smoking and Tobacco Control Monograph No. 10

Study &

Study area

Kabat et al.

(1995)

Four U.S. cities

Wu et al. (1985)

Los Angeles

Kabat and

Wynder (1984)

U.S.A.

Sobue (1990)

Japan

Sex

M

F

M

F

F

M

F

F

Cases/

Controls

15 41

25 76

18 53

7 22

22 81

47 106

39 82

8 23

28 83

13 34

6 28

7 5

26 68

43 119

34 93

9 25

18 29

11 33

19 20

6 5

37 36

16 17

35 143

109 588

127 668

17 63

113 587

31 114

Odds Ratio

(95% CI)

for exposed

1.00

0.90 (0.43-1.89)

1.12 (0.46-2.70)

1.13 (0.34-3.75)

1.00

1.55 (0.95-2.79)

1.75 (0.91-3.35)

1.27 (0.43-3.78)

1.00

1.13 (0.53-2.45)

0.64 (0.19-2.13)

4.15 (1.34-12.87)

1.00

0.95 (0.53-1.67)

0.96 (0.50-1.84)

0.94 (0.34-2.63)

1.0

0.6 (0.2-1.7)

1.00

1.26 (0.33-4.83)*

1.00

0.92 (0.40-2.08)*

1.00

0.79 (0.52-1.21)

1.00

1.33 (0.74-2.37)

1.00

1.18 (0.76-1.84)

ETS exposure

Childhood exposure

no

yes

#smokers: 1

#smokers: 2+

no

yes

#smokers: 1

#smokers: 2+

Adulthood household exposure

no

yes

#smokers: 1

#smokers: 2+

no

yes

#smokers: 1

#smokers: 2+

Parents smoked

no

yes

Current ETS exposure at home

no

yes

no

yes

During childhood

father

no

yes

mother

no

yes

Other household member

no

yes

Table 7.6 (Continued)

STUDIES CONDUCTED IN ASIA
293

Chapter 7

Study &

Study area

Shimizu et al.

(1988)

Japan

Gao et al. 

(1987)

Shanghai

Koo et al. 

(1987)

Hong Kong

Wu-Williams 

et al. (1990a)

North China 

Pershagen et al.

(1987)

Sweden

Svensson et al.

(1989)

Sweden

Sex

F

F

F

F

F

F

Cases/

Controls

27 49 

48 68

13 20 

235 352

182 250

298 410

119 192

38 NAb

9 NA

19 98

12 71

19 98

3 5

Odds Ratio

(95% CI)

for exposed

1.1a

4.0 (p < 0.05)

3.2 (p < 0.05)

0.8

0.8

0.8

1.1 (0.7-1.7)

1.0

1.73 (0.6-6.4)

1.35 (0.6-5.0)

1.0

1.1 (0.8-1.4)*

1.0

0.9 (0.6-1.1)* 

1.0

1.0 (0.4-2.3)b

1.0

0.9 (0.4-2.3)

1.0

3.3 (0.5-18.8)

ETS exposure

During childhood and/or 

adult life (distribution of exposure presented for controls)

father

mother

father-in-law

mother-in-law

brother(s) or sister(s)

son(s) or daughter(s)

Lived with a smoker during 

childhood

# cohabitants who smoked 

(included spouse, parents, inlaws, children, or other cohabitants) 0

1

2+

father smoked

no

yes

mother smoked

no

yes 

parental smoking

neither parent smoked 

one or both parents smoked

father smoked

no

yes

mother smoked

no

yes

Table 7.6 (Continued)

STUDIES CONDUCTED IN EUROPE

* Calculated from data provided in the study publication

a Shimizu et al. reported p-values for findings, but did not report confidence intervals, and confidence

intervals could not be calculated from the reported information.

b The numbers presented are shown in Table 5 of Pershagen et al. (1987). Although the numbers

(and %) of cases and controls with at least one parent who smoked are shown in Table 2 of

Pershagen et al. (1987), we cannot reproduce the OR of 1.0 shown in their Table 5 if we impute the

number of controls by parental smoking habits.
mined, a series of detailed questions were asked on the type of tobacco

used, duration of exposure, intensity of exposure, and average number of

hours per day exposed. In the analyses restricted to lifetime nonsmokers,

adjustment included age and history of previous lung diseases. Although

initially examined, adjustment was not made for dietary beta-carotene and

dietary fat because these factors did not confound the associations in this

study.

In an analysis restricted to lifetime nonsmokers, there was no increase

in risk associated with “ever-exposed” to spousal ETS (adjusted OR = 1.0,

95% CI = 0.8-1.2) or exposure to fewer than 40 pack-years (see Table 7.5).

However, analysis of the highest category of exposure to spouses’ smoking

(greater than 40 pack-years) yielded an OR of 1.3 (95% CI = 1.0-1.7) (Table

7.5). Analyses by histologic type showed the largest increase in risk for

other/mixed-cell types and for small-cell carcinomas, but these results were

for lifetime nonsmokers and ex-smokers combined. Results were not presented separately for self-respondents and surrogate respondents. There was

no association between risk of lung cancer and ETS exposure from parents

(adjusted OR = 0.7, 95% CI = 0.5-0.9) or other household members (adjusted OR = 0.8, 95% CI = 0.6-1.1) during childhood (Table 7.6). These investigators also noted that there was no overall elevated lung-cancer risk in this

study associated with any ETS exposure in the workplace. However, lifetime nonsmokers showed an increase in risk at the highest quartile of workplace ETS exposure (OR = 1.2, 95% CI = 0.9-1.7) (Table 7.7). Although the

extent of exposure among the highest quartile of workplace was not specified, this OR is similar to the U.S. EPA report’s risk estimate for spousal

smoking obtained from the meta-analysis.

Fontham et al. (1991 and 1994) Fontham et al. (1991 and 1994) conducted a population-based case-control study of women in five geographic areas in the

U.S.—New Orleans, Louisiana; Atlanta, Georgia; Houston, Texas; Los

Angeles County, California; and San Francisco Bay Area, California—

referred to as the U.S. multicenter study (Table 7.4). Eligible cases included

women with microscopically confirmed primary carcinoma of the lung that

were diagnosed between December 1, 1986, and November 30, 1988,

among residents of Atlanta and Houston, and during 2 additional years—

1989 and 1990—among residents of New Orleans, Los Angeles County, and

San Francisco Bay Area. Additional eligibility criteria included age at diagnosis (20 to 79 years), language (English, Spanish, Chinese), history of previous cancer (none), and lifetime non-tobacco use (fewer than 100 cigarettes smoked and no use of any other form of tobacco for more than 5

months). One pathologist independently reviewed and confirmed histologic classification of 85 percent of the lung tumors in this study. 

A population-based control group was selected by random-digit dialing

and supplemented by random sampling from the U.S. Health Care

Financing Administration files for women 65 years and older. Controls

were frequency matched to cases on race and age in a two to one ratio of

controls to cases and met the same residence, language, and tobacco-use

criteria as cases. In-person interviews were completed for 665 of 800 incident lung cancer cases and 1,278 of 1,826 population controls; the respec294

Smoking and Tobacco Control Monograph No. 10
295

Chapter 7

tive response rate was 83 percent and 70 percent. The proportion of interviews conducted with self-respondents was 63 percent for lung cancer

patients and 100 percent for controls. The considerably higher percentage

of self-respondents in this study compared to the studies conducted by

Stockwell et al. (1992) and Brownson et al. (1992) may be due to the more

rapid identification of patients and thus contact of lung cancer cases in this

multicenter study.

The lifetime nonsmoking status of study subjects was confirmed using a

multistep procedure which included checking: 1) medical records, 2) with

physicians’ offices, 3) at the time of contact to set up the interview, and 4)

at the beginning of the interview. In addition, the subjects’ current nonsmoking status was corroborated by measurement of urinary cotinine levels.

Cotinine, a sensitive and specific biologic marker of recent tobacco exposure (Haley et al., 1983) was measured on 81 percent of self-respondent

cases and 83 percent of controls. Levels of urinary cotinine/creatinine

exceeding 100 ng/mg were found in 0.6 percent of cases and 2.3 percent of

controls, indicating a low percentage of misclassification of smokers as nonsmokers (Fontham et al., 1994). 

The in-person interviews followed an extensive structured questionnaire

designed to obtain information on household, occupational, and other

exposures to ETS during each subject’s lifetime, as well as other exposures

associated with lung cancer. Exposure to ETS was examined by source during childhood (father, mother, and other household members who lived in

the home for at least 6 months) and during adult life (spouse, other household members, occupational, and social exposures). 

Spousal smoking was associated with a statistically significant increased

risk of lung cancer; adjusted ORs of 1.29 (95% CI = 1.04-1.60) for ever

exposed to spouses’ smoking and 1.79 (95% CI = 0.99-3.25) (p for trend =

0.03) for 80 or more pack-years of exposure to spouses’ smoking were

observed (Table 7.5). Exposure to other sources of ETS during adult life was

also associated with an increased risk of lung cancer. Adjusted ORs of 1.39

(95% CI = 1.11-1.74) for ever exposed to ETS at the workplace and 1.86

(95% CI = 1.24-2.78) for 31 or more years of exposure at the workplace

were observed (Table 7.7). In addition, increased risks were associated with

ETS exposure in social settings (see section 7.2.4.3). When all sources of

ETS exposure during adult life were considered jointly as years of exposure,

women with 48 years or more of exposure showed an OR of 1.74 (95% CI =

1.14-2.65) compared with women with no ETS exposure (data not shown).

The increased risks associated with ETS exposure from spouses, at the workplace, and other social settings were observed for adenocarcinomas as well

as other histologic types of lung cancer. 

The findings for ETS exposure were similar when the analysis was

restricted to self-respondents only. For example, among self-respondents

only, an OR of 1.67 (95% CI = 1.03-2.70) was found for women with 48

years or more of exposure for all sources combined in adult life compared

with women with no exposure (the OR was 1.74 for all respondents combined—data not shown). These results for ETS exposure were observed after
296

Smoking and Tobacco Control Monograph No. 10

Study/

Year of study

Kabat & Wynder

(1984)

1961-1980

Garfinkel et al.

(1985)

1971-1981

Wu et al. (1985)

1981-1982

Janerich et al.

(1990)

1982-1984

Brownson et al.

(1992)

1986-1991

Stockwell et al.

(1992)

1987-1991

Fontham et al.

(1994)

1985-1991

Kabat et al.

(1995)

1983-1990

Questions on

ETS exposure

current or last job

males

females

#hrs/day exposed to smoke of

others at work: Past 5 years

Past 25 years

# years exposed at each job

# smokers at work (lifetime),

amount of time working with

smokers

current/most recent job,

exposed to other’s smoke

not described

# years exposed at each job

(lifetime years of exposure at

work)

By years of exposure

0

1-15

16-30

31+

four (4) jobs that lasted 

1 year or more

males

females

#unexposed/

#exposed

controls

14/11

22/31

262/52

135/118

31/31

NA

NA

NA

491/756

controls

491

450

223

83

52/65

64/85

OR (95% CI)

for exposed

3.3 (1.0-10.4)

0.7 (0.3-1.5)

0.88 (0.7-1.2)

0.93 (0.7-1.2)

1.3 (0.5-3.3)

no association

0.9 (0.8-1.04)

no association

overall

1.2 (0.9-1.7)a

no association

1.39 (1.1-1.7)b

1.00c

1.30 (1.01-1.67)

1.40 (1.04-1.88)

1.86 (1.24-2.78)b

1.02 (0.50-2.09)

1.15 (0.62-2.13)

#unexposed/

#exposed

cases

7/18

27/26

80/14

42/34

13/16

NA

NA

NA

224/385

cases

224

213

118

54

18/23

23/35

Table 7.7

Studies on ETS Exposure at the Workplace and Lung Cancer

Among Lifetime Nonsmoking Subjects

STUDIES IN THE UNITED STATES
adjustment for age, race, study area, education, intake of fruits and vegetables and use of supplemental vitamins, dietary cholesterol, family history of

lung cancer, and employment in high-risk occupations. 

In this study, ETS exposure during childhood/adolescence from father,

mother, or other household members was not associated with risk of lung

cancer. The OR for any childhood exposure to ETS (i.e., any household

member) was 0.89 (95% CI = 0.72-1.10) (Table 7.6) (data from table 4 of

Fontham et al. (1994)). However, there was some suggestion that the risk

associated with adult ETS exposure varied according to childhood ETS exposure. Significantly elevated risks associated with adult ETS exposures were

observed in women with and without childhood exposures. The elevations

in risk for women exposed during childhood were twice as high as for those

297

Chapter 7

Study/

Year of study

Lee et al.

(1986)

1977-1982

Kalandidi et al.

(1990)

1987-1989

Koo et al. 

(1984)

1981-1983

Shimizu et al.

(1988)

1982-1985

Wu-Williams 

et al. (1990)

1985-1987

Questions on

ETS exposure

timing of job not specified,

exposure as no, little, a lot

males

females

#smokers at work

current/last job:

any ETS exposure at work

(all jobs)

most recent/current job, any

smokers at work

exposure at each job

#unexposed/

#exposed

controls

40/57

113/47

40/78

NA

NA

301/301

OR (95% CI)

for exposed

1.61 (0.4-6.6)

0.63 (0.2-2.3)

1.39 (0.8-2.5)d

0.91 (0.15-5.37)

1.2

1.2 (0.9-1.6)e

1.06 (0.8-1.4)f

#unexposed/

#exposed

cases

3/7

12/3

24/65

NA

NA

187/228

STUDIES IN THE UNITED KINGDOM AND GREECE

STUDIES IN ASIA

a For highest quartile of exposure

b p < 0.01

c Trend, p = 0.001

d Calculated from entries on exposure at work in Table 2 of publication

e Adjusted for center, age, and education

f Adjusted for center, age, education, previous lung disease, and heating practices

Table 7.7 (Continued)
without childhood exposures. For example, at the highest level of ETS

exposure (48 adult smoke-years or more), the authors reported an adjusted

OR of 3.25 (95% CI = 1.42-7.46) among women reporting childhood exposures compared to 1.77 (95% CI = 0.98-3.19) for those reporting no childhood exposure (data not shown). 

Kabat et al. (1995) Kabat et al. (1995) conducted a hospital-based case-control study

of women and men between 1983 and 1990 as part of a long-standing

study of tobacco-related cancers. This study was carried out in six hospitals

located in four U.S. cities (New York City, New York; Chicago, Illinois;

Detroit, Michigan; and Philadelphia, Pennsylvania). Newly diagnosed, histologically confirmed cases of primary cancer of the lung were ascertained

in the collaborating hospitals. For each case enrolled, up to three control

patients who were lifetime nonsmokers matched on age (+5 years), sex,

race, hospital, and date of interview (within 2 months) were interviewed.

Control patients were admitted for various cancer and noncancer outcomes.

About 30 percent of the controls were diagnosed with cancer of the stomach/intestine, genitourinary tract, or lymphatic and hematopoietic system,

cancer sites which may be positively associated with tobacco use (see

Sections 7.3.3, 7.4.2, and 7.4.4). Thus, the ETS exposure among some controls may be higher than the general population, leading to a bias towards

the null. 

Subjects were considered lifetime nonsmokers if they had never consumed as much as one cigarette per day for a year, or had smoked fewer

than 365 cigarettes over their lifetime. In the structured interview, detailed

questions regarding the initiation of smoking early in life were included

and provided a basis for excluding ex-smokers who quit decades prior to

diagnosis but had smoked more than this minimum amount. The proportion of never-smokers among all lung cancer cases in this study was 3 percent in males and 8 percent in females.

All subjects were interviewed in person in the hospital. The questionnaire included a detailed history of exposure to ETS, during childhood and

adult life. Questions were also asked about adult ETS exposures inside and

outside the home (at work, in cars and other forms of transportation, and

in social settings). Interviews were conducted with 41 male and 69 female

never-smoking lung cancer cases and 117 male and 187 female never-smoking controls. 

There were no significant associations between spouses’ smoking and

risk of lung cancer in male (OR = 1.60, 95% CI = 0.67-3.82) or female (OR =

1.08, 95% CI = 0.60-1.94) subjects (Table 7.5). The calculated OR for lung

cancer in males and females combined was calculated to be 1.19 (95% CI =

0.76-1.87) in association with spousal ETS exposure. Wives’ smoking 11+

cigarettes/day was associated with a significant increased risk (OR = 7.48,

95% CI = 1.35-41.36) of lung cancer in men (Table 7.5). However, this result

was based on small numbers and thus unstable, and a similar result was not

observed in women associated with their husbands’ smoking. For males

and females combined, the calculated OR for having a spouse who smoked

11+ cigarettes/day was 1.57 (95% CI = 0.81-3.07). The OR for lung cancer

298

Smoking and Tobacco Control Monograph No. 10
associated with spouses who smoked in the bedroom was slightly higher

than that associated with any smoking by spouses, but this association was

not statistically significant in males (OR = 5.02, 95% CI = 0.72-35.01) or

females (OR = 1.09, 95% CI = 0.49-2.42) (data not shown)(the crude OR for

males and females combined was 1.20, 95% CI = 0.6-2.4).

Results for any household ETS exposure during adult life were similar to

the results described above for spousal ETS exposure; household exposure

was not significantly associated with risk of lung cancer (Table 7.6). The

exception was that, among males, there was a statistically significant

increased risk (OR = 4.15, 95% CI = 1.34-12.87) of lung cancer associated

with two or more smokers in the adult household, but this was not

observed among females (OR = 0.94, 95% CI = 0.34-2.63). 

Sources of ETS exposure outside of the home during adult life were also

evaluated, including ETS exposure at the workplace, in social situations,

and inside cars. Workplace ETS exposure was not associated with increased

risk of lung cancer in males or females (Table 7.7) in this study. There were

small increased risks for lung cancer associated with ETS exposures in social

situations and inside cars (see 7.2.4.3). The elevated risk associated with

ETS exposure inside cars was statistically significant in an analysis which

combined male and female subjects (see 7.2.5.3). 

Exposure to ETS during childhood was not associated with any

increased risk in males (OR = 0.90, 95% CI = 0.43-1.89), but in females it

was associated with an increased risk which was of borderline statistical significance (OR = 1.55, 95% CI = 0.95-2.79) (Table 7.6). There were no significant dose-response relationships between number of smokers in childhood

households and risk of lung cancer in male or female subjects in this study. 

Liu et al. (1993) present the results of a hospital-based

case-control study of indoor air pollution and lung

cancer in Guangzhou, China. Newly diagnosed cases

of primary lung cancer selected from eight major

hospitals over a one-year period were included.

Controls were individually matched to cases on age, sex, residential district,

and date of diagnosis or hospital admission. Six of the eight hospitals

(excluding the Tumor Hospital and Chest Hospital) which provided cases

also provided controls for this study. Patients with certain diseases were

excluded as eligible controls, but the diagnoses of controls included in the

study were not presented. Of the 327 lung cancer cases identified, a total of

224 male and 92 female incident lung cancer cases and an equal number of

individually matched male and female hospital controls were interviewed. 

The main objective of the study was to investigate the role of indoor air

pollution and ventilation on risk of lung cancer in smokers and nonsmokers. Questions on spouse’s smoking habits were also asked. An unmatched

analysis was conducted to examine the effect of ETS exposure among the 38

female cases and 69 female controls who had never smoked. Compared to

nonsmoking women who were not exposed to husbands’ smoking, women

exposed to 1-19 and 20+ cigarettes per day of husbands’ smoking showed

299

Chapter 7

7.2.2.2 Other Case-Control

Studies Providing Information

on ETS and Lung Cancer

Liu et al. (1993)
ORs of 0.7 and 2.9, respectively (p for trend = 0.03) after adjusting for education, occupation, and living area. Risk of lung cancer was increased in

association with living in a house with poor air circulation. The crude OR

comparing women ever exposed to those with no exposure to husbands’

smoking was 1.66 (95% CI = 0.73-3.78). No air circulation and lack of a

separate kitchen were other significant risk factors for lung cancer in this

study. There is no discussion of whether the analysis of ETS exposure in

nonsmokers considered air circulation or presence of a separate kitchen as

adjustment variables.

Schwartz et al. (1996) The main objective of this case-control study was to investigate the role of familial risk factors in the etiology of lung cancer. Cases

and controls in this study had previously participated in the Occupational

Cancer Incidence Surveillance Study (OCISS). OCISS subjects were identified among metropolitan Detroit area residents with specific cancers which

included lung cancers. Population controls (without cancers) selected by

random digit dialing were identified for the original OCISS study. For this

analysis, all lung cancer cases who did not smoke cigarettes, cigars, and/or

pipes (it was, however, never specified whether they were lifetime nonsmokers) were eligible. Controls represented a random sample, approximately one-third of all eligible nonsmoking controls, and they were frequency-matched to nonsmoking lung cancer cases by 5-year age group, sex,

race, and county of residence. The final eligible sample included 314 cases

and 345 controls, of whom 257 case and 277 control interviews were

obtained. Some 72 percent of the case and 64 percent of the control subjects were females.

Telephone interviews were conducted. Because of the high case fatality

associated with lung cancer, 83 percent of the case interviews had to be

conducted with proxies which included spouses, siblings, offspring, or parents. In contrast, 22 percent of the control interviews were completed with

proxies. After adjustment for age, race, and sex, exposure to ETS at home

was not a significant risk factor for lung cancer (OR = 1.1, 95% CI = 0.8-

1.60), while exposure to ETS at work was of borderline statistical significance (OR = 1.5, 95% CI = 1.0-2.2). However, it is unclear whether ETS

exposure at home included exposures during childhood and/or adult life. It

was also not specified whether ETS exposure at all jobs or the most current

or longest job was asked. Limitations of this study include the fact that

almost all the information on cases was obtained from proxy interviews

and that relevant details regarding ETS exposure variables were not

described. This study was not designed to investigate the role of ETS exposure in the etiology of lung cancer in nonsmokers.

Ko et al. (1997) This was a hospital-based case-control study conducted in

Kaohsiung, Taiwan, a heavily industrialized city. All eligible lung cancers

were identified during a 2-year period in a leading teaching hospital in this

study area. Of the 128 eligible female lung cancer patients identified, 117

were interviewed while they were in the hospital. Control women were

ophthalmic patients (n = 62) or women admitted for a health check (n =

55), and they were matched to cases on age and date of interview. The

study was designed to investigate various suspected risk factors for lung

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Smoking and Tobacco Control Monograph No. 10
cancer including active and passive smoking, previous lung diseases, cooking practices, and indoor environment. Questions on ETS exposure asked

about smoking habits of parents, husbands, cohabitants and coworkers.

There were 11 cases and 3 controls who were active smokers. The analysis

on ETS exposure was conducted among the 105 case-control pairs of nonsmokers. In matched analyses adjusted for socioeconomic status, residential area, and education, risk of lung cancer in nonsmoking women was not

associated with ETS exposure from parents (OR = 0.8; 95% CI = 0.4-1.6),

cohabitants (OR = 1.0; 95% CI = 0.4-2.3), or coworkers (OR = 1.1; 95% CI =

0.4-3.0), but there was a small nonsignificant increased risk associated with

ETS exposure from spouses (OR = 1.3; 95% CI = 0.7-2.5). It was not specified whether exposure from parents and other cohabitants covered exposures during both childhood and adult life. It was also not specified

whether exposure from coworkers covered all jobs or the last or longest job.

ETS exposure was one of several sources of indoor air pollution investigated

in this study. It is not clear whether information on extent (i.e., duration

or amount) of ETS exposure was obtained.

The analysis by Cardenas et al. (1997) utilized data

from the CPS-II, which enrolled approximately 1.2 million men and women in 1982. By December 1989,

91.2 percent (1,080,689) were still living, 8.6 percent

(101,519) had died, and the remainder had unknown vital status. Death

certificates were obtained for 96.8 percent of subjects known to have died.

Among never-smokers in this study, two analyses on ETS exposure and

risk of lung cancer were conducted. The main and more complete analysis

on long-term ETS exposure was based on information on active smoking

habits of spouses obtained directly from spouses who were linked to the

index never-smoker. With less than 2 percent of subjects excluded due to

missing data, a total of 150 lung-cancer deaths in 192,234 never-smoker

women and 97 lung-cancer deaths in 96,542 never-smoker men were available for this analysis. In approximately half of the never-smoker women,

information on amount smoked by husbands and years in marriage to husbands who smoked was also available (i.e., for 74 lung-cancer deaths in

92,222 never-smoker women). A second and less complete analysis was

based on self reporting of current ETS exposure at home, at work, or in

other areas. Thirteen percent of male to 30 percent of female subjects had

missing information in one of the three questions on sources of recent ETS

exposure. Based on the assumption that individuals with missing data on

one of the sources of ETS exposure had no exposure from that source, these

analyses included 246 lung cancer deaths in 281,536 never smoking women

and 116 lung cancer deaths in 110,687 never smoking men. The analyses

were conducted with adjustment for the main confounders which included

age, race, years of education, occupation, dietary intake of various fruits,

vegetables and fat, and history of previous lung diseases.

In the analyses based on spousal smoking habits (Table 7.5b), neversmoking women married to smokers showed a small increased risk of lung

cancer (RR = 1.20, 95% CI = 0.8-1.6); the risk was 1.2 (95% CI = 0.8-1.8)

301

Chapter 7

7.2.3 A U.S. Cohort Study

Published Since 1991

Cardenas et al. (1997)
associated with husbands who were current smokers and 1.1 (95% CI = 0.6-

1.6) for husbands who were former smokers. There was an increasing trend

of risk associated with number of cigarettes smoked by spouses; the ORs

were 1.0, 1.1, 1.2, and 1.9, respectively, for 0, 1-19, 20-39, and 40+ cigarettes smoked per day (p for trend = 0.03). Similarly, there was an increasing trend of risk with increasing pack-years smoked by spouse (p for trend =

0.10). There was, however, not a smooth trend of increasing risk with

increasing years of ETS exposure. The ORs were 1.0, 1.5, and 1.1, respectively, associated with 0, 1-17, 18-29, and 30+ years of exposure (p for trend

= 0.5). Based on fewer lung-cancer deaths in men and a lower prevalence

of men married to smokers, the risk of lung cancer among never smoking

men married to smokers was 1.1 (95% CI = 0.6-1.8); the risk was 1.0 (95%

CI = 0.5-2.0) associated with wives who were current smokers and 1.1 (95%

CI = 0.6-2.2) for wives who were former smokers.

Cardenas et al. (1997) reported that none of the self-reported current

ETS exposure measures (any exposure or total hours of exposure) was associated with increased lung cancer risk. The multivariate RRs among women

who reported 0, 1-2, 3-5, or 6+ hours of ETS per day in all settings were 1.0,

0.8, 0.7, and 1.1, respectively. The corresponding RRs in men were 1.0, 0.6,

1.0, and 1.3.

There are several notable advantages of this cohort study. Possible

selective recall bias and information bias with the use of surrogate respondents, concerns raised by some regarding case-control studies, are avoided.

Because the main analysis identified only married couples, this precluded

any bias introduced as a result of married and unmarried persons describing

ETS exposure differently. Moreover, this cohort analysis has an added

advantage compared to previous cohort studies in that a large number of

potential confounders were accounted for in the analysis and an association

with ETS exposure from spouses was present.

The main limitations of this study are the relatively small number of

lung cancer deaths available for analysis. In addition, information on

amount smoked by husbands and years of marriage to smokers was available on approximately half of the never-smoker women. These investigators calculated that approximately 1,000 expected cases are needed to

achieve 80 percent statistical power (assuming an RR of 1.2, alpha of 0.05,

2-sided, and an ETS exposure rate of 60 percent). A second limitation is

that spousal ETS exposure was based on the smoking habits of current

spouse and that information on ETS exposure from previous marriages or

from other household members was not available. Even for current spouses, information on amount smoked and duration of smoking was available

on only about half of the never-smokers in this study.

The results from the recent U.S. studies are compatible with

the pooled estimate of the U.S. EPA (1992) report, which

found a summary OR of 1.19 (90% CI = 1.04-1.35) for ever exposed to ETS

from spouses (for U.S. studies). Results from the largest population-based

study, the U.S. multicenter study (OR = 1.29, 95% CI = 1.04-1.60, for ever

exposed) (Fontham et al., 1994) were closest to the pooled estimate from

302

Smoking and Tobacco Control Monograph No. 10

7.2.4 ETS Exposure

from Spouses
the U.S. EPA report. Of the two other population-based studies, the association found in the Florida study (Stockwell et al., 1992) was stronger (OR =

1.6, 95% CI = 0.8-3.0; although it did not achieve statistical significance

except for the highest exposure category: OR = 2.4, 95% CI = 1.1-5.3), and

that from the Missouri study (Brownson et al., 1992) was weaker (overall OR

= 1.0, 95% CI = 0.8-1.2; for highest exposure category of spousal smoking,

OR = 1.3, 95% CI = 1.0-1.7) than the pooled estimate result. Although the

authors of the fourth study—the hospital-based case-control study (Kabat et

al., 1995)—reported their findings as unsupportive of an association

between ETS exposure and risk of lung cancer, the odds ratio were elevated

for males (OR = 1.60, 95% CI = 0.67-3.82) and females (OR = 1.08, 95%CI =

0.60-1.94), though not statistically significant, and the results of this small

study do not contradict an increased risk on the order of 20 percent. The

cohort study by Cardenas et al. (1997) also showed a small increased risk of

lung cancer (RR = 1.2, 95% CI = 0.8-1.6) associated with being married to a

smoker. In addition, positive increasing trends in risk of lung cancer in

nonsmokers were observed for increasing ETS exposure indices in all three

of the population-based studies (Table 7.5) and in the U.S. cohort study

(Table 7.5a). The concordance in these study results gives further credibility

to the finding of a causal association between spousal ETS exposure and risk

of lung cancer described in the U.S. EPA (1992) report. 

The sample sizes of the three population-based U.S. studies (Stockwell et

al., 1992; Brownson et al., 1992; Fontham et al., 1994) were considerably

larger than previously published case-control studies in the U.S. (Correa et

al., 1983; Buffler et al., 1984; Kabat and Wynder 1984; Dalager et al., 1986;

Wu et al., 1985; Garfinkel et al., 1985; Humble et al., 1987; Brownson et al.,

1987; Janerich et al., 1990). Spousal ETS exposure was not associated with a

significant increased risk of lung cancer in males and females in the Kabat

et al. (1995) study. However, this study was considerably smaller than the

other three U.S. studies published in the 1990s and had limited statistical

power to detect a significant association. The recent cohort study

(Cardenas et al., 1997) was limited by the relatively small number of lung

cancer deaths available for analysis.

Another important feature of the post-1991 studies is that they

addressed many of the criticisms (Mantel, 1983; Lee, 1986 and 1989;

Katzenstein, 1992) directed at previous studies of ETS exposure and lung

cancer. Although the extent to which these criticisms were addressed in

each of the four case-control studies varied, the concerns were addressed

collectively in these studies. Specifically, concerns regarding selection bias,

misclassification bias of smokers as lifetime nonsmokers, misclassification

of some non-lung cancers as lung cancers, misclassification of ETS exposure,

and the lack of adjustment for potential confounders were addressed.

Concerns regarding possible selective recall bias and information bias of

case-control studies are avoided in the cohort study by Cardenas et al.

(1997). Moreover, because the main analysis included only married couples

who reported their own smoking habits, misclassification of ETS exposure

due to reporting bias is also avoided.

303

Chapter 7
The three population-based studies were careful to minimize the possibility of selection and misclassification biases. Selection bias associated

with cases from selected hospitals is eliminated since, in all three population-based studies, lung cancer patients were identified from the cancer registries and hospitals covering a specific study area. The use of populationbased controls instead of other patients as controls is also advantageous,

since ETS exposure of patients with certain diagnoses may be higher and

not representative of the exposure distribution of the source population

from which cases were drawn. In addition, the U.S. multicenter study

(Fontham et al., 1991) examined the issue of differential recall between

lung cancer cases and controls by interviewing colon cancer patients as a

second control group during the first three years of the study. The findings

on ETS exposure were comparable when lung cancer patients were compared to population controls and to colon cancer controls, suggesting that

recall bias resulting from having a diagnosis of cancer could not explain the

observed association with ETS.

Another source of misclassification bias that is of concern (Wald et al.,

1986; Lee, 1989) pertains to the misclassification of smokers as nonsmokers.

In two of the four case-control studies (Fontham et al., 1994; Stockwell et

al., 1992), the definition of lifetime nonsmokers was limited to individuals

who had smoked fewer than 100 cigarettes and had no more than 6

months of tobacco use in their lifetime. In one study (Kabat et al., 1995),

subjects were considered lifetime nonsmokers if they had never consumed

as much as one cigarette per day for a year, or had smoked fewer than 365

cigarettes over their lifetime. Both the U.S. multicenter study (Fontham et

al., 1994) and the Florida study (Stockwell et al., 1992) used multiple

sources of information to verify the lifetime nonsmokers’ status. In addition, the U.S. multicenter study corroborated the subjects’ self-reported current nonsmoking status using the urinary cotinine level. These results

showed a very low percentage of cases (0.6 percent) and controls (2.3 percent) had levels of urinary cotinine exceeding 100 ng/mg, suggesting minimal misclassification of smokers as nonsmokers (Fontham et al., 1994).

Although the urinary cotinine/creatinine concentration only assesses current smoking (there are currently no biomarkers that allow assessment of

past tobacco exposure), these results provided an additional verification of

the current nonsmoking status. 

Misclassification of lung cancer is also minimized by the requirement of

microscopic diagnosis (Stockwell et al., 1992; Fontham et al., 1994; Kabat et

al., 1995) and an independent review of diagnostic material (Brownson et

al., 1992; Fontham et al., 1994). In the three population-based studies

with data by cell type (Stockwell et al., 1992; Brownson et al., 1992;

Fontham et al., 1994), adenocarcinoma of the lung was the predominant

cell type of lung cancer in nonsmoking women, accounting for over 60 percent of the lung tumors. 

Because of the high fatality rate of lung cancer, all three U.S. population-based studies interviewed surrogate respondents to obtain information

on a percentage of lung cancer cases who could not participate because

they were too ill or were deceased. In all three studies, controls were self304

Smoking and Tobacco Control Monograph No. 10
respondents. The percentage of lung cancer self-respondents was considerably higher for the U.S. multicenter study (63 percent) compared with the

other two U.S. studies (33 percent for the Florida and 34 percent for the

Missouri study). Since a surrogate’s knowledge of the ETS exposure of an

index subject is variable and dependent on their relationship and the exposure period of interest, it is likely that the quality of information on ETS

exposure is higher in studies in which a high percentage of interview is

conducted with self-respondents. On the other hand, the use of surrogate

respondents was avoided in the U.S. hospital-based study since all interviews were conducted with the lung cancer cases and hospital patient controls while the subjects were still in the hospital (Kabat et al., 1995).

Another criticism of previous studies of ETS exposure and lung cancer is

that a small increased risk associated with ETS exposure may be due to lack

of adjustment for potential confounding factors. In particular, it has been

suggested that nonsmokers living with smokers have lower dietary intakes

of specific micronutrients (Koo et al., 1988; Hebert and Kabat, 1990; Sidney

et al., 1989; Le Marchand et al., 1991; Matanoski et al., 1995), including

beta-carotene, which may be protective for lung cancer. However, there is

little evidence of confounding by dietary factors in the U.S. multicenter

study (Fontham et al., 1994) or in a study conducted in Greece (Kalandidi et

al., 1990). In fact, similar trends of increased risk of lung cancer associated

with increasing duration of exposure were observed at all levels of dietary

factors (including intake of fruits and vegetables, supplemental vitamin use,

and dietary cholesterol) (Fontham et al., 1994). Other factors including

employment in high-risk occupations (Fontham et al., 1994) and previous

lung diseases (Brownson et al., 1992; Wu et al., 1995) were examined, and

they did not confound the association of ETS exposure and lung cancer.

Thus, the recent large, well-conducted study (Fontham et al., 1994) assessed

all potential confounders that should be considered in evaluating the association of ETS with lung cancer in nonsmokers; the association was

observed with adjustment for these potential confounders.

Because of the importance of obtaining a comprehensive

measure of lifetime ETS exposure (Cummings et al.,

1989), all four U.S. case-control studies included questions to assess ETS

exposure at home (from spouses, parents, and other household members

during childhood and adult life), at the workplace and in other social settings. However, the exact questions asked and the level of detail obtained

varied in these studies. Only a subset of the studies published prior to 1991

included questions on ETS exposures from sources other than spouses. 

Table 7.6 summarizes the case-control studies conducted

since 1981 in the U.S. (n = 7) and outside of the U.S. (n = 7)

that included questions on ETS exposure from household

members other than spouses—represented mainly by exposure from parents during childhood—but also including other household

members during childhood and adult life. The study by Akiba et al. (1986),

which reported “no association,” was not included in Table 7.6 since no

information on the association or the distribution of subjects by exposure

status was provided. 

