AGENDA

FIFRA SCIENTIFIC ADVISORY PANEL (SAP)

OPEN MEETING

September 14 - 17, 2010

FIFRA SAP WEB SITE http://www.epa.gov/scipoly/sap/

OPP Docket Telephone: (703) 305-5805

Docket Number: EPA-HQ-OPP-2010-0481

U.S. Environmental Protection Agency

Conference Center - Lobby Level

One Potomac Yard (South Bldg.)

2777 S. Crystal Drive, Arlington, VA 22202

Reevaluation of the Human Health Effects of Atrazine: Review of
Non-cancer Effects and Drinking Water Monitoring Frequency

Please note that all times are approximate (see note at end of Agenda).

Day 1

Tuesday, September 14, 2010





8:30 a.m.	Opening of Meeting and Administrative Procedures – Joseph
Bailey, Designated Federal Official, Office of Science Coordination and
Policy, EPA

8:35 a.m. 	Introduction and Identification of Panel Members – 

	Steven G. Heeringa, Ph.D., FIFRA Scientific Advisory Panel Session
Chair

8:40 a.m.	Welcome and Opening Remarks – Steven Bradbury, Ph.D., Acting
Director, Office of Pesticide Programs, EPA

8:50 a.m.	Welcome and Introductions – Tina Levine, Ph.D., Director,
Health Effects Division, Office of Pesticide Programs, EPA

9:00 a.m.	Atrazine Re-evaluation:  Introduction and Status – Anna
Lowit, Ph.D., Health Effects Division, Office of Pesticide Programs, EPA

9:30 a.m.	Evaluation of Atrazine Non-Cancer Epidemiology Literature - 

	Carol Christensen, Ph.D., M.P.H., Health Effects Division, Office of
Pesticide Programs, EPA

10:30 a.m.	Break

10:45 a.m.	Atrazine: Proposed Updates to the Dose-Response Assessment -
Chester Rodriguez, Ph.D., Health Effects Division, Office of Pesticide
Programs, EPA

12:00 p.m.	Lunch

1:15 p.m.	Approaches to Evaluating Water Sampling Strategies and
Frequency of Monitoring - Nelson Thurman, M.S. and Mary Frankenberry,
Environmental Fate and Effects Division, Office of Pesticide Programs,
EPA

2:15 p.m.	Scientific Considerations in Potential Sensitivity of Infants
and Children and Implications of MOA on Water Monitoring Strategy -

	Anna Lowit, Ph.D., Health Effects Division, Office of Pesticide
Programs, EPA

3:15 p.m.	Break

3:30 p.m.	Atrazine Re-evaluation: Summary and Next Steps - 

	Anna Lowit, Ph.D., Health Effects Division, Office of Pesticide
Programs, EPA

5:00 p.m.	Adjourn

Day 2

Wednesday, September 15, 2010





8:30 a.m.	Opening of Meeting and Administrative Procedures – Joseph
Bailey, Designated Federal Official, Office of Science Coordination and
Policy, EPA

8:35 a.m. 	Introduction and Identification of Panel Members – 

	Steven G. Heeringa, Ph.D., FIFRA Scientific Advisory Panel Session
Chair

8:45 a.m.	Follow-up from Previous Day’s Presentations

9:15 a.m.	NIEHS Presentation - Suzanne Fenton, Ph.D., Cellular and
Molecular Pathology Branch, National Institute of Environmental Health
Sciences

10:00 a.m.	Break

10:15 a.m.	Public Comment

12:30 p.m.	Lunch

1:30 p.m.	Public Comment

3:30 p.m.	Break

3:45 p.m.	Charge To Panel - Question 1.0 - Non-cancer Epidemiology

Section 3.0 and Appendix B of the draft Issue Paper provide the Agency
reviews and synthesis of the non-cancer epidemiology studies available
for atrazine. These include studies on a variety of topics, notably
female and male reproductive outcomes and birth outcomes in addition to
other topics.   Section 4.0 integrates the findings of the epidemiology
and experimental toxicology studies.  

Question 1.1

Please comment on the sufficiency of the Agency’s non-cancer
epidemiology reviews with respect to identifying the major strengths and
limitations of each study.

