Number range CHAPTERAugust 29, 2003

# MEMORANDUM

SUBJECT: Transmittal of Meeting Minutes of the FIFRA Scientific Advisory
Panel Meeting Held July 17, 2003

TO: James J. Jones, Director

> Office of Pesticide Programs

FROM: Steven M. Knott, Designated Federal Official

> FIFRA Scientific Advisory Panel
>
> Office of Science Coordination and Policy

THRU: Larry C. Dorsey, Executive Secretary

> FIFRA Scientific Advisory Panel
>
> Office of Science Coordination and Policy
>
> Joseph J. Merenda, Jr., Director
>
> Office of Science Coordination and Policy

Attached, please find the meeting minutes of the FIFRA Scientific
Advisory Panel open meeting held in Arlington, Virginia on July 17,
2003. This report addresses a set of scientific issues being considered
by the Environmental Protection Agency regarding the characterization of
epidemiology data relating to prostate cancer and exposure to atrazine.

Attachment

cc:

Susan Hazen

Adam Sharp

Anne Lindsay

Janet Andersen

Debbie Edwards

Steven Bradbury

Jay Ellenberger

Arnold Layne

Tina Levine

Frank Sanders

Betty Shackleford

Margaret Stasikowski

Randolph Perfetti

Jerome Blondell

Esther Rinde

William Jordan

Antonio Bravo

Douglas Parsons

Sandy Evalenko

David Deegan

Vanessa Vu (SAB)

OPP Docket

FIFRA Scientific Advisory Panel Members

Christopher J. Portier, Ph.D. (Session Chair)

Stephen M. Roberts, Ph.D. (FIFRA SAP Chair)

Stuart Handwerger, M.D.

Steven G. Heeringa, Ph.D.

Gary E. Isom, Ph.D.

FQPA Science Review Board Members

Frank Bove, Sc.D.

Ellen Gold, Ph.D.

Claudia Hopenhayn, Ph.D.

Lynda Knobeloch, Ph.D.

Ray M. Merrill, Ph.D.

John S. Reif, D.V.M.

Martha S. Sandy, Ph.D.

Elaine Symanski, Ph.D.

Heather Young, Ph.D.

##### SAP Minutes No. 2003-02

**July 17, 2003**

**FIFRA Scientific Advisory Panel Meeting,**

**held at the Sheraton Crystal City Hotel,**

**Arlington, Virginia**

**A Set of Scientific Issues Being Considered by the**

**Environmental Protection Agency Regarding:**

> Characterization of Epidemiology Data Relating to Prostate Cancer and
> Exposure to Atrazine

####### NOTICE

These meeting minutes have been written as part of the activities of the
Federal Insecticide, Fungicide, and Rodenticide Act (FIFRA), Scientific
Advisory Panel (SAP). These meeting minutes represent the views and
recommendations of the FIFRA SAP, not the United States Environmental
Protection Agency (Agency). The content of these meeting minutes do not
represent information approved or disseminated by the Agency. These
meeting minutes have not been reviewed for approval by the Agency and,
hence, the contents of this report do not necessarily represent the
views and policies of the Agency, nor of other agencies in the Executive
Branch of the Federal government, nor does mention of trade names or
commercial products constitute a recommendation for use.

The FIFRA SAP is a Federal advisory committee operating in accordance
with the Federal Advisory Committee Act and was established under the
provisions of FIFRA, as amended by the Food Quality Protection Act FQPA
of 1996. The FIFRA SAP provides advice, information, and recommendations
to the Agency Administrator on pesticides and pesticide-related issues
regarding the impact of regulatory actions on health and the
environment. The Panel serves as the primary scientific peer review
mechanism of the EPA, Office of Pesticide Programs (OPP) and is
structured to provide balanced expert assessment of pesticide and
pesticide-related matters facing the Agency. Food Quality Protection Act
Science Review Board members serve the FIFRA SAP on an ad hoc basis to
assist in reviews conducted by the FIFRA SAP. Further information about
FIFRA SAP reports and activities can be obtained from its website at
[http://www.epa.gov/scipoly/sap/]{.underline} or the OPP Docket at (703)
305-5805. Interested persons are invited to contact Larry Dorsey, SAP
Executive Secretary, via e-mail at [dorsey.larry@.epa.gov]{.underline}.

In preparing these meeting minutes, the Panel carefully considered all
information provided and presented by the Agency presenters, as well as
information presented by public commenters. This document addresses the
information provided and presented within the structure of the charge by
the Agency.

######## CONTENTS

[PARTICIPANTS 7](#__RefHeading___Toc24430690)

[INTRODUCTION 8](#__RefHeading___Toc24430691)

[PUBLIC COMMENTERS 9](#__RefHeading___Toc24430692)

[CHARGE 11](#__RefHeading___Toc24430693)

[SUMMARY OF PANEL DISCUSSION AND RECOMMENDATIONS
12](#__RefHeading___Toc24430694)

[PANEL DELIBERATIONS AND RESPONSE TO CHARGE
13](#__RefHeading___Toc24430695)

[REFERENCES 26](#__RefHeading___Toc24430696)

######### SAP Minutes No. 2003-02

**July 17, 2003**

**FIFRA Scientific Advisory Panel Meeting,**

**Held at the Sheraton Crystal City Hotel,**

**Arlington, Virginia**

A Set of Scientific Issues Being Considered by the Environmental
Protection Agency Regarding:

Characterization of Epidemiology Data Relating to Prostate Cancer and
Exposure to Atrazine

**Steven M. Knott, M.S. Christopher J. Portier, Ph.D.**

**Designated Federal Official FIFRA SAP, Session Chair**

**FIFRA Scientific Advisory Panel FIFRA Scientific Advisory Panel**

**Date: August 29, 2003 Date: August 29, 2003**

**Federal Insecticide, Fungicide, and Rodenticide Act**

**Scientific Advisory Panel Meeting**

**July 17, 2003**

**Characterization of Epidemiology Data Relating to**

**Prostate Cancer and Exposure to Atrazine**

[]{#__RefHeading___Toc24430690 .anchor}**PARTICIPANTS**

**FIFRA SAP, Session Chair**

Christopher J. Portier, Ph.D., Director, Environmental Toxicology
Program, National Institute of Environmental Health Sciences, Research
Triangle Park, NC

**Designated Federal Official**

Mr. Steven M. Knott, FIFRA Scientific Advisory Panel Staff, Office of
Science Coordination and Policy, EPA

