AGENDA

FIFRA SCIENTIFIC ADVISORY PANEL (SAP)

OPEN MEETING

July 26 - 29, 2011

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

OPP Docket Telephone: (703) 305-5805

Docket Number: EPA-HQ-OPP-2011-0399

U.S. Environmental Protection Agency

Conference Center - Lobby Level

One Potomac Yard (South Bldg.)

2777 S. Crystal Drive, Arlington, VA 22202

Re-Evaluation of the Human Health Effects of Atrazine: Review of
Non-Cancer Effects, Drinking Water Monitoring Frequency and Cancer
Epidemiology

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

Day 1

Tuesday, July 26, 2011





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. 	Welcome and Introduction of Panel Members – Daniel Schlenk,
Ph.D., FIFRA Scientific Advisory Panel Session Chair

8:45 a.m.	Opening Remarks – Steven Bradbury, Ph.D., Director, Office
of Pesticide Programs (OPP), EPA

9:00 a.m.	Opening Remarks – John R. Fowle III, Ph.D., Deputy Director,
Health Effects Division (HED), OPP, EPA

9:05 a.m.	Atrazine Re-evaluation:  Introduction and Status – Elizabeth
Mendez, Ph.D., HED, OPP, EPA

9:20 a.m.	Atrazine:  Adverse Outcomes and Mode of Action - Ralph C.
Cooper, Ph.D., National Health and Environmental Effects Research
Laboratory, Office of Research and Development, EPA

10:15 a.m.	Break

10:30 a.m.	Review of Atrazine Cancer Epidemiology - Carol H.
Christensen, Ph.D., HED, OPP, EPA

11:00 a.m.	Integration of Epidemiology and Toxicity Data into Health
Risk Assessment - Elizabeth Mendez, Ph.D., HED, OPP, EPA

11:30 a.m.	Atrazine:  Updates to the Dose-Response Assessment with
Implications for Water Monitoring Frequency - Chester Rodriguez, Ph.D.,
HED, OPP, EPA

12:30 p.m.	Lunch

1:30 p.m.	Evaluating Atrazine Drinking Water Monitoring Data for Use in
Human Health Assessments - Nelson Thurman, M.S., Environmental Fate and
Effects Division, OPP, EPA

2:30 p.m.	Atrazine Re-evaluation:  Scientific Considerations in
Potential Sensitivity of Infants and Children -  Elizabeth Mendez,
Ph.D., HED, OPP, EPA

3:00 p.m.	Break

3:15 p.m.	Case Studies:  Application of Pharmacokinetic Modeling to
Inform Water Monitoring - Chester Rodriguez, Ph.D. and Nelson Thurman,
M.S., OPP, EPA

4:00 p.m.	Public Comments

6:00 p.m.	Meeting Adjourns

Day 2

Wednesday, July 27, 2011





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 of Panel Members – Daniel Schlenk, Ph.D.,
FIFRA Scientific Advisory Panel Session Chair

8:45 a.m.	Public Comment 

10:15 a.m.	Break

10:30 a.m.	Charge to Panel - Charge Question 1 - One approach for
evaluating the

 performance of monitoring sampling designs is to simulate different
sampling frequency

 strategies using robust (daily or near-daily sampling during the high
use/runoff period)

 monitoring data. As noted in previous SAPs (April 2010 and September
2010), Heidelberg

 University’s National Center for Water Quality Research (NCWQR)
monitoring of selected

 watersheds in Ohio and the Atrazine Ecological Exposure Monitoring
Program (AEEMP)

 monitoring of headwater streams in the corn belt provide the most
robust datasets for

 atrazine. Using examples from these datasets, the USEPA presented a
matrix approach for

 deriving a bias factor for different sampling frequencies (e.g., 4, 7,
14, 28 day intervals) for

 use in estimating concentrations for different exposure durations of
concern (e.g., 4, 14, 28,

 90 day durations). 

a)  Given that the factors are likely to vary based on watershed size
and water body type, comment on the level of detail we would need to
develop (e.g., flowing water vs. reservoir; small vs. medium vs. large
watershed area). How many datasets would we need to analyze to provide a
reasonable representation of a bias factor for each category? 

b)  Please comment on the advantages and disadvantages of deriving bias
factors based on analyses of individual sites and years compared to
taking percentiles of averages across sites/years.

