### 202-234-4433 Neal R. Gross & Co., Inc. Page 1 U.S. ENVIRONMENTAL PROTECTION AGENCY (EPA)

+ + + + + FEDERAL INSECTICIDE, FUNGICIDE AND RODENTICIDE ACT SCIENTIFIC ADVISORY PANEL (FIFRA SAP)

+ + + + + REEVALUATION OF THE HUMAN HEALTH EFFECTS OF ATRAZINE: REVIEW OF EXPERIMENTAL ANIMAL AND IN VITRO STUDIES AND DRINKING WATER MONITORING FREQUENCY

+ + + + + DOCKET NO.: EPA-HQ-OPP-2010-0125

+ + + + +

MONDAY, APRIL 26, 2010

+ + + + + The Panel convened at 1:00 p.m. in the Hamilton Ballroom of the Hamilton Crowne Plaza

Hotel, located at 1001 14th Street, N.W., Washington, D.C., Steven G. Heeringa, Ph.D., Chair, and Kenneth M. Portier, Ph.D., Session Chair, presiding. FIFRA SAP MEMBERS PRESENT:

STEVEN G. HEERINGA, Ph.D., Chair KENNETH M. PORTIER, Ph.D., Session Chair JOHN R. BUCHER, Ph.D., DABT JANICE E. CHAMBERS, Ph.D., DABT, ATS GERALD A. LeBLANC, Ph.D. DANIEL SCHLENK, Ph.D.

### 202-234-4433 Neal R. Gross & Co., Inc. Page 2 FQPA SCIENCE REVIEW BOARD MEMBERS PRESENT: SUSAN F. AKANA, Ph.D. RICHARD H. COUPE, Ph.D. KENNETH BARRY DELCLOS, Ph.D. PENELOPE A. FENNER-CRISP, Ph.D., DABT ROBERT J. GILLIOM, Ph.D. RICHARD GREENWOOD, Ph.D. WILLIAM L. HAYTON, Ph.D. STEVEN D. HOLLADY, Ph.D. TERESA H. HORTON, Ph.D. KANNAN KRISHNAN, Ph.D.

HERBERT K.H. LEE, Ph.D. KEVIN T. O'BYRNE, Ph.D. NU-MAY RUBY REED, Ph.D., DABT JEAN F.L. REGAL, Ph.D. DANIEL J. SELVAGE, Ph.D. CARMEN J. WILLIAMS, M.D., Ph.D. LINDA J. YOUNG, Ph.D.

ALSO PRESENT:

JOSEPH E. BAILEY, Designated Federal Official

### 202-234-4433 Neal R. Gross & Co., Inc. Page 3 C-O-N-T-E-N-T-S Page Opening of Meeting & Admin Procedures 4

Introduction & Identification of 6 Panel Members Welcome & Opening Remarks 12 Welcome & Introductions 30

Intro: Status of Reevaluation of the 34 Health Effects of Atrazine Reevaluation of Human Effects of 43 Atrazine

Proposed MOA for Atrazine & Atrazine 53 Metabolites

Review of Atrazine Immunotoxicity 134

Neurological Effects of Atrazine 171

Summary of Non-Cancer Mammalian 199

Toxicity Reevaluation

Approaches to Evaluating Water Sampling 217 Strategies & Frequency of Monitoring

Adjournment 261

### 202-234-4433 Neal R. Gross & Co., Inc. Page 4 1 P-R-O-C-E-E-D-I-N-G-S 2 1:09 p.m. 3 MR. BAILEY: Good afternoon, everyone. 4 My name is Joe Bailey, and I'm with the FIFRA 5 Scientific Advisory Panel staff. I'll be serving 6 as the Designated Federal Official for this 7 meeting, and I want to welcome everyone, this

8 afternoon. 9 We have a three and a half day meeting 10 set up here, and I'm very pleased to kick this 11 meeting off this morning -- this afternoon, and 12 get it underway. 13 As the DFO, I serve as a coordinator 14 between the Panel, the Agency and the public, in 15 putting this meeting together. 16 The FIFRA Scientific Advisory Panel 17 only provides advice and recommendations to the 18 Agency. All decision making and regulatory 19 decisions are left up to the Agency, and they 20 take the advice and recommendations as they see 21 fit. 22 We have worked with all of the Panel

### 202-234-4433 Neal R. Gross & Co., Inc. Page 5 1 members, in reviewing ethics requirements. They 2 have all submitted financial disclosure 3 information that we, at the Agency, have reviewed 4 and made sure that we -- that all of the ethics 5 requirements have been met. 6 Part of the requirements, under the 7 Federal Advisory Committee Act, is that this is a 8 public meeting. We do provide an opportunity for 9 public comment, and the -- that is set aside for 10 tomorrow morning. 11 So, if anyone has a desire to present 12 public comments, please, let me know. If you 13 haven't registered ahead of time, I ask that you 14 keep your comments to five minutes or less. 15 There is a public docket that we've 16 set up for the meeting. It should be on the 17 agenda, the docket number. Everything that is 18 presented in this meeting will be in the docket. 19 The presentations that EPA will be 20 putting forward today are current -- they should 21 be available in the docket, as of now, and any 22 public -- any additional public comments or other

### 202-234-4433 Neal R. Gross & Co., Inc. Page 6 1 materials that come of -- become available during 2 the meeting will also be placed in that docket. 3 I'm very pleased to introduce Dr. Ken 4 Portier, sitting to my right, who will be serving 5 as the Chair for this meeting, and without any 6 further adieu, I'll turn the mic over to Dr. 7 Portier.

8 SESSION CHAIR PORTIER: Good afternoon. 9 I want to welcome all of you to this meeting of 10 the FIFRA Scientific Advisory Panel on the 11 Reevaluation of the Human Health Effects of 12 Atrazine Review of Experimental Animal and In 13 Vitro Studies and Drinking Water Monitoring 14 Frequency. 15 I'll give a special thanks to our 16 audience. I think they have ordered a few more 17 chairs. We're going to accommodate everyone. 18 As many of you know, this is kind of 19 the second in a series of three meetings that the 20 Panel is having on atrazine this year. 21 We've put together -- the SAP staff 22 has put together a very good panel of experts, a

### 202-234-4433 Neal R. Gross & Co., Inc. Page 7 1 mixture of experienced panelists, with some new 2 people, some new voices. 3 So, at this point, I'd like to 4 introduce the Panel. I'll start with myself. I 5 am the Director of Statistics with the American 6 Cancer Society National Office in Atlanta. I'm a 7 bio-statistician and a permanent member of the 8 SAP Panel, and I'll move to Dr. Heeringa here, on 9 my right. 10 CHAIR HEERINGA: Good afternoon, 11 everyone. I'm Steve Heeringa of the University 12 of Michigan. I'm presently the Chair of the 13 permanent FIFRA SAP and look forward to this 14 three and a half day session, and I want to thank 15 my colleague, Ken Portier, for agreeing to Chair 16 this.

17 DR. KRISHNAN: Good afternoon. I'm 18 Kannan Krishnan from the University of Montreal. 19 SESSION CHAIR PORTIER: What's your 20 expertise? 21 DR. KRISHNAN: I'm an agriculturist and 22 toxicologist by training. My expertise is in

### 202-234-4433 Neal R. Gross & Co., Inc. Page 8 1 PBPK modeling, risk assessment of drinking water 2 contaminants and chemical mixtures. 3 DR. GREENWOOD: I'm Richard Greenwood 4 from University of Portsmouth in the United 5 Kingdom, and I've got a broad background in 6 pesticide toxicology and also in 7 pharmacokinetics.8 DR. FENNER-CRISP: I'm Penny Fenner9 Crisp. I'm currently a consultant and live in 10 Charlottesville, Virginia, a one-time employee of 11 EPA, including the Office of Pesticide Programs 12 for a few years, and the newest member of 13 Virginia's Pesticide Control Board. So, I'm back 14 in the regulatory milieu. 15 DR. REED: I'm Nu-may Ruby Reed from 16 California Environmental Protection Agency. I do 17 pesticide risk assessment and address pesticide 18 risk assessment issues for our group.

19 DR. LEE: I'm Herbert Lee. I'm a 20 statistician at the University of California,

21 Santa Cruz. 22 DR. YOUNG: I'm Linda Young. I'm

### 202-234-4433 Neal R. Gross & Co., Inc. Page 9 1 Professor and Associate Chair of the Department 2 of Statistics, University of Florida. 3 DR. COUPE: Richard Coupe, I'm with the 4 U.S. Geological Survey. I've worked on fate and 5 transport of pesticides or agricultural 6 chemicals. 7 SESSION CHAIR PORTIER: Dr. Selvage? 8 DR. SELVAGE: Yes, I'm Dan Selvage, 9 Idaho State University, specializing in HPA axis 10 and how gonadal hormones affect it. 11 DR. O'BYRNE: My name is Kevin O'Byrne 12 and I'm from King's College London and my 13 interests are in the effect of stress on 14 fertility.

15 DR. AKANA: I'm Susan Akana. I'm from 16 the University of California, San Francisco. I'm 17 a physiologist and my area is the stress axis and 18 its interaction with energy balance.

19 DR. HORTON: I'm Theresa Horton. I'm 20 from the Department of Neurobiology and 21 Physiology at Northwestern University in 22 Evanston, Illinois. My specialty is reproductive

### 202-234-4433 Neal R. Gross & Co., Inc. Page 10 1 neuroendocrinology and maternal fetal 2 interactions in the developing neuroendocrine 3 system. 4 DR. DELCLOS: I'm Barry, or Kenneth 5 Delclos from the FDA's National Center of 6 Toxicological Research and I'm working on 7 reproductive and chronic toxic effects of 8 endocrine-active agents. 9 DR. WILLIAMS: I'm Carmen Williams. 10 I'm at the National Institute of Environmental 11 Health Sciences in North Carolina, and I'm in a 12 reproductive endocrinology and infertility 13 training position. I do research on reproductive 14 track development. 15 DR. REGAL: Jean Regal, Professor of 16 Pharmacology, University of Minnesota Medical 17 School, Duluth, Immunotoxicology and Allergy. 18 DR. HOLLADAY: I'm Steve Holladay. I'm 19 from the University of Georgia. I'm an 20 immunotoxicologist. Most of what we've done is 21 developmental immunotoxicology. 22 DR. LEBLANC: I'm Gerry LeBlanc and I'm

### 202-234-4433 Neal R. Gross & Co., Inc. Page 11 1 head of the Department of Environmental and 2 Molecular Toxicology at North Carolina State 3 University and my area of interest is in 4 endocrine-toxicology. 5 DR. SCHLENK: Good morning. I'm Dan6 Schlenk. I'm a Professor of Aquatic Eco7 Toxicology in Department of Environmental 8 Sciences, University of California, Riverside. 9 I'm a member of the permanent Panel and my 10 expertise is on fate and effects of pesticides on 11 aquatic organisms.

12 DR. BUCHER: I'm John Bucher. I'm the 13 Associate Director of the National Toxicology 14 Program. I'm a member of the permanent Panel and 15 with a background in general toxicology.

16 DR. CHAMBER: I'm Jan Chambers. I'm a 17 Professor in the College of Veterinary Medicine 18 at Mississippi State University. I'm a pesticide 19 toxicologist with emphasis on neurotoxicology and 20 metabolism, and I'm a member of the permanent

21 Panel.

22 SESSION CHAIR PORTIER: Thank all of

### 202-234-4433 Neal R. Gross & Co., Inc. Page 12 1 you for being here. A couple of, kind of, notes. 2 The agenda has been published, but 3 just note that the times that are published are 4 approximate. We're going to proceed through the 5 agenda as it goes, and my goal today is to get 6 through the EPA presentations before we leave 7 this evening, hopefully, depending on the number 8 of questions the Panel has on the presentations. 9 The second thing is, tomorrow morning, 10 we're going to have a session on public 11 commenters and if anyone wishes to speak before 12 the Panel tomorrow, please, let Joe Bailey know, 13 at this point, so we can schedule you in. If you 14 have any materials for that public presentation 15 that you want to make before the Panel, give it 16 to Joe. It will get onto the docket. 17 All of the public commenters, as well 18 as the EPA presentations are on the meeting 19 docket on the internet. 20 At this point, I'm going to turn it 21 over to Steven Bradbury, the Acting Director, 22 Office of Pesticide Programs, to make his opening

### 202-234-4433 Neal R. Gross & Co., Inc. Page 13 1 remarks. Steve. 2 DR. BRADBURY: Thank you, Ken. I'd 3 like to start off, first, by thanking the Panel, 4 all the members, the standing permanent members 5 of the Panel, as well as all the ad hoc Panel 6 members for this week's peer review. 7 I greatly appreciate the time and 8 effort it takes in preparing for these meetings, 9 the time it takes while you're at the meeting and 10 then, preparing the report, following the 11 deliberations, and the Agency greatly appreciates 12 your investment of your time and efforts and 13 talents in our peer review process. 14 So, ahead of the week, thank you very 15 much and again, I'll be thanking you, as we 16 finish the week. 17 I'd also like to thank Joe Bailey and 18 the staff that -- the Designated Federal Official 19 who helped make these meetings happen. It takes 20 a lot of work to prepare for the meetings and get 21 all the logistics in place and I want to thank 22 Joe Bailey and his colleagues, in all the work

### 202-234-4433 Neal R. Gross & Co., Inc. Page 14 1 that they've been undertaking to get ready for 2 this meeting, as well as the previous meeting 3 that we already had with atrazine. 4 I'd also like to, in advance, thank 5 the public for their participation in the 6 deliberations. 7 As Ken Portier indicated, tomorrow 8 morning is our time for public input into this 9 peer review process and we take the input of the 10 public very seriously and it's a very important 11 part of the overall peer review process that 12 we're going forward with, and I can't stress 13 enough, the importance of the public 14 participation and transparency that an SAP review 15 brings to the decision making process that we do 16 in the Agency. 17 And it's a concept of public 18 participation, transparency and the quality of 19 science in the Agency's decision making 20 processes. There are a couple of the very 21 important principles that Administrator Jackson 22 brings to the Agency.

### 202-234-4433 Neal R. Gross & Co., Inc. Page 15 1 And so, as we go through the Science 2 Advisory Panel process, which our program has 3 done for many, many years, it reinforces these 4 important concepts of the new administration, in 5 terms of ensuring that the science that we do 6 that's a foundation of all the decision making 7 that we make in the pesticide program is based on 8 the best available information and the highest 9 quality science that we can bring to bear, and 10 that includes the very important part of peer 11 review, to ensure that we're getting input from 12 our colleagues in the scientific community, as we 13 look at some very complex issues. 14 The other important aspect of a 15 meeting like this is the openness and the public 16 participation process, so that the public can 17 participate and provide input to the 18 deliberations and that the proceedings of the 19 meetings and the notes from the meetings are all 20 open and transparent, so that as people see us 21 moving forward in our decision making process, 22 the various components that are important to that

### 202-234-4433 Neal R. Gross & Co., Inc. Page 16 1 process aren't mysterious. It's not a black box. 2 In fact, it's quite the opposite, very open 3 process with a lot of lights shining on it, so 4 everyone can see how we're integrating very 5 complex scientific issues with the regulatory 6 decision making that we need to do. 7 And in that context of sound science, 8 high quality science and public participation, 9 chemical safety also reflects one of the areas of 10 emphasis of the administration, in both 11 industrial chemicals, as well as with pesticides. 12 And so, ensuring, as we go forward in 13 our pesticide decision making, that our decisions 14 are those kinds of decisions that ensure safety 15 to human health and the environment, as we go 16 forward with our decision making process. 17 I'd like to spend just a couple of 18 minutes reviewing the processes that we go 19 through, in making our regulatory decisions and 20 then how that connects with the efforts that 21 we're undertaking with atrazine. 22 As we make decisions about new

### 202-234-4433 Neal R. Gross & Co., Inc. Page 17 1 pesticide products and whether or not they should 2 be allowed to go on the market, there's a very 3 extensive amount of scientific information that's 4 required by the registrants, so that companies 5 that own the products, need to bring quite a 6 large amount of information to the Agency, 7 everything from the fate and transport properties 8 of the chemical, human toxicology, ecological 9 effects, a wide variety of information needed to 10 ensure that any decisions we make about the 11 registration of a pesticide will ensure, again, 12 protection of human health and the environment, 13 including worker protection, including 14 protection, if the product is in the food source, 15 including that dietary exposures are safe, as 16 well as any drinking water exposures. 17 The information that is brought to 18 bear in the processes that we use are, in many 19 ways, similar to activities undertaken around the 20 globe. Much of the information and scientific 21 processes that we use have been developed in 22 concert with the European Union, our colleagues

### 202-234-4433 Neal R. Gross & Co., Inc. Page 18 1 to the north in Canada, as well as in Australia. 2 So, the information base and the 3 processes that we use, while unique to our 4 statutes and our approach, as also integrated or 5 collaborative in nature in many ways, with our 6 colleagues around the globe, at the federal 7 level, and as well as with our collaboration with 8 our partners in the state governments, that also 9 undertake risk assessments and regulatory review 10 steps. 11 So, the importance of science starts 12 at the beginning of the life of the chemical, in 13 terms of when we decide whether or not we're 14 going to register a chemical. 15 We also have, through our statutes, a 16 requirement that we periodically reevaluate all 17 pesticides that are on the market, to ensure over 18 time, that as the science change or policies 19 change, in terms of the law or the science, that 20 all the pesticides are current, in terms of the 21 state of the science and the state of scientific 22 approaches and policy.

### 202-234-4433 Neal R. Gross & Co., Inc. Page 19 1 And we have one system that we used in 2 reevaluating pesticides, that ended in the 3 2006/2008 time frame and that reevaluation 4 program, we termed the `re-registration program', 5 and that's when we completed, between 2006 and 6 2008, a reevaluation of all the pesticides that 7 were registered prior to 1984. 8 In 2007, we started our next round of 9 reevaluation, which we call the registration 10 review program, in which we're looking at all 11 currently registered pesticides, to ensure that 12 they're meeting the current scientific standards 13 and policy standards. 14 In the case of atrazine, it completed 15 its re-registration process in 2003, was the last 16 time that atrazine went through its formal step 17 of re-registration. 18 But I want to stress an important 19 concept, in terms of the process that starts the 20 chemical or a pesticide, in determining whether 21 or not it would be registered and in this 22 reevaluation process, which is on a specific time

### 202-234-4433 Neal R. Gross & Co., Inc. Page 20 1 frame, is that the Agency is always looking at 2 all the pesticides, all the time, to ensure that 3 if any new information comes to light, or new 4 perspectives in interpreting the toxicology or 5 the ecological effects of a pesticide, that at 6 any time, the Agency can pause, take a look at 7 the compound and ensure that the current science 8 is such that it meets our continued requirements 9 for safety, in terms of human health and the 10 environment. 11 Now, in the case of atrazine and many 12 other products, as these products went through 13 re-registration, we required additional data or14 confirmatory data to come in after the re15 registration decision, and in the case of 16 atrazine, in particular, we were focused on 17 drinking water and ensuring that we would have a 18 system in place that would allow us to keep track 19 of what was going on in drinking water sources, 20 to ensure the concentrations of atrazine weren't 21 exceeding our level of protection or our 22 benchmark for protection of human health.

### 202-234-4433 Neal R. Gross & Co., Inc. Page 21 1 Just an example of many times 2 activities that are going on with a pesticide on 3 a periodic, sort of regular basis, a dynamic 4 process, in terms of tracking the science and the 5 status of a pesticide. 6 Now, as I mentioned before, atrazine 7 completed its re-registration in 2003, and over 8 the course of the last seven years, there's been 9 quite a bit of research done on atrazine, looking 10 at mode of action, looking at dosimetry. 11 There's also been a lot of information12 coming into the Agency, as a condition of re13 registration, which is in part, a significant 14 amount of drinking water monitoring data required 15 of the registrant. 16 So, the Agency felt that over -- a 17 year or so ago, that the time was right to take a 18 look at the new science that had been emerging 19 with atrazine and the context of the very full 20 monitoring information that we had for drinking 21 water sources, to do a check-in, to ensure that 22 our science is current, that our risk assessment

### 202-234-4433 Neal R. Gross & Co., Inc. Page 22 1 of 2003 is still reasonable, in light of the new 2 information, and to see if whether or not we need 3 to make any adjustments in our current risk 4 assessment for atrazine, in light of the new 5 information that's come out over the last seven 6 or so years. 7 And this Science Advisory Panel 8 meeting is one of several, in which we're 9 systematically taking a look at the scientific 10 information regarding atrazine, as well as some 11 underlying methodology, to ensure that we're 12 current, in terms of the state of the science and 13 our underlying risk assessment. 14 So, back in February, we had our first 15 Science Advisory Panel meeting, which was 16 actually broader than atrazine. It was looking 17 at a number of issues, some of which are very 18 relevant to our work with atrazine, and the 19 February Science Advisory Panel meeting was 20 taking a look at epidemiology data, incidence 21 data, and asking some questions and getting some 22 feedback from the Panel, in terms of a framework,

### 202-234-4433 Neal R. Gross & Co., Inc. Page 23 1 is how do you approach an integration of 2 experimental toxicology data with epidemiology 3 data, as one prepares a risk characterization, as 4 one starts to understand and better express what 5 the uncertainties may be, with the risk

6 assessment. 7 And we brought forward some example 8 atrazine epidemiology studies, as part of that 9 process of understanding, getting some feedback, 10 as to how to approach different kinds of 11 epidemiology studies and to get some initial 12 feedback, as to how to best integrate 13 experimental data with epidemiology data. 14 The Panel's report was made available 15 late last week, and we thank the Panel for their 16 efforts in working on that first peer review that 17 we had and getting the report out, and we're, of 18 course, looking at it over the weekend and 19 appreciate the input that we received thus far. 20 Today's or this week's Science 21 Advisory Panel, as you know, is focusing on 22 primarily experimental toxicology information,

### 202-234-4433 Neal R. Gross & Co., Inc. Page 24 1 both in vivo and in vitro, and taking a look at 2 the non-cancer effects associated with atrazine, 3 everything from mode of action to dosimetry, as 4 well as beginning to get some feedback around 5 that transition from understanding the dosimetry 6 around the toxicology and how do you translate 7 that into monitoring frequencies in drinking 8 water, to understand what's the right time frame, 9 in terms of looking at drinking water exposures 10 in the context of the dosimetry evaluations 11 coming out of the toxicology work, so that our 12 exposure and that our effects information are 13 properly integrated. 14 In today's -- this week's peer review 15 panel will give us some important feedback, as we 16 make a progress towards our September peer 17 review, which will be taking a look, with a 18 little modification that we had to do last week, 19 will be focusing on non-cancer effects and 20 looking at experimental toxicology, as well as21 epidemiology information in the context of non22 cancer effects, and again, taking a look at

### 202-234-4433 Neal R. Gross & Co., Inc. Page 25 1 drinking water, sampling designs and frequency of 2 sampling, to ensure that our interpretation of 3 what's going on in drinking water sources can be 4 properly interpreted, in terms of the risk

5 assessment. 6 We originally had hoped to be able to 7 also take a look at cancer effects, both 8 experimental toxicology and epidemiology data in 9 September and our goal for the September 10 assessment was based on the National Cancer 11 Institute completing some key studies that 12 they've been doing in the agricultural health 13 study, and our hope that it would be at -- those 14 studies would be available during the spring, so 15 that we could have a fall review on those 16 studies. 17 Our colleagues at NCI haven't been 18 able to hit that target, so, we're looking 19 towards 2011, when the NCI studies would be 20 available and then the 2011 time frame, we'll 21 focus on cancer, looking at experimental 22 toxicology information and epidemiology data, and

### 202-234-4433 Neal R. Gross & Co., Inc. Page 26 1 take a look at the cancer issue in 2011. 2 In the coming months, we'll be able to 3 give you all a better handle on the time frame 4 for taking on that specific task. 5 So, one other sort of broad comment, 6 as I wrap up, is that clearly, the information 7 that we're providing you all, and information we 8 get from the public and then the feedback we'll 9 get through the peer review process will be 10 critical for our ongoing evaluation of atrazine 11 and ensuring that our regulatory decisions are 12 based on the most current and sound science. 13 But I want to point out that a lot of 14 the topics that we'll be talking about over the 15 course of the week, also, are very important for 16 our broader program, in terms of how we undertake 17 the emerging fields or issues in toxicology and 18 risk assessment and exposure assessment. 19 And so, taking a look at mode of 20 action and understanding toxicity pathways, how 21 to understand relationships of perturbations 22 across different levels of biological

### 202-234-4433 Neal R. Gross & Co., Inc. Page 27 1 organization, while clearly, very relevant to our 2 discussions on atrazine, those concepts also play 3 out in many of our risk assessments, and as we 4 move forward in the context of the National 5 Academy of Sciences report on toxicology testing 6 in the 21st century and the use of toxicity 7 pathways, to better understand what adverse 8 outcomes may be associated with perturbations in 9 biological systems, the feedback we get on 10 atrazine will also be very helpful, as we think 11 about frameworks and approaches for other kinds 12 of chemicals.

13 As we learn more about how to 14 integrate epidemiological information and 15 experimental toxicology information with 16 atrazine, we're assuming, and I'm confident we 17 will, learn ideas and concepts that will be 18 broadly applicable to the other types of 19 chemicals we deal with and the broad activities 20 that we do in our risk assessment process. 21 Looking at life stage susceptibility, 22 obviously, critical for atrazine, but also

### 202-234-4433 Neal R. Gross & Co., Inc. Page 28 1 critical for many of our risk assessments in the 2 scenarios that we deal with. 3 So, a number of broad range of 4 applicability of the work we're going to be 5 doing, and in the context of drinking water and 6 looking at monitoring frequencies and 7 understanding how to better capture information 8 in source water and drinking water systems and 9 how do you interpret that in the context of a 10 risk assessment, it's not only very important for 11 the pesticide program, but also, very important 12 for our colleagues in the office of water, who 13 implement the Safe Drinking Water Act. 14 And so, as we move forward in ensuring 15 protection of source water and drinking water 16 sources, the lessons that we'll learn today and 17 tomorrow and over the course of the next year or 18 so, are also very important for how we move 19 forward as an Agency, in terms of drinking water 20 protection and moving forward, both in monitoring 21 designs, as well as in the science of doing 22 toxicology and risk assessments.