**FIFRA Scientific Advisory Panel Members**

Number range CHAPTERStephen M. Roberts, Ph.D. (FIFRA SAP Chair),
Professor & Program Director, University of Florida, Center for
Environmental & Human Toxicology, Gainesville, FL

Stuart Handwerger, M.D., Director, Division of Endocrinology, Cincinnati
Children\'s Hospital Medical Center, University of Cincinnati,
Cincinnati, OH

Steven G. Heeringa, Ph.D., Number range CHAPTERResearch Scientist &
Director for Statistical Design, University of Michigan, Institute for
Social Research, Ann Arbor, MI

Gary E. Isom, Ph.D., Professor of Toxicology, School of Pharmacy and
Pharmacal Sciences, Purdue University, West Lafayette, IN

**FQPA Science Review Board Members**

Number range CHAPTERFrank Bove, Sc.D., Senior Epidemiologist,
Epidemiology & Surveillance Branch, Division of Health Studies, Agency
for Toxic Substances and Disease Registry, Atlanta, GA

Ellen Gold, Ph.D., Professor, Department of Epidemiology and Preventive
Medicine, University of California Davis, Davis, CA

Claudia Hopenhayn, Ph.D., Assistant Professor, School of Public Health
and Markey Cancer Control Program, University of Kentucky, Lexington, KY

Lynda Knobeloch, Ph.D., Research Scientist Supervisor, Research and
Toxicology Unit, Bureau of Environmental Health, Wisconsin Department of
Health and Family Services,

Madison WI

Ray M. Merrill, Ph.D., Associate Professor, Department of Health
Science, Brigham Young University, Provo, UT

John S. Reif, D.V.M., Professor of Epidemiology, Department of
Environmental Health, Colorado State University, Fort Collins, CO

Martha S. Sandy, Ph.D., Senior Toxicologist and Chief, Cancer Toxicology
and Epidemiology Unit, Reproductive and Cancer Hazard Assessment, Office
of Environmental Health Hazard Assessment, California Environmental
Protection Agency,

Oakland, CA

Elaine Symanski, Ph.D., Assistant Professor of Environmental Sciences,
University of Texas Health Science Center at Houston, School of Public
Health, University of Texas,

Houston, TX

Heather Young, Ph.D., Assistant Research Professor, George Washington
University,

Washington, DC

[]{#__RefHeading___Toc24430691 .anchor}**INTRODUCTION**

The Federal Insecticide, Fungicide, and Rodenticide Act (FIFRA),
Scientific Advisory Panel (SAP) has completed its review of the set of
scientific issues being considered by the Agency pertaining to the
characterization of epidemiology data relating to prostate cancer and
exposure to atrazine. Advance notice of the meeting was published in the
*Federal Register* on May 30, 2003. The review was conducted in an open
Panel meeting held in Arlington, Virginia, on July 17, 2003. Dr.
Christopher Portier chaired the meeting. Mr. Steven Knott served as the
Designated Federal Official.

Dr. Jerome Blondell, (Health Effects Division, Office of Pesticide
Programs, EPA) provided the Agency presentation on the characterization
of epidemiology data relating to prostate cancer and exposure to
atrazine. Dr. Blondell presented results from 3 studies: an occupational
cohort study at a manufacturing plant in St. Gabriel, Louisiana; a
prospective cohort study of commercial and private applicators in Iowa
and North Carolina (the Agricultural Health Study); and a county based
study in California that compared pesticide use with cancer incidence
rates. In addition, Dr. Blondell presented the Agency\'s charge
questions to the Panel. Ms. Margaret Stasikowski (Director, Health
Effects Division, Office of Pesticide Programs, EPA) provided an
introduction to the session and also participated in the meeting.

In preparing these meeting minutes, the Panel carefully considered all
information provided and presented by the Agency presenters, as well as
information presented by public commenters. These meeting minutes
address the information provided and presented at the meeting,
especially the response to the charge by the Agency.

[]{#__RefHeading___Toc24430692 .anchor}**PUBLIC COMMENTERS**

**Oral statements were presented as follows:**

On behalf of Syngenta Crop Protection, Inc.:

> Charles Breckenridge, Ph.D., Syngenta Crop Protection, Inc.
>
> James Simpkins, Ph.D., University of North Texas Health Science Center
>
> Jack Mandel, Ph.D., Emory University, Robert W. Woodruff Health
> Sciences Center
>
> Hans-Olov Adami, M.D., Karolinska Institutet
>
> Dimitrios Trichopoulos, M.D., Harvard School of Public Health
>
> Patrick Hessel, Ph.D., Exponent
>
> Thomas Smith, Ph.D., Harvard School of Public Health
>
> Harris Pastides, Ph.D., University of South Carolina, Norman J. Arnold
> School of Public Health

On behalf of the Children\'s Environmental Health Network, Physicians
for Social Responsibility, and American Public Health Association:

> Ms. Carol Stroebel, Children\'s Environmental Health Network

On behalf of the Natural Resources Defense Council, Northwest Coalition
for Alternatives to Pesticides, Consumers Union, Beyond Pesticides,
American Bird Conservancy, Defenders of Wildlife, Sierra Club and
Environmental Working Group:

> Jennifer Sass, Ph.D., Natural Resources Defense Council

On behalf of the American Water Works Association:

> Alan Roberson, P.E., American Water Works Association

On behalf of the National Center for Food and Agricultural Policy:

> Mr. Leonard Gianessi, National Center for Food and Agricultural Policy

On his own behalf:

> Daniel Byrd III, Ph.D., D.A.B.T.

On behalf of the Triazine Network:

> Mr. Jere White, Triazine Network
>
> Donald Ridley, Ph.D., CANTOX Health Sciences International

On behalf of CropLife America:

> James Stevens, Ph.D., Wake Forest University, School of Medicine

On behalf of the National Grain Sorghum Producers Association:

> Mr. Edward Gray, law firm of McDermott, Will, and Emery

On behalf of the Hawaii Agriculture Research Center:

> Ms. Stephanie Whalen, Hawaii Agriculture Research Center

On behalf of the Center for Regulatory Effectiveness:

> Mr. Scott Slaughter, Center for Regulatory Effectiveness

On behalf of the Weed Science Society of America:

> Mr. Robert Hedberg, Weed Science Society of America

**Written statements were provided by or on behalf of the following
groups and individuals:**

American Bird Conservancy

American Public Health Association

American Water Works Association

Beyond Pesticides

Daniel Byrd III, Ph.D., D.A.B.T.