4:30 p.m.	Charge To Panel 

Question 1.2

At this time, atrazine’s non-cancer epidemiologic database is not
robust enough for inclusion in quantitative risk assessment and does not
support the ability to determine causal associations. There are several
limitations present in the current database, and the quality of atrazine
exposure assessment is paramount among the limitations.  In Section 4.0
of the draft Issue Paper, the Agency describes the qualitative
similarities and differences between the epidemiologic findings and the
experimental toxicology database.  In short, the observational studies
– particularly those related to reproductive effects in adult females,
as well as small for gestational age in newborns – lend further
support for the human relevance of the laboratory animal findings.

a.  	Please comment on the scientific information that does and does not
support the Agency’s conclusions (as described in Section 3.0) with
respect to the characterization of quality, and limitations of the
non-cancer epidemiologic database and its utility in hazard
characterization, dose response analysis, and quantitative risk
assessment.

5:00 p.m.	Charge to Panel

b.	Please comment on scientific information that does and does not
support the integrative analysis and conclusions, contained in Section
4.0, with respect to the similarities, differences, and uncertainties of
the experimental toxicology and epidemiologic findings. 

5:30 p.m.	Meeting Adjourns

Day 3

Thursday, September 16, 2010





8:30 a.m.	Opening of Meeting and Administrative Procedures – Joseph
Bailey, Designated Federal Official, Office of Science Coordination and
Policy, EPA

8:35 a.m. 	Introduction and Identification of Panel Members – 

	Steven G. Heeringa, Ph.D., FIFRA Scientific Advisory Panel Session
Chair

8:45 a.m.	Charge to Panel - Question 2.0 - Review of Studies on Mammary
Gland Development

At the April SAP, the Agency evaluated effects of atrazine on a number
of apical endpoints including neuroendocrine, neurotoxicity, and
immunotoxicity effects.  At that time, the Agency deferred review of
experimental toxicology studies on mammary gland development to the
September SAP meeting.  Development of mammary tissue occurs in defined
stages linked to sexual maturation and reproduction including embryonic,
pre- and peripubertal periods, as well as pregnancy and lactation. 
Given that atrazine affects the hormonal environment and reproductive
system, it is not unreasonable to hypothesize that it may also affect
mammary gland development.  The database of mammary gland development
studies includes four studies---three from same the research group
(Rayner et al., 2004; Rayner et al., 2005; Enoch et al., 2007) in
addition to one conducted by Coder (2010).  It is important to note that
the key events leading to reported delays in mammary gland development
in the young following gestational exposure to atrazine are not known
and none of these studies propose a mechanism/mode of action.   

Question 2.1  

The studies from the two different research groups yielded different
results regarding the impact of atrazine on mammary gland development. 
While the Rayner and Enoch studies report delays in mammary gland
development, the Coder study does not.  The basis of these different
findings is unknown.  However, one notable difference in the study
design used by the two research groups is the scoring system.  The
Rayner et al. and Enoch et al. studies used a subjective scoring scale
with a 1-4 scoring system (1 = poor development/structure; 4 = normal
development/structure) with criteria which vary depending on the age of
the pups. In contrast, Coder employed a quantitative morphometric
analysis to evaluate mammary gland development.  In addition, the Coder
study also included the use of BrDU labeling to assess cell
proliferation in the mammary tissue.  

Please comment on the quality, strengths, and limitations of the mammary
gland development studies by Rayner et al. (2004, 2005) and Coder (2010)
studies.  Please discuss in your comments factors which could lead to
different findings.  Please comment on the Agency’s conclusions
regarding these studies on atrazine.

9:30 a.m.	Charge to Panel 

Question 2.2.

In three of the studies considered in Question 2.1 (Rayner et al., 2004
and 2005; Coder, 2010), effects have only been observed at an atrazine
dose of 100 mg/kg/day.   In contrast, Enoch et al. (2007) report delays
in mammary gland development as low as 0.09 mg/kg/day following exposure
to atrazine and a mixture of several metabolites/degradates (DEA, DIA,
DACT, hydroxy-atrazine).   The Agency’s review of this mixture study
is provided in Appendix A (Section A.10)    Please comment on the Enoch
et al. (2007) study and the degree to which the Agency’s review
accurately reflects the strengths and limitations of the study.  Please
include in your comments a consideration of the study design of the
mixtures experiment and how this design impacts the interpretation of
the results. 

10:15 a.m.	Break

10:30 a.m.	Charge to Panel

Question 2.3.