### 202-234-4433 Neal R. Gross & Co., Inc. Page 29 1 So, not surprisingly, many of the 2 individuals that you'll be hearing from over the 3 course of the week aren't just from the Office of 4 Pesticide Program and our Health Effects Division 5 and our Environmental Fate and Effects Division, 6 but also, you'll be hearing from our colleagues 7 from the Office of Research and Development, who 8 back in 2000, were instrumental in our thinking 9 about atrazine and how to move forward in our 10 understanding of mode of action, back in the 11 early 2000s, but you'll also be hearing from a 12 colleague from the Office of Water, in reflecting 13 the interaction that we had with our colleagues 14 in the Safe Drinking Water Office, in terms of 15 how to advance the science, in terms of 16 monitoring and linking that into risk assessments 17 and toxicological interpretation. 18 So, while it's OPP and we're looking 19 at issues of our statutes and how to ensure that 20 our decisions around atrazine are bringing the 21 best science to the table, again, the principles 22 that we're learning broadly applicable and

### 202-234-4433 Neal R. Gross & Co., Inc. Page 30 1 reflect sort of, a broad Agency perspective, as 2 we move forward with the state of the science. 3 So, with that, unless there's any 4 specific questions, I'd like to turn it over to 5 Dr. Tina Levine, who can introduce the whole team 6 and provide some more detailed introduction into 7 the activities over the next week. Thanks. 8 DR. LEVINE: Thank you, Steve. I'm 9 Tina Levine and I'm the Director of the Health 10 Effects Division in the Office of Pesticide 11 Programs, a job that I will point out, Penny 12 Fenner-Crisp used to have, when she worked in the 13 Office of Pesticide Programs, and I would like to 14 add my welcome and my thanks to everybody that 15 Steve welcomed and thanked, including the SAP 16 Panel, certainly, and the staff of the SAP, Joe 17 Bailey, and the public, who are going to come 18 here -- who are coming here to observe and

19 comment. 20 Particularly to the Panel, we greatly 21 appreciate your time and efforts. Your feedback 22 is an important component of improving the

### 202-234-4433 Neal R. Gross & Co., Inc. Page 31 1 scientific foundation for our regulatory 2 decisions, and we're particularly appreciative of 3 your commitment this year, especially the 4 permanent Panel, as we've been working hard to 5 prepare for multiple SAP meetings on atrazine, 6 and we understand the large amount of material 7 you need to consider and we appreciate your 8 commitment to the high quality science. 9 I want to acknowledge a number of 10 people who have helped work -- are presenting 11 today and have worked -- or have worked behind 12 the scenes, the OPP team, first of all, Dr. Anna 13 Lowit, who is the overall lead for our atrazine 14 efforts, Dr. Elizabeth Mendez, Dr. John Liccione, 15 Dr. Marquea King and Jessica Kidwell, among many 16 toxicologists in HED who reviewed close to 100 17 new atrazine studies. 18 I also want to thank, from the 19 Environmental Fate and Effects Division, Mary 20 Frankenberry and Nelson Thurman, and from the 21 Office of Water, Michael Messner. I don't know 22 if they're doctors or not, I'm sorry, if I've

### 202-234-4433 Neal R. Gross & Co., Inc. Page 32 1 cited somebody without giving the proper titles. 2 I should have stopped, and I'm just going to give 3 people's names from now on. 4 Nelson Thurman and Mary Frankenberry, 5 and perhaps, Michael Messner too, developed the 6 paper and will be presenting the drinking water 7 aspect of the meeting today. 8 I want, of course, to thank the Office 9 of Research and Development, our ORD team, Ralph 10 Cooper, Susan Laws, Tammy Stoker and Bob Luebke. 11 Both Ralph and Bob will be speaking today. Our 12 colleagues at ORD are vital to this ongoing 13 reevaluation and we truly appreciate their time

14 and talent. 15 As Steve said, the Agency signed the 16 RED for atrazine in 2003. The human health risk 17 assessment that supported the RED was based on 18 the best available science at that time. 19 The science which supports the 20 previous risk assessment, was reviewed by the SAP 21 on at least three occasions and we relied heavily 22 on your input to improve the science in our risk

### 202-234-4433 Neal R. Gross & Co., Inc. Page 33 1 assessments and to inform our decisions. 2 In this current year-long review, we 3 are conducting an objective and thorough review 4 of new science. 5 In this process, we continue to build 6 on our belief, that by understanding how a 7 chemical works in the body, its mode of action, 8 we can better interpret dose response data and 9 better understand life stage susceptibility, and 10 that factors that lead to susceptibility. 11 In this SAP, we will also discuss the 12 connection between atrazine's dosimetry revealed 13 by the toxicological analysis and its -- the 14 connection between this and potential exposure to 15 atrazine, as revealed by drinking water 16 monitoring. 17 We plan to use this information to 18 determine the frequency of water monitoring 19 necessary to ensure the continued protection of 20 public health. 21 As you will hear from the next 22 speakers, the literature review contained in our

### 202-234-4433 Neal R. Gross & Co., Inc. Page 34 1 draft issue paper represents a moment in time 2 with respect to the state of the science. 3 We are aware of important new studies, 4 which further elucidate the mode of action for 5 atrazine, that are not yet available for review. 6 We expect some of these studies to 7 become available, as we move toward preparing 8 materials for the September SAP. We believe 9 these new data will provide information to more 10 confidentially establish the causal links between 11 key events in the pathway to toxicity for the 12 hypothalamic-pituitary-adrenal axis and the dose 13 response of these key events. 14 Dr. Mendez will mention some of these 15 key ongoing studies in her presentation later 16 this afternoon. 17 So, I would like again, to thank you 18 all for your commitment and your efforts, on our 19 behalf. We look forward to your thoughtful 20 deliberations over the next few days, and I would 21 like to introduce our next speaker, Dr. Anna 22 Lowit.

### 202-234-4433 Neal R. Gross & Co., Inc. Page 35 1 DR. LOWIT: The large green button, 2 yes. 3 We're going to spend the next few days 4 talking about a lot of very detailed, very 5 technical, very sophisticated, very exciting 6 science, about some fairly diverse topics, from 7 drinking water statistics, all the way down to 8 hormone regulation, which on the surface, could 9 be -- you would not expect to talk about those 10 same things at the same meeting. 11 But what I wanted to do, before we get 12 into the technical presentations, is just take a 13 few minutes and sort of start from the beginning, 14 start from -- talk about where we need to be, how 15 we're getting there, and really, what the goal 16 is, over the next -- that we're in the middle of, 17 and we'll keep working. 18 The 2009 science and decisions report 19 from the NAS, one of the key messages in that 20 report is that the Agency needs to do a better 21 job at aligning risk assessment and risk 22 management, and specifically, putting more

### 202-234-4433 Neal R. Gross & Co., Inc. Page 36 1 emphasis on problem formulation, at the very 2 beginning of the process, beginning of analysis 3 for the risk assessors and risk managers, to sit 4 down and have very detailed dialogue about the 5 goal of the analysis, what the purpose is, what 6 the scope is, what the data available for 7 analysis is, and what the risk management 8 possibilities are, so that the risk assessors can 9 work with those possibilities in mind, to put 10 together a risk assessment that the risk managers 11 can use, to make them much more -- improve 12 utility. 13 In this example of what we're going to 14 talk about today, and what this atrazine effort 15 is really about, is exactly what the NAS wants us 16 to be doing. 17 It's about taking a risk management 18 need, which is drinking water monitoring, and 19 ensuring safe drinking water and aligning that 20 with a lot of very sophisticated science to get 21 there. That's exactly what we're going to talk

22 about.

### 202-234-4433 Neal R. Gross & Co., Inc. Page 37 1 So, the risk management goal here is 2 really to have safe drinking water, whether it's 3 all over the country or just in the Midwest. So, 4 we're going to talk about two major topics. 5 We're going to talk about hazard 6 assessments and the basic goals of hazard 7 assessment are to think about sensitive 8 populations and life stages, thinking about 9 durations of exposure and dose response 10 relationships. 11 In exposure assessment, we really want 12 to think about the residues in the drinking water 13 and how confident or uncertain we are about those 14 values, because the relative confidence and 15 uncertainty gets at how much monitoring we need 16 to be doing. 17 So, we're on a very long process, you 18 know, it's a very big process, it's accelerated. 19 We started the SAP process in February. Some of 20 you were at that meeting. 21 As Steve said, the report from that 22 meeting just came out a few days ago, and I would

### 202-234-4433 Neal R. Gross & Co., Inc. Page 38 1 say my first read of the report is that the 2 report is very consistent with what we heard of 3 the meeting, that the Panel was overall, very 4 supportive of the approach we're proposing, with 5 some very appropriate versions, I think, in fact, 6 they've already started making. 7 So, to the -- the meeting this week is 8 about thinking about animal toxicology, in vitro 9 toxicology and drinking water monitoring. 10 Originally, we had hoped in September, 11 to do a cancer/non-cancer harmonization, in a 12 weight of the evidence analysis, and to take that 13 and to merge it with drinking water and have a 14 new proposal, but as you heard from Dr. Bradbury, 15 our friends at the National Cancer Institute will 16 not have their studies from the Agricultural 17 Health Study ready in time for that. So, that's 18 been postponed. The cancer component has been 19 postponed to 2011. 20 However, we are maintaining the 21 schedule for September, on the non-cancer effects 22 and largely, as I said at the beginning, this is

### 202-234-4433 Neal R. Gross & Co., Inc. Page 39 1 really the rubber meets the road analysis. At 2 the end of the day, this is about drinking water 3 monitoring and is the drinking water adequate, 4 and largely we believe that that's going to be 5 driven by the non-cancer effects, as they tend to 6 be shorter duration. 7 The longer term cancer outcomes are 8 much longer in duration, which would be less 9 frequent monitoring. 10 Okay, so, a lot of what we're going to 11 talk about over the next few days is about the 12 hazard assessment component. 13 As you will hear from Dr. Mendez, this 14 is -- what we're going to talk about today and 15 what's in the Agency's issue paper is really a 16 snapshot in time. 17 People are doing atrazine work all 18 over the world, all over the country. People 19 that are in labs are continuing atrazine work. 20 It's really a snapshot in time, of where the 21 state of the science was at the end of January.

22 We know that between now and the

### 202-234-4433 Neal R. Gross & Co., Inc. Page 40 1 summer, there are going to be more studies, and 2 in fact, probably some important studies to think 3 about dose response and life stages, and Dr. 4 Mendez will talk to you about those later. 5 But our goal for September is to take 6 our current issue paper with the revisions that 7 we hear from all of you, the suggestions that we 8 get, the comments we get from the public, and to 9 blend in that new analysis with all the new data 10 and to do a formal weight of the evidence 11 analysis, like that we proposed back in February, 12 at the February meeting. 13 Where we will take the animal 14 toxicology data, the in vitro, the modeling, the 15 epidemiology and put it together in a mode of 16 action framework, to think about key events 17 leading to toxicity, dose response and temporal 18 concordance, do explicit evaluation of life 19 stages pre, post and perinatal effects, and we're 20 going to talk about human relevance of those 21 effects, that the qualitative and the 22 quantitative difference between the animals,

### 202-234-4433 Neal R. Gross & Co., Inc. Page 41 1 particularly rodents and humans, and all these 2 effects, and that's largely where the 3 epidemiology will come in. 4 On the exposure side, on the drinking 5 water, you will hear us talk almost exclusively 6 about drinking water, because that is the pathway 7 of concern for this chemical, and as we talk 8 about the rubber hitting the road, on this 9 analysis, it's the thinking about the duration, 10 the temporal aspects of the toxicology, that will 11 drive those frequencies, and there are a variety 12 of ways to think about this, single day peaks, or 13 you can do multiple day averages of any of 14 duration you choose, basically. 15 I believe we'll show some examples of 16 shorter ones, maybe three to seven days. The 90 17 day rolling average, it was done in the last 2003 18 risk assessment. 19 A large component of the drinking 20 water analysis has to do with really 21 understanding the confidence and the data, the

22 data that we have and the data that could be

### 202-234-4433 Neal R. Gross & Co., Inc. Page 42 1 collected if there was a different frequency. 2 It's important to think about it, both 3 temporally and spatially, and you'll hear Nelson 4 Thurman talking about that later. 5 You'll also see this map later. 6 Nelson will talk about it quite a bit in a little 7 while, but I think it's a nice illustration that, 8 as you look at the blue and the dark-blue and the 9 red areas, that the areas in the middle part of 10 the country, particularly those where large row 11 crops are grown, are really the areas where 12 levels of atrazine -- we're concerned about in 13 drinking water. 14 Okay, so, in light of the new science 15 that we'll talk about, particularly on the hazard 16 assessment, in the feedback we hear from you, the 17 feedback we get from the public, we're going to 18 do two things. 19 We're going to decide if a full-blown 20 risk assessment has to be done, and what that 21 means in practice is that right now, the focus is 22 on updating the literature review, deciding of

### 202-234-4433 Neal R. Gross & Co., Inc. Page 43 1 the points of departure, i.e., the line in the

2 sand where the assessment needs to move. The 3 uncertainty factors need to be changed. The 4 duration needs to be changed. 5 If one or all of those need to change, 6 based on the new science, we'll think about that, 7 if a new risk assessment needs to be done, and 8 we'll also decide if the drinking water 9 monitoring requirements for Syngenta need to be 10 changed, and that's all I've got. 11 SESSION CHAIR PORTIER: Before we go on 12 to Dr. Mendez's presentation, are there any 13 questions from the Panel, any clarifying 14 questions? 15 (No audible response.) 16 SESSION CHAIR PORTIER: Okay, we'll 17 move on. Dr. Mendez is going to be talking on

18 the human health effects.

19 DR. MENDEZ: Good afternoon. Before I 20 get started, I want to apologize. I started 21 coming down with a cold over the weekend. So, if 22 my voice breaks in and out, or if I start

### 202-234-4433 Neal R. Gross & Co., Inc. Page 44 1 coughing, I apologize for that. 2 So, the goal of this presentation is 3 really to give you a very brief overview of the 4 review of the mammalian toxicity data that's been 5 conducted, as part of this reevaluation. 6 I'm going to talk a little bit about 7 our peer review history. I'm going to talk a 8 little bit about the 2003 risk assessment, to put 9 this evaluation into context, and then talk a 10 little bit about the current reevaluation. 11 I'm going to defer the really 12 technical talks to our colleagues from the Office 13 of Research and Development, but I just wanted to 14 set the stage, so you know what's coming, over

15 the next few hours. 16 Atrazine is very widely used in the 17 United States. It's approximately 70 million 18 pounds of the active ingredient per year. It's 19 used primarily on corn. It has been registered 20 in the U.S. since the 1950s, and it has been the 21 subject of numerous SAPs over the years, both on 22 topics relating to human health and ecological

### 202-234-4433 Neal R. Gross & Co., Inc. Page 45 1 effects. 2 Today, what we'll be doing is, we'll 3 be concentrating on human health effects. Review 4 evaluation of ecological effects will be coming 5 in the next year. 6 All right, so, a little bit about the 7 peer review history. We had first review of the 8 rat mammary gland tumors. We were seeing tumors 9 in the Sprague Dawley rats and so, we came to the 10 SAP, the first time around, to talk about that. 11 The SAP, at that point, pointed to the 12 Agency, that we should consider the possibility 13 that there was an endocrine component to this, 14 and to try to further evaluate what the mode of 15 action for this might be. 16 Back in 2000, the SAP evaluated the 17 mode of action on mammary gland tumors, 18 reproductive and developmental findings in the 19 rat, and also weighed in on the human relevance. 20 In 2003, we had the evaluation of the 21 prostate cancer and the epi studies and the 22 relationship between atrazine exposure and

### 202-234-4433 Neal R. Gross & Co., Inc. Page 46 1 prostate cancer in workers at an atrazine 2 manufacturing plant, and as Dr. Lowit just 3 mentioned, in 2009, we had a very brief meeting 4 for the permanent members of the Panel, telling 5 you about our plans to re-open or to start the 6 evaluation of the atrazine human health effects 7 evaluation and in February 2010, we had -- we 8 presented to the Panel a draft framework for 9 incorporating epidemiology and human incident 10 data into the risk assessment using a couple of 11 epidemiology studies from atrazine as part of our 12 case studies. 13 So, very briefly, the 2003 human 14 health risk assessment, and the points of 15 departure for the 2003 risk assessment are based 16 primarily on our understanding of the mode of 17 action at the time, the perturbation of the 18 hypothalamic-pituitary-gonadal axis. 19 In 2003, there were a series of key 20 events that were identified, the hypothalamic 21 effects resulting in changes in catecholamine 22 function and regulation of the pulsatile release

### 202-234-4433 Neal R. Gross & Co., Inc. Page 47 1 of GnRH, leading to the attenuation of the LH 2 surge, sensation of ovulation with ensuing 3 persistent release of estrogen, increased 4 prolactin release of the pituitary as a secondary 5 consequence, resulting from the elevated estrogen 6 levels, and the prolactin in estrogen induced 7 proliferative processes in the mammary gland 8 leading to tumorigenesis. 9 So, basically, what the HPG axis 10 perturbation told us is, we had attenuation of 11 the LH surge, which led to our mammary gland 12 tumorigenesis that we were seeing in the rats, as 13 well as the delayed puberty onset. 14 When we came to the SAP back in 2000, 15 what their -- the recommendations of the Panel, 16 or what the input of the Panel was, that these 17 mammary tumors were not relevant for humans, and 18 the reason for that is that the processes that 19 lead to these tumorigenesis in the rats are very 20 different from what would happen in the human. 21 What we are seeing with the LH surge 22 is that we have a constant stimulate, with the

### 202-234-4433 Neal R. Gross & Co., Inc. Page 48 1 attenuation of the LH surge, is that we have a 2 constant stimulation of the mammary gland by the 3 elevated levels of estrogen and prolactin, and 4 that is what leads us to that mammary tumor 5 development. 6 In turn, in the humans, that's -- this 7 entire process of reproductive senescence, which 8 is what's happening in the rat, is not happening 9 in the humans. 10 However, the Panel also recognized 11 that these effects may be relevant to assess 12 potential non-cancer adverse reproductive effects 13 in the humans, and that's how our 2003 risk 14 assessment is based on. 15 So, these are the non-cancer effects. 16 The acute exposure, which for the Agency is one 17 day exposure, is based on delayed ossification in 18 rat fetuses and decreased body weight gain in 19 dams. We do not believe that that is the result 20 of the LH attenuation.

21 It has an NOAEL and an LOAEL of 10 and 22 70 milligrams per kilogram per day. These short

### 202-234-4433 Neal R. Gross & Co., Inc. Page 49 1 exposures are based on the delayed puberty onset 2 in males, with an NOAEL of 6.25 and LOAEL of 12.5 3 milligrams per kilogram, and the intermediate and 4 long-term exposures are based on the attenuation 5 of the luteinizing hormone surge. 6 Okay, so, our current analysis, what 7 are the objectives? And some of these, Dr. Lowit 8 had mentioned. 9 We wanted to conduct an objective and 10 thorough review of the new data, integrate new 11 information with existing data, to evaluate the 12 hazard ID and the dose response relationship, 13 determine the extent to which this new science 14 leads us to believe that we may need to develop a 15 new risk assessment, and reconsider, if 16 appropriate, the frequency of drinking water 17 monitoring conducted by Syngenta, with the 18 atrazine registrar. 19 The scope of the current analysis, we 20 restricted this analysis to mammalian toxicity 21 and in vitro studies. Three databases were 22 searched, EMBASE, PubMed and Medline, and we

### 202-234-4433 Neal R. Gross & Co., Inc. Page 50 1 actually cast a very wide net in an attempt to 2 collect all relevant information generated since 3 the IRED was signed in 2003. 4 A database query yielded close to 300 5 articles. However, some 200 were excluded6 because either the studies were conducted on non7 mammalian species, the articles were commentaries 8 or letters to the editor, they were abstracts 9 that lacked sufficient detail in methods and 10 results, or they were topic reviews that did not 11 present original work, or they were epidemiology 12 studies that we will be looking at, as part of 13 our epidemiology data analyses. 14 In addition to all of that, we also -- 15 of the peer reviewed articles, we've also 16 included some studies submitted by the atrazine 17 registrant, and those have been placed in the

18 docket. 19 So, now, to give you sort of an 20 "upcoming attractions". The presentations that 21 you will hear this afternoon, Dr. Ralph Cooper 22 will be speaking about the mode of action

### 202-234-4433 Neal R. Gross & Co., Inc. Page 51 1 analysis. Dr. Bob Luebke will be talking about 2 the immunotoxicity analysis. Dr. John Liccione 3 will be speaking about the neurotoxicity 4 analysis. 5 At the end of their presentations, 6 I'll be coming back to sort of give you a summary 7 of what that -- those analysis lead us. 8 Then, our colleagues from EFED and the 9 Office of Water will be coming in. Dr. Nelson 10 Thurman will be talking about a purchase to 11 evaluating water sampling strategies. 12 Dr. Mary Frankenberry will be talking 13 about evaluating the performance of sampling 14 strategies, and Dr. Michael Messner will be 15 speaking about artificial neural network 16 modeling, and one little bullet that's not 17 included there is, at the end of the day, Dr. 18 Lowit will come back and sort of, wrap mammalian 19 toxicology and the drinking water evaluations 20 together. 21 So, if there are no other questions, 22 I will turn the mic over to Dr. Cooper.

### 202-234-4433 Neal R. Gross & Co., Inc. Page 52 1 SESSION CHAIR PORTIER: Dr. Chambers? 2 DR. CHAMBERS: Let me clarify one thing 3 that you said there. On slide eight, you talk

4 about the NOAEL and the LOAEL for acute. You 5 really mean just one exposure, don't you, and not 6 per day? That wasn't an extended exposure under 7 acute, was it? 8 DR. MENDEZ: No, for acute, we assumed 9 one exposure. 10 DR. CHAMBERS: One, so, it's not per 11 day, just -- 12 DR. MENDEZ: But it's from a study that 13 has multiple exposures. It's a developmental 14 toxicity study on the rat, where animals are 15 exposed -- parental animals, maternal animals, 16 are exposed, typically from gestation day six 17 through gestation day 21. 18 It is the Agency's policy that we 19 assume that developmental effects of that nature, 20 because of a rapidly changing environment during 21 development, may be the outcome of a single 22 exposure.

### 202-234-4433 Neal R. Gross & Co., Inc. Page 53 1 SESSION CHAIR PORTIER: Dr. LeBlanc? 2 DR. LeBLANC: In your discussion of the3 literature review, you mentioned that non4 mammalian studies were not included, and I was 5 wondering, were they excluded, with respect to 6 evaluating mode of action? 7 DR. MENDEZ: Well, we looked at them 8 briefly, but they were not -- to the extent that 9 they did inform the data, we considered them. 10 But primarily, we were trying to concentrate on 11 the mammalian toxicity. 12 SESSION CHAIR PORTIER: Okay, let's 13 move on to Dr. Cooper, who will be talking on the 14 MOA of atrazine. 15 DR. COOPER: Thanks, Liz and Anna. My 16 presentation this afternoon is divided into, 17 essentially, three parts, where again, this time, 18 I'm going to do a little historical review of 19 what we considered the mode of action, back in20 2003, that atrazine alters the hypothalamic21 pituitary-gonadal axis, and do a more pictorial 22 than Liz did, but with some added details that I

### 202-234-4433 Neal R. Gross & Co., Inc. Page 54 1 think will help us interpret some of the more 2 recent findings. 3 The second part of this presentation 4 will look at the rationale and studies that we've 5 been looking at over the last several years, 6 indicating that atrazine may have an effect on 7 the hypothalamic-pituitary-adrenal axis, clearly 8 showing an activation of that axis, and trying to 9 fit that into the mode of action and then, the 10 last part is a brief attempt to do some synthesis 11 with the effects that we've observed and that 12 literature has reported of both these different 13 regulatory systems. 14 I put some background slides in here, 15 just to get everyone on the same track. This is 16 the way we look at the estrous cycle in the

17 female rat. 18 Most of the studies, I'll talk about 19 in the adult animal are in the female, and the 20 regulation of the LH surge, of course, was the 21 key event, endocrine event, that was used for 22 interpreting the mode of action, back in the last

### 202-234-4433 Neal R. Gross & Co., Inc. Page 55 1 Science Advisory meeting. 2 The rat has a four-day reproductive 3 cycle, four-to-five-day reproductive cycle that's 4 readily identifiable and measured by just simply 5 following the vaginal smear of the animals and 6 see if distinct changes take place over the 7 course of those four or five days. 8 The key day is, to us -- the 9 endocrinologically key day, anyway, is the day of 10 vaginal proestrus, which is right here, and I've 11 got in cartoon fashion, the indication that what 12 happens on that day is in response to rising 13 levels of estrogen and subsequently, increases in 14 serum progesterone, coming from the ovary and 15 perhaps, the adrenal gland, there is a triggering 16 of a massive outpouring of luteinizing hormone 17 from the pituitary gland that occurs at a very 18 distinct time on the afternoon, approximate -- 19 and peaks approximately two hours before dark. 20 That event is what then leads to 21 ovulation and over the evening hours, the animal 22 is sexually receptive. So, the timing of

### 202-234-4433 Neal R. Gross & Co., Inc. Page 56 1 ovulation synchronized with the behavior of the 2 animal. 3 Because the rats are spontaneous 4 ovulators, there's a lot of homology between the 5 neuroendocrine regulation of the rodent 6 reproductive cycle, ovarian cycle, and the human. 7 This is another cartoon of how we see 8 the different parts, and again, to address the 9 mode of action of the HPG, I have the rat brain, 10 the hypothalamic, the hypothalamus, which is the 11 origin of the -- the neuropeptide is secreted 12 from the brain, through the portal system that 13 bathes the interior pituitary gland, GnRH 14 stimulates luteinizing hormone, luteinizing 15 hormone then stimulates the maturing follicle to 16 rupture. 17 Part of this whole system is that you 18 have other hormones, FSH and prolactin. We've 19 shown in the past that prolactin also appears to 20 be a target of atrazine disturbances, and then 21 this whole process involves feedback from the 22 ovary itself, the steroid hormones estrogen and

### 202-234-4433 Neal R. Gross & Co., Inc. Page 57 1 progesterone, feeding back onto the brain, to 2 further regulate -- regulate regulation and 3 reproduction and behavior. 4 This is the kind of data that you see 5 when you measure luteinizing hormone on the 6 vaginal proestrus. 7 This particular slide was taken from 8 a series of studies that we did, looking at the 9 intact female that was dosed with what I guess 10 now, we can -- based on the earlier work, 11 relatively low doses of atrazine, where we sought 12 to find a low LOAEL and NOAEL for this compound13 in the intact animal, and you can see a dose14 dependent decrease in luteinizing hormone 15 occurring on the afternoon of proestrus at 1800 16 hours, which as I mentioned, was approximately -- 17 is two hours prior to the time lights are out in 18 these studies, and that was the only time that 19 you see the suppression and importantly, the 20 suppression of the surge isn't a complete 21 blockade of the surge. It's lowered in a dose 22 response fashion. But these animals may, at this

### 202-234-4433 Neal R. Gross & Co., Inc. Page 58 1 time, since they're young adults, still be able

2 to ovulate. 3 Again, by way of background, these are 4 data taken from an earlier study that we did, 5 showing that atrazine did block the LH surge, in 6 two different strains of animals, the Long-Evans 7 and the Sprague Dawley rat. 8 This first slide makes the point that 9 in the Long-Evans rat, if we dose one day with 10 increasing concentrations of atrazine, this is 11 all by gavage, you can see that a single exposure 12 really doesn't do a whole lot to the secretion of

13 LH. 14 What I have here is the dose response 15 on the side. These are animals that received the 16 different doses at 16, 18 and an hour before and 17 an hour after lights out, and even up to 200 18 milligrams per kilogram per day, we're still 19 getting an LH surge in the animals, to 300. You 20 seem to see suppression. 21 If we dose those animals, however, for 22 three days in a row, you see a dramatic decrease

### 202-234-4433 Neal R. Gross & Co., Inc. Page 59 1 in the amount of LH that's secreted, the control 2 animals here, being in the open bars and the 3 different doses you see there. 4 There was the lower dose, an apparent 5 delay in the peak, where it occurred at 2000 6 hours, an hour after lights out, and I should add

7 that other work we've done showed that those 8 higher doses, those animals don't peak, even if 9 you test them or evaluate them later on, in the 10 dark phase of the cycle. 11 If you look at that figure on the 12 right, the three day dosing in the Long-Evans 13 rat, it brings up another interesting thing. 14 First, of course, the main point I 15 wanted to make with this slide, is that as the 16 duration of the dosing increases, the effect that 17 the -- the effective dose decreases. 18 But the other point was that when you 19 compare strains, three days later, there's -- 20 we've ran Sprague Dawley rats in the exact same 21 study that you're reviewing here with Long-Evans, 22 and you'll see that when you look at those

### 202-234-4433 Neal R. Gross & Co., Inc. Page 60 1 animals, which I have plotted on the right figure 2 over here, there was still no effect in the 3 Sprague Dawleys, even after three days of dosing.4 These are ovariectomized, estrogen5 primed animals, given the compound for three 6 days, whereas the Long-Evans were affected at 7 three days, the Spragues kept a pretty good size 8 LH surge. 9 However, if we continued dosing both 10 strains for a longer period of time, then 11 eventually, you would see that this compound had 12 an effect on the peak amplitude in all the 13 different doses in both strains, and the way this 14 works is that over here on the right panel, when 15 we dose for 21 days, we only looked at 1800 16 hours. We're pretty convinced that at those 17 doses, we'd see the peak there. 18 So, these are animals that were killed 19 at that time, control animals at 1800 in both 20 strains, and then you dose response down. 21 So, again, the longer the duration of 22 dosing, the more effective the dose would be.