Children\'s Environmental Health Network

Consumers Union

CropLife America

Consultants in Toxicology, Risk Assessment and Product Safety

Defenders of Wildlife

Hawaii Agriculture Research Center

James Huff, Ph.D.

National Center for Food and Agricultural Policy

National Grain Sorghum Producers Association

Natural Resources Defense Council

Northwest Coalition for Alternatives to Pesticides

Physicians for Social Responsibility

Steve Sheffield, Ph.D.

Sierra Club

Syngenta Crop Protection, Inc.

Triazine Network

Weed Science Society of America

[]{#__RefHeading___Toc24430693 .anchor}**CHARGE**

Number range CHAPTER Multiple epidemiologic studies have been performed
on the herbicide atrazine. These studies have looked at various cancer
endpoints, including prostate cancer. The results of a cancer
epidemiology study of manufacturing workers found an excess of prostate
cancer, but there is strong evidence that some or all of this finding
could be an effect of increased screening of workers.

The National Cancer Institute (NCI) and EPA are cooperating on a
prospective cohort study of about 90,000 pesticide applicators and their
spouses in Iowa and North Carolina. Published results from this study
did not find an excess of prostate cancer among commercial or private
applicators, primarily in agricultural settings. However, these workers
would be expected to have lower exposure to atrazine, at least in terms
of duration of exposure, compared to workers at the manufacturing plant.

**Question 1**

After reviewing the study of manufacturing workers at the Syngenta St.
Gabriel plant; the comments of EPA external peer reviewers; public
comments from the Syngenta sponsored peer review and the Natural
Resources Defense Council; and the supplemental exposure analysis
conducted for the St. Gabriel plant workers, EPA has concluded that the
increase in prostate cancer observed in the St. Gabriel manufacturing
plant workers could be explained by the increase in PSA screening for
these workers. Due to the lack of a detailed exposure analysis based on
job history and the limited statistical power due to the small sample
size, atrazine could not be ruled out as a potential cause but a role
for atrazine seems unlikely. Please comment on EPA\'s conclusion. Please
identify any additional data or analyses of the St. Gabriel cohort that
the Agency should consider before reaching a final conclusion.

**Question 2**

Other available studies may assist the assessment of the potential
association between atrazine exposure and prostate cancer. Agricultural
workers generally have a much shorter duration of exposure compared to
workers at a manufacturing plant. In addition, agricultural workers are
expected to have a different pattern of exposure compared to
manufacturing workers (e.g., intensity, seasonality, routes of
exposure). Please comment on comparing the results of the epidemiology
study of prostate cancer conducted in the St. Gabriel plant to the
results of the Agricultural Health Study, considering that the
participants in these two studies were likely to have experienced
different exposures. Discuss what such a comparison indicates about the
relationship between exposure to atrazine and prostate cancer.

[]{#__RefHeading___Toc24430694 .anchor}**SUMMARY OF PANEL DISCUSSION AND
RECOMMENDATIONS**

The Panel concluded that the increase in Prostate Specific Antigen (PSA)
screening at the St. Gabriel plant likely led to an increase in the
detection of cases of prostate cancer. The younger mean age of the cases
and the shift to earlier stage at diagnosis compared to the comparison
population lend support to this conclusion. However, the Panel also
concluded that the evidence presented does not clearly indicate that all
of the observed increase in prostate cancer can be attributed to the
intensive PSA screening program offered to the St. Gabriel workers.
Likewise, the Panel could not rule out the possibility that atrazine
exposure may be a contributing factor in the observed increase in
prostate cancer incidence. Given the limitations in both the study
design and the analysis of the cohort study, at this time a role for
atrazine as a potential cause of prostate cancer cannot be considered
unlikely.

The St. Gabriel cohort study suffered from several limitations that
could lead to negative findings in epidemiologic studies of similar
design, particularly with regard to the very small sample size, which
can greatly hinder the statistical power to detect an effect, and the
limited exposure assessment data and methodology, which could lead to
misclassification of worker exposure. Finally, some characteristics of
the cohort, particularly its relative young age and the short follow-up
period, also limit interpretation of the findings.

The Panel compared the results of the St. Gabriel cohort study to those
of the Agricultural Health Study (AHS), which included agricultural
workers exposed to atrazine. Although the AHS conducted a detailed
exposure assessment, the follow-up period was short, and
misclassification of exposure may have occurred, both of which could
lead to the findings showing no association between atrazine and
prostate cancer.

The comparison of the AHS and the St. Gabriel study found that the
patterns of atrazine exposure were quite different across the two
cohorts. Differences could be found in the anticipated magnitude (peak
and average levels) and in the duration (seasonal versus constant; acute
versus chronic) of atrazine exposure, as well as in the potential for
having other atrazine exposures, particularly from contaminated drinking
water in regions where the herbicide was applied. In summary, given the
striking differences between the two studies in the patterns of exposure
and the limitations in their study design and/or exposure assessment, a
comparison of these studies may not be useful. Neither study, alone or
in combination, is sufficient to conclude that no causal association
exists between atrazine exposure and prostate cancer.

At the meeting, the Syngenta team presented the design and preliminary
results of a nested case-control study of the St. Gabriel workers. The
Panel did not receive a written report and, therefore, was unable to
review this study fully. From the preliminary results presented at the
meeting, it seems additional analyses are necessary, particularly with
respect to exposure assessment and to the confounding effect of PSA
screening. As with the cohort study, the very small size of the study
will continue to be a challenge in interpreting these data given the
inherent statistical limitations.

The Panel repeatedly stressed the need to recognize the lack of
statistical power to see an increased cancer risk given the limited size
of the cohort and the nested case-control studies. The Panel
recommendations included: a more detailed exposure assessment of the
workers in the St. Gabriel cohort and nested case-control studies;
re-analysis of the data by specific sub-groups of workers and
time-periods; and extension of the cohort study, both retrospectively
and prospectively, to increase the study size and the length of
follow-up. The Panel also suggested that a full report of the nested
case-control study be provided, which should include essential elements
such as methods of subject selection, exposure assessment and
statistical analyses. Efforts also should be directed toward
investigating the possibility of conducting studies at other atrazine
manufacturing plants, both in the United States and in other countries.
In addition, the Panel members recommended a broader review of
epidemiologic data concerning the relationship of all cancers to
exposure to atrazine and other triazines and that such a review could
serve as the subject of a future meeting of the SAP.