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7.2.5 Other Sources of

ETS Exposure

7.2.5.1 ETS Exposure

From Parents and Other

Household Members 

(Other Than Spouses)
Among the U.S. studies, the strongest evidence for an effect of parental

smoking is from studies conducted by Janerich et al. (1990) and Stockwell et

al. (1992). In the study by Janerich et al. (1990), exposure during childhood up to age 21 accounted for about one-third of the lifetime duration

(expressed in smoker-years) of ETS exposure. The highest level of childhood exposure (25 or more smoker-years) was associated with a statistically

significant increased risk (OR = 2.07, 95% CI = 1.16-3.68), although there

was no statistically significant elevated risk with 1-24 years of exposure. In

the study by Stockwell et al. (1992), exposure to ETS from mothers, fathers,

and siblings during childhood/adolescence was associated with a 10 to 70

percent increase in risk. Women who experienced 22 years or more of

exposure to ETS from all household members combined during

childhood/adolescence showed a significantly elevated risk of 2.4 (95% CI =

1.1-5.4) (Table 7.6). On the other hand, risk of lung cancer in nonsmokers

was not associated with ETS exposure during childhood in the U.S. multicenter study (Fontham et al., 1994), the Missouri study (Brownson et al.,

1992), the U.S. hospital-based study (Kabat et al., 1995), or a small study

conducted in Los Angeles County (Wu et al., 1985). However, in the U.S.

multicenter study, subjects who were exposed to ETS exposure during both

childhood and adult life showed the highest increase in risk of lung cancer

(Fontham et al., 1994). In a hospital-based study conducted in the 1970’s

(Kabat and Wynder, 1984) and a subsequent one conducted in the 1980’s

(Kabat et al., 1995), smoking by family members during adult life was not

associated with risk of lung cancer in nonsmoking males and females. 

In two studies conducted in Japan (Shimizu et al., 1988; Sobue, 1990),

an increased risk of lung cancer was associated with mothers’ smoking; the

result was statistically significant in one study (Shimuzu et al., 1988) but

not the other (Sobue, 1990). A significantly increased risk of lung cancer

was also associated with smoking by the father-in-law in one Japanese study

(Shimizu et al., 1988). In Shanghai, China (Gao et al., 1987) and in

Northern China (Wu-Williams et al., 1990), exposure to ETS during childhood did not differ significantly between lung cancer cases and controls.

In a study conducted in Hong Kong, risk of lung cancer in nonsmokers was

increased in households with smokers, although there was not a smooth

trend of increasing risks with increasing number of smokers in the household (Koo et al., 1987). In Sweden, no association between parents’ smoking and risk of lung cancer was reported in one study (Pershagen et al.,

1987), whereas in another study, a statistically nonsignificant 3-fold

increased risk of lung cancer was found for mothers’ smoking (Svensson et

al., 1989). 

Quality of information on parents’ smoking (or other household members) during childhood may be compromised in some studies, particularly

those in which this information is provided by surrogate respondents.

Although there is generally good agreement of responses on ETS exposure

when subjects themselves were asked on two different occasions whether

specific household members smoked, the level of agreement diminished on

quantitative aspects of smoking by household members (Pron et al., 1988;

Coultas et al., 1989; Brownson et al., 1993a). Studies which show high

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concordance on the reporting of exposure to ETS during childhood and parents’ smoking habits (Coultas et al., 1989; Brownson et al., 1993a) were

based on responses obtained from the subjects themselves. The degree of

agreement when the responses on smoking habits of the other household

members are provided by surrogate respondents is not known. The fact

that exposures from household members other than spouses are reported

less reliably may partially explain the inconsistent results regarding the

association between the risk of lung cancer and ETS exposure from these

household members (i.e., other than spouses); it may also explain the failure of most studies to observe stronger associations with exposure from

household members other than from spouses.

7.2.5.2 Workplace ETS Exposure Table 7.7 summarizes case-control studies which

included questions on ETS exposure at the workplace. Indicators of workplace ETS exposure varied (the actual questions asked were not provided).

In some studies, the indicators of workplace ETS exposure were limited to

the most recent job or the last job (Kabat and Wynder, 1984; Shimizu,

1988; Kalandidi et al., 1990; Brownson et al., 1992), at other specific times

(Garfinkel et al., 1985), or the timing of the question was not specified (Lee

et al., 1986; Stockwell et al., 1992). In one study, number of smokers at

work (lifetime) and amount of time working with smokers was assessed

(Janerich et al., 1990). In other studies, questions were asked regarding ETS

exposure at each workplace of at least 3 months (Koo et al., 1987) or the

last four jobs of at least 1 year duration (Kabat et al., 1995). In three other

studies, lifetime occupational history was obtained and exposure to ETS was

assessed for each job (Wu et al., 1985; Wu-Williams et al., 1990; Fontham et

al., 1994). 

Studies in which the assessment of workplace exposure to ETS was complete (covering all jobs) with considerable ETS exposure of subjects in the

studies are generally supportive of an association between workplace ETS

exposure and risk of lung cancer (Wu et al., 1985; Wu-Williams et al., 1990;

Fontham et al., 1994). In particular, results from the U.S. multicenter study

(Fontham et al., 1994) suggested a trend of increasing risks with increasing

duration of ETS exposure at the workplace. Compared to women who had

no ETS exposure at the workplace, women who reported exposure for 1-15,

16-30, and 30 or more years showed adjusted odds ratios of 1.30, 1.40, and

1.86, respectively (p for trend = 0.001) (Table 7.7). In a subsequent analysis

that selected workers only and adjusted for other adult ETS exposure

sources, the RRs associated with workplace exposure were modestly

enhanced (Reynolds et al., 1996). The overall odds ratios associated with

any reported workplace exposure increased from 1.39 in the earlier analysis

to 1.56 (95% CI = 1.21-2.02) and the corresponding point estimates for 1-

15, 16-30, and 30 or more years of exposure were likewise elevated; the

adjusted odds ratios were 1.46, 1.58, and 2.08, respectively. Occupational

exposure to carcinogens is an important confounder for lung cancer in

nonsmokers, and the U.S. multicenter study (Fontham et al., 1994) is the

only one which adjusted for such exposures.

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In addition to the incomplete assessment of exposure to ETS at the

workplace in some studies, respondents, particularly surrogate respondents,

may be less able to provide information on the subjects’ exposure to ETS at

the workplace. In a study in which a test-retest design was used to examine

the reliability of passive smoke histories reported in personal interviews,

self-respondents more reliably reported residential exposure than exposure

at work (Pron et al., 1988). This may be a particularly important problem

in studies in which the proportion of surrogate respondents was high

(Brownson et al., 1992; Stockwell et al., 1992).

Despite some of the above-mentioned difficulties in obtaining histories

of lifetime ETS exposure at the workplace, there is reason to believe this

source of ETS exposure also increases the risk of lung cancer, as does ETS

exposure from spouses. The workplace has been a major source of ETS

exposure outside the home (Cummings et al., 1989 and 1990; Emmons et

al., 1992; Siegel, 1993), although the relative importance of workplace ETS

exposure may be declining in California as the result of increasing restrictions on smoking in the workplace. In the International Agency for

Research on Cancer (IARC) ten-country, collaborative study which correlated urinary cotinine levels to self-reported recent exposure to ETS at home

(from spouses), in the workplace, and other social settings, Riboli et al.

(1990) found that exposure to ETS at the workplace was a significant predictor of cotinine levels, similar to ETS exposure from spouses.

7.2.5.3 ETS Exposure in Other Settings Two of the four U.S. case-control studies

published since 1991 (Fontham et al., 1994; Kabat et al., 1995) also asked

questions about ETS exposure in social settings (other than the workplace)

or in modes of transportation. In the U.S. multicenter study, increased

risks were associated with ETS exposure in social settings. Women who

were exposed for 1-15, 16-30, and >30 years at other social settings compared to no exposure showed adjusted ORs of 1.45, 1.59, and 1.54, respectively (p for trend = 0.002) (Table 6 of Fontham et al., 1994). In the U.S.

hospital-based study, associations with ETS exposure in social situations and

risk of lung cancer were not statistically significant in males (OR = 1.39,

95% CI = 0.67-2.86) or females (OR = 1.22, 95% CI = 0.69-2.15) (Table 2 of

Kabat et al. (1995)); the calculated OR for males and females combined was

1.26 (95% CI = 0.81-1.95). ETS exposure in cars was associated with nonsignificant increased risks of lung cancer in both males (OR = 1.55, 95% CI

= 0.63-3.78) and females (OR = 1.84, 95% CI = 0.96-3.53) in the Kabat et al.

(1995) study. Although the risks for males and females considered separately were not significantly different from controls, the calculated risk for

males and females combined was significantly elevated (OR = 1.73 (95% CI

= 1.03-2.92). No male cases were exposed to ETS in other modes of transportation, whereas there was a significant excess of female cases compared

to female controls who reported such exposures (OR = 5.17, 95% CI = 1.46-

18.24). ETS exposure in other modes of transportation was associated with

an OR of 2.23 (95% CI = 0.83-5.99) for lung cancer in males and females

combined in the Kabat et al. (1995) study.

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7.2.6 Summary Despite the compelling biologic plausibility of an effect of ETS

exposure on risk of lung cancer, detection of an effect has been difficult

because a small excess in risk is difficult to establish in a single epidemiologic study. The U.S. EPA (1992), NRC (1986), and Surgeon General (U.S.

DHHS, 1986) all undertook comprehensive reviews of the literature and

determined on the basis of the overall evidence that ETS exposure causes

lung cancer. Since the publication of the most recent authoritative review

of lung cancer and ETS exposure (U.S. EPA, 1992), three large U.S. population-based studies (Stockwell et al., 1992; Brownson et al., 1992; Fontham et

al., 1991 and 1994), a smaller hospital-based case-control study (Kabat et al.,

1995), and a cohort study (Cardenas et al., 1997) have been published. The

three population-based studies were designed to and have successfully

addressed many of the weaknesses for which the previous studies on ETS

and lung cancer have been criticized (i.e., small sample size, possible selection bias, possible misclassification biases, inadequate adjustment for potential confounders). Results from these studies and the cohort study are consistent with the conclusions of the U.S. EPA (1992), NRC (1986), and

Surgeon General (U.S. DHHS, 1986) reports. Each of the three populationbased studies shows a statistically significant increased risk of lung cancer

in nonsmokers associated with long term exposure to ETS as well as increasing risk with increasing ETS exposure. The smaller hospital-based study

lacked the statistical power to find the effect observed in the other studies.

The results of the cohort study, though not statistically significant, were

similar to the risk estimated by the U.S. EPA. Taken together, the recent

studies provide additional evidence that ETS exposure is causally associated

with lung cancer. The consistency of the findings in the five recent studies

and the meta-analysis result of the U.S. EPA indicate about a 20 percent

increased risk of lung cancer in nonsmokers. 

Active smoking is firmly established as a

causal factor for cancers of the lung, larynx,

oral cavity, esophagus, bladder, and nasal

sinus cavity; in addition, evidence exists

which suggests that smokers are at increased

risk for kidney and cervical cancer. As reviewed above, the role of ETS

exposure and risk of cancers in nonsmokers has been investigated mainly

for lung cancer (U.S. DHHS, 1986; NRC, 1986; U.S. EPA, 1992). There are

some data on the role of ETS for other cancer sites, including cancers of

nasal sinus cavity, cervix, and bladder (U.S. DHHS, 1982 and 1989; IARC,

1986).

Cancers of the nasal cavity and paranasal sinuses are

extremely rare, accounting for 0.2 percent of all invasive incident cancers and 1.4 percent of all newly diagnosed respiratory cancers in the U.S. Use of tobacco

products, various occupational exposures (e.g., wood dust), and history of

nasal polyps, have been implicated as risk factors for these tumors (Elwood

et al., 1981; Brinton et al., 1984; Hayes et al., 1987; Strader et al., 1988;

Zheng et al., 1992). Although the risk associated with any use of tobacco is

modest (OR about 1.5), up to a 5-fold increased risk has been observed with

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Chapter 7

7.3 ETS AND CANCER SITES

OTHER THAN LUNG THAT ARE

ASSOCIATED WITH ACTIVE

SMOKING: NASAL SINUS,

CERVICAL AND BLADDER

7.3.1 Nasal Sinus Cancer

7.3.1.1 Active Smoking and

Nasal Sinus Cancer
heavy smoking (Elwood et al., 1981). The evidence suggests that the effect

of smoking, particularly current or recent tobacco use, is stronger for squamous cell carcinoma than for other cell types (mainly adenocarcinomas) of

nasal sinus cancer (Elwood et al., 1981; Brinton et al., 1984; Hayes et al.,

1987; Strader et al., 1988; Zheng et al., 1992). The proportion of squamous

cell nasal sinus cancers included in the different studies may influence the

overall strength of the relationship between active smoking and all nasal

sinus cancers combined. Studies which did not find a significant association between active smoking and nasal sinus cancer were generally small

studies (i.e., <50 cases and controls) (Tola et al., 1980; Merler et al., 1986), or

had included few squamous cell carcinomas of the nasal sinus. For example, the study by Merler et al. (1986) included less than 20 percent squamous cell carcinomas compared to at least 40 percent of this cell type in

other studies finding a positive association with smoking (Elwood et al.,

1981; Brinton et al., 1984; Hayes et al., 1987; Strader et al., 1988; Tola et al.,

1980; Zheng et al., 1992).

7.3.1.2 ETS and Nasal Sinus Cancer The role of ETS exposure in the etiology of

nasal sinus cancer in nonsmokers has been investigated in one cohort and

two case-control studies (Table 7.8). 

Hirayama (1983 and 1984) Using data from a Japanese prospective study (see Section

7.1 for detailed description), Hirayama (1983 and 1984) reported an

increased risk of para-nasal sinus cancer (based on 28 nasal sinus cancer

deaths) among nonsmoking women exposed to husbands’ smoking.

Relative risks increased with amount husbands smoked: compared to

women married to nonsmokers, the RR was 1.7 (95% CI = 0.7-4.2), 2.0

(95% CI = 0.6-6.3), and 2.6 (95% CI = 1.0-6.3, p ≤ 0.05), for women whose

husbands smoked 1-14, 15-19, and 20+ cigarettes per day respectively, when

husbands’ age and occupation were adjusted for. The dose-dependent

increase in risk was statistically significant (p < 0.03). Active smoking was

not associated with nasal sinus cancer in this study; the OR was 0.9 (90%

CI = 0.5-1.4) for males and females combined (Hirayama, 1990). Cell type

distribution of nasal sinus cancer in nonsmokers and smokers was not available in this Japanese cohort study.

Fukuda and Shibata (1988 and 1990) The second study was conducted by Fukuda

and Shibata (1988 and 1990) in Japan using a case-control study design.

The 1988 report presented preliminary findings, and the 1990 report

included results on 169 (125 men and 44 women) squamous cell maxillary

sinus cancer cases and 338 controls (250 men and 88 women). Controls

were selected from the general population. All subjects were interviewed

directly. Nine of 125 male cases and 48 of 250 male controls had never

smoked. Active smoking was a significant risk factor in men; the RR was

4.6 for smoking >39 cigarettes per day compared to nonsmokers. Based on

a small number of nonsmoking men, exposure to ETS was associated with a

small, nonsignificant increased risk of nasal cancer. Most of the female

cases and controls in this study were nonsmokers (35 of 44 cases and 74 of

88 controls had never smoked). Active smoking was associated with a nonsignificant increased risk of nasal cancer in women. Among nonsmoking

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women, domestic exposure to ETS, represented by the number of smokers

in the household, was a significant risk factor. Compared to nonsmoking

women with no reported ETS exposure, nonsmoking women who reported

one, and two or more smokers in the household showed RRs of 1.4 and 5.7,

respectively (95% CIs = 0.6-1.5 and 1.7-19.4; p for trend = 0.02). The OR

associated with any passive smoke exposure (i.e., none versus any exposure)

is 1.96 (95% CI = 0.8-4.5). Information on duration or intensity of ETS

exposure was not reported. The effect associated with passive smoking persisted with adjustment for other risk factors including sinusitis and/or

polyps, nasal trauma, and woodworking. 

Zheng et al. (1993) The third study was a case-control analysis of cancer of the nasal

cavity and sinuses among white men in the U.S. using data from the 1986

National Mortality Followback Survey (Zheng et al., 1993). The study

included a total of 147 cases (76 maxillary sinus, 11 nasal cavity, 4 auditory

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Chapter 7

Studies Exposure to Relative Risk 

Passive Smoking (95% CI)

Cohort Studies

Hirayama (1984) Spouse’s smoking

in cig/day:

No (5)a 1.0

Ex-smoker or Smokers

1-14 (9) 1.7 (0.7-4.2)

15-19 (4) 2.0 (0.6-6.3)

20+ (10) 2.6 (1.0-6.3)

Case-Control Studies

Fukuda and # Smokers in household

Shibata (1990) 0 (11/35)b 1.0

1 (15/34) 1.4 (0.6-3.5)

2+ (9/5) 5.7c (1.7-19.4)

1+ (24/39) 2.0 (0.8-4.5)

Zheng et al. (1993) Ever exposedd

No 1.0

Yes 3.0 (1.0-8.9)

Table 7.8

Association Between Passive Smoke Exposure and Risk of Nasal Sinus Cancer

in Nonsmokers

a Number of nasal sinus cancer deaths.

b Number of cases/controls.

c p for trend = 0.02.

d Number of cases/controls by exposure category was not presented.
and middle ear, 56 other accessory sinuses cancer) and 449 controls who

died of other causes. All information was obtained from a surrogate who

responded to a mailed questionnaire. There was an increased risk of nasal

cancer among cigarette smokers, with a nearly 2-fold increased risk among

heavy or long-term smokers for all nasal cancer sites. Compared to nonsmokers, heavy smokers showed an OR of 2.7 (95% CI = 1.2-6.4) for maxillary sinus cancers and an OR of 1.3 for other nasal cancer (95% CI = 0.5-

3.3). Twenty-eight cases and 99 controls had never smoked. Among nonsmokers, more cases than controls had a wife who smoked cigarettes (OR =

3.0, 95% CI = 1.0-8.9, p ≤ 0.05), but the authors stated there was not a

smooth trend of increasing risks as the number of cigarettes smoked by the

spouse increased (data on dose-response were not presented). The 3-fold

risk associated with having a wife who smoked is somewhat surprising since

more than half (15 of 28) of the tumors in nonsmokers were other nasal

sinus cancer and this subgroup was less strongly associated with active

smoking. However, the histologic cell type of nasal sinus cancer among

smokers and nonsmokers was not available in this study, making it difficult

to make direct comparisons of findings in smokers and nonsmokers. 

7.3.1.3 Summary Existing studies consistently show a significant positive association between exposure to ETS and nasal sinus cancer in nonsmokers, presenting strong evidence that ETS exposure increases the risk of nasal sinus

cancers in nonsmoking adults. The results have been observed in studies in

white American males and Japanese females, in cohort and case-control

study designs, and with some adjustment for possible confounders. The

risks associated with ETS exposure ranged from 1.7 to 3.0. 

Future studies need to confirm the magnitude of risk associated with

ETS exposure, to characterize the risk by the source of ETS exposure (i.e.,

spouse, other household members, coworkers) and by timing of ETS exposure (current versus past exposure), and to establish the dose-response relationship. It is also important that future studies examine the association

between ETS and nasal sinus cancer by histologic type and subsite of nasal

sinus cancers, and the role of other potential confounders in the association. Studies designed to investigate the mechanism(s) of action of active

smoking and ETS exposure will help to elucidate their respective roles in

the development of nasal sinus cancer. 

Numerous epidemiologic studies conducted in different

populations of varying age groups exhibiting different

degrees of cervical lesions have provided supportive evidence that women who smoke cigarettes are more likely

to develop cervical cancer than women who do not (Winkelstein, 1990).

The statistical association between active smoking and cervical cancer is

reduced with adjustment for sexual activity variables (e.g., number of partners, age at first intercourse) or infection with human papilloma virus

(HPV), which has been accepted as the sexually transmitted etiological factor in cervical cancer (Brinton, 1990; Schiffman et al., 1993; Munoz et al.,

1994; zur Hausen, 1986). However, an association between smoking and

cervical cancer/intraepithelial neoplasia (CIN) has been found in case-con312

Smoking and Tobacco Control Monograph No. 10

7.3.2 Cervical Cancer

7.3.2.1 Active Smoking and

Cervical Cancer
trol studies that have been able to control for these behavioral risk factors

(Buckley et al., 1981; Hellberg et al., 1983; Brinton et al., 1986; Clarke et al.,

1982; La Vecchia et al., 1986; Becker et al., 1994). 

In most studies, the excess risk of cervical cancer for smokers is about 2-

fold, with the highest risks generally observed for heavy or current smokers,

suggesting that tobacco smoke may have a late-stage effect on cervical cancer development. The data also suggest that tobacco smoke may be a cofactor in the development of particularly high-grade CIN (Brinton and Hoover,

1992; Schiffman et al., 1993) by acting with or enhancing other infectious

agents, such as cervical HPV (zur Hausen, 1986; Burger et al., 1993) in the

promotion of cervical neoplasia. A possible mode of action of tobacco

smoke is to compromise immune function (Barton et al., 1988). 

In addition to the epidemiological evidence, an association between

smoking and cervical cancer is biologically plausible since carcinogens in

tobacco smoke can be absorbed in the lung and transported to distant sites

by the blood. Tobacco constituents, including cotinine and nicotine, have

been detected in the cervical mucus of smokers (see below). Higher levels

of DNA adducts in cervical biopsies of smokers compared to nonsmokers

have also been reported (Simons, 1994, see below). Among women with

cervical dysplasia, higher levels of mutagenicity in the cervical mucus of

smokers compared to nonsmokers have been found (Holly et al., 1986),

although this result has not been observed in studies of women without

cervical dysplasia (Schiffman et al., 1987; Holly et al., 1993). 

The relationship between ETS exposure and cervical cancer was investigated in one cohort and three case-control

studies (Table 7.9). 

As part of the Japanese cohort study, Hirayama (1981)

presented results on risk of cervical cancer in women by husbands’ smoking

habits. Based on 250 cervical cancer deaths in nonsmokers, the RRs were

1.15, and 1.14 for women whose husbands were ex-smokers or smoked 1-19

cigarettes/day, and >20 cigarettes/day, respectively, compared to women

whose husbands were nonsmokers (p value for trend = 0.25). In the same

study, women who ever smoked showed a high risk of cervical cancer compared to nonsmokers (RR = 1.6, 90% CI = 1.3-1.9), and there was some suggestion of increasing risks with increasing amounts smoked (the RRs associated with smoking 1-9, 10-19, and 20+ cigarettes/day were 1.7 (90% CI =

1.3-2.2), 1.3 (90% CI = 1.0-1.8) and 2.4 (90% CI = 1.4-3.9), respectively

(Hirayama, 1990)). The findings on active smoking and passive smoking

were not adjusted for potential confounders including subjects’ or husbands’ sexual activity. 

Sandler (1985a) A case-control study which provided some data on the role of ETS

exposure and risk of cervical cancer in nonsmokers (see Section 7.1.1 for

details) was a study on childhood and adult life ETS exposure and risk of

various cancer outcomes (Sandler, 1985a). Because this study included different cancer outcomes, information typically obtained in studies of a specific cancer site (e.g., sexual activity in studies of cervical cancer) was not

313

Chapter 7

7.3.2.2 ETS Exposure and

Cervical Cancer

Hirayama (1981)
314

# Cases/# Controls Cervical Cytology Passive Smo

Study (among cases) Active Smoking (Among Nev

Adj. ORa 

Hirayama Total number of Ever smoked 1.6 (1.3-1.9) NS (1981, 1990) cervical cancer 1-9 cigarettes/day 1.7 (1.3-2.3) Ex/1-19/day 

deaths was 589; 10-19 1.3 (1.0-1.8) ≥20/day number of cervical 20+ 2.4 (1.4-3.9) cancers in never smokers was 250 Sandler et al. 56 cervical cases Exposed 

(1985a & b) among nonsmokers to Spouse’s 

-data on nonsmoking smokingcontrols not presented(there were a total of Mother 

330 female controls) smoking 

Father smoking 

CA/CO Adj. ORd Hrs/daye 

Slattery et al. 266 cases/408 Never 81/305 1.0 None 

(1989) controls (cases: Ex-smoker 37/48 1.4 (0.8-2.5) 0.1-0.9 

78% carcinoma Current 1.0-2.9 in situ, 22% smoker 148/55 3.4 (2.1-5.6) ≥3.0 

invasive cancer)

Table 7.9Relationship Between Active and Passive Smoke Exposure and Risk of Cervical Cancer
315

# Cases/# ControlsCervical Cytology Passive Smo

Study (among cases) Active Smoking (Among Nev

At Home

CA/CO Adj. ORf Yrs Exposure 

Coker et al. 103 cases/268 Never 37/170 1.0 Not exposed (1992) controls (All Ever smoked 66/96 1.7 (0.9-3.3) <17 yrs 

biopsy-confirmed Currentcervical smoker 66/49 3.4 (1.7-7.0) ≥18 yrs 

intraepithelialneoplasia,class II or III)

At WorkYrs Exposure 

Not exposed 1-4 yrs ≥5 yrs 

Table 7.9 (Continued)a 90% CI.b p value was 0.25.c Number of cases and controls was calculated from Table 4 of Sandler et al., 1985e.d Adjusted for age, church attendance, education, and number of sexual partners of the women.e Number of hours of exposure per day inside and outside of the home.f Adjusted for age, years of education, race, number of pap smears, number of partners, and genital warts.

Abbreviations: NA = not available, CA/CO = cases/controls, OR = odds ratio.
316

Smoking and Tobacco Control Monograph No. 10

collected. There were a total of 518 cancer patients; 101 had cervical cancers, of which 56 occurred in women who had never smoked. The 56 nonsmokers with cervical cancer were compared to 235 nonsmoking control

women. Spouses’ smoking habits were associated with an increased risk of

cervical cancer in nonsmokers (OR = 2.1, 95% CI = 1.2-3.9) after adjustment

for age, race, education, and smoking habits of parents. In the same study,

husbands’ smoking also increased risk of cervical cancer in women who

were smokers (OR = 2.0, 95% CI = 0.9-4.1); the effect was observed after

adjustment for the above-mentioned variables as well as personal smoking

habits of women. Sandler et al. (1985b) also examined the association

between parental smoking during childhood and risk of cervical cancer.

Maternal smoking was not associated with risk of cervical cancer (OR =

0.66, 95% CI = 0.19-2.29) whereas paternal smoking was associated with a

statistically nonsignificant increased risk (OR = 1.67, 95% CI = 0.81-3.45).

The difference in results for mothers’ versus fathers’ smoking is likely due

to chance; among controls the prevalence of mothers who smoked was low

(11 percent) compared to fathers who smoked (43 percent). 

Slattery et al. (1989) A second case-control study on this subject was designed to

investigate the role of active smoking and passive smoking in the etiology

of cervical cancer. This study included 266 women with cervical cancer and

408 population controls, selected by random-digit dialing in Utah (Slattery

et al., 1989). Eighty-one cases and 305 controls had never smoked. Women

were asked whether they were exposed to “a lot, some, a little, or no”

tobacco smoke inside or outside their homes and the number of hours of

exposure per day, during the 5 years before interview. Among nonsmokers,

ETS exposure inside and outside of the home was associated with a significantly increased risk with adjustment for potential confounders which

included age, education, church attendance, and number of sexual partners

of the woman. A 3-fold increased risk (OR = 3.4, 95% CI = 1.2-9.5) was

observed for three or more hours of exposure per day. The increased risks

associated with ETS exposure among nonsmoking women were comparable

to the risks associated with active smoking in this study (Table 7.5).

Although specific information on HPV infection and partners’ sexual activity was not available, the effect of active smoking was strongest among

women who had a few (none to one) sexual partners (OR = 14.2, 95% CI =

9.2-38.9) and weakest for women with four or more partners (the highest

category of partners in this study, OR = 2.3, 95% CI = 1.4-3.9). The authors

interpreted this finding to suggest that cigarette smoking, and presumably

ETS exposure, as risk factors for cervical cancer may be more important

among women who have not experienced other major risk factors for this

cancer (i.e., HPV infection). 

Coker et al. (1992) Another case-control study which was designed to examine the

role of active and passive smoking included 103 CIN cases (40 percent CIN

II, 60 percent CIN III) and 268 controls; 37 CIN cases and 170 controls had

never smoked (Coker et al., 1992) (Table 7.9). All subjects had attended a

family practice clinic, and controls were women with normal cervical cytology at enrollment. Subjects were asked about tobacco smoke exposure at

the workplace and whether they had ever lived with a smoker who had
smoked for at least 1 year. The total number of years of exposure and the

relationship of the smoker to the index subject were also asked. For nonsmokers, after adjusting for potential confounders, there was no significant

or consistent association between ETS exposure at work or at home and risk

of CIN. Analysis by source of ETS exposure showed no association with

parents’ smoking (OR = 0.4, 95% CI = 0.1-1.2), a positive association with

husbands’ smoking (OR = 1.5, 95% CI = 0.3-6.2) or others’ smoking (OR =

1.8, 95% CI = 0.4-8.4) after adjustment for age, education, race, number of

Pap smears, number of partners, and genital warts. The crude OR was calculated for any smoking by husbands (i.e., combine smoking of husband

only and of parent) is 2.2 (95% CI = 0.9-5.7); the crude OR for any parents’

smoking (i.e., combine smoking of parents only and of parent and husband) is 0.9 (95% CI = 0.4-2.1) (calculated based on Table 5 of Coker et al.,

1992). In this study, active smoking was a risk factor irrespective of HPV

status; its effect was stronger among women classified as HPV-negative than

those classified as HPV-positive. 

Additional epidemiological information on cervical cancer Data from several other studies on cervical cancer show that husbands of women with cervical cancer

are more likely to be smokers than husbands of control women, although

the effect of husband’s smoking generally diminished with adjustment for a

woman’s smoking. In a study conducted by Buckley et al. (1981), husbands’ smoking was associated with an increased risk even after adjustment

for wives’ smoking habits although its effect diminished. There were too

few nonsmoking women to evaluate the role of husbands’ smoking in this

subgroup. In a study by Hellberg et al. (1983 and 1986), the effect of husbands’ smoking diminished and was no longer statistically significant after

adjustment for wives’ smoking habits, whereas the effect of wives’ smoking

persisted with adjustment for husbands’ smoking. There was, however, a

statistically nonsignificant excess of husbands who smoked among nonsmoking wives (Hellberg et al., 1986). In a third study, Zunzunegui et al.

(1986) reported an excess of husbands who smoked. Although this excess

risk was not adjusted for wives’ smoking habits, the authors argued that

there was a deficit of smokers among wives and thus wives’ smoking is an

unlikely explanation for the finding on husbands’ smoking. 

Two case-control studies of cervical cancer, one conducted in Spain, a

low risk area (Bosch et al., 1996) and one conducted in Cali, Columbia, a

high risk area (Munoz et al., 1996) offered some additional information on

the role of husbands’ smoking in the etiology of wives’ risk of cervical cancer. The study in Spain included 306 cases and 327 controls, while the

study in Cali included 210 cases and 262 controls. Prevalence of active

smoking among cervical cancer cases and controls was not presented in

either study. In the study conducted in Spain, in all women, after adjustment for the woman’s own active smoking habits, there was a significant

trend of increasing risk in association with spouse’s smoking. The ORs for

cervical cancer were 1.0, 1.8, 2.1, and 2.5 associated with no, 0.1-3.2, 13.3-

26.1, ≥26.2 pack-years of spouse’s smoking (Bosch et al., 1996). In the Cali

study, although husbands’ smoking was also associated with an increased

risk of cervical cancer in wives, this result was not statistically significant

317

Chapter 7
after adjustment for wives’ smoking habits (Munoz et al., 1996). Both studies are limited in that they did not present results on nonsmoker controls

and nonsmoker cervical cancer patients. 

In addition to questionnaire-based data, several small studies

have been conducted to determine whether there are measurable levels of tobacco-smoke constituents in cervical epithelial cells of

nonsmokers. Detectable levels of nicotine and cotinine were found in the

cervical mucus of nonsmokers; the levels ranged from <1 to about 6 percent

of those of active smokers (Sasson et al., 1985; Hellberg et al., 1988; Jones et

al., 1991; McCann et al., 1992, see Table 7.10). In three of these studies

(Hellberg et al., 1988; Jones et al., 1991; McCann et al., 1992), data were presented separately for nonsmokers exposed to ETS and those with no reported exposure to ETS. In two studies (Hellberg et al., 1988; McCann et al.,

1992), levels of nicotine/cotinine in cervical mucus were not distinguishable between nonsmokers with and without ETS exposure, whereas in a

third study, higher levels of nicotine were found in women with ETS exposure compared to those with no reported exposure (Jones et al., 1991) (Table

7.10). None of the studies on cervical cancer has examined risk of cancer

in relation to presence or absence of nicotine/cotinine in the cervical

mucus, but this evidence from cross-sectional clinical studies supports the

hypothesis that cervical exposure to tobacco constituents occurs from

exposure to tobacco smoke.

The presence of carcinogen-DNA adducts in human tissues has been

used as evidence of smoking-induced DNA damage. Using 32P-postlabelling

techniques, a linear relationship between cigarette consumption and levels

of aromatic DNA adducts has been demonstrated in human bronchial

epithelium (Phillips et al., 1990a) and other tobacco-related sites, including

the cervical epithelium (Phillips et al., 1990b; Cuzick et al., 1990). Recently,

Simons (1993) measured levels of DNA adducts in cervical biopsies of 39

women admitted for hysterectomy for benign disease or colposcopy. In this

group, 18 were smokers (11 current, 4 ex-smokers who stopped in the last 6

months, 3 longer-term ex-smokers) and 21 had never smoked. Of the nonsmokers, 75 percent (n = 16) reported exposure to ETS at work or in the

home. Urinary cotinine/creatinine levels were also available on these subjects; a ratio of 0.06 or greater was used to indicate active smoking in the

previous 24-48 hours. 

The median DNA adduct level (per 108 nucleotides) was 4.62 in selfreported smokers, which was significantly higher than that in self-reported

nonsmokers (3.47). Seven self-reported nonsmokers showed a urinary cotinine/creatinine ratio of 0.06 or greater, and they were reclassified as smokers (n = 25). The median DNA adduct level in self-reported and reclassified

smokers was 4.45 compared to 3.52 (p = 0.07) in confirmed nonsmokers

(i.e., urinary cotinine/creatinine <0.06). The presence of adducts in cervical

epithelium and the correlation with smoking habits strongly suggest that

the adducts are a consequence of exposure to tobacco constituents. These

results provide direct biochemical evidence that potentially carcinogenic

agents may affect the DNA of cervical epithelial cells. It is notable that all

318

Smoking and Tobacco Control Monograph No. 10

7.3.2.3 Biomarkers of

Cervical ETS Exposure
the women in the study had detectable proportions of DNA adducts regardless of their smoking status. The relatively high DNA adduct levels in nonsmokers may reflect exposure to ETS, reported by 75 percent of nonsmokers

in this study. Future studies on DNA adduct levels by self-reported exposure to ETS in nonsmokers are needed to confirm these suggestive results. 

319

Chapter 7

Study Levels (ng/ml) of

Nicotine Cotinine

Sasson et al., 1985a

Smokers (n = 10) 740 316

Nonsmokers (n = 8) 16 3

Hellberg et al., 1988a

Smokers (n = 17) 1,056 1,061

Nonsmokers with ETS exposure

Yesb (n = 4) 20 51

No (n = 14) 43 78

Levels of Nicotine (ng/ml)

Mean Median Range

Jones et al., 1991c

Smokers (n = 31) 34.3 11.8 2.8-383.4

Nonsmokers with

ETS exposured

at home (n = 32) 0.1 0.8 <0.2-8.2

outside of home (n = 42) NAf 0.4 <0.2-5.2

none (n = 70) NA 0.2 <0.2-3.8

McCann et al., 1992c

Smokers (n = 25) 107.2 56 4-358

Nonsmokers with

ETS exposured

Yese (n = 12) 3.6 3.5 <0.2-12

No (n = 12) 3.9 3.5g <0.2-14

Table 7.10

Nicotine and Cotinine Measured in the Cervical Mucus of Smokers, Passive 

Smokers and Nonsmokers

a Cervical mucus collected using aspiration methods.

b Exposed at home or work, time of passive smoke exposure relative to specimen collection

not specified.

c Cervical mucus collected using cervical flush techniques.

d Passive smoke exposure in the last 24 hours.

e Nonsmokers with ETS exposure at home or at work.

f NA = not available.

g Excluded one outlier who was usually exposed to passive smoking several hours/day, but

had no exposure within the last 24 hours.
7.3.2.4 Summary There is supportive evidence from epidemiological and biochemical studies implicating a role for ETS exposure in the etiology of cervical

cancer in nonsmokers. A positive, but nonsignificant association was

reported in one cohort study (Hirayama, 1981) and a significant, positive

association was observed in two (Sandler et al., 1985a; Slattery et al., 1989)

of three case-control studies. In the third case-control study, conducted by

Coker et al. (1992), spousal ETS was associated with an increased the risk of

cervical cancer/intraepithelial neoplasia in nonsmokers although the result

was of borderline statistical significance. Any exposure to ETS (i.e., parents

and spouses combined) was not a risk factor in the study by Coker et al.

(1992); this finding is not too surprising since risk of cervical cancer appears

to be most affected by current tobacco use. In one of three biochemical

studies, levels of nicotine in the cervical mucus of nonsmokers exposed to

ETS were reported to be higher than levels in those with no exposure.

Demonstration of detectable levels of nicotine and cotinine in cervical

mucus of nonsmokers suggests that constituents of cigarette smoke may

reach more distant sites such as the cervix and play a direct mutagenic role

in the etiology of cervical cancer. In addition, the presence of DNA adduct

levels in the cervical epithelium of nonsmokers supports the hypothesis

that carcinogenic constituents of tobacco smoke may adversely effect the

cervical epithelium. 

Little is known about the transport of nicotine and cotinine throughout

the body and about its metabolism in distant organ sites. Mutagenicity of

semen due to smoking is plausible, and direct cervical contact with semen

of smoking partners may represent another source of exposure to tobacco

constituents. It is important to confirm these findings, to determine the

importance of recent exposure to ETS (i.e., within recent 5 years) versus lifetime exposure to ETS, and to determine the effect of exposure from spouses

versus other household members or coworkers. It is also important to evaluate the effect of passive smoking by stage of cervical cancer (e.g., invasive

and pre-invasive), and by history of potential confounding factors, including HPV infection. Measurement of levels of cotinine/nicotine in cervical

mucus as well as DNA adducts in cervical epithelium of nonsmokers will

complement the epidemiological findings from questionnaires, although

such measurements may not be available for cervical cancer cases who are

enrolled in studies after surgical treatment for their cancers.