### 202-234-4433 Neal R. Gross & Co., Inc. Page 61 1 Another series of studies that we did 2 back in 2000, were to look at whether or not the 3 disruption of the LH surge was dependent upon 4 changes that were occurring in the brain or the 5 pituitary or the broader axis itself, and in 6 those studies, we took apart the system, 7 essentially. 8 First, ovariectomized the animals, 9 thus removed the ovary. We still saw effects on 10 the LH, so we sort of thought we were ruling out 11 the ovary at that time. 12 Other studies we did is, we took the 13 pituitary out of the animal, that was dosed, and 14 looked at whether or not it could still release 15 luteinizing hormone the same way control animals 16 would do, and what you have here is a perifusion 17 system, where the animal's pituitaries were 18 placed in a bath where the medium was flowed over 19 the tissue for a period of time, went to20 baseline, and then we dosed with gonadotropin21 releasing hormone, which is the peptide that 22 normally stimulates luteinizing hormone.

### 202-234-4433 Neal R. Gross & Co., Inc. Page 62 1 Pulsed it once, saw a response, pulsed 2 it again, pulsed it -- I'm sorry, then we looked 3 at KCL, but the point is, is that there was no 4 difference there, which indicated to us that 5 these pituitaries taken out of animals that were 6 dosed for four days, were perfectly capable of 7 responding to the natural releasing factor. 8 Another study that was done by Dr. Lee 9 Tyrey, who was a visiting professor from Duke 10 OB/GYN, working in our lab, looked at the 11 pulsatile release of GnRH and here, what we have 12 is a 28 day ovariectomized animal who will start 13 to spontaneously surge -- show LH pulses that 14 occur at a frequency of about two per hour, and 15 in the control animals -- and these are mean 16 data, so they're not really as pretty as what we 17 really had, but he puts it together through a 18 program, and can show you the means. 19 But control animals, you'll see these 20 pulses, which reflects the activity of the GnRH 21 neurons in the brain. We can measure the LH and 22 every pulse of LH is reflective of increased

### 202-234-4433 Neal R. Gross & Co., Inc. Page 63 1 activity in GnRH. 2 When we increase -- expose the animals 3 to 50 or 200 milligrams per kilogram -- I can't 4 read that, I hope it's 200 -- 50 and a higher 5 dose, from my eyes, I'm sorry, immediately prior 6 to this time, you can see that the 50 had a 7 little disruptive effect, but with the pulsar 8 analysis that they did, we didn't see any real 9 statistical difference, but that higher dose 10 totally flattened out the pulses. 11 What this meant to us is that 12 atrazine, in some way, was disrupting the brain's 13 control of the release of the hormone itself. 14 The next study, or in another study, 15 later on, in the same series of studies, where we 16 were looking at the intact animal, we measured 17 the amount of GnRH in the basal part of the 18 brain, where the neurons -- or the basal part of 19 the brain, where you have gonadotropin releasing 20 hormone neurons, and we saw that the 21 concentration of GnRH tended to go up in the 22 atrazine-treated animals, which would be

### 202-234-4433 Neal R. Gross & Co., Inc. Page 64 1 consistent, again, changes in the brain occurring 2 and would be consistent with the decreased pulses 3 that we saw when we looked at them in the longer 4 ovariectomized model. 5 And then finally, we did a study where 6 we blocked the LH surge in ovariectomized animals 7 with a very high dose of atrazine and went in and 8 injected IV gonadotropin releasing hormone, and 9 it showed that the pituitary was perfectly 10 capable of responding to the neuropeptide, again. 11 So, these kinds of things told us that 12 it appears as though atrazine was working on the 13 central nervous system to disturb the pulsatile 14 release of GnRH, and I haven't showed it, 15 prolactin release, and in that way, we thought 16 that it was disrupting the ability of the animal 17 to maintain normal ovarian cycles. 18 Another key point, and again, Liz may 19 have touched on it, was, what's actually 20 happening is that as we dose these animals, we 21 were lowering the LH surge and, in a way, that 22 was analogous to what you see during the aging

### 202-234-4433 Neal R. Gross & Co., Inc. Page 65 1 process of the animal. 2 Normally, the female rat, under a 3 four-day cycle, has an abundance of LH secreted 4 between -- just prior to time of lights out. But 5 actually, to get ovulation, you only need a small

6 amount of that. 7 Back with the old reference prep, it 8 was about 2,500 nanograms per mL for a peak, and 9 the people that work showed that you only needed 10 about 200, or less than a tenth of the LH, to 11 actually cause ovulation, which used to lead them 12 to speculate what the rest of that LH is doing. 13 But as the animal ages normally, or if 14 the animal is treated with atrazine, sufficient 15 doses, what happens to the LH secretion is that 16 the peak lowers and actually, the onset of the 17 surge occurs a little bit later, sort of like 18 what we saw with that 50 milligram per kilogram

19 dose. 20 It can still cycle, again, because 21 just like those animals I showed, even though 22 they're statistically bound, they can still

### 202-234-4433 Neal R. Gross & Co., Inc. Page 66 1 function to cause ovulation. 2 As the animal continues to age 3 further, it goes below that threshold. The 4 animal doesn't ovulate anymore, which I show up 5 here in this picture that everyone loves, my 6 symbol for ovulation. Those animal's eggs are 7 retained in the follicles and those follicles are 8 secreting estradiol only into the serum, but not 9 progesterone. 10 Another thing that happens, and again, 11 as Liz mentioned, because of that increased 12 estradiol, you end up with diurnal and a 13 nocturnal peak of prolactin being secreted. 14 So, you have an endocrine milieu, 15 that's totally out of bounds with what it should 16 be, and the hypothesis that we worked with on 17 that MOA was that atrazine, like aging, causes a 18 decrease in this LH surge, which leads to an 19 early reproductive aging in the animals, and when 20 the animals show the persistent or constant 21 estrus then, it will lead to the early appearance 22 of mammary gland tumors.

### 202-234-4433 Neal R. Gross & Co., Inc. Page 67 1 So, again, that's just it, in bullet 2 form. And the summary is that atrazine disrupts 3 hypothalamic control of gonadal function and it 4 contributes to early reproductive senescence, 5 producing that hormonal environment, and again, a 6 key point is, it's well known that reproductive 7 aging in the rat, as I have up there, is driven 8 by brain. 9 We could argue that. I know the work 10 of Tuck Finch and Brower argue that ultimately, 11 it's the amount of estrogen that that brain sees 12 over its lifetime, but really, the events taking 13 place within the central nervous system are 14 what's disrupting the ability of the animal to 15 produce the LH surge and it still has plenty of 16 follicles left in its ovary, so that when the 17 ovary stops cycling, there's lots of estradiol 18 that's put out there into the blood. 19 Reproductive aging in the human is 20 quite different. It's apparently driven by a 21 depletion of the follicles in the ovaries. 22 In turn, you have a situation where

### 202-234-4433 Neal R. Gross & Co., Inc. Page 68 1 with aging, you have a relatively low 2 concentration of estradiol and different 3 endocrine milieu altogether. 4 So, that's where the Agency concluded 5 that the mode of action for mammary gland tumors 6 in the rat was not relevant to, or would be 7 predictive of anything that would happen in

8 humans. 9 But what happened in those studies, 10 when we were doing that work, was, a number of 11 different outcomes showed that there were clear 12 other relevant reproductive effects that were 13 occurring when the animals were dosed with 14 estradiol. 15 Some of those are briefly mentioned 16 here, and we talk about different life stages and 17 that kind of thing. This is part of what was 18 driving some of that. 19 Atrazine will delay puberty in 20 animals. There was a study done by Tammy Stoker 21 and Susan Laws, in the male and female rats, 22 respectively. Those studies were replicated by

### 202-234-4433 Neal R. Gross & Co., Inc. Page 69 1 other laboratories. Those studies were -- or 2 similar studies were conducted with the 3 validation of the pubertal assays in the -- for 4 the endocrine disrupting screening program. 5 So, it was a robust effect that was 6 repeatable, that delayed puberty does occur when 7 you dose animals with atrazine.

8 Other adverse outcomes -- and we know 9 the toxicity pathways for some of these were 10 prostate -- prostatitis, if the dam is dosed 11 during specific developmental periods. 12 We know the disruption of ovarian 13 cycles occur, and I should mention that the 14 registrant did a very nice study, looking at the 15 age-dependent changes in ovarian cycle, or 16 estrous cycles in the rat and again, showed that 17 the reproductive cycle does decrease earlier. It 18 wasn't just a hypothesis, that in fact, these 19 things occur. 20 And more recently, there's been a 21 number of studies looking at testosterone 22 synthesis that I think again, are going to become

### 202-234-4433 Neal R. Gross & Co., Inc. Page 70 1 -- maybe, we can interpret them easier, once we 2 understand what's going on with the adrenal axis, 3 but I think -- in the background paper that you 4 received, I think there was four or five studies 5 that have been published in different strains of 6 animals, saying that atrazine, for an extended 7 period of time, relatively high doses, will 8 impair testosterone synthesis in the developing - 9 - most of the studies, in the developing male

10 rat. 11 So, again, where we were with the 2003 12 SAP, there was general agreement that this 13 pesticide or herbicide was working through a 14 disruption of CNS-mediated decrease in LH and 15 that was the relevant mode of action, and the key 16 event in this whole process was a decrease in 17 luteinizing hormone that contributed to those 18 adverse outcomes, of course, with the exception 19 of the prostatitis studies, which were linked 20 more with changes in prolactin availability. 21 That's what the considered mode of 22 action was, but yet, there were still some

### 202-234-4433 Neal R. Gross & Co., Inc. Page 71 1 nagging questions that existed, at least, in my 2 mind. One of them was that delay. 3 When you dose animals and you disrupt 4 the LH surge, we've worked with a number of 5 different environmental chemicals, and you do 6 this, usually, it's a very -- if it's working 7 through the brain, it's a very rapid, almost -- 8 you know, within hours kind of effect that you 9 see, and that business where we saw, it took 10 several days to start to see, there is this 11 trade-off between dose and time that tended to 12 have an effect on the LH surge, always was kind 13 of intriguing to me, and I -- I just couldn't put 14 together what it was that was responsible for

15 that. 16 Secondly, in Dr. Stoker's study, where 17 she looked at everything that she could get her 18 hands on in the pubertal male, she looked at the 19 concentrations of estradiol that were present in 20 those animals, and found a significant increase 21 in the serum estradiol in the males treated for 22 21 days. That's peripubertally. They start the

### 202-234-4433 Neal R. Gross & Co., Inc. Page 72 1 treatment on PMD-21 and kill on PMD-42. 2 Susan Laws -- we asked the question 3 whether or not that was true in adult animals as 4 well, because you really see, at the right dose 5 of atrazine, an increase in estrone and estradiol 6 in these animals, and Susan Laws replicated that 7 study here, with only a four-day exposure. 8 And what she found was an increase in 9 both those estrogens, in both the developing 10 animal and in the adult, and you know, a high 11 dose and -- it was something that we, you know, 12 really didn't know what to make of, at the time. 13 But, at that time, there were a number 14 of other studies reported, either in vitro or in 15 vivo, looking at atrazine and the enzyme 16 aromatase, which was the enzyme that's 17 responsible for the production of estrogens from 18 androgens. 19 So, that led us to look at little more 20 closely at what might be going on, both in vitro 21 and in vivo, with aromatase and estrogen, and 22 whether or not that might be part of some of this

### 202-234-4433 Neal R. Gross & Co., Inc. Page 73 1 -- something that we missed, in terms of the mode 2 of action. 3 So, at that time, because of the in 4 vitro studies, we were looking at -- we were 5 looking at aromatase or one of the cytochrome 6 P450s, which converts the androgens to estrogens. 7 Aromatase is present in a number of 8 different tissues in the body, some there 9 listed, the brain, the gonads, fat and placenta. 10 In the brain, it's responsible or plays a key 11 role in sexual differentiation of the rodent 12 brain. 13 Its regulation is different in the 14 different tissues looked at. You have different 15 promoters and other regulatory factors that are 16 involved, whether you look in the ovaries or the 17 placenta or the breast, and then there is 18 alterations in -- it's been shown that 19 alterations in gene expression that disrupt the 20 estrogen availability are going to eventually 21 impact not only reproductive development, but a 22 lot of other normal functioning of different

### 202-234-4433 Neal R. Gross & Co., Inc. Page 74 1 tissues.

2 So what we want to do over the next 3 few slides is to review the evidence that 4 atrazine does alter aromatase activity, both in 5 vivo and in vitro, and I think set the stage for 6 why a lot of the things that we're looking at, if 7 we stick with this one enzyme, wasn't really 8 necessarily making sense, that we may have to 9 broaden our scope of investigation a little bit 10 bigger, to look at the whole process of 11 steroidogenesis. 12 This is the study, including -- 13 actually, the second in a series of studies by 14 Thomas Sanderson, that -- looking at the 15 chlorotriazines, and put everyone onto the idea 16 that atrazine and its metabolites might be 17 affecting the production of estrogens, and what 18 Sanderson did is he used this cell-line up here, 19 the H295R human adrenal carcinoma cell-line, 20 which is kind of a neat and unique cell-line 21 because it possesses all the key enzymes, P450s 22 that are necessary to produce a number of

### 202-234-4433 Neal R. Gross & Co., Inc. Page 75 1 different steroids, right on out to estradiol. 2 So, it does contain aromatase. 3 What Sanderson showed was that at, you 4 know, fairly decent concentrations, around three 5 micromolars -- decent, I'm saying compared to 6 what some of the studies I've seen in the 7 literature show, around three micromolars, you 8 start to see an increase in what he termed the 9 activity of that enzyme. 10 You saw an increase in the production 11 of either tritiated water or the estrone itself, 12 if -- in those cells. 13 But what was also interesting is that 14 he found that only atrazine, the two intermediate 15 metabolites that I call them, that's isopropyl 16 and desethylatrazine, increased aromatase 17 activity. 18 Sanderson also looked at the ability 19 of atrazine to change the message in these cells 20 and reported that there was a modest twofold 21 increase in the message, along with that, 22 indicating that exposure to these compounds, to

### 202-234-4433 Neal R. Gross & Co., Inc. Page 76 1 these three metabolites, anyway, could increase 2 the overall production of estrogens. And 3 importantly, and we'll come back to it in a 4 moment, DACT had no effect on these endpoints, 5 and that's the one there in the square blocks, in 6 red, if you can see it. 7 So that's the -- one of the -- if you 8 look in the blood of the rat, anyway, that's one 9 of the really prominent metabolites, that that 10 had no real effect on aromatase activity in this 11 -- in the H295Rs, and one of his colleagues 12 replicated these studies, looking at the JEG

13 cells. 14 What that did for a time was put a lot 15 of focus on aromatase itself. The light was 16 shining there, and a number of different studies, 17 looking at changes in estrogen production, all 18 came to the conclusion that you could see 19 increased estrogen synthesis, and again, this 20 cell-line was used for the validation of some of 21 the in vitro tests, and I think nine labs 22 replicated the effects of atrazine on aromatase,

### 202-234-4433 Neal R. Gross & Co., Inc. Page 77 1 so -- or, the production of estrogens. 2 But one of the interesting things that 3 we found was that in addition to just estradiol 4 alone or estrone alone in there, you could see 5 increases in other hormones, and recently, a 6 paper published by Higley said that not only does 7 atrazine increase estradiol or estrone, depending 8 on what you're measuring, it also increases

9 testosterone. 10 And in our own lab and others have 11 also shown that some of these other earlier 12 steroids in that pathway are increased when you 13 stimulate with atrazine, or certain of the 14 atrazine metabolites, which suggested to us that 15 it's not just aromatase that is the target here, 16 but in fact, increased steroidogenesis might be 17 really what the whole series of changes that are 18 taking place is. 19 There are some other studies focusing20 on SF-1, as a target site for this SF-1, as a co21 factor involved in the regulation of aromatase. 22 Others have said that that's not necessarily the

### 202-234-4433 Neal R. Gross & Co., Inc. Page 78 1 case. You may see changes in SF-1, but in fact, 2 that's not necessarily the only target, that in 3 fact, you do see a broader increase in a number - 4 - activity of a number of different singling 5 pathways, and that's what these different studies 6 down here show, and again, these are in the 7 background document. 8 But the point is, is that in addition 9 to aromatase per se, there is this overall effect 10 on steroidogenesis that seems to be the "mode of 11 action" within the cell. We're not sure exactly

12 what all the molecular events are. 13 There is an argument that put forth, 14 actually earlier on, by Sanderson, that atrazine, 15 in some way, increases cyclic AMP activity, 16 perhaps through a decrease in phosphodiesterase. 17 That's something that can be -- has been 18 substantiated by other labs, but the papers 19 aren't published yet. 20 There is a study that I just read, 21 where they block protein kinase activity and that 22 reversed the effects of atrazine on the

### 202-234-4433 Neal R. Gross & Co., Inc. Page 79 1 activation of steroidogenesis in Leydig cells. 2 So, that paper is going to be out 3 shortly, so I guess it's okay if I tip my hat on 4 that one, but the point is again, somewhere 5 upstream, a broader effect on signal transduction 6 seems to be the cellular toxicity pathway and 7 that the aromatase per se is not necessarily the 8 sole target for these chemicals. 9 In vivo, again, as I mentioned, we 10 were interested in whether or not atrazine can 11 affect aromatase in vivo. 12 Walter Modic, who was a student with 13 Dr. Laws' lab, did a series of studies looking at 14 male rats to see if he could identify changes in 15 aromatase activity or the message for aromatase, 16 after being treated with atrazine at relatively 17 high doses for -- in several different ways, and 18 to make a long story short, it's nice to have a 19 lot of slides, but when you get no effects, you 20 end up with a slide like this that says, "Yes, 21 you can induce increases in serum-estrone and 22 estradiol in the male rat."

### 202-234-4433 Neal R. Gross & Co., Inc. Page 80 1 This is a different study that we did, 2 showing that in the ovariectomized female, you 3 can see increases in estrone activity at 4 relatively high doses of atrazine, but nowhere 5 was there -- were they able to identify changes 6 in aromatase, either looking at microsomes taken 7 from testes of animals treated, or, could they 8 see changes in the message, looking in brain 9 testes or adipose tissue. 10 So, it just -- if it's there, it's 11 real difficult to find any specific change in 12 aromatase activity. 13 This summarizes that series of 14 studies, so we still have increases in those 15 hormones. It increases the estrogens. There was 16 little or no evidence to support the idea that it 17 was working specifically through aromatase, 18 either increasing the activity or the message. 19 What we had, and I don't want to get 20 into it, because there's a lot of controversy

21 over whether or not the adrenal hormones can 22 produce -- the rodent adrenals can produce

### 202-234-4433 Neal R. Gross & Co., Inc. Page 81 1 androgens, such as androstenedione, and this 2 literature is -- depends on which side you want 3 to take, but the point is, is that these animals 4 did have increases of estrogen in them, and we 5 were thinking that perhaps one of the sources of 6 this was from the adrenal gland. 7 And that led us to ask the question 8 whether or not atrazine might have some kind of 9 direct effect on adrenal steroidogenesis. 10 Here it is, 2007, and we've been 11 looking at this for all this time and it seemed a 12 little odd that no one else would have reported

13 that. 14 There were dribbles and drabs in the 15 literature and there was a couple of elegant 16 studies by Dr. Pruett's lab, that said in mice, 17 at the time, that atrazine does increase 18 steroidogenesis from the adrenals. 19 So, we decided to look into this axis, 20 arguing about whether or not the adrenal hormone 21 secretion would be altered by atrazine, whether

22 or not that effect would occur because of some

### 202-234-4433 Neal R. Gross & Co., Inc. Page 82 1 kind of central targeting of the compound or 2 whether or not the adrenals may actually be 3 targets themselves, since we know in vitro, there 4 were effects on steroidogenesis. 5 So, Susan Laws published this study, 6 some time late last year, demonstrating that 7 there is really a clear effect of atrazine on 8 both ACTH secretion and corticosteroidal -- or I 9 should say ACTH secretion and a number of 10 different adrenal steroids, and this is from that 11 paper, where she gave doses ranging from five to 12 200 milligrams per kilogram orally, and looked at 13 the production of atrazine -- I'm sorry, the 14 production of ACTH and corticosterone at 15 different doses. 16 And I should just mention here that 17 these animals are all dosed for five days prior 18 to testing. They're dosed with the vehicle 19 carboxymethyl cellulose, that they're all dosed 20 at the same time of day, at the nadir, I think 21 it's nine o'clock in this study, when the 22 concentrations of corticosterone and ACTH are

### 202-234-4433 Neal R. Gross & Co., Inc. Page 83 1 low, and so, when you look at the control animals 2 there, the actual dosing procedure itself seemed 3 to have minimal effects on the secretion of ACTH 4 or corticosterone, which speaks well for the 5 ability of that lab to conduct these studies. 6 But what happens is, as you increase 7 that dose though, there is a clear increase in 8 both ACTH and corticosterone, as well as 9 progesterone and we're -- I'm pretty confident 10 that this is adrenal-derived progesterone. 11 It's in male rats, and if you look at 12 the testosterone that's being secreted, this is 13 probably from -- or more than likely from the 14 test, as you can see a significant increase 15 there, as well. The time course is a little 16 later. The dose required is a little higher. 17 Another important thing that Susan 18 found was that when you dose with DACT, you saw 19 no comparable increase in ACTH or corticosterone, 20 which was sort of like what Sanderson had 21 reported for the H295R cells. 22 Now, for some reason, that particular

### 202-234-4433 Neal R. Gross & Co., Inc. Page 84 1 metabolite of atrazine wasn't active, in terms of 2 increasing the adrenal axis, and I have their 3 DACT and ACT and atrazine on the right side, just 4 so you can compare, there were significant 5 changes, if you, as Liz likes to say, worship at 6 the altar of the star, but I don't think they 7 were really as dramatic as what you see over here 8 with atrazine. 9 And the other thing is that the timing 10 there, I don't think there was a delayed response 11 in that, but again, nothing like what you see 12 with the parent compound itself. 13 Another thing that Melanie Fraites is 14 working on in our lab, did, was a series of 15 studies to further get at whether or not this was 16 a chemically specific activation of the pituitary 17 adrenal axis or it was still some artifact that 18 we were introducing, that we didn't know about, 19 and we thought every -- tried to think of 20 everything that we could to get at that, but up 21 to this point, what we've done so far is, Melanie 22 has shown that if you do things like cut the

### 202-234-4433 Neal R. Gross & Co., Inc. Page 85 1 vagus nerve, it doesn't interfere with it. 2 So, it didn't look like atrazine was 3 getting down into the gut and causing some type 4 of intestinal distress that was going to feed

5 back. 6 There didn't seem to be any change in 7 some of the endocrine components of feedback from 8 the gut to the brain, and I think, to me, anyway, 9 one of the most convincing things that you can 10 get around the -- any signals from the gut being 11 the cause -- the root-cause for this increase in 12 ACTH, is her observation that you can get the 13 same response if you give the chemical IV. 14 So here, you have an animal that's 15 sitting there with an in-dwelling catheter, you 16 dose with atrazine and you see the same immediate 17 15-minute increase in atrazine -- I mean, in ACTH 18 and corticosterone. 19 Another thing that Dr. Laws did was 20 look at not only atrazine in DACT, but the other 21 two intermediate metabolites, not shown here, is 22 DEA, but both atrazine and DIA do cause the same

### 202-234-4433 Neal R. Gross & Co., Inc. Page 86 1 type of adrenal response. 2 In this case, I think it's important 3 to note that the LOEL for that study was 10 4 milligrams per kilograms, which is the equimolar 5 dose to 12 and a half milligrams per kilogram of 6 atrazine, and the other interesting thing in this 7 study was, it wouldn't go away. 8 The increase in corticosterone -- now, 9 she only measured corticosterone in these 10 animals. She didn't measure ACTH here, but in 11 these animals, that response persisted. It was 12 there at the higher dose at four days and even 13 out to 21 days, there was a significant elevation 14 of corticosterone. 15 And this is something that was 16 indicated in the female, in a study by Dr. 17 Fraites, who showed that one dose of atrazine -- 18 again, in this case, she used 75 equimolar dose 19 of DIA, caused an increase in both ACTH and in 20 corticosterone, but then, if she dosed for four 21 days, an interesting pattern was present there, 22 that we're still working on, in terms of

### 202-234-4433 Neal R. Gross & Co., Inc. Page 87 1 interpreting it. 2 But if you look at this, this is a 3 single dose, and this is ACTH. The green here, 4 the darker green, is the same animals. This is 5 one dose; this is four doses. These are intact 6 animals that are dosed on the day of vaginal 7 estrus, diestrus one, diestrus two and the 8 morning of proestrus, and they're killed 15 9 minutes after dosing. So, that response, that 10 ACTH response there is markedly attenuated. 11 But if you look at the cort response 12 in these animals, it's almost the same as it was 13 on the first day. That's what you see when you 14 restraint-stress the animals. 15 So, it's a response that's seen, at 16 least in this case, to persist, and the other 17 thing is, in these animals, I wanted to point it 18 out, was that when she dosed with both DIA and 19 atrazine, that lower dose is 12 and a half 20 milligrams per kilogram, or 10 milligrams, the 21 equimolar dose for DIA, and again, there was no 22 real clear effect with this on -- with that. It

### 202-234-4433 Neal R. Gross & Co., Inc. Page 88 1 didn't change the adrenal axis. 2 And in those animals -- or in another 3 population of animals treated the same way, she 4 looked at the LH surge and showed that again, as 5 we showed, I think, on the first slide, that 6 there is a decrease in the LH in the afternoon at 7 the same dose as the 12 and a half milligrams per 8 kilogram for atrazine and the 10 milligrams for

9 DIA. 10 There was a suppression of the surge 11 with DACT. It wasn't significant in this figure; 12 it was significant in others. The point is, is 13 that DACT, I think you can get an effect, but you 14 have to go longer and higher, to see inhibition 15 of the surge, or a suppression. 16 So, in summary, in this series of 17 studies in the male, both ACTH and adrenal 18 steroid hormone production increased within -- as 19 early as 15 minutes following a single injection 20 of atrazine and DIA and DEA. 21 The dose response for the male study, 22 at the moment, with that data that Dr. Laws had,

### 202-234-4433 Neal R. Gross & Co., Inc. Page 89 1 the lowest dose was five. Her next highest was 2 50. So, it was somewhere between 50 and five,

3 but the LOEL that she found for DIA was at 10 4 milligrams per kilogram. 5 Compared to atrazine and DIA, the 6 increases in ACTH and the adrenal steroid 7 hormones is markedly less when you dose with DACT 8 in equimolar doses. 9 That, in the male, corticosterone 10 release was sustained for up to three weeks and 11 in the female, we only went out to four days, we 12 started to see a decline in the amount of ACTH 13 secreted in those animals, suggesting, again, 14 that there may be some direct effect of atrazine 15 on the pituitary gland itself, in addition to 16 that major increase in corticosterone release, in 17 response to ACTH after the first injection. 18 And again in the female, we have a low 19 or no NOEL, of 12 and a half milligrams there, 20 and it's important that I mention this, and we 21 just only have -- I'm already going on too long, 22 but atrazine also induces comparable changes in

### 202-234-4433 Neal R. Gross & Co., Inc. Page 90 1 adrenal progesterone secretion in the female. 2 Take the female's ovary out, you can see -- 3 unmask those kinds of effects that are 4 significant, both at one and four days of 5 exposure. 6 Comparing those effects with what you 7 saw, and I'm going back to what we saw with the 8 effects on the LH surge, either in the 9 ovariectomized estrogen-primed animal or in the 10 intact animal, what we found was that in those 11 earlier studies, which is the first three bullets 12 there, with different LOELs, you have a single

13 dose. You needed more than 200. 14 With three doses, we dropped it down 15 to 50 and in an intact animal, we could get it

16 down even lower. 17 It still indicated that you needed a 18 number of days to see an effect on the surge, and 19 we did a lot of studies early on, looking only on 20 the day of vaginal proestrus, trying to either 21 block ovulation or decrease the amplitude or 22 timing of the -- often, the timing of the LH

### 202-234-4433 Neal R. Gross & Co., Inc. Page 91 1 surge, and we couldn't get anything, again, with 2 a single dose up to 200, and if we gave 300, the 3 animals went pseudo-pregnant on us. So they were 4 still ovulating, apparently, or appeared to be 5 ovulating. 6 So, the timing of this and the fact 7 that you see these instantaneous changes in the 8 pituitary adrenal axis, and given the literature, 9 arguing that the adrenal axis is involved in -- 10 or could be, if there is hyperactivity in the 11 adrenal axis, could be involved in the disruption 12 of LH, it suggested to us that we see changes 13 that precede and may likely contribute to the 14 disruption of the LH surge. 15 And so, that's what I tried to put 16 together on this figure, where we have our 17 hypothalamic-pituitary-gonadal axis, wherein we 18 know that, time and again, people have published 19 that when you expose in vivo to atrazine, you get 20 a decrease in the amplitude of LH, you end up 21 with, eventually, acyclic animals and the 22 disruption of reproduction.