[]{#__RefHeading___Toc24430695 .anchor}**PANEL DELIBERATIONS AND
RESPONSE TO CHARGE**

The specific issues addressed by the Panel are keyed to the Agency\'s
background documents, and the Agency's charge questions.

**General Comments**

The panel members expressed concern that the SAP review was limited to
the epidemiologic studies of the prostate cancer findings. Partly, this
concern was due to previous SAP recommendations "that the
epidemiological data should be discussed as extensively as the animal
data," (FIFRA Scientific Advisory Panel Meeting, June 27-29, 2000,
Atrazine: Hazard and Dose Response Assessment and Characterization) and
the concern that the review of the prostate cancer studies in isolation
could be misleading. The June 2000 SAP report (SAP Report No. 2000-05)
suggested that the epidemiologic studies of non-Hodgkin's lymphoma "were
discounted even though they suggested . . . adverse health effects." The
panel members recommended a broader review of these studies of other
cancers, including recent studies, and that such a review could serve as
the subject of a future meeting of the SAP. Further, because of the
common mechanism of action of the triazines, epidemiologic studies
relating to cancers and exposure to simazine and other triazines also
should be included in such a review.

**Response to Charge**

**Question 1**

**After reviewing the study of manufacturing workers at the Syngenta St.
Gabriel plant; the comments of EPA external peer reviewers; public
comments from the Syngenta sponsored peer review and the Natural
Resources Defense Council; and the supplemental exposure analysis
conducted for the St. Gabriel plant workers, EPA has concluded that the
increase in prostate cancer observed in the St. Gabriel manufacturing
plant workers could be explained by the increase in PSA screening for
these workers. Due to the lack of a detailed exposure analysis based on
job history and the limited statistical power due to the small sample
size, atrazine could not be ruled out as a potential cause but a role
for atrazine seems unlikely. Please comment on EPA\'s conclusion. Please
identify any additional data or analyses of the St. Gabriel cohort that
the Agency should consider before reaching a final conclusion.**

**Response**

1\. Comment on EPA's conclusion that "the increase in prostate cancer
observed in the St. Gabriel manufacturing plant workers could be
explained by the increase in PSA screening for these workers. Due to
lack of detailed exposure analysis based on job history and the limited
statistical power due to small sample size, atrazine could not be ruled
out as a potential cause but a role for atrazine seems unlikely."

Substantive and persuasive arguments have been made to support the EPA's
conclusion that PSA screening could explain the observed increase in
prostate cancer incidence in these workers. However, it is possible that
PSA screening is only a partial explanation and that other factors may
have contributed to the observed increased risk. The conclusion that
atrazine cannot be ruled out as a potential cause is also appropriate.
The conclusion that a role for atrazine is unlikely was not supported
given the severe limitations of the St. Gabriel study, particularly
those pertaining to small sample size, questionable exposure assessment
and lack of an appropriate comparison group.

# 

The strongest arguments supporting the importance of PSA screening in
explaining at least part of the excess prostate cancer in the St.
Gabriel, LA plant were: 1) while the majority of this workforce was
under the age of 60, the excess in prostate cancer was entirely in
workers under the age of 60 (Tables 10 and 18 in Delzell et al., 2001),
which is the age group that would be overall at lower risk of prostate
cancer and would be likely to have clinically undetected cases revealed
by screening; 2) up through 1999, most (nine out of twelve) of the cases
were asymptomatic, and 86% were localized (higher than the general
population rate of 63% in Louisiana in men under age 60, though perhaps
not statistically significantly higher given the very small number of
cases in the St. Gabriel data.), which are the characteristics that are
indicative of early detection by screening; 3) most of the excess
prostate cancer was among active company employees (Tables 10 and 18 in
Delzell et al., 2001) who were the ones who received free screening from
the company; and 4) the excess of prostate cancer occurred mostly in the
mid- to late 1990's when PSA screening of active workers ages 45 years
and over was nearly complete (Tables 19-24 in Delzell et al., 2001).

Some public commenters presented arguments against atrazine exposure
explaining the increased prostate cancer in this worker population, but
these were not entirely persuasive for a number of reasons. First, the
argument that no biologic or epidemiologic evidence shows that atrazine
is a human carcinogen would not appear to be correct, since both
biologic and epidemiologic data were cited in the materials the SAP
received that suggest a possible relationship of atrazine to cancer
and/or to biologic effects that might be related to cancer. For example,
evidence of endocrine disruption has been observed in several species.

Second, while "no established environmental risk factor" has been shown
to double the incidence of prostate cancer, this does not mean that such
a factor does not exist. In addition, a number of occupational and
environmental exposures have less than a doubling effect on cancer rates
but are still of great public health significance.

Third, the statement that environmental factors are likely "to operate
early in life, since the change in \[prostate cancer\] incidence
requires the passage of at least a generation" lacks substantiation and
validity. While it is true that changes in incidence of the magnitude of
those seen for prostate cancer in such a short period of time are
usually indicative of a non-genetic and sometimes artifactual cause
(such as a new screening test), environmental carcinogens do not require
generations to show an increase. Examples can be found in cancer
epidemiology research of environmental factors whose exposures occur
only or largely in adult life, and yet changes in incidence are observed
in less than a generation (e.g., smoking and lung cancer).

Fourth, although there are no known or suspected non-genetic risk
factors for prostate cancer that differentially affect incidence by age,
we cannot rule out the possibility that such factors may exist. Examples
in cancer epidemiology suggest that different factors have different
strengths of association at different ages or stages of life, so that we
cannot rule out a similar possibility for prostate cancer. For example,
diethylstilbestrol and tamoxifen, both known human carcinogens with
endocrine-disrupting activity, pose greater risk when exposures occur
earlier in life, based on observations in humans and animals.

Fifth, the reviewers disagreed with the assertion by Adami et al. (2002)
that environmental factors have shown an influence on promoting, rather
than initiating, cancer, which would be related to advanced rather than
early stages of disease. Both initiating and promoting environmental
carcinogens are known, and atrazine exposure could result in early stage
prostate cancer.