Active smoking is firmly established as a cause of bladder

cancer; the relative risks for active smoking ranged from 2

to 10 in different studies (IARC, 1986). The estimated

attributable risk for bladder cancer due to smoking is 47

percent in men and 38 percent in women (Shopland et al., 1991). The

range in relative risk estimates has been explained partly by the different

types of tobacco smoked in different countries and the differences in carcinogenicity of tobacco types. Black tobacco products, commonly smoked

in countries such as Italy and Argentina, are associated with higher risks of

bladder cancer (Vineis et al., 1984; Iscovich et al., 1987) than blond tobacco

products, smoked in the U.S. and Canada (Hartge et al., 1990; Burch et al.,

1989). Black tobacco, compared to blond tobacco, contains higher concen320

Smoking and Tobacco Control Monograph No. 10

7.3.3 Bladder Cancer

7.3.3.1 Active Smoking and

Bladder Cancer
trations of various aromatic amines, including 4-aminobiphenyl, an established bladder carcinogen (Patrianakos and Hoffmann, 1979; IARC, 1972).

Risk of bladder cancer in nonsmokers in relation to ETS

exposure was evaluated in two studies (Table 7.11). 

The first study was conducted by Kabat et al. (1986) as

part of a large on-going case-control study of smoking and cancer. Between

1976 and 1983, a total of 948 bladder cancer cases (751 male and 197

female) were interviewed, 152 of whom (76 male and 76 female) were lifetime nonsmokers (i.e., smoked less than one cigarette, cigar, or pipe per day

for 1 year). Hospital controls who were also lifetime nonsmokers were

matched to each case on age, sex, race, hospital, and year of interview.

There were a total of 492 nonsmoking controls (238 male and 254 female).

Questions on ETS exposure were added to the questionnaire in 1979; this

information was available on only 40 of 152 cases and 75 of 492 controls

interviewed. Questions were asked regarding exposure to ETS inside the

home, represented by spouses’ smoking, and exposure outside of the home,

including exposure at work or in transportation. Results were presented in

terms of hours of ETS exposure per week.

The findings on the relationship between ETS exposure and bladder

cancer were inconsistent by gender and by source of exposure. For nonsmoking males, there was a nonsignificant increased risk of bladder cancer

associated with ETS exposure at home but not at work, whereas among

nonsmoking females, a nonsignificant increased risk was observed for ETS

exposure at work but not at home (Table 7.11). This study has several limitations, however. The most serious ones include the small sample size of

nonsmokers and the fact that controls were selected from among hospital

patients. Although controls were diagnosed with presumably non-tobaccorelated diseases (specific diagnoses were not specified), many malignant and

non-malignant diseases are causally related to tobacco smoke. Hence, it is

quite conceivable that hospital controls may be more likely to be exposed

to ETS than the general population.

Burch et al. (1989) A second study was conducted by Burch et al. (1989) in Canada

between 1979 and 1982. This study included 826 histologically-confirmed

bladder cancers and 792 randomly selected controls (Table 7.11). Of these,

142 cases and 217 controls were nonsmokers (defined as having smoked

fewer than 185 cigarettes in total). Subjects were asked about their exposure to the tobacco smoke of others at home and at work. For all subjects

and for nonsmokers, there was no association between risk of bladder cancer and ETS exposure at home or at work. The authors suggested that

because of the modest risk associated with active smoking (RR = 2.7) in this

study, any association between ETS and bladder cancer in nonsmokers may

be too weak to be detectable in questionnaire-based epidemiologic studies. 

Aside from questionnaire-based epidemiologic studies, some data are available from biochemical measurement studies which evaluated the effect of ETS

and risk of bladder cancer in nonsmokers. These studies measured hemoglobin (Hb) adducts of 4- or 3-aminobiphenyl (4-ABP or 3-ABP) which are

321

Chapter 7

7.3.3.2 ETS and Bladder

Cancer

Kabat et al. (1986)

7.3.3.3 Biomarkers of Exposure 

to Bladder Carcinogens from 

ETS Exposure
322

Smoking and Tobacco Control Monograph No. 10

Study Males Females

# Exposed OR # Exposed OR

Cases/Controls (95% CI) Cases/Controls (95% CI)

Kabat et al. (1986)a

Exposed to passive smoking

At home 6/10 1.5 (0.5-4.5) 6/13 0.6 (0.5-1.2)

At work or in transportation 11/25 0.7 (0.2-1.8) 6/5 2.5 (0.6-10.1)

Burch et al. (1989)b

Exposed to passive smoking

At home 37/72 0.9 (0.5-2.0) 66/90 0.8 (0.3-1.7)

At work 25/45 1.0 (0.5-1.9) 26/38 0.9 (0.5-1.8)

Table 7.11

Passive Smoking and Bladder Cancer Among Nonsmokers

a Total number of nonsmokers were: males-23 cases, 44 controls; females-17 cases, 28 controls.

b Total number of nonsmokers were: males-61 cases, 112 controls; females-81 cases, 105 controls.

formed over the 120-day lifespan of the erythrocyte and therefore may

serve as dosimeters of average exposure over the previous 4 months. As

mentioned above, the aromatic 4-ABP is a potent human bladder carcinogen (IARC, 1972). 

In one study, concentrations of adducts of 4- and 3-ABP were measured

in 57 nonsmokers. Subjects who reported exposure to ETS and had

detectable serum cotinine levels showed higher median and mean levels of

both adducts than subjects who reported no exposure to ETS and had no

detectable cotinine levels. The result was of borderline significance for 4-

ABP-Hb and was statistically significant for 3-ABP-Hb (MacClure et al.,

1989) (Table 7.12). In a second study, Barstch et al. (1990) extended the

investigation of 4-ABP-Hb levels in smokers and nonsmokers by N-acetylation phenotype, a marker of susceptibility for bladder cancer (Table 7.13).

It has been established that at the same level of exposure to active smoking

and other exposures to xenobiotics, slow acetylators are at higher risk of

bladder cancer than fast acetylators (Cartwright et al., 1982; Vineis et al.,

1990). Among nonsmokers in this study, those with ETS exposure showed

higher levels of ABP adducts than those with no ETS exposure. However,

the relative increase in ABP adducts differed for “slow” and “fast” acetylators. Among nonsmokers with no ETS exposure, the ABP levels were at

least two times higher among “slow” than “fast” acetylators. However, the

ABP levels among nonsmokers with ETS exposure were comparable for

“fast” and “slow” acetylators. Thus, the increase in ABP levels in relation to

ETS exposure was more apparent for “fast” than “slow” acetylators (Table

7.13). It is of note that in both studies, nonsmokers showed levels of

hemoglobin adducts of 4-ABP that were 28-35 percent of those of smokers,

and the levels of 4-ABP were somewhat higher in nonsmokers exposed to
ETS than those not exposed. Levels of 4-ABP were 7 percent higher in nonsmokers exposed to ETS compared to nonsmokers not exposed in one study

(MacClure et al., 1989). In a second study, 4-ABP levels were 14 percent

higher in nonsmokers exposed than nonsmokers not exposed among

“slow” acetylators, and were almost two times higher among exposed “fast”

acetylators compared to non-exposed “fast acetylators.”

Future studies need to confirm and better characterize the relationship

between levels of hemoglobin adducts in nonsmokers and their exposure to

ETS by acetylator status.

7.3.3.4 Summary In summary, the evidence from questionnaire-based epidemiologic studies of ETS and bladder cancer is inadequate. There have been two

case-control studies to date, both showed no significant increased risk associated with ETS exposure. These studies, however, had serious limitations

including small sample sizes and crude assessment of exposure to ETS. On

the other hand, the evidence from two biochemical studies is suggestive. In

both studies, nonsmokers exposed to ETS showed higher levels of hemoglobin adducts of an established bladder carcinogen than nonsmokers not

exposed to ETS, providing supporting evidence that nonsmokers exposed to

ETS may be at increased risk of bladder cancer. 

A large number of epidemiologic studies have

investigated the association of active smoking and

risk of breast cancer (Baron, 1984; MacMahon,

1990; Palmer and Rosenberg, 1993; Calle et al.,

1994; Baron et al., 1996), and the results are inconclusive. A few case-control (Williams and Horm,

1977; Vessey et al., 1983; O’Connell et al., 1987)

and cohort studies (Hammond, 1966) have found a

protective effect associated with smoking.

However, the majority of studies have found no association (Smith et al.,

1984; Adami et al., 1988; Baron et al., 1986; Rosenberg et al., 1984; Porter

and Jick, 1983; Brinton et al., 1986; London et al., 1989; Schechter et al.,

1989; Vatten and Kvinnsland, 1990; Field et al., 1992) or a weak positive

association with smoking (Le et al., 1984; Rohan and Baron, 1989; Palmer et

al., 1991; Schechter et al., 1985; Brownson et al., 1988; Stockwell and

Lyman, 1987; Calle et al., 1994). The case-control studies which have

found an increased risk with smoking tended to have selected cases and

controls from cancer screening programs (Schechter et al., 1985; Brownson

et al., 1988) or have found the increased risk among premenopausal women

(Schechter et al., 1985; Rohan and Baron, 1989; Brownson et al., 1988);

other studies found effects for selective smoking variables such as starting at

an early age (Brinton et al., 1986; Palmer et al., 1991) or among former

smokers (Hiatt et al., 1988; Baron et al., 1996). Meara et al. (1989) showed

that bias in selection of cases and controls in hospital-based series would

spuriously show a decreased risk of breast cancer with increasing amounts

smoked. On the other hand, bias associated with selecting subjects from a

cancer-screening population would spuriously produce an increased risk of

breast cancer with increasing amounts smoked. 

323

Chapter 7

7.4 ETS AND CANCER SITES 

WHERE EVIDENCE FOR THE 

ROLE OF ACTIVE SMOKING 

IS EQUIVOCAL

7.4.1 Breast Cancer

7.4.1.1 Active Smoking 

and Breast Cancer
In the one prospective study which found a small, significant increased

risk of fatal breast cancer with current smoking, the authors hypothesized

that these findings could reflect either a poorer prognosis among breast

cancer cases who smoke or a delayed diagnosis among current smokers

(Calle et al., 1994).

The above epidemiologic studies investigated the risk of breast cancer in

active smokers compared to all nonsmokers in the baseline group. A recent

study (Morabia et al., 1996) investigated the effect of active smoking compared to nonsmokers not exposed to ETS. Data were also presented which

allowed comparison of the effect of active smoking compared to all nonsmokers and to nonsmokers not exposed to ETS. We calculate that compared to all nonsmokers (126 cases and 621 controls), the crude ORs associated with ever smoking 1-9, 10-19, and 20+ cigarettes per day were 1.1, 1.5,

and 1.6, respectively (p trend = 0.007). The corresponding adjusted ORs

when compared to nonsmokers not exposed to ETS (28 cases and 241 controls) were 2.4, 3.6, and 3.7 (p trend = 0.09; from Table 2 of Morabia et al.,

1996). Similar results were obtained when current active smokers were

compared to all nonsmokers and to nonsmokers not exposed to ETS.

A role of passive smoking in the etiology of breast cancer was

first hypothesized by Horton (1988), who noted that countries

with high mortality rates of lung cancer in males generally had high rates

of breast cancer, whereas countries with low rates of lung cancer had low

rates of breast cancer. Based on this observation, Horton then (1988 and

1992) tested the hypothesis and found that passive smoking (using male

lung cancer rates as a proxy variable) is a risk factor for female breast cancer. There was, however, little support for this hypothesis in another correlational study which investigated the relationship between female breast

cancer and male lung cancer within five countries (Williams and Lloyd,

1989). Deleterious effects of smoking on the breast are plausible since carcinogens in smoke (e.g., 3-4 benzo[a]pyrene) or their metabolites are

absorbed systemically (Kotin et al., 1959), and have been detected in nipple

aspirates of non-lactating women (Petrakis et al., 1980). 

Four analytic epidemiologic (one cohort and three case-control) studies

have investigated the association between ETS exposure and risk of breast

cancer among nonsmokers. Known risk factors for breast cancer (i.e., reproductive factors, alcohol intake, social class) were not accounted for in the

analysis of ETS exposure in the first two studies (Hirayama, 1984; Sandler et

al., 1985a) but they were accounted for in the two recent studies (Smith et

al., 1994; Morabia et al., 1996). Only one study (Morabia et al., 1996) was

designed specifically to investigate the role of ETS and breast cancer.

Hirayama (1984) The first study was a Japanese cohort study (Hirayama, 1984)

which included 115 breast cancer deaths in never-smoking women.

Nonsmoking women whose husbands smoked showed a small, nonsignificant increased risk of breast cancer (RR = 1.3, 95% CI = 0.8-2.0). 

Sandler et al. (1985a) In a case-control study conducted in North Carolina, husbands’ smoking was associated with an increased risk of breast cancer (RR =

1.9, 95% CI = 0.9-4.2). The association was observed among pre324

Smoking and Tobacco Control Monograph No. 10

7.4.1.2 ETS and

Breast Cancer
325

Chapter 7

4-ABP 3-ABP

Population (pg/g Hb) (pg/g Hb)

Ex-smokers (at baseline) 130.4 16.0

Ex-smokers (after stopping smoking 33.3 1.7

for two months)

Nonsmokers

ETS exposure (-)a and 45.9 1.2

Cotinine level (-)

ETS exposure (+)b and 49.2 1.9

Cotinine level (+)

Table 7.12

Mean Levels of Hemoglobin Adducts of 4- AND 3- Aminobiphenyls 

in nonsmokers

Reference: Maclure et al. (1989)

a Based on 44 subjects-15 subjects had low levels of self-reported ETS exposure and no detectable cotinine levels; 29 subjects had no reported ETS exposure and no detectable cotinine levels.

b Based on 13 subjects-7 subjects had low levels of self-reported ETS exposure

and detectable cotinine levels, 6 subjects had high levels of self-reported ETS

exposure and detectable cotinine levels. The 6 subjects who reported high

exposure to ETS showed the highest mean levels of 4-ABP (54 pg/g) and 3-ABP

(2.4 pg/g) and median levels of 4-ABP (48 pg/g) and 3-ABP (2.6 pg/g).

Acetylator Phenotype

Population Slow Fast

Black-tobacco smokers (n = 16) 175.0 117.5

Blond-tobacco smokers (n = 31) 111.8 86.4

Nonsmokers (n = 50) 31.7 19.4

Exposed to ETS

No (n = 35) 30.4 12.3

Yes (n = 15) 34.8 33.6

Table 7.13

Mean Levels of 4-ABP Hemoglobin Adducts (PG/G of Hemoglobin) Among Smokers

and Nonsmokers by Acetylator Phenotype

Reference: Bartsch et al. (1990)
menopausal women (RR = 7.1, 95% CI = 1.6-31.3), but not among postmenopausal women (RR = 0.9, 95% CI = 0.4-2.2) (Sandler et al., 1985a;

Wells, 1991). In a further analysis of the case-control data from North

Carolina, Wells (1992) reported that compared to nonsmoking women married to never-smokers, the age-adjusted RRs were 1.62 among nonsmoking

women married to smokers, 0.64 among smoking women married to nonsmokers, and 1.51 among smoking women married to smokers. 

Smith et al. (1994) The role of active and passive smoking was investigated in a casecontrol study conducted among young (diagnosed before the age of 36)

breast cancer patients who were diagnosed between 1982 and 1985 and

were residents in one of 11 health regions in the UK (Smith et al., 1994).

This study was designed specifically to study the role of reproductive factors, oral contraceptives, active smoking, and use of alcohol and caffeine.

Questions on passive smoking were added and were administered to

respondents who resided in three of the 11 participating health regions. In

this study, one control was matched to each case interviewed. Each

case/control pair were patients of the same general practitioner; the control

was randomly selected from the list of patients of the general practitioner

who cared for the case and was matched to the case on age (date of birth

within 6 months). A mailed questionnaire was used to gather information

on passive smoking exposure after the subjects had already participated in

an in-person interview for the main study. The main study included a total

of 755 breast cancer cases and an equal number of controls. A subset of

409 women (208 breast cancer cases and 201 controls) of whom 94 cases

and 99 controls were nonsmokers, provided information on ETS exposure. 

Active smoking was not associated with risk of breast cancer in this

study; the crude OR for having ever smoked was 1.04, and the adjusted OR

was 1.01 (adjustment included age at menarche, parity, age at first full-term

pregnancy, breastfeeding, family history, use of oral contraceptives, alcohol

use, and biopsy for benign breast disease). Based on calculations that 114

of the 208 cases and 102 of the 201 controls who responded to questions

on ETS exposure had ever smoked, the effect of active smoking was similar

in the subset of subjects who responded to questions on passive smoke

exposure (crude OR = 1.18 for women who had ever smoked) and for all

subjects combined (i.e., OR = 1.04). 

Results on the association between passive smoking and risk of breast

cancer were presented for smokers and nonsmokers combined. There was

some suggestion that risk was highest among individuals who were exposed

to ETS during both childhood and adult life. Compared to women who

were not exposed to ETS, exposure during childhood only, adult life only,

and during both childhood and adult life were associated with ORs of 1.98

(95% CI = 0.35-11.36), 2.65 (95% CI = 0.80-8.83), and 3.13 (95% CI = 1.05-

9.38), respectively. Although there was an increased risk of breast cancer

associated with childhood ETS exposure, adult exposure to ETS from partners, from other smokers at home and at work, and total lifetime exposure,

there was no consistent dose trend of increasing risks with increasing levels

of any of these sources of ETS exposure. However, the investigators noted

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that the passive smoking findings among nonsmokers were similar to those

for smokers and nonsmokers combined. The relative risks were consistently

elevated, but again there was no evidence of a significant dose response for

any exposure variable. 

Morabia et al. (1996) A population case-control study conducted in Geneva,

Switzerland (Morabia et al., 1996) offered additional information on the

role of active smoking and passive smoking in the etiology of breast cancer.

In this study, 244 of 344 breast cancer patients aged less than 75 and diagnosed over a 2-year period consented to an in-person interview. Using an

age-stratified random sampling scheme, population controls were identified

from a listing which included all residents in Geneva. A total of 1,032 of

the 1,473 eligible controls participated in this study. 

All participants were asked specific questions on active and passive

smoking including passive smoke exposure at home, at work, and during

leisure time. Active and passive smoking exposure were recorded year by

year, between the age of 10 years and the date of the interview. An

episode of exposure is defined as at least 6 months of exposure when the

woman was passively or actively exposed to tobacco smoke. For each

episode of exposure, the woman was asked the age at which she was

exposed and the corresponding calendar years. The number of hours per

week of each passive smoking episode was recorded. An active smoker had

smoked at least 100 cigarettes in her lifetime. Passive smokers were

women who reported having been exposed to passive smoke at least 1 hour

per day for at least 12 consecutive months during their lifetime.

Of the 244 breast cancer patients and 1,032 controls who were interviewed, 126 cases (51 percent) and 621 (60 percent) controls were lifetime

nonsmokers. We calculate that compared to nonsmokers, the crude RRs for

breast cancer associated with being a former smoker and a current smoker

were 1.78 and 1.15, respectively. Among the 126 nonsmoking cases and

621 nonsmoking controls, 28 cases and 241 controls reported no ETS exposure. This group of nonsmokers with no ETS exposure comprised the baseline comparison group in the analyses reported by Morabia et al. (1996).

Risk of breast cancer was elevated in nonsmokers who were exposed to ETS

exposure from spouses and from all sources combined (i.e., including from

spouses). Compared to nonsmoking women who were not exposed to any

ETS, the OR was 2.6 (95% CI = 1.6-4.3) for women who were exposed to

passive smoking from spouses and 2.3 (95% CI = 1.5-3.7) for women who

were ever exposed to passive smoking from all sources combined. The OR

associated with high exposure (>50 hours/day-years) from spouses (OR =

2.7, 95% CI = 1.5-4.7) was essentially the same as lower exposure (1-50

hours/day-years) from spouses (OR = 2.3, 95% CI = 1.3-5.0). The OR associated with high exposure (>50 hours/day-years) from all sources combined

(OR = 2.5, 95% CI = 1.5-4.2) was also similar to that associated with lower

exposure (1-50 hours/day-years, OR = 2.2, 95% CI = 1.3-3.7). 

Using nonsmokers never exposed to passive smoking as the baseline

group, the magnitude of risks associated with ETS exposure were similar to

the risks associated with active smoking. The risk of breast cancer was

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Chapter 7
increased among active smokers who smoked <20 pack-years (OR = 2.2,

95% CI = 1.2-4.3) and 20+ pack-years (OR = 3.2, 95% CI = 1.8-5.9). These

findings on ETS exposure and active smoking were adjusted for age, education, body mass index, age at menarche, age at first birth, oral contraceptive

use, and family history of breast cancer. 

7.4.1.3 Summary All four studies on ETS exposure and breast cancer suggest that

exposure to ETS is associated with an increased risk of breast cancer.

Despite the consistency of this apparent observation, these results cannot

be considered conclusive and must be interpreted cautiously for several reasons. In two studies, the associations with ETS exposure were present in

select subgroups, younger women in one study (Hirayama, 1984) and premenopausal women in another study (Sandler et al., 1985a; Wells, 1992).

In three studies (Wells, 1992; Smith et al., 1994; Morabia et al., 1996), there

is either no association between active smoking and risk of breast cancer or

the effect of active smoking is weaker or comparable to the effect of passive

smoking. Given that active smokers are also passively exposed to tobacco

smoke, these findings on ETS exposure need to be reconciled. Moreover,

in all the studies, there is no indication of increasing risk of breast cancer

with increasing dose or measures of intensity of passive smoking. The

apparent findings may be due to a deficit of cases who reported they had

never been exposed or an excess of controls who reported they had been

exposed to passive smoking, but at this time, there are also no obvious

explanations why this would have occurred in each of the four studies.

Results from a recent study suggest that tobacco smoke may influence the

risk of breast cancer only in certain susceptible groups of women

(Ambrosone et al., 1995 and 1996). 

7.4.2 Stomach Cancers The epidemiological evidence in support of active smoking as a risk factor for stomach cancer is equivocal. The 1982 Surgeon

General’s Report (U.S. DHHS, 1982) and the 1986 IARC report (IARC, 1986)

concluded that tobacco smoke is associated with an increased risk of stomach cancer, but it is uncertain whether the relationship is causal. The

hypothesis that tobacco smoke is a causal risk factor for stomach cancer is

biologically plausible, since high concentrations of N-nitroso compounds

are found in both mainstream and sidestream smoke. Exposure to Nnitroso compounds has been established as important in the development

of stomach cancers (Preston-Martin and Correa, 1989). 

Results from a cohort study conducted in Japan (Hirayama, 1984) are

not supportive of an association between ETS exposure and risk of stomach

cancer in nonsmokers. In this study, the risk of stomach cancer in nonsmokers married to nonsmoking husbands was similar to that of nonsmokers married to husbands who were ex-smokers or smoked 1-19

cigarettes/day (RR = 1.03) and those married to husbands who smoked

greater than 20 cigarettes/day (RR = 1.05). The RR for stomach cancer in

relation to active smoking in the same cohort was 1.3 for females and 1.6

for males (Hirayama, 1979). However, these associations with active smoking were not adjusted for dietary or other risk factors of stomach cancer. In

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summary, thus far there is no epidemiologic evidence for an association

between ETS exposure and stomach cancer, but research on this issue has

been extremely limited.

7.4.3 Brain Tumors The age-incidence curve for brain tumors displays a bimodal

distribution, peaking at ages 5 and 60. Brain tumors are a heterogeneous

disease with different types of tumor occurring in the cranial cavity or in

the spinal canal. The most common types of brain tumors are gliomas and

meningiomas. Causes of brain tumors are not known, but exposure to Nnitroso compounds and certain occupations have been suspected (PrestonMartin and Correa, 1989). The hypothesis that ETS exposure increases the

risk of brain tumors in adults and children is biologically plausible, since

precursors of endogenously formed N-nitroso compounds are present in

ETS. Moreover, in animal studies, neurogenic as well as other tumors were

induced after transplacental exposure to a number of compounds present in

tobacco smoke, including several nitrosamines (Preston-Martin and Correa,

1989). Some data suggest that active smoking may be related to brain

tumors in adults, but the evidence is not consistent (Burch et al., 1987). 

7.4.3.1 In Adults A possible role of passive smoking in the etiology of brain tumors

was first suggested in a prospective study conducted in Japan (Hirayama,

1984) (see Section 7.1.1 for study details). Based on 34 brain tumor deaths,

there was an increased risk associated with ETS exposure. Nonsmoking

women married to men who smoked 1-14, 15-19, and 20+ cigarettes per

day showed RRs of 3.0 (95% CI = 1.1-8.6), 6.3 (95% CI = 2.0-19.4), and 4.3

(95% CI = 1.5-12.2), respectively, when the age and occupations of husbands were adjusted for in the analysis. Smokers showed a statistically nonsignificant increased risk of brain tumors compared to nonsmokers (RR =

1.2, 90% CI = 0.80-1.9) risk estimates by amount smoked were not presented (Hirayama, 1990).

In a case-control study which included all cancer outcomes, Sandler et

al. (1985b) investigated the association between parental smoking and risk

of brain tumors in adults (ages 15-59 years). Based on 11 cases among nonsmokers, there was a nonsignificant increased risk associated with father’s

smoking (OR = 1.65, 95% CI = 0.44-6.24), but not with mother’s smoking

(OR = 0.82, 95% CI = 0.10-6.64).

Ryan et al. (1992) published a case-control study on meningiomas and

gliomas. This Australian study was one of 10 studies on adult brain tumors

coordinated by the IARC. Classification of ETS exposure status was based

on whether subjects were regularly exposed to smoking of parents, spouses,

or coworkers. The authors reported an effect due to ETS, particularly for

meningiomas. However, it is difficult to interpret these results because the

analysis included all subjects who were not exposed to ETS in the baseline

group, irrespective of the subject’s active smoking habits. Thus, although

there was an increased risk associated with ETS exposure for meningioma

(RR = 2.5, 95% CI = 1.0-6.1) and for glioma (RR = 1.3, 95% CI = 0.6-2.7), it

is not possible to rule out the effect of active smoking among those exposed

to ETS.

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Chapter 7
The effect of passive smoking and risk of brain/nervous system

tumors in children has been evaluated in ten studies (Table

7.14). Five studies were designed specifically to identify risk factors for all

brain tumors combined (Gold et al., 1979; Preston-Martin et al., 1982; Howe

et al., 1989; Gold et al., 1993; McCredie et al., 1994), one study was focused

on astrocytoma (Kuijten et al., 1990), and four studies included all childhood cancers and results were presented for cancers of the brain or nervous

system (Stjernfeldt et al., 1986; McKinney and Stiller, 1986; John et al.,

1991; Pershagen et al., 1992) (see Section 7.1.2 for study details).

Findings from four studies on childhood brain tumors (Preston-Martin

et al., 1982; Howe et al., 1989; John et al., 1991; McCredie et al., 1994) show

a small increased risk in relation to paternal smoking (Table 7.14); results

were statistically significant in two studies (Preston-Martin et al., 1982;

McCredie et al., 1994). Each of the four studies shows no association

between maternal smoking during pregnancy and risk of childhood brain

cancers.

Gold et al. (1979) Gold et al. (1979) conducted a hospital-based case-control study in

Baltimore, MD which included all children under the age of 20 years, diagnosed with primary malignant brain tumors during the period 1965-1975.

Children with brain tumors were compared to two types of controls; normal controls selected from birth certificates and controls with malignancies

other than brain tumors. Each control was individually matched to children with brain tumors on sex, date of birth (plus or minus 1 year), race,

and age at diagnosis (for cancer controls only). The response rate was 66

percent for brain tumor cases, 63 percent for cancer controls, and 21 percent for normal controls. There were a total of 73 matched-pairs of children with brain tumors and normal controls and 78 matched pairs of children with brain tumors and other cancer controls. Parents of cases and

controls were interviewed. Maternal smoking prior to the index pregnancy

did not differ between mothers of children with brain tumors and mothers

of control children. However, mothers of children with brain tumors were

more likely to have continued to smoke during the pregnancy compared to

mothers in either control group (RR = 5.0, p = 0.22 for normal controls; RR

= ∞, p = 0.13 for cancer controls). This finding, however, was not confirmed in a later study by the same investigators (Gold et al., 1993, see

below). Neither study presented data on the percentage of mothers who

stopped smoking during pregnancy, and there is no apparent explanation

for the discrepancy in findings. 

Preston-Martin et al. (1982) Preston-Martin et al. (1982) conducted a populationbased case-control study of brain tumors in Los Angeles County. Eligible

subjects had a histologically confirmed brain tumor, diagnosed at or under

25 years of age between 1972 and 1977. Of the 317 eligible cases identified,

mothers of 226 patients were interviewed. For each case interviewed, a

friend (n = 153) or a neighborhood control (n = 56) was interviewed. Case

and control mothers did not differ significantly in consumption of cigarettes during the index pregnancy (OR = 1.1, p = 0.42). However, there was

a significant excess of case mothers who lived in a household with someone

else who smoked (OR = 1.5, p = 0.03) compared to controls. 

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7.4.3.2 In Children/

Young Adults
Howe et al. (1989) Howe et al. (1989) conducted a hospital-based case-control study

of childhood brain tumors in southern Ontario between 1977 and 1983.

Eligible cases consisted of all cases of brain tumors diagnosed in children

under age 20 at two main hospitals in Toronto. Of the 123 cases identified,

74 were interviewed (60 percent). Up to two randomly selected controls,

matched to each case by sex, date of birth (within 2 years), and area of residence, were identified from population lists maintained by the Ontario government. The study included a total of 74 cases and 138 controls.

Maternal (OR = 1.42, p = 0.36) and paternal smoking (OR = 1.13, p = 0.69)

during index pregnancy was associated with a small, nonsignificant

increased risk of brain tumor. 

Gold et al. (1993) Gold et al. (1993) conducted a large multi-centered populationbased case-control study on childhood brain tumors. Cases were identified

from eight population-based registries under the Surveillance,

Epidemiology, and End Results (SEER) program; cases were 18 years of age

or younger at the time of diagnosis of a histologically confirmed brain

tumor between January 1977 and December 1981, and they resided in the

catchment areas of the registries at the time of diagnosis. Three control

children, selected mainly by random-digit dialing, were matched to each

case by age, sex, and mother’s racial/ethnic classification, as well as by area

code and telephone prefix. In-person, structured interviews were conducted with parents of 361 cases and 1,083 controls. The participation rate was

85 percent for both cases and controls. Smoking habits of mothers and

fathers during preconception, prenatal, and early postnatal periods were

available. Most of the paternal information was supplied directly by the

fathers (71 percent of interviews) and the remainder was supplied by the

mothers (26 percent). In addition, information on various potential confounders (e.g., intake of alcohol, coffee and tea, parental educational level),

histologic type, and location of tumor were obtained. 

There was no association between risk of childhood brain tumor and

maternal or paternal smoking at any time, specifically during the year the

index child was born, or in the 2 years before the index child was born

(Table 7.14). Compared to children whose parents were both nonsmokers,

the ORs for brain tumors was 0.95 (95% CI = 0.66-1.36) when both parents

smoked, 0.94 (95% CI = 0.66-1.33) when only fathers smoked, and 1.06

(95% CI = 0.82-1.37) when only mothers smoked. The results were

unchanged when analyses were stratified by histologic type of tumor (astrocytoma, medulloblastoma, other) and location of tumor (supratentorial,

infratentorial, other), or when adjustment was made for potential confounders. Information on parental smoking before, during, and after the

index pregnancy was obtained—there was no increase or decrease in the

percentage of case and control parents who did not smoke in the year during which the index subject was born compared to the two previous years,

and only minor changes in the percentage of case and control fathers and

mothers who smoked less than a pack/day versus greater than a pack/day

during these two time periods. Smoking habits during the early postnatal

periods were not presented separately but were included as part of the year

the index child was born. Thus, the effects of maternal or paternal smoking before, during, or after the index pregnancy could not be distinguished. 

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Chapter 7
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Smoking and Tobacco Control Monograph No. 10

Study # Cases/ OR for Smoking Habits of

(Age of Subjects) Controls Mother Father

continued smoking during

pregnancya

Gold et al., 1979 84/73 5.0 No data

(Age < 20) (population)

84/78 ∞

(hospital)

During pregnancy During pregnancy

Preston-Martin 209/209 1.1 1.5a

et al., 1982

(Age < 25)

# cig/day during pregnancy

Stjernfeldt et al., 1986 0 1-9 10+ cig/day

(Age ≤ 16) 43/340 1.0 1.0 0.9 No data

# cig/day during pregnancy

McKinney and 0 1-9 10+ cig/day

Stiller, 1986 78/156 1.0 1.1 1.0 No data

(Age ≤ 15)

During pregnancy During pregnancy

Howe et al., 1989 74/132 1.4 1.1

(Age ≤ 20)

During first trimester 12 months prior to birth

John et al., 1991 48/196 1.0 1.4

(Age ≤ 14)

Mother’s smoking alone Father’s smoking alone

* 1.9 (0.9-4.2)

at 2-3 mos of pregnancy

0 <10 10+ cig/day

Pershagen et al., 1992 81b 1.0 0.9 1.1 No data

(Age ≤ 5)

McCredie et al., 1994 82/104 During pregnancy During pregnancy

(Age ≤ 14) 1.3 2.2a

4.2c

1.1d

Kuijten et al., 1990 163e/163 During pregnancy During pregnancy

(Age ≤ 14) 1.0 0.8

Table 7.14

Brain Tumors in Children and Exposure to Parent’s Smoking
McCredie et al. (1994) McCredie et al. (1994) conducted a population-based case-control study of incident primary malignant brain tumors diagnosed in children aged 0-14 years in New South Wales, Australia from 1985 to 1989.

Each case was aged matched (±3 to 12 months of age) to two controls

selected from electoral rolls. The response rate was 85 percent for cases and

60 percent for controls, resulting in completed personal interviews with

mothers of 82 cases and 164 controls. Most of the information was provided by the mothers of cases and controls. In addition, fathers of 45 cases

and 60 controls were also present at the interview or were interviewed

directly about themselves over the telephone. Based on the smoking habits

presented for mothers and fathers, and compared to subjects whose parents

were both nonsmokers, increased risks were found in relation to smoking

by either parent (OR = 1.61, 95% CI = 0.94-2.75) and to mothers’ smoking

(OR = 1.33, 95% CI = 0.72-2.46). A significant increased risk of brain

tumors was associated with fathers’ smoking (OR = 2.19, 95% CI = 1.25-

3.85). Fathers’ smoking is presumed to explain the association with mothers’ smoking which, when examined alone, was not associated with an

increased risk (OR = 0.4, 95% CI = 0.1-1.3). Risk of brain tumors was significantly increased if fathers’ smoked before pregnancy (OR = 2.0, 95% CI =

1.0-4.1) or if mothers’ reported they were exposed to fathers’ smoking during pregnancy (OR = 2.2, 95% CI = 1.2-3.8). 

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Chapter 7

Study # Cases/ OR for Smoking Habits of

(Age of Subjects) Controls Mother Father

Gold et al., 1993 361/1083 Ever smoked Ever smoked

(Age ≤ 18) 0.9 1.1

During yr of birth During yr of birth

0 <1 pack/day pack/day 0 <1 pack/day pack/day

1.0 0.8 1.0 1.0 0.7 1.1

2 yrs before birth 2 yrs before birth

0 <1 pack/day pack/day 0 <1 pack/day pack/day

1.0 0.8 1.0 1.0 0.9 1.2

Mother’s smoking alone Father’s smoking alone

1.1 0.9

Table 7.14 (Continued)

a p < 0.05

b cohort study

c OR if data obtained from mother

d OR if data obtained from father

e Cases restricted to astrocytoma

* 0 exposed cases, 8 exposed controls
McCredie et al. (1994) interpreted the effect of fathers’ smoking to be

due to recall bias by mothers. According to the authors 

“no increasing risk was seen with increasing use of cigarettes and

after stratification by source of information (father or mother), the

increased risk was present in the proxy data (ORs of 5.5 and 4.2,

respectively, for the 2 smoking variables just mentioned) but not in

those obtained directly from the father (ORs of 1.0 and 1.1).

Moreover, no increased risk was found with mother’s exposure to

tobacco smoke either of other household members (OR = 1.3, 95%

CI = 0.6 to 2.8) or at work (OR = 0.4, 95% CI = 0.4-1.4).” 

However, based on the data presented, it cannot be determined whether the

increased risk associated with fathers’ smoking is explained by selective

recall by mothers or whether the finding of no association is due to case

fathers’ denial of their own smoking. The distribution of fathers’ smoking

by respondent (i.e., mothers or fathers) or by case/control status was not

presented. The authors also indicated that control women who were interviewed were of higher social class than the eligible controls who refused to

participate, raising the possibility that control fathers who participated may

be less likely to smoke because of the inverse association between smoking

and social class. 

Kuijten et al. (1990) A study conducted by Kuijten et al. (1990) was designed to identify risk factors for astrocytoma, the most frequently occurring central nervous system tumors in children. Eligible cases included children diagnosed

with this type of brain tumor before age 15 years, between 1980-1986, in

one of eight tumor registry hospitals in Pennsylvania, New Jersey, and

Delaware. Controls were selected by random-digit dialing and were pairmatched to cases for age (±2 years), race, and telephone exchange.