### 202-234-4433 Neal R. Gross & Co., Inc. Page 92 1 I have over here, the adrenal axis, 2 where we know that -- and we're not clear, 3 exactly whether or not -- obviously, I think, 4 there's got to be a central effect, either 5 hypothalamus or pituitary, given the rapid 6 response that you see with AC -- and the response 7 that you see with ACTH. 8 However, you see that sustained 9 response in the adrenal. Whether that's due to 10 direct effect of atrazine on the adrenal in vivo, 11 we don't know, but I'd bet a dollar that you'd 12 see it in the primary adrenal cells. And, given 13 that effect and the speed with which we saw that 14 and the timing for the pituitary effects, and the 15 rich literature on this stuff, it argues that one 16 of the primary effectors in -- or one of the 17 events responsible for the decrease of the LH 18 surge, may be that feedback of the adrenal 19 steroids onto the brain and pituitary and the 20 ability of it to regulate the LH surge. 21 Another thing that I think this kind 22 of conceptual framework argues is that, if you

### 202-234-4433 Neal R. Gross & Co., Inc. Page 93 1 look at the high dose 21-day exposure of male 2 studies, that seem to be popping up in the 3 literature time and again, that that decrease in 4 testosterone, in the gonads of the males exposed, 5 that that effect may be due to a direct action of 6 corticosterone on the Leydig cells. 7 Again, there is a literature, quite a 8 strong literature, that shows that Leydig cells 9 do have glucocorticoid receptors and when 10 activated, and they're regulated by a -- a 11 process within the Leydig cell itself. 12 But when there's over-stimulation of 13 those glucocorticoid receptors, there is actually 14 a down regulation of the enzymes involved in the 15 production of testosterone, including the key one 16 like STAR and some of the other CYPs, so -- and 17 that's well recognized. 18 So there is another pathway that may 19 explain the data that we see in the male rat, and 20 then, finally, there is the data that shows that 21 there is perhaps, a direct activation -- or I'm 22 sorry, a direct inhibition of the GnRH pulses by

### 202-234-4433 Neal R. Gross & Co., Inc. Page 94 1 CRF in the brain, wherein, stress and other 2 events that increase the activity of that 3 neuropeptide, which acid increases CRF -- or, I'm 4 sorry, increases the activity of CRF and ACTH, 5 that you get a direct innovation -- inhibition on 6 the pulses. 7 So those things make me argue, or 8 feel, that a key part of this whole mode of 9 action on the gonadal axis is this increase, at 10 least early on, increase in the activity of the 11 pituitary adrenal axis, and that's what's 12 summarized here. 13 Again, it has a clear, acute effect on 14 the HPA. We just don't know, haven't well 15 characterized the longer-term effect, increasing 16 both ACTH in the adrenal steroid hormones, that 17 the temporal aspects of atrazine induce changes 18 in the pituitary adrenal axis, and the pituitary 19 gonadal axis, along with the similarities in the 20 dose response -- that's what I was trying to get 21 at there -- for four more days, suggest that the 22 changes in the adrenal axis contribute to the

### 202-234-4433 Neal R. Gross & Co., Inc. Page 95 1 disruption of LH secretion and impairments in 2 reproductive function. 3 And so, the current studies broaden 4 our understanding of this mode of action for 5 atrazine, incorporating those changes that we've 6 already identified and others, in the pituitary 7 adrenal axis, and those that likely contribute to 8 the disruption of LH in the rat. Questions? 9 SESSION CHAIR PORTIER: At this point, 10 do we have any questions from the Panel? 11 Comments? Yes, Dr. Horton? 12 DR. HORTON: Yes, actually, I have a 13 lot, but I'll save some. 14 I'll start with another possible 15 model, besides the reproductive aging and the 16 reduction of the LH surge, and ask, do you have 17 measures or does anyone have measures, on what 18 the LH levels look like on diestrus or metestrus,

19 for the rats?

20 DR. COOPER: Yes. 21 DR. HORTON: And what are they? 22 DR. COOPER: The one thing we've seen

### 202-234-4433 Neal R. Gross & Co., Inc. Page 96 1 consistently, even on the morning of proestrus 2 too, is no change. 3 DR. HORTON: They're not elevated? 4 DR. COOPER: The majority of studies 5 that we've personally done, when we look at it, 6 it appears as though baseline hangs in there. 7 If we really increase the 8 concentrations of atrazine up to 200, I'd even 9 argue 50 and above, it's lower. 10 DR. HORTON: Okay. 11 DR. COOPER: But we haven't seen any 12 indication -- well, I have seen one, we do have 13 one set of data that says we can get an increase, 14 but it's in the afternoon, when we looked at very 15 low doses. So, I don't know whether it's -- 16 DR. HORTON: Okay. The reason I'm 17 asking is, I'm wondering if it might fit a PCOS, 18 a polycystic ovarian syndrome model; and also, 19 has anyone looked at the body weights or body 20 compositions in these rats? 21 DR. COOPER: In the earlier -- 22 DR. HORTON: In the females, yes.

### 202-234-4433 Neal R. Gross & Co., Inc. Page 971 DR. COOPER: When you do the longer2 term studies at those high doses, they're down. 3 DR. HORTON: They're down? Okay. 4 DR. COOPER: Significantly, but when 5 you do the -- like, the first slide I showed -- I 6 mean, the early studies that were done were, I 7 think, hitting them with a hammer --

8 DR. HORTON: Yes. 9 DR. COOPER: -- and you do see marked 10 decreases in body weight, but when we look at the 11 shorter-term, lower dose things, we don't see a 12 whole lot of difference. 13 DR. HORTON: Okay. 14 DR. COOPER: I mean, we don't see a 15 difference. It's the same. 16 DR. HORTON: Okay.

17 DR. COOPER: That's not -- I should -- 18 I have to qualify that, because sometimes, you 19 say you don't see a lot of difference and they're 20 not eating. But no, that's -- 21 DR. HORTON: Okay, okay, but that's in 22 terms of body weight, but no one has actually

### 202-234-4433 Neal R. Gross & Co., Inc. Page 98 1 looked at body composition? 2 DR. COOPER: Not to my knowledge. 3 DR. HORTON: Okay, no one has done a 4 glucose tolerance test? 5 DR. COOPER: We have, yes. 6 DR. HORTON: Yes, from what I -- 7 DR. COOPER: I'm sorry, yes, we've 8 measured glucose, and we haven't found any change 9 with blood glucose over the four days that we did 10 the study. 11 DR. HORTON: Okay, thank you. 12 DR. COOPER: So, we didn't do a glucose 13 tolerance test, no. 14 DR. HORTON: Okay, thank you.

15 SESSION CHAIR PORTIER: Dr. LeBlanc? 16 DR. LeBLANC: There's a lot going on 17 here. A couple of questions, for clarification 18 first. 19 In these studies, have you ever looked 20 at the adrenal mass? Do the adrenals enlarge in 21 size? 22 DR. COOPER: Yes, I'm trying to think

### 202-234-4433 Neal R. Gross & Co., Inc. Page 99 1 of the -- again, we got into looking at the 2 adrenals kind of late. So, I'm sort of 3 embarrassed to say, we don't have a real 4 characterization of changes in body weight, nor 5 histopath, and they may have it in some of the 6 longer term studies that were submitted for 7 registration. I haven't had a chance to look at

8 them. 9 But what we see is almost an immediate 10 enlargement in the adrenal gland, dose dependent, 11 and then it settled back down. 12 PARTICIPANT: Did you have one in the -

13 - 14 DR. COOPER: And in the pubertal assay, 15 they were increased, the male pubertal. But, 16 yes. 17 DR. LeBLANC: The 2009 study by Laws, 18 these were done in animals that were not 19 gonadectomized, is that right? 20 DR. COOPER: Right. 21 DR. LeBLANC: Because you said, you 22 thought the testosterone came from the testes.

### 202-234-4433 Neal R. Gross & Co., Inc. Page 100 1 So, obviously, they had testes, and I guess I 2 agree with that presumption. 3 In terms of where the progesterone is 4 coming from, is that because most of the 5 progesterone in the blood comes from the adrenal? 6 You said you thought the progesterone -- 7 DR. COOPER: In females, on vaginal 8 proestrus, there is a number of studies. One of 9 my PhD mentors, was his claim to fame, with -- 10 showed that the majority of progesterone comes 11 from the adrenal vein -- 12 DR. LeBLANC: Okay. 13 DR. COOPER: -- on the day of 14 proestrus. 15 DR. LeBLANC: Okay. 16 DR. COOPER: I wanted to just throw 17 this up. This was a slide -- this is a 18 gonadectomized slide, where the animals were -- 19 again, it was a study that Laws did earlier, 20 wherein, she looked at both androstenedione and 21 testosterone, here on the right, in response to 22 50 to 200 milligrams, and the estrogen production

### 202-234-4433 Neal R. Gross & Co., Inc. Page 101 1 over here on the left, and what was -- and this 2 was an intact animal. 3 So, this is your testosterone here, 4 and this is androstenedione -- I'm sorry, this is 5 androstenedione in the intact animal, and in the 6 castrated animal, and this is testosterone in the 7 intact animal and there is nothing there, in the 8 castrated animal. 9 And we've actually looked at the 10 adrenals of these animals, to see if we can find 11 androstenedione using HPLC, and we see it, and 12 you know, you're not suppose to have CYP17 in the 13 adrenals, and there are papers that say under 14 certain circumstances and during development, you 15 can see CYP17, that there is a methylation 16 silencing that's taking place, and I just don't 17 understand it. 18 But the point is, is that those data, 19 to me, argue pretty strongly, A) that it's 20 something coming out of those adrenals, if 21 nothing else, it's androstenedione, and over 22 here, there is a production of estrogens that

### 202-234-4433 Neal R. Gross & Co., Inc. Page 102 1 persisted and if you look at the Y-axis, they're 2 not that different, after castration in the male. 3 So, back to your progesterone 4 question, I'm sorry. 5 DR. LeBLANC: One last point, for 6 clarification. 7 The cartoon you had at the end, the 8 conceptual cartoon, I thought it was very 9 helpful, and in there, you had the inhibition of 10 steroidogenesis by clinical steroids, at the

11 bottom. 12 DR. COOPER: Yes, right there. 13 DR. LeBLANC: Right, so, over and above 14 all of this, are you suggesting that there is 15 something else going on, that's contributing to 16 the increase in testosterone, that -- we're not 17 seeing a great increase, but we are seeing 18 increases. 19 DR. COOPER: Right, okay, good 20 question. Number one, I think those studies, 21 looking at decreased steroidogenesis are really 22 the result of some pretty high doses, 50, 200

### 202-234-4433 Neal R. Gross & Co., Inc. Page 103 1 milligrams per day.

2 I know that there was one that went 3 five, ten, 50, 75 and 100 milligrams per day, 4 from -- in the perinatal, even. But most of them 5 are in the intact animals, peripubertal or going 6 on into adults. 7 So, they're high and I think what's 8 happening there, if you do a single dose with 9 this, you'll always see an increase in 10 testosterone. You'll see an increase in 11 testosterone, and if you take the Leydig cell 12 out, and you stimulate the Leydig cell, you'll 13 see an increase in testosterone, you'll see an 14 increase in progesterone, okay. 15 That's been done at APA, with Gary 16 Klinefelter and there is a publication coming out 17 soon, that that's the case. 18 You put that cell back in the body and 19 can expose it to the glucocorticoids for an 20 extended period of time, increasing 21 glucocorticoid activity by a number of different 22 means, if you want to stress them, and you do

### 202-234-4433 Neal R. Gross & Co., Inc. Page 104 1 that really mean stress, where you put them in 2 the restraint cage, and -- for an hour a day and 3 shine a light on them, and you know, you really 4 keep the cort up, that will overwhelm the 5 protective mechanism within the Leydig cell and 6 you do see this decrease. 7 And there is studies now, even showing 8 that that process, that glucocorticoid 9 activation, stimulation -- hyperstimulation, that 10 receptor is even bad for the developing animal. 11 So, it's a biphasic or bimodal effect. 12 Initially, what you see in vitro and what you see 13 with a single dose is increased T, extended 14 dosing -- and I'm hypothesizing through increased 15 adrenal activity, you're seeing perhaps, a direct 16 effect on the gonads, and then of course, what 17 you're supposed to see is that when you decrease 18 T, the compensatory increase in LH, and the 19 studies that Susan and Walter Modic did, didn't 20 really show a whole lot of decreased baseline LH 21 in those males, and we can go back and look at

22 that.

### 202-234-4433 Neal R. Gross & Co., Inc. Page 105 1 So, that's why I'm leaning a little 2 bit, towards it being a direct gonadal inhibition

3 there. 4 But again, it could be a central 5 mechanism, but I think -- that's central -- you 6 know, I -- there is a paper by Zerkin and Ewing, 7 years ago, that said, "How much LH do I need to 8 keep secreting testosterone," and so, they took 9 the pit out and they put silastic capsules in, or 10 somehow, they fed them LH at real low levels, and 11 it is -- you'd be surprised how low they went, 12 before they would see a decrease in T. 13 SESSION CHAIR PORTIER: Dr. Selvage? 14 DR. SELVAGE: Yes, I just had a 15 question regarding the CORT/ACTH measurements. 16 Do you have any time points that 17 aren't in that -- where you measured these, that 18 aren't in that frame, right after the atrazine 19 administration, in the chronic studies? 20 So, for instance, are you disrupting 21 circadian rhythm or anything like that? 22 DR. COOPER: Yes, Melanie, in the

### 202-234-4433 Neal R. Gross & Co., Inc. Page 106 1 female, what we did -- in other words, if you 2 perturb it in the morning, is this -- the 3 afternoon is going to be altered -- 4 DR. SELVAGE: Yes, or the -- yes, or 5 was it -- before, you know, you would normally6 give it in the morning, and what would be CORT7 level? 8 DR. COOPER: The data that we have in 9 the -- it's a four-day exposure. We looked at 10 the dose immediate responses, but then we also 11 looked at the afternoon increase in progesterone, 12 because if you -- we were thinking that maybe 13 progesterone later on in the day was being 14 impaired. 15 And there -- in CORT, and Susan -- 16 well, number one, is that there -- I think it was 17 the high dose -- Melanie, was the high dose of -- 18 which one knocked down P4 in the afternoon? 19 Yes, the high dose DIA did decrease 20 progesterone in the afternoon, but for the rest 21 of the things that we treated with and doses that 22 we treated, there was nothing there, which was

### 202-234-4433 Neal R. Gross & Co., Inc. Page 107 1 surprising to me. 2 DR. SELVAGE: How many hours was that? 3 DR. COOPER: That would be -- yes, 4 let's see, that would be treat 9:00 a.m. and 5 you're looking at an hour before. So, you're 6 looking from three hours, one hour and one hour 7 after lights out -- three hours before lights 8 out, 1600, 1800 and 2000 hours. 9 DR. SELVAGE: Okay. 10 SESSION CHAIR PORTIER: Dr. Delclos, 11 please, use your mic. 12 DR. SELVAGE: I'm sorry, but you don't 13 have it like, at say, eight? You're dosing them 14 at nine, right? 15 DR. COOPER: When we did the proestrus, 16 we did the -- the day of proestrus, we measured 17 every two hours, up to 2000, from nine to 2000, 18 and most of the dramatic changes we saw were the 19 early -- 20 DR. SELVAGE: Right. 21 DR. COOPER: -- ones, because, you 22 know, it's coming up, and one of the things that

### 202-234-4433 Neal R. Gross & Co., Inc. Page 108 1 Susan found in the male was that when you look in 2 the afternoon, if you try to increase cort in the 3 afternoon, that's one of the things she wanted to 4 do, you could get it to go any higher. 5 There's sort of like, a ceiling effect 6 there. She couldn't get it to go up. 7 PARTICIPANT: It was still up then. 8 DR. COOPER: It was still up? Right, 9 yes. 10 SESSION CHAIR PORTIER: Dr. Delclos, I 11 think was next, and then, Dr. Akana. 12 DR. DELCLOS: I just wanted to make 13 sure I understood. Does this mechanism play 14 into the delay of puberty at all? Where you take 15 the DACT having effect on that, but not having 16 effect on the -- it was something that confused 17 me, as I read the document. 18 DR. COOPER: There's two questions 19 there, and the answer is, I don't know, to number

20 one. 21 I mean, boy, you read the pubertal -- 22 and you guys are the experts, and you read the

### 202-234-4433 Neal R. Gross & Co., Inc. Page 109 1 pubertal and adrenal literature, especially 2 earlier stuff, I was really -- it's really hard 3 for me to understand it, because you get this -- 4 when you do things like adrenalectomy and all 5 this kind of stuff, you seem to see the -- you 6 seem to have an impact on the body weight of the 7 animal, that might confound this a little bit. 8 Conceptually, I could make that 9 argument, and there have been some kind of 10 sophisticated explanations, as to how, if you 11 dose with particular things that either inhibit 12 or activate the glucocorticoid receptor, you 13 could impair -- slow down puberty. 14 But the question about DACT, it's a 15 separate question, because I think DACT -- I'm 16 almost confident that it has to eventually impact 17 regulation of the LH surge, and when I say it has 18 to eventually do it, I mean, by dose, and by 19 duration. 20 If you look at the blood levels in the 21 rat, and we have limited data for this, but when 22 we look at it, DACT is present in such high

### 202-234-4433 Neal R. Gross & Co., Inc. Page 110 1 concentrations, even -- no matter what you give 2 them, and then you give them DACT, this equimolar 3 dosing thing is -- it's nothing like what you 4 really see inside the animal, when you measure 5 it. You have very high concentrations of DACT. 6 And that's even if you -- you know, if 7 you dose them with atrazine, the amount of DACT 8 is way up there. 9 So, why in the pubertal assays, you 10 see that, I don't know whether there's another 11 mechanism kicking in or what, but it is -- it is 12 something over there, that you can't dismiss. It 13 doesn't always fit the picture. 14 I guess, if you were really making the 15 argument that the adrenal was involved, you'd 16 want no effects, with DACT, but that's not what - 17 - the way the system was designed, and it bothers 18 -- or it's something that we can't explain at the

19 moment.

20 SESSION CHAIR PORTIER: Dr. Akana? 21 DR. AKANA: Could you repeat that 22 finding in the hypothalamus, in the Modic study?

### 202-234-4433 Neal R. Gross & Co., Inc. Page 111 1 What I'm thinking about is the 2 possibilities of central action of atrazine, and 3 there are aromatases in the hypothalamus and4 there are some nice papers showing very site5 specific brain localizations, like BNST, and a 6 lot of those sites are also very gonadal-steroid 7 sensitive. 8 So, it seems the framework could be 9 there for some central regulation. 10 DR. COOPER: If I understand your 11 question right, do you mean in the adult or the 12 developing animal, first? 13 DR. AKANA: Adult first. 14 DR. COOPER: Okay, Susan, you looked at 15 -- go ahead, do you want to -- 16 SESSION CHAIR PORTIER: Please identify 17 yourself, if you come up. 18 DR. COOPER: This is Dr. Susan Laws,

19 and she's the -- 20 DR. LAWS: Hi, I'm Susan Laws, from 21 EPA. The question you were asking, the Modic 22 study, we were looking at the hypothalamus for

### 202-234-4433 Neal R. Gross & Co., Inc. Page 112 1 message, for aromatase CYP19, and those studies 2 indicated that after they were treated in vivo, 3 there were no differences in the message, and we 4 looked at -- after a single dose multiple time 5 points, we looked after three doses, daily doses, 6 and then at -- I think, that had a couple of time 7 points also, and we were not able to see any 8 differences in that. 9 So, it's -- it's challenging to 10 measure, so it's a no-effect study, is what we

11 have.

12 DR. COOPER: But the reason I asked 13 about the developing animal, of course, is then, 14 that's a whole new ball game or a whole different 15 ball game, because of A) the concentration. 16 Susan tells me they're much greater in the 17 neonate, and so, if maybe there is one 18 opportunity where there may be effects that we 19 haven't looked at, that might be important.

20 DR. AKANA: Also wasn't there also some 21 discussion of a critical period, in development

22 for the aromatase?

### 202-234-4433 Neal R. Gross & Co., Inc. Page 113 1 DR. COOPER: Yes, well, early on, I 2 mean, that was one of the driving forces behind 3 her actually measuring the younger animal, 4 because during development, the aromatase was 5 coming down and we figured if we -- what Stoker 6 found was a reflection of the earlier increased 7 importance of the animal. 8 But we didn't look at the peripubertal 9 or anything that would -- we haven't, yet, looked 10 at the peripubertal -- we haven't looked around 11 birth. That's what I'm trying to say, not 12 puberty, perinatal period. 13 SESSION CHAIR PORTIER: Dr. Williams? 14 DR. WILLIAMS: I just want to switch 15 gears a little bit, to get you to clarify the 16 comments you made several hours ago, regarding 17 the mammary gland tumors. 18 You said with aging, the cycles become 19 irregular, the LH surge doesn't happen and this 20 endocrine milieu in the rat promotes a 21 development of mammary tumors, and then in your 22 summary slide, you said that reproductive aging

### 202-234-4433 Neal R. Gross & Co., Inc. Page 114 1 is driven by the brain in the rat and by the 2 ovary in the human, and therefore, the mammary 3 gland tumor development isn't relevant to humans. 4 I don't really see that connection, 5 though. It seems to me that you should be more 6 concerned about the reproductive endocrine 7 milieu, potentially leading to mammary gland 8 development in humans, whether or not 9 reproductive senescence is an issue as a separate 10 story. Can you clarify that for me? 11 DR. COOPER: Let me repeat the 12 question, because that was a long one. 13 DR. WILLIAMS: Okay. 14 DR. COOPER: I want to make sure I get 15 it right. You're asking me, you said that we 16 looked at the aging animal, but you're talking 17 about mammary gland development, or are you 18 talking about mammary gland tumor development? 19 DR. WILLIAMS: So, this is directly 20 from your own slides, the nine and ten. 21 DR. COOPER: Okay. 22 DR. WILLIAMS: So, basically, you said

### 202-234-4433 Neal R. Gross & Co., Inc. Page 115 1 that you don't get the LH surge, so you don't 2 have regular cycling and you end up getting in 3 the -- in the rat, loss of CNS regulation, and 4 that this endocrine milieu causes development of 5 mammary gland tumors, and then in your summary 6 slide, you said, because reproductive aging is 7 different in humans, then the endocrine milieu 8 isn't really relevant to human mammary 9 development -- mammary -- 10 DR. COOPER: If I said that, I 11 misspoke. The hormonal environment, I think, is 12 important, in both species, I mean, obviously. 13 I think that what happens with normal 14 aging, and the fact that atrazine appears to 15 accelerate that aging process in the rodent, is 16 different than what you would anticipate in the 17 humans, okay. 18 So, in the humans -- I mean, in the 19 rat, what we're doing is, we're driving a faster 20 pace, disruption of regular cycles and earlier 21 onset, and really, I think once that cyclicity is 22 disturbed, the pattern of constant estrus sets

### 202-234-4433 Neal R. Gross & Co., Inc. Page 116 1 the clock for when you're eventually going to get

2 a tumor. 3 How long you expose estradiol, how 4 long you keep your other hormones out of balance, 5 the more likely you're going to see the tumor 6 over time. 7 When I said it wasn't relevant, from 8 the standpoint of these studies to humans is, 9 that humans don't go constant estrus when they 10 stop cycling. They have not -- they have 11 insufficient number of follicles to -- the reason 12 they stop ovulate -- I'm sorry, the reason they 13 stop cycling their menstrual cycle is because 14 they lose the follicles, critical mass there, and 15 there is a few still left in there, like, 200,000 16 or something. 17 DR. WILLIAMS: Right, but as Dr. Horton 18 brought up earlier, in cases where women don't 19 really ovulate, for example, polycystic ovarian 20 syndrome, they actually do have elevated levels 21 of estradiol that are fairly, you know, prevalent 22 throughout the cycle, rather than the nice peak

### 202-234-4433 Neal R. Gross & Co., Inc. Page 117 1 at pre-ovulatory and then lower during the rest 2 of the cycle. 3 And so, it seems like the hormonal 4 milieu may be fairly similar and -- 5 DR. COOPER: Oh, yes, if you want to go 6 -- okay, now, I understand your question better. 7 Yes, especially in light of some of 8 the recent papers in the rodent modeling, trying 9 to develop a model for polycystic ovarian 10 disease, wherein they argue that the induction of 11 constant estrus in the rat is going to produce, 12 not only the endocrine environment, but also, 13 some of the histological changes down within the 14 ovary itself, that are reminiscent of, you know, 15 the persistent follicles that you see. 16 Earlier on, in that literature, people 17 -- and where I did my turnaround was the work 18 that Ojeda has done lately, you may be familiar 19 with -- or not lately, but when he started 20 publishing on it, I began to believe that 21 polycystic ovarian disease may be something that 22 might fit into this picture, with the rodent

### 202-234-4433 Neal R. Gross & Co., Inc. Page 118 1 literature. 2 Now, in that case, I don't -- I would 3 agree, that that's an important consideration. 4 How that plays into the whole atrazine thing, I'm 5 not sure of, because it's different. 6 I mean, those studies would probably - 7 - those studies with the persistent estrous 8 animal are done in a young adult female, and I'm 9 not familiar, if there are any where they started 10 to look at that kind of homology, if you will, 11 between what you see in the aging female rat and 12 what you see in someone with PCOS. 13 But, yes, now I understand your 14 question and I'm in agreement with you. 15 SESSION CHAIR PORTIER: Dr. O'Byrne. 16 DR. O'BYRNE: Point of clarification. 17 You said that you've tried blocking the LH surge 18 with atrazine, in an acute fashion, and failed 19 miserably. With other compounds, it works. 20 DR. COOPER: Right. 21 DR. O'BYRNE: To block the surge. 22 DR. COOPER: Yes, we've done a number

### 202-234-4433 Neal R. Gross & Co., Inc. Page 119 1 of studies using things like dithiocarbamates, 2 which -- or and other fungicides that works to 3 specifically disrupt neuroadrenergic 4 transmission, and usually, we give them, 5 somewhere during the critical period, usually 6 about 15 minutes prior, in our -- between two and 7 four o'clock in the afternoon, and very rapidly, 8 you see the decrease in neuroendocrine and then 9 the decrease in pulses. 10 DR. O'BYRNE: Okay, so, you know the 11 mechanism action is quite clear?