11:30 a.m. 	Charge to Panel - Charge Question 2 - The September 2010
FIFRA SAP on atrazine recommended combining a regression model such as
WARP with either a deterministic model such as PRZM or a geostatistical
approach in order to estimate a time series of atrazine concentrations
from less frequent monitoring. In developing methods based on the
SAP’s recommendations, the USEPA was able to derive reasonable
estimations of the time series for sampling intervals of 7-days or
shorter using conditional simulations of variogram models without
incorporating additional models. Although the simulations underestimated
the 1-day maximums, they appeared to provide reasonable bounds for
rolling average concentrations as short as 4 days. 

a)  Please comment on the Agency’s method of estimating time series
using conditional simulations of variograms for monitoring data sets
such as the AMP CWS monitoring that have 7-day sampling frequencies. 

b)  Based on the USEPA’s analysis using WARP with longer duration
sampling intervals (Appendix D.1), what advantages does the SAP see of 
including WARP modeling in this approach (i.e., better estimation of the
daily maximum value)?

12:30 p.m.	Lunch

1:30 p.m.	Charge to Panel - Charge Question 3 - Given that most
monitoring data for pesticides are based on less frequent sampling
intervals (e.g., bi-weekly, monthly), the USEPA also explored additional
approaches that combined variogram models with covariate approaches –
in particular, correlation with flow within a narrow window – or with
WARP. We also considered methods of filling in time series
concentrations using a deterministic model such as PRZM or a mass
balance model, although such approaches would be more resource/data
intensive. 

Please comment on these additional modeling approaches for interpreting
sparse (less frequently sampled) monitoring datasets.

2:30 p.m.	Charge to Panel - Charge Question 4 - In characterizing
overall uncertainty in exposure estimates from monitoring data, the
USEPA must also consider how many years of monitoring are necessary to
provide a reasonable bound on the year-to-year variability or,
alternatively, develop methods of placing the existing monitoring data
in context of likely exposures that may occur over a time period of
interest (for instance, 15 year cycles for registration review). 

a)	Please comment on the sufficiency of existing atrazine/triazine
monitoring data available to the Agency – in particular the Atrazine
Monitoring Program (AMP) coupled with the earlier Voluntary Monitoring
Program (VMP), which conceivably span from 1993 to the present for some
CWS – for use in characterizing the likely range in year-to-year
variability in atrazine/TCT concentrations. 

b)	Please comment on the Agency’s suggestion for using a PRZM hybrid
model, calibrated on the current years of monitoring, to provide
estimates for a wider time frame by modeling additional years using
weather data that span a 30- to 50-year period. 

c)	What other possible approaches can the SAP recommend for capturing
year-to-year variability?

3:30 p.m.	Break

3:45 p.m.	Charge to Panel - Charge Question 5 - In 2000, the SAP agreed
with the Agency’s proposal for atrazine’s neuroendocrine MOA, and
they further concluded that it is unlikely that the mode of action by
which atrazine induces mammary tumors in adult female Sprague Dawley
rats could be operational in humans.  The SAP further concluded that it
is not unreasonable to expect, however, that atrazine might cause
adverse effects on hypothalamic-pituitary-gonadal (HPG) function in
humans if exposures were sufficiently high and that perturbation of the
HPG axis was relevant for developmental and reproductive effects (FIFRA
SAP, 2000). In the 2003 IRED, the Agency identified perturbations of the
neuroendocrine system (particularly LH regulation) leading to
reproductive toxicity as the most biologically plausible and sensitive
effects attributable to atrazine exposure.  The adverse outcomes
occurring as a consequence of disruptions to the HPG axis in rats
include disruption of estrous cyclicity and delays in puberty onset
(males and females).   An additional effect – not directly linked to
LH disruption – is the decreased suckling-induced prolactin release in
milk early in life (perinatally), which leads to increased incidence of
prostatitis in young adult rats.  All of these effects can be linked to
and/or occur at higher doses than the atrazine-induced changes in LH
secretion.  Research conducted since the 2003 IRED continues to point to
LH surge attenuation as the most sensitive effect in the atrazine
database.   Consequently, the Agency will continue to use changes in LH
secretion as a sentinel endpoint for HPG perturbations and the basis of
the atrazine risk assessment. The September 2010 SAP “ agreed with the
Agency's conclusion that, based on the available data, a benchmark dose
(BMD) modeled from data on suppression of the LH surge appears to be
protective for other endpoints, since this phenomenon occurs at doses
lower than for the wide range of effects identified in a rather
extensive toxicological database.”

a)  Currently available data show that in the rat a brief exposure (as
brief as 4 days) to low levels of atrazine can elicit decreases in LH. 
Please comment on the biological plausibility of these brief changes
leading to an adverse outcome taking into account typical variability
and how long and how much a LH surge reduction is needed to cause the
observed adverse effects (i.e., disruptions in cyclicity, delayed
puberty, and prostatitis).