Information was available on mothers of 163 cases and controls, and

fathers of 160 cases and controls. Mothers and fathers were interviewed

separately by telephone, and presumably each was asked about their own

smoking habits. Mothers’ smoking (OR = 1.0, 95% CI = 0.6-1.7) and mothers’ exposure to sidestream smoke (OR = 0.8, 95% CI = 0.5-1.3) were not

associated with risk of astrocytoma (Kuijten et al., 1990). 

Other studies’ results on brain tumors in children. Data from three (Stjernfeldt et al.,

1986; McKinney and Stiller, 1986; Pershagen et al., 1992) of the four studies

focusing on all childhood cancers showed no association between maternal

smoking during pregnancy and risk of cancers of the brain/nervous system.

In all three studies, the RRs were close to 1.0 irrespective of the amount

smoked by mothers (1-9, 10+ cigarettes/day) (Stjernfeldt et al., 1986;

McKinney and Stiller, 1986; Pershagen et al., 1992). Information on father’s

smoking was not available in these studies (Stjernfeldt et al., 1986;

McKinney and Stiller, 1986; Pershagen et al., 1992; see Table 7.14). In the

study by John et al. (1991), mothers’ smoking was also not associated with

risk, but fathers’ smoking was associated with an elevated risk (RR = 1.4,

95% CI = 0.7-2.8). The effect of fathers’ smoking on brain tumor risk was

more apparent in the absence of mothers’ smoking (RR = 1.9, 95% CI = 0.9-

4.2). 

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7.4.3.3 Summary In adults, the epidemiologic evidence for an association between

ETS exposure and risk of brain tumor is inadequate, but the effect has not

been fully researched. Although a cohort (Hirayama, 1984) and a case-control study (Ryan et al., 1992) are suggestive of a positive association in

adults, the results were based on small numbers (Hirayama, 1984) and may

be confounded by active smoking (Ryan et al., 1992). In a second case-control study (Sandler et al., 1985a & b), a non-significant increase was

observed with fathers’ but not mothers’ smoking.

In children, data from the ten available studies do not support an effect

due to mothers’ smoking during pregnancy or the year before pregnancy.

The only suggestive finding was for mothers who continued to smoke during pregnancy compared to mothers who stopped smoking during pregnancy in one study (Gold et al., 1979), but this finding was not confirmed in a

larger study conducted by the same investigators (Gold et al., 1993). Six of

the ten studies also collected information on fathers’ smoking during the

index pregnancy. In four studies, there was an association between paternal smoking and risk of brain tumors (Preston-Martin et al., 1982; Howe et

al., 1989; John et al., 1991; McCredie et al., 1994); results were statistically

significant in two studies (Preston-Martin et al., 1982; McCredie et al.,

1994). In a third study, the effect of fathers’ smoking in the absence of

mothers’ smoking was of borderline statistical significance (John et al.,

1991). The range of ORs for paternal smoking in the positive studies was

1.5 to 2.2.

The positive association between paternal smoking and childhood brain

tumors reported (Preston-Martin et al., 1982; John et al., 1991; McCredie et

al., 1994) and the biologic plausibility of the hypothesis justify further

research to clarify the relationship. Given that purported relationships with

risk of childhood brain tumors have been reported for electromagnetic field

exposures, parental occupation, and radon exposures, future studies on ETS

and brain tumors would need to account for the effects of these other suspected risk factors.

There is increasing evidence that cigarette smoking may

be causally related to leukemia in adults (Austin and

Cole, 1986; Brownson et al., 1993b). Smoking has

emerged as a risk factor for leukemia in a number of

prospective studies, including the first (Hammond, 1966; Garfinkel and

Boffetta, 1990) and second American Cancer Society studies (Garfinkel and

Boffetta 1990), the U.S. Veteran cohort study (Kahn, 1966; Rogot and

Murray, 1980; Kinlen and Rogot, 1988; McLaughlin et al., 1989), and the

Adventist Health study (Mills et al., 1990). In two other cohort studies with

small numbers of leukemia deaths (<75 in each study), smoking was associated with statistically nonsignificant increased risks of leukemia (Weir and

Dunn, 1970; Linet et al., 1992). Smoking was not a risk factor for leukemia

in the British doctors’ cohort in which more than 70 percent of the deaths

from marrow and reticuloendothelial malignancies were lymphomas and

myelomas (Doll and Peto, 1976). Case-control studies which have compared smoking histories of leukemia patients with population controls have

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Chapter 7

7.4.4 Leukemia

7.4.4.1 Active Smoking and

Leukemia
found statistically significant positive associations with tobacco use (Sandler

et al., 1993; Brown et al., 1992; Severson, 1987; Severson et al., 1990).

Tobacco use was also a significant risk factor in a case-control study in

which all leukemia patients diagnosed between 1984 and 1987 in the

Missouri Cancer Registry were compared to other cancer patients (excluding

lip, oral cavity, esophagus, lung, and bladder) (Brownson, 1989). No association with smoking was found in two U.S. hospital-based case-control studies (Kabat et al., 1988; Spitz et al., 1990) in which selection bias of leukemia

cases was likely or in a third study restricted to chronic lymphatic leukemia

(Flodin et al., 1988). The association with smoking is most consistent for

myeloid leukemias, particularly acute myeloid leukemia, and less consistent

for chronic lymphocytic leukemia (Kinlen and Rogot, 1988; McLaughlin et

al., 1989; Garfinkel and Boffetta, 1990; Mills et al., 1990; Brownson, 1989).

Cigarette smoke contains many compounds, some of which have been

associated with increased risk of leukemia. These include benzene,

nitrosamines, urethane, and radioactive compounds (Austin and Cole,

1986). In animal studies, leukemia can also be induced by transplacentallyacting carcinogens, many of which are found in tobacco smoke (Coghlin et

al., 1991; Sorsa and Husgafuel-Pursiarnen, 1988). 

The association between ETS exposure and risk of

hematopoietic tumors including leukemia was reported in

one study. Among nonsmoking women with tumors of

hematopoietic tissues (including Hodgkins disease, non-Hodgkins disease

lymphomas, and acute leukemias), Sandler et al. (1985b) reported an

increased risk in relation to mothers’ (OR = 2.18, 95% CI = 0.69-6.92) and

fathers’ (OR = 2.42, 95% CI = 0.88-6.61) smoking during the childhood

years of the index subjects (see Section 7.1.1 for study description).

Although smoking habits of husbands were available in the same study,

their effect on risk was not reported (Sandler et al., 1985a).

One of the first studies to investigate the role of parental

smoking and risk of leukemia in children was conducted by

Manning and Carroll (1957) (see Section 7.1.2 for a detailed description).

In this hospital-based study, smoking habits of mothers of 188 children

with acute leukemia were compared to those of mothers of controls.

Thirty-nine percent of mothers of children with leukemia smoked 10 or

more cigarettes a day at interview compared to 38 percent among mothers

of children admitted for orthopedic reasons. A second study included

1,416 childhood cancers (677 were leukemia) and an equal number of population controls in the United Kingdom (Stewart et al., 1958) (see Section

7.1.2 for a detailed description). There was little case-control difference in

smoking habits of fathers, but there was a slight excess of case mothers who

smoked. A third study (Neutel and Buck, 1971) compared rates of leukemia

by smoking habits of mothers during pregnancy (see Section 7.1.2 for

details). The rate of leukemia in children was higher among mothers who

smoked (6.0 per 100,000 child-years) compared to mothers who did not

smoke (3.4 per 100,000 child years) (RR = 1.8). However, these results were

based on a small number of events (<12 cases of leukemia) among subjects

with nonsmoking and smoking mothers.

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7.4.4.2 ETS and Risk of

Hematopoietic Tumors 

in Adults

7.4.4.3 ETS and Risk of

Leukemia in Children
Since the 1980s, one cohort study and seven case-control studies offer

additional information on the possible effect of parental smoking on childhood leukemia (Table 7.15). Three of the studies included only acute lymphocytic leukemia (ALL) (Van Steensel-Moll et al., 1985; Stjernfeldt et al.,

1986; Buckley et al., 1986), one study was limited to acute myeloid

leukemia (Severson et al., 1993), whereas four studies included all leukemias

(McKinney and Stiller, 1986; Magnani et al., 1990; John et al., 1991;

Pershagen et al., 1992). In two studies, risk estimates were presented for

ALL and non-acute lymphocytic leukemia (non-ALL) separately (Magnani et

al., 1990; John et al., 1991).

In the Swedish cohort study (Pershagen et al., 1992) (see Section 7.1.2

for a detailed description), cancer incidence in some 50,000 children born

between 1982 and 1987 was determined. Maternal smoking at 2 to 3

months of pregnancy was categorized as none, 1-9 cigarettes/day, and >10

cigarettes/day. There were 129 cancers of the lymphatic and hematopoietic

system (84 lymphatic leukemia, 15 myeloid leukemia, 16 reticulosis, and 14

other hematopoietic and lymphatic system). There was no increased risk

associated with mothers’ smoking during pregnancy for lymphatic leukemia

when year and county of birth, birth order of index subject, and maternal

age were adjusted for in the analysis (Table 7.14). Mothers’ smoking during

the entire pregnancy was not available. An association would have been

missed only if there was a differential number of case mothers (compared to

control mothers) who smoked later in the pregnancy, and if smoking in the

second and third trimesters are more likely to be associated with risk. More

importantly, the follow-up period only allowed ascertainment of leukemia

up to 5 years of age so that associations between risk of leukemia at older

ages and maternal smoking could not be evaluated.

Of the case-control studies on childhood leukemia (Van Steensel-Moll et

al., 1985; Severson et al., 1993) or childhood cancers which included

leukemia (Stjernfeldt et al., 1986a & b; McKinney and Stiller, 1986; Buckley

et al., 1986; Magnani et al., 1990; John et al., 1991) (see Section 7.1.2), a significant association between mothers’ smoking during the index pregnancy

and risk of ALL was observed in two studies (Stjernfeldt et al., 1986a & b;

John et al., 1992) (see Section 7.1.2 for study details). Compared to children of nonsmokers, subjects whose mothers smoked 10+ cigarettes/day

showed about a 2-fold increased risk in one study (RR = 2.1, 95% CI = 1.3-

3.3) (Stjernfeldt et al., 1986a & b) and a 3-fold increased risk in another (RR

= 2.9, 95% CI = 1.2-6.8) (John et al., 1991) (Table 7.14). A subsequent

report by Stjernfeldt et al. (1992) confirmed that the effect of mothers’

smoking was independent of the risk associated with diagnostic X-rays.

Among subjects whose mothers had not had X-ray exposure during pregnancy, the ORs for ALL were 1.3 and 2.2, respectively if mothers smoked 1-

9 and 10+ cigarettes/day compared to children of nonsmokers. The corresponding ORs were 1.8 and 3.6 in the group whose mothers had had X-ray

exposure. In the other positive study (John et al., 1991), mothers’ and

fathers’ smoking together was associated with about a 2-fold increased risk

(OR = 2.2, 95% CI = 1.0-5.0). The OR for ALL was 2.9 (95% CI = 0.8-10.3)

when only mothers smoked and 1.7 (95% CI = 0.7-3.8) when only fathers

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Chapter 7
smoked. Mothers’ smoking prior to conception, during the first trimester

of pregnancy, and during the entire pregnancy were all associated with

increased risks of ALL, and it was not possible to determine the effect of

mothers’ smoking prior to versus during pregnancy. The effect of parental

smoking was specific to ALL. There was no increased risk of other

leukemias in relation to smoking of mothers and fathers (OR = 1.0, 95% CI

= 0.2-4.2) (John et al., 1991).

Five case-control studies are not supportive of an association between

childhood leukemia risk and ETS exposure. One study was conducted in the

Netherlands, using a complete nationwide register of histologically-confirmed childhood leukemia cases diagnosed between 1973 and 1980 (Van

Steensel-Moll et al., 1985). Seven hundred and thirteen children, aged less

than 15 years, were diagnosed with leukemia during this time period.

Using the census lists available by municipality, two controls with the same

date of birth (within two months), the same sex, and who lived in the same

municipality as the case at the time of diagnosis were randomly selected.

The second control served as replacement if the first control did not

respond. Between 1981 and 1982, parents of cases and controls were sent a

questionnaire which asked about maternal events before and during pregnancy of the index subjects. A total of 625 leukemia patients and 615 controls responded, representing response rates of 90 percent, 70 percent, and

68 percent, respectively, for the parents of leukemic patients, and first and

second controls. Analyses were restricted to 519 patients with ALL and 507

controls. Mothers of ALL cases and controls did not differ in their smoking

habits in the year before pregnancy (age- and sex-adjusted RR = 1.0, 95% CI

= 0.8-1.3) or during pregnancy (age- and sex-adjusted RR = 1.0, 95% CI =

0.7-1.3).

A second study not supportive of an association was reported by

McKinney and Stiller (1986) (see Section 7.1.2 for study details). In this

study, 93 of the 171 leukemias were non-ALL (McKinney et al., 1987).

Thus, if an association between ETS and leukemia is specific for ALL, an

analysis including all leukemias combined may have diluted an ETS effect.

Another study which did not find an association between ALL and parental

smoking during the index pregnancy was reported by Buckley et al. (1986)

(see Section 7.1.2). This study was published as a letter to the editor, and

few details were provided.

No association between parental smoking and risk of leukemia in children was found in a hospital-based case-control study conducted in the

main pediatric hospital in Turin, Italy between 1981 and 1984 (Magnani et

al., 1990). There were a total of 142 children with ALL, 22 with non-ALL,

and 19 with non-Hodgkins lymphoma (NHL). These were compared to 307

controls who were identified by a random sampling of children hospitalized

in the medical or surgical wards of the hospital. Data on parental smoking

habits, parental occupation, ionizing radiation, and childhood diseases were

collected using a standard questionnaire administered to a relative of the

child while the child was still in the hospital. After adjusting for socioeconomic status, risk of ALL was not associated with mothers or father’s smoking habits up to the birth of index subject (Table 7.15). It is difficult to

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Smoking and Tobacco Control Monograph No. 10
interpret results from this study because of several methodologic limitations. Factors such as residence and socioeconomic status may have affected the selection of cases and controls in this hospital-based study. In addition, there were no records of potential hospital controls that were missed

because of early discharge during the first two years of this study. Finally,

both incident and prevalent cases were included as eligible cases.

A fifth study, restricted to acute myeloid leukemia (AML) also did not

find an association with maternal smoking. AML is the most frequently

diagnosed leukemia in adults and is the subtype most consistently associated with active smoking (Austin and Cole, 1986; Brownson et al., 1993b).

However, AML is less common in children, representing about 15 percent of

leukemia in children. This case-control study was a multicentered study

conducted as part of the Childrens Cancer Group studies of in utero and

postnatal exposures. Cases were identified through the registration files of

the Children’s Cancer Group, a cooperative clinical trials group which

included about 100 primary and affiliate institutions throughout North

America. Eligible cases in this study included patients newly diagnosed

with AML from January 1980 through December 1984 who were 18 years of

age or younger at the time of diagnosis. A total of 187 matched case-control pairs were interviewed, representing completion rates of 71 percent

among eligible cases (n = 187) and 78 percent among eligible controls (n =

262). The objective was to interview one control per case matched to cases

on age, race, and telephone area code and exchange, and selected by random digit dialing. 

Mothers and fathers of study subjects were interviewed separately by

telephone. As part of the interview, both the mother and the father were

asked about cigarette smoking status (current, past, or never) and smoking

practices during: a) the month immediately preceding the index pregnancy;

b) the index pregnancy; and c) nursing. Detailed information was requested regarding the trimesters in which the parent smoked and the number of

cigarettes smoked per day during the pregnancy. Mothers of children with

AML were less likely to be current smokers, i.e., smoking cigarettes at the

time of interview. However, mothers of children with AML were more likely to have ever smoked (OR = 1.32, 95% CI = 0.85-2.09) or smoked during

pregnancy (OR = 1.20, 95% CI = 0.77-1.86) although these results were not

statistically significant. The authors indicated that paternal smoking was

also not associated with risk of AML (results on paternal smoking were not

shown). 

7.4.4.4 Summary In adults, the association between ETS exposure and hematopoietic tumors was addressed in only one study. That study (Sandler et al.,

1985b) reported increased risk in relation to mothers’ and fathers’ smoking

during childhood. The epidemiologic evidence for parental smoking and

risk of leukemia in children is conflicting. No association between ETS

exposure and risk of leukemia was found in the only cohort study, and a

significant positive association, specifically for ALL was observed in 2 of the

7 case-control studies. In one of the two studies which found an increased

risk with mothers’ smoking, fathers’ smoking was available and appeared to

have an independent effect on risk. The range of ORs associated with

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Chapter 7
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# Cases Smoking OR (95% CI) OR (95% CI)

Cohort Studies (Type of Habits Maternal Paternal 

(Age of Subjects) Leukemia) (cig/day) Smoking Smoking

Pershagen et al., 1992 All Leukemia 2-3 mos of pregnancy

(Age ≤ 5) 72 No 1.0 Not available

18 1-9 0.9 (0.6-1.6)

9 10+ 0.7 (0.4-1.5)

21 (lymphatic) Yes 0.8 (0.5-1.3)

6 (myeloid) Yes 1.6 (0.6-4.8)

# Cases/ Smoking OR (95% CI) OR (95% CI)

Case-Control Studies # Controls Habits Maternal Paternal 

(Age of Subjects) (Type)a (cig/day) Smoking Smoking

Van Steensel-Moll 519/507 Yes, yr before

et al.,1985 (ALL) Pregnancy 1.0 (0.8-1.3) Not available

(Age ≤ 15)

Yes, during

pregnancy 1.0 (0.7-1.3)

During pregnancy

Stjernfeldt et al., 1986 132/340 1-9 1.3 (0.7-2.6) Not available

(Age ≤ 16) (ALL) 10+ 2.1 (1.3-3.3)

During pregnancy

McKinney et al., 1986 171/342 1-10 1.0 (0.6-1.7) No association

(Age ≤ 15) (78 ALL, 11+ 0.6 (0.4-1.0)

93 non-ALL)

During pregnancy

Buckley et al., 1986 742/740 1-9 1.0 (0.6-1.5) No association

(Age ≤ 15) (ALL) 10+ 0.9 (0.7-1.1)

Magnani et al., 1990 142/307 Smoking up to child’s birth

(Not specified) (ALL) Yes 0.7 (0.5-1.1) 0.9 (0.6-1.5)

1-15 cig/day 0.6 (0.4-1.0) 0.9 (0.5-1.6)

16+ cig/day 1.0 (0.4-2.7) 0.9 (0.6-1.5)

22/307

(non-ALL) Yes 2.0 (0.8-4.8) 0.9 (0.3-2.1)

Table 7.15

Maternal or Parental Smoking During Pregnancy and

Childhood Leukemia
mothers’ smoking at least 10 cigarettes per day during pregnancy was 2.1 to

2.9 and 1.6 for fathers’ smoking at least 10 cigarettes per day. With respect

to the relationship of ETS exposure and childhood leukemia, there is no satisfactory explanation for the inconsistent results between the case-control

studies not supportive of an association (Van Steensel-Moll et al., 1985;

McKinney and Stiller, 1986; Buckley et al., 1986; Magnani et al., 1990;

Severson et al., 1993) and those supportive of an association (Stjernfeldt et

al., 1986a & b; John et al., 1991).

There are several difficulties in trying to reconcile these different findings. First, most of the studies did not present sufficient information to

allow comparison of the prevalence of maternal and paternal smoking in

the studies. Second, it is not known whether the age distributions of

leukemia or ALL were similar in the studies showing an association and

those showing no association. It is conceivable that the effect of ETS on

risk of leukemia may vary by age. Risk factors for leukemia diagnosed in

children aged 3-4 are likely to differ from those in children diagnosed with

leukemia in their teens. Thus, the relative roles of intrauterine ETS exposure, prenatal esposure, and postnatal exposure to ETS may differ depending on the age at onset of leukemia. Third, the source and types of subjects

used as controls may be particularly important. Controls selected from general practitioner lists and hospital admissions for minor conditions may be

biased with respect to tobacco-smoke exposure since maternal smoking has

been associated with various conditions, including nonmalignant lung dis341

Chapter 7

# Cases Smoking OR (95% CI) OR (95% CI)

Cohort Studies (Type of Habits Maternal Paternal 

(Age of Subjects) Leukemia)a (cig/day) Smoking Smoking

During 3 During 

trimesters pregnancy

John et al., 1991 73/196 1-10 2.0 (0.7-5.9) 2.6 (0.9-7.9)

(Age ≤ 14) (ALL) 11-20 2.9 (1.2-6.8) 1.6 (0.7-3.7)

21+ 1.6 (0.7-4.0)

Parent smoking in 

absence of other parent

2.9 (0.8-10.3) 1.7 (0.7-3.8)

(non-ALL) During 3 During 

trimesters pregnancy

Yes 0.6 (0.1-3.0) 0.8 (0.2-2.3)

Severson et al., 1993 187/187 During pregnancy

(Age ≤ 18) (acute Yes 1.2 (0.8-1.9) No association

myeloid 

leukemia)

Table 7.15 (Continued)

a ALL = Acute lymphocytic leukemias, non-ALL = non acute lymphocytic leukemias.
eases. Fourth, the role of potential confounders including the effect of

socioeconomic status may be especially important. In some studies, adjustment for paternal education level reduced the risks in relation to ETS exposure (John et al., 1991), suggesting that perhaps both paternal and maternal

education level should be adjusted for in the analysis.

Despite the fact there are eight studies on ETS exposure and parental

smoking, and that most of these studies had relatively large sample sizes, a

conclusion regarding the association cannot be reached for the reasons

mentioned above. Future studies would need to distinguish between ALL

and non-ALL, and to examine the risk pattern by age of diagnosis of

leukemia (e.g., ≤5, 6-10, ≥11 years of age). In addition, the studies should

be designed to minimize selection bias of cases and controls (i.e., by making

sure that factors such as residence, medical coverage, and socioeconomic

status do not influence selection into study), to minimize information bias

(i.e., by obtaining necessary information on maternal and paternal smoking

during, and after the index pregnancy), and to be able to adjust for potential confounders in the analysis.

The effect of ETS exposure and risk of lymphomas and nonHodgkin’s lymphomas (NHL) was examined in six studies of

childhood cancers (Table 7.16). In one case-control study

with 169 cases of NHL (Buckley et al., 1986), there was no association

between maternal smoking during pregnancy and risk (Table 7.15), whereas

increased risks were reported in two small studies (less than 20 cases of NHL

in each) (Stjernfeldt et al., 1986a & b; Magnani et al., 1990). Two studies

offered information on risk of lymphomas and exposure to ETS (McKinney

and Stiller, 1986; John et al., 1991). McKinney and Stiller, (1986) found a

90 percent increase in risk of lymphomas in subjects whose mothers’

smoked 1-10 cigarettes/day during pregnancy, but there was no increased

risk for subjects whose mothers who smoked more. John et al. (1991)

reported an increased risk of lymphoma in relation to fathers’ smoking during the index pregnancy (RR = 1.9, 95% CI = 0.7-4.8) and mothers’ smoking

during all three trimesters of pregnancy (RR = 1.9, 95% CI = 1.0-7.6). There

were, however, too few cases in this study (n = 26) to investigate the association by amount smoked by mothers or fathers. In the cohort analysis by

Pershagen et al. (1992), maternal smoking was associated with an increased

risk for cancers of the hematopoietic and lymphatic system (excluding

leukemia). Children whose mothers smoked at 2-3 months of pregnancy

showed an elevated risk for reticulosis (RR = 1.7, 95% CI = 0.6-5.0, based on

16 cases) and tumors of other hematopoietic and lymphatic systems (RR =

2.0, 95% CI = 0.7-5.5, based on 14 cases). For this group of cancers combined, the RR was 2.4 (95% CI = 1.0-5.5) for subjects whose mothers’

smoked less than 10 cigarettes/day, but an increased risk was not observed

for subjects whose mothers smoked more.

In summary, the data on ETS exposure and risk of lymphomas and NHL

are inadequate. Although small increased risks have been reported in some

studies, the results are difficult to interpret given that they were based on

small numbers, with wide confidence limits, and the dose-response trends

were largely not smooth.

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7.4.5 Lymphomas

and Non-Hodgkin’s

Lymphomas 
A few epidemiologic studies have examined the potential impact of maternal smoking and ETS exposure on

rare childhood cancers. These studies are discussed

below.

Neuroblastoma is an embryonal tumor of the sympathetic nervous system diagnosed primarily in infancy. Extrinsic factors that

influence the risk of neuroblastoma are likely to act while the child is in

utero, or perhaps upon parental germ cells prior to conception. Thus, the

focus of etiologic investigations is on parental exposures during and prior

to the prenatal period.

Kramer et al. (1987) conducted a case-control study of neuroblastoma

focusing on both family medical history and parental medical and drug

exposures prior to birth of the index child. Histologically confirmed cases,

identified by the Greater Delaware Valley Pediatric Tumor Registry between

1970 and 1979, were included. One population control per case was selected by random-digit dialing. Controls were matched to cases by date of

birth (±3 years), race, and cases’ telephone number (area code and first five

digits). Of the 139 eligible cases (74.8 percent), 104 were successfully interviewed. These cases were compared to 101 of 177 controls who were interviewed (57.1 percent). A small increased risk was observed for mother’s

smoking during pregnancy (OR = 1.26, 90% CI = 0.76-2.09) and at any time

prior to conception of the index child (OR = 1.26, p = 0.20). Father’s smoking during the 2 years prior to birth of the index child conferred a similar

increase in risk (OR = 1.30, 90% CI = 0.83-2.05). The RR for father’s smoking was stronger (OR = 1.60, 90% CI = 0.94-2.74) when his smoking habits

any time prior to the index child’s birth was considered.

Smoking is an established risk factor for cancers of the kidney

and renal pelvis in adults (IARC, 1986). Induction of Wilms’

tumors in rodents by transplacental N-ethylnitrosourea has been described

(Hard, 1985), suggesting that nitrosamines, including tobacco-specific

nitrosamines, may have an etiologic role in these tumors. 

The role of ETS exposure and risk of Wilms’ tumor of the kidney has

been evaluated in four studies. One study was designed specifically to identify risk factors for Wilms’ tumors (Bunin et al., 1987), whereas in three

other studies Wilms’ tumors were one of the childhood cancers presented

in the analysis (Stjernfeldt et al., 1986; McKinney and Stiller, 1986; Buckley

et al., 1986).

Bunin et al. (1987) conducted a hospital-based case-control study of

Wilms’ tumor to examine the role of gestational risk factors. Histologically

confirmed Wilms’ tumor diagnosed among whites aged 15 years or younger

between 1970 and 1983 were included. Controls were selected by randomdigit dialing and were pair-matched to cases on year of birth (±3 years),

race, and telephone area code and exchange. Of the 124 eligible cases, 88

were included and were compared to 88 of the 159 controls identified (participation rates were 71 percent and 55 percent, respectively). The authors

reported that there is no association between maternal smoking during

pregnancy and risk of Wilms’ tumor (data were not presented).

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Chapter 7

7.4.6 Other Rare

Childhood Cancers

7.4.6.1 Neuroblastoma

7.4.6.2 Wilms’ Tumor

of the Kidney
There is no evidence for a role of maternal smoking and risk of Wilms’

tumor in the study conducted by McKinney and Stiller (1986). Based on 32

cases of Wilms tumors, the RRs were 0.86 (95% CI = 0.3-2.6) and 1.17 (95%

CI = 0.4-3.5), respectively, for subjects whose mothers smoked 1-10, and

11+ cigarettes during pregnancy compared to subjects whose mothers were

nonsmokers. However, in two studies, there was some suggestion of a small

increased risk in relation to maternal smoking. Buckley et al. (1986) (n = 61

kidney cancers) reported RRs of 1.58 (95% CI = 0.60-4.18) and 0.93 (95% CI

= 0.47-1.83), respectively, for subjects whose mothers smoked 1-9 and 10+

cigarettes per day during pregnancy compared to children of nonsmokers.

In the other study, the corresponding RRs were 0.70 (95% CI = 0.1-5.6) and

2.53 (95% CI = 0.9-7.2) in an analysis which included only 16 cases of kidney cancer (Stjernfeldt et al., 1986a & b).

7.4.6.3 Germ Cell Tumors Germ cell tumors include teratomas, yolk sac tumors,

and germinoma. In 1980-1982, the Inter-Regional Epidemiological Study of

Childhood Cancer (IRESCC) interviewed the parents of 555 children with

newly diagnosed cancer and the parents of 1,100 control children chosen

from hospital admissions and general practitioner lists (see 7.1.2, case-control studies). Two controls were individually matched to each case interviewed. Characteristics of mothers and their exposures during the index

pregnancy were compared for 41 children with germ cell tumors and 82

controls (McKinney and Stiller, 1986). Mothers of cases and controls did

not differ in their smoking habits during 1 year prior to or 1 month prior to

the index pregnancy (44 percent of case mothers smoked compared to 42

percent of control mothers). Smoking patterns of fathers were also comparable (56 percent of case fathers compared to 57 percent of control fathers

smoked).

Bone and soft tissue sarcomas account for about 10 percent of

childhood cancers (Li, 1982). The main types of bone tumors

are osteosarcoma and Ewing’s tumor, and the main type of soft-tissue sarcoma is rhabdomyosarcoma (RMS).

Grufferman et al. (1982) conducted a case-control study of childhood

RMS by including the families of 33 cases and 99 controls. All incident

cases of childhood RMS diagnosed in North Carolina residents during 1967-

1976 were considered eligible (37 were eligible). For each of the cases interviewed, 3 controls of the same age (±2 months), sex, and race were randomly selected from North Carolina birth certificates. Of the 99 controls first

selected, 70 were successfully interviewed. Risk of RMS was not related to

mothers’ smoking at any time (RR = 0.8, 95% CI = 0.3-2.0), or mothers’

smoking during the pregnancy of the index subject (RR = 1.0, 95% CI = 0.4-

2.4). On the other hand, fathers’ smoking was a statistically significant risk

factor (RR = 3.9, 95% CI = 1.5-9.6). The point estimate of the risk in relation to fathers’ smoking diminished when the analysis accounted for family

income and fathers’ education and occupation (RR = 2.8, p = 0.07).

As part of the IRESCC study (see 7.1.2, Case-control studies), characteristics of mothers and their prenatal exposures were compared for 43 cases

with soft tissue tumors, 30 cases with bone sarcomas, and their 146

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7.4.6.4 Bone and SoftTissue Sarcomas
345

Chapter 7

Relative

Studies Exposure to Passive Smoking Risk 95% CI

Stjernfeldt et al., 1986 Non-Hodgkins Lymphoma (n = 16)

Mother’s smoking during pregnancy

0 (cig/day) 1.0

1-9 1.9 (0.3-6.7)

10+ 2.1 (0.7-6.4)

Hodgkins Lymphoma (n = 15)

0 (cig/day) 1.0

1-9 1.1 (0.2-4.9)

10+ 0.3 (0.1-2.2)

Buckley et al., 1986 Non-Hodgkins Lymphoma (n = 169)

Mother’s smoking during pregnancy

0 (cig/day) 1.0

1-9 0.8 (0.3-1.8)

10+ 1.0 (0.7-1.4)

Magnani et al., 1990 Non-Hodgkins Lymphoma (n = 19)

Mother’s smoking up to child’s birth 1.7 (0.7-4.5)

Father’s smoking up to child’s birth 6.7 (1.0-43.4)

McKinney and Lymphomas (n = 74)

Stiller, 1986 Mother’s smoking during pregnancy

0 (cig/day) 1.0

1-10 1.9 (0.9-4.0)

11+ 1.0 (0.5-2.1)

John et al., 1991 Lymphoma (n = 26)

Mother’s smoking

-Three months prior to conception 1.9 (0.7-5.2)

-First trimester of pregnancy 2.5 (0.9-7.0)

-All three trimesters of pregnancy 2.7 (1.0-7.6)

Father’s smoking during pregnancy 1.9 (0.7-4.8)

Pershagen et al., 1992 Hematopoietic and Lymphatic

excluding leukemia (n = 30)

Mother’s smoking at 2-3 months of pregnancy

0 (cig/day) 1.0

1-9 2.4 (1.0-5.5)

10+ 1.1 (0.3-3.6)

Table 7.16

Association Between Exposure to Passive Smoking and Risk of Non-Hodgkins

Lymphoma and Lymphoma in Children
matched controls (McKinney and Stiller, 1986; Hartley et al., 1988).

Compared to children whose mothers were nonsmokers, children whose

mothers smoked 1-10, and 11+ cigarettes/day during pregnancy showed RRs

of 1.37 (95% CI = 0.53-3.55) and 1.47 (95% CI = 0.56-3.84) respectively for

soft tissue sarcomas. The corresponding RRs were 1.48 (95% CI = 0.46-4.74)

and 2.16 (95% CI = 0.68, 6.85) for bone tumors (McKinney and Stiller,

1986). In a more detailed report on risk factors for these two tumor sites,

Hartley et al. (1988) described that “mothers’ and fathers’ smoking history

before and during the index pregnancy did not show any case excess” and

did not elaborate on the findings.

No association between paternal and maternal smoking habits and risk

of RMS and non-RMS-soft tissue sarcomas (STS) was reported by Magnani et

al. (1989). In this hospital-based case-control study conducted in 1983-

1984 in Torino and Padova, Italy, there were a total of 36 RMS, 16 nonRMS-STS, and 326 controls. The RRs for fathers’ smoking 0, 1-15, and 16+

cigarettes/day up to the index child’s birth were 1.0, 0.7 (95% CI = 0.3-2.0),

and 0.8 (95% CI = 0.4-1.8), respectively. The corresponding RRs for mothers’ smoking were 1.0 (95% CI = 0.4-2.3), and undefined (0 cases and 17

controls) (Magnani et al., 1989).

The role of ETS in the etiology of soft tissue sarcomas is unclear, particularly in the case of RMS. Although the association between RMS and

fathers’ smoking reported by Grufferman et al. (1982) is intriguing, it has

not been confirmed. These authors proposed that there may be a direct

carcinogenic effect introduced either in a prezygotic manner or by passive

inhalation of cigarette smoke by the patients. Evans et al. (1981) found

morphologic sperm abnormalities in cigarette smokers, in support of a

direct mutagenic effect of fathers’ cigarette smoking.

7.4.6.5 Summary The epidemiologic evidence on ETS exposure and other rare

childhood cancer is inadequate. Given that these are rare events, most of

the studies are limited by small sample sizes, and any effect of ETS exposure

is not likely to be statistically significant. Thus, it is important to evaluate

these studies in terms of the collective evidence, the direction of the risk

estimates from individual studies, and possible biases (i.e., confounding by

social class, or other antenatal exposures) in explaining the findings. 

In studies on all cancers (combined), there is limited

evidence (two cohort and one case-control study) that

exposure to spousal smoking may increase overall risk of cancer (including

lung) in nonsmoking women. However, when cancers of the lung were

excluded from the analysis, risk elevations for other cancers were not significant.

With respect to lung cancer, three large U.S. population-based studies

and a smaller hospital-based case-control study have been published since

the most recent comprehensive review (U.S. EPA, 1992); the three population-based studies were designed to and have successfully addressed many

of the weaknesses for which the previous studies on ETS and lung cancer

have been criticized. Results from these studies and the smaller case-con346

Smoking and Tobacco Control Monograph No. 10

7.5 CHAPTER SUMMARY

AND CONCLUSIONS
trol study are compatible with the causal association between ETS exposure

and risk of lung cancer in nonsmokers already reported by the U.S. EPA

(1992), Surgeon General (U.S. DHHS, 1986) and NRC (1986).

Although there have been only three studies on ETS exposure and nasal

sinus cancers, all three studies showed a consistent association between

exposure and risk, presenting strong evidence that exposure to ETS increases the risk of nasal sinus cancers in nonsmoking adults. Future studies need

to characterize the magnitude of risk between nasal sinus cancer and ETS

exposure and the dose-response relationship. The epidemiological and biochemical evidence suggests that exposure to ETS may increase the risk of

cervical cancer in nonsmokers. On the other hand, although the biochemical data suggest that ETS is a plausible carcinogen for bladder cancer in

nonsmokers, the limited epidemiologic data are not supportive of an association. There is insufficient evidence to draw any conclusion regarding the

relationship between ETS exposure and adult cancers of the bladder, breast,

stomach, or brain at this time. 

In children, the evidence is unclear as to whether paternal smoking

increases the risk for all childhood cancers, and specifically acute lymphoblastic leukemia and brain tumors, the two leading cancer sites in children (Li, 1982). The uncertainty about the association between ETS exposure and increased risks in these two tumor sites is due largely to the conflicting results reported and the limitations of the studies finding no association. On the other hand, the association between ETS exposure and other

childhood tumors is difficult to study because of the limited number of subjects with the specific cancers in most studies.

Despite the uncertainty in epidemiological data on childhood cancers

and ETS exposure, an ETS effect on risk of childhood cancer is a concern

due to both transplacental and passive smoke exposure. Studies to date

were not designed to distinguish between transplacental exposure (i.e.,

mother’s smoking during pregnancy), prenatal ETS exposure (i.e., father’s

smoking during pregnancy), and postnatal ETS exposure (i.e., mother’s and

father’s smoking after birth and any other relevant sources of ETS exposure). In fact, most studies only had information on mother’s smoking during pregnancy, or mother and father’s smoking during pregnancy.

However, even if the data were available, it would be a challenge to separate

the long-term effects of in utero exposure to maternal smoking, and the

effects of prenatal and postnatal ETS exposure on the risk of cancer in children. This is because maternal and paternal smoking behavior during pregnancy and after delivery are closely linked. In any case, a transplacental

effect or an ETS effect is biologically plausible. The demonstration of a 4-

fold higher mean level of carcinogen-hemoglobin adducts in fetuses of

smoking mothers as compared to fetuses of nonsmoking mothers, and the

approximately 60 percent higher hemoglobin adduct levels in nonsmoking

mothers with high levels of ETS exposure compared to those with low

exposure, suggest that in utero exposure may be more concentrated

(Coghlin et al., 1991; Hammond et al., 1993) (see Section 7.1.2; Table 7.2).