As described in the Introduction of the draft Issue Paper (Section 1.0),
the Agency’s problem formulation is being conducted in a step-wise
manner.  One important component of this problem formulation is the
evaluation of the overall database and the quality of the available
experimental toxicology studies.  In the case of mammary gland
development, the Agency is proposing to acknowledge these four studies
(Rayner et al., 2004; Rayner et al., 2005; Enoch et al., 2007; Coder,
2010) in the hazard characterization but place little emphasis on them
in its proposed updates to the dose-response assessment for atrazine. 
The only findings reported in the Rayner et al., (2004), Rayner et al.,
(2005), and Coder (2010) studies, occurred at a high dose (100
mg/kg/day) which is approximately 50-fold higher than the PoD of 1.86
for LH attenuation being proposed by the Agency.  In the Enoch et al.
(2007) study, there are significant limitations with the conduct and
reporting the Agency believes which preclude the study from use in
quantitative risk assessment.  

In light of Panel discussion on Questions 2.1 and 2.2, please comment on
the manner in which the Agency has proposed to use the mammary gland
development studies in the hazard assessment for atrazine.

11:15 a.m.	Charge to Panel - Question 3.0:  Proposed Updates to the
Dose-			Response Assessment

At the April, 2010 SAP, the Panel made two key recommendations related
to dose-response assessment:  1) consider pursuing a dose-response
analysis based on an internal dose metric, as an alternative to the
administered dose metric used in the previous risk assessment; and 2)
identify the sensitive endpoint associated with functional impairment
and perform benchmark dose (BMD) modeling.  The Agency conducted both
recommended analyses (Section 5.0 of the draft Issue Paper) in response
to these recommendations.  LH attenuation, as a key event in
atrazine’s MoA, is the most sensitive internal dose metric that is
associated with a number of endocrinopathies

Question 3.1

Given that there is no robust pharmacokinetic model yet available, a
non-

compartmental analysis of the existing pharmacokinetic data was
conducted and described in Section 5.2 of the draft Issue Paper.  EPA
thinks this represents the best method to estimate an internal dose
metric without exceeding the limits of the available data.

a.   Please comment on the Agency’s analysis of the pharmacokinetic
data contained in Thede (1987) to estimate internal dose reflective of
atrazine and its metabolites in rat plasma.

11:45 a.m. 	Charge to Panel

b.   Based on Figure 5.5 in the draft Issue Paper, the Agency has
preliminarily concluded that plasma levels of atrazine and its
metabolites reach (or nearly reach) pharmacokinetic pseudo-steady state
in the rat plasma after approximately four daily oral exposures over a
wide range of doses.   Please comment on the extent to which the data do
and do not support this finding.

12:15 p.m.	Lunch

1:15 p.m.	Charge to Panel

c.   Figure 5.8 of the draft Issue Paper shows a plot of LH attenuation
data versus administered atrazine across a range of exposure durations
(i.e., four days up to six months).  The data contained on this figure
were collected from several different laboratories and involved two
modes of oral administration (dietary, oral gavage) and two different
rat strains.  Attenuation of LH, as measured by percent of control, is
remarkably similar across studies, strains, laboratories, and most
notably duration of exposure.  The Agency has preliminarily concluded
that the findings on Figure 5.8 strongly support the hypothesis that
pseudo-steady state is achieved (or nearly achieved) in adult rats after
four daily consecutive oral exposures.  The Agency also believes that
pseudo-steady state is strongly associated with the attenuation of the
LH surge following atrazine exposure in rats. Please comment on the
analysis shown in Figure 5.8 and the Agency’s preliminary conclusions
related to these findings in rats.

2:00 p.m.	Charge to Panel

Question 3.2

In Section 5.3, the Agency describes a benchmark (BMD) analysis
conducted for LH attenuation studies.  As described in the draft Issue
Paper, the Agency initially considered a wide range of toxicological
endpoints for inclusion in the BMD analysis.  In considering all of the
data, this analysis focused on studies measuring LH attenuation where
female rats were exposed orally for four days and/or longer. This was
not only the most sensitive endpoint but it’s temporal and dose
response are well defined experimentally. The LH effect originates from
atrazine’s effect on the hypothalamic control of pituitary function
through its interference with GnRH neurotransmitters.  Thus, protection
from LH attenuation as a precursor event to several functional
impairments would be protective of atrazine’s neuroendocrine effects.

a.   Please comment on the BMD analysis summarized in Section 5.3 of the
draft Issue Paper with details provided in Appendix C.