Finally, the fact that no excess incidence was noted for cancers other
than of the prostate in company workers at the St. Gabriel plant could
be due to a number of factors, including: a) the small size of the study
may not provide adequate statistical power to detect potential
significant increases in other cancer types, including those that have
been observed to be in excess in other studies; b) the young age of the
worker cohort made it unlikely to observe many cancers whose incidence
increases with age; c) the median time since hire of the workers
followed was not sufficient to account for the latency time typically
associated with cancer development; and d) given the small number of
women employed in atrazine production, the St. Gabriel plant does not
offer a suitable worker population to study tumor induction in
estrogen-sensitive tissues.

 The conclusion that atrazine is unlikely to have played a role in the
excess of prostate cancers at the St. Gabriel plant is not adequately
supported by the materials provided for a number of reasons.

First, while it is true that overall the excess of prostate cancers
among the St. Gabriel workers was in the range of increase in incidence
of prostate cancer that may be expected due to PSA screening, an excess
of prostate cancer incidence was evident before intensive PSA screening
commenced in 1993. The published article (MacLennan et al., 2002) stated
that, "Prostate cancer was of particular interest because an earlier
investigation (unpublished) of cancer incidence during 1985-1993 among
workers at the plant found five observed compared to two expected cases
of this disease" (p. 1049). During 1989-1991, very few of the company
employees received PSA screening (1 in 1989, none in 1990, 3 in 1991).
In 1992, 20 of the 233 workers received PSA screening (\<9%). Some of
the material submitted to the SAP (Syngenta No. 2207-01) stated that the
year of diagnosis for five of the 17 cases of prostate cancer was
1989-1992 (page 29 of document, or page 39 of 170).  Thus, the excess in
prostate cancer incidence during 1989-1992 cannot be explained by
intensive PSA screening.

In addition, a few of the subgroups showed excesses potentially beyond
the magnitude expected from a screening effect alone. For example, from
1985-1993 when plant-sponsored PSA screening was relatively infrequent
among the St. Gabriel employees, those under age 55 showed a significant
increase in risk of prostate cancer, 7.5 times beyond that expected
based on the reference population. Since subgroups have smaller sample
sizes and thus greater variability, these excesses are not definitive,
but suggest that other factors in addition to screening may be involved.
Moreover, although the numbers are small and time-specific denominators
are needed, five prostate cancer cases were identified in the 4-year
period 1989-92, and five in the 5-year period 1993-97, in spite of the
clear difference in the prevalence of PSA screening across these two
time periods. Most striking is the fact that in the 2-year period
1998-99, another six cases were identified (see Figure 8 in summary of
atrazine exposure document, Breckenridge, 2002). It might be expected
that after a few years of intensive PSA screening, the incidence of
prostate cancer would begin to decline after most of the sub-clinical
cases are detected, but this does not appear to be the case in this
cohort. From 1993 on, nearly all of those ages 45 and over were
screened, and the 6 additional cases ascertained in 1998-1999 ranged in
age at diagnosis from 48 to 56 years. Denominators are needed to assess
this adequately, but these data may indicate that the excess is
continuing or even growing after nearly complete screening of the male
workforce had been in place for a number of years. It also is important
to note that in examining the induction period for prostate cancer, the
study found that all but one case in the entire cohort (and all the
cases among company employees) occurred ≥10 years since hire. These
facts suggest that a factor, in addition to screening, may be
contributing to the excess, and that the longer latency and/or duration
of exposure may be making the excess more evident.

Second, based on information on job title and plant area dust levels,
Syngenta estimated that 77% of the company's employees had employment
histories indicating that they worked primarily in areas of the plant
with low dust levels or low proximity to atrazine. This contrasted,
however, with the fact that only 50% of the 14 prostate cancers were
classified as having low proximity to atrazine. Similarly, only 23% of
all employees had moderate or high proximity, while more than twice that
proportion, 49%, of prostate cancer cases had moderate or high proximity
to atrazine operations. If the proportions of low (77%), and medium +
high (23%) proximity are applied to the total number of company
employees, the relative risk of prostate cancer comparing those
classified with moderate or high proximity to those with low proximity
is about 3.4 (high vs low =1.9). PSA screening alone cannot explain
these differences. These findings also suggest that atrazine may have
played a role in the observed increase in prostate cancer incidence and
merit further investigation.

Third, with respect to the classification into the 3 exposure groups
described above, no evidence was provided that those classified as
having moderate or high exposure were screened more intensively than
those classified as having low exposure. Both EPA and Syngenta compared
the high exposure group with the combined group of low and moderate
exposure. The effect of this approach is to obliterate the effect
evident in the moderate exposure group in which the prostate cancer
incidence was 20%. Generally, one should either use the low exposure
group as the reference group, or should combine groups with similar
incidence in a reference group. Given the likelihood of considerable
non-differential exposure misclassification, it is reasonable to combine
the moderate and high exposure groups. The lack of an exposure-response
relationship (i.e. the much higher incidence in the moderate group vs
the high group) is to be expected in a situation with considerable
non-differential exposure misclassification and very small numbers.

Fourth, the exposure classification scheme used did not incorporate
information on the time frame of jobs for those workers whose job titles
changed throughout the duration of their work career at the St. Gabriel
plant. For example, based on the information provided, it appears
possible that long-term workers who were employed during the early years
of plant operation in jobs with high proximity to atrazine
manufacturing, handling, or packaging exposures and later moved to jobs
with a lower potential for exposure may have been classified in the low
exposure group, along with workers who spent the early part of their
careers in remote areas of the plant followed by more recent assignments
in high proximity areas. This may have introduced misclassification of
exposure, particularly if the relevant exposures were those received
during periods distant from the time of prostate cancer detection.

  

Fifth, African Americans in the company employee cohort were screened
much more intensively in the 40-44 year age group and slightly more
intensively in the 45+ group, yet they have a slightly smaller excess
risk (Standardized Incidence Ratio (SIR)=146, 2 obs/1.4 exp) than
'whites' in the same cohort (SIR=183, 9 obs/4.9 exp), which adds further
uncertainty to the conclusion that increased PSA screening accounted for
the entire increase in prostate cancer incidence.

 

Sixth, the study's failure to find an excess among contract employees
does not argue against a causal relationship between atrazine exposure
and prostate cancer. The small numbers of cases expected for the
contract production workers (N=0.8) and the short duration of employment
in this group (median = 1.4 years) would make it difficult to detect an
effect of atrazine exposure even though exposures to this group may have
been high. Similarly, contract maintenance employees also had a short
duration of work (median = 2.5 years) and were likely to have lower
exposures than contract production workers.