347

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8.0 INTRODUCTION In this chapter, epidemiologic studies and other human

data regarding the relationship between coronary heart disease (CHD) and

exposure to environmental tobacco smoke (ETS) by nonsmokers are

reviewed, and the overall weight of evidence for an association is presented.

In addition to the human evidence, there is confirmatory animal evidence

(e.g., Glantz and Parmley, 1991 and 1995) which is summarized briefly.

CHD includes a spectrum of clinical manifestations, the major forms of

which are myocardial infarction (MI), angina pectoris (AP), and sudden

unexpected death (SUD) which occurs in persons with no prior history of

CHD. Etiology for the various heart-disease endpoints and their occurrence

have been examined in detail (U.S. DHHS, 1983 and 1990; Kannel, 1976).

Different terms have been used to represent CHD in the literature, including ischemic heart disease (IHD), and arteriosclerotic heart disease (AHD).

For uniformity, CHD will be used throughout this chapter. Results by specific endpoints (i.e., MI, SUD, or AP) or for cardiovascular mortality versus

morbidity will be presented separately when such data are available.

8.0.1 Active Smoking A causal association between active smoking and CHD is

well established (U.S. DHHS, 1983 and 1990). Evidence from case-control

and cohort studies has clearly revealed a higher risk of MI, SUD, and other

deaths from CHD in cigarette smokers than in nonsmokers. Although

smoking clearly provokes AP (Friedman et al., 1975) and risks of AP are elevated in smokers compared to nonsmokers in some studies (Willett et al.,

1987; Beard et al., 1989; Hagman et al., 1987), the association has not been

observed consistently, and the association with smoking tends to be weaker

for AP than for other heart disease endpoints (Kannel, 1976 and 1981). The

excess risk of CHD morbidity and mortality in relation to smoking extends

to all age groups, to both genders, and to populations within and outside

the U.S. The data are generally supportive of a dose-response relationship

in that the risks increase with increasing duration of smoking, increasing

number of cigarettes smoked, and with increasing depth of inhalation. 

Since 1984, some 18 studies have examined the association between environmental tobacco smoke (ETS)

and risk of CHD in nonsmokers. In 1986, this literature was first reviewed qualitatively in A Report of the

Surgeon General (U.S. DHHS, 1986) and a report from the National Research

Council (NRC, 1986). Available for the 1986 reviews were data from three

cohort studies (Hirayama, 1984; Gillis et al., 1984; Garland et al., 1985) and

one case-control study (Lee et al., 1986). Both 1986 reviews concluded that

an association between ETS and CHD was biologically plausible but the epidemiological evidence was inconclusive. A 1990 review (Wu-Williams and

359

Cardiovascular Health Effects

8.0.2 Previous Reviews on

Environmental Tobacco

Smoke and Coronary Heart

Disease in Nonsmokers
Samet, 1990) included results from two additional cohort studies (Svendsen

et al., 1987; Helsing et al., 1988). These authors concluded that in all

“prospective studies, there was an excess of heart disease mortality among

nonsmokers with ETS exposure although the exposure-response relationship

is not clear.”

In addition, five more quantitative reviews have been published: Wells

(1988); Glantz and Parmley (1991); Steenland (1992); Wells (1994); Glantz

and Parmley (1995). Four of these reviews included a meta-analysis to calculate a pooled relative risk for CHD in relation to ETS exposure (Wells,

1988; Glantz and Parmley, 1991; Wells, 1994; Glantz and Parmley, 1995).

The 1988 review by Wells included five cohort studies (Hirayama, 1984;

Gillis et al., 1984; Garland et al., 1985; Svendsen et al., 1987; Helsing et al.,

1988) and two case-control studies (Lee et al., 1986; Martin et al., 1986

(unpublished)). Based on 1,522 CHD events in females and 443 CHD

events in males, Wells (1988) calculated that the odds ratio (OR) for CHD in

relation to ETS exposure was 1.23 (95% CI = 1.1-1.4) for females and 1.31

(95% CI = 1.1-1.6) for males.

The subsequent review by Glantz and Parmley (1991a) summarized

results from ten studies; four were new studies published between 1989 and

1990, which were not covered in previous reviews (He et al., 1989; Hole et

al., 1989; Humble et al., 1990; Butler, 1988). These authors presented

results from the individual studies separately for males and females and calculated a significantly elevated pooled risk estimate for males (relative risk

(RR) = 1.3, 95% CI = 1.1-1.6), for females (RR = 1.3, 95% CI = 1.2-1.4), and

for both genders combined (RR = 1.3, 95% CI = 1.2-1.4). This review also

discussed possible mechanisms for an ETS effect on heart disease in nonsmokers. An updated review of this subject was published by the same

authors in 1995 (Glantz and Parmley, 1995).

Wells’ 1994 review included results from 13 studies; eight of these studies were not included in his 1988 review (Hole et al., 1989; Humble et al.,

1990; Butler, 1988; Dobson et al., 1991a; He et al., 1994; La Vecchia et al.,

1993; Jackson, 1989; Sandler et al., 1989 (this covered the same study as

Helsing et al., 1988)). Pooled risk estimates for CHD morbidity and mortality in relation to ETS exposure were presented for males and females both

separately and combined. Risk estimates were presented with and without

correction for misclassification bias of smokers as nonsmokers. In women

the OR was 1.51 (95% CI = 1.2-2.0) for CHD morbidity and 1.23 (95% CI =

1.11-1.36) for CHD mortality in association with ETS exposure. The corresponding ORs in men were 1.28 (95% CI = 0.91-1.81) and 1.25 (95% CI =

1.03-1.51). The ORs for CHD morbidity and mortality in women and men

were almost unchanged after correction for misclassification bias. 

Also included in some of these reviews were estimates of the number of

CHD deaths in nonsmokers that could be attributed to ETS exposure (Wells,

1988; Steenland, 1992; Wells, 1994). Steenland’s review (1992)1 covered

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Smoking and Tobacco Control Monograph No. 10

1 Steenland’s review included a 1991 study (Dobson et al., 1991); excluded the abstract by

Butler (1988); and did not cite Gillis et al. (1984), who presented preliminary findings on the

same study population covered by Hole et al. (1989).
essentially the same studies as the review by Glantz and Parmley (1991a),

and in addition, estimated the number of CHD deaths in nonsmokers and

former smokers that could be attributable to ETS. Steenland concluded

that some 28,000 deaths in U.S. never-smokers and 19,500 deaths in U.S.

former smokers (who had stopped smoking at least 15 years before the

study) could be attributed to ETS exposure. To conduct this analysis,

Steenland applied the age- and sex-specific CHD rates for U.S. never-smokers estimated from cohort studies conducted in the 1970s and 1980s; the

prevalence of exposure to ETS among nonsmoker controls reported in casecontrol studies conducted during the same time period; and the relative risk

of CHD in nonsmokers associated with ETS exposure from the study by

Helsing et al. (1988), the largest U.S. study on ETS and risk of CHD in nonsmokers. These results are very similar to those presented by Wells (1988,

1989, 1990) who used somewhat different methods and assumptions in his

calculations. In another study, Wells (1994) estimated that 62,000 deaths

from ischemic heart disease in the U.S. in 1985 were due to ETS exposure.

One possible reason for the considerably higher estimate in the 1994 review

is the higher CHD death rates in 1985, both overall and in never-smokers

compared to the never-smoker death rates that were used in the earlier risk

assessments. Moreover, Wells (1994) assumed that the ETS exposure from

background sources (i.e., other than from spouses) was higher than that

assumed in the previous reviews and applied methodology that the U.S.

EPA (1992) used in estimating the lung cancer burden of ETS exposure.

The conclusions of the reviews by Glantz and Parmley (1991a) and

Steenland (1992) were endorsed by the American Heart Association (Taylor

and Johnson, 1992). However, critics of the review by Glantz and Parmley

(Huber and Brockie, 1991; Simmons, 1991; Holcomb, 1991; Decker, 1991;

Mantel, 1992) questioned the reviewers’ interpretation of the epidemiological data and the meaningfulness of relative risk estimates that were less

than 3.0. They also questioned the authors’ method of deriving the pooled

risk estimate, and the inclusion of “positive” findings that were not statistically significant. The critics attributed the observed association between

ETS and heart disease to biases, including inadequate adjustment or lack of

adjustment for potential confounders in some studies. Glantz and Parmley

(1991b, 1991c, 1992) discounted these criticisms in their responses. A second line of criticism questioned the fundamental relationship between

active smoking and CHD in women (Seltzer, 1991a & b) and whether the

magnitude of effect observed between CHD and passive smoking is plausible after asserting that the association with active smoking is relatively

weak (Mantel, 1992; Skrabanek, 1992). 

8.0.3 Chapter Overview This chapter will include, first, a description of each of

the studies on ETS and CHD in terms of the design of study, measures of

exposures, information on potential confounders, and the main study findings (Section 8.1). The studies included in this review represent all the published studies on this topic that had been included in either the review by

Glantz and Parmley (1991a) or by Steenland (1992), as well as five case control studies (Jackson et al., 1991; He et al., 1994; La Vecchia et al., 1993;

Layard, 1995; Muscat and Wynder, 1995), two analyses of the same cohort

361

Chapter 8
data set (LeVois and Layard, 1995; Steenland et al., 1996), and a recent

report of a cohort analysis (Kawachi et al., 1997) of the Nurses’ Health

Study. Second, in Section 8.2 the effect of bias on the risk estimates in

these studies will be discussed. The main sources of bias are misclassification of smokers as nonsmokers, the lack of control for potential confounders, and misclassification of ETS exposure. Also in Section 8.2, the

biological plausibility of an association between ETS and CHD will be discussed by comparing this link to the association between active smoking

and CHD. Finally, in Section 8.3 supportive data, primarily the acute

effects of ETS on cardiovascular function in nonsmokers will be presented.

These include a discussion of the effects of ETS exposure on internal and

common carotid wall thickness, endothelium function, exercise tolerance,

lipid profile, platelet function, and fibrogen levels.

The relationship between ETS and CHD in nonsmokers has

been examined in ten cohort and eight case-control studies

(summarized in Table 8.1). Eight of the cohort studies

were conducted in the United States, one in Japan, and one in Scotland.

The case-control studies were conducted in the United Kingdom, China,

Australia, New Zealand, Italy, and the United States.

In the Japanese cohort study (Hirayama, 1984), adults at

least 40 years of age who were residents in one of 29

health-center districts in Japan were enrolled in 1965.

About 90 percent of the targeted population participated in

the study and completed a questionnaire on various

lifestyle factors including smoking habits, drinking habits, and occupational

history. Mortality of the cohort was monitored by review of the annual

census of residents and death certificates. The relationship between CHD

mortality and ETS was evaluated in cohort subjects followed between 1966

and 1981.

There were 494 deaths from CHD identified among 91,540 lifetime

non-smoking women. Compared to nonsmoking women married to nonsmokers, women married to ex-smokers or smokers of 1-19 cigarettes/day,

and to smokers of 20+ cigarettes/day, showed relative risks of 1.10 (90% CI

= 0.91-1.33), and 1.31 (90% CI = 1.06-1.63), respectively for CHD (onesided p for trend = 0.019—Hirayama, 1984). The increase in relative risk of

CHD in relation to husband’s smoking was observed when the analysis was

adjusted for husband’s age (40-49, 50-59, 60-69, 70+) and occupation (Table

8.1). A later update (Hirayama, 1990) showed that similar results were

observed when adjustment was made for wife’s age. Despite the strengths

of a large sample size of nonsmoking women and of CHD deaths in this

cohort, the study’s value is lessened by the lack of information on potential

confounders of CHD, which made it impossible to adjust for other heart

disease risk factors in the analysis.

Lee (1990a) questioned the results of this study because the analysis

based on 14 years of follow-up data (i.e., from 1966-1979) did not yield a

statistically significant association, whereas the results based on 16 years of

follow-up data (i.e., with an additional 94 CHD deaths between 1980-1981)

362

Smoking and Tobacco Control Monograph No. 10

8.1 DESCRIPTION OF

EPIDEMIOLOGIC

STUDIES

8.1.1 Cohort studies

Japanese cohort study

(Hirayama, 1981, 

1984, 1990)
363

Results

Relative

Population Risksat Risk # Events (95% CI)21,895 118 1.044,184 240 1.0 (0.9-1.325,461 136 1.3 (1.1-1.6

203 2 1.0395 15 3.0

97 2 2.3

Exposure to ETSHusband’s smokinghabits:

nonsmokerex-smoker or smoked

1-19 cig/day20+ cig/day

Husband’s smoking

habits:

never-smokerex-smokercurrent smoker

GeographicalArea(Reference)Japan(Hirayama, 

1984)

San Diego(Garland 

et al., 1985)

Cohort-Yearsof Follow-up; # of Deaths Due to Heart Disease91,540 nonsmokingwomen.study conducted in1966-1981subjects followedfor 16 years494 coronary heartdisease (CHD)deaths695 currently married nonsmokingwomen.study conducted in1972-1974subjects followedfor 10 years19 CHD deaths

Table 8.1 Cohort Studies on ETS Exposure and Heart Disease
364

Results Relative Person # Events Risks Years (CHD deaths) (95% CI) 43,053 60 1.00 8,092 16 0.96 (0.6-1

2,487 4 1.40 (0.5-3

12,826 33 1.00 3,301 9 1.46 (0.7-3

8,215 28 1.53 (0.9-2

13,870 44 1.0

5,802 13 1.85 (1.0-34,670 13 1.86 (1.0-38,725 62 1.001,729 3 0.41 (0.1-13,126 10 0.61 (0.3-17,999 53 1.003,160 13 1.26 (0.7-22,420 9 0.76 (0.4-1

Exposure to ETSSpouse Pair CohortHusband’s smoking:

NeverPastCurrent

AHSMOG CohortFemalesLived with a smoker:

01-10 yrs11 + yrs

Worked with a smoker:

01-10 yrs11 + yrs

MalesLived with a smoker:

01-10 yrs11 + yrs

Worked with a smoker:

01-10 yrs11 + yrs

GeographicalArea(Reference)Loma Linda,California(Butler, 1988)

Cohort-Yearsof Follow-up; # of Deaths Due to Heart DiseaseSpouse Pair Cohort9,785 nonsmokingSeventh-DayAdventistsfollowed between1976 and 198287 CHD deaths innonsmoking womenAHSMOG Cohort2,345 males and4,122 females ofwhom 1,489 malesand 3,488 neversmokedfollowed between1976 and 198270 female deathsand 76 male deathsfrom CHD in neversmokers

Table 8.1 (Continued)
365

Results

Relative

Population Risksat Risk # Events (95% CI)(CHD deaths)

959 8 1.0286 5 2.23 (0.7-6

(Fatal and nonfatal CHD)

959 48 1.0286 21 1.61 (1.0-2

(For CHD deaths)

NA NA 1.0NA NA 2.6 (0.5-12

(Fatal and nonfatal CHD)

NA NA 1.0NA NA 1.4 (0.8-2.5

Exposure to ETSWives smoking habits:

never-smokersmokernever-smokersmoker

Coworkers smoked:

NoYes

Coworkers smoked:

NoYes

GeographicalArea(Reference)18 Cities in theUnited States(Svendsen, 1987)

Cohort-Yearsof Follow-up; # of Deaths Due to Heart Disease1,245 never smoking married menstudy conducted in 1973subjects followedfor 7 years, until1982endpoints includedCHD, fatal, andnonfatal events

Table 8.1 (Continued)
366

Results Relative Population Risks at Risk # Events (95% CI) 2,434 248 1.0 1,020 122 1.31 (1.1-1

459 56 1.38 (1.1-1561 66 1.25 (1.0-1

4,259 437 1.08,086 551 1.24 (1.1-13,412 252 1.20 (1.0-14,674 299 1.27 (1.1-1

Exposure to ETSHousehold passivesmoking score:

Males:

01+1-56-12

Females:

01+1-56-12

GeographicalArea(Reference)WashingtonCounty, Maryland(Helsing, 1988)

Cohort-Yearsof Follow-up; # of Deaths Due to Heart Disease3,454 white menand 12,348 whitewomen who neversmokedstudy conducted in1963subjects followedthrough mid-1975370 CHD deaths inmen and 988 CHDdeaths in women

Table 8.1 (Continued)
367

Results

Relative

Population Risksat Risk # Events (95% CI)Angina

917 43 1.00

1,538 74 1.11 (0.7-1

IHD deaths

917 30 1.00

1,538 54 2.01 (1.2-3

Exposure to ETSMales and females:

never-smokerpassive smoker

Males and females:

never-smokerpassive smoker

GeographicalArea(Reference)Western Scotland(Hole, 1989)

Cohort-Yearsof Follow-up; # of Deaths Due to Heart Disease15,399 residentsaged 45-64, completed self-administered questionnairebetween 1972 and1976followed for anaverage of 11.5years917 never-smokers,1,538 passivesmokersendpoints: heartdisease symptomsincluding angina,and ischemic heartdisease (IHD) death

Table 8.1 (Continued)
368

Results

Relative

Population Risksat Risk # Events (95% CI)

513 76 1.59 (1.0-2.6185 NA 1.78 (0.9-3.7161 NA 1.97 (0.7-5.3167 NA 0.79 (0.3-2.0

Exposure to ETSHusband smoker vs.nonsmokerAll subjects

BlacksWhites (by socialclass): high

low

GeographicalArea(Reference)Evans County,Georgia(Humble, 1990)

Cohort-Yearsof Follow-up; # of Deaths Due to Heart Disease1,127 women, 943were nonsmokers,513 were married tonever or currentsmokersstudy conducted in1960-1961 subjects followed for20 yearsendpoints includedcardiovascular disease death (CVD),smoking relatedCVD, and all causes

Table 8.1 (Continued)
Females

OR 95% C1.08? 0.98-1.0.99 0.93-1.1.04 0.97-1.1.06 0.98-1.0.96 0.78-1.1.00 0.88-1.0.99 0.86-1.1.14 0.86-1.0.98 0.75-1.1.27 0.80-2.

369

Males

OR 95% CI0.97 0.90-1.050.95 0.83-1.090.99 0.89-1.090.98 0.85-1.180.96 0.78-1.150.97 0.87-1.080.81 0.70-0.981.36 1.10-1.681.28 1.00-1.581.13 0.81-2.11

Exposure to ETSExposed to: 

Any smoking spouse

Former smoker

#cigarettes/day

1-1920-3940+

Exposed to:

Any smoking spouse

Former smoker

#cigarettes/day

1-1920-3940+

GeographicalArea(Reference)United States(Le Vois and

Layard, 1995)

Cohort-Yearsof Follow-up; # of Deaths Due to Heart DiseaseCPS-ITotal of 88,458 maleand 247,412 femalenever-smokersCHD deaths:7,768 in males 7,133 in femalesCPS-II108,772 male and226,067 femalenever-smokers;smoking status ofspouses was knownCHD deaths:1,966 in males 1,099 in females

Table 8.1 (Continued)
370

Females OR 95% C

1.10 0.96-1.1.15 0.90-1.1.07 0.90-1.0.99 0.87-1.1.04 0.88-1.1.00 0.88-1.1.18 0.91-1.1.08 0.90-1.0.84 0.59-1.0.99 0.73-1.1.20 0.91-1.1.20 0.96-1.

Males

OR 95% CI1.22 1.07-1.401.33 1.09-1.611.17 0.92-1.481.09* 0.77-1.630.96 0.83-1.111.48 1.21-1.800.97 0.79-1.201.14 0.80-1.631.13 0.80-1.691.14 0.84-1.561.25 1.01-1.53* For those whose

spouses smoke >21 

cigarettes per day.

Exposure to ETSExposed to:

Current smokerCigarettes/day<20

2021-3940+Former smoker

Exposed to:

Current smokerFormer smoker

Years exposed to cigarette smoke

1-1213-2122-2930+

GeographicalArea(Reference)United States (Steenland 

et al., 1996)

Cohort-Yearsof Follow-up; # of Deaths Due to Heart DiseaseAnalysis 1Spousal cohort of101,227 male and208,372 femalenever-smokersCHD deaths:2,494 men1,325 womenAnalysis 2Spousal subcohortwith single marriageand data on amountand duration ofexposure to smoking during marriage58,530 male and99,821 femalenever-smokersCHD deaths:1,299 men572 women

Table 8.1 (Continued)
371

Females

OR 95% C1.19 0.97-1.0.70 0.45-1.1.21 0.85-1.1.28 1.10-1.1.22 0.88-1.1.14 0.83-1.1.02 0.66-1.1.28 0.81-2.1.07 0.96-1.1.06 0.84-1.0.91 0.83-1.

Males

OR 95% CI1.23 1.03-1.471.23 0.81-1.071.35 0.95-1.901.13 0.84-1.611.37 1.04-1.791.15 0.86-1.531.12* 0.77-1.831.15 1.01-1.321.03 0.89-1.191.03 0.93-1.13* For those whose

spouses smoke >21 

cigarettes per day.

Exposure to ETSExposed currently

Self-report:

1-2 hours/day3-4 hours/day

>4 hours/day

Smoking reported 

by spouse:

cigarettes/day

<20

20 21-3940+

Exposed at homeExposed at workExposed elsewhere

GeographicalArea(Reference)United States (Steenland 

et al., 1996)

(Continued)

Cohort-Yearsof Follow-up; # of Deaths Due to Heart DiseaseAnalysis 3Subjects concordantfor both self-reportedcurrent exposure tocigarettes and exposure based onspousal report54,668 male and80,549 female neversmokers[?]CHD deaths:1,180 men,426 womenAnalysis 4Restricted to thosecurrently employed76,710 male and75,237 female neversmokersCHD deaths:1,751 men768 women

Table 8.1 (Continued)
372

Comments All ORs were body mass insion, diabetemenopausal physical activfat, use of as

Females OR 95% CI Total CHD 1.00 1.71 (1.03-2.84) 1.58 (0.93-2.68) 1.81 (1.11-3.28) Nonfatal MI 1.00 1.73 (0.99-3.03) 1.64 (0.92-2.93)

1.86 (1.04-3.42)Fatal CHD1.001.87 (0.56-8.20)1.50 (0.42-5.36)2.55 (0.71-9.12)Total CHD1.001.19 (0.75-1.90)1.54 (0.99-2.40)1.11 (0.89-1.77)1.50 (0.97-2.32)

Exposure to ETSExposure to ETSat home or at work:

neveranyoccasionalregularneveranyoccasionalregularneveranyoccasionalregular

By years of living withsmoker in adult life:

<11-910-1920-2930+

GeographicalArea(Reference)United States Nurses’ HealthStudy (Kawachiet al., 1997)

Cohort-Yearsof Follow-up; # of Deaths Due to Heart Disease121,700 nurses aged30-55 years enrolledin 1976Questions on ETSexposure asked in afollow-up questionnaire in 198232,046 women werenever-smokersfollow-up between1982 and 1992152 incident CHD (127 nonfatal MI, 25 fatal CHD)

Table 8.1 (Continued)
were statistically significant. This criticism is ill-founded since the results

based on 14 years of follow-up (and 410 CHD deaths) showed the same pattern of increased risks—the RRs were 1.05 (90% CI = 0.86-1.29), and 1.21

(90% CI = 0.95-1.53) when husbands were ex-smokers or smoked 1-19 cigarettes/day, and when they smoked 20+ cigarettes/day, respectively, compared to husbands who did not smoke (Hirayama, 1990). However, what is

unclear and warrants explanation is the discrepancy in the results based on

14 years of follow-up in Hirayama’s first report (1981) and his second report

(Hirayama, 1984). In the 1981 report, Hirayama found RRs of 0.97 when

husbands were ex-smokers or smoked 1-19 cigarettes/day and 1.03 for 20+

cigarettes/day (p = 0.39) (based on 406 CHD deaths).

San Diego study (Garland et al., 1985) A second report on the role of ETS and heart

disease utilized data collected in a cohort of predominantly white, upper

middle-class subjects in San Diego (Garland et al., 1985). This cohort was

established between 1972 and 1974 and successfully enrolled 82 percent of

the subjects contacted. A standardized interview was administered and covered cigarette use; past hospitalizations for heart attack, heart failure, or

stroke; and duration of marriage. Questions on smoking included smoking

status at enrollment (current, former, or never) and among current smokers,

the number of cigarettes smoked per day. In addition, blood pressure,

weight, height, and plasma cholesterol were measured at study enrollment.

The analysis on ETS and heart disease was based on 695 married nonsmoking women, classified by their husbands’ self-reported smoking status

at enrollment; it excluded women who had a history of heart disease or

stroke and women who had smoked. Vital status of the cohort was determined by annual mailings for 10 years. Follow-up was almost complete

and death certificates were obtained for all deaths. After 10 years of followup, there were 19 deaths due to CHD (International Classification of

Diseases, Adapted (ICDA) 410.0-414.9) among nonsmoking married

women. The age-adjusted mortality rates were 1.2, 3.6, and 2.7, respectively, for women married to nonsmokers, ex-smokers, and current smokers

(one-sided p for trend, <0.10). The corresponding RRs for the adjusted mortality rates were 1.0, 3.0, and 2.3. The relative risk for CHD mortality

among women married to current or former smokers compared to women

married to never-smokers was 2.7 (p value <0.10) after adjustment for age,

systolic blood pressure, total plasma cholesterol, obesity index, and years of

marriage (Table 8.1).

Most of the information on CHD risk in this study was based on nonsmoking women married to ex-smokers at study enrollment. A possible

explanation for the higher risk among nonsmoking women married to former smokers than to current smokers is that this group of husbands had

been very heavy smokers and had stopped smoking for health reasons.

Thus, wives of these former smokers may have been heavily exposed. The

findings in relation to “any ETS exposure” are only suggestive, given the

small numbers of CHD deaths and the fact that the analysis was conducted

by husbands’ smoking status and not amount smoked by husbands.

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MRFIT - 18 cities study (Svendsen et al., 1987) The role of ETS and risk of heart disease

was evaluated in a cohort of men aged 35-57 years who were recruited in 18

U.S. cities beginning in 1973 for the Multiple Risk Factor Intervention Trial

(MRFIT) (Svendsen et al., 1987). At enrollment, extensive information was

collected, including smoking history of the index subjects and of their

wives, family members, and coworkers. In addition, markers of exposure to

tobacco smoke, including serum thiocyanate and expired air carbon

monoxide were measured, and pulmonary function tests were conducted.

Pulmonary function tests and measurements of thiocyanate were conducted

at entry into the study (baseline) and at each of six annual examinations,

whereas expired carbon monoxide was measured at baseline, and at the

third and sixth examination.

Cause of death was classified by a committee of three cardiologists who

reviewed the hospital/physician records, death certificates, autopsy reports,

and next-of-kin interviews. Subjects were followed an average of 7 years

and the effect of ETS was investigated for CHD death (including documented MI, SUD, congestive heart failure, and death associated with surgery for

CHD) and fatal or nonfatal CHD events combined.

Analyses were conducted for all never-smokers and nonsmokers (i.e.,

ever-smokers who stopped prior to entry into the study) at entry. Of the

12,866 men, there were 1,245 married men who never smoked, of whom

286 were married to smokers and 959 to nonsmokers. Among men who

never smoked, there were 13 deaths due to CHD and 56 nonfatal CHD

events (Table 8.1). Compared to men married to nonsmokers, men married to smokers showed a higher risk of death from CHD (adjusted RR =

2.23, 95% CI = 0.72-6.92) and for fatal and nonfatal CHD combined

(adjusted RR = 1.61, 95% CI = 0.96-2.71) after adjusting for other risk factors for heart disease (age, blood pressure, cholesterol, weight, drinks per

week, and education). The adjusted relative risks were slightly higher than

the unadjusted values.

The effect of ETS exposure from wives’ smoking was also evaluated

among all nonsmoking men. Both men who never smoked and those who

stopped smoking prior to entry into the study were included (numbers of

subjects and number of CHD events in the latter group were not specified).

Nonsmoking men whose wives smoked showed a higher risk of death from

CHD (adjusted RR = 1.59, 95% CI = 0.84-3.02) and a higher risk of fatal and

nonfatal CHD combined (adjusted RR = 1.32, 95% CI = 0.95-1.84) as compared to men whose wives did not smoke. However, these risk estimates

are lower than those presented above for men who never smoked, suggesting that the effect due to ETS exposure may have been diluted substantially

by including ex-smokers in the analysis.

In the same study, there is a suggestion of an ETS effect from coworkers’

smoking after adjusting for age and wives’ smoking habits (these RRs were

presumably not adjusted for other CHD risk factors). The adjusted RR was

2.6 (95% CI = 0.5-12.7) for CHD death and 1.4 (95% CI = 0.8-2.5) for fatal

or nonfatal CHD combined for men who never smoked but were exposed

to coworkers’ smoking. The joint effect of ETS exposure from wives and

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Smoking and Tobacco Control Monograph No. 10
coworkers was also evaluated. Relative to men whose wives and coworkers

did not smoke, the RRs for fatal and nonfatal CHD combined were 1.0

(95% CI = 0.5-1.9) when coworkers smoked but wives did not, 1.2 (95% CI

= 0.4-3.7) when wives smoked and coworkers did not, and 1.7 (95% CI =

0.8-3.6) when both smoked.

This study has several strengths. First, misclassification of active smokers as nonsmokers is minimized since there were baseline and regular measurements of various biomarkers to assess long-term (based on thiocyanate)

and short-term (based on carbon monoxide) exposure to tobacco smoke. In

this study, nonsmoking men married to smokers had significantly higher

levels of expired air carbon monoxide, significantly lower levels of maximum FEV1, and thiocyanate levels comparable to those of nonsmoking

men married to nonsmokers. Although thiocyanate is not specific to ETS

exposure and is not considered a sensitive marker for exposure to ETS,

serum thiocyanate levels have been used successfully to distinguish

between active smokers and nonsmokers (U.S. DHHS, 1986). Second, ETS

exposure was based on both wives’ and coworkers’ smoking habits at baseline, thus covering the main sources of domestic and non-domestic exposure. Third, information on potential confounders for CHD was available.

At entry into the study, nonsmoking men married to smokers were similar

to those married to nonsmokers in age, diastolic or systolic blood pressure,

total, high and low density lipoprotein cholesterol, and income, but differed significantly in weight (heavier), drinking habits (drank more), and

education (fewer years). However, the differences in weight and drinking

habits between the two groups did not persist by the sixth annual examination. The effect of ETS was observed when potential confounders for heart

disease, education, and measures of social class were accounted for in the

analysis. Finally, this study examined the effect of ETS on both fatal and

non-fatal CHD events. Point estimate of risks were higher for fatal events

than for fatal and nonfatal events combined, suggesting that the association between ETS exposure and nonfatal events may be relatively weak

(adjusted RRs were not presented separately for nonfatal events).

The main limitation of this study is that this study population may be

unrepresentative of the general population. Men selected in the MRFIT

study were already at high risk for heart disease, defined by their levels of

serum cholesterol and diastolic blood pressure.

Maryland study (Helsing et al., 1988) The role of ETS in the etiology of heart disease

mortality in men and women was investigated by Helsing et al. (1988), who

utilized data from a private census conducted in 1963 covering some 98

percent of the households in Washington County, Maryland. The subcohort for this analysis comprised of 3,454 males and 12,345 females who

never smoked and were available for follow-up in 1971. These subjects

were followed between 1963 and 1975, and the risk of heart disease mortality was evaluated relative to their household exposure to ETS. CHD listed

as an underlying or contributing cause of death was included as a heart disease mortality outcome.

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Chapter 8
Information on sex, age, race, marital status, years of schooling, and

housing characteristics were available and were adjusted for in the analyses.

Use of any tobacco products, including cigarettes, cigars, and pipes was

recorded for all subjects and their household members. In brief, a score

ranging from 0 to 12 was assigned to each adult in the household based on

his/her smoking history. A total household smoking score was then calculated by summing the smoking contribution scores of all persons living in

that household. Each individual’s household ETS exposure was calculated

by subtracting his or her own contribution from the total household score.

Among nonsmoking men, 29.5 percent reported any household exposure to

ETS compared to 65.5 percent among nonsmoking women.

In the never-smokers, there were a total of 370 deaths in men and 988

in women, for whom CHD was listed as the underlying cause of death. The

adjusted relative risk for any ETS exposure was 1.31 (95% CI = 1.1-1.6) for

men and 1.24 (95% CI = 1.1-1.4) for women (note: in Sandler et al. (1989),

the RR in women was 1.19 (95% CI = 1.04-1.35); the reason for the discrepancy is not known). There was no clear dose-response trend with increasing ETS exposure in men (i.e., scores of 0, 1-5, 6+), but there was some suggestion of a trend in women (Table 8.1). When data were stratified by gender and by age of study subjects at enrollment in 1963 (25-44, 45-54, 55-64,

and 65+), risk for CHD in relation to ETS exposure was increased in seven

of eight age-sex groups. The RRs were increased in all age groups of men

exposed to ETS and were statistically significant for two subgroups. In

women, increased risks were observed in all but the 55-64 age group, and

the results were statistically significant for the 65+ age group. Results were

similar when the analyses included all deaths with CHD listed as the underlying or contributing cause of death (i.e., a total of 461 and 1,281 deaths in

nonsmoking men and women, respectively).

This is one of the larger studies on ETS and heart disease in nonsmoking men and women. The larger sample size allowed analysis stratified by

age group and by sex. In addition, exposure to ETS included all household

exposures. Unfortunately, the effect due to spouse’s smoking alone, typically used as a measure of ETS exposure in other studies, was unavailable for

comparison. Data on potential confounding factors for heart disease were

not collected so that the RRs were adjusted for demographic factors only.

Scottish study (Hole et al., 1989) This study was conducted to investigate the risk of

cardio-respiratory symptoms and CHD mortality among residents, aged 45-

64 years, in two western Scottish towns between 1972 and 1976 (preliminary results were presented by Gillis et al., 1984). With about an 80 percent

response rate, 15,399 residents completed a standardized self-administered

questionnaire on smoking habits, other lifestyle factors, and symptoms of

respiratory and cardiovascular disease. By identifying couples living in the

same household, the effect of exposure to ETS was investigated in a subsample of 3,960 men and 4,037 women. Eleven percent of the males (n = 428)

and 12 percent of the females (n = 489) were lifetime nonsmokers, and their

cohabitants were also nonsmokers; they served as controls. Six percent of

the males (n = 243) and 32 percent of the females (n = 1,295) were passive

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Smoking and Tobacco Control Monograph No. 10
smokers, i.e., the case had never smoked but his or her cohabitant smoked.

Thirty-six percent of the males (n = 1,420) and 8 percent of the females (n =

323) were active smokers or ex-smokers and had lived with a cohabitant

who never smoked. Forty-seven percent of the males (n = 1,869) and 48

percent of the females (n = 1,922) were active smokers and their cohabitants

also smoked. Through a national registry system, incidence of cancer and

mortality was followed for 11.5 years (Hole et al., 1989).

The cohort consisted of the 917 (428 men and 489 women) controls

and the 1,538 passive smokers (243 men and 1,295 women). Passive smokers compared to controls did not differ in self-reported prevalence of angina

(age- and sex-adjusted RR = 1.02) and the relative risk estimate was not significantly changed (RR = 1.11, 95% CI = 0.73-1.70) after adjusting for

potential confounders including age, sex, social class, diastolic blood pressure, serum cholesterol, and body mass index. Controls and passive smokers also did not differ in self-reported prevalence of major abnormalities

found on electrocardiogram; the age- and sex-adjusted relative risk was 1.10

which increased to 1.27 (95% CI = 0.48-3.35) after adjusting for potential

confounders. The effect of passive smoking was more apparent for fatal

CHD events. Passive smokers experienced a higher age- and sex-adjusted

mortality rate of CHD (47.4 per 10,000) than controls (27.3 per 10,000)

(crude RR = 1.74). The relative risk was statistically significant when the

analysis was adjusted for the potential confounders mentioned above (RR =

2.01, 95% CI = 1.21-3.35). 

Among female subjects, the relationship between ETS exposure and risk

of various CHD endpoints was evaluated by intensity of ETS exposure,

defined as “low” if their cohabitants smoked <15 cigarettes/day and “high”

if they smoked >15 cigarettes/day. There was no suggestion of increasing

risk of abnormalities on electrocardiogram with increasing intensity of

exposure. However, the risk for angina was elevated (RR = 1.61) for those

more highly exposed to ETS smoking. A trend of increasing risk with

increasing level of ETS exposure was most apparent for fatal CHD events.

Compared to women with no exposure, the relative risk was 2.09 for

women with low ETS exposure and 4.12 for women with high ETS exposure

(no confidence limits were provided).

Although history of angina and abnormalities on the electrocardiogram

were based on self-reports, results were believable since the risks associated

with ETS and active smoking were stronger for fatal cardiovascular events

than for nonfatal events or symptoms of disease. Risk for angina (adjusted

for age and sex) increased 2 percent for passive smokers, 67 percent for

active smokers living with nonsmokers, and 98 percent for active smokers

living with smokers, compared to controls. The corresponding increase in

risk for abnormalities on the electrocardiogram was 10 percent, 40 percent

and 50 percent, respectively. Compared to controls, risk of death due to

CHD increased 75 percent for passive smokers, 123 percent for active smokers living with a nonsmoker, and 122 percent for active smokers living with

another smoker (i.e., exposed to ETS). Thus, this study demonstrates that

ETS exposure may have considerable effect on risk of both cardiovascular

symptoms and CHD death, with a stronger effect for fatal CHD events.