2:45 p.m.	Charge to Panel

b   The selection of a suitable benchmark response (BMR) is an important
component of conducting a BMD analysis.  As described in Section 5.3,
for continuous endpoints, like LH attenuation, the BMR most often
represents an X% change from background levels (or untreated controls). 
 Typically, the BMR is selected on the basis of a combination of
biological (mode of action, quantitative link between key events and
adverse outcomes, historical/concurrent controls) and statistical
considerations (sample size, variability, etc). LH attenuation may be
potentially associated with several adverse outcomes and the level of
attenuation of the LH surge considered to be adverse is a function of
several factors including the functional outcome and the life-stage. 
There is an absence of information concerning the level of response (or
% change) associated with the various functional impairments.  Also, the
differences in reproductive cycles/aging between rodents and humans add
an additional level of complexity to establishing a specific BMR value.
When an X% change can not be defined, the Agency’s draft BMD 

guidance suggests that the BMD and BMDL corresponding to a change in the
mean response equal to one standard deviation from the control mean be
used as the BMR.  This approach was applied to atrazine.  Please comment
on the scientific factors important for establishing a BMR for LH
attenuation as part of the BMD analysis for atrazine.  

3:30 p.m.	Break

3:45 p.m.	Charge to Panel - Question 4.0: Approaches To Evaluating Water
			Sampling Strategies And Frequency Of Monitoring

The ultimate utility of pesticide monitoring data for drinking water
exposure estimations in human health risk assessments depends on how
well the monitoring data characterize the spatial and temporal
variability of pesticide concentrations in drinking water, with an
emphasis on the upper end of the exposure distribution.  In addition,
the method used to estimate concentrations from monitoring data depends
on the duration of concern and how critical it is to estimate peak
concentrations. 

Question 4.1

A well-designed drinking water monitoring study takes into account both
spatial and temporal patterns of exposure. Please comment on the
USEPA’s recommended framework for designing a monitoring study by
targeting the most vulnerable areas, targeting seasonal times for more
intensive sampling, basing sampling frequency on the toxicological
exposure duration of concern, and using autosamplers to supplement
monitoring data (see Section 7.2 of the draft Issue Paper).

4:15 p.m.	Charge to Panel

Question 4.2

The April 2010 SAP recommended that simulations of candidate monitoring
strategies and evaluations of the utility of different exposure
estimation methods be benchmarked against intensive empirical data that
cover a representative range of sites.  In response, the USEPA proposes
using more intensively sampled ambient water monitoring for flowing
waters and PRZM/EXAMS modeling for static water bodies, matching them to
the CWS based on similar chemograph shapes (see Section 7.3).

a.   Please comment on the Agency’s proposal to use chemograph shapes
(number, duration, and magnitude of peaks) to match CWS with more
intensively monitored datasets.  In particular, the Agency is interested
in recommendations on approaches for matching chemograph shapes given
the loss of short-duration peaks that occurs with less frequent
sampling.

4:45 p.m	Charge to Panel

b.   Please comment on the strengths and weaknesses of using more
intensively sampled datasets from Heidelberg and AEEMP for analysis of
flowing water and PRZM/EXAMS for lakes and reservoirs.

5:15 p.m.	Meeting Adjourns

Day 4

Friday, September 17, 2010





8:30 A.M.	Opening of Meeting and Administrative Procedures – Joseph
Bailey, Designated Federal Official, Office of Science Coordination and
Policy, EPA

8:35 A.M. 	Introduction and Identification of Panel Members – 

	Steven G. Heeringa, Ph.D., FIFRA Scientific Advisory Panel Session
Chair

8:45 A.M.	Charge to Panel

Question 4.3

Once the magnitude and duration of exposure of toxicological concern are
identified, the USEPA will determine which method(s) to use to analyze
the existing atrazine CWS monitoring data for use in drinking water
exposure estimates.  Based on the April 2010 SAP recommendations, the
Agency is focusing on regression-based modeling combined with random
function modeling (for example, a revised WARP model coupled with
kriging or the USGS SEAWAVE-Q model).

Please comment on the strengths and weaknesses of these proposed
approaches and provide any recommendations for improving the model
applications.

9:30 a.m.	Charge to Panel

Question 5.0:  Scientific Considerations in Potential Sensitivity of
Infants & Children 

As described in Section 6.0 in the draft Issue Paper, the FFDCA, as
amended by the FQPA (1996), requires the Agency to give special
attention to infants and children by placing emphasis on the
availability of toxicology and exposure information to estimate the
potential risk to these age groups.  The 2003 Registration Eligibility
Decision (RED) notes that the Agency reduced the FQPA Safety Factor for
those localities which are part of the drinking water monitoring program
conducted by Syngenta, as required by EPA.  This reduction in the Safety
Factor was based on more intensive monitoring required in the monitoring
program that reduced the uncertainty for estimating concentrations of
atrazine and its metabolites in drinking water for the 90-day rolling
average identified in the previous risk assessment as the appropriate
duration of concern.   Based on the newest studies, our understanding of
atrazine’s temporal pharmacokinetic and pharmacodynamic
characteristics has changed and it appears that shorter durations may be
appropriate.   In light of the potential need to shorten the critical
duration of exposure and as discussed by the Panel in Questions 4.1-4.3,
the Agency is evaluating appropriate methods for assessing the drinking
water monitoring data.  

