Review of Atrazine Cancer 

Epidemiology

Carol H. Christensen, Ph.D., MPH

Epidemiologist

Health Effects Division, OPP
Previous Reviews

• Previous FIFRA SAP Reviews

• J 2000 une 2000: B tO i P tt Breas

t, 

Ovarian, 

Pros

t

a

te, nonHodgkin lymphoma (NHL)

• July 2003 July 2003: Prostate Cancer : Prostate Cancer

• Triazine Manufacturing Plant Worker Studies

• EPA Preliminary Conclusion October 2003 (IR

• “The Agency does not find any results among the av

studies that would lead us to conclude that potential risk is likely from exposure to atrazine...”

• Re-visit when additional studies available, particular

Agricultural Health Study (AHS)

• Current Evaluation U

pdates and Extends

• Emphasis publications since 2003
Use of Epidemiology 

in Risk Assess

m

e

n

t

Use of Epidemiology 

in Ris ssess e t k Assess

m

e

n

t

• OPP “Framework” utilized to review atrazine c

epidemiology literature epidemiology literature:

• Identified studies evaluating atrazine risk

• Described methodology (Appendix B 2) Described methodology (Appendix

B.2)

• Evaluated strengths and limitations (Appendices B.3

• A li ti i l i / l i it i Application inclusion

/exclusion criteria

• Method of exposure, outcome, and confounder 

measurement

• Potential systematic error (bias) Potential systematic error (bias)• Statistical Analysis and study power• Informative sensitivity analyses

Generali abilit

• Generali

zabilit

y
Use of Epidemiology 

in Risk Assess

m

e

n

t

Use of Epidemiology 

in Ris ssess e t k Assess

m

e

n

t

• Results of cancer epidemiology studies synthe

and inte

grated with ex

perimental database

• Use of “Framework” document, considering postulat

key events as well as: key events as well as:

• Exposure-response• Temporality• Strength of association Strength of association• Consistency • Biological plausibility• Scientific Judgment Scientific Judgment

• Formulate overall conclusion overall conclusion
Literature Review Method

• Performed comprehensive review, broad rang

• Searched major biomedical databases Searched major biomedical databases

(PubMed/Web of Science)

• Aid of reference librarian (search string)• No date restriction, hand-search reference lists

• Broad criteria: atrazine/triazine, cancer

• Excluded: no full text available or exposure Excluded: no full text available, or exposure

-only 

only

editorial/review articles

• Multiple raters qualitatively adjudicated relevanc

• 40 studies in current cancer epidemiology revi

• Mid

-1980 s’ through May 2011 through May 2011
Atrazine Cancer 

Ep

idemio

logy Databas

Atrazine Cancer 

Ep de o ogy atabas

idemio

logy Databas

• Endocrine/Reproductive 

System

• Other Anatomica

Cancer Sites

• Prostate, Breast, 

Ovarian, Thyroid

Cancer Sites

• Brain/glioma, 

pediatric canc

• Lymphohematopoietic 

Tumors

• Other AHS Risk 

Estimates (2003+

• Multiple Myeloma, 

Non-Hod

gkin 

Estimates (2003+

• Oral, colorectal, 

esophageal, pan

l bl dd 

g

lymphoma (NHL), other sub-types

lung, bl

adder, me

kidney, larynx, liv

• 2 Cohort

• 6 Nested Case-C
Prostate Cancer

• Triazine manufacturing 

plant studies

• AHS Studie

plant studies

• Initial SIR elevated

• 300 (110-652)

• Bias partial explanation

• 1) Nested Case C

• OR 0.94 

(95% C

• Bias partial explanation

• Individual exposure 

measures, no association among PSA tested

(

1.14)

• 2) Cohort (2004)

• OR Q5 v Q1: OR 

• Cancer Registry (CA) 

and Pesticide Use Data

• Ecologic study

• OR Q5

v. Q1: OR

(95% CI 0.63, 1.linear tren

d

3) C h t (2011)

• Ecologic study

• Black males (

ρ=0.67)

• Nested case control (UFW)

• Simazine OR 1 5 (95% CI

• 3)

C

o

hor

t (2011)

• OR Q4 v. Q1: OR 

(95% CI 0.89, 1.