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Chapter 8
An advantage of this prospective study is that it covered the entire population of men and women aged 45-64 years in two towns. In addition,

information on other risk factors for heart disease is available for adjustment in the analysis. Unlike most studies in which smoking habits of

spouses were obtained from the nonsmokers under study, the cohabitees

(most of whom were spouses) directly provided information regarding their

smoking habits, reducing the possibility of misclassification. 

Evans County, Georgia (Humble et al., 1990) The association between ETS exposure

and CHD mortality was investigated among nonsmoking women living in

Evans County, Georgia (Humble et al., 1990). From 1960 to 1961, 92 percent of all residents aged 40-74 years in this rural county participated in a

cardiovascular disease study that included complete physical examinations

and an interview on demographic and medical history. At enrollment,

there was a total of 1,127 women, of whom 943 (554 white, 389 black)

reported they had never smoked. The analysis on ETS was restricted to 513

women (328 white, 185 black) who were married to never-smokers or current smokers at baseline. The authors excluded nonsmoking women married to ex-smokers in the analysis on the basis that there may be more misclassification of the smoking habits of index subjects and their husbands if

they were ex-smokers. Vital status was determined on May 1, 1980. All

mortality due to circulatory diseases (including strokes—codes 390-456, ICD

8th Revision) listed as an underlying cause of death on the death certificates were considered in this analysis.

Results on ETS exposure were presented for all subjects combined, and

separately by race and social class. The social class index was based on the

occupation, education, and income of the head of household, applicable for

rural settings. Nonsmoking women married to current smokers showed

higher risks for all CHD mortality than women married to never-smokers.

For all subjects combined, the age-adjusted relative risk for all CHD mortality was 1.34. A higher relative risk value was obtained after adjusting for

potential confounders including age, diastolic blood pressure, total serum

cholesterol, and body mass index (RR = 1.59, 95% CI = 0.99-2.57). The

increased risk was observed for all black women (adjusted RR = 1.78, 95%

CI = 0.86-3.71) and for white women of high social class (adjusted RR =

1.97, 95% CI = 0.72-5.34), but not for white women of low social class

(adjusted RR = 0.79, 95% CI = 0.32-1.96).

There are no obvious explanations for the inconsistent finding between

white women of different social classes. However, the numbers of CHD

deaths by race and social class were not presented. Subgroup analysis based

on small numbers may have produced unstable risk estimates. The authors

stated that results were similar for all CHD and for smoking-related CHD,

without describing which diseases included under all CHD would be

excluded under smoking-related CHD.

This study presented data on subjects’ smoking habits both at enrollment and at a later time, providing an assessment of the stability of smoking habits in index subjects as well as in their spouses. Comparison of subjects’ smoking status in 1960 and 1967 showed that 98 percent of non378

Smoking and Tobacco Control Monograph No. 10
smoking women again reported that they never smoked in 1967. Similarly,

an equal percentage of never smoking husbands maintained their nonsmoking status in 1967, while 25 percent of husbands who smoked in 1960

described themselves as nonsmokers in 1967. This suggests that some husbands who were ex-smokers at baseline might have reported themselves to

be lifetime nonsmokers. Although no details were provided regarding how

the questions were asked, they are presumed to have been asked in the

same way in 1960 and in 1967. These results suggest it is not likely that an

index subject or spouse who was a nonsmoker at baseline became a smoker

whereas some smokers at baseline would be expected to have stopped

smoking over time.

California Seventh Day Adventists (Butler, 1988 [unpublished dissertation]) A large

cohort study of Seventh-Day Adventists (SDAs) in California was initiated

in 1974 and was designed to investigate the association of lifestyle and

nutritional factors with morbidity and mortality. A basic demographic

questionnaire containing a question on smoking status was sent to all registered Adventist households with a 58 percent response rate. To examine

the role of ETS exposure in this population, two analyses were conducted.

One analysis was based on some 11,000 married couples (referred to as the

spouse pairs cohort). A second analysis involved 6,467 subjects (referred to

as the AHSMOG cohort) who were participants in an air pollution study.

The cohort was followed between 1976 and 1982 for cancer incidence

and mortality. Incidence of cancer was based on responses to a questionnaire which was sent annually to all cohort subjects and asked about hospitalizations in the past year. Medical records relating to reported hospitalizations were then reviewed. Mortality rates were determined via linkage with

the California Death Files and National Death Index Systems, and reviewing all deaths entered in church records. Death certificates were obtained

on all reported fatalities, and information on underlying and contributing

causes of death was abstracted.

The definition of ETS exposure differed for the spouse pair cohort and

for the AHSMOG cohort. In the spouse pair cohort, ETS exposure was

based on the husbands’ smoking status at the time of marriage. However,

this measure of ETS exposure was crude since subjects were not asked

specifically when they started or stopped smoking. A married woman was

classified as not exposed if her spouse was a never-smoker or if the spouse’s

age at marriage equaled or was greater than his age of baptism. This is

based on the assumption that the age of baptism was the latest age at

which a baptized SDA adult stopped smoking since smoking is a church

proscription. On the other hand, a married woman was classified as

exposed to ETS if her spouse was a current smoker, or if her spouse was an

ex-smoker who was not a baptized SDA, or if the spouse’s age of baptism

was greater than his age at marriage. In the AHSMOG cohort, specific questions were asked about ETS exposure including the number of years a subject lived or worked with a smoker.

In the spouse pair cohort, there were a total of 9,785 nonsmoking

women; of these, 7,246 were married to nonsmokers and 2,309 to smokers

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(in 230 subjects, the smoking status of the husband was not known). Based

on 87 CHD deaths in nonsmoking women, those married to ex-smokers did

not show any elevation in risk (age adjusted RR = 0.96, 95% CI = 0.66-1.66)

compared to nonsmoking women married to nonsmokers. However, there

was some suggestion of an increased risk for nonsmoking women married

to smokers (age adjusted RR = 1.40, 95% CI = 0.51-3.84). The increased risk

observed among nonsmokers married to current smokers was based on only

four CHD deaths. It is presumed that current exposure in this context

means that the spouse was a current smoker and not a past smoker.

In the AHSMOG cohort, there were a total of 70 female deaths and 76

male deaths from CHD occurring among never-smokers during the period

of follow-up. Living with a smoking spouse was not associated with an

increased risk of CHD in men, but was associated with an increased risk of

CHD in women. Compared to women who did not live with a smoker,

those who lived with a smoker for 1-10 years or 11+ years showed adjusted

RRs of 1.46 (95% CI = 0.7-3.1) and 1.53 (95% CI = 0.9-2.5), respectively (p

for trend = 0.21). Years of working with a smoker was also not associated

with risk of CHD in men but was associated with an increased risk of CHD

in women after adjusting for age. The relative risks for years working with

a smoker changed from less than 1.0 in unadjusted analysis to close to 2.0

when the analyses were adjusted for age (Table 8.1).

Thus, the evidence from the spouse pair cohort and the AHSMOG

cohort suggest that exposure to ETS at home and at work increased the risk

of heart disease mortality in nonsmoking women but not in nonsmoking

men. The effect of ETS exposure from work was of borderline statistical significance. There are no apparent reasons for the difference in results by

gender. Although ETS exposure in the spouse pair cohort is derived by

comparing the surrogate measure for smoking cessation (age at Baptism) to

the age at marriage, the extent of misclassification of ETS exposure can be

evaluated in a subset of women who responded to specific questions on

spouses’ smoking in the AHSMOG cohort and were included in the spouse

pair cohort. There was an agreement in classification by ETS exposure in 86

percent of subjects included in both cohorts. However, 5.9 percent of the

women responded they were not exposed to spouses’ smoking in the

AHSMOG cohort but were classified as exposed in the spouse pair cohort,

and 5.8 percent who responded that their spouse smoked were classified as

not exposed.

CPS-I and CPS-II (LeVois and Layard, 1995) The analysis by LeVois and Layard (1995)

utilized data from the American Cancer Society CPS-I and CPS-II studies. In

brief, the CPS-I study included more than one million men and women

who were enrolled in 1959-1960. This analysis was based on 13 years of

follow-up (1960-1972). Follow-up was 92.7 percent complete. The CPS-II

study included approximately 1.2 million subjects who were enrolled in

1982. For this analysis, the cohort was followed for 6 years (1983-1988).

Vital status was ascertained for 98.2 percent of the cohort, and death certificates were obtained for 94 percent of decedents. Both CPS-I and CPS-II collected data on smoking habits, including the number of cigarettes smoked

per day. Only self-reported never-smokers who had spouses with known

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Smoking and Tobacco Control Monograph No. 10
smoking habits were included in these analyses. Each spouse was categorized as a nonsmoker, former smoker or smoker of 1-19, 20-39, and 40 or

more cigarettes per day.

In the CPS-I cohort there was a total of 88,458 male and 267,412 female

never-smokers with spouses having known smoking habits. After 13 years

of follow-up, there were 7,758 CHD deaths in men and 7,133 CHD deaths

in women. As discussed in more detail below, major limitations of the

LeVois and Layard analysis of these data include the lack of clarity on selection of subjects for analysis and the inconsistency in their reporting of the

results. 

In CPS-I, the age- and race-adjusted RR for CHD mortality associated

with any ETS exposure from spouses was 0.97 (95% CI = 0.90-1.05) in men

and 1.03 (95% CI = 0.98-1.08) in women. Results were unchanged when

the amount smoked by spouses was considered. For men whose wives

smoked 1-19, 20-39, and 40 or more cigarettes per day, the RRs for CHD

mortality were 0.99, 0.98, and 0.74, respectively. For women whose husbands smoked 1-19, 20-39, and 40 or more cigarettes per day, the RRs for

CHD mortality were 1.04, 1.06, and 0.96, respectively. Nonsmoking men

and women whose spouses were former smokers showed risks for CHD that

were close to 1.0 (Table 8.1).

In the CPS-II cohort, among a total of 108,772 male and 226,067 female

never-smokers with spouses having known smoking habits, there were

1,966 CHD deaths in men and 1,099 CHD deaths in women. After adjusting for age and race, there was no association between any ETS exposure

from spouses and risk of CHD mortality in men (RR = 0.97, 95% CI = 0.87-

1.08) or in women (RR = 1.00, 95% CI = 0.88-1.14). However, in both men

and women, there was some increase in risk when amount smoked by

spouses was considered. The risk of CHD mortality among men who were

never-smokers married to women who smoked 1-19, 20-39, and 40 or more

cigarettes per day were 1.36, 1.28, and 1.13, respectively, compared to men

married to nonsmokers (Table 8.1). The corresponding RRs in never-smoking women were 1.14, 0.98, and 1.27. However, never-smoking men married to women who were former smokers showed a significantly lower risk

of CHD mortality (RR = 0.81, 95% CI = 0.70-0.98). The RR for CHD mortality was 0.99 (95% CI = 0.86-1.13) for never-smoking women married to

husbands who were former smokers. 

LeVois and Layard (1995) combined the CPS-I and CPS-II studies and

reported a significant decreased risk of CHD (RR = 0.79, 95% CI = 0.80-0.97)

in nonsmoking men married to wives who were former smokers. However,

the value of the combined RR presented in the text (RR = 0.88, 95% CI =

0.79-0.97; see p. 188 of LeVois and Layard (1995)) differed from the combined RR presented in Table 4 (RR = 0.79, 95% CI = 0.80-0.97; see p. 189 of

LeVois and Layard (1995)). It is unclear which of the combined RRs is correct. The results obtained are inconsistent with those of Steenland et al.

(1996); these investigators conducted a more complete analysis of the same

data set (see below).

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Although this study has the advantage that the results were based on

the largest number of subjects and CHD events, LeVois and Layard (1995)

presented few details about the subjects not included in the analysis. For

example, it is unclear what percentage of subjects were excluded in either

study because their own smoking habits were missing or because the smoking habits of spouses were unknown. The investigators examined an effect

they described as “any” ETS exposure, which encompassed exposure due to

any level of cigarette smoking by either current spouses or former spouses,

but they did not investigate the effects of ETS exposure due only to cigarette

smoking (any level combined) by current spouses. The significant finding

these investigators emphasized was the reduction in risk among men married to ex-smokers when results from the two CPS studies were combined;

we question whether the combined RR is correct (see above).

As pointed out by Steenland et al. (1996) and Glantz and Parmley

(1995), ETS exposure may have both acute and chronic effects on the heart.

The emphasis of LeVois and Layard on “any” (i.e., current or former) ETS

exposure from spouses and on exposure from spouses who were former

smokers strongly biased the results toward the null. First, results for “any”

exposure to spousal ETS diluted the effects associated with exposure to current smokers by including ex-smokers. This is evident when one compares

the RRs associated with any ETS exposure versus the RRs associated with

amounts currently smoked by spouses (Table 4 of LeVois and Layard, 1995)

(RRs associated with any current smoke exposure were not presented and

could not be computed on the basis of the data presented). The RRs associated with any ETS exposure was less than 1.0 for men (RR = 0.97) and close

to 1.0 for women (RR = 1.0 and 1.03) in the CPS-I and CPS-II analyses.

However, almost all the RRs associated with each exposure category (based

on amount currently smoked by spouses: 1-19, 20-39, 40+ cigarettes per

day) were above 1.0 for women in both CPS-I and CPS-II and for men in

CPS-II. In fact, in the CPS-II analysis, five of the six RRs associated with

varying amounts smoked by spouses were above 1.13. These RRs by

amounts currently smoked by spouses suggest that the RR for any exposure

to current smokers is above 1.0. Second, the effect of exposure from former

smokers may be negligible, similar to the rapid reduction in heart disease

risk seen among active smokers upon cessation of smoking.

CPS-II Cohort (Steenland et al., 1996) The analysis by Steenland et al. (1996) utilized

data from the CPS-II cohort based on 7 years of follow-up. The original

CPS-II cohort consisted of 1,185,102 men and women who were enrolled in

1982. By December 1989, 91.2 percent (1,080,689) were alive, 8.6 percent

(101,519) had died, and the remainder had unknown vital status.

Including only participants who had never smoked, for whom information

on marital status was available and whose spouses had classifiable smoking

habits, there remained 353,180 women and 126,500 men. Death due to

CHD was reported in 4,911 women and 3,251 men. 

Results from four analyses were presented in this report. The first three

analyses dealt specifically with ETS exposure from spouses, whereas the

fourth analysis investigated the effects of ETS exposure at home, at work,

and in other settings. The first analysis was conducted only among those

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Smoking and Tobacco Control Monograph No. 10
married individuals with spouses also enrolled in the CPS-II study, and for

whom there were valid dates of marriage and sufficient data on smoking

cessation to indicate whether the spouses had smoked during marriage.

CHD deaths included in this analysis were those which had occured in

101,277 men (2,494 CHD deaths) and 208,372 women (1,325 CHD deaths)

after 7 years of follow-up. The second, third, and fourth analyses utilized

subsets of eligible subjects derived from the first analysis. The second

analysis was conducted only among those with single marriages for whom

information on amounts and duration of exposure to smoking during marriage were available. These restrictions led to 58,530 men and 99,821

women and a corresponding number of 1,299 and 572 CHD deaths. The

third analysis measured the risk of CHD among individuals who reported

current exposure at home and were married to currently smoking spouses

as compared to those who reported no current ETS exposure at home and

were married to never-smoking spouses. This analysis included 54,668 men

with 1,180 CHD deaths and 80,549 women with 426 CHD deaths. The

fourth analysis was conducted on nonsmoking individuals who provided

information regarding their exposure to ETS at home, at work, or in other

social settings. This analysis was based on 1,751 CHD deaths in some

76,710 men and 2,403 deaths in 186,368 women (the number of subjects

and CHD events were lower in the analyses on ETS exposure at work or in

other social settings). Each of the four analyses adjusted for variables

including age; self-reported history of heart disease and use of heart-disease

medication; self-reported history of hypertension, diabetes or arthritis;

body-mass index; education; use of aspirin, diuretics or estrogens (women

only); alcohol use; employment history; and exercise. 

Small increased risks for CHD mortality in men and women in association with current exposure to spouses’ smoking were found in each of the

analyses (analyses 1 to 3, Table 8.1). In the first analysis, nonsmoking men

exposed to currently smoking wives showed a RR of 1.22 (95% CI = 1.07-

1.40) for CHD mortality whereas nonsmoking women exposed to currently

smoking husbands showed a RR of 1.10 (95% CI = 0.96-1.27). These RRs

were strengthened slightly when the analyses were restricted to spouses

with single marriages (analysis 2). The RR was 1.48 (95% CI = 1.21-1.80) in

men and 1.18 (95% CI = 0.91-1.46) in women. An increased RR associated

with exposure to a currently smoking spouse was also observed in the third

analysis, in which self-reported exposure to ETS concurred with the spouses’

reporting of their tobacco use (analysis 3). In this analysis, the RR for CHD

mortality in association with currently smoking spouses was 1.23 (95% CI =

1.03-1.47) in nonsmoking men and 1.19 (95% CI = 0.97-1.45) in nonsmoking women. There was, however, no association between risk of CHD mortality in nonsmoking men and women and their being married to spouses

who were former smokers (analyses 1 and 2, Table 8.1).

Dose-response relationships in terms of amounts smoked by spouses,

duration of ETS exposure, and pack-years of ETS exposure were evaluated.

There was no evidence of a smooth trend of increasing risk with increasing

number of cigarettes smoked by spouses (analyses 1 and 3, Table 8.1) or

with increasing pack-years of ETS exposure (analysis 3, Table 8.1). There

383

Chapter 8
was some suggestion of a trend of increasing risk of CHD mortality in nonsmoking men and women with increasing number of years exposed to

spouses’ smoking (analysis 2, Table 8.1).

The fourth analysis examined the association between risk of CHD mortality and exposure to ETS at home, at work, and in other settings. Small

elevated risks were associated with all sources of ETS exposure, although

only the association between CHD risk in nonsmoking men and ETS exposure at home was statistically significant (Table 8.1).

Analyses were also presented separately for subjects aged <65 at baseline

and for individuals with a history of heart disease and those without a history of heart disease. Nonsmoking subjects who were aged <65 at study

entry showed a slightly higher increased risk of CHD mortality in relation

to exposure to currently smoking spouses. For example, nonsmoking men

aged <65 at baseline who were married to currently smoking women

showed a RR of 1.33 for CHD mortality (this RR was 1.22 for all nonsmoking men). There is also some suggestion that the risk of CHD mortality

associated with exposure to a smoking spouse was more apparent in individuals who had heart disease at baseline. For example, the risk of CHD

mortality in nonsmoking men associated with exposure to wives who were

current smokers was 1.18 (95% CI = 0.98-1.41) among those who had no

history of heart disease at baseline and 1.24 (95% CI = 1.01-1.53) among

those who had a history of heart disease at baseline. 

The differences in findings in this study and those reported by LeVois

and Layard (1995) are noteworthy given that both analyses utilized data

from the CPS-II study. The size of the relevant study population and the

number of CHD deaths included by Steenland et al. (1996) differed from

those included by LeVois and Layard (1995). In contrast to the detailed

description of the inclusion and exclusion criteria presented by Steenland et

al. (1996), LeVois and Layard (1995) provided few details regarding their

study methods. Differences in the follow-up period, in the definition of

spousal smoking, or other criteria for inclusion and exclusion may have

contributed to the differences in these two reports. The analytic methods

used in the two studies also differed. Steenland et al. (1996) investigated

separately the effects of current and former exposure to ETS from spouses,

whereas LeVois and Layard (1995) examined the effects of any spousal ETS

exposure. Given that there is little evidence of an increased risk associated

with being married to former smokers, LeVois and Layard’s (1995) analysis

of any spousal exposure to ETS may have diluted the effects of current

exposure to spousal smoking on CHD mortality in nonsmokers.

Nurses’ Health Study (Kawachi et al., 1997) Kawachi et al. (1997) investigated the

association between exposure to ETS and risk of CHD using the Nurses’

Health Study, a cohort which was established in 1976 and included 121,700

female nurses in the U.S. A self-administered baseline questionnaire was

completed by study participants which included information on active

smoking history and a large number of lifestyle and dietary factors. Followup questionnaires have been completed by participants every two years to

update information on cardiovascular disease risk factors and the occur384

Smoking and Tobacco Control Monograph No. 10
rence of major illnesses. In the 1982 follow-up questionnaire, questions

related to exposure to ETS were asked. Specifically, two questions were

asked to assess current ETS exposure at home and at the workplace. Extent

of exposure was categorized as none, occasional, and regular. In addition,

subjects were asked the total number of years they had lived as an adult

with someone who has smoked regularly.

This analysis comprised incident cases of nonfatal MI (n = 127) and

fatal CHD events (n = 25) which occurred after the 1982 questionnaire but

before June 1, 1992 among the 32,046 women who had never smoked and

remained nonsmokers during the follow-up period (1982 to 1992). The

CHD events were confirmed by review of medical records and death certificates by physicians who were blinded to exposure status. Risk estimates

were calculated with adjustment for age and multiple risk factors including

alcohol intake, body mass index, history of hypertension, diabetes, hypercholesterolemia, menopausal study, use of hormone replacement and oral

contraceptives, physical activity patterns, and relevant dietary factors.

Compared to nonexposed women, those reporting occasional exposure

to ETS at home or work had a multivariate adjusted RR for total CHD of

1.56 (95% CI = 0.93-2.68), while those reporting regular exposure had an

RR of 1.97 (95% CI = 1.11-3.28). In this study population, exposure to ETS

was associated with increased risks of both nonfatal MI and fatal CHD

events (Table 8.1). ETS exposure, both at work and at home, was associated

with an increased risk of CHD. Among women exposed only at work, the

multivariate RRs of total CHD were 1.49 (95% CI = 0.71-3.14) among those

occasionally exposed and 1.92 (95% CI = 0.88-4.18) among those regularly

exposed to ETS. Among women exposed to ETS only at home, the corresponding RRs were 1.19 (95% CI = 0.63-2.23) and 2.11 (95% CI = 1.03-

4.33). Self-reported duration of years lived with a smoker was also associated with an increased risk of incident CHD events although there was not a

smooth trend of increasing risk with increasing years of exposure. The multivariate adjusted RRs associated with 1-9, 10-19, 20-29, and 30+ years compared to less than one year of exposure were 1.0, 1.19, 1.54, 1.11 and 1.58,

respectively.

This study has several important strengths. This analysis was conducted using a cohort study that is widely accepted as one of the best designed

and most well conducted prospective studies and has been an extremely

valuable resource in identifying and elucidating causes of various disease

endpoints. Because of the availability of a large number of lifestyle factors

in this study, these analyses controlled for a large number of lifestyle and

dietary factors that have been suggested to potentially confound the CHDETS association. Although there is some diminution in the RRs with adjustment of these potential confounders, the risks remained elevated and were

statistically significant in many of the analyses. This cohort study also provided information on ETS exposure at home and at work, and showed clearly that risk of CHD is increased in association with ETS at home alone, at

work alone, and for both exposures combined. Moreover, these investigators showed that the risks associated with ETS exposure in never-smokers

are quite compatible with the active smoking findings in this study popula385

Chapter 8
tion. Women who smoked 1 to 4 cigarettes per day had an RR for total

CHD of 1.94 compared to all never-smokers; this RR was increased to 2.61

when the reference category was set to never-smokers not exposed to ETS.

Thus, the RR of 1.97 among women regularly exposed to ETS at home or at

work is not incompatible with the active smoking findings.

In a case-control study originally initiated to examine the relationship between types of cigarettes smoked and risk of lung

cancer, chronic bronchitis, CHD, and stroke, Lee et al. (1986)

evaluated the relationship between ETS exposure and these

health outcomes (Table 8.2). The original study began in

1977, and the questionnaire was modified in 1979 to assess ETS exposure

for married patients in four of the ten hospital regions included in the

study. Controls were patients without one of the four diagnoses mentioned

above; each control was individually matched to a case on sex, age, hospital

region, and when possible, hospital ward and time of interview. A total of

507 (286 male, 221 female) currently married patients with CHD answered

questions on ETS exposure. It is unclear whether these 507 subjects were

nonsmokers since these numbers do not agree with subsequent numbers on

CHD presented in the paper.

In one analysis, 118 subjects with CHD and 451 controls were compared in terms of whether his/her spouse smoked and the number of manufactured cigarettes smoked per day. Male CHD patients whose wives

smoked during the entire marriage showed a relative risk of 1.24, but the

association was absent for female patients (RR = 0.93). In a second analysis,

66 CHD cases and 254 controls quantified their ETS exposure at each of

four settings (home, work, during daily travel, and during leisure time)

using a 4-point scale (a score of zero indicated no exposure, a score of 3

indicated heavy exposure). To obtain a combined index of ETS exposure,

the scores for each setting were summed. There was no association

between this combined index of ETS exposure and risk for CHD in men and

women. The relative risks were 1.00, 0.52, and 0.61 for the combined

indices of ETS exposure of 0-1, 2-4, and 5-12, respectively.

Results from this study and the conclusion of no association are questionable. Information on passive smoking was obtained on a subset of

cases and controls, and the different analyses on ETS exposure included

substantially different numbers of cases and controls. Thus, selection bias

of cases and controls who answered the questions on passive smoking cannot be excluded. In addition, information on potential confounders for

CHD was not available.

China (He et al., 1989) He et al. (1989) conducted a case-control study on ETS exposure and CHD in the Peoples’ Republic of China; the study included 34

women with CHD and 68 controls (34 hospital-based, 34 populationbased). Subjects were interviewed regarding their smoking habits and those

of their husbands. Population controls were matched to cases on age, race,

residence, and occupation, but it is unclear whether the matching criteria

were applied to hospital controls. A significant, 3-fold increase in relative

risk (95% CI = 1.3-7.2) for CHD was observed for nonsmoking women

386

Smoking and Tobacco Control Monograph No. 10

8.1.2 Case-control

Studies

United Kingdom 

(Lee et al., 1986)
387

Cases/Controls 

26/9315/4022/89

55/229

15/2712/55

3/15

23/75

9/614/21

Exposure to ETSNonsmoking menexposed to spouse 

NoYes

Nonsmoking womenexposed to spouse

NoYes

Nonsmoking menexposed to combinedsources:score 0-1

2-45-12

Nonsmoking womenexposed to combinedsources:score 0-1

2-45-12

GeographicalArea(Reference)United Kingdom(Lee, 1986)

Subjects (cases, controls)control type507 males andfemales with IHDhospital controlsa subset of cases andcontrols responded toquestions on passivesmoking 

OR (95% CI)1.001.24 (0.6-2.8)1.000.93 (0.6-1.7)1.00.43(0.2-0.9)0.43(0.1-1.4)1.00.59 (0.2-1.1)0.81 (0.2-2.0)

Table 8.2Case Control Studies on ETS Exposure and Heart Disease
388

Cases/Controls 161/259 22/34 48/126 27/79 117/433 43/99

5/73

12/124

9/38

16/25

Exposure to ETSNonsmoking men

Not exposed at homeExposed at homeNot exposed at workExposed at work

Nonsmoking women

Not exposed at homeExposed at homeNot exposed at workExposed at work

Nonsmoking women

Husband smoked

YesNo

GeographicalArea(Reference)New SouthWales, Australia(Dobson et al.,1991a)People’sRepublic ofChina (He et al., 1989)

Subjects (cases, controls)control typeSubjects with myocardial infarction (MI) orcoronary death, age35-69, between July1988-October 1989Controls selected froma community basedrisk-factor surveyCases interviewed bynurses while in hospital, controls completedself-administered questionnaire34 women CHD (12MI, 22 diagnosed bycoronary arteriography)68 controls (34 population, 34 hospital control)

OR (95% CI)1.000.97 (0.50-1.86)1.000.95 (0.51-1.78)1.002.46 (1.47-4.13)1.000.66 (0.17-2.62)1.03.0 (1.3-7.2)

Table 8.2 (Continued)
389

Cases/Controls 

Males Femalescas/ctrl cas/ctrl55/140 11/17 2/4 15/197/17 17/205/11 6/8 2/6 11/12 cases controls11 50 15 33 10 18 23 25 cases controls26 83 16 36 12 6 

5 1

Exposure to ETSSpousal smoking habits

never-smokerformer smokercurrent smoker<15 cigarettes/dy15+ cigarettes/dy

Passive smoking fromhusband work

no noyes nono yesyes yesPassive smoking at workNumber of smokers

01-234+Test for trend

GeographicalArea(Reference)Italy(La Vecchia 

et al., 1993)

People’s Republicof China(He et al., 1994)

Subjects (cases, controls)control typeAcute MI patients113 cases (44 females, 69 males)Controls admitted tosame hospitals foracute conditions notrelated to CHD Non-fatal CHD femalecases in lifelong nonsmokers; identifiedfrom the 3 large teaching hospitals in Xianbetween 1989 and1992Controls were fromthree sources andwere combined in allanalyses because theydid not display significant differences byvarious characteristics

OR (95% CI)1.00.91 (0.4-2.3)1.21 (0.6-2.5)1.13 (0.5-2.8)1.30 (0.5-3.4)1.02.07 (0.8-5.6)2.42 (0.8-7.8)4.18 (1.6-10.9)1.001.16 (0.5-2.8)5.06 (1.4-18.0)4.11 (0.4-43.7)

Table 8.2 (Continued)
390

Cases/Controls Males 38/68 12/15 5/8 13/17 Females 13/20 12/8 5/9 16/13 

Males

378/783 

38/107 

45/92

6/12 

Females

459/969 139/336 224/405 

52/111 

Exposure to ETSAdult exposure

None1-20 years21-30>30None1-20 years21-30>30

Spousal smoking

cigarettes/day

none1-1515-3435+

cigarettes/day

none1-1515-3435+

GeographicalArea(Reference)United States(Muscat and

Wynder, 1995)

United States(Layard, 1995)

Subjects (cases, controls)control typeSubjects with MI identified in four hospitals inthe U.S. between 1980and 1990; hospital controls were used. Cases and controlsinterviewed while in thehospital.Cases and controlswere from NationalMortality FollowbackSurvey conducted in1986. Next-of-kin completed a self-administered questionnaire

OR (95% CI)1.01.7 (0.7-4.5)1.5 (0.4-5.2)1.1 (0.4-2.8)1.02.0 (0.5-8.1)0.9 (0.2-4.4)1.7 (0.5-5.9)1.00.8 (0.5-1.1)1.1 (0.7-1.6)0.9 (0.9-2.6)1.00.9 (0.7-1.1)1.2 (0.9-1.4)1.1 (0.7-1.5)

Table 8.2 (Continued)
391

Cases/Controls 

Males: 28 acute MIcases compared to123 controls; 21 fatal CHD casescompared to 61controlsFemales: 11 acuteMI cases compared to 112 controls; 9 fatal CHD casescompared to 62controls

Exposure to ETSQuestions on ETSwere added to anongoing case-controlstudy conducted inNew Zealand. 

GeographicalArea(Reference)New Zealand(Jackson, 

unpublished)

Subjects (cases, controls)control typeCases included acuteMI patients and fatalCHD patientsSelf-respondent population controls andnext-of-kin of controlswere compared todirectly interviewedcases and next-of-kinof fatal CHD patients

OR (95% CI)Acute MI:

M 1.0 (0.3-4.3)F 2.7 (0.6-13.6)Fatal CHD:

M 1.1 (0.2-4.5)F 5.8 (1.3-48.0)

Table 8.2 (Continued)

Abbreviations: MI = myocardial infarction; CHD = coronary heart disease; IHD = ischemic heart disease
whose husbands were smokers. The risks increased with increasing number

of cigarettes smoked and with increasing duration of smoking by the husband. The relative risk associated with ETS exposure diminished substantially (RR = 1.50, p < 0.01) when other CHD risk factors (including personal

and familial history of hypertension, familiar history of CHD, drinking,

physical exercise, previous history of hyperlipidemia) were adjusted for in

the analysis. Analysis by specific heart disease outcome showed a relative

risk of 4.7 (p < 0.05) for angina (n = 21), and a relative risk of 2.5 (p > 0.05)

for MI (n = 13) in relation to husbands’ smoking.

There are several important limitations of this study. First, the study is

small, based on 34 cases and 68 controls. Second, only partial information

about the study methods was presented. The 34 CHD patients represented

cases who were diagnosed by coronary arteriography or had MI during

1985-1987 in one hospital in Xian, China. The criteria for selecting these

cases were not described, and it is unclear what percentage of cases diagnosed during the study period was selected. Furthermore, the types of

patients included as hospital controls were not described. Some population

controls had presumably taken the exercise electrocardiogram test, questioning whether they are truly representative population controls. Thus,

selection bias of cases and controls cannot be ruled out. It is also uncertain

whether uniform methods were used to collect information from cases, hospital controls, and neighborhood controls.

The significant findings from the study must be interpreted with caution given these serious limitations in study methods. It is also questionable whether the point estimates for angina and MI separately are meaningful given these results were based on 21 and 13 cases respectively.

New South Wales, Australia (Dobson et al., 1991a) A case-control study of ETS exposure and risk of heart attack and CHD death was conducted by Dobson et

al. (1991a) in New South Wales, Australia. Cases were residents of the study

area, aged 35-69 years who had a fatal or non-fatal definite or possible MI,

or a coronary death with insufficient information for more specific classification, during the study period (July 1, 1988 to October 31, 1989). To

ensure completeness of case ascertainment, the hospital morbidity data system and the official death records were compared. If more than one CHD

event occurred during the study period, only the first event was included in

the analysis. In addition to diagnostic information, data on medical history, cigarette smoking, and exposure to passive smoking at home and at

work were obtained by an interview conducted by the study nurses while

subjects were still in the hospital. For subjects who had died, the next-ofkin was contacted (the number of interviews conducted with the subjects

themselves versus next-of-kin was not specified). Information on ETS exposure was missing for about 15 percent of all nonsmoking CHD patients

because they had died and a next-of-kin interview could not be conducted.

Controls had previously participated in a community-based risk prevalence

study. For this study, they completed a self-administered questionnaire

which covered demographic characteristics, smoking behavior, and medical

history. Controls were also asked to donate a blood sample and complete

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Smoking and Tobacco Control Monograph No. 10
physical measurements. The participation rate among controls was 63 percent for all three components of the study, and 80 percent for the questionnaire interview.

The study included 183 male CHD patients who had never smoked and

336 who were ex-smokers; the corresponding female CHD patients were

160 nonsmokers and 80 ex-smokers. Male cases were compared to 293

male nonsmoker and 332 ex-smoker controls, respectively, whereas female

cases were compared to 532 female nonsmoker and 151 ex-smoker controls.

Controls were selected to match cases on age (between ages 35 to 69), but

how closely cases and controls were age-matched was not specified.

The ETS effect was considered separately for nonsmokers and ex-smokers after adjustment for age (in 5-year intervals), sex, and prior history of

heart disease. Exposure to ETS at home was not associated with risk of

heart attack in nonsmoking men (adjusted RR = 0.97, 95% CI = 0.50-1.86)

but was associated with an increased risk in nonsmoking women (adjusted

RR = 2.46, 95% CI = 1.47-4.13). Based on a small sample of nonsmokers

who worked outside the home (75 male cases versus 205 male controls; 17

female cases versus 197 female controls), ETS exposure at work was not

associated with risk of heart attack in men (RR = 0.95, 95% CI = 0.51-1.78)

or in women (RR = 0.66, 95% CI = 0.17-2.62).

This case-control study has several methodologic deficiencies which

may have biased the estimated effect of ETS on risk of heart disease. The

percentage of nonsmoking male and female cases and controls who reported exposure to ETS at home was low in this study: 12.0 percent nonsmoking male cases and 11.6 percent nonsmoking male controls reported ETS

exposure; the corresponding figures in females were 26.9 percent and 18.6

percent. The percentages of controls who reported ETS exposure were 40-60

percent among controls in most lung cancer studies (U.S. EPA, 1992).

Controls in this study were participants in a previous health survey and

may have been “healthier” and thus were less likely to have had exposure

to ETS. However, this reasoning does not explain the low prevalence of ETS

exposure among cases. The precise questions on ETS exposure that were

asked were not described (Dobson et al., 1991a), limiting our ability to fully

interpret these findings. In addition, different methods were used to obtain

information from cases and controls. Whereas most cases were interviewed

by nurses while they were in the hospital, controls completed a self-administered questionnaire. Information bias cannot be ruled out, and the direction of bias cannot be determined. Lastly, potential confounders including

other risk factors for heart disease and socioeconomic status were not available.

New Zealand (Jackson et al., 1991; Jackson, 1989 [unpublished dissertation]) Jackson et

al. (1991) conducted a population-based case-control study of non-fatal MI

and fatal heart disease in New Zealand. A population register identified

nearly 99 percent of the CHD occurring in the study population, which

included all white men and women aged 25-64 living in the Auckland statistical area between March 1986 and February 1988 who were also registered on the general electoral rolls. All patients with non-fatal MI requiring

393

Chapter 8
admission to a hospital were invited to participate. The next of kin of subjects who had died of CHD were also invited to participate. Controls were

randomly selected from the study population by using the electoral rolls as

the sampling frame. For each male and female case who was interviewed,

approximately 1.5 male controls and 3 female controls were interviewed.

Cases and controls were matched on respondent type (i.e., self-respondent

versus next-of-kin respondent). This matching was achieved by using the

controls for the subjects with MI (self-respondents) as controls also for

those who had died of CHD by interviewing their next of kin about them

(the self-respondent controls). The interviews asked about use of tobacco

products, current drug treatment of hypertension, leisure time physical

activity, and prevalence of angina. Questions on passive smoking were

added during year 2 of the study. Specifically, questions were asked about

tobacco smoke exposure from any cohabitant and at work.

