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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
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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 
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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. 

a) 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 
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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.

a) 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.
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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.

a) 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 
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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.

a) 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. 

b) 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 

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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.
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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:

o 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).

o 14 days: Proposed to serve as a midpoint between the other two durations for better 

characterization of water monitoring frequencies.

o 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.
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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 

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th 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