• Simazine OR 1.5 (95% CI

1.0, 2.3) [grouped exposure]

linear trend
Prostate Cancer

• Summary: 

• Among available studies those with stronger design 

Among available studies, those with stronger design 

methods do not suggest a positive association in postudied

• St th f St di Strengths o

f St

udies:

• Consistent across study design, populations

• Case-control, cohort; and, manufacturing, application

• AHS evaluations performed with sufficient statistical 

• Limitations of Studies: 

• Relatively few studies available (n=10) Relatively few studies available (n=10)• Aggregate exposure assessment method used in se• Stronger studies, primarily white, male applicators (A

• C l ti bl k l t d (Mill 1998) Correlation among blac

k males repor

t

e

d (Mills 1998)
Breast Cancer

• Ecologic Studies

• Significant 10-20%

• Case Control Stu

Significant 10-20% (WI)

increased risk, not replicated in follow-up 

• Significant association in

(WI)

• OR Q5/Q1: OR 1

CI 0.3, 5.8), adju

Significant association • Drinking water r

in

1 of 2 geographic study sites 

• Cancer Registry (CA)

• Drinking water, r

methods, range 3.0 ppb)

AHS St di • Cancer Registry (CA)

and Pesticide Use Data

• No association observed 

CA L i

• AHS Studies 

• Indirect (spouses

(n=309 cases) O

among CA Latinas (95% CI 0 7 1 6

• Ecologic-type exposure 

assessment

(95% CI 0.7, 1.6

• Direct (applicato

(n=36 cases) OR 

(95% CI 0 5 2 5(95% CI 0.5, 2.5

• Ever-use atrazin
Breast Cancer

• Summary: 

• Although available epidemiology database is limited 

Although available epidemiology database is limited

indicate strong positive associations unlikely 

• Strengths:

• Consistent across available analytic studies among 

exposed populations (high use area, ag workers, ap

• Breast cancer risk factors measured in studies

• Exposure measurement: sophisticated methods (dri

water), direct and indirect exposures measured, lifet

• Limitations:

• Limited exposure range or ever/never metric, ecolog

exposure measures used in 4 of 7 studies

• Small number exposed/highly exposed cases Small number exposed/highly exposed cases
Ovarian Cancer

• Ecologic Studies (2)

• Inverse; no association

• Cancer Registry 

Inverse; no association and Pesticide Us

• Population Based Case 

Control (Italy, 1989)

and Pesticide Us

• OR triazine: 1.3 

0.8, 2.3) (n=20 expo

• OR atrazine: 0 7

• Cancer Registry, 

pesticide use questionnaire, interview

OR atrazine:

0.7

CI 0.2, 3.6) (n=2 e

cases)

• <10% triazine ex

• Triazine OR 2.7 (95% CI 

1.0, 6.9)

• Lack adjustment other 

10% triazine ex

questionnaire daresponse rate 

• AHS Cohort pesticides

• Relatively small sample

AHS Cohort

• Ever-Atrazine: O

(95% CI 0.6, 13.

• A ii pr or anali

ys s; 

• 4 atrazine expos
Ovarian Cancer

• Summary: 

• Although available epidemiological database is limit

Although available epidemiological database is limit

positive associations observed, however alternative explanations may exist 

• Strengths:

• Positive, suggestive associations observed in analyt

studies, including prospective study (AHS) 

• Hypothesis testing studies, based upon a priori know

• Highly exposed agricultural populations (worker, app

• Limit

aos ti

o

n

s: 

• Small number exposed cases, imprecise estimates• Lack exposure-response, adjustment other pesticide
Thyroid Cancer

• Prospective, large 

lifetime exposure 

Exposure 

Days

(PPE)

# 

Cases

OR 95% CI

other confounder i

• Male applicato

(n=29 cases)

(PPE)

0-<20 3 1.0

≥20 56 12 4 55 1 27 16 24

• Adjusted BMI, 

pesticides

• All thyroid canc

≥20-56 12 4.55 1.27, 16.24

56-178.5 3 1.16 0.23, 5.89

y 

grouped

• Test linear trend s

at p<0.10, non-mo

≥178.5 11 4.84 1.31, 17.93

Trend 

(p-value)

0.08

p ,

• n<5 cases in spec

exposure categori

(p value)

Beane-Freeman et al. 2011
Thyroid Cancer

• Summary:

• Based upon only one epidemiologic study positive Based upon only one epidemiologic study, positive

associations observed, and replication required

• Strengths:

• Strong association observed in study lack significan

bias

• Exposure-response evaluated

• Limitations:

• One study only• Grouped thyroid cancer sub Grouped thyroid cancer sub

-types

• No link hypothyroidism in other AHS investigation• Biologic mechanism not determined
Lymphohematopoietic

Cancers

Multiple Myeloma (MM), 

Leukemia

Non-Hodgkin Lym

(NHL)

• Case control (Midwest)

• No association: MM, 

Leukemia 

• Case control (Mid

• Non-significant, 

associations ear

• Strong design, low 

potential systematic error, small number cases

adjustment atten(range OR: 1.1, 2

• Pooled OR 

(n=6

• Hospital based studies 

(France) (leukemias/lymphomas)

El d i k f

( 

• 1.5 (95% CI 1.

• t(14:18) positive

• OR 1 7 (95% C

• Elevate

d ris

ks, 

few 

statistically significant (HCL), noted 

F d

OR

1.7 (95% C

• AHS Cohort

• Initial, suggestive 

•

Few expose

d cases, no i NHL M

adjustment other pesticides

increase NHL, M

replicated in extefollow-up (n=152 
Lymphohematopoieti

Ca

nce

rs

Lymphohematopoieti

Ca ce s n

rs

• Summary

• Among all available studies those with stronger des

Among all available studies, those with stronger des

methods do not suggest a positive association in postudied

• Strengths:

• Recent studies prospective, large sample, evaluate 

ex

p p osure res

ponse and sub-typ p es of cancer, ex

posu

(reliable/valid)

• Control for use of other pesticides

• Limitations:

• Small number cases for some LHP sub-types• Possible effect modification by t(14:18), not replicate• Primarily white, male target population
Other Cancer Sites

• Brain/Glioma

• Case

-Control High

-use

Pediatric Acute 

Case

-Control, High

-use Lymphocytic Leu

area

• Atrazine OR 1.1 (95% CI 

0 7 1 8)

Lymphocytic Leu(ALL)

• Case control (CA)

M t l id

0.7, 1.8)

• No association among 

men, women

• Case ascertainment

•

M

a

ternal residen

proxy pesticide e

• OR triazines 4.1

• Case ascertainment 1 5 11 1) ti 

issues, other limitations

1.5, 11.1), pesti

c

adjusted, mid-ragroup

• Ti i t i T

riazines: a

trazin

cyanazine, prompymetrozine, and 

• O l t d il 

O

nly s

t

u

dy avail

a
Other AHS Cancer Site

• Other AHS Point Estimates

• Based upon preliminary research

• 2 Cohort Studies (2004, 2011)• 6 Nested Case Control Studies (2003+)

• No evidence association: 

• Oral, colorectal, esophageal, pancreas, 

bladder, melanoma, kidney, larynx, liver
Other Cancer Sites

• Summary

• Available preliminary studies do not strongly sugges

Available preliminary studies do not strongly sugges

possible associations

• Strengths:

• Several hypothesis generating reports, several amo

studies with strong design and methods (AHS)

• Limitations:

• Few a priori hypotheses• Pediatric ALL: one study available, data are inconcl• Lack biological plausibility at this time Lack biological plausibility at this time
Synthesis of Epidemiology 

Anatomical

Cancer Sites

Synthesis of 

Epidemiologic Data

Curr

Database L

L

y p m

phoma

/ Stron

ger studies (desi

gn Relativel

y few 

Leukemia, Prostate 

g (g

and methods) do not suggest a positive association in populations studied

y

available eacpopulations pwhite, males

populations studied

Breast, Thyroid, Ovarian Although available 

epidemiological database 

is limited, some positive

Relatively few available eac

is limited, some positive number expo

associations observed, however alternative explanations may exist 

number expo

lack exposure(except thyro

Oral, colorectal, esophageal, pancreas, lung, bladder, melanoma, kidney larynx liver

Available hypothesisgenerating epidemiology studies do not strongly suggest a positive

Small numbesome instanctypes; lack bio

kidney, larynx, liver, plausibility a brain/glioma, pediatriccancers) 

suggest

a positive

association in populations studied

plausibility, a hypotheses
Weight of Evidence

“Fra

m

e

work” An

a

lys

i

Weight of Evidence

“Fra e o a ys 

m

e

work” An

a

lys

i

• Cancer Mode of Action (MOA): Mammary glan

tumors in rats due to HPG axis disruption tumors in rats due to HPG axis disruption

