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# AGENDA FIFRA SCIENTIFIC A DVISORY PA NEL (S AP )

OPEN MEETING September 14 - 17 , 2010

FIFRA S AP WEB SITE http://www.epa.gov/scipoly /sap/ OPP Docket Telephone: (703) 305 - 5805 Docket Number: EPA- HQ - OPP -20 10 -0 481 U.S. Environmental Protection Agency Conference Center - Lobby Level One Potomac Yard (South Bldg.) 2777 S. Crystal Drive, A rlington, VA 22202 

## Reevaluat ion of the Human Health Effects of At razine : Reviewof Non cancer Effects and Drinking Water Monitoring Frequenc y Please note that all times are approximate (see note at end of Agenda)
. 

## Da y 1 Tuesda y, September 14 , 2010

8 : 3 0 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,

Of fice of Pesticide Programs , EPA 8:50 a.m. Welcome and Introducti ons – Tina Levine , Ph.D. , Director , Health Effects

Division, Office of Pesticide Programs , EPA 9:00 a.m. Atrazine Re -evaluation : Introduction and Status

– An na Lowit, Ph.D. ,

Health Effects Division, Office of Pesticide Programs , EPA 9: 30 a.m. Evaluation o f 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 A ssessment - Chester Rodriguez, Ph.D. , Health Effects Division, Office of Pesticide Programs, EPA 12:00 p.m. Lunch

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1:15 p.m. Ap proaches to Evaluating Water Sampling Strategies and Frequency of Monitoring
- Nelson Thurman, M.S. and Mary Frankenberry , Environmental Fate and Effects Division, Of fi ce 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
- An na Low it, 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
- An na Low it, Ph.D. , Health Effects Division, Office of Pesticide Programs, EPA 5 : 0 0 p.m. Adjourn


## Da y 2

Wednesda y , September 15 , 2010

8 : 3 0 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. Foll ow - up from Previous Day ’s Presentations 9: 15 a.m. NIEHS Presentation
- Su zanne 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: 4 5 p.m. Charge To Pane l - Question 1.0 - Non -cancer Epidemiology Section 3.0 and Appendix B of the draft Issue Paper provide the Agency reviews and s ynthesis of the non
cancer epidemiology studies available for atrazine. These include studies on a variety of topics, notably fe ma le and m ale 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 Plea se comment on the sufficiency of the Agenc y’s non
- cancer epidemiology reviews with respect to identifyi ng 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 databa se is not robust enough for inclusion in quantitative risk assessment and does not support the ability to determine causal associations. There are several lim itations present in the current database, and the quality of atrazine exposure assessment is param ount am ong the limitations. In Section 4.0 of the draft Issue Paper, the Agenc y describes the qualitative

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similarities and differences between the epidemiologic findings and the experimental toxicology database. In short, the observational studies

– part icularly those related to reproductive effects in adult females, as well as sm all for gestational age in newborns

– lend further support for the human relevance of the laboratory anim al 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 q uantitative 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


## Da y 3

Thurs da y, September 16 , 2010

8 : 3 0 a.m. Opening of Meeting and Administrative Procedures

– Joseph Bailey ,

Designated Federal Official, Office of Scie nce 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 - Reviewof Studies on Mammary Gland

Developm ent 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 gla nd 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 a ffects 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. Wh ile the Ray ner 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.

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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 atrazi ne. 

### 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 ma mmary 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 experim ent 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 Agenc y is proposing to ackn owledge 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 i n 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 A

ssessment 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 atraz ine’s MoA, is the most sensitive internal dose me tric that is associated with a number of endocrinopathies Question 3.1 Given that there is no robust pharmacokinetic model yet available, a non
com partm ental 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.

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

### 1 1 : 45 a .m. Charge to Panel b. Based on Figure 5.5 in the draft Issue Paper, the Agency has preliminarily concluded that pl asma 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 n ot 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 da ta 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 Agenc y has prelim inarily concluded that the findings on Figure 5.8 strongly support the hypothesis that pseudo
- steady state is achieved (or nearly achieved) in adult rats af ter four daily consecutive oral exposures. The Agenc y 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: 0 0 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 Agenc y 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. T his was not only the most sensitive endpoint but i t’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 neurotran smitters. Thus, protection from LH attenuation as a precursor event to several functional im pairm ents 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 wit h 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). T yp ically, the BMR is selected on the basis of a combination of biological (mode of action, quantitative link between key events and adverse outcomes, historical/concu rrent 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. W hen 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 stand ard deviation from the control mean be used as the BMR. This approach was applied to atrazine.

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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: A pproaches To Evaluating Water

Sampling Strategies A nd Frequency Of Monitoring The ultimate utility of pesticide monitoring data for drinking water exposure estimations in human health risk assessments depends on ho w 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 monito ring 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 US EPA’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 mo nitoring data (see Section 7.2 of the draft Issue Paper). 

### 4: 1 5 p.m. Charge to Panel Question 4.2 The April 2010 SAP recommended that simulations of candidate monitoring strategies and evaluations of the utilit y of different exposure estim ation m ethods 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 b odies, matching them to the CW S based on similar chemograph shapes (see Section 7.3).
a. Please comment on the Agency’s proposal to use chemograph shapes (number, duration, and ma gnitude of peaks) to match CWS with m ore 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 : 4 5 p.m Charge to Panel b. Please comment on the strengths and weak nesses 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


## Da y 4 Friday , September 17 , 2010

8 : 3 0 A.M. Opening of Meeting and Administra tive 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

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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 m onitoring data for use in drinking water exposure est im ates. Based on the April 2010 SAP recommendations, the Agency is focusing on regression
- based modeling combined with random function modeling (for example, a revised W ARP m odel coupled with kriging or the USGS SEAW AVE
- Q model). Please comment on the st rengths 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 r isk 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 re duction 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 appro priate. 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 Agen cy 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 tim e 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 Agenc y will work towards completing the scientific analysis that will inform whether or not a new FQPA Sa fety Factor should be applied in the atrazine risk assessment. The Agenc y 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

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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 frequenc y of drinking water monitoring needed. Two important issues related to achieving these goals are determining the point of departure a nd 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. Wi th respect to the critical duration of concern, the frequenc y of drinking water monitoring i s 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 tim ing of sampling become more important in determining how well the sample data capture short
- duration exposures. Observation epidemiology studies raise hypot heses and suggest possible links between atrazine exposure and reproductive and developmental outcomes, but these epidemiology studies suffer from lim itations which prevent firm conclusions. Although certain studies some provide qualitative support for th e hum an 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 Agenc y has used a variety of approaches to extrapolate findings from experimental animal data to hum ans 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 correspo nd 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 potentia l 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