5:00 p.m.	Meeting Adjourns

Day 3

Thursday, July 28, 2011





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 of Panel Members – Daniel Schlenk, Ph.D.,
FIFRA Scientific Advisory Panel Session Chair

8:45 a.m.	Charge to Panel - Charge Question 6 - During the September
2010 SAP, the Panel raised the issue of single vs. multiple atrazine
exposure effects on the LH surge.  In their report to the Agency the SAP
commented:

“Data are clear in identifying that a greater-than-one pulse of
exposure to atrazine is necessary for attenuation of the LH surge. For
example, single high doses (over 100 mg/kg) administered on the morning
of proestrus did not alter characteristics of the LH surge occurring
later the same day. Additional data clearly demonstrate a once daily
dose for 4 days and beginning on estrus can induce significant
inhibition of the LH surge peak. In this instance, a dose response is
observed. However, what is not clear is if less than 4, but greater than
1 days’ exposure is sufficient to alter the LH surge. Further
complicating the matter, it is not clear if a 4-day exposure, beginning
on a different day of the cycle, will result in changes in the LH surge
similar to those when dosing begins on the morning of proestrus.
Understanding of the relationship between duration of exposure and phase
of the cycle will be key in translating rodent data to humans for risk
assessment purposes.”

In response to the Panel’s comments, EPA scientists in the Office of
Research and Development have undertaken a series of experiments to try
to elucidate the nexus between phase of the cycle and duration of
exposure.  This research is in the early stages.  Initial results
suggest that a single high dose of atrazine (100 mg/kg bw) can affect
the LH surge.  However, the effect seen was an increase in LH rather
than the decrease observed after 4 days of exposure.

Please comment on the potential relevance of one day exposure to elicit
an adverse outcome(s) and the significance of an increase vs. a decrease
in LH.

9:30 a.m.	Charge to Panel - Charge Question 7 - An increased incidence
of prostatitis has been observed in the offspring of rats exposed to
atrazine from PND 1 to 4.  This effect was not linked to an LH
alteration, but rather the atrazine related suppression of
suckling-induced prolactin release in the lactating dams.  Prolactin
plays a crucial role in the neonatal brain for normal TIDA neuron
development.  In the adult offspring, the impaired TIDA regulation is
reflected by elevated prolactin levels (hyperprolactinemia).  It is this
elevated level of circulating prolactin in the adult male rats that has
been linked to an increased incidence of prostatitis.  It is unknown
when the TIDA neurons develop in the human fetus or whether this
development is dependent on the maternal prolactin concentrations.

Given the biological processes involved in the atrazine-mediated
prostatitis in rats, please comment on the human relevance of these
findings in rats for the overall hazard characterization for atrazine.

10:15 a.m.	Break

10:30 a.m.	Charge to Panel - Charge Question 8 - When evaluating the
data on mammary gland development, the September 2010 SAP report
concluded that the “use of the existing data on rat mammary gland
development to assess the potential human risk of atrazine is not
warranted at the present time.”  Regarding the methodological
differences between the Rayner et al., and the Coder studies, the Panel
commented that “it is surprising that they did not employ both
qualitative and quantitative scoring measures of mammary gland
development, which would have provided a definitive inter-study
comparison.”  In response to this comment, the Agency has conducted a
set of experiments investigating the potential impact of in utero
atrazine exposure on mammary gland development (MGD) in Sprague Dawley
rats using both the subjective scoring methodology described by Rayner
et al. and a computer-based quantitative methodology (morphometric
analysis). Using either quantitative or subjective measures to evaluate
mammary gland development, no differences in MGD were found between
control or atrazine-exposed rats indicating that gestational atrazine
exposure had no demonstrable effect on normal mammary gland development.
 

a)  Please comment on the Agency’s findings in addressing the issues
raised by the SAP during the September 2010 meeting.  Please comment on
whether this study (along with the negative studies by Coder) adds to
the weight of evidence that it is unlikely that atrazine impacts mammary
gland development.