12 DR. COOPER: Yes. 13 DR. O'BYRNE: Just another point, if I 14 may. I'm sure we're desperate for some break and

15 some tea or coffee. 16 Your pulsatile data, I don't know 17 whether it was yours or somebody else's, but 18 averaging pulsatile data and then trying to 19 describe it as pulses, is -- it's very difficult 20 to appreciate. 21 DR. COOPER: Well, yes. 22 DR. O'BYRNE: But you said you had the

### 202-234-4433 Neal R. Gross & Co., Inc. Page 120 1 individual data and you put it through the pulsar 2 program, and the 50 milligrams, which is a 3 whooping great dose, had no effect. Is that -- 4 DR. COOPER: In the mean, right. 5 DR. O'BYRNE: No, no, no, in the 6 individuals, and I don't know how many animals

7 were -- 8 DR. COOPER: Yes, this model -- 9 DR. O'BYRNE: Do you have access to

10 that?

11 DR. COOPER: Do we have access to the

12 data?

13 DR. O'BYRNE: I have not seen those 14 individual profiles. I'm just curious, as to 15 whether there was a suppression of frequency, 16 which you can't read from this average data. 17 DR. COOPER: Right, boy, that was 1997. 18 When we did DMDC, we did the -- these are 28-day 19 females, you put the catheter in, beautiful 20 pulses, okay, and what you see, in the individual 21 animal -- and the question that you're asking is, 22 you inject them with the dithiocarbamate. It's

### 202-234-4433 Neal R. Gross & Co., Inc. Page 121 1 pulse, pulse, boom, okay, like, some data I've 2 seen, other people have pub, and it's immediate, 3 you know. 4 You know, and then they'll hang down 5 there for three or four hours until it clears and 6 then, you can see the pulses resume. 7 For Dr. Tyrey's data, for the 50 -- I 8 know -- I can tell you, what it looked like for 9 the 200, okay, pulse, pulse, flat, all right, and 10 then D-flat, and then you'd see an occasional 11 burst-through with the different -- now, an 12 individual animal, you would see this gigantic 13 pulse, like the GnRH hormones have to dump, that 14 kind of thing. 15 But the 50, I think with the 16 individual animals, you'd see a broader -- the 17 broader pulses. So, it's a slowing frequency, 18 but the amplitude was not down all that much. 19 They're still doing okay, and boy, that was an 20 old memory trace that, to pull back. 21 SESSION CHAIR PORTIER: I think at this 22 point, we are going to take a break. Dr. Young?

### 202-234-4433 Neal R. Gross & Co., Inc. Page 122 1 (Off the record comments.) 2 DR. YOUNG: So, I've been kind of 3 looking at this, you have to understand, I'm a 4 statistician, so, that's going to be my kind of 5 question. 6 So, do you do analysis for each time 7 period or do you synthesize and to one large 8 analysis? 9 DR. COOPER: For which study?

10 DR. YOUNG: Well --

11 DR. COOPER: For the -- 12 DR. YOUNG: -- pretty much, all of 13 these? So, for example -- 14 DR. COOPER: When we do this -- 15 DR. YOUNG: -- the ones on page 20 -- 16 on slide 26, the ones on slide 23? 17 DR. COOPER: Twenty-six and 23, boy, 18 Stoker, I hope these are your data. 19 SESSION CHAIR PORTIER: So, you're 20 talking about coming up at the little stars on 21 the top? 22 DR. YOUNG: Yes, how do you get that

### 202-234-4433 Neal R. Gross & Co., Inc. Page 123 1 star? 2 SESSION CHAIR PORTIER: How do you get

3 those stars? 4 DR. YOUNG: Yes, you're right. 5 (Off the record comments.) 6 DR. YOUNG: I saw, on one of your -- 7 well, on -- I couldn't find the Tyrey paper, if 8 that's the way you --

9 DR. COOPER: That's an abstract. 10 DR. YOUNG: Okay, I saw the abstract, 11 but where I -- no, I couldn't -- no, I didn't see

12 that. 13 DR. COOPER: We have it in the 2007,

14 but I don't -- 15 DR. YOUNG: Okay, I couldn't -- one, I 16 couldn't find the 1997 one. 17 DR. COOPER: Yes, please don't take me 18 to task on the pulsar, because -- 19 DR. YOUNG: No, no, I'm just --

20 DR. COOPER: -- we can -- 21 DR. YOUNG: I'm just trying to figure 22 this out.

### 202-234-4433 Neal R. Gross & Co., Inc. Page 124 1 DR. COOPER: Right, but here is 25, is 2 that what you want? 3 DR. YOUNG: No, no. 4 DR. COOPER: Oh, the LH surge? 5 DR. YOUNG: Something like that. 6 DR. COOPER: Right, these are -- who 7 did this? 8 DR. YOUNG: So, did you do one at each 9 time point, or did you do one analysis for the 10 whole graph? 11 DR. COOPER: The whole graph. 12 DR. YOUNG: Because sometimes -- in the 13 captions, it talks about by time point. So, my 14 assumption was, analysis was by time point and -- 15 but I'm not sure that's right. 16 DR. HOLLADAY: I think that is, for 17 this. 18 DR. YOUNG: This is the time point -- 19 DR. COOPER: She did the analysis, let 20 her speak. 21 (Off the record comments.) 22 SESSION CHAIR PORTIER: Can I suggest

### 202-234-4433 Neal R. Gross & Co., Inc. Page 125 1 that we hold this and that you guys talk about it 2 at the break, and then we'll come back with that 3 question? 4 DR. YOUNG: Excellent suggestion. 5 Thank you very much. 6 SESSION CHAIR PORTIER: I know it's a 7 large group of people, and a 15 minute break is 8 very difficult, but my watch says 3:15 p.m. So, 9 we'll be back at 3:30 p.m., on the dot. Thank 10 you. 11 (Whereupon, the above-entitled matter 12 went off the record at 3:15 p.m. and resumed at 13 3:33 p.m.) 14 SESSION CHAIR PORTIER: I was ready to 15 get started, but Dr. Cooper wasn't here, so, I

16 can't. 17 So, we're going to continue on and see 18 if first, EPA can answer Dr. Young's question 19 about analysis, and then, I think Dr. Williams 20 wanted to come back to her question, to see if we 21 can get that clarified. 22 DR. YOUNG: All right, I --

### 202-234-4433 Neal R. Gross & Co., Inc. Page 126 1 SESSION CHAIR PORTIER: I remind the 2 Panel, this is our time to get clarification on 3 the presentations and the material on the white 4 paper. 5 So, it's not quite right on the 6 slides, but you've got something in the white 7 paper you can point to, we can go with that, as 8 well. So, Dr. Young? 9 DR. YOUNG: I think I got clarification 10 in the break. Some of the more recent papers do 11 look at the whole study, some of the older 12 papers, even though an effort has been made to 13 look for proper analysis, do do time-by-time 14 analysis, and some, we don't have the data to 15 even know one way or the other. 16 In addition, I think there was a 17 slight misspeaking, in that, one study in which 18 we talked about a rat, after one dose, in the 19 same rat, four doses later, those were actually 20 different rats. So -- 21 DR. COOPER: They had to be different 22 rats. They were killing them.

### 202-234-4433 Neal R. Gross & Co., Inc. Page 127 1 But the one other thing that's 2 important is that these data aren't transformed, 3 and usually, when they do hormone data, they do 4 the transformation and so, it's my estimation 5 that these are really conservative evaluations, 6 and I may be wrong in that approach, that if we 7 didn't do the transformations because of the 8 transformations, the amount of variance that you 9 see, may change. Susan has just re-did a data 10 set, doing that. 11 DR. LAWS: My data was -- 12 SESSION CHAIR PORTIER: Identify 13 yourself. 14 DR. LAWS: Susan Laws, U.S. EPA. My15 data that you see the -- the ACTH and the CORT16 data, those that had the different time points, 17 they were first analyzed with analysis of 18 variants in -- for time and time of dose 19 interactions. 20 But however, there is heterogeneity of 21 variance in those data. So, those data, we 22 actually used a non -- rather than transform

### 202-234-4433 Neal R. Gross & Co., Inc. Page 128 1 them, do a live transformation, which is usually 2 done with hormone data, or can be done with 3 hormone data, we used a non-parametric test for 4 those and we did do those by time, each time it 5 was done, in between. 6 And so, it was the analysis of the 7 variants and then, there was a post hoc test for 8 those stars, that you see. 9 Recently, we've transformed some data 10 -- used a live transformation, and actually, it 11 looks like they -- we have lower doses that are 12 significant, not in this data set, but another

13 data set. 14 So, I think the non-parametric test 15 that we used for that report was fairly 16 conservative, when it looked at differences 17 between groups. 18 SESSION CHAIR PORTIER: Dr. Williams? 19 DR. WILLIAMS: Just to try to clarify, 20 the mammary gland tumor development in women 21 versus rats, and the mechanism of action you were 22 talking about, can you clarify, maybe not what's

### 202-234-4433 Neal R. Gross & Co., Inc. Page 129 1 on your slide, but what is in the white paper, in 2 terms of causing -- causative concerns regarding 3 atrazine, LH surge lag, the endocrine milieu and 4 mammary gland tumor developments? 5 DR. COOPER: You mean, the -- 6 essentially, the strain difference? You mean, 7 essentially, the strain difference, if you will, 8 in humans versus rats? 9 DR. WILLIAMS: Why is it that you don't 10 believe that the LH and endocrine milieu changes 11 wouldn't be relevant to human mammary development

12 tumor -- 13 DR. COOPER: No, no, no, that's -- if 14 I'm giving you that impression -- 15 DR. WILLIAMS: That's why I wanted to 16 clarify it. 17 DR. COOPER: That's not true, okay, 18 that's not what we're implying, or I'm implying, 19 is that the -- that environment that you see in 20 the rat, is what's conducive for the growth of 21 tumors, hyperplasia and then eventually, the

22 tumors.

### 202-234-4433 Neal R. Gross & Co., Inc. Page 130 1 The human doesn't get to that 2 condition, is what we're saying that, during 3 aging in the human, what you see is a depletion 4 of the follicles, and therefore, that you don't 5 develop the high levels of estrogen when they go 6 through menopause. Menopause is a period of low 7 estradiol, or estrogen. 8 DR. WILLIAMS: So, then potentially, 9 the mechanism of action would be relevant to a 10 non-menopausal human, though? 11 DR. COOPER: If you can -- yes, that 12 was a question that came up during the break. I 13 would assume that if you could get a constant 14 estrous human, a polyfollicular human maybe, I'm 15 not familiar with one, a model like that, but if 16 it's the case, then I don't know why that 17 wouldn't be the same endocrine environment, yes. 18 So, yes, I apologize if I mislead you. 19 I'm not -- it's -- that hormonal environment is 20 the consequence of differential patterns of 21 aging, rat versus human, and that's why the 22 argument that the relevance that we see for that

### 202-234-4433 Neal R. Gross & Co., Inc. Page 131 1 particular outcome, in the rat, it doesn't appear 2 to apply to humans. 3 And so, there is a -- it's sort of 4 like, you know, I guess we make assumptions and 5 this was our -- that argument was what we tried 6 to make clear, the last meeting, and I -- rushing 7 through that, sometimes, you don't get the -- all 8 the little key events, like that. They don't 9 come out right. 10 But your question is on target from 11 the comment that, if you create this environment, 12 rat or human or even -- you know, no matter what 13 the strain -- I know there's a mouse strain. 14 They say that atrazine doesn't induce mammary 15 gland tumors in mouse, but there is a mouse 16 strain that they used in aging, that was -- 17 showed similar patterns of pituitary and mammary 18 gland development in the female, when she grows

19 older. 20 They showed it as a consequence of 21 altered ovarian cycles and perhaps, if that 22 strain is -- you should see the -- if that was

### 202-234-4433 Neal R. Gross & Co., Inc. Page 132 1 what you see, then you brought about the same 2 premature reproductive aging as the experimental 3 -- the studies show in that mouse strain, that 4 you would see the same thing. 5 It's how you get there, or can you get 6 there, in a human.

7 SESSION CHAIR PORTIER: Dr. Fenner8 Crisp? 9 DR. FENNER-CRISP: Ralph, back in the 10 stone age, when we were working on the mammary 11 tumor MOA, this -- one could only say that 12 atrazine had some effect, not otherwise defined, 13 with respect to direct or indirect. The work 14 hadn't been done to sort anything out, 15 specifically, yet, adequately. 16 Now, with this new body of data, 17 describing the disturbances in the HPA axis, the 18 inferences, although you haven't stated it 19 explicitly yet, that -- that may have to proceed 20 the disturbance in the HPG axis for the mammary 21 tumors, which would be indirect. 22 What evidence exists for or against

### 202-234-4433 Neal R. Gross & Co., Inc. Page 133 1 the -- a direct pathway being at play, and what 2 could you do or have you done, to separate the 3 two, to show whether or not there's still an 4 opportunity for direct effects?

5 DR. COOPER: For the tumors outcome? 6 There is a study that the registrant did, I 7 think, that might speak to it, is that if the 8 adrenal gland was actually driving the 9 development of the tumors, independent of altered 10 gonadal function, then you would see it, if you 11 removed the gonads and dosed with atrazine for an 12 extended period of time, removed the ovaries, in 13 this case, and didn't they submit that study? 14 (Off the record comments.)

15 DR. COOPER: That would -- 16 DR. FENNER-CRISP: Maybe that would -- 17 DR. COOPER: That's the statistician -- 18 DR. FENNER-CRISP: Maybe then the 19 registrar could speak to my question, tomorrow. 20 DR. COOPER: I thought that that study 21 was done. I guess, I misspoke. 22 DR. FENNER-CRISP: Okay.

### 202-234-4433 Neal R. Gross & Co., Inc. Page 134 1 SESSION CHAIR PORTIER: I think there 2 was a hand in the audience, indicating that 3 tomorrow, probably the registrant will speak to 4 that, if we can -- 5 I think at this point, we've kind of 6 picked through this part and we're ready to move 7 on to the discussion of the immunotoxicity. Dr.

8 Luebke?

9 DR. LAWS: Go back to the -- whatever 10 it's called, the hard drive. Go back to the hard 11 drive. Thank you. 12 DR. LUEBKE: Okay, so I'm going to talk 13 about some atrazine immunotox studies and 14 basically, just summarize some of the work that 15 has been done. I will not be going into the 16 level of detail that Ralph did. 17 And because this is the first time 18 through for immunotox, for the SAP Panel, I know 19 that we have a couple of experts here, but for 20 the rest of you, I thought it would be a good 21 idea, just to cover just a couple of very general 22 topics first.

### 202-234-4433 Neal R. Gross & Co., Inc. Page 135 1 So, immunotox is essentially 2 unintended modulation of the immune system, and 3 this can take the form of suppression or 4 enhancement of certain functions that the cells 5 do, and that the body does, and this can result 6 in an increase in allergy, it can increase the 7 risk of hyper-sensitivity, or autoimmune disease, 8 and in very general terms, these mode of actions 9 includes things like an altered supply in the 10 cells, that would be coming in to perform these 11 different duties. 12 There could be altered maturation of 13 the cell types. There could be a difference in 14 how the cells function or in the case of 15 autoimmune disease, which we see up there, this16 could be a failure just to control auto17 reactivity by some fairly sophisticated 18 processes. 19 And the proximal cause of 20 immunotoxicity can either be direct, so there are 21 effects right directly on the immune system cells 22 themselves or on their supporting tissues, or

### 202-234-4433 Neal R. Gross & Co., Inc. Page 136 1 they could be indirect, where there are effects 2 that might perturb some other system and the 3 fall-out from that perturbation would actually 4 change how the immune cell functions. 5 So, host factors, as we have been 6 talking about for the last little while here, can 7 also have a dramatic effect. 8 So, up here at the top, you see that 9 during -- well, that doesn't work, okay. During 10 development and maturation of the immune system, 11 it seems to be one of the more critical times for 12 adverse effects on the immune system. 13 During this maintenance phase, when 14 everyone is young and healthy, we can still get 15 effects, and do, and we see those in adult 16 immunotoxicity studies. 17 Gender and genotype can also have a 18 big effect. Females tend to make a more robust 19 response than males do, immunologically, and 20 genotype controls a wide array of things. 21 So, the wide array of what constitutes 22 normal function in an individual, normal function

### 202-234-4433 Neal R. Gross & Co., Inc. Page 137 1 across a broad scale of the population, and it 2 also, as we've heard for effects on endocrine 3 disruption, with Ralph, it can also control how 4 an animal responds to exposure to an 5 immunotoxicant. 6 So, mice exposed to very small amounts 7 of dioxin get immunosuppression and doses many, 8 many times, 30 times that high, don't have much

9 of an effect on rats. 10 So, why would we do immunotox hazard 11 IV studies? Sometimes, there is some clues from 12 general tox studies, and these can be things like 13 a change in organ weight, input organ weights 14 with the cellularity. These tend to be sort of 15 observational snapshots captured at one in time 16 and it tells you sort of like, what the immune 17 system was like, right then. 18 There may be a known or suspected mode 19 of action. So, if -- we know that the compound 20 alters protein-synthesis or cell division or 21 alters neuroendocrine effects, that may be a clue 22 that we need to look for immunotoxicity.

### 202-234-4433 Neal R. Gross & Co., Inc. Page 138 1 In some cases, testing is actually 2 mandated for certain types of compounds, and they 3 may be planned, like the NTP would look for 4 effects, and these are generally functional 5 effects that people are going to be looking for. 6 So, in those assays, you'll have some 7 of those -- these observational snapshots, but 8 what you might not have are these functional 9 assays and what you will not have in the general 10 tox studies. 11 So, in these functional studies, we 12 ask the immune system to do something. So, it's 13 generally challenged with an antigen, and then we 14 measure the response to that. 15 So, the critical mode of action for 16 evaluation of the immunotoxicity of atrazine was 17 obviously, endocrine function. 18 We know that there are a variety of 19 industrial compounds and pesticides and other 20 compounds that are endocrine-active compounds, 21 and they also have an effect on the immune 22 system.

### 202-234-4433 Neal R. Gross & Co., Inc. Page 139 1 So, this first study that I'm going to 2 talk about was done in my laboratory, at EPA in 3 Research Triangle Park, and it was done by a 4 postdoctoral student, Andrew Rooney, when he came 5 through my lab. 6 He came out of Lou Gillette's lab at 7 University of Florida, where he had studied the 8 Lake Apopka alligators. So, he was very 9 interested in endocrine disfunction and he had 10 measured some endpoints in the immune system, as 11 well, and this seemed like a perfect project for 12 him. 13 So, he picked a dose of atrazine that 14 would be just above what Susan Laws had reported 15 for changes in the onset of puberty in female 16 pups, and for a reduction in the NOEL of 17 prolactin, in Tammy Stoker's studies. 18 Rather than including a dose response 19 here, we included a couple of pharmacological 20 agents, because we wanted to see if we could 21 produce the same effects by altering prolactin 22 production and we chose our dose there, to be the

### 202-234-4433 Neal R. Gross & Co., Inc. Page 140 1 LOEL for prostitis, and we also included PTU, 2 propylthiouracil, to see if there was -- if we 3 could do this by altering thyroid hormone 4 production. 5 So, after the moms gave birth, we took 6 the pups away. We segregated them out by gender 7 and dose and then we re-distributed five males 8 and five females to all the -- all the dams. We 9 didn't make any attempt to return animals to 10 their biological mom or to not return them, and 11 we also got weights on the animals, at that day. 12 Then on day 14, we took one pup from 13 each gender and we got thyroid hormone -- we got 14 thyroid hormone levels on those animals and we 15 also took a spleen and a thymus weight at that 16 day, to see if anything had happened to those 17 immune systems organs. 18 Then, once the animals became 19 immunologically mature, we asked their immune 20 system to do something by immunizing them to have 21 them make antibodies or to make a cell mediated 22 immune response.

### 202-234-4433 Neal R. Gross & Co., Inc. Page 141 1 We also looked at the ability of cells 2 to produce phagocytosis, which can be the first 3 step in resistance to certain sorts of 4 infections, and we also evaluated natural killer 5 cell activity, which is something done by 6 specialized lymphocytes that kills tumor cells. 7 And we did these -- the assays -- the 8 functional assays at a couple of time points, to 9 see if the effects were persistent, and if you 10 look at these data here, you can see that there 11 was a real increase in the percent mortality. 12 So, two-thirds of the atrazine litters 13 actually lost pups, and the numbers of litters 14 that actually lost pups was also increased for 15 bromocryptine. This didn't happen for PTU. 16 As Ralph mentioned earlier, we know 17 that changes in prolactin levels will alter 18 maternal behavior and we think, but don't know 19 for a fact, that the reason that we had this 20 increased mortality in the atrazine pups was for 21 the same reason we did in the bromocryptine pups, 22 because maternal behavior had been altered, and

### 202-234-4433 Neal R. Gross & Co., Inc. Page 142 1 they just weren't as good a mom. 2 We looked at the pup weights, to see 3 how well they did during development, just as 4 sort of a general measurement of pup health, and 5 as you can see, we didn't really have any effects 6 at all of atrazine in these animals at PND2. 7 We did pick up what was a 8 statistically significant effect in the males, on 9 PND7, but if you also look at the n value there, 10 you can see that we had a lot of pups who -- this 11 was a very large study and because of this, the 12 one gram difference between the controls and the 13 atrazine pups showed up as being statistically 14 significant. 15 So, the bromocryptine and PTU had some 16 effects as well, particularly on PND7. 17 Now, this one, I know is sort of busy. 18 I'm going to try and show you here. These are 19 body weights, going across here at the top, and 20 you can see, there was no effect on PND14, in the 21 body weights of the offspring, in the atrazine 22 group, although the bromocryptine and the PTU

### 202-234-4433 Neal R. Gross & Co., Inc. Page 143 1 animals were still suppressed. 2 We also looked at the spleen to body 3 weight ratio, sort of a somatic index, and spleen 4 weights were not affected, nor were thymus 5 weights affected in the atrazine-exposed animals. 6 They were, in the thymus -- I mean, in 7 the PTU and the bromocryptine groups as well, but 8 those were transient effects and PND62, they had

9 all recovered. 10 So, this was a functional assay, where 11 we immunized a large group of mice and then, we 12 bleed them and we measured antibody titers, and 13 what we found was there was actually a 14 suppression in the male mice, but not in the 15 female mice that were exposed to atrazine, and 16 these effects were not re-capitulated by 17 bromocryptine or PTU, and then a sub-group of 18 those animals was given another dose a week -- 19 two weeks later, of the same antigen, and we 20 measured the IgG response and in this case, there

21 was on effect on males or females. 22 We did a cell mediated immune assay,

### 202-234-4433 Neal R. Gross & Co., Inc. Page 144 1 where we had the animals respond to the swelling 2 response to an antigen and what we found again 3 here, was this sexually dimorphic effect, where 4 there was suppression in the males, but not in

5 the females. 6 This occurred at nine weeks, and I 7 should mention here, on the antibody response, we 8 looked again at six months and the effects that 9 we saw on the primary antibody response were no 10 longer apparent at six months, just at the -- at 11 eight weeks of age. 12 So, here, we see that there was 13 suppression of cell mediated immune responses at 14 nine and 12 weeks. This did not persist out to 15 six months. 16 So, in both of these cases, where IgM 17 was suppressed and cell mediated immune function 18 was suppressed, although it recovered, there was 19 a time period there where the suppression could 20 have rendered the animals more susceptible to 21 certain sorts of infections, and these include 22 viral infections and certain types of bacterial

### 202-234-4433 Neal R. Gross & Co., Inc. Page 145 1 infections. 2 There were also a number of negative

3 effects that we had here. There was no effect on 4 maternal weight gain, so, these effects, we don't 5 think, were due to any sort of overt toxicity on

6 mom. 7 There was on effect on phagocytic 8 activity of these phagocytes at all. These 9 phagocytes also do other things, like 10 participating in antibody responses. So, we 11 don't know whether they were responsible at all 12 for suppressed antibody responses, but their 13 phagocytic activity was not affected. 14 Natural killer cell activity was not 15 affected and at least, you think these things 16 might be refractory to any sort of developmental 17 effects. Diethylstilbestrol given to neonatal 18 female mice will suppress natural killer cell 19 activity almost for life, in these animals. So, 20 it is possible for an endocrine disrupting 21 compound to change that. 22 We didn't see any effect on the