The analysis on ETS exposure was limited to never-smokers with no history of MI or angina and included 28 male MI cases and 123 male controls,

21 male fatal CHD and 61 male controls, 11 female MI cases and 112

female controls, and 9 female fatal CHD and 62 female controls. The ageand social-class-adjusted OR for MI in relation to ETS exposure at home

(and/or work) was 2.7 (95% CI = 0.57-12.3) in women and 1.03 (95% CI =

0.27-3.9) in men. The adjusted OR for fatal CHD was 5.8 (95% CI = 0.95-

35.2) in women and 1.1 (95% CI = 0.23-5.2) in men. 

Although this study was part of a large case-control study of alcohol

intake and risk of CHD conducted in collaboration with the World Health

Organization MONICA project (Jackson et al., 1991), questions on ETS

exposure were added during year 2 of the study and were unpublished

(Jackson, 1989 [unpublished dissertation]). Only a small number of nonsmokers were included in this analysis. Selection bias cannot be excluded

since it is unclear what percentage of never-smoker cases and controls

answered questions on ETS exposure. 

Italy (La Vecchia et al., 1993) This Italian case-control study of acute MI was conducted from 1988-1989 within the framework of the GISSI-2 study (a randomized clinical trial of alteplase versus streptokinase and heparin versus

no heparin) which included 12,490 cases of acute MI (GISSI-2, 1990;

Roncaglioni et al., 1992). From the original study population, 113 cases of

acute MI (44 women and 69 men aged 34-74) occurred in never-smokers.

Two hundred and twenty-five controls (60 women and 125 men, aged 29-

74) were compared to the cases; controls were admitted to the same network of hospitals for acute diseases not related to any known or potential

cardiovascular risk factors and were also never-smokers. Exposure to passive smoking at home was based on spouse’s smoking habits which included smoking status (never-smoker, ex-smoker, current smoker), number of

cigarettes smoked per day, number of years the couple had lived together

(presumably as a measure of duration of ETS exposure), and the number of

years since the spouse had stopped smoking if he/she was a former smoker.

Compared to subjects married to never-smokers, the adjusted OR for

acute MI associated with being married to ex-smokers was 0.91 (95% CI =

0.36-2.28), and the OR for those married to current smokers was 1.21 (95%

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Smoking and Tobacco Control Monograph No. 10
CI = 0.57-2.52). Gender, age, education, coffee consumption, body mass

index, serum cholesterol, hypertension, diabetes, and family history of

acute MI were adjusted for in the analysis. Among subjects married to current smokers, the risk was higher (RR = 1.30, 95% CI = 0.50-3.40) among

those whose spouses smoked 15 or more cigarettes per day than those

whose spouses smoked less than 15 cigarettes per day (RR = 1.13, 95% CI =

0.45-2.82).

This study has the advantage of being part of a larger study in which

some information on passive smoking, other heart disease risk factors, and

dietary factors were available. The dietary data from this study suggest that

subjects who lived with a smoking spouse and those who lived with a nonsmoking spouse did not differ in the dietary intake of selected indicator

foods. 

Xian, China (He et al., 1994) He et al. (1994) conducted a second case-control study

in Xian, China. Cases included 59 Chinese women with CHD and 126

controls; all subjects had full-time jobs and had never smoked. Cases had

non-fatal, incident CHD and were identified from one of three large teaching hospitals in the study area between December 1989 and November

1992. Three types of controls were interviewed, including patients admitted because of suspected CHD (these subjects were later found to be free of

CHD)(n = 26), other hospital controls (n = 65), and a random sample of

healthy subjects identified from a community screening program (n = 35).

In-person interviews were conducted with cases and controls using a

structured questionnaire which collected information on demographic

characteristics; history of hypertension, hyperlipidaemia and diabetes mellitus; family history; history of smoking and passive smoke exposure from

husbands and coworkers; drinking history; and exercise. 

There were no significant differences between cases and controls in age,

marital status, occupation, or education, although a higher percentage of

cases were over age 55, were not married, were factory workers and had

fewer than 9 years of education. Risk of CHD was significantly increased

in relation to ETS exposure from husbands (defined as living with a smoking husband for over 5 years) (crude OR = 2.12, 95% CI = 1.06-4.25) and

coworkers (defined as working with smoking coworkers for over 5 years)

(crude OR = 2.45, 95% CI = 1.23-4.88). Crude analysis showed that when

ETS exposure from husbands and coworkers were considered jointly, the

risks increased approximately 2-fold for ETS exposure from husbands only

and at work only, and by 4-fold for exposures both at work and from husbands. Although the ORs in relation to passive smoke exposure from husbands (adjusted OR = 1.24, 95% CI = 0.56-2.72) and at work (adjusted OR =

1.85, 95% CI = 0.86-4.00) were substantially reduced after adjustment for

other risk factors for CHD (age, history of hypertension, type A personality,

total cholesterol, high density lipoprotein), the adjusted OR for any passive

smoke exposure (from husband and/or coworkers) remained statistically significant (adjusted OR = 2.36, 95% CI = 1.01-5.55). There were also significant trends of increasing risks with increasing intensity (amount smoked

daily, number of smokers) and duration (in years) of ETS exposure at work

(Table 8.2).

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The main limitation of this study is the modest sample size of cases and

controls and the fact that prevalent CHD cases may have been included.

However, this study has the advantage of detailed information on ETS

exposure at home and at work and on other heart disease factors, and it

adjusted the analyses on ETS exposure for other potential confounding factors. Moreover, the opportunity to examine the role of ETS exposure at

work was maximized given that all subjects worked full time. This study

also attempted to assess the extent of information bias in several ways.

First, there is no evidence of selective recall bias for being a patient with

CHD: ETS exposure among controls who were initially suspected of CHD

but were later found to be free of CHD by coronary arteriography (n = 26)

was similar to the ETS exposure experience of other hospital controls (n =

65). Second, there was high concordance (over 70 percent) in responses

regarding passive smoke exposure. Some 30 percent of subjects were interviewed a second time by a different interviewer who was blinded to the

case-control status of the subject. Some of the husbands were also interviewed directly to validate the passive smoking information provided by

their wives.

National Mortality Followback Survey (Layard, 1995) Layard (1995) conducted a casecontrol analysis to examine the association between CHD mortality and

spousal cigarette smoking using data on never-smoking decedents from the

1986 National Mortality Followback Survey, which was conducted in 1986

by the U.S. National Center for Health Statistics. The survey was based on a

national probability sample of about 1 percent of all deaths in 1986 of U.S.

residents aged 25 years or older. 

This analysis included all deaths due to CHD (ICD 9, codes 410-414)

among males aged 25-44 years and females aged 25-54 years who were

reported by next of kin to be lifetime never-smokers (i.e., had smoked fewer

than 100 cigarettes in their entire lives). Decendents were excluded from

the analysis if they had never married, their marital status was unknown, or

the smoking history of their spouses was unknown (549 males and 692

females subjects were excluded from the analysis for these reasons). After

these exclusions, the case group included 1,389 (475 males and 914

females) CHD deaths. Controls (996 males and 1,930 females) were selected

from the same study population from those whose causes of death were

considered to be non-smoking related. However, the actual causes of death

among controls were not presented. Next of kin of both cases and controls

completed a mailed questionnaire which provided information on demographic characteristics, dietary patterns, cigarette smoking habits of index

subject and their spouses, alcohol use, education, income, and history of

other diseases. 

In this study, there was no association between exposure to spouse’s

smoking and risk of CHD death in men (OR = 0.97, 95% CI = 0.73-1.28) or

in women (OR = 0.99, 95% CI = 0.84-1.16). Analysis by amount smoked by

spouses (<15, 15-34, 35+ cigarettes/day) also did not reveal any association

between amount smoked by the spouses and risk of CHD mortality. These

results were unchanged after adjustment for potential confounders which

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Smoking and Tobacco Control Monograph No. 10
included dietary factors, relative weight, history of diabetes or hypertension, family history of heart attack, education, and family income. 

It is, however, difficult to interpret these results. First, it appears that

the controls were not matched to cases on age at death or race, since the

mean age at death for cases was significantly higher (72.6 years of age in

men and 78.2 in women) than that of controls (64.8 years of age in men

and 71.9 in women). The percentage of white cases (74.9 percent in males,

73.9 percent in females) was also significantly higher than that in the control group (68.2 percent in males, 68.4 percent in females). Although the

OR was adjusted for age, the specific type of age adjustment used was not

described. Broad age groups used in age adjustment may not be adequate.

Furthermore, the study was supposed to include all deaths among males

aged 25-44 years and females aged 25-54 years but the mean ages of male

cases were considerably older. The reason for this discrepancy was not

explained. Moreover, since the actual causes of death among controls were

not presented, whether their causes of death may be related to tobacco

smoke exposure cannot be ascertained. 

Muscat and Wynder (1995) Muscat and Wynder (1995) conducted a hospital-based

case-control study between 1980 and 1990 in four U.S. cities to evaluate the

association between exposure to ETS during childhood and adult life and

the risk of MI. Cases were newly diagnosed incident cases with MI who

were admitted to teaching hospitals in New York, Philadelphia, Chicago,

and Detroit. Controls were patients who did not have heart disease and

were hospitalized for conditions unrelated to tobacco use. Controls were

frequency matched to cases on the basis of age (±5 years), race, and year of

diagnosis. Ninety percent of both eligible cases and controls were interviewed. Only patients who reported never smoking cigarettes were included in this analysis. 

A standardized questionnaire was administered to all subjects in the

hospital by trained interviewers. Subjects who smoked one or less than one

tobacco product per day for 12 or fewer months were considered neversmokers. An extensive series of questions were asked regarding exposure to

ETS. These questions included childhood exposure, adult exposure, exposure to other people’s smoke at work and on any form of transportation.

Each set of questions included identifying all sources of exposure (e.g.

mother, father, spouse, children, other relatives, and roomers) and the duration of exposure in years.

A total of 114 cases (68 males and 46 females) and 158 controls (108

males and 50 females) were interviewed. Cases were somewhat older than

controls (55.7 years for male cases versus 52.4 years for male controls; 58.7

years for female cases versus 57.9 years for female controls). Adult ETS

exposure was associated with an elevated risk of MI in men (crude OR = 1.3,

95% CI = 0.7-2.4) and in women (crude OR = 1.7, 95% CI = 0.7-3.7). The

OR was 1.5 (95% CI = 0.9-2.6) for men and women combined after adjustment for gender, age, education, and hypertension. There was, however, no

smooth trend of increasing risk with increasing duration (1-20, 21-30, 31+

years) or pack-years (1-10, 11+ pack-years) of ETS exposure in adult life,

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Chapter 8
although all the ORs were greater than 1.0 (see Table 8.2). Exposure to ETS

at work was associated with a small increased risk in men (OR = 1.2, 95% CI

= 0.6-2.2) but not in women (OR = 1.0, 95% CI = 0.4-2.5) whereas exposure

to ETS in transportation was associated with an increased risk in women

(OR = 2.6, 95% CI = 0.9-8.0) but not in men (this OR was not presented).

In both men and women, there was no association between exposure to

ETS during childhood and risk of MI.

To date there are 18 studies (ten cohort studies, eight casecontrol studies) which have examined the association

between ETS exposure and risk of CHD. In 15 studies (nine

cohort studies, six case-control studies) there was some suggestion of a

small increased risk of CHD associated with ETS exposure. This result was

statistically significant in six studies (Hirayama, 1984; Helsing et al., 1988;

Hole et al., 1989; He et al., 1989 and 1994; Kawachi et al., 1997) and in one

gender group in two studies (Dobson et al., 1991a; Steenland et al., 1996).

A statistically nonsignificant increased risk was observed in the other seven

studies, most of which had modest sample sizes (Jackson, 1989; Muscat and

Wynder, 1995; La Vecchia et al., 1993; Humble et al., 1990; Helsing et al.,

1988; Garland et al., 1985; Butler, 1988). Two (Layard, 1995; LeVois and

Layard, 1995) of the three studies (Lee et al., 1986; Layard, 1995; LeVois and

Layard, 1995) which did not find an association between ETS exposure and

risk of CHD were, in fact, very large studies. However, these three studies

had other methodologic limitations. First, all three studies investigated the

association between CHD risk and exposure to any smoking spouse (i.e.,

including former smokers) when there is some suggestion that only current

exposure to ETS may influence the risk of CHD (see below). The suitability

of the control group and the quality of information on ETS exposure are

questionable in the large case-control study conducted by Layard (1995).

This study relied exclusively on information provided by the next-of-kin of

subjects who died of CHD or other causes, and the completeness of the

information is debatable. Moreover, causes of death among the controls

were not presented. Thus, selection bias of controls and misclassification

bias of ETS exposure cannot be ruled out in this study. Third, LeVois and

Layard (1995) combined the data from the CPS-I and CPS-II studies and

found a significant reduced risk of CHD associated with exposure to spouses

who were former smokers. This RR from the combined dataset is due mainly to a reduced risk (RR = 0.81) in nonsmoking men associated with wives

who were former smokers in the CPS-II study. In Steenland’s analysis

(1996) of the CPS-II study, the RR in nonsmoking men associated with

wives who were former smokers was 0.99. Reasons for the discrepancy in

study results between the two analyses of the CPS-II study are not apparent.

However, as noted above, Steenland et al. (1996) conducted a more thorough and comprehensive analysis of the same data set. Moreover, the

results reported by Steenland et al. (1996) were more credible because

increased risks were observed in multiple analyses using different criteria to

define eligible subjects. Increased risks were also observed in the analysis,

which was restricted to subjects who were concordant for self-reported current exposure to smoking and spousal reporting of current smoking.

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8.2 DISCUSSION OF

EPIDEMIOLOGIC

STUDIES
A strength of these collective data which support an association

between risk of CHD and exposure to ETS is that nine of the 15 studies

were prospective studies (Hirayama et al., 1984; Garland et al., 1985;

Svendson et al., 1987; Butler, 1988; Helsing et al., 1988; Hole et al., 1989;

Humble et al., 1990; Steenland et al., 1996; Kawachi et al., 1997). The

cohorts were diverse and included high-risk men (Svendson et al., 1987),

subjects in an affluent community (Garland et al., 1985), lower-risk subjects

in a rural community (Humble et al., 1990), Seventh Day Adventists (Butler,

1988), nurses in the U.S. (Kawachi et al., 1997) and the general population

in the U.S. (Helsing et al., 1988; Steenland et al., 1996), the UK (Hole et al.,

1990), and Japan (Hirayama, 1981, 1984, 1990). Although the sample sizes

of some of the cohort studies were modest (Svendson et al., 1987; Butler,

1988; Hole et al., 1989; Humble et al., 1990; Garland et al., 1985), the analysis based on the CPS-II study (Steenland et al., 1996) included some 3,000

CHD deaths. Almost all of the case-control studies were also relatively

small (He et al., 1989; Dobson et al., 1991a; La Vecchia et al., 1993; He et al.,

1994; Muscat and Wynder, 1995; Jackson, 1989) but these studies had an

advantage in that specific questions on different sources of ETS exposure

were asked and that almost all the cases and controls were interviewed

directly regarding their ETS exposure. Although the case-control study conducted by Layard (1995) was large, information on ETS exposure may be

less complete and was obtained exclusively from next-of-kin.

Misclassification of ETS exposure is a concern in examining these studies. Almost all the studies used spousal smoking as a measure of ETS exposure, while a few studies included questions on ETS exposure from other

settings (see below). Because of the small sample sizes in some studies or

because of the way information on smoking was originally obtained, some

studies described spousal smoking as “yes” or “no” (Svendson et al., 1987;

Hole et al., 1989; Humble et al., 1990; Lee et al., 1986; Dobson et al., 1991a;

He et al., 1989) without distinguishing whether spouses were ex-smokers or

current smokers. In studies of active smoking and heart disease, risk of

heart disease decreases rapidly upon cessation of smoking, although there is

still some residual risk of CHD attributable to past smoking (U.S. DHHS,

1990). Thus, any increased risk of heart disease in nonsmokers in relation

to living with a spouse who is an ex-smoker needs to be interpreted cautiously. A spouse who was an ex-smoker at study enrollment may have

resumed smoking during the period of follow-up. As a different possibility,

an ex-smoker spouse may have been a very heavy smoker with the nonsmoking spouse heavily exposed, and the subsequent increased risk

observed would be a residual effect of intense previous exposure.

Alternatively, subjects married to ex-smokers may be at an increased risk for

CHD because of other characteristics in their lifestyles that are also associated with an increased risk of heart disease.

A few studies have provided information on the risk of CHD in association with ETS exposure from ex-smoking spouses (Garland et al., 1985;

Butler, 1988; La Vecchia et al., 1993; LeVois and Layard, 1995; Steenland et

al., 1996). In one study, nonsmokers married to former smokers and those

married to current smokers both showed increases in risk of CHD compared

to nonsmokers married to nonsmokers (Garland et al., 1985). In three

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Chapter 8
other studies (Butler, 1988; La Vecchia et al., 1993; Steenland et al., 1996),

an increased risk of CHD was found in association with exposure to spouses

who were current smokers but not with exposure to spouses who were former smokers. In one study (LeVois and Layard, 1995), a lower risk of CHD

was found in association with exposure to spouses who were former smokers. The association between risk of CHD and exposure to spouses who

were current smokers was not evaluated in this study.

Information on a dose-response relationship between exposure to

spousal smoking and risk of CHD was available in several studies. A trend

of increasing risk with increasing amounts smoked by spouses was suggested in four studies (Hirayama, 1984; He et al., 1989; La Vecchia et al., 1993;

Kawachi et al., 1997). However, in other studies, there is little evidence of a

smooth trend of increasing risk with increasing amounts smoked by spouses (Helsing et al., 1988; Steenland et al., 1996; Muscat and Wynder, 1995) or

with increasing duration of ETS exposure (Steenland et al., 1996; Butler,

1988).

An advantage of the cohort studies is that information bias was largely

avoided because information on the smoking status of index subjects and

their spouses or other sources of ETS exposure was collected at study enrollment, prior to their illness or death. However, cohort studies are susceptible to misclassification resulting from cessation or resumption of smoking

by spouses or family members. In one study which compared smoking

habits at baseline and at some later time, there was a high concordance in

the nonsmoking status of the index subjects (98 percent) and of their

spouses (98 percent) over a 20 year period, although some 25 percent of

spouses who were smokers in 1960 reported they had stopped smoking by

the late 1960’s (Humble et al., 1990). This suggests that misclassification of

nonsmokers (i.e., nonsmokers who became smokers) is probably minimal,

but that exposure to smoking of spouses or other household members at

enrollment may be higher than exposures in follow-up years. Thus, in

studies with a relatively long follow-up period without reassessment of the

smoking status (Hirayama, 1981; Humble et al., 1990) the reported risk estimates may be associated with spouses’ smoking for only part of the followup period, suggesting that the risk estimates associated with spouses who

smoked during the entire follow-up period may be even higher.

The inclusion of smokers who claimed to be nonsmokers at study

enrollment produces an upward bias in the observed relative risk for CHD

from ETS exposure (Lee, 1989). The basis for this argument is the smoking

concordance between husband and wife, i.e., a smoker is more likely than a

nonsmoker to have been married to a smoker (Sutton, 1981).

Consequently, an active smoker misclassified as a nonsmoker is more likely

than a true nonsmoker to have had exposure to ETS, i.e., by being married

to a smoker. Smoking causes heart disease, and thus a misclassified smoker

has a greater chance of having heart disease than a nonsmoker. The net

effect is that an observed association between ETS exposure and CHD

among people who claim to be never-smokers may be partially explained

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Smoking and Tobacco Control Monograph No. 10
by current or former active smoking by some of them. However, the extent

of misclassification of smokers as nonsmokers in these studies is not

known, but is likely to be small.

Two studies provided information on the effect of ETS exposure among

ex-smokers. These results differed, probably because ex-smokers are a heterogeneous group of individuals who stopped smoking for different reasons.

Ex-smokers who have given up smoking because of heart disease and other

health problems may be more likely to avoid other smokers. In the study

by Svendsen et al. (1987), the risks for CHD death, and for fatal and nonfatal CHD combined in relation to ETS exposure, were substantially weaker in

the analysis including ex-smokers than that conducted among never-smokers only, suggesting a relatively weak ETS effect in ex-smokers. On the

other hand, in the case-control study conducted by Dobson et al. (1991a),

the ETS effect was stronger in men who were ex-smokers than nonsmokers,

but this was not true in women. Results from these studies suggest that

there is not a consistent direction of upward bias if some ex-smokers had

misclassified themselves as nonsmokers at baseline.

Information on risk of CHD in relation to ETS exposure from workplace

or other settings is available in a few studies (Butler, 1988; Steenland et al.,

1996; Muscat and Wynder, 1995; He et al., 1994; Dobson et al., 1991a;

Kawachi et al., 1997). In the CPS-II study, any effect of workplace ETS exposure was small and was not statistically significant (Steenland et al., 1996).

However, in the Nurses’ Health Study (Kawachi et al., 1997), there was a

strong effect of ETS at work and risk of CHD. A strong effect of ETS at work

was also reported in a case-control study conducted in China (He et al.,

1994). This study in China differed from other case-control studies in that

all cases and controls had full-time jobs and thus had the opportunity to be

exposed at work. Most of the other studies (Muscat and Wynder, 1995;

Butler, 1988; Dobson et al., 1991a) had limited ability to investigate the role

of workplace ETS exposure since only small numbers of subjects had jobs

outside the home.

A second concern is the lack of or inadequate control for confounding

factors. Although information on the established risk factors for CHD were

not available in all studies, including two large cohort studies (Hirayama,

1984; Helsing et al., 1988), the recent large cohort studies conducted by

Steenland et al. (1996) using the CPS-II cohort and by Kawachi et al. (1997)

using the Nurses’ Health Study included a large number of dietary and nondietary potential confounders in their analyses. A concern is that nonsmokers with smoking spouses may differ from nonsmokers with nonsmoking spouses in other lifestyle habits that are related to heart disease. There

is, however, little evidence that this could have explained the observed

findings. In the studies which presented data on other heart disease risk

factors (blood pressure, cholesterol, body mass index) and dietary habits

among nonsmokers stratified by the smoking status of their spouses

(Garland et al., 1985; Svendsen et al., 1987; Humble et al. 1990; La Vecchia

et al., 1993), nonsmoking women married to nonsmokers and those married to smokers were generally similar in other risk factors for heart disease.

401

Chapter 8
More importantly, in the studies which presented relative risks adjusting for

demographic factors only (i.e., age and sex), and relative risks adjusting for

demographic factors and other CHD risk factors, the latter relative risks

were not invariably lower after such adjustment (Garland et al., 1985;

Svendsen et al., 1987; Butler, 1988; Humble et al., 1990). In the Nurses’

Health Study (Kawachi et al., 1997), although there was some reduction in

the relative risk with adjustment of various potential confounders, the risks

remained elevated and were statistically significant.

A more fundamental question is whether the ETS association observed

is biologically plausible (see Section 8.3) and whether the magnitude of the

effect is consistent with the active smoking relationship with CHD.

Although the majority of studies have found a significant positive association between active smoking and CHD in men and in women (U.S. DHHS,

1983), there have been some inconsistent findings (Kannel, 1976). The evidence most often cited as demonstrating no association between CHD and

active smoking is the negative finding for uncomplicated angina pectoris in

women reported in the Framingham study (Seltzer 1991a and 1991b;

Skrabanek, 1992). This negative finding has been attributed to the low percentage of women who smoked in this population, and to the fact that

even among women who smoked, most were light smokers, and thus the

study did not have the power to detect a significant association (Kuller and

Meilahn, 1991). A significant positive association between active smoking

and CHD in women has been observed repeatedly in more recent cohort

studies and in numerous case-control studies (Table 8.3). The strongest evidence is from a large U.S. cohort study of nurses in which significant

increased risks for nonfatal MI, angina, and fatal CHD were observed for

smokers compared to nonsmokers, demonstrating an increasing trend in

risk with increasing amounts of cigarettes smoked (Willett et al., 1987)

(Table 8.3). The relative risks for CHD in relation to light smoking reported

in recent studies are considerably higher than the risk estimates reported in

studies conducted in the 1950’s and 1960’s. Specifically, in earlier cohort

studies, relative risks of 1.2 to 1.6 were generally reported for men smoking

1-9 cigarettes/day compared to nonsmokers, as noted in a previous review

(Wu-Williams and Samet, 1990). In more recent studies, relative risks of 2

to 3 were reported for women (Willett et al., 1987; Palmer et al., 1989)

(Table 8.3) and men (Rosengren et al., 1992) who were light smokers (1-4 or

5-14 cigarettes/day) compared to nonsmokers. The higher relative risks for

CHD in more recent cohorts may be due to the earlier age of smoking initiation or deeper inhalation during smoking. The 2- to 3-fold risk between

active smoking and CHD in contemporaneous studies suggests that the

increased risk of about 30 percent for ETS exposure and CHD is believable.

As described above, the Nurses’ Health Study (Kawachi et al., 1997) allowed

direct comparison of the risk of active smoking versus passive smoking relative to the same baseline group (that is, never-smoking women not exposed

to ETS) and showed that the effect of ETS exposure at home and at work

combined was approximately 75 percent of that of active smoking of 1-4

cigarettes per day.

Because there is some variation in the strength of the association

between active smoking and various CHD endpoints, it is also important to

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distinguish between the different CHD outcomes in studies of ETS. In studies on active smoking and heart disease, the relative risks observed for MI

and CHD deaths are usually stronger than the relative risks for angina

(Willett et al., 1987; Beard et al., 1989) (Table 8.3). In studies of ETS and

heart disease, some studies included fatal and nonfatal endpoints (Svendsen

et al., 1987; Hole et al., 1989; Dobson et al., 1991a; Kawachi et al., 1997)

while other studies included only fatal endpoints (Hirayama, 1984; Garland

et al., 1985; Helsing et al., 1988; Humble et al., 1990; Layard, 1995; LeVois

and Layard, 1995; Steenland et al., 1996) or only nonfatal endpoints (Lee et

al., 1986; He et al., 1989 and 1994; LaVecchia et al., 1993; Muscat and

Wynder, 1995). It is difficult to directly compare these results since most

cohort studies provided information on fatal CHD whereas most of the

case-control studies provided information on nonfatal CHD endpoints.

Two studies allow direct comparison of the association between ETS exposure and risk of fatal and nonfatal endpoints. In one study (Hole et al.,

1989), results were presented separately for angina pectoris and for CHD

deaths, and the effect of ETS was stronger for CHD deaths than for angina

or other cardiovascular disease symptoms. In another study, the relative

risks presented for fatal CHD events were higher than the relative risks for

fatal and nonfatal endpoints combined, suggesting that the effect for nonfatal events was weaker and had diluted the overall association (Svendsen et

al., 1987). 

There is some suggestion that the association between active smoking

and CHD may be stronger in younger subjects than in older subjects (Bush

and Comstock, 1983; Rosenberg et al., 1985), although in some studies, the

difference in relative risks by age was only apparent among the very heavy

smokers (Willett et al., 1987; Gramenzi et al., 1989) (Table 8.4). Two studies

presented findings on ETS and CHD by age group. In one study, there was

an apparent effect in both the younger age group (25-44 years) and the

older age group (65+) (Helsing et al., 1988). In another study (Steenland et

al., 1996), the association between risk of CHD mortality and exposure to

spouses’ ETS seemed to be more apparent for subjects aged <65 years old.

This finding suggests that age-specific and cohort effects of ETS exposure on

risk of heart disease should be monitored in future studies.

It is important to identify the mechanisms whereby exposure to

ETS increases the risk of CHD in nonsmokers, and to understand

reasons for the relatively large effects of ETS on heart disease in

nonsmokers compared to the magnitude of the effect of active smoking on

heart disease. At least five interrelated processes have been proposed to

contribute to the clinical manifestations of MI, including atherosclerosis,

thrombosis, coronary artery spasm, cardiac arrhythmia, and reduced capacity of the blood to deliver oxygen (U.S. DHHS, 1990). The evidence that

active smoking influences these mechanisms is convincing (U.S. DHHS,

1990). Supportive evidence is accumulating that exposure to ETS may also

increase the risk of some of these same interrelated processes. The effects of

ETS on intermediate processes including internal and common carotid wall

thickness, endothelial function, exercise tolerance, lipid profile, platelet

function, and fibrinogen levels have been investigated and are reviewed

below.

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Chapter 8

8.3 OTHER

SUPPORTIVE

EVIDENCE
404

Cohort Study Willett, 1987 Smoking Status Nonsmoker Ex-smoker Current (cig/day) 1-14 1-4 5-14 15-24 25+ Person-Years 302,375 174,237 61,400 15,765 45,635 95,430 63,359 Fatal CHD # Event RR 15 1.0 11 1.2 5 1.9 NA NA NA NA 17 4.3 17 5.4 Nonfatal MI #Event RR 48 1.0 44 1.5 21 2.5 NA NA NA NA 65 4.7 64 6.3 Angina # Event 

31 30 11 NA NA 19 17 

Fatal CHD & Nonfatal MI #Event RR 63 1.0 55 1.5 26 2.3 7 2.4 19 2.1 82 4.7 81 6.1 

Table 8.3 Risks of Heart Disease and Active Smoking in Women Case-control StudiesBeard, 1989Palmer, 1989

Smoking StatusSmoker

YesNo

Active Smoking

NonsmokerEx-smokerCurrent Smoker(cig/day)

1-45-1415-2425-3435-44≥45any tobacco

RRFor CHD1.05.11*For MI1.01.4 (1.0-1.8)2.4 (1.1-5.1)2.5 (1.7-3.6)3.0 (2.3-3.8)5.1 (3.6-7.1)4.9 (3.5-6.8)22 (12-39)3.7 (3.0-4.7)

CA/CO44/11784/115

RRFor Angina

1.02.77*

CCdeSMbaC* 

CA/CO17/7069/80191/940149/55011/3654/140213/412110/136120/12958/21570/885
405

Case-controlStudiesGramenzi, 1989Rosenberg, 1985

Smoking StatusActive Smoking

NonsmokerEx-smokerCurrent(cig/day)

1-1415-2425+

Active Smoking

NonsmokerEx-smokerCurrent(cig/day)

1-1415-2425-3435+

RR for CHDFor MI1.01.5 (0.6-3.6)2.3 (1.4-3.7)5.9 (3.2-9.3)11.0 (5.1-23.7)For MI1.01.0 (0.7-1.6)1.4 (0.9-2.1)2.4 (1.8-3.3)5.0 (3.6-6.9)7.0 (5.2-9.4)

CHNagMbaS

CA/CO90/34610/1657/9165/4840/1873/57135/26740/211139/44996/152171/190

Table 8.3 (Continued)
406

# Event RR Age 40-49 20 1.0 7 1.6 (1.1-2.4) 24 3.6 (2.4-5.5) 33 7.0 (4.8-10.5) Age 45-64 219 1.0 18 0.738 1.173 1.436 2.2Age 45-64116 1.011 0.924 1.351 1.924 2.8

# Event RRAge 30-395 1.00 -6 4.3 (1.3-13.7)3 3.5 (0.8-14.5)Age 25-4412 1.04 1.84 1.510 3.78 2.4Age 25-445 1.04 4.61 1.18 4.16 7.5

SmokeActive Smoking

NonsmokerCurrent(cig/day)

1-1415-2425+

Active Smoking

NonsmokerEx-smokerCurrent(cig/day)

1-910-2021+

Active Smoking

NonsmokerEx-smokerCurrent(cig/day)

1-910-2021+

Case-control StudiesWillett, 1987Bush and Comstock, 1983

# Event RRAge 50-5938 1.019 2.4 (1.5-352 4.1 (2.9-545 5.3 (3.7-7Age 65-74355 1.013 0.820 1.017 0.81 0.1Age 65-74171 1.010 1.211 1.110 0.31 0.4

Table 8.4Risks of Heart Disease and Active Smoking in Women by Age
407

CA/CO RR

Age >50

NA 1.0NA 1.0NA 2.7NA 7.3NA NA

Age 40-44

18/156 1.04/86 0.48/56 1.240/154 2.328/56 4.358/61 8.2

CA/CO RR

Age <50

NA 1.0NA 2.2NA 2.1NA 4.6NA 7.7

Age 25-39

10/117 1.05/48 1.24/47 1.025/101 2.923/27 1041/37 13

SmokeActive Smoking

NonsmokerEx-smokerCurrent(cig/day)

<1515-24≥25

Active smoking

NonsmokerEx-smokerCurrent(cig/day)

1-1415-2425-34≥35

Case-control StudiesGramenzi, 1989Rosenberg 

et al., 1985

CA/CO RR

Age 45-49

45/298 1.026/133 1.328/108 1.774/194 2.545/69 4.372/92 5.2

Table 8.4 (Continued)
408

Smoking and Tobacco Control Monograph No. 10

Hospital-based and population-based studies (Howard et al.,

1994; Tell et al., 1994) have demonstrated that active smoking

is associated with significantly greater internal and common

carotid wall thickening. The relationship between ETS exposure and

carotid wall thickening has been investigated in a large cross-sectional

(Howard et al., 1994) and a longitudinal study (Diez-Roux et al., 1995).

The cross-sectional study was conducted among participants in the

Atherosclerosis Risk in Communities (ARIC) Study. At the baseline examination conducted in 1987 through 1989, carotid artery intimal-medial

thickness (IMT) was measured using B-mode real-time ultrasound, and

exposure to active and passive smoking was assessed by questionnaires

administered to about 15,800 adults aged 45 to 65 years. Sixty percent of

the study subjects were either current or past smokers and the remainder

were never-smokers. Never-smokers were considered exposed to ETS (n =

3,339) if they reported current exposure for one or more hours per week to

ETS and as not exposed (n = 1,774) if they had no regular weekly exposure

to ETS. Mean IMT (mm) was higher in nonsmokers exposed to ETS (0.711)

than in nonsmokers not exposed to ETS (0.700), but the mean IMT values

in both groups of nonsmokers were considerably lower than those in past

smokers (0.772) or current smokers (0.775). These differences in IMT

between ETS-exposed and non-exposed nonsmokers were observed in each

age, race, and gender group. After adjustment for age, race, and gender, a

significant difference in IMT of 0.017 mm was estimated between ETSexposed and non-exposed nonsmokers. Further adjustments for other risk

factors reduced the difference to 0.013 mm, which remained statistically

significant (Table 8.5). The number of hours of ETS exposure was significantly associated with IMT in men but not in women in this study. Among

nonsmoking men with ETS exposure (n = 885), after adjustment for age and

race, there was an increase of IMT of 0.00792 mm per 10 hours of weekly

ETS exposure (p < 0.001). In women with ETS exposure (n = 2,340), the

increase of IMT was 0.0011 mm per 10 hours of weekly ETS exposure (p =

0.43).

Results from a longitudinal study further support the association

between ETS exposure and carotid artery IMT. In 1975, a population census

which also asked about active smoking and household smoking was conducted in Washington County, MD, one of the study populations of the

ARIC study (Howard et al., 1994). Diez-Roux et al. (1995) linked the household smoke exposure data obtained in 1975 to carotid IMT measurements

obtained 12-14 years later in the ARIC baseline visit to establish the temporality of the association of ETS exposure with carotid wall thickening.

Information on ETS exposure in 1975 and 1987-1989, and carotid artery

IMT was available on 2,073 subjects who had never smoked. In males and

females combined, the adjusted mean IM wall thickness was 0.706, 0.731,

0.738, and 0.734 mm, respectively, for subjects who had no ETS exposure,

were exposed to ETS in 1975 only, were exposed to ETS in 1987-1989 only,

and were exposed to ETS in both study periods. This represented a 3.5 to

4.5 percent increase in intimal thickness in relation to ETS exposure. Mean

wall thickness was found to be lowest among never-smokers who had never

been exposed to ETS, and ETS exposure in one or both time periods was

8.3.1 Internal and

Common Carotid

Wall Thickness
409

CommentsCrude means are sThe difference betwers and never-smoThis difference chaafter adjustment fogender (p ≤ 0.0001

after additional adjfactors including edactivity, alcohol intaindex, and Key’s s

Mean wall thicknesgender, age, systoLDL cholesterol, prscore, physical actintake, and educatlinear regression.

Mean IMT wallthickness (in mm)0.7750.7720.7110.700Adjusted means ± standard error0.807 ± 0.0090.757 ± 0.0090.734 ± 0.0120.738 ± 0.0110.731 ± 0.0220.706 ± 0.013

ExposureActive smokersEver-smokersPassive smokersNever-smokers not 

exposed to ETS

Current smokers in1987-1989Former smokers in 1987-1989 and in 1975ETS in 1975, 1987-1989ETS in 1987-1989 onlyETS in 1975 onlyNo ETS

Number of subjects 3,5254,3153,3391,774Males andfemales45644825928277211

StudyHoward et al.

(1994)Diez-Roux et al.(1995)

Table 8.5Carotid Artery Intimal-Medial Thickness (IMT) as Measured by B-Mode Ultrasound inCurrent Smokers, Ever-Smokers, and Never-Smokers
410

Smoking and Tobacco Control Monograph No. 10

associated with an increase in wall thickness ranging from 0.023 to 0.035

mm, after adjustment for other risk factors. All three groups exposed to ETS

had consistently greater wall thickness than the no-exposure group. 

The significance of small increases in wall thickness in relation to ETS

exposure is unclear. Analysis based on the entire ARIC cohort found that

an IMT increase of 0.16 mm was associated with a 24 percent increase in

risk of coronary heart disease events in men and a 44 percent increase

among women, over a 2.2 year follow-up period (Howard et al., 1994).

Among Finnish men, for each 0.1 mm increase in IM wall thickness the risk

of MI increased by 11 percent (Salonen and Salonen, 1991 and 1993). The

magnitude of the differences in carotid wall thickness associated with passive smoking is about one-fourth to one-fifth of that observed with active

smoking and may contribute to the risk of future cardiovascular events.