11:30 a.m.	Charge to Panel - Charge Question 9 - In 2003, an FQPA Safety
Factor was retained in part to address the lack of data evaluating the
potential for differences in sensitivity across life stages.  Since
then, multiple studies evaluating atrazine’s potential impact
following exposure during the prenatal, perinatal, prepubertal, and
adult stages of life have been conducted to address these data gaps. 
None of the new studies has identified an enhanced sensitivity in the
young and the LH surge attenuation observed in females of reproductive
age continues to be the most sensitive endpoint.

a)  Please comment on the weight of the evidence analysis conducted by
the Agency and the extent to which the uncertainties related to the
potential for differential sensitivity of the young are addressed with
the additional data.

12:15 p.m.	Lunch

1:15 p.m.	Charge to Panel - Charge Question 10 - Section 3.0 and
Appendices B-3 through B-5 of the draft Issue Paper provide the
Agency’s reviews and synthesis of the atrazine cancer epidemiology
studies. These studies examine a variety of cancer endpoints, notably
reproductive and endocrine system tumors including prostate, breast,
ovarian and thyroid tumors, cancers of the lymphohematopoietic system
including non-Hodgkin lymphoma (NHL), and other cancer types including
glioma, pediatric cancers and colon cancer. Section 3.3 integrates the
findings of the epidemiology and experimental toxicology studies.

a)  Please comment on the sufficiency of the Agency’s cancer
epidemiology reviews with respect to identifying the major strengths and
limitations of each study, and overall synthesis of results by cancer
types.

2:15 p.m.	Charge to Panel - Charge Question 11 - There is no compelling
evidence in the available experimental toxicology database that atrazine
may be carcinogenic in humans. This database was reviewed by the SAP in
April 2010. Briefly, the results of both guideline and non-guideline in
vivo as well as in vitro studies do not suggest atrazine has mutagenic
or carcinogenic properties. With regard to mammary tumors, several
internal and external peer reviews have concluded that the mode of
action through which atrazine influences mammary tumor development is
not operational in humans. Further, EPA’s current review of the
atrazine cancer epidemiology database did not identify evidence across
any of the cancer-specific databases evaluated as to the carcinogenic
potential of atrazine that EPA finds sufficiently convincing to change
its conclusions. Therefore, in view of the evidence in the experimental
toxicology and epidemiologic databases, EPA concludes atrazine is not
likely to be carcinogenic in the human population. The observational
data lend further support for the human relevance of the laboratory
rodent tumor findings, i.e., the databases lack evidence of an
association between atrazine and cancer in the human population.

Please comment on the extent to which the scientific information
supports the integrative analysis contained in Section 3.3 with respect
to the similarities, differences of the experimental toxicology and
epidemiologic findings. Please comment on any significant uncertainties
in the epidemiologic findings. 

Please comment on whether the epidemiology literature published since
the last SAP review including the AHS findings is sufficient to justify
changing the Agency’s conclusions that atrazine is not likely to be
carcinogenic to humans. 

3:15 p.m.	Break

3:30 p.m.	Charge to Panel - Charge Question 12 - The proposed refined
dose response assessment for atrazine will be based on internal measures
of exposure. At the September 2010 SAP meeting, the Agency presented
estimates of area under the concentration-time curve (AUC) for plasma
triazines based on a rat [14C]-atrazine study (i.e., Thede 1987). The
Panel concluded that “…on the basis of the currently available data,
plasma appears to be a reasonable biological compartment that is
reflective of tissue dose, and that use of area under the plasma
concentration time curve (AUC) provides an appropriate measure of
internal exposure.”  The Panel also noted that “the use of total
chlorotriazine based on total 14C-compounds is a reasonable first step
(particularly in the absence of information on the pharmacodynamic
activity of the parent compound and individual metabolites). However,
the Panel believed that the Thede (1987) data, had limitations, and
should be interpreted with caution.” In response to the comments by
the Panel, the Agency has evaluated additional pharmacokinetic studies
involving different species including humans and two additional
rat14C-atrazine studies that support the plasma clearance estimates
obtained from the Thede 1987 study. Based on the consistent linear
pharmacokinetic behavior of plasma triazines resulting from orally
administered doses of atrazine across the different studies, the Agency
proposes to use an interim pharmacokinetic modeling approach based on a
one-compartment linear model to inform internal dosimetry that seems to
adequately describe the pharmacokinetics of plasma triazines in rats
from orally administered atrazine.