# 

# Finally, while the study did not find a relationship between duration of exposure and prostate cancer risk, the number of workers was too small to perform a meaningful assessment of dose-response with duration (which was further hampered by the inadequate exposure information available). 

# Aside from the documents, commentaries, reviews and the presentations on the Syngenta St. Gabriel studies, the SAP members were provided with a few published epidemiologic studies of the relationship between atrazine exposure and prostate cancer. One study described an ecologic analysis that found a borderline statistically significant positive association of atrazine use by county with prostate cancer incidence rates in African American males (Mills, 1998). A second study reported a cohort analysis of pesticide applicators that showed no association of self-reported atrazine exposure with prostate cancer (Alavanja et al., 2003, discussed in more detail in the response to question 2). These studies did not alter the Panel\'s opinion that the evidence presented is inadequate to support the Agency\'s conclusion of atrazine as an \"unlikely\" cause of prostate cancer. A more thorough and systematic review of the biologic and epidemiologic literature on the topic of the potential or observed carcinogenic effects of atrazine exposure is required before concluding that atrazine exposure is an unlikely explanation for at least part of the excess of prostate cancer in the St. Gabriel workers. Further, because of the common mechanism of action of the triazines, studies of simazine and other triazines should also be included in such a thorough and systematic review of the biologic and epidemiologic literature.

2\. Identify any additional data or analyses of the St. Gabriel cohort
that the Agency should consider before reaching a final conclusion.

The small number of prostate cancers identified in the St. Gabriel
cohort study is a limiting factor in drawing conclusions. Thus,
possibilities for increasing the number of cases studied should be
explored and might include not only extending the observation of the St.
Gabriel cohort but also determining if other plants have useful
information for future studies of atrazine and prostate cancer.
Additional information also could be obtained from a historical cohort
study for cases prior to 1985 at the St. Gabriel plant. Both in the St.
Gabriel population and in any other industrial cohort to be examined,
efforts should be made to ascertain exposures using biologic and
environmental monitoring as well as extensive job descriptions, job
histories, work activity and exposure duration information, which would
need to be gathered and analyzed. In this context, it would be worth
supplementing the standardized incidence ratio analysis with a
longitudinal cohort analysis by exposure opportunity, intensity and
duration, in the St. Gabriel cohort, and any other atrazine plants that
can be studied. Other comparable occupational populations without known
exposures to atrazine, but with similar PSA screening programs available
to workers, should be considered for a reference population.

To provide additional perspective regarding the role of PSA screening in
the incidence of prostate cancer among workers in the St. Gabriel
cohort, the Panel recommended that a series of SIR calculations should
be performed, based on various periods of study. For example, it may be
useful to explore temporal trends in the SIR using follow-up data
through 1992, 1995, 1998, 2001, etc. Figure 8 in the supplemental data
provided by Breckenridge of Syngenta (2002) shows the temporal sequence
of new case identification through 1999. The pattern of future prostate
cancer incidence will be important in evaluating the potential relative
contributions of PSA screening and atrazine. The graph in figure 3 of
the same document shows the relationship between estimated exposure and
age. A more useful indication of a potential relation to dose on
induction time would be an analysis of estimated exposure with time to
hire. Unless all cohort members were hired at the same age, age would be
a less useful indicator of a potential dose effect. More information on
age at diagnosis also should be provided.

Several of the studies examined are considered greatly limited by their
small sample size (e.g., the St. Gabriel cohort study and the St.
Gabriel nested case-control study presented for the first time at the
public meeting). To provide a quantitative perspective regarding the
probability of detecting an effect if one is present, the Panel
recommended that EPA provide tables of power calculations at various
levels of relative risk for the data being evaluated.

In the nested case-control study that focused on 'regular' employees of
the manufacturing plant, a retrospective exposure assessment was
conducted for cases and non-cases. In constructing the job-exposure
matrix and in developing the exposure metrics, several assumptions were
made regarding the relative magnitude of exposure levels among the job
categories at different time periods, rates of decline in exposure
levels, and the degree of homogeneity in exposure among workers in each
of the job categories stratified by time period. The basis for these
assumptions and, importantly, the validity of the assumptions could not
be ascertained from the information that was presented during the public
comment session. It is possible that different assumptions could have
resulted in different estimates of the workers\' exposure profiles with
unknown effects on the results.

Overall, data concerning the analyses and results of the nested
case-control study in St. Gabriel workers are considered preliminary at
this time. The Panel suggested that a full text describing the methods
of subject selection, exposure assessment and analysis be provided to
the EPA. This could serve as one topic for a future meeting of the SAP
addressing a broader review of epidemiologic data concerning the
relationship of all cancers to exposure to atrazine. The Panel also
recommended prospective collection of exposure monitoring data (using a
random sampling strategy) that could permit an evaluation of some of the
assumptions that were made in the retrospective exposure assessment.
Further analyses should include a complete evaluation of all exposure
metrics with both the logistic regression and Generalized Linear Model
(GLM) approaches, and the role of PSA screening as a potential
confounder and effect modifier should be thoroughly explored. The
job-exposure matrix that was used in the nested case-control study
should be validated against the biologic and environmental monitoring
data and revised accordingly. However, the Panel recognizes that the
small sample size will continue to be a challenge and a limitation of
future assessment of atrazine as a potential carcinogen if such
assessment is restricted to the St. Gabriel cohort and its nested
case-control subjects.

It is also critical to assess and obtain data on other potential risk
factors (such as smoking, diet and previous work history, and
non-occupational or pre-employment exposure to triazine herbicides). In
addition, since family history is a risk factor for prostate cancer,
suggesting that genetic susceptibility factors for prostate cancer may
exist (e.g., polymorphisms), data on this factor as well as on history
of prostate disease (e.g., benign prostatic hypertrophy and prostatitis)
also should be collected. Additional biologic samples that allow DNA
extraction could be obtained and stored, so when techniques become
available, they can be used to explore the possibility of
gene-environment interaction with atrazine in a susceptible subset of
the cohort.

The Panel repeatedly stressed the need to recognize the lack of
statistical power to detect an increased cancer risk given the limited
size of the cohort and the nested case-control studies, and the need to
seek ways to increase the size, both by extending the cohort
retrospectively and prospectively, and by identifying other potential
atrazine manufacturing plants where additional studies of the workforce
could be undertaken.