### 202-234-4433 Neal R. Gross & Co., Inc. Page 146 1 relative or absolute spleen and thymus weights, 2 which suggests that there wasn't any sort of 3 effect on the supply of cells that these animals 4 had to work with, but clearly, somehow, their 5 function had been altered, and we didn't seem to 6 reproduce effects whatsoever, by using these 7 pharmacological inhibitors. 8 So, this made us think that low levels 9 of prolactin and low levels of thyroid hormone 10 were not really to blame for the effects that we 11 saw in the immune response, and so, since Andy 12 had a background in endocrine disruption, he came 13 up with the idea, before he talked to Ralph 14 Cooper, that the GnRH may have something to do 15 with this. 16 We know from a variety of different 17 subjects, different studies, that this is 18 sexually dimorphic, GnRH expression and the 19 protein and the receptor expression are set early 20 in development. They're sexually dimorphic. 21 Antagonists that are given to primates 22 actually do suppress cell mediated and humoral

### 202-234-4433 Neal R. Gross & Co., Inc. Page 147 1 immunity in the males, but not in the females. 2 The agonists, ironically, up-regulate effects on 3 cell populations, not on function, but on cell 4 populations in the female offspring, and we know 5 that once this receptor is bound by its agonist 6 on the lymphocytes, this leads to increased 7 antibody production and it leads to increased 8 cytokine production. 9 So, now, for the caveat, we did all -- 10 we did those studies that I just described twice. 11 Each time we did them, the data came out pretty 12 much the same. Then, we moved about half a mile 13 down the road, to a new facility, and because we 14 didn't have a dose response, we went back to 15 generated dose response, which we were unable to

16 do. 17 We did the study three or four times. 18 The same people were involved, that did the 19 studies both times. We had used different lots 20 of atrazine in the first study, and it didn't 21 have any effect. So, I don't think that could 22 have any -- you know, out -- bearing on the

### 202-234-4433 Neal R. Gross & Co., Inc. Page 148 1 outcome. 2 We did monitoring for parasites, the 3 normal sentinel animal stuff in both facilities. 4 There was no difference in infections. 5 I have a whole lot of confidence in 6 both data sets, because of the things that I've 7 just told you about. What I don't know is what 8 this unknown environmental factor is, that in one 9 case, the animals were suppressed, but in another 10 case, at the same dose, they were not. 11 It could be something, just sort of an 12 additive thing, with cage movement or something 13 like that, some change in the way they were cared 14 for, but we have not been able to figure out what

15 that was. 16 So, there was another developmental 17 immunotox study done. This time, it was done in 18 mice and these mice were done for again, going

19 back to these host factors that we talked about 20 earlier, to see if there were differences in 21 genotype. 22 The exposure here was quite a bit

### 202-234-4433 Neal R. Gross & Co., Inc. Page 149 1 different because they used a little implant that 2 constantly delivered a trickling dose of 3 atrazine, the same amount within a 24 hour 4 period, and so, when they started dosing, they 5 were at about our same level. They chose these 6 doses, based on the studies that we had done. 7 But this had gone down to about 23 8 milligrams per kilogram per day, at the time that 9 the animals were born, and then, they weaned the 10 animals a little bit later than we did, at 28 11 days and then they assayed them, once they were

12 mature. 13 They also found sexually dimorphic 14 effects here, but what they found was that 15 humoral immunity, the antibody response, was 16 actually increased in the mice, where we had seen 17 suppression, and it didn't matter how you -- how 18 they expressed the data, whether they 19 standardized it to the number of cells in the 20 spleen or the number of cells in the spleen that 21 were precursors to the antibody-forming cells. 22 They also found that there was an

### 202-234-4433 Neal R. Gross & Co., Inc. Page 150 1 effect on cell mediated immunity. They used 2 different assays than what we did. The one on 3 the left actually has -- causes cells to 4 proliferate in response to foreign antigens. The5 one on the right, specifically armed cytotoxic T6 cells kill target cells. 7 But just as was the case with the 8 humoral immunity, what they found was increased 9 reactivity in the mice. 10 And so, we talked about suppression in 11 our animals, leading to a greater risk of 12 infection. There are a lot of animal models out 13 there that are shown. Compounds that cause this 14 unwanted increase in immune reactivity can also 15 make auto-immune disease worse or can lead to 16 hyper-sensitivity and allergic effects in 17 susceptible individuals. 18 They found the same sort of negative 19 effects that we did. So, mom wasn't really 20 affected in her weight gain, pregnancy rate, 21 litter rate, things like that, were not really 22 affected. There was no effect on offspring

### 202-234-4433 Neal R. Gross & Co., Inc. Page 151 1 weight gain, when they looked at it, at a single 2 time period, so, the pups weren't particularly 3 sick or anything like that, and because they 4 didn't find any effects on the spleen weight, or 5 they looked at the distribution of lymphocytes 6 from within the spleen, for various types of 7 cells. They didn't see any effects there, which 8 would suggest that the supply of cells was not 9 altered, but once again, the function of the 10 cells was clearly altered because of what the

11 outcome was. 12 So, what might have caused all of 13 this? Well, we heard a great deal, a few minutes 14 ago, about how much of a dose and for how long a 15 dose, and what effects that might have on the

16 outcome. 17 Rowe et al. put their doses sub-Q, and 18 so, that means that not the same proportion of 19 parent and metabolite is going to be produced in 20 those animals. 21 But also, from the work that was done 22 by Ralph Cooper and Tammy Stoker, it looks like

### 202-234-4433 Neal R. Gross & Co., Inc. Page 152 1 we might be looking at some sort of a qualitative 2 -- I mean, quantitative effect there, by the 3 amount of atrazine that was given, metabolite 4 that actually reached the brain, but not a 5 qualitative one. 6 So, that doesn't seem to explain the 7 difference. The functional assessment end points 8 were well recognized, and I think that they were 9 really measuring the same thing that we were. 10 So, it comes down to species, 11 differences in mouse strains, and we've already 12 talked about how we can have very different 13 effects, depending on what's the species of 14 exposure. 15 The mice that they used were sort of 16 prone to make antibody and allergic responses, 17 but that might explain some of the effects that 18 they saw, but not all of them, because both cell 19 mediated and humoral immunity were up-regulated 20 in those. 21 So, then the question is, are those 22 results really in conflict? What are these

### 202-234-4433 Neal R. Gross & Co., Inc. Page 153 1 results telling us? 2 Well, we know that the effects on -- 3 of gender were constant and the supply of cells 4 seems to be pretty constant. It's genotype 5 that's sort of, out of phase, and we can't really 6 explain this. 7 However, we've realized, in the 8 immunotox community, in the last maybe five to 10 9 years, that the thing that we really need to 10 think about is immunomodulation and not really 11 worry about whether we've suppressed the response 12 or whether we've enhanced the response or whether 13 it's allergy or what have you, we've caused 14 something to happen that we didn't intend to 15 happen, and so, immunomodulation is the thing

16 that we tend to focus on. 17 So, those were sort of full gestation 18 studies. There was one study that looked at just 19 the late part of development. This was a study 20 that was done in C57 black 6 mice, and you can

21 see the doses that were used there. 22 They exposed these mice, starting at

### 202-234-4433 Neal R. Gross & Co., Inc. Page 154 1 four weeks of age, and these animals become 2 immunologically mature around seven or eight 3 weeks of age. So, what they did was expose the 4 animals, just for this last period of the immune 5 system development. 6 But rather than spend a lot of time on 7 the details of the study, we can summarize it by 8 saying that most of the effects that they saw, 9 particularly at the lower doses, say, 25 and 10 five, were sort of ephemeral and they were gone 11 by a day. 12 Even at the higher doses, most of the 13 effects had resolved by seven days, and all of 14 the data that they used -- unfortunately, all of 15 the data that they collected here were 16 observational endpoints, and that can give you 17 some really important information, if you know 18 that there is a defect, and it will help you 19 maybe choose what path to go down, to figure out 20 what the defect is. 21 But all we know right now is that 22 something happened in these animals and they

### 202-234-4433 Neal R. Gross & Co., Inc. Page 155 1 recovered fairly quickly.

2 There have been a number of adult 3 exposure studies here, and probably the most 4 complete one that has been done to date was one 5 that was contracted by the National Toxicology 6 Program, and was carried out by a contractor up 7 at Medical College of Virginia, and they looked 8 at a whole bunch of these different functional 9 endpoints and observational endpoints, and they 10 found very few effects in these animals at the 11 lower dose group. 12 The one thing that is sort of 13 interesting is that second bullet point there, 14 where they found a 35 percent increase in 15 antibody production, at 25 milligrams per 16 kilogram, but it was perfectly flat across the 17 rest of the spectrum, and so, I'm not really sure 18 what that might mean. 19 They challenged the animals with tumor 20 cells. They found that at the top two doses that 21 -- the resistance to this tumor cell challenge 22 was decreased in these animals, but when you go

### 202-234-4433 Neal R. Gross & Co., Inc. Page 156 1 back -- they also went back and looked at the 2 primary effector cells in these animals, and 3 those cells weren't really suppressed. 4 And so, I'm not exactly sure how to 5 interpret those data either, but they were -- 6 they occurred at some pretty large doses. 7 And they also had a lot, as I 8 mentioned, these observational endpoints -- and 9 none of those things really pointed to any sort 10 of a clear picture of immunotoxicity. 11 They did look for antibody -- changes 12 in antibody production, using the same assay that 13 we did, and didn't find anything. They 14 challenged the animals with bacteria that would - 15 - that live inside cells and take a response of 16 their adaptive immune response T-cells to get 17 over it. They didn't really see anything there. 18 And so, we don't really have any clear 19 picture in the NTP study, even at doses up to 500 20 milligrams per kilogram. 21 There was another study that was done 22 in C57 black 6 mice and here, they based their

### 202-234-4433 Neal R. Gross & Co., Inc. Page 157 1 doses on percentages of the LD50, and you can see 2 that the -- on the second line, the next to the 3 highest dose, that should be 433, not 4,300. I 4 think those animals would have been dead, without 5 any questions, if you could have gotten that much 6 into them. 7 So, there was really no effect on body 8 weights in these animals. They had sort of a 9 mixed bag, and I don't mean to be insulting, when 10 I say a mixed bag of changes, but that's 11 essentially what it was. There was no clear 12 arrow pointing and even suggesting even one 13 direction. 14 They didn't seem to have any effects 15 whatsoever on the supply of cells, because they 16 did the same sort of thing where they looked at 17 spleen cellularity and the distribution of these 18 cells, and there was no effect on the phagocytic 19 activity of the animals. 20 They also took spleen cells out of 21 these guys at different time points, and they 22 immunized these spleens in vitro and then they

### 202-234-4433 Neal R. Gross & Co., Inc. Page 158 1 looked at the number of antibody producing cells 2 that resulted from that, and it was sort of 3 interesting there, at their lowest dose, at 25 4 milligrams per kilogram, they were initially 5 suppressed and then, as they were allowed to 6 recover out over time, over a period of about 7 three weeks, that lowest dose came back to about

8 control levels. 9 But at other doses, you didn't see 10 that picture at all. The very highest dose 11 jumped right back up to control levels at 14 days 12 and then sort of dove back down to being 13 suppressed and then went back up to being 14 enhanced by 21 days, and the doses that came in 15 between there were also somewhat mixed, like 16 that, and again, I'm not really sure what to make 17 of these studies, other than, most of the effects 18 that they saw tended to be at the higher doses, 19 with these effects on the antibody response, that 20 I just don't understand. 21 Then, there were a number of really 22 excellent studies that were done by Steve Pruett

### 202-234-4433 Neal R. Gross & Co., Inc. Page 159 1 and his co-workers, and they chose large doses of 2 atrazine and large doses of ethanol, and large 3 doses of some other compounds that they knew 4 would induce a stress response, that they knew 5 would really increase corticosteroid production, 6 and their goal here was not really to do a hazard 7 ID study for whether or not atrazine is toxic to 8 the immune system or not, but rather, to see 9 whether they could use this rate of production of 10 corticosterone over time, as a predictor for how 11 they would affect a variety of endpoints, 12 including antibody production and things like

13 that. 14 I happen to see that Steve Pruett is 15 here at the meeting and I -- he may be talking 16 about some of this tomorrow. He may not be, I'm 17 not really sure. But these studies -- we know 18 that at these levels, that corticosterone levels 19 will definitely be up. 20 The interesting thing about one of 21 Steve's studies was that he never did habituate 22 the cort response after 28 days, the restraint

### 202-234-4433 Neal R. Gross & Co., Inc. Page 160 1 stress habituated alcohol habituated, but this 2 didn't. This was sort of in keeping with what 3 Ralph was talking about a few minutes ago, where 4 you continue to see, when you expose the system 5 to atrazine, that there's an increase in cort 6 production. 7 So, if I was to try and sum everything 8 up here in just one sentence, it would be that, 9 we have pretty clear evidence that it's the 10 developing immune system that seems to be the one 11 that's more sensitive than the adult immune 12 system, and it seems to be working through what 13 might be similar mechanisms. 14 We never got a chance to pursue the 15 GnRH thing, because we applied for funding, for 16 Andy to continue his postdoctoral fellowship and 17 that did not work out. 18 So, the other thing that I can say is 19 that we really don't have any evidence to suggest 20 that the developing immune system is any more 21 sensitive than the neuroendocrine system, at 22 least from the studies that we've done.

### 202-234-4433 Neal R. Gross & Co., Inc. Page 161 1 Then, just to sum it up, there's one 2 more type of study that's been done, which is an 3 in vitro study, and this is where they put 4 different amounts of atrazine or the same amount 5 of atrazine on the spleen cells, over time. They 6 harvested those spleen cells and then they sent 7 them onto one of these natural killer cell 8 assays, and as you can see in the graph on the 9 left, that the more atrazine that was given, the 10 more suppression of the natural killer cell 11 activity went on in vitro. 12 In the graph on the right, the dark 13 black bars there -- I know that they're sort of 14 hard to see, and I apologize. I copied and 15 pasted out of a PDF, and it did not really work

16 out well. 17 But the dark black bar is the atrazine 18 on the right and as you can see there, the longer 19 you put those cells in culture with 10 micromolar 20 atrazine, the more suppression of the natural 21 killer cell activity there is. 22 But if you look at the graph at the

### 202-234-4433 Neal R. Gross & Co., Inc. Page 162 1 bottom, these are the natural killer cell. This 2 is natural killer cell activity from the mice in 3 the NTP study, and what you can see there at the 4 bottom is -- if I can make this arrow appear, 5 right here is this one little blip, and this is 6 at 250 milligrams per kilogram per day, and it is 7 at the very lowest effector to target cell ratio. 8 So, in this assay, what you do is, you 9 mix more natural killer cells in there with the 10 numbers of target cells that you have in there, 11 and so, at the very lowest level of natural 12 killer cell activity, at this medium dose, they 13 found this one in vivo effect on natural killer 14 cell activity, which sort of makes me dismiss the 15 other ones as it was -- they were interesting 16 studies, there's no doubt about it. 17 Rowe found, in these studies, that he 18 did, that there was a specific defect in the 19 natural killer cells, that prevented them from 20 delivering a lethal hit to the target cells. 21 But these two studies don't tell us a 22 whole lot more about the effects, potential

### 202-234-4433 Neal R. Gross & Co., Inc. Page 163 1 effects from natural -- of atrazine on natural 2 killer cells, because all of the animal studies 3 have tended to point to no effects on natural 4 killer cells, particularly at rational doses, and

5 that's all. 6 SESSION CHAIR PORTIER: Why don't we 7 open it up to any questions? Dr. Regal? 8 DR. REGAL: Yes, do you know in the 9 Rowe study, with the mice, was there any 10 mortality in the litters? 11 DR. LUEBKE: No, according to their 12 paper, they didn't see -- they didn't even see 13 any effects on pup numbers or weight gain or 14 anything, in those. 15 SESSION CHAIR PORTIER: Any other 16 questions? Yes, Dr. Holladay? 17 DR. HOLLADAY: Yes, Steve Holladay, 18 good overview. I think we've all been there 19 before, where something works well and then for 20 some reason, something changes and it doesn't 21 quite come back, but you know you did it well the 22 first time, and not much more Balb/c mouse work

### 202-234-4433 Neal R. Gross & Co., Inc. Page 164 1 has been done. The B6C3F1's and the C57's are 2 more T-helper 1 strains on the Balb/c, T-helper

3 2. 4 You commented in rats that a much 5 higher dose of dioxin could be used before you 6 see the immune changes in mice, and it made me 7 think of Ralph Smialowicz in that. What do you 8 use, like one-tenth of a microgram per kilogram, 9 and suppress the DTH? 10 DR. LUEBKE: That was a developmental 11 study. Now, in that study, the developmental 12 exposure to rats caused life long suppression of 13 DTH in the offspring, and the male were a little 14 bit more sensitive than the female, and that was 15 in rats, and the same sort of thing happens in 16 mice. 17 I was talking about an adult study. 18 So, the ID50 for suppression of the antibody 19 response in a C57 black 6 mouse is .7 micrograms 20 per kilogram of TCDD, and doses in rats with 21 STARS and F344's, up to 25 or 30 micrograms per 22 kilogram, don't do anything, and once you get

### 202-234-4433 Neal R. Gross & Co., Inc. Page 165 1 above 30, you get some enhancement of the immune 2 response. 3 DR. HOLLADAY: I guess we've got 4 automatic shutoff switch here. 5 Some of the differences, I think, are 6 undoubtedly strain related. The rat is not a 7 mouse. You have the Balb/c as a T-helper 2 8 skewed strain, or that's likely the case. 9 It makes me think too, that we're 10 seeing more and more with different compounds, 11 when we realize where we need to look. 12 I can remember when we said DES 13 produced transient effects on the immune system 14 of mouse and then we realized, if we looked in 15 different places, that these were actually 16 permanent changes. 17 Then the same became true with dioxin. 18 We described them as transient in the early 90's, 19 and then they became permanent shifts, and with 20 your different mouse models, are different models

21 of rodents. 22 In one case, you're describing immune

### 202-234-4433 Neal R. Gross & Co., Inc. Page 166 1 suppression and in the other case, immune 2 enhancement is being described, and I'm wondering 3 if we look in the right places, in the same or 4 different models, if we're going to see that 5 actually both occur and they co-exist, which is 6 kind of a strange phenomenon, but we're finding 7 out that in fact, it's true, when you treat an 8 animal with dioxin, they are both immune 9 suppressed and skewed toward immune enhancement. 10 It just depends on which area you're looking, 11 what part of the immune system you're evaluating. 12 So, I don't know, I wonder if some of 13 this is going on with atrazine and that's part of 14 why we're seeing these differences and -- between 15 the models. What do you think? 16 DR. LUEBKE: Okay, so, that was a 17 question. So, yes, I think that it's strain 18 related and that was the first thing I thought, 19 when I saw Rowe's antibody data. 20 The problem is, it would be 21 interesting to go back and challenge these 22 animals with a dust mite allergen and see what

### 202-234-4433 Neal R. Gross & Co., Inc. Page 167 1 happens, because that's the sort of model that 2 you're talking about there, and it's not just 3 endocrine disruptors that do that. We know that 4 heavy metals and a variety of things do that. 5 So, you're right, you have to use the 6 right assay, to see what's suppressed. 7 Hexachlorobenzene is a perfect example, where you 8 have some effects going this way and that way and 9 the other way, and they're auto-immune and it's a

10 real mess. 11 So, we may not have done enough assays 12 on these animals, and you know, if -- in terms of 13 immunotox hazard ID, I think the best way to look 14 at this is that we had unintended modulation at 15 the same dose in two different strains of rodent, 16 that behave immunologically different, somewhat, 17 but that's still unintended, and I think that's 18 probably the crux of the matter here. 19 DR. HOLLADAY: Something else too, that 20 I was curious about. In your mice, the thymic 21 weight didn't go down, but T-cell function was 22 changed. Do you think it's corticosteroid

### 202-234-4433 Neal R. Gross & Co., Inc. Page 168 1 independent, based on that, or is it too early to 2 say that? 3 DR. LUEBKE: Well, we didn't measure 4 cort levels in these animals. From all the work 5 that's been done by our colleagues over in the 6 reproductive tox group, I would have to say that 7 cort is involved here, some place. It just -- 8 I mean, even if it's going to be 9 alteration of GnRH, you know, that seems to trace 10 back to an initial effect on -- you know, on the 11 HPA axis. 12 But I don't think that this is the 13 sort of sledge-hammer effects that you see, when 14 people start talking about, "Well, that's not 15 immunotoxicity. It's generalized toxicity," 16 because you have huge levels of cort. 17 I almost wish now, that we had gone 18 back and measured cort levels on these, because 19 it would give us some idea early on in those 20 pups' lives, what their cort levels were like, 21 how long it took for them to smooth out, how long 22 before they came back to normal and whether that

### 202-234-4433 Neal R. Gross & Co., Inc. Page 169 1 -- you know, there are a number of studies that 2 have shown that if you do restraint stress on an 3 animal and then you come back and challenge that 4 animal later, if you -- I'm sorry, if you stress 5 mom, and you look at her offspring later, that 6 they make a much more pronounced stress response, 7 and that can have real consequences, just in 8 resistance to infectious disease, when you 9 challenge those animals with bacteria and 10 viruses. 11 But I wish that I could connect that, 12 I wish that I could tell you what prolactin 13 levels were like. I wish I could have, you know,

14 but I can't.

15 SESSION CHAIR PORTIER: Dr. LeBlanc? 16 DR. LeBLANC: What happened to thyroid 17 hormone levels in the Rooney study? 18 DR. LUEBKE: I can show you the -- no, 19 I can't. Yes, I have that on my laptop. They 20 were suppressed. They were non-detectable in the 21 day 14 PTU animals. 22 DR. LeBLANC: Okay.

### 202-234-4433 Neal R. Gross & Co., Inc. Page 170 1 DR. LUEBKE: Surprisingly enough, there 2 were some papers that showed that if you 3 compromise thyroid function, in -- particularly 4 in adults, you also compromise immune function. 5 That certainly did not happen here, 6 and I was, frankly, surprised, when -- you know, 7 when we did the repeat study, we got exactly the 8 same thing, that there were -- you could tell 9 that those PTU treated animals just weren't quite 10 right, as they say, but their immune function was 11 fine. 12 SESSION CHAIR PORTIER: Yes, Dr. Akana?

13 DR. AKANA: Just a small comment on the 14 troublesome sets of data that didn't repeat. 15 We lost a whole year of research and 16 it was because our university decided to do 17 construction, unplanned, all around us, and it 18 had an amazing effect, but we did publish a paper 19 afterwards called "Beware Construction." 20 So, unplanned, unpredictable 21 vibration, which they like to do at the night, so 22 they don't bother the investigators or the

### 202-234-4433 Neal R. Gross & Co., Inc. Page 171 1 patients, is just -- it was deathly for us, and 2 my other personal observation is, when we repeat 3 an experiment and we shift to the new barrier 4 facility, with the filtered air flow, that had a 5 decided effect on HPA. 6 So, small things, environmental, that 7 are not atrazine conducing. 8 SESSION CHAIR PORTIER: Okay, I don't 9 see any additional questions. We're going to 10 move on to Dr. Liccione and discussions of 11 neurological effects of atrazine. 12 DR. LICCIONE: Good afternoon, 13 everyone. In this presentation, I will be 14 discussing new studies that have been published 15 since 2003 on the broader effects of -- the 16 broader neurological effects of atrazine, and I 17 will be presenting our assessment of these 18 studies. 19 Okay, four new studies since 2003 have 20 been identified and were reviewed. The first two 21 pertain to monoamine systems in the brain and the 22 third one was reported on potential effects on

### 202-234-4433 Neal R. Gross & Co., Inc. Page 172 1 the brain somatostatinergic system, and the last 2 one was on neurobehavioral development. 3 I will just go briefly through these 4 studies. The Rodriguez study examined, in part, 5 the broad effects of atrazine on various 6 monoamines that included dopamine, serotonin and 7 norepinephrine in the hypothalamus and various 8 extrahypothalamic areas of the brain. 9 However, the focus primarily in the 10 study was still on the nigrostriatal dopaminergic 11 system. 12 This was a six month dietary study to 13 several doses of atrazine. Monoamine levels were 14 measured only at the end of the study. Locomotor 15 activity following and acute D-amphetamine 16 administration was monitored at one time, and 17 then spontaneous locomotor activity was monitored 18 at several points in the study.19 The number of dopaminergic and non20 dopaminergic neurons in the substantia nigra and 21 the ventral tegmental area were measured and 22 micro-dialysis was included to examine dopamine

### 202-234-4433 Neal R. Gross & Co., Inc. Page 173 1 release from the striatum. 2 Coban and Filipov focused specifically 3 on the dopaminergic system, and in particular, 4 the nigrostriatal dopaminergic system and the 5 ventral tegmental area. 6 This was a 14 day oral gavage study, 7 and included various doses. Dopamine and its 8 metabolites, as well as the number of 9 dopaminergic neurons were measured in this study. 10 The third study, Giusi, reported 11 effects of atrazine on the mouse 12 somatostatinergic system in the hypothalamus in 13 various extrahypothalamic areas. 14 Dams were given atrazine in corn oil 15 solution and the rats were actually trained to 16 self-administer the solution from drinking it 17 from a syringe, and that was administered on 18 gestation day 14, through postnatal day 21. 19 The authors were trying to simulate 20 what they refer to as environmentally relevant 21 concentrations of atrazine as has -- that had 22 been detected in the drinking water.