a)  Please comment on the strengths and limitations associated with this
simplified pharmacokinetic modeling approach for human extrapolation.

b)  Compare and contrast the strengths and weaknesses of using total
radioactivity for a pharmacokinetic analysis (as presented in the
Agency’s issue paper) as opposed to using available pharmacokinetic
data for the parent and the chloro-s-triazine metabolites that have
similar toxicological properties to the parent?  

c)  As pointed out in the Agency issue paper, we are still reviewing a
PBPK model submitted by Syngenta.  As we complete our review of the
Syngenta model, please comment on key aspects that EPA should be
considering concerning a PBPK model including model credibility (e.g.,
structure, parameter values, documentation), model reliability (e.g.,
how well does the model simulate the dose metrics relevant to the mode
of action), and model applicability (e.g., does the model have essential
features for intended application). 

d)  Please comment on the extent to which the one-compartment linear
model of total plasma radioactivity derived from 14C labeled atrazine
may account for interspecies differences in pharmacokinetics.

5:00 p.m.	Meeting Adjourns

Day 4

Friday, July 29, 2011





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 of Panel Members – Daniel Schlenk, Ph.D., FIFRA
Scientific Advisory Panel Session Chair

8:45 a.m.	Charge to Panel - Charge Question 13 - Any risk assessment of
atrazine ideally should account for the temporal relationship between
exposure and toxicological endpoint (i.e., LH attenuation). The Agency
is relying on rat studies involving constant dosing frequency and dose
level to elucidate this relationship.  The time-to-effect in rats
appears to be based on the build-up of plasma triazines to pseudo steady
state (i.e., plasma triazine levels stay within a constant range).  The
Agency is using this information to estimate the allometrically scaled
equivalent human time-to-pseudo steady state plasma triazine levels.
However, the Agency is cognizant that human exposure is different from
controlled rat studies in that both the dose level and the frequency of
exposure through drinking water are variable. Thus, the Agency has
identified several possible durations of human exposure, which
collectively bracket the exposure intervals of concern for LH
attenuation in humans:

28 days: a duration predicted by allometrically scaling the rat plasma
elimination kinetics. In both rats and humans, the time estimated to
reach pseudo steady state plasma triazines coincides with the respective
length of their ovarian cycles (i.e., 4 and 28 days, respectively).

14 days: Proposed to serve as a midpoint between the other two durations
for better characterization of water monitoring frequencies.

4 days: the duration of exposure needed to reach pseudo steady state in
rats and corresponding to the follicular phase in the human menstrual
cycle.  

a)	Please comment on the rationale used by the Agency for selecting
these exposure duration options. Please discuss the rationale for other
alternative durations of concern, if any.

b)	Please comment on which exposure duration in humans most closely
corresponds to the exposure duration found to cause adverse effects in
rats.

c)	Please comment on the approach used by the Agency (i.e., the
one-compartment linear model) to relate atrazine levels from the water
chemographs to predict corresponding human plasma triazine levels for
the proposed durations of concern.   In particular, please comment on
the Agency’s proposed approach to use water AUC estimates to calculate
a time-weighted daily average of atrazine exposure for a given duration
of concern. Please suggest alternative approaches as appropriate.

 

9: 45 a.m.	Charge to Panel - Charge Question 14 - For the case study,
the Agency used the 95th and 5th percentile of conditional simulations
of daily concentrations from variogram models based on 7-day sampling
intervals to predict human plasma AUC for triazines. The estimations of
daily concentrations from weekly sampling were used to calculate the
rolling average concentrations for the potential critical window of
exposure from 4 to 28 days. The simulation models underestimated a
single day peak concentration but appear to provide reasonable
approximations of rolling average concentrations with durations as short
as 4 days as well as the length of time of the potential exceedance.

      a)  Please comment on the use of a 95th percentile of the
conditional simulations for providing an upper bound on rolling average
concentrations in the case study.

10:30 a.m.	Break

10:45 a.m.	Charge to Panel

12:00 p.m.	Lunch

1:00 p.m.	Charge to Panel

3:00 p.m. 	Break

3:15 p.m.	Charge to Panel 

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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