**Question 2**

**Other available studies may assist the assessment of the potential
association between atrazine exposure and prostate cancer. Agricultural
workers generally have a much shorter duration of exposure compared to
workers at a manufacturing plant. In addition, agricultural workers are
expected to have a different pattern of exposure compared to
manufacturing workers (e.g., intensity, seasonality, routes of
exposure). Please comment on comparing the results of the epidemiology
study of prostate cancer conducted in the St. Gabriel plant to the
results of the Agricultural Health Study, considering that the
participants in these two studies were likely to have experienced
different exposures. Discuss what such a comparison indicates about the
relationship between exposure to atrazine and prostate cancer.**

**Response**

Prior to making any comparisons between results of the epidemiologic
study of prostate cancer conducted in the St. Gabriel plant to the
results of the Agricultural Health Study, it is important to underscore
the differences in exposure patterns in the two cohorts, differences in
the assessment of exposures in the two studies, the strengths and
limitations of the two studies, and the implication of these differences
for interpretations and comparisons of findings of these studies. Since
the St. Gabriel study and its limitations were discussed in detail in
the Panel's response to Question 1, the following section is a
description of the Agricultural Health Study, followed by the comparison
of the two studies with respect to their respective patterns of atrazine
exposure and its relationship to prostate cancer.

 

[The Agricultural Health Study (Alavanja et al., 2003)]{.underline}

 

The Agricultural Health Study (AHS) provided extensive details on the
exposure assessment methodology. The exposure assessment relied on
questionnaire data that gathered information about application methods
and use of personal protection. From this information, the intensity of
exposure to individual pesticides was estimated and coupled to
information about frequency and duration of use. The study classified
exposures by ever/never use as well as an index for cumulative exposure.

The AHS was well conducted; however, the findings reported to date from
this ongoing cohort investigation are based on a short follow-up period
(\< 5 years). The cohort was followed prospectively with exposure
information collected at the start of follow-up. In addition to the
short follow-up period, the study had several additional limitations.
Ever/never use is likely an inappropriate exposure metric for
determining the potential effect of agents such as atrazine for which
the pattern of exposure may be important (i.e., continuous vs.
intermittent). The information on potential determinants of exposure
(e.g., days of use per year, years of use, application methods, and
personal protective equipment use) was solicited for general classes of
compounds and did not differentiate by time period (also note that
responses to the questionnaire collecting this information were not
validated by a review of sales or application records). Moreover, for
each determinant of exposure, weights were assigned based upon
professional judgment and evidence from the pesticide literature
(Dosemeci et al., 2002). It is possible that error was introduced in
estimating exposure due to: 1) differing practices dependent upon the
particular herbicide or pesticide applied; 2) changing practices over
time (which resulted in temporal changes in exposure levels); 3)
inaccurate recall of herbicide use; and/or 4) inaccuracy in the
weighting factors in the exposure intensity algorithm (Dosemeci et al.,
2002), which may not correctly describe atrazine exposure among
applicators in North Carolina or Iowa. As a result, errors in exposure
assessment may have diluted associations that were present.

  Odds ratios for prostate cancer of less than 1.0 were found for "ever
exposed" to atrazine and for levels of cumulative exposure above the
lowest level. One could interpret these findings as supporting the
hypothesis of no causal relationship between atrazine exposure and
prostate cancer. On the other hand, one could interpret the findings as
evidence that the pattern of atrazine exposure in this cohort (i.e.,
intermittent exposure) is not causally related to prostate cancer, but
that a causal relationship between chronic exposure to atrazine and
prostate cancer cannot be ruled out. An interesting finding in this
study was that the odds ratio for "ever exposed" among the subgroup of
the cohort with a family history of prostate cancer was 1.28 (reference
group = positive family history and never exposed) and the "interaction
odds ratio" was 1.52 (ever exposed and positive family history compared
to never exposed and no family history). This result suggests that even
intermittent atrazine exposures might be associated with increased
prostate cancer risk in a highly susceptible population.

 

The AHS is ongoing and a planned re-analysis will approximately double
the number of prostate cancer cases, compared with the number of cases
available for analysis in the recently published study (Alavanja et al.,
2003). Therefore, EPA should utilize the results from the planned
re-analysis in decisions regarding the association of atrazine and
prostate cancer.

Biomonitoring data, based on urine concentrations of atrazine
metabolites could be used to compare exposure to atrazine among cohort
members in the AHS and St. Gabriel populations. These data are currently
available from some persons at the St. Gabriel plant. The AHS protocols
include plans for urine biomonitoring for some pesticide metabolites.
EPA should explore the availability of atrazine metabolite sampling in
the AHS with NCI. If data are available and can be standardized to
account for the time elapsed between recent exposure and sample
collection, the data may constitute a useful metric for comparing
exposures between the cohorts. The study also should take into account
possible exposures to atrazine via contaminated drinking water in the
regions where the herbicide is applied (see Hopenhayn et al., 2002;
Scribner et al., 2000; and Wilson et al., 1987).

1\. Differences in exposure pattern and duration between the 2 cohorts

 

The workers in the AHS cohort likely experienced a different pattern of
exposure than the workers at the St. Gabriel triazine plant.
Specifically, these differences would occur in the magnitude of
exposures received (peak and average exposure level), the pattern and
duration of exposure (intermittent/seasonal vs constant, short vs long
duration), the potential for concomitant exposures (in particular,
exposures to atrazine-contaminated drinking water in the regions where
the herbicide is applied), the potential for spills in agricultural
applications and in manufacturing (resulting in peak exposures), and in
the primary route(s) of exposure. In general, the company employees at
the St. Gabriel plant likely experienced a relatively constant, chronic
exposure, whereas the agricultural cohort experienced a more
intermittent, seasonal exposure with long intervals between exposures.
From the information provided in the St. Gabriel study (and subsequent
information provided by Syngenta), it remains unclear whether the St.
Gabriel company employees had higher average (or peak) exposures than
the agricultural workers.

 

Differences in the pattern and duration of exposures may be important
depending upon the etiology of the disease, the target organs of injury,
and the specific mechanisms of action of the toxicant at the cellular or
molecular level. Differences in the exposure profiles between farm
workers and manufacturing plant workers would be important if chronic,
long-term exposures, rather than intermittent exposures, are implicated
in the risk of prostate cancer.