### 202-234-4433 Neal R. Gross & Co., Inc. Page 174 1 The dams were removed, the F1- 2 offspring were continued with treatment. Then 3 they were sacrificed at postnatal day 60 to 65, 4 and the measurements in this study included the 5 various somatostatinergic receptor sub-types. 6 There are five receptor sub-types, and neuronal 7 degeneration. 8 Belloni, who was actually a co-author 9 to Giusi study, investigated the potential 10 neurobehavioral development in the mouse, and 11 dams were given atrazine as was done in the Giusi 12 study, on post-day -- on gestation day 14 to 13 postnatal day 21. 14 Various neurobehavioral parameters 15 were measured. This included writing reflex, 16 cliff aversion, four-paw grasp, auditory startle. 17 They also look at pup ultrasound vocalization. 18 Auxiliary temperature and body weight were also

19 measured. 20 This slide summarizes our overall 21 assessment of the monoamine studies. The brain 22 monoaminergic studies indicated potential broad

### 202-234-4433 Neal R. Gross & Co., Inc. Page 175 1 effects of atrazine on dopamine, norepinephrine 2 and serotonin, as well as a decrease in the 3 numbers of dopaminergic and non-dopaminergic 4 neurons in the substantia nigra and the ventral 5 tegmental area. 6 Only one study, that's the Rodriguez 7 study, actually provided some evidence of altered 8 behavioral responses. The overall findings from 9 these studies, however, are inconclusive because 10 of the number of limitations that I will discuss 11 briefly in the next slide. 12 Okay, limitations of the study include 13 the very small sample size that were used for the 14 stereology, the reverse transcriptase polymerase 15 chain reaction and the immunohistochemistry 16 experiments, to illustrate the impact of this. 17 In the Rodriguez studies, the results 18 of the stereology were based on a very small 19 sample size, and there was high individual 20 variability in the count data, when you looked 21 across all of the groups, and the decrease count 22 that was reported at the high dose, reflects a

### 202-234-4433 Neal R. Gross & Co., Inc. Page 176 1 decrease in the counts in a few individuals when 2 you're considering the variability range. 3 They only presented median values. 4 Other statistical data, such as the mean and 5 standard deviation, coefficient variation, 6 interquartile range were not available, that 7 would help interpret the statistical dispersion 8 that you can see in the data. 9 The high variability raises some 10 questions in the precision of the stereological 11 estimates. 12 There was limited information on the 13 sampling procedure that they used and there was 14 no statistical data that would give you a clue on 15 the biological variation and the coefficient 16 variation, because these estimates, along with 17 the coefficient of error would give a better 18 assessment of the precision of the study, which 19 is very important in stereological examinations, 20 and insight that will give you an idea of the 21 biological variation between individuals and the 22 variance of the estimates at the level of the

### 202-234-4433 Neal R. Gross & Co., Inc. Page 177 1 respective individual brain regions.

2 There was also a lack of a dose 3 response in these studies and there was also 4 overall, minimal alterations in the monoamine

5 levels. 6 The minimal changes in the dopamine 7 was also noted in the Rodriguez's micro-dialysis 8 experiment, which they commented on, when they 9 tried to interpret the lack of the change of 10 dopamine metabolites, DOPAC and HPA. 11 And the lack of dose response was also 12 evident in the count data for the dopaminergic 13 neurons, that was reported in the Coban and the 14 Filipov study. 15 There's also a lack of supporting 16 evidence. For example, in all of these studies, 17 there were either no photomicrographs on the 18 reverse transcriptase polymerase chain reaction 19 and immunochemistry results or only a few that 20 were of very poor quality. 21 Both studies also relied on positive 22 tyrosine hydroxylase immunoreactivity in those --

### 202-234-4433 Neal R. Gross & Co., Inc. Page 178 1 as well as the stereology, to assess the actual 2 changes in the number of neurons, and Coban and 3 Filipov expressed this very well, the limitations 4 of this, where he acknowledges that it is unknown 5 if the decrease in the positive tyrosine 6 hydroxylase immunoreactivity is actually due to 7 neuron mortality or the loss of the positive 8 tyrosine hydroxylase phenotype. 9 Other quantitative approaches, for 10 example, morphological methods, would have been 11 useful to support their conclusions, given the 12 limitations, such as the small sample size, the 13 variability, the minimal changes in dopamine, the 14 lack of a dose response and limited or no 15 behavioral measures. 16 Now, to discuss a little bit about 17 behavior, I want to just elaborate, just a little

18 more. 19 In the Rodriguez study, it was not 20 possible to fully correlate the reported 21 increased locomotor activity with the levels of 22 dopamine levels, which were measured only at the

### 202-234-4433 Neal R. Gross & Co., Inc. Page 179 1 end of the study. 2 A rationale for D-amphetamine 3 selection was not given and only one dose was 4 examined. 5 The persistent locomotor activity that 6 was reported as puzzling and is uncertain, as to 7 what -- how to interpret this. 8 There was no inclusion of any direct 9 dopamine receptor agonist and antagonist, as well 10 as any kind of receptor binding assays in the 11 study design. 12 All of these limitations are important 13 to consider because the authors concluded that 14 the altered behavioral response to D-amphetamine 15 may be due to an up-regulation of the striatal 16 dopamine receptors by atrazine, yet, they 17 provided no support for this critical hypothesis. 18 Their alternate hypothesis, that the 19 response may be due to dopamine release produced 20 by atrazine is actually not supported by their 21 own data, and that of Coban and Filipov, and in 22 Rodriguez's micro-dialysis study, it actually

### 202-234-4433 Neal R. Gross & Co., Inc. Page 180 1 shows that atrazine actually attenuated the basal 2 and high potassium stimulated release of striatal 3 dopamine. 4 Coban and Filipov did not include any 5 behavioral measurements at all, to assess any of 6 the relevancy of the reported changes in the 7 dopamine and the metabolites in the dopaminergic

8 neuron counts. 9 This is important because in the Coban 10 and Filipov study, the reported loss of dopamine 11 neurons did not correlate well with the dopamine 12 and metabolite changes at the various time points 13 that were measured. In addition, there was no 14 inclusion of dopamine receptor agonist and 15 antagonist, or any receptor binding assays that 16 would clarify the observations. 17 And another problem with the Coban and 18 Filipov study is although they studied the total 19 neuronal population that would include some of 20 the non-dopaminergic neurons, at various time 21 points, they did not actually present this data 22 with very good stereological estimates and that

### 202-234-4433 Neal R. Gross & Co., Inc. Page 181 1 is another limitation of the study. 2 Okay, finally, another important point 3 that I want to address is that the authors, in 4 particular, Coban and Filipov, suggest a link 5 between atrazine exposure and human neurological 6 disorders, in particular, Parkinson's disease. 7 But the data did not support this for several

8 reasons. 9 Although it is limited, the Rodriguez 10 study suggests potential non-specificity of 11 atrazine effects on monoamine levels in neuronal 12 populations other than dopimangeric neurons, 13 which contrasts with the clinical picture of 14 Parkinson's disease and what was known with 15 animal models of Parkinson's disease, which 16 reflected clearly a selective degeneration of 17 nigrostriatal dopaminergic pathway. 18 More over, the results of the 19 Rodriguez study suggest potential effects on 20 hypothalamic serotonin, as possibly more 21 sensitive than dopamine, and -- but no additional 22 investigation of this was actually performed.

### 202-234-4433 Neal R. Gross & Co., Inc. Page 182 1 This is important because the authors, 2 in turn then, concluded that the effects on the 3 hypothalamic serotonin are consistent with 4 atrazine's neuroendocrine alterations, which we 5 know to date, are the most sensitive effects of 6 atrazine. 7 They did not explore this further, but 8 simply focused on the nigrostriatal dopaminergic 9 system. 10 In addition, the Coban and Filipov 11 study suggests that there is a maximal limit in 12 the loss of dopaminergic neurons, which again, in 13 contrast what is known with the clinical picture 14 of Parkinson's disease, which involves a 15 progressive loss of neurons, which can culminate 16 in greater than 50 percent of the neuronal loss. 17 There is also a lack of histological 18 behavioral correlates that you see with 19 Parkinson's disease. Neither in vivo study 20 demonstrated any significant increase in dopamine 21 turnover rates, which would be typical of the 22 clinical picture in Parkinson's disease and what

### 202-234-4433 Neal R. Gross & Co., Inc. Page 183 1 you see in -- with animal models of Parkinson's 2 disease. 3 None of them included any clear 4 positive controls for Parkinson's disease, like 5 6-hydroxydopamine or MPTP, that would help to 6 support or -- their claims. 7 The limitations of the studies, 8 besides the limitations that I mentioned, another 9 limitation that would impact any conclusion on 10 Parkinson's disease relates to the lack of the 11 examination of neuronal loss in the striatum, per 12 se. The focus was only on the substantia nigra 13 pars compacta and the ventral tegmental. 14 Now, since Rodriguez' study indicates 15 non-selectivity of neuronal loss, this would be 16 important and had they looked at this, this might 17 clarify some of the potential effects that 18 they're seeing, and also, it would be a good 19 comparison with what is known with Parkinson's 20 disease. 21 Finally, the epidemiological evidence 22 itself, to date, does not support a link between

### 202-234-4433 Neal R. Gross & Co., Inc. Page 184 1 atrazine exposure and Parkinson's disease or any 2 other neurological disorders. 3 Okay, moving onto the brain 4 somatostatinergic system, the Giusi study 5 reported altered expression of specific 6 somatostatin receptor sub-types in the 7 hypothalamus and various extra hypothalamic 8 regions of the brain in the males and female 9 mice. 10 However, the findings are inconclusive 11 because of serious limitations that limited its 12 use in risk assessment. 13 Limitations of the study include the 14 small sample size that they used for the staining 15 to assess neuronal degeneration, the reverse 16 transcriptase polymerase chain reaction and the 17 in situ hybridization experiments. 18 There was a lack of supporting 19 evidence. For example, somatostatin, per se, was 20 not measured, that would have supported the 21 neuronal degeneration and possibly provide some 22 insight into the up-regulation and the down-

### 202-234-4433 Neal R. Gross & Co., Inc. Page 185 1 regulation that they were reporting in the 2 various receptor sub-types.3 No in situ hybridization photo4 micrographs were provided for support. There was 5 no functional assessment of the reported changes, 6 for example, behavioral tests, growth hormone 7 measurements, which was one of the rationales for 8 looking at the study, or any other hormonal

9 measurements. 10 There was no -- the study design also 11 did not include any specific somatostatin 12 receptor antagonist, that would help to explain 13 all of this up-regulation and down-regulation 14 that is very confusing to understand. 15 There were some discrepancies between 16 statements made in the text, that were not 17 supported by the reference citations. There was 18 a lack of details on the age and body weights of 19 the mice used in the source and purity of 20 atrazine. 21 The study also did not include any 22 measurements of systemic toxicity that might be

### 202-234-4433 Neal R. Gross & Co., Inc. Page 186 1 confounding factors, and the photo-micrographs of 2 the amino cupric silver staining were of poor 3 quality. This is important because this is the 4 evidence that they used to support the neuronal 5 degeneration. 6 Finally, there was actually no 7 quantification of the neuronal degeneration, 8 especially in supporting an important conclusion 9 by the authors who state, in the dentagyros, the 10 neurons showed a rather significant overall 11 reduction in the total number of neuronal cells. 12 But yet, no quantitative data were 13 provided with appropriate statistical analysis to14 support a very critical conclusion and no photo15 micrographs of the dentagyros were actually 16 provided. 17 And all of these limitations would 18 help to help in assessing the -- what is going 19 on, because it was very difficult to correlate 20 the neuronal degeneration with -- consistently 21 with the changes in neuronal expression of the 22 somatostatin receptors, as an example, in the

### 202-234-4433 Neal R. Gross & Co., Inc. Page 187 1 high dose female, you will see some hippocampal 2 degeneration, but no change in the neuronal 3 expression. 4 Okay, now, for the neurobehavioral 5 development study, the Belloni study reported 6 alterations in writing and grasping reflex and 7 also, ultrasound vocalization in mouse pups. 8 They also reported decreased auxiliary 9 temperature. 10 The findings, we think, are 11 inconclusive because of the serious limitations 12 of the study. 13 Limitations include inappropriate 14 statistical analysis. The authors relied 15 primarily on the pup as the statistical unit. 16 The failure to count for the litter effects can 17 result in an increase in Type-1 errors and 18 overestimate any of the effects, thus, reducing 19 the validity of the findings. 20 In addition, there was no convincing 21 statistical evaluation of the potential 22 interactions, for example, sex, age and

### 202-234-4433 Neal R. Gross & Co., Inc. Page 188 1 treatment, which the authors claim.

2 There were two -- there were a number 3 of discrepancies in the reported number of pups 4 that were evaluated in the tables, which raises 5 questions about the accuracy of the results that 6 were reported. 7 There was no clear dose response 8 relationship for the reported effect on the 9 number of ultrasound vocalization and auxiliary 10 temperature. These effects were noted only in 11 the low dose mice, but not in the high dose mice, 12 and the authors did not provide any support for 13 their hypotheses that were put forth, to explain 14 the lack of the dose response. 15 They hypothesized effects on aromatase 16 modulation and hormone levels, but no 17 measurements -- such measurements were actually 18 made to support in -- at their conclusion. 19 In addition, Belloni acknowledged that 20 they cannot exclude the possibility that the 21 hormonal alterations in the dams may have 22 resulted in altered maternal care and

### 202-234-4433 Neal R. Gross & Co., Inc. Page 189 1 consequently, in altered pup behavior, and as I 2 mentioned, those -- the study did not examine 3 hormonal levels, which would clarify this as a 4 possible confounding factor. 5 And another important point is that 6 the spectrographic analysis of the ultrasound 7 vocalization were very limited. It's not clear 8 to me, why considerably less number of pups that

9 were evaluated for the number of ultrasound 10 vocalization were subsequently examined for 11 spectrographic analysis, and this was an 12 important measurement to assess the various 13 specific parameters of the ultrasound 14 vocalization, especially since the authors 15 conclude that lower atrazine exposure was more 16 effective than the higher dose in modifying 17 behavioral response. 18 There was also a lack of objective and 19 validated behavioral methods. The authors relied 20 on methods published in 1965 and the final point 21 was that there was no neuropathology that would 22 help to clarify some of the results.

### 202-234-4433 Neal R. Gross & Co., Inc. Page 190 1 In conclusion, the recent 2 neurotoxicity studies of atrazine on the brain 3 monoaminergic and somatostatinergic system and 4 neurobehavioral development, because of the many 5 numerous limitations, are -- did not provide any 6 definitive conclusions, and the effects on 7 neuroendocrine function, we think, are still the 8 most sensitive effects of atrazine. 9 SESSION CHAIR PORTIER: Okay, any 10 questions? Dr. Chambers? 11 DR. CHAMBERS: John, I was trying to 12 assess the dose levels of these things, and I was 13 confused when I read the Rodriguez paper. 14 Since that was a dietary study, how 15 did they go about assessing that those were the

16 dose levels? 17 Not the rationale, it's just, I didn't 18 get a sense of how they assumed it was five 19 milligrams per kilogram per day, when it was a 20 dietary study. They didn't describe that very 21 well, did they? 22 DR. LICCIONE: No, they did not

### 202-234-4433 Neal R. Gross & Co., Inc. Page 191 1 describe it. They reported the results at five 2 milligrams and 10 milligrams per day, but they 3 don't provide any information to verify how that 4 was derived. 5 A lot of these studies don't give any 6 information on quantification of the samples, any 7 analytical measurements, food consumption. I 8 think that would have helped to support their 9 conclusion. 10 So, I agree with you, that that's 11 another limitation that one could actually add to 12 the study.

13 SESSION CHAIR PORTIER: Dr. LeBlanc? 14 DR. LeBLANC: Do you have any idea if 15 the Giusi and the Belloni studies represent the 16 same experiment, with different analyses 17 performed? 18 DR. LICCIONE: Well, the study design 19 is the same, but there are -- there were some 20 differences in a sense, that the Giusi study -- 21 they removed the dams -- then the F1s were 22 treated for a longer time, but as far as I can

### 202-234-4433 Neal R. Gross & Co., Inc. Page 192 1 tell, they were not part of the same experiment, 2 but one wonders, if they were two overlapping 3 studies, if that's what you're asking. 4 DR. LeBLANC: So, in the Belloni study, 5 the pups weren't treated? 6 DR. LICCIONE: Right, that's true. 7 They were trying to look at lactational and it -- 8 in gestational lactational exposure to the pups 9 only. In fact, they actually state that they 10 prevented the pups from drinking from the 11 syringe. 12 So, there are differences in the 13 study. 14 SESSION CHAIR PORTIER: Yes, Dr. Reed? 15 DR. REED: I think what the Rodriguez 16 study -- I think -- I thought they restricted the 17 diet, so that they can do the calculation. They 18 didn't just let the animal eat as much as they 19 want. So, that was how they calculate the dose. 20 I think there was -- 21 DR. LICCIONE: It wasn't clear to me,

22 from --

### 202-234-4433 Neal R. Gross & Co., Inc. Page 193 1 DR. REED: But I have a separate 2 question. I agree, then when I was looking at 3 these studies, they're not -- you know, they have 4 holes and gaps. 5 When I see your conclusion, saying 6 that the other, you know, endpoints were still 7 more sensitive, so, my question to you is, would 8 you be thinking of -- because some of the 9 deficiencies are reporting deficiencies and so 10 forth, that you might be able to go back to the 11 authors and say, "You know, if you have 12 something, some information, some protocol and 13 study design," you cannot. 14 DR. LICCIONE: Right. 15 DR. REED: The litter effects and how 16 they called the litters, and stuff like that. 17 DR. LICCIONE: That's an interesting 18 question, because give this some thought. If you 19 look at the Rodriguez study, which is a very 20 interesting -- is that the very first initial 21 results that they report are on brain 22 norepinephrine, dopamine and serotonin,

### 202-234-4433 Neal R. Gross & Co., Inc. Page 194 1 indicating a non-specificity of effect. 2 Then they jump in to the nigrostriatal 3 dopaminegric pathway, without any good rationale. 4 The only thing I can think of is maybe the lab is 5 comfortable with that, they're specialized in 6 that. Same thing with Filipov. 7 However, given that you're seeing 8 hypothalamic serotonin -- and Rodriguez actually 9 acknowledges that, this may be related to the 10 neuroendocrine effects, it seems like, to me, the 11 more proving experiment would have been to study 12 that, rather than focusing so much on dopamine 13 and Parkinson's -- and trying to -- you know, 14 with Filipov's study, I thought I was reading a 15 new model of Parkinson's disease. 16 So, I think the right experiment would 17 be to look at this, especially since the 18 serotonin was reported, it looks like it may be 19 more potential, but the results are limited, 20 because they only did a preliminary assessment of 21 these monoamines. 22 It seems like to me, that the

### 202-234-4433 Neal R. Gross & Co., Inc. Page 195 1 neuroendocrine in serotonin thing might be more 2 fished out, rather than relying on dopamine. 3 DR. REED: And that was actually one of 4 the questions that I was curious about, in that 5 given all the gaps and deficiencies these studies 6 have, my question was since -- you know, your 7 conclusion is that they're still not the most 8 sensitive endpoints, but apparently, you have 9 some idea of how the study could be conducted, as 10 you were just describing. 11 Would you be interested in designing 12 something, just to see, you know, what the 13 endpoint is going to fall out to be, because for 14 example, I think most of them were very high dose 15 studies -- 16 DR. LICCIONE: Right. 17 DR. REED: -- but the Rodriguez study 18 was, you know, five -- 19 DR. LICCIONE: Five milligrams, the

20 lowest dose. 21 DR. REED: And they were seeing some 22 effects. So, my question to you, so, it's

### 202-234-4433 Neal R. Gross & Co., Inc. Page 196 1 getting close to the endpoint issue, in terms of 2 what is most sensitive. Are you thinking of 3 designing something that could get the answer 4 that you were looking for? 5 DR. LICCIONE: I haven't given -- 6 DR. LOWIT: John, if we could answer 7 that. Liz, do you want to jump in?

8 SESSION CHAIR PORTIER: That's Anna 9 Lowit. 10 DR. LOWIT: Yes, sorry, and I've been 11 moving around chairs. That's a good question. I 12 think the short answer would be, we're not sure 13 of the value of what those studies would be, and 14 if there is an argument that those studies would 15 be valuable, with respect to keeping in mind, 16 that at the end of the day, we're asking risk 17 assessment questions, and if you could design an 18 experiment that will lead you to something of a 19 lower endpoint, of a shorter duration, that's in 20 a separate direction from where the HPA, 21 particularly new data, is leading us, which we 22 think was going to really drive many of those

### 202-234-4433 Neal R. Gross & Co., Inc. Page 197 1 regulatory decisions. 2 So, you're a regulator, you know how 3 it goes. If it's something that's going to -- 4 that you believe would change the direction of 5 the assessment, I think those would be valuable. 6 But that's the question, how valuable would those 7 experiments be?

8 SESSION CHAIR PORTIER: Dr. Horton?

9 DR. HORTON: I have more of a comment 10 than a question here, because I think, in 11 response to your question, in terms of the 12 development of the neuroendocrine system, with13 respect to both the hypothalamic-pituitary14 gonadal axis and the hypothalamic-pituitary15 adrenal axis, both of those are in play, at this 16 point. 17 Anything that's going to influence the 18 development, and since things seem to be pointing 19 back to the developing axes, we do know that in 20 the development of those, both the BNST and the 21 brain regions that we're talking about right now 22 play important roles.

### 202-234-4433 Neal R. Gross & Co., Inc. Page 198 1 Also, the hippocampus plays important 2 role in the regulation of those areas, and that 3 if there's anything that's going to have a toxic 4 effect, or not even a toxic effect, but alter the 5 developmental pathways of those in a plastic way, 6 we need to be aware of it. 7 And so, if there's anything in this 8 data that suggests that that might be there, then 9 it's probably worth going back and evaluating 10 those under-properly controlled and properly 11 designed studies. 12 DR. LOWIT: Just one follow up and we 13 can probably close this. 14 To the extent that, you know, that 15 there is science to support those things, we 16 would encourage it to appear in your report, or 17 in your deliberations over the next few days. 18 I just want to be weary, that -- and 19 in the days of limited resources and moving 20 towards less animals and not more, that we design 21 those experiments in a way that we get the most

22 out of them.

### 202-234-4433 Neal R. Gross & Co., Inc. Page 199 1 SESSION CHAIR PORTIER: I think we will 2 go on. I would like to say, I'd like to see one 3 of these studies done with adequate sample sizes, 4 though. 5 We've seen a lot of neurotox studies 6 and they're always under-powered, for the kind of 7 results they're looking for, and it's very 8 frustrating, because I think we all kind of 9 agree, that this should be important, but why 10 aren't we putting the effort into those studies? 11 Dr. Mendez, you have a summary. 12 DR. LOWIT: And we're doing a computer 13 pass, as we speak. Well, maybe Liz can start 14 talking, since we're running really late. 15 SESSION CHAIR PORTIER: How many mics 16 can we drop? He's got it untangled. Now, watch 17 the water jug. 18 DR. MENDEZ: I sure require a lot of 19 assistance, don't I? Just give me one second. 20 Okay, I don't think this is mine. 21 All right, I promise, I'm going to try 22 and move quickly, and pick up the pace here.

### 202-234-4433 Neal R. Gross & Co., Inc. Page 200 1 So, what I wanted to sort of do is 2 bring us back, wrap things up, as to where we are 3 and where we hope to go, between now and 4 September. 5 The status of the reevaluation, we 6 have reviewed approximately 100 studies that have 7 a wide range of topics, from mode of action, 8 reproductive and developmental effects, 9 immunotox, neurotoxicity and carcinogenesis. 10 You'll notice that we did not talk 11 about the carcinogenesis when we were putting 12 this paper together. We were hoping that we 13 would be able to address cancer issues in 14 September. 15 As that is not the case, we've chosen 16 to defer that conversation so that we can look at 17 both the animal and the epi data together. 18 We still believe that the effects of 19 neuroendocrine function are the most sensitive 20 effects, based on the data that we have in front 21 of us today. 22 We continue to evaluate additional

### 202-234-4433 Neal R. Gross & Co., Inc. Page 201 1 studies that have become available since 2 February, and studies that will become available, 3 hopefully, in the spring and summer. 4 Having said that, where are we right 5 now? Mode of action, our understanding of the 6 mode of action is expanded. 7 In 2003, it all hinged about the 8 perturbation of the HPG axis and that is still 9 applicable. The activation of the HPA axis, 10 however, has come into play over the past seven 11 years, and we think that it may precede the 12 effects on HPG axis, and Dr. Fenner-Crisp 13 actually alluded to that a little earlier, in one 14 of her questions. 15 We see changes in ACTH, corticosterone 16 and progesterone, within minutes of exposure. 17 However, the toxicological significance of these 18 adrenal hormone changes per say is still unclear 19 to us. Were those 15 minute blips sufficient to

20 cause an adverse health outcome? 21 From the data that Dr. Cooper 22 discussed earlier today, we believe that there is

### 202-234-4433 Neal R. Gross & Co., Inc. Page 202 1 a general stimulatory effect in steroidogenesis, 2 not necessarily a direct effect on aromatase. 3 We see the delays in puberty onset in 4 both genders. Prostatitis is related to decrease 5 in prolactin and atrazine exposed dams during 6 lactation, and we didn't talk a lot about that 7 today, but it's described in the paper in some 8 detail, and the mammary gland tumor development, 9 based on the findings in the -- and the 10 conclusions of the 2000 SAP and what we have in 11 front of us today, still do not appear to be 12 relevant to humans, in terms of the mode of 13 action that we're addressing today. 14 Oh, this is a little skewed, but this 15 is a schematic that appears in the paper, about 16 the mode of action. Can I have the pointer, 17 please? 18 And what -- I'm not going to go 19 through each one of these steps. I think that 20 what's important to keep in mind is that we had 21 some of these steps back in 2003. We had the 22 GnRH pulses going down. We had the decreases in

### 202-234-4433 Neal R. Gross & Co., Inc. Page 203 1 LH and prolactin, and we had the gonadal changes 2 that led us to the altered reproductive function. 3 As important as the understanding of 4 the additional steps are, as they pertain to the 5 HPA axis, one of the things that I find very 6 important about this, one of the reasons why I 7 like this particular schematic is, to my mind's 8 eye, this almost looks like a house, and the idea 9 that in 2003, we had this mode of action data, 10 and the foundation of that house is still solid, 11 seven years later. It still stands, and that's 12 important, that's an important message to take 13 home, in my mind. 14 Immunotoxicity, I'm going to really 15 fly over this. Immunotoxicity exposure during 16 development may lead to altered immune function 17 of the offspring. However, that does not appear 18 to be more sensitive than the atrazine induced 19 effects on neuroendocrine function, and as Dr. 20 Luebke alluded to, during his talk, it may be 21 related to some of that GnRH changes, that we're 22 seeing.

### 202-234-4433 Neal R. Gross & Co., Inc. Page 204 1 Immunotoxicity, we've just had a 2 discussion about that. Based on the data that we 3 have in front of us, it does not appear to be 4 more sensitive than the atrazine induced changes 5 in neuroendocrine function, and it does not 6 appear to be related to Parkinson's disease. 7 So, where does that leave us? Well, 8 that leaves us with the understanding that the 9 toxic effects are due to multi-level interactions 10 of a variety of systems, neuroendocrine, 11 reproductive, nervous, immune. 12 At the activation of the HPA axis is 13 followed by the disruption to the HPG axis, which 14 then leads us to the most sensitive effects 15 attributed to atrazine exposure, but what is 16 still not clear is the extent of HPA activation, 17 both in terms of duration or dose level, that 18 meet -- that are needed to elicit the decrease in 19 GnRH, and subsequent LH surge attenuation. 20 All right, so, I just told you where 21 we are, as of today, and we sort of give you the 22 coming attractions.

### 202-234-4433 Neal R. Gross & Co., Inc. Page 205 1 The next steps in preparation for 2 September, as we want to apply the mode of action 3 framework to analyze the data that we have in 4 front of us. We want to further characterize the 5 HPA/HPG axis interactions, describing the 6 temporal relationship between HPA axis activation

7 and adverse health outcome. 8 We want to better describe the dose 9 response relationship between atrazine exposure, 10 HPA axis activation and adverse health outcomes. 11 We have some data that we hope will be coming in, 12 in the spring and the summer, that will help us 13 address these two issues. 14 Once we have that data, we intend to 15 conduct benchmark dose analysis, to better 16 characterize the dose response curve for the

17 effects on HPA and HPG. 18 Dr. Cooper alluded that some studies 19 we had in NOAEL-5 and in LOAEL-50, we'd like to 20 be able to define that a little bit better. 21 We have additional review of data that 22 is coming in, in the spring and summer. Again,

### 202-234-4433 Neal R. Gross & Co., Inc. Page 206 1 data available between February 2010 and July 2 2010, in the mammary gland development, which is 3 a separate issue from the tumorigenesis. 4 We have decided to postpone that 5 conversation because we are aware that there are 6 data that will be hopefully published very, very 7 shortly, that will really help us have a fuller 8 picture and a fuller understanding of that issue, 9 and we felt that it was best that rather than 10 roll it out piecemeal, to bring it all together. 11 We need to start thinking the duration 12 of exposure. How long must somebody be exposed,

13 before an adverse outcome occurs? 14 Life stages, we all know that response 15 to chemical exposure may vary through life 16 stages. How do we do that, in terms of atrazine? 17 We've seen that we have a variety of18 effects, whether we have animals expose pre19 natal, perinatal or postnatal. So, we need to 20 start thinking about that, as we think about the 21 risk assessment. 22 What is the life stage that we really

### 202-234-4433 Neal R. Gross & Co., Inc. Page 207 1 need to be protecting and therefore, will protect 2 all other life stages? 3 We are going to review the available 4 non-cancer epi data. We're going to start 5 working on a weight of evidence analysis 6 integrating the experimental tox data and the epi

7 data. 8 If warranted, we intend to propose new 9 points of departure. We will reevaluate the FQPA 10 safety factor and we will reconsider the drinking 11 water sampling strategy, in relationship to the 12 toxicological duration of concern, because we all 13 understand that the shorter duration of 14 toxicological concern may lead us to more 15 frequent sampling. 16 So, as I said, we're going to apply 17 the moral framework. Let me tell you where we 18 are, within that process. 19 Postulating the MOA, can the MOA be 20 established in animals? Well, we already had the 21 HPG axis that's been going through review, so, we 22 have the MOA in the animals.