The magnitude of difference between active and passive smoking in terms

of changes in carotid-wall thickness is similar to the magnitude of difference in excess risk for these groups in terms of coronary heart disease endpoints.

8.3.2 Endothelium Function Endothelial dysfunction is considered an important marker of early vascular damage. Celermajer et al. (1996) conducted a

study which compared the endothelial function in the arteries of three

groups of healthy teenagers and young adults: active smokers (n = 26), lifelong nonsmokers who were exposed to ETS (passive smokers, n = 26), and

lifelong nonsmokers who reported to have never been regularly exposed to

ETS at home or at the workplace (n = 25). Regular exposure to ETS was

defined as self-reported exposure at home, at work, or both for at least one

hour per day for at least three years (see Table 8.6). 

Vascular reactivity of the brachial artery was analyzed. The ultrasound

method was used to measure brachial artery vascular responses to increased

flow (an endothelium-dependent dilator stimulator) and to nitroglycerin

(an endothelium-independent dilator). The diameter of the vessel was

measured in every case by two independent observers who were blinded to

the active and passive smoking status of the study subjects. Flow-mediated

dilatation and nitroglycerin-induced dilatation were calculated by each

observer, and the average results of the two observations were recorded.

Subjects in the three groups were similar in baseline characteristics

including their age, systolic and diastolic blood pressure, total cholesterol,

low-density and high-density lipoprotein cholesterol, vessel size at rest, and

flow at rest. Not unexpectedly, the salivary cotinine levels (ng/ml) were significantly higher in the active smokers (170 ng/ml) compared to the passive

smokers (3.7 ng/ml) and the nonsmokers (1.2 ng/ml).

The degree of reactive hyperemia produced by cuff inflation and release

was similar in the three groups studied. In response to this increase in flow,

arterial dilatation was 8.2 percent in the nonsmokers, 3.1 percent in the

passive smokers, and 4.4 percent in the active smokers. Among the passive

smokers, the percentage of flow-mediated dilatation was 4.1 in the subjects

with light exposure to ETS, 3.1 in those with moderate exposure to ETS,
411

Chapter 8

Flow-mediated dilatation 

(mean values + SD; in %)

4.4* ± 3.1

3.1* ± 2.7

8.2 ± 3.1

3.2 ± 2.5

3.0 ± 2.9

7.3 ± 1.9

9.1 ± 3.9

4.1 ± 3.3

3.1 ± 2.2

1.8 ± 2.0

Exposure

Active smokers

Never-smokers 

exposed to ETS

Never-smokers not 

exposed to ETS

By gender

Never-smokers 

exposed to ETS

Males

Females

Never-smokers not 

exposed to ETS

Males

Females

By level of ETS exposure

Never-smokers 

exposed to ETS

Lighta

Moderateb

Heavyc

Study

Celermajer 

et al. (1996)

Number of 

Subjects

26

26

26

13

13

13

13

9

9

8

Table 8.6 

Endothelium-Dependent Arterial Dilation in Active Smokers, Never-Smokers Exposed

to ETS, and Never-Smokers not Exposed

a "Light" is defined as never-smokers who were exposed to 1 to 3 hours of ETS at home

or at work for at least 3 years.

b "Moderate" is defined as never-smokers who were exposed to 4 to 6 hours of ETS at

home or at work for at least 3 years.

c “Heavy" is defined as never-smokers who were exposed to >6 hours of ETS at home or

at work for at least 3 years.

* P value < 0. 05 for never-smokers exposed to ETS compared to never-smokers not

exposed, and for active smokers compared to never-smokers not exposed to ETS. 

and 1.8 in those with heavy ETS exposure. There was no difference in the

nitroglycerin-induced dilation in the three groups.

In this study, passive smokers have significantly impaired arterial

endothelial function. Impaired bioavailability of nitric oxide, the endothelium-derived relaxing factor, may be particularly important, since nitric

oxide acts to inhibit platelet aggregation (Cooke and Tsao, 1994; Deanfield,

1996). Dilatation mediated by brachial-artery flow is endothelium-dependent and is mediated in part by the release of nitric oxide. The activity or
production of endothelial nitric oxide may be impaired in young passive

smokers as well as in active smokers. Although only superficial systemic

arteries can be studied with this ultrasound-based method, endothelial dysfunction in the brachial artery appears to be well correlated with both coronary endothelial physiology and coronary atherosclerosis.

8.3.3 Exercise Tolerance Of the many toxic agents in ETS, carbon monoxide is a

main candidate to influence cardiovascular function, through several possible mechanisms. Carbon monoxide (CO) interferes with oxygen transport

by binding to hemoglobin, forming carboxyhemoglobin (COHb), resulting

in the displacement of oxygen and the lowering of the oxygen-carrying

capacity of the blood. On a cellular level, carbon monoxide can interfere

with intracellular oxidation processes and can increase platelet adhesiveness

(Anthony, 1989; U.S. DHHS, 1983; U.S. DHHS, 1990). Thus, exposure to

ETS, which is rich in carbon monoxide, may result in increased myocardial

oxygen demand, which in turn may outstrip the oxygen supply and produce ischemia. Carbon monoxide has also been reported to lower the ventricular fibrillation threshold and may accelerate atherogenesis by altering

lipid metabolism or by altering vessel permeability to cholesterol. The

COHb levels in nonsmokers exposed to ETS may be up to 1.5 percent. This

level of COHb can be compared to levels of 4 to 6 percent among active

smokers and 2 to 3 percent among certain occupational groups (e.g., blast

furnace workers, traffic officers) (Schievelbein and Richter, 1984).

In four studies, the exercise performance of healthy subjects and subjects with a history of heart disease were evaluated under two conditions: in

the absence of ETS exposure, and in the presence of ETS exposure. The

conditions with ETS exposure simulate exposure levels typically encountered in public settings (Aronow, 1978; McMurray et al., 1985; Leone et al.,

1991; Pimm et al., 1978) (Table 8.7).

The study conducted by Aronow (1978) evaluated the exercise tolerance

of ten men who had classical stable exertional angina. This study tested

the hypothesis that exposure to ETS may result in earlier onset of angina.

The men were exposed to ETS in a well-ventilated room and in an unventilated room. Exposure to ETS resulted in elevation in resting heart rate,

blood pressure, and carboxyhemoglobin levels under both room conditions,

although the increase was more apparent when patients were exposed to

ETS in an unventilated room. Corresponding with the increases in COHb

levels, the duration of exercise until angina developed decreased 22 percent

(p < 0.001) after ETS exposure in the well-ventilated room and 35 percent (p

< 0.001) when the exposure occurred in the unventilated room. The carboxyhemoglobin level increased 42 percent (p < 0.001) when exposure to

ETS occurred in a well-ventilated room and 75 percent (p < 0.001) when in

an unventilated room.

Extending the findings of Aronow (1978), Leone et al. (1991) evaluated

the acute effects of passive smoking on cardiac performance in nine healthy

subjects and ten subjects with a history of MI. Healthy subjects were

younger (mean age 30.5) than subjects with MI (mean age 53.8). Each subject underwent two exercise stress tests on a bicycle ergometer. The first

412

Smoking and Tobacco Control Monograph No. 10
test took place in an enclosed space not polluted by smoking whereas the

second test occurred when the ambient atmosphere was polluted by 30-35

ppm CO.

The peak exercise power of healthy men was not altered by exposure to

ETS. However, men with a history of MI experienced a 33 percent (p <

0.01) reduction in peak exercise power (Table 8.7). The time to recovery of

pre-exercise heart rate (in minutes) was significantly prolonged for both

groups of men when they were exposed to ETS (p < 0.01). Measured levels

of expired carbon monoxide (ppm) pre-exercise and post-exercise were similar when there was no exposure to ETS, but were four times higher in

healthy men and nine times higher in men with previous MI when there

was ETS exposure. Levels of plasma CO were also higher post-exercise than

pre-exercise in the ETS-exposed group, although a significant increase was

observed only among men with a history of MI.

McMurray et al. (1985) evaluated the effects of ETS on submaximal and

maximal exercise performance in eight young healthy women (4 smokers, 4

nonsmokers) who were regular participants in an aerobics class. Subjects

ran on a motor driven treadmill at submaximal and maximal exercise

speeds when there was no ETS exposure and with ETS exposure by breathing air mixed with cigarette smoke (Table 8.7). At maximal exercise capacity, exposure to ETS reduced maximal oxygen uptake (11 percent, p < 0.05)

and duration of exercise (9 percent, p < 0.05). Increased values in the following parameters occurred: maximal respiratory exchange ratio (8 percent,

p > 0.05), maximal blood lactate (24 percent, p < 0.05), ratings of perceived

exertion (9 percent, p < 0.05), and the ratio of ventilation to oxygen uptake

(Ve/VO2 ratio, in liter/min) (10 percent, p < 0.05). Similar adverse effects of

ETS exposure were observed under submaximal exercise although statistically significant differences were observed for only some of the parameters

measured (Table 8.7).

In a fourth study (Pimm et al., 1978), the exercise responses of 20

healthy young men and women were compared after 7 minutes of exercise

on an electronic bicycle ergometer when they were not exposed to ETS and

when they were exposed to an environment contaminated with about 24

ppm of carbon monoxide, equivalent to that produced by the smoking of

four cigarettes. Heart rate, number of breaths per minute, ventilation rate

(liter/min), and maximum oxygen uptake (VO2, liters/min) were measured

as an assessment of exercise response. For both men and women, carboxyhemoglobin levels increased significantly when exposed to ETS, but there

were few consistent changes in measures of lung volumes or in exercise

responses. The lack of significant changes in exercise responses in these

healthy subjects is in fact consistent with results in more recent studies.

Compromised exercise performance was more easily demonstrated in subjects with a history of heart disease than in healthy subjects (Leone et al.,

1991). Moreover, the exercise test in this study is similar to the submaximal exercise challenge in the study of McMurray et al. (1985) in which

fewer significant differences were observed compared to the maximal exercise challenge. Most of the parameters studied by McMurray et al (1985)

were not measured by Pimm et al. (1978).

413

Chapter 8
414

233

1.3

1

11111

In Well-Ventilated Room

Exposure to ETS

No Yes

232.3 ± 68.4 181.1 ± 52.4a

1.25 ± 0.20 1.77 ± 0.16a

Healthy Subjects, 

Exposed to ETS

No Yes

220 ± 30 220 ± 308.50 ± 4 19 ± 4b

2.3 ± 2 2.3 ± 2.01

2.1 ± 1.9 8.5 ± 1.6d

1.2 ± 0.4 1.4 ± 0.21.2 ± 0.4 1.7 ± 0.4

ParameterDuration of exercisein seconds (SD)Plasma Carboxyhemoglobin (%)Peak exercise(in seconds ± SD)Time to recovery(# min ± SD)Expired CO (ppm)pre-exercisepost-exercisePlasma CO (%)pre-exercisepost-exercise

Study Subjects/Test10 men with stableangina exposed to 3smokers who eachsmoked cigarettesover 2 hourssubjects exercised onbicycle ergometer untilonset of angina19 nonsmoking males,9 healthy and 10 withhistory of MI exposedin an enclosed spacewith 30-35 ppm CO(with combustion of15-20 cigarettes within30 minutes)subjects underwentexercise stress test ona bicycle ergometertwice

StudyAronow (1978)Leone (1991)Table 8.7Effect of Exposure to ETS on Excersise Tolerancea p < 0.001 = Comparing exposed to ETS to not exposed under different ventilation conditionsb p < 0.01 = Comparing exposed to ETS to not exposedc p < 0.05 = Comparing exposed to ETS to not exposedd p < 0.01 = Comparing post-exercise to pre-exercise level among subjects exposed to ETS
415

Submaximal Exercise 

Exposure to ETS

No Yes

1.82 1.85

-- --

0.86 0.91

-- --

11.8 13.8a

27.5 28.4

173 178a

ParameterMax 02 uptake (l/min) 

Duration of exercise(minutes)Maximal R valueLactate (mM)Ratings of perceivedexertion (units)Ve/V02 (l air/l 02)

Heart rate (beats/min)

Study Subjects/Test8 normal women,4 smokers and 4 nonsmokers exposed topure air and air contaminated with ETSsubjects completed anexercise trial whichincluded running 20min at about 70%VO2max.increase treadmillgrade by 2-1/2% every2 min until subjectcould not continuewith exercise

StudyMcMurray (1985)Table 8.7 (Continued)a p < 0.05, comparing exposed to ETS to not exposed under submaximal or maximal exercise.
416

Females (n = 10) Exposure to ETSa No Yes 48.1 48.3 31.5 30.7 164.1 168.7b 1.51 1.48 Parameter Ventilation (l/min) Number of breaths per minute Heart rate (beat/min) VO2 (l/min) Study Subjects/Test 20 healthy men and women, ages 18-30 exposed for 2 hours on alternate days to room air or air contam- inated with tobacco smoke (about 24 ppm of CO) subjects performed a 7-minute exercise test on an electronic bicy- cle ergometer (submaximum bicycle test) Study Pimm (1978) Table 8.7 (Continued)

a Values measured at 7 minutes of submaximum bicycle test.b p< 0.01 by paired to test.c p< 0.05 by paired to test.
In two other studies (Allred et al., 1989; Sheps et al., 1990), exercise performance of subjects with a history of coronary artery disease was shown to

be compromised when carbon monoxide was introduced into the environment, resulting in exacerbated ventricular arrhythmias (Sheps et al., 1990)

and myocardial ischemia (Allred et al., 1989). These studies differed from

previous studies (see Table 8.7) in that the amount of carbon monoxide

introduced into the chambers was higher, ranging from 100 to 250 ppm,

exceeding levels generally reported for public places such as restaurants and

bars with tobacco-smoke exposure. The carboxyhemoglobin levels in test

subjects were 4 to 6 percent in one study (Sheps et al., 1990) and 2 to 4 percent in another study (Allred et al., 1989). 

In summary, the collective evidence suggests that exposure to ETS containing levels of carbon monoxide that may be encountered in public settings with tobacco-smoke exposure has deleterious effects on the heart by

increasing the demands on the heart during exercise and reducing its capacity to respond. This imbalance increases the ischemic stress of exercise in

patients with existing coronary artery disease and may precipitate symptoms. The data also suggest that even among healthy subjects, exposure to

ETS may similarly impair exercise tolerance, although to a lesser extent.

8.3.4 Lipid profile An altered serum lipid profile is an established risk factor for

CHD. Determinants of the serum concentrations of the various lipids

include diet, exercise, smoking, and genetic factors. A mechanism whereby

smoking influences the risk of CHD is by changing the serum lipid fractions

into a more atherogenic profile, i.e., higher levels of low-density lipoprotein

cholesterol (LDL-C) and reduced levels of high-density lipoprotein cholesterol (HDL-C) (U.S. DHHS, 1990). The strongest and most consistent effect

of smoking on lipid profile is to lower concentrations of high-density

lipoproteins (HDL). In different studies, HDL levels were 3 to 8 percent

lower in male smokers compared to male nonsmokers and 11 to 13 percent

lower in female smokers compared to female nonsmokers (Anthony, 1989).

There is also the suggestion that smokers have higher levels of triglyceride

and total cholesterol compared to nonsmokers, but the differences were

generally small, and the data are not consistent (Anthony, 1989). The effect

of smoking on HDL cholesterol levels may be through the effect of nicotine

on catecholamine levels (Anthony, 1989).

Two studies have examined the relationship between ETS exposure and

lipid profiles in healthy adolescents (Table 8.8). The results from these

studies suggest that ETS exposure may elevate plasma lipid levels and

change lipoprotein distribution, resulting in an elevated ratio of total cholesterol (C) to HDL-C (total C/HDL-C ratio). The total C/HDL-C ratio is

used as a predictor of the risk of CHD since a high ratio generally means

high levels of total C and low levels of HDL.

Moskowitz et al. (1990) studied the effects of ETS exposure on the cardiovascular and oxygen transport system of 216 preadolescent twins, 105 of

whom had at least one parent who smoked and 111 of whom had both

nonsmoking parents. Blood samples were collected on almost all subjects

and levels of thiocyanate and cotinine were used as measures of smoke

417

Chapter 8
418

Results Exposure Thiocyanate Cotinine Cholesterol LDL HD

to ETS (mg/l) (ng/ml) (mg %) (mg %) (mg No 3.1±5.0 NDa 172.2 86.1 49.Yes 7.1±4.3 1.5±3.1 164.1* 81.3 46.

Total Cholesterol/HDL-C Ratios (±SD) by Serum Cotinine Level <2.5 ng/ml (n = 347)b 2.5 ng/ml (n 

3.51b 3.92

Exposure to ETSNone 3.47 (±0.87) 3.77 (±0.76)Friend/sib only 3.55 (±0.90) 3.70 (±1.13)Mother, not father 3.34 (±0.55) 4.06 (±1.00)Father, not mother 3.64 (±0.78) 4.22 (±1.04)Father & mother 3.68 (±0.85) 3.91 (±1.02)

Study Subjects111 adolescents with bothnonsmoking parents105 adolescents with atleast one smoking parent274 boys, 117 girls34% no exposure; 15%mother smoked only;17% father smoked only;12% both parentssmoked; 22% friends/siblings smoked.

StudyMoskowitz (1990)Feldman (1991)

a ND = non-detectable. Data presented are the mean levels of cholesterol, lipoproteins, and 2-3 DPG, adju

weight, height, and sex.

b The Total-C/HDL-C for the group with cotinine level <2.5 ng/ml was 3.51, and 3.92 for the group with cotin

mg/ml. These values are calculated based on data presented in table (i.e., Table 2 of reference).

* p < 0.05** p < 0.001Table 8.8Effect of Exposure to ETS on Lipid Profile in Children
exposure in the children. Levels of total cholesterol and subfractions were

also assessed. Only data from a single twin randomly selected from each

family were used for statistical analysis.

Children who were passively exposed to parents’ smoking showed significantly higher levels of thiocyanate (7.1 versus 3.1 mg/l, p < 0.0001),

cotinine (1.5 ng/ml versus non-detectable levels), and 2-3 diphosphoglycerate (DPG) (2.09 versus 1.97 μm/ml, p < 0.001) compared to children not

exposed to parents’ smoking. The level of DPG is used as a marker of the

body’s response to hypoxia—i.e., the oxygen demands of body tissues.

Corresponding to these increases, there were significant reductions in levels

of HDL (6.3 percent, p < 0.05) and total cholesterol (4.7 percent, p < 0.05)

among children passively exposed compared to those not exposed when

age, weight, height, and gender were adjusted for in the analysis. There is

internal consistency in the data such that within smoking families, significant positive correlations were observed between thiocyanate levels and

total number of cigarettes parents smoked per day (r = 0.35, p < 0.0001),

between thiocyanate and cotinine levels (r = 0.44, p < 0.0001), and between

thiocyanate and DPG levels (r = 0.29, p < 0.02).

In another study, Feldman et al. (1991) compared the ratio of total

C/HDL-C in children stratified by exposure to ETS. Included in this analysis were 391 adolescents (presumed to be nonsmokers), of whom 44 percent

reported that one or both parents currently smoked, 22 percent reported

exposure to smoking of friends/siblings only, and 34 percent reported no

exposure. In the main analysis, total C/HDL-C ratio in adolescents whose

plasma cotinine levels were ≥2.5 ng/ml (n = 57) (the level considered indicative of exposure) was compared to those with lower cotinine levels. Eightytwo percent of subjects with cotinine levels ≥2.5 ng/mL reported exposure

to ETS. Plasma cotinine levels ≥ 2.5 ng/mL were associated with low HDL-C

and a higher ratio of total C to HDL-C levels. The total C/HDL-C ratio was

8.9 percent (p < 0.003) greater and the mean HDL-C level was 6.8 percent (p

< 0.03) lower in adolescents with higher plasma cotinine concentrations

(≥2.5 ng/ml), compared to those with lower cotinine levels. The calculated

total C/HDL-C ratios were 3.92 and 3.51, respectively, for children with

cotinine levels ≥2.5 ng/ml and <2.5 ng/ml (based on Table 4.2 of Feldman

et al., 1991). The higher total C/HDL-C ratios among adolescents with

higher cotinine levels were observed regardless of their source of ETS exposure. Information on dietary habits and socioeconomic status were not

available in either the Feldman et al. (1991) or the Moskowitz et al. (1990)

study, precluding adjustment for potential confounding effects on the

observed association.

The change in lipid profiles among nonsmoking children exposed to

ETS compared to nonsmoking children not exposed is compatible with the

change observed when children who smoke are compared to nonsmoking

children. In a meta-analysis which examined cigarette smoking associated

changes in blood lipid and lipoprotein levels in 8 to 19 year olds, Craig et

al. (1990) reported that active smokers showed significantly lower serum

levels of HDL-C (8.5 percent) compared to nonsmoking children in the

419

Chapter 8
same age range. The HDL-C levels were 9 percent lower in active smokers

compared to nonsmokers (Craig et al., 1990) and 6-7 percent lower in nonsmokers exposed to ETS compared to nonsmokers not exposed (Moskowitz

et al., 1990; Feldman et al., 1991).

Information on lipid profiles in nonsmoking adults exposed to ETS and

those not exposed is available in the case-control study of He et al. (1989).

Similar to the results in children, nonsmoking adults who were exposed to

ETS also showed lower levels of HDL-C. The average levels were 1.29

nmol/l in nonsmoking women not exposed, and 1.41 nmol/l in nonsmoking women exposed to spouses’ smoking (8.5 percent reduction, p < 0.05).

In summary, the findings by Moskowitz et al. (1990) and Feldman et al.

(1991), which show the effects of exposure to ETS on lipid levels, provide

support for another mechanism whereby risk of heart disease in those

exposed to ETS may be increased. The reduction in HDL-C levels among

passive smokers is about two-thirds of that reported for active smokers, providing a possible explanation for the relatively large effect of ETS on heart

disease in nonsmokers compared to the effect of active smoking on heart

disease. 

Platelets have an important role in the development and

progression of atherosclerosis. Although studies on the

effect of smoking on platelet function are not all consistent,

most studies point to an effect of smoking on the behavior of platelets (U.S.

DHHS, 1990; Anthony, 1989; Ozdemir et al., 1992; Rangemark et al., 1992;

Chiang et al., 1992). Specifically, some of the changes in platelets that have

been demonstrated in smokers compared to nonsmokers include shorter

platelet survival (Mustard, 1981), increased response to aggregation induced

by various agents including adenosine diphosphate (ADP) or thrombin

(Renaud et al., 1984; Blache et al., 1992; Rival et al., 1987), elevated serum

and urinary levels of thromboxane and its metabolites (Dotevall et al.,

1992; Rangemark et al., 1992; Nowak et al., 1987), decreased endothelial

prostacyclin (PGI2) synthesis (Madsen and Dyerberg, 1984), and decreased

platelet sensitivity to PGI2 (Burghuber et al., 1982 and 1986). In smokers, an

increase in levels of thrombaxone (a platelet aggregating agent and vasoconstrictor) in conjunction with a reduction in the levels of PGI2 (an

inhibitor of platelet aggregation and a vasodilator), suggests an imbalance

in hemostatic function in favor of aggregation. The overall effect of smoking tends to increase the ease with which platelets aggregate and the ease

with which platelet mediators are released (Anthony, 1989).

Of the various measures of platelet functions that have been investigated in active smokers (see above), platelet sensitivity to PGI2 in smokers and

nonsmokers exposed to ETS has been investigated (Sinzinger and Kefalides,

1982; Burghuber et al., 1986).

In one study, platelet sensitivity to the anti-aggregatory prostaglandins

before, during, and after ETS exposure in smokers and nonsmokers was

measured (Sinzinger and Kefalides, 1982). The unit of measurement of

platelet sensitivity is the ID50—the amount of prostaglandins (PG) in ng/ml

420

Smoking and Tobacco Control Monograph No. 10

8.3.5 Platelet

Aggregation and

Endothelial Damage
421

Chapter 8

Study

Sinzinger (1982) b

Exposed to passive smoking

Nonsmokers

Smokers

Burghuber (1986) c

Exposed to active smoking d

Nonsmokers

Smokers

Exposed to passive smoking e

Nonsmokers

Smokers

Before

1.26 ± 0.11

1.75 ± 0.26

1.61

3.33

1.25

1.89

After

2.16 ± 0.21 (p < 0.01)

2.08 ± 0.19 (nonsig.)

2.08 (p < 0.01)

3.13 (nonsig.)

1.82 (p < 0.01)

2.04 (nonsig.)

Table 8.9

Platelet Sensitivity to Antiaggregatory Prostaglandinsa Before and After

Exposure to ETS

a Values represent the concentration of protascyclin necessary to inhibit ADP induced

platelet aggregation to 50%. Values are in units of PG in ng/ml platelet-rich plasma, means

± serum.

b Exposure to passive smoking occurred in an 18m3 room where 30 cigarettes were

smoked to give a smoke concentration resembling that in discos or restaurants. Subjects

were exposed for 15 minutes. Blood was collected before and immediately after the smoking period, as well as 20 and 60 minutes later.

c Values shown are calculated in the following way: Sensitivity index of PGI2 were

obtained from extrapolating values in Figures 3 and 4 in reference. From these figures, we

estimated that the sensitivity iindices were 0.62, 0.48, 0.30, 0.32, 0.80, 0.55, 0.53, 0.49 (values are presented in the order under ‘Before’ and ‘After’ columns, for each of the 4 rows).

Since sensitivity index equals 1/ID50, where ID50 is the concentration of PGI2 necessary to

inhibit ADP-induced platelet aggregation to 50 percent, ID50 was calculated is 1/sensitivity

index (e.g., 1/0.62 = 1.61).

d Active smoking experiment: Fourteen healthy males smoked two cigarettes within 10

minutes. Blood specimens were collected immediately before and 15 minutes after smoking.

e Passive smoking experiment: Twenty-two healthy males were exposed for 20 minutes in

an 18 m3 room in which 30 cigarettes were smoked. Blood specimens were collected immediately before and 15 minutes after the passive smoking period.

platelet-rich plasma necessary to halve the aggregation induced by 1 μmol/l

ADP. Exposure to ETS, simulating the concentrations encountered in nightclubs and restaurants (i.e., exposing nonsmokers to smokers who smoked 30

cigarettes) reduced platelet sensitivity to the anti-aggregatory PG. The

reduction was marked and was statistically significant in nonsmokers but

not in smokers. It is of note that the baseline values were significantly

lower (p < 0.01) in smokers compared to nonsmokers, and that platelet sensitivity returned to basal values more quickly in nonsmokers than smokers

(Table 8.9).
422

Smoking and Tobacco Control Monograph No. 10

Platelet

Aggregate Ratios

0.80 ± 0.06

0.65 ± 0.07

0.81 ± 0.10

0.78 ± 0.10

0.88 ± 0.05

0.88 ± 0.04

0.87 ± 0.06

0.78 ± 0.07

Endothelial

Cells/Chamber

2.3 ± 0.5

4.8 ± 1.3

2.5 ± 1.1

3.0 ± 1.1

2.2 ± 0.8

2.3 ± 1.0

2.8 ± 0.9

3.7 ± 1.1

Exposure

Smoked tobacco

cigarettes 

Beforea

After

Smoked non-tobacco

cigarettes 

Before

After

Control Period

Before

After

Exposed to ETSb

Before

After

Number of

Subjects

20

20

20

20

10

10

10

10

Study

Davis et al. (1985)

Davis (1989)

Table 8.10

Measures of Platelet Function in Relation to Exposure to Active Smoking

and Passive Smoking

Platelet Function

a All the ‘before’ and ‘after’ differences were statistically significant at p < 0.01.

b Nonsmokers were exposed to ETS for 20 minutes in open hospital corridors by sitting next

to smokers.

In another study, Burghuber et al. (1986) studied the response of

platelets to exogenous PGI2 in terms of the sensitivity index of PGI2 in

chronic smokers and nonsmokers; levels in groups were measured under

two sets of conditions: prior to and after actively smoking two cigarettes,

and prior to and after exposure to an ETS contaminated atmosphere, respectively. To enable us to compare the results reported by Sinzenger and

Kefalides (1982) and by Burghuber et al. (1986), we converted the latter

results to the same units of measurement as the former study. Specifically,

we calculated the ID50 by taking the reciprocal of the sensitivity index. In

smokers and nonsmokers, the sensitivity index before and after active

smoking and before and after ETS exposure is estimated from the data presented in Figures 3 and 4 of Burghuber et al. (1986) (Table 8.9). Similar to

the findings of Sinzinger and Kefalides (1982), platelet sensitivity to PGI2 in

Burghuber et al. (1986) was significantly reduced after active smoking and

after exposure to ETS. As shown in the study by Sinzinger and Kefalides

(1982), the baseline values were in fact significantly lower in active smokers

than in nonsmokers. The levels in nonsmokers, even after active smoking

or ETS exposure, only approached the baseline levels of smokers. This

study also suggests that platelets of smokers are less sensitive to the anti-
aggregatory action of exogenous PGI2 compared to platelets of nonsmokers.

Acute inhalation of tobacco smoke decreases platelet sensitivity to PGI2

only in nonsmokers, whereas no further decrease could be demonstrated in

smokers. Thus, chronic active smoking or passive smoke exposure can

desensitize blood platelets to PGI2. Such platelets may be more ready to

aggregate and participate in plug formation, leading to arterial thrombosis.

In addition to the effects on platelet function, smoking has been shown

to have a desquamating effect on human endothelium, manifested by an

increase in the concentration of anuclear carcasses of endothelial cells in

venous blood (Prerovsky and Hladovec, 1979).

In a series of studies, Davis et al. compared the endothelial cell counts

and platelet aggregate ratios when different types of tobacco products were

smoked (Davis et al., 1985; Davis et al., 1990) and when nonsmokers were

exposed to ETS (Davis et al., 1989) (Table 8.10). In brief, these studies

showed that the number of endothelial cells (per 0.9 μl chamber) more

than doubled after smoking tobacco cigarettes, increased by 20 percent after

smoking non-tobacco cigarettes (made from wheat, cocoa, and citrus

plants), and increased by 32 percent after ETS exposure compared to less

than 5 percent increase under control conditions (i.e., no exposure to ETS).

Platelet aggregate ratios decreased 19 percent (p < 0.0002), 4 percent (p =

0.004), and 10 percent (p = 0.002) respectively, after smoking tobacco cigarettes, non-tobacco cigarettes, and after exposure to ETS. There was no

change in platelet aggregate ratios under control conditions (Table 8.10).

Nicotine is a potential cause of the observed changes in endothelial

cells and platelet aggregate ratios after smoking tobacco cigarettes, although

other components of cigarette smoke may be important. The modest

changes in endothelial cells and platelet aggregate ratios after exposure to

ETS may be related to the increase in nicotine and carboxyhemoglobin levels in the blood after exposure to ETS. The changes observed in relation to

smoking non-tobacco cigarettes may be explained by the release of small

amounts of catecholamines and modest elevation in nicotine levels even

when non-tobacco cigarettes are smoked (Davis et al., 1990). These studies

demonstrate that brief exposure to ETS under naturally occurring environmental conditions has consistent acute effects on the endothelium and

platelets similar to those of active smoking. The exact roles of carbon

monoxide, nicotine, and other components of tobacco smoke as causes of

observed effects on platelets and the endothelium remain unclear; however,

both of the effects seen following exposure of nonsmokers to ETS, platelet

activation and endothelial damage, are prominent among the mechanisms

thought to be involved in atherosclerosis and arterial thrombosis. These

observations suggest another mechanism whereby exposure to ETS may

increase the risk of heart disease in nonsmokers.

8.3.6 Fibrinogen Levels In numerous cross-sectional, case-control, and cohort

studies (U.S. DHHS, 1990; Dobson et al., 1991b; Meade et al., 1993), fibrinogen levels have been found to be consistently elevated among smokers

compared to nonsmokers. Fibrinogen levels are strong predictors of risk of

CHD (Wilhelmsen et al., 1984; Meade et al., 1986; Kannel et al., 1987) and

423

Chapter 8
are thought to act by promoting thrombogenesis (Meade et al., 1987;

Kannel et al., 1987). Studies of ex-smokers show that fibrinogen levels

decreased with smoking cessation; the reduction is observed within 1 to 2

months of smoking cessation. There is some suggestion that fibrinogen levels in ex-smokers approach those of never-smokers 2 to 5 years after smoking cessation (Meade et al., 1987; Dobson et al., 1991b).

In one case-control study (Dobson et al., 1991a), levels of serum fibrinogen were determined among controls to test the hypothesis that fibrinogen

concentrations would be higher in smokers than nonsmokers, and higher

in nonsmokers exposed to ETS than in non-exposed nonsmokers.

Fibrinogen concentrations were highest in current smokers, intermediate in

ex-smokers and lowest in nonsmokers, both in men and in women.

Nonsmoking men exposed to ETS at home showed higher fibrinogen levels

than nonsmoking men not exposed, but this was not observed in women.

There was also no difference in levels of fibrinogen for nonsmokers exposed

to ETS at work and those not exposed (the mean fibrinogen concentrations

and corresponding confidence intervals were presented in two figures in

Dobson et al. (1991a), but the actual values could not be accurately determined from the figures).

8.3.7 Animal Studies Some animal studies have demonstrated that short-term

exposure to ETS promotes the atherosclerotic process. Exposure to high levels of ETS significantly accelerated the development of atherosclerosis in the

aorta and pulmonary artery in male New Zealand White rabbits maintained

on a high cholesterol diet (Zhu et al., 1993). In a follow-up study in test

animals of the same sex and strain, exposure to ETS significantly accelerated the development of arteriosclerosis; while these investigators found that

ß-blocker metoprolol decreased the development of arteriosclerosis, it did

not protect against the effects of ETS on atherosclerosis (Sun et al., 1994),

suggesting that the ß-adrenergic receptor system is not involved in the

mechanism of ETS-induced atherosclerosis. In another study, the growth of

existing atherosclerotic plaques was accelerated in young cockerels exposed

to ETS compared to those not exposed (Penn and Snyder, 1993).

Specifically, inhalation of ETS did not influence the number of plaques in

this study, but caused a marked increase in plaque size as determined by

plaque index measurements. The investigators hypothesized that ETS exposure did not induce formation of plaques but that it stimulated the proliferation of normally quiescent cells. In a subsequent study, ETS exposure levels were decreased by a factor of five and the effect was still seen (Penn et

al., 1994). The investigators noted that ETS exposure at levels equal to or

below those routinely encountered by people in smoke-filled environments

were sufficient to promote arteriosclerotic plaque development. In SpragueDawley rats, ETS acutely increased LDL accumulation in perfused carotid

arteries after a single exposure (Roberts et al., 1996).

Exposure to ETS increased myocardial infarct size in a (Sprague-Dawley)

rat model of ischemia and reperfusion, and longer ETS exposure produced a

larger effect on infarct size (Zhu et al., 1994). In an investigation of the

mechanism by which ETS exposure causes this effect, L-arginine blocked

the increase in myocardial infarct size produced by ETS in the same animal

424

Smoking and Tobacco Control Monograph No. 10
model, but had no effect on increased platelet aggregation resulting from

ETS exposure (Zhu et al., 1996). Since L-arginine is a precursor to nitric

oxide, the authors postulated that the protective effect on infarct size might

be related to an inhibitory effect of nitric oxide on leukocyte- or free-radical-induced injury.

In summary, the epidemiologic data, from prospective and casecontrol studies conducted in diverse populations, in males and

in females, in western and eastern countries, are supportive of a

causal association between ETS exposure from spouses and CHD mortality

in nonsmokers. Prospective studies have the advantage that information on

smoking status and exposure to ETS was obtained prior to diagnosis of

heart disease, minimizing selective recall bias and misclassification bias

associated with disease status. On the other hand, in some case-control

studies, information on ETS exposure was more detailed and included exposure from spouses as well as from other sources. To the extent possible, estimates of risks were determined with adjustment for demographic factors,

and often for other factors related to heart disease (e.g., blood pressure,

serum cholesterol level, obesity index, dietary factors) which may potentially confound the ETS and heart disease association. Estimates of risks associated with ETS exposure were almost always strengthened when there was

adjustment for other cofactors. An overall risk of about 30 percent is supported by the collective evidence and is within the range of risk estimates

observed for active smoking and CHD in contemporaneous studies published since the 1970’s and 1980’s (e.g., RR = 2.4 for fatal CHD and nonfatal

MI in women who smoked 1-4 cigarettes/day) (Willett et al., 1987). The

association between ETS and CHD is also consistent with the active smoking and CHD association in that the relationship is stronger for fatal CHD

outcomes than for nonfatal outcomes and angina. 

Supporting the epidemiologic evidence, there are data accumulating

from clinical studies which suggest various mechanisms for a causal association between ETS and heart disease. In a number of studies in which nonsmokers were exposed to ETS, carotid wall thickening and compromise of

endothelial function were similar but less extensive than that experienced

by active smokers. In nonsmokers, including well subjects and those with a

history of heart disease, exercise performance is compromised when exercise tests occur under conditions with ETS exposure. There are also data

which show that nonsmokers exposed to ETS compared to those with no

exposure show a lipid profile that is more atherogenic. In studies of adolescents as well as adults, the reduction of HDL-C levels in nonsmokers

exposed to ETS was about two-thirds of that observed when active smokers

were compared to nonsmokers. Of the different parameters of platelet

function that may be affected by active smoking, platelet sensitivity to the

anti-aggregatory effect of PGI2 has been investigated in nonsmokers. In

nonsmokers exposed to ETS, the concentration of PGI2 required to inhibit

platelet aggregation increased 40-70 percent. There was also an increase in

the number of desquamating endothelial cells in nonsmokers exposed to

ETS. These data collectively show that deleterious effects seen following

ETS exposure may account for both short-term and long-term effects of ETS

exposure on the heart.

425

Chapter 8

8.4 CHAPTER

SUMMARY AND

CONCLUSIONS
426

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