 

2\. Differences in exposure assessment between the two studies

 

A limited exposure assessment was conducted in the St. Gabriel study.
The study provided general information on differences in exposure
potential for company employees compared to contract employees.
Subsequently, some aggregate information on job titles and the likely
proximity of each job title to production areas in the plant, with high
measured dust levels of atrazine, was submitted by Syngenta.
Nevertheless, at best the information permits only a very crude
assessment of relative exposure among company employees. Bias towards
the null and distortion of dose-response relationships can be expected
from the non-differential misclassification bias resulting from the use
of this information to classify exposures.

 

Although it might be expected that workers involved in manufacturing
atrazine would have higher exposures than agricultural workers, this may
not be the case for many company employees. The exposure information
provided by Syngenta is general and imprecise, but it appears that
contract production workers had the highest exposures, although they
also tended to be short-term employees. The company employees were
employed long-term, but only a small proportion either worked in
production or worked in areas in proximity to contaminated areas of the
plant (e.g., only 23% of company employees had work histories that
predominantly involved working in proximity to areas in the plant with
medium or high dust levels of atrazine, according to Syngenta). Some of
the production workers also may have shifted from production work to
supervisory or managerial work. In addition, dust levels at the plant
were reduced in 1975 (due to the addition of automatic bagging machines)
and again in the early 1980s (due to ventilation controls). Given this
information, it appears that many of the company employees might not
have had chronic exposure to high levels of atrazine for long duration.
However, the exposure information provided in the published article
(MacLennan et al., 2002) and additional submissions by Syngenta is
extremely limited. Still, it is very likely that exposures to the
company employees would be relatively constant and chronic compared to
exposures among agricultural workers.

 

In contrast, the AHS conducted a detailed exposure assessment of
occupational exposures based on questionnaire information provided by
pesticide applicators. Information was obtained on the use of atrazine,
including days of use per year, years of use, application methods, and
personal protective equipment use. The quality of the exposure
assessment in this study helped to minimize exposure misclassification
bias. The occupational exposures to this cohort are likely to be
intermittent and seasonal, with long intervals between exposure periods.
Peak exposures can be high due to spills, splashes and immersions
(Alavanja et al., 2003). Agricultural workers could also be exposed to
low levels of atrazine via contaminated drinking water supplies. The
latter exposure would tend to be chronic with seasonal peaks.

 

3\. Limitations of the 2 studies

 

Both studies had important limitations. The AHS had a short follow-up
time (\<5 years) and involved a relatively young cohort (mean age of
farmer applicators was 47 years). The St. Gabriel cohort was also young
(median age of 41 years), and the size of the company employee subcohort
was small. A limited exposure assessment was conducted in the St.
Gabriel study. The AHS conducted an extensive exposure assessment, but
possible sources of inaccuracies in the exposure assessment included:
the use of weightings in the exposure index algorithm that may not
reflect the actual situations in Iowa and North Carolina, the possible
inaccurate recall of herbicide use, possible inaccurate assignment of
atrazine use based on information gathered for general classes of
compounds, and possible exposures in the AHS cohort to
atrazine-contaminated drinking water in the regions where the herbicide
was applied. Inaccuracies in exposure assessment would be expected to be
non-differential with respect to disease status and would most likely
result in underestimating the risk from atrazine exposure

 

4\. Conclusion

 

Given the striking differences in the patterns of exposure and the
quality of the exposure assessments, the two studies are not directly
comparable. Given their overall limitations, neither study, alone or in
combination, is sufficient for EPA to conclude that there is no causal
association between atrazine exposure and prostate cancer.

 

[]{#__RefHeading___Toc24430696 .anchor}**REFERENCES**

Adami H, Graham C, Mandel J, and Trichopoulos D. An evaluation of the
report by Dr. Delzell et al., 2001 on \"A follow-up study of cancer
incidence among workers in triazine operations at the Novartis St.
Gabriel plant\" \[Technical Report submitted to Syngenta Crop
Protection, Inc., July 2002\].

Alavanja M, Samanic C, Dosemeci M, Lubin J, Tarone R, Lynch C, Knott C,
Thomas K, Hoppin J, Barker J, Coble J, Sandler D, and Blair A. Use of
agricultural pesticides and prostate cancer risk in the Agricultural
Health Study cohort. *Am J Epidemiol* 157:800-814, 2003.

Breckenridge C. Summary of information on potential atrazine exposure
for 12 out of 17 prostate cancer cases reported by Delzell et al., 2001
\[Technical Report prepared by Syngenta Crop Protection, Inc., October
31, 2002\].

 

Dosemeci M, Alavanja M, Rowland A, Mage D, Hoar Zahm S, Rothman N, Lubin
J, Hoppin J, Sandler D, and Blair A. A quantitative approach for
estimating exposure to pesticides in the Agricultural Health Study. *Ann
Occup Hyg* 46:245-260, 2002.

 

Delzell E, Sathiakumar N, MacLennan P, Grizzle W, and Cheng H. A
follow-up study of cancer incidence among workers in triazine-related
operations at the Novartis St. Gabriel Plant. \[Technical Report
submitted to Syngenta Crop Protection, Inc., October 12, 2001\].

Hopenhayn-Rich C, Stump M, and Browning S. Regional assessment of
atrazine exposure and incidence of breast and ovarian cancers in
Kentucky. *Arch Environ Contam Toxicol* 42: 127-136, 2002.

 

MacLennan P, Delzell E, Sathiakumar N, Myers S, Cheng H, Grizzle W, Chen
V, and Wu X. Cancer incidence among triazine herbicide manufacturing
workers. *J Occup Environ Med* 44:1048-1058, 2002.

Mills P. Correlation analysis of pesticide use data and cancer incidence
rates in California counties. *Arch Environ Health* 53: 410-413, 1998.

Scribner E, Battaglin W, Goolsby D, and Thurman E. Changes in herbicide
concentrations in Midwestern streams in relation to changes in use,
1989-1998. *Sci Total Environ* 248: 255-263, 2000.

U.S. EPA SAP. FIFRA Scientific Advisory Panel Meeting, June 27-29, 2000,
Atrazine: Hazard and Dose Response Assessment and Characterization. SAP
Report No. 2000-05.

Wilson M, Savage E, Adrian D, Aaronson M, Keefe T, Hamar D, and Tessari
J. Groundwater transport of the herbicide atrazine, Weld County
Colorado. *Bull Environ Contam Toxicol* 39: 807-814, 1987.