Previously, the Agency noted data gaps related to “information on
Atrazine concerning exposure throughout all critical developmental
periods (i.e., gestation through puberty in both sexes), in particular,
early in development…. (emphasis added, FQPA memo, 2002).”   At the
time of the previous risk assessment, there were only a few available
studies which included measures sensitive to endocrine disruption on
specific early life exposure periods (e.g., peripubertal).  Since that
time new studies have become available (Section 6.0) which add to the
existing database and support the findings of the older studies.  In
addition, new tissue dosimetry studies provide information on the
transfer of atrazine and its chlorinated metabolites to the fetus and to
the lactating pup.  Further, a study evaluating exposure to atrazine
from multiple critical developmental periods identified previously by
the Agency as a data gap is on-going.   The results of this research
will inform our understanding of the potential for differential life
stage sensitivity.

In the coming months, as the drinking water exposure analysis develops
further and the on-going toxicology studies become available, the Agency
will work towards completing the scientific analysis that will inform
whether or not a new FQPA Safety Factor should be applied in the
atrazine risk assessment.  

The Agency requests the Panel to comment on important scientific factors
for the Agency to consider in its analysis.  Please include in your
comments specific consideration of uncertainties in estimating drinking
water exposures and remaining uncertainties in atrazine’s
toxicological profile across life stages, particularly as they pertain
to assessing risk to infants and children.

10:30 a.m.	Break

10:45 a.m.	Charge to Panel

Question 6.0:  Implications of MOA & Toxicity Profile on Water
Monitoring

As described in the Introduction of the draft issue Paper (Section 1),
the goals of the current atrazine re-evaluation are: 1) to determine the
extent to which new science indicates a need for the Agency to develop a
revised human health risk assessment for atrazine and 2) to re-consider,
as appropriate, the frequency of drinking water monitoring needed.  Two
important issues related to achieving these goals are determining the
point of departure and identifying the critical effect and its
associated duration of exposure.  Proposed updates to the point of
departure are considered in Questions 3.1 and 3.2.  With respect to the
critical duration of concern, the frequency of drinking water monitoring
is related to the temporal pattern of the toxicological endpoint of
concern used for the risk assessment.  Generally, longer durations of
toxicological concern (e.g., a long-term chronic effect) require a less
frequent drinking water sampling design to approximate longer term
exposures.  However, as the duration of concern shortens, the frequency
and timing of sampling become more important in determining how well the
sample data capture short-duration exposures.  Observation epidemiology
studies raise hypotheses and suggest possible links between atrazine
exposure and reproductive and developmental outcomes, but these
epidemiology studies suffer from limitations which prevent firm
conclusions.  Although certain studies some provide qualitative support
for the human relevance of the endpoints identified through the
experimental toxicological database, they provide little to no
information on the critical duration of exposure.  In addition, the MOA
and PK database are also lacking in human specific information on the
effects of atrazine which could be used to quantitatively extrapolate
between species.  As such, the information available to evaluate the
critical duration of exposure lacks quantitative precision. Thus, the
critical duration of exposure is instead derived by inferring generic
knowledge from a variety of scientific disciplines.  

The Agency has used a variety of approaches to extrapolate findings from
experimental animal data to humans including allometric scaling and
human-specific information on the physiology of the menstrual cycle
inferred from the IVF literature.  According to the Agency’s analysis
of the pharmaceutical data and allometric scaling of the rodent
pharmacokinetics data, the potential durations of human exposure that
would correspond to the exposure period of interest in rats lie between
a few days to approximately 4 weeks of exposure. 

Please comment on the Agency’s analysis and preliminary conclusions
contained in Section 8.0 of the draft Issue Paper as it relates to the
potential critical windows of exposure.  Please include in your comments
additional or alternative approaches or data that may inform this issue.

12:00 p.m	Lunch

1:00 p.m.	Charge to Panel continued

3:00 p.m. 	Break

3:15 p.m.	Charge to Panel continued

5:00 p.m.	Adjourn

Please be advised that agenda times are approximate; when the discussion
for one topic is completed, discussions for the next topic will begin.
For further information, please contact the Designated Federal Official
for this meeting, Joseph Bailey, via telephone: (202) 564-2045; fax:
(202) 564-8382; or email: bailey.joseph@epa.gov

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