• Mechanism not operative in humans• Current Cancer classification: Not likel

y

• No other tumors identified in experimental toxi

data

• W i ht f id d t t t i 

W

eight o

f evidence 

does no

t suppor

t geno

toxi

mutagenicity of atrazine

• Experimental evidence does not indicate a role 

Experimental evidence does not indicate

a role 

atrazine in carcinogenic process in humans
Weight of Evidence:

Prostate Cancer 

• Experimental toxicology and epidemiology data 

consistent, supportive of the conclusion of no as

• Experimental toxicology

• No evidence of prostate hyperplasia or tumorigenesis 

No evidence of prostate hyperplasia or tumorigenesis 

 Rodent bioassay poor predictor of human prostate cancer

• Observational Epidemiology

• Among available studies, those with stronger design a

methods do not suggest a positive association in popu

studied

• Available data do not support association be

atrazine exposure and prostate cancer atrazine exposure and prostate cancer
Weight of Evidence:

Breast Cancer Breast Cancer

• Experimental toxicology and available epidem

data consistent data consistent

• Experimental toxicology

• Mammary gland tumors in female (SD) rats, not mic• MOA not relevant in humans

• Observational Epidemiology

• Although epidemiology database is limited available 

Although epidemiology database is limited, available 

indicate strong positive associations unlikely 

• Available data do not support association 

between atrazine exposure and breast canc
Weight of Evidence:

O

varian Ca

nce

r

Weight of Evidence:

O a a Ca ce varian Ca

nce

r

• Some inconsistencies between experimental 

toxicology and epidemiology data toxicology and epidemiology data

• Experimental Toxicology

• No evidence ovarian pathology or tumorigenesis• Tumors may result from an altered endocrine enviro

MOA supports reduced risk ovarian cancer

 “incessant ovulation” hypothesis

• Observational Epidemiology

• Although available epidemiological database is limit

positive associations observed however alternative positive associations observed, however alternative

explanations may exist 

• Available data do not support association Available data do not support association

between atrazine exposure and ovarian can
Weight of Evidence:

Th

yro

id Ca

nce

r

Weight of Evidence:

Th

y o d Ca ce ro

id Ca

nce

r

• Experimental toxicology and only available 

epidemiology study inconsistent epidemiology study inconsistent

• Experimental Toxicology

• No evidence thyroid hyperplasia or tumor formation, 

alteration of thyroid hormones in rodents

• Rat sensitive to thyroid (follicular cell) carcinogenesis (T-P) 

• Observational Epidemiology

• Based upon only one epidemiologic study, positive 

associations observed, and replication required

• Available data do not support association 

between atrazine exposure and thyroid can
Weight of Evidence:

L

ymp

h

o

h

e

matopo

ietic Ca

Weight of Evidence:

L

y p o e atopo et c Ca 

mp

h

o

h

e

matopo

ietic Ca

• Experimental toxicology and epidemiological 

evidence consistent evidence consistent

• Experimental Toxicology

• No evidence increase in LHP tumor formation• No evidence HPG, hormonal component to LHP can

• Observational Epidemiology

• Among available studies those with stronger design 

Among available studies, those with stronger design 

methods do not suggest a positive association in postudied

• Available data do not support association 

between atrazine exposure and lymphohematopoietic cancers
Weight of Evidence:

Oth

er 

S

ites

Weight of Evidence:

Ot e S tes h

er 

S

ites

• Experimental and observational databases con• Experimental Toxicology Experimental Toxicology

• No evidence of tumor formation in rodent bioassays

• Observational e

p gy idemiology

• Available preliminary epidemiology studies do not st

suggest possible associations

• Available data do not support association 

between atrazine exposure and these other cancers
EPA Conclusion

• “While some epidemiology studies are weakly 

suggestive of an association suggestive of an association between atrazine between atrazine

exposure and cancer incidence in the human population, the preponderance of the different 

evidence 

– i l di b th i t l d including 

b

oth experimen

t

al an

d

epidemiology studies – does not strongly sugg

role of atrazine on human carcinogenesis. Thweight of the evidence, at this time, supports tatrazine is not likely to be carcinogenic in the hpopulation. ”
Questions for Clarificat

• Thank You