### 202-234-4433 Neal R. Gross & Co., Inc. Page 208 1 We're going to describe the key 2 events. We've been starting to do that, as we 3 talked about the changes in ACTH, the changes in 4 cort, changes in progesterone. That's where we 5 are at this point. 6 We're going to start working on 7 establishing the dose response concordance and 8 establish the temporal concordance. 9 Once we've narrowed that down a little 10 bit further, then we'll proceed with the 11 analysis, talking about the strength and 12 consistency of the finding, the biological 13 possibility, whether other MOA's can be ruled 14 out, and the statement of confidence analysis and 15 implications. 16 So, additional data that we expect in 17 the spring and summer, sort of wet your appetites 18 for what's coming. 19 We have studies coming on in effect of 20 four day atrazine exposure on ACTH, cort, 21 progesterone and LH. Effect of atrazine on 22 steroidogenesis in rat granulosa cells, and that

### 202-234-4433 Neal R. Gross & Co., Inc. Page 209 1 study has actually been submitted for 2 publication. 3 Effect of atrazine exposure on GnRH 4 and kisspeptin neuron regulation. Effect of 5 gestational exposure to atrazine, an oral gavage 6 immunotoxin and hormone evaluation study for the 7 effect of atrazine in male rats, and male 8 prostate inflammation on low dose metabolite 9 exposure, and that manuscript is in preparation. 10 Other data that we expect is oral 11 study of effects of atrazine on estrous cyclicity 12 and the estrogen induced hormone surge in female 13 rats, comparison of effects of atrazine on14 pulsatile LH release and the LH surge in non15 adrenal-ectomized compared to adrenal-ectomized 16 female Wistar rats, and I believe that somebody 17 in the Panel asked about that. We know that the 18 study is underway, we just don't have the data 19 yet. 20 Use of a PBPK model, to characterize 21 atrazine by transformation to inactive moieties, 22 in relationship to dynamic changes in hormone

### 202-234-4433 Neal R. Gross & Co., Inc. Page 210 1 levels, and potential adverse outcomes, and a 2 dose response modeling and determination of 3 points of departure for risk assessment and the 4 validation methods for that. 5 So, what we hope to do with the dose 6 response concordance is establish the extent of 7 corticosterone changes needed to result in 8 adverse health outcome, incorporate this data in 9 the point of departure and determinations as 10 needed, and with regards to temporal concordance, 11 situation of changes in GnRH, ACTH, 12 corticosterone and progesterone needed for an 13 adverse health outcome, changes seen within 14 minutes, sustain changes need to elicit the 15 adverse outcome, one day, four days, one week. 16 We do know that atrazine and its 17 metabolites are quickly absorbed and distributed 18 in the body, so, we need to take that into 19 consideration, as we move forward in our 20 analysis. 21 And just a little bit about the 22 mammary glands development. These are some of

### 202-234-4433 Neal R. Gross & Co., Inc. Page 211 1 the data that are currently available and it's 2 the adverse effects. You can see -- you can read

3 them as well as I can. 4 A number of studies are currently 5 available in the literature, about potential 6 adverse effects on mammary gland development and 7 a few more are coming. 8 Atrazine dose dependent effects on 9 mammary gland development in Sprague Dawley's and 10 Long-Evans rats, the effects of atrazine induced11 mammary gland effects in Sprague Dawley and Long12 Evans rats and carcinogen induced tumor incident, 13 and an oral development study of atrazine in the 14 rat, including cross-fostering and pair feeding. 15 The Agency already has that last 16 study, but because it speaks to the mammary gland 17 development, we have deferred the discussion to 18 it for a later date.

19 And then the 2011 SAP on 20 carcinogenesis, AHS epidemiology study on 21 atrazine in human cancer publication, we hope 22 that that will happen some time by the end of

### 202-234-4433 Neal R. Gross & Co., Inc. Page 212 1 this year. We integrate experimental 2 carcinogenesis data and the epi data, AHS and 3 other cancer epidemiology studies, and we will be 4 seeing you then, in 2011. 5 So, if there are no questions -- 6 SESSION CHAIR PORTIER: Any questions? 7 Dr. Krishnan? 8 DR. KRISHNAN: A minor one, related to 9 the -- your house pictorial, number five slide. 10 Actually, I was -- since it's more of 11 a statement of the mode of action, I was looking

12 for some level of statement about the dose 13 metrics involved or the consideration of 14 alternative dose metrics. 15 So, I know if it's a split-level or 16 cottage, I could see that, but I don't see the 17 final connects of this. So, if you just want to 18 clarify what level of thinking has gone into that 19 or is it only the pharmaco-dynamic, if you will, 20 without potential toxic being captured in here? 21 What was intended? 22 DR. MENDEZ: At this point in time, my

### 202-234-4433 Neal R. Gross & Co., Inc. Page 213 1 intent with the little house was to sort of 2 illustrate the key events. 3 We are thinking about the PK aspects 4 of it, but that's not at this point, in there, 5 just yet.

6 SESSION CHAIR PORTIER: Dr. Fenner7 Crisp? 8 DR. FENNER-CRISP: I guess my question 9 earlier, goes to whether or not your roof is 10 leaking. The point being whether or not the 11 whole left side of the roof exists. That was -- 12 I interpreted that step one as being the old 13 direct effect. 14 DR. MENDEZ: So, your question was 15 about step seven? 16 DR. FENNER-CRISP: No, one, one. 17 DR. MENDEZ: Okay.

18 DR. FENNER-CRISP: The roof. Does the 19 whole roof exist? That was the essence of my 20 question earlier. Is there evidence to support a 21 direct effect of atrazine in this whole thing, or 22 is it all going to be shown to be indirect

### 202-234-4433 Neal R. Gross & Co., Inc. Page 214 1 through initial disruption in HPA to get to the 2 disruption in the HPG? 3 DR. MENDEZ: Ralph, you want to attempt 4 it? 5 DR. COOPER: Yes, I think I understand 6 the question. I think that right now, the -- I 7 just told Dr. Levine, this looks more like -- it 8 needs an arm out there, to be a children's swing 9 set, and -- 10 But one and seven, seven are the -- if 11 we put it this way, I think based again, on the 12 temporal aspects, at least for the CNS ACTH 13 response, I'd argue that one is centrally up 14 there. If it's not at the brain, it's so rapid, 15 it would have to be brain impaired. So, that one 16 still exists. 17 Whether GnRH is still the target, I 18 think it's -- those shingles are still there, but 19 seven, there's an increasing number of shingles 20 on that roof, that says that seven is growing 21 credence, if nothing else. 22 So, but so, that means then -- and you

### 202-234-4433 Neal R. Gross & Co., Inc. Page 215 1 know, we always think linearly, or we always 2 think sequentially, and they say tox pathways 3 paint us in these boxes that are lines, and this 4 is more -- we understand, given the assumption, 5 anyway, right now, that we're dealing with a very 6 basic cellular mechanism, disruption of maybe 7 cyclic AMP signaling, and we're going to have a 8 lot of pits in the whole neuroendocrine axis. 9 So, I'm not going to place my bets on 10 whether that roof is going to hold up under a lot 11 of scrutiny, but seven seems to be winning out, 12 right at the moment. 13 SESSION CHAIR PORTIER: Okay, is most 14 of this team going to be available tomorrow 15 morning, because I doubt if we're going to get 16 through all of the EPA presentation today, at 17 this point, since we're running about 45 minutes 18 behind. 19 I'm just wondering if the Panel has 20 questions in the morning, and we have kind of an 21 open -- Anna, will any, or most of these people 22 be available?

### 202-234-4433 Neal R. Gross & Co., Inc. Page 216 1 DR. AKANA: We're all here, all the 2 meeting. 3 SESSION CHAIR PORTIER: Okay, good. 4 DR. AKANA: Including our colleagues 5 from North Carolina. 6 SESSION CHAIR PORTIER: Okay, good. 7 Okay, I think we need probably a few minutes, for 8 you to change over to the hydrology groups and 9 so, we can stand, but don't leave the room, 10 unless you really have to. 11 (Whereupon, the above-entitled matter 12 went off the record at 5:13 p.m. and resumed at 13 5:16 p.m.) 14 SESSION CHAIR PORTIER: Let's begin 15 again. Just for the Panel's -- just so you know 16 my thinking, I think we probably will try to get 17 through six o'clock, but depending on the -- I 18 guess, we'll ask the -- Mr. Thurman, when he 19 wants to make the break, but I'm certain that 20 we're going -- we probably won't get the summary 21 and conclusion until tomorrow morning, and maybe 22 -- you know, the water sampling summary, until

### 202-234-4433 Neal R. Gross & Co., Inc. Page 217 1 tomorrow morning and maybe the artificial neural 2 network might be a good topic for tomorrow 3 morning. 4 Okay, Mr. Thurman is going to be 5 starting the discussion on evaluating the water 6 sampling strategies. 7 MR. THURMAN: Okay, I thought I'd start 8 out, because it seems odd to have water sampling 9 in the middle of a toxicity SAP. So, I'm going 10 to kind of remind you why we're here. 11 You know, in light of new science, we 12 may end up looking at a different endpoint than 13 we looked at for the 2003 -- based on 2003 RED, 14 and if that's the case, the question is going to 15 become, we had registrants do monitoring study in 16 community water systems in vulnerable areas with 17 a sampling frequency sufficient to characterize 18 in 90 day exposure period. 19 They sampled weekly during that -- 20 during the use and run-off season and biweekly in 21 other parts of the year. If we end up with a 22 shorter duration, the questions that are going to

### 202-234-4433 Neal R. Gross & Co., Inc. Page 218 1 be coming to us are, well, how well does that 2 existing monitoring design characterize the 3 shorter durations of exposure, if they don't, do 4 you need to sample more frequently, in order to

5 do that?

6 We want to be able to answer those 7 questions when they come, instead of having to 8 say, well, wait, we've got to go separately. 9 One thing I'm going to point out, this 10 is a question that doesn't just apply to 11 atrazine. It's the type of question we wrestle 12 with, with other pesticides as well. 13 Atrazine is a little unique, and we're 14 going to be focusing on atrazine because it's 15 probably got more monitoring data than you're 16 going to see in all of the other pesticides 17 combined, and that may be a hyperbole, but the 18 point is, atrazine may be one of the few 19 pesticides where we're able to do drinking water 20 exposure almost entirely on monitoring, rather 21 than supplementing monitoring and modeling 22 together.

### 202-234-4433 Neal R. Gross & Co., Inc. Page 219 1 So, that does make it unique, but we 2 are interested in what may apply beyond this. 3 Very quickly, I'm going to provide you 4 with some considerations, you need to take into 5 account, both in designing a monitoring study and 6 evaluating existing monitoring studies. Then, 7 I'm going to provide an overview of some of the 8 approaches we've been looking at, for analyzing 9 monitoring data of varying sampling frequencies 10 and in terms of applying through various 11 durations of exposures. 12 Then, we will either get to one or 13 both of these example approaches that are in the 14 background paper we gave you, today, or split it 15 between today and tomorrow, and then I'll come 16 back and provide you with a summary. 17 The next few slides are going to 18 illustrate the -- how -- the complex spatial and 19 temporal patterns we find in pesticides in water.

20 Some of the other -- these factors all -- from 21 the temporal and spatial patterns, to the 22 temporal autocorrelation, which means the

### 202-234-4433 Neal R. Gross & Co., Inc. Page 220 1 pesticide concentrations you measure on one day 2 are related to exposures that you would find the 3 day before, and the day after. 4 We also tend to find, when we talk 5 about sensor data, we're talking about pesticide 6 concentrations that are below a level of 7 detection, and we often see infrequent sampling. 8 All of this provides us with 9 challenges, both in terms of looking at a 10 monitoring study design, as well as interpreting 11 that, and so, I want to make sure we have that 12 background, as we go forward. 13 You saw this map in Anna's 14 presentation. I'm not going to spend too, too 15 long on this, I hope. When you're looking at 16 spatial -- and we know atrazine has widespread 17 use, but at the same time, there's enough 18 information on atrazine that we know that we can 19 zoom into certain parts of the country, and 20 that's where we expect to find community water 21 systems with higher concentrations than in other 22 parts.

### 202-234-4433 Neal R. Gross & Co., Inc. Page 221 1 When you're trying to address spatial 2 variability, there's a number of ways of doing 3 that. On one extreme, you could sample every 4 community water system in the country. That's 5 several thousand of them, and you're probably not 6 going to get that with any level of intensity. 7 On the other end of it, you may look 8 it -- and this is what we did for an ecological 9 monitoring study that we brought to the SAP in 10 the past. So, you've heard that, this one is 11 focusing on drinking water. 12 We started out by using a model 13 developed by U.S. geological survey, a watershed 14 regression on pesticide, which was developed 15 using atrazine monitoring data, to identify the

16 watersheds that would be most vulnerable to 17 atrazine exposure, based on that model, and 18 that's what you see in the dark blue. 19 What we did in that case is, we 20 basically had a study set up, that sampled 21 watersheds that represent those most vulnerable 22 areas and we looked at how far we could apply

### 202-234-4433 Neal R. Gross & Co., Inc. Page 222 1 that. 2 The drinking water is a little 3 different than that, in that, what we did for 4 this is, as a result of the 2003 IRED, atrazine 5 is already being monitored quarterly at each of 6 the community water systems, as part of the Safe 7 Drinking Water Act. 8 We were looking at a 90 day exposure 9 period, so, we said, you know, quarterly sampling 10 probably isn't frequent enough to characterize a 11 90 day exposure period. 12 So, what we did is, we looked at 13 community water systems that had annual average 14 concentrations above a certain threshold of 15 concentration, and those were put into more 16 intensive sampling. 17 The interesting thing that I want to 18 show here is that almost -- the vast majority of 19 those community water systems fell into this area 20 as identified as the most vulnerable watersheds 21 using the WARP modeling. 22 So, that helps us know that -- we've

### 202-234-4433 Neal R. Gross & Co., Inc. Page 223 1 already a good bit, and we're working with what 2 we've learned, but it tells us that we know we 3 can zoom in on certain areas. Even within those 4 areas, we're seeing that there are some water -- 5 community water systems that tend to have higher 6 concentrations of atrazine more frequently than

7 others. 8 So, there is localized variability 9 that further drives that. Some of this, we're 10 learning and it is a result of ecological 11 monitoring and some of the feedback we've gotten 12 from the SAP on that, that we hope to pass on.

13 But because of the nature of the fact 14 that we're looking at individual community water 15 systems that get thrown into this because of the 16 monitoring data, spatial patterns aren't as much 17 of a challenge for us in this regard as the 18 temporal patterns, and because we were looking at 19 these individual community systems, each of which 20 serves its own population, and each person -- 21 each population potentially drinks the same 22 concentration of atrazine, as their neighbors do.

### 202-234-4433 Neal R. Gross & Co., Inc. Page 224 1 So, I'm going to go into the temporal 2 patterns. One of the things, when you're trying 3 to show temporal patterns and try to show daily 4 variations, you quickly find that there's not a 5 whole lot of monitoring data out there, that 6 samples daily or almost daily. 7 What I'm showing you here are some 8 monitoring that was done with the ecological -- 9 atrazine ecological exposure monitoring program. 10 They tend to be a little farther upstream then 11 what you would see for most of the community 12 water systems, although there are a few community 13 water systems that are in those same type of

14 stream networks. 15 These were flowing water systems and 16 what you would expect for flowing water body is, 17 you expect to see a short, higher pulse moving 18 through than you would for a reservoir, which 19 would tend to dampen it out and spread it out. 20 But what I wanted to do is illustrate, 21 this is -- when we're talking about seasonal 22 variations, this is -- typically, what you'll see

### 202-234-4433 Neal R. Gross & Co., Inc. Page 225 1 is one or two short pulses, where you get 2 elevated concentrations that decline fairly 3 rapidly and a lot of times, either low in 4 negligible detections. 5 This is in one year. The previous 6 year at that site, the same site, we got a little 7 different pattern, and a different pattern can 8 result from different application periods, 9 different rain fall events, different ways it's

10 used. 11 There's a couple of things I wanted to12 show you. When we're talking about the auto13 correlation, you can really see it here, where 14 you see how the concentrations are related to the 15 neighbors. You also tend to see a tail coming 16 out, where you could -- a rapid, initial peak and 17 then a tail, tailing out. This is common in a 18 lot of our -- particularly, flowing water, but it 19 is a common thing that we see, and just to throw 20 in another one, when Mary Frankenberry starts 21 talking about short exposures, longer exposure 22 chemographs, shapes of the chemographs, this is

### 202-234-4433 Neal R. Gross & Co., Inc. Page 226 1 an illustration of one where you do -- what you 2 actually have is multiple peaks running together, 3 so that you get a longer duration of exposure. 4 This is interesting because it does 5 make a difference on how frequently you have to 6 sample. We're not always able to predict those 7 shapes of those chemographs A-priority, but to 8 the point that we can, it helps us interpreting 9 the results of the monitoring data. 10 It's not enough just to worry about 11 how much -- how -- variability you have in a 12 season, but you do have year-to-year variability. 13 The first slide I showed you happens 14 to be this year, and the second one was -- this 15 was the double-peaks. What you tend to see from 16 the year-to-year, and this is a six year period, 17 is not only do you see differences in the 18 magnitude of your exposures, but you also see 19 different shapes in the chemographs. 20 And just to drive home the spatial 21 variability again, this site is 50 miles south, 22 same years, and you can see the difference in

### 202-234-4433 Neal R. Gross & Co., Inc. Page 227 1 your exposures from year to year, so that it does 2 thrown in the fact that it's -- that a lot of 3 these differences are also localized and it does 4 present some challenges to us. 5 So, now, all we have to do is figure 6 out how to take that into account, when you're 7 looking at designing a monitoring study. 8 When we're looking at monitoring study 9 proposal, a protocol that would be submitted to 10 us, we need -- the questions we have is, how is 11 it going to account for spatial and temporal 12 patterns in exposure, and a lot of that is by 13 targeting areas where the pesticide is used and 14 when it's used. 15 So, you have a limited number of 16 samples. Instead of spreading them out 17 throughout the year, you would concentrate them 18 in the times when you expect to find it. There 19 are a lot of variabilities, additional 20 variabilities, based on the nature of the 21 pesticide itself, how it's applied, the weather 22 patterns, it's mentioned some of the water body

### 202-234-4433 Neal R. Gross & Co., Inc. Page 228 1 types. 2 It's also important, as you've -- as 3 we've heard referred to throughout the day, the 4 exposure duration of concern is also very 5 important, in terms of how frequently you have to 6 sample, and it makes sense that you're going to 7 have to have more intensive sampling, if you're 8 looking at shorter duration exposure, than a 9 longer term duration. 10 If we were to come out with an 11 exposure period that's 90 -- similar to what we 12 have now, 90 days or longer, we're probably okay 13 with it, but we are okay with the monitoring data 14 we have. But if it's a much shorter duration 15 exposure, that's where we have some questions. 16 On top of that, we're also looking at 17 the consequences of rather -- of failing to 18 detect high exposure, exposures above our level 19 of concern, when they do occur, or on the other 20 hand, estimating an exposure that's above the 21 level of concern when, in fact, it turns out not

22 to be.

### 202-234-4433 Neal R. Gross & Co., Inc. Page 229 1 Because FTPA requires us to come to a 2 conclusion of reasonable certainty of no harm, we 3 tend to err on the side of false negatives, more 4 so than false positives, but at the same time, we 5 want to try to be as reasonable with our exposure 6 estimates as possible. We don't want to end up 7 with an outrageously high exposure estimate that 8 really doesn't do anybody any good in that 9 regard. 10 Finally, the reality is, we can't 11 overlook the cost. It's prohibitively expensive 12 to sample daily, at enough sites, in enough 13 years, to give a full characterization of any 14 potential exposure you're looking at. 15 So, we end up with less frequent 16 sampling and less -- and fewer monitoring sites. 17 In a lot of cases, we rely on modeling to fill in 18 the holes, and sort of help us focus on more

19 vulnerable areas. 20 What we're coming to you today isn't 21 inventing a new wheel. It's building on things 22 that have already been done in the past.

### 202-234-4433 Neal R. Gross & Co., Inc. Page 230 1 Shortly after FTPA was passed and we 2 had to look -- and we started looking at drinking 3 water exposures routinely, International Life 4 Science Institute convened a pattern that -- a 5 panel that provided some recommendations on how 6 frequently you'd have to sample for -- for 7 instance, in estimating peak exposures. 8 We brought some information to an SAP 9 on what kind of monitoring study design you would 10 need to estimate chronic exposures. So, we've 11 built from that. 12 Charlie Crawford provided some -- 13 evaluated some varying sampling strategies and 14 you'll see in our paper, that we refer to a lot 15 of a Crawford's work and tried to take advantage 16 of what he found, to build on that. 17 And both of these particular authors 18 noted that the number and frequency of sampling 19 will depend on the time frame of concern. So, 20 that's, once again, bringing it back to that, 21 linking it together. 22 What I'm going to do is, spend a

### 202-234-4433 Neal R. Gross & Co., Inc. Page 231 1 little bit of time now, talking about how we 2 analyze and interpret existing monitoring data, 3 because most of the time, we're not designing new 4 studies, but we're looking at existing monitoring 5 data that's already out there. 6 In the case of atrazine, we're looking 7 at several years of monitoring community water 8 systems, and once again, we're going to be asked 9 that question very soon, is that adequate for a 10 new exposure duration? 11 So, we want to be able to get at that. 12 I'm going to begin with some of the basic 13 approaches and then walk through to more complex 14 approaches, as we go along. 15 Let's go back to that chemograph we 16 had, that I showed you earlier, that has two 17 exposure peaks, one that occurs in late April and 18 another one, about a month later, and let's say, 19 for this particular thing, we know -- this is an 20 actual -- the true chemograph that you would see, 21 and let's say, we had monitoring that was done on 22 a weekly basis, beginning April 1st.

### 202-234-4433 Neal R. Gross & Co., Inc. Page 232 1 So, those red dots you see are the 2 actual samples, and what you see is, well, we did 3 -- the timing of sampling happened to hit this 4 first peak pretty well. 5 For the second peak, we're on the 6 down-slope side of that, and what we ended up 7 with is roughly about half of what the actual 8 maximum concentration was, in that regard. 9 So, we already know that if we're 10 looking at an acute exposure, that we're going to 11 end up with an under-estimate. 12 We're still at the point is, if we're 13 looking at an average concentration over another 14 duration, exposure duration of concern, to get to 15 that, we've got to figure out, how best do you 16 fill in the holes in between? We've got these 17 seven day snapshots. How do we fill in the

18 holes? 19 Well, one way to fill them is to 20 assume the same concentration on subsequent days, 21 until you get your next monitoring, kind of a 22 stair step approach, and you end up with a blocky

### 202-234-4433 Neal R. Gross & Co., Inc. Page 233 1 chemograph, which, if you blur it, a little bit, 2 it's not too bad, but it's still kind of blocky. 3 Another one that's done, probably more 4 commonly, is kind of doing a linear interpolation 5 between the sampling points, it's like connecting

6 the dots. 7 If you're looking at a short term 8 exposure of concern, and particularly, if you're 9 looking at duration of exposure that is less than 10 your sampling, then there's a good chance, in 11 most cases, you're going to miss your highest 12 exposures. 13 If you're looking at longer term 14 durations, that may not be as much a problem, 15 because of the -- it will average out over time. 16 In fact, if you look at some of the things that 17 Mary will talk about later, that we do find that 18 for the longer your exposure duration of concern, 19 the less error we see in the estimates, but 20 shorter duration, the more error we see. 21 Now, even weekly sampling is still 22 kind of a Cadillac in a lot of monitoring

### 202-234-4433 Neal R. Gross & Co., Inc. Page 234 1 studies. Typically, we will see studies that may 2 be sampled biweekly or monthly or quarterly. So, 3 we're going to go back to our original site and 4 instead of sampling monthly -- I mean, weekly, 5 we're going to sample every other week. 6 And so, you see, we still hit that 7 first peak, but suddenly, we're way down on the 8 tail of the second peak. So, any type of -- no 9 matter what interpolation you do, you see -- you 10 have missed where the highest exposure is. 11 What we'd like to do is, try to figure 12 out -- you know, at some point, the sampling is 13 going to be so infrequent, that your exposure 14 estimate is probably not going to reflect a whole

15 lot of what we see out there. 16 Some of the questions we've been 17 wrestling with over the years is, how do you know 18 if you've missed this? Are the ways that can 19 help us know when we may have missed the exposure 20 point of long term concern? 21 We're still wrestling with that. Some 22 of the modeling methods that we mentioned at the

### 202-234-4433 Neal R. Gross & Co., Inc. Page 235 1 end of our chapter are ways that we think might 2 help us start to get at that, but it's still a 3 challenge we have. 4 And so, the basic interpolation 5 approach, as I just showed you, like I said, 6 these are the ones that are commonly used. 7 They're quick and they're simple and if you have 8 a long enough exposure duration, and in 9 particular, your sampling frequency is more 10 frequent than your exposure duration, that may be 11 fine, within incertain error bounds. 12 The disadvantages are, they assume no 13 concentration is greater than the maximum that 14 they measured. They're likely to under-estimate 15 your peak or your short term exposures, and how 16 well they characterize actual concentration 17 profile depends on the timing of sampling 18 frequency. The farther apart it is, the more 19 likely those methods are to fall apart. 20 So, what if we, instead of trying to 21 draw boxes or connecting dots, we want to try to 22 fit that monitoring data with more some type of a

### 202-234-4433 Neal R. Gross & Co., Inc. Page 236 1 curvilinear pattern or something that may better 2 reflect what you're actually seeing there, or we 3 want to provide some type of confidence interval 4 around our exposure estimates. 5 You're going to see some of this 6 illustrated in Mike Messner's talk. He's going 7 to talk about one way, one approach, using 8 artificial neural networks, to try to fit that 9 pattern, the pattern of the monitoring data, and 10 some of the things that can be done, in terms of 11 providing some kind of confidence intervals and - 12 - and also, in terms of looking at how frequently 13 you did monitor, or where do you have to set your 14 threshold of exposure to kind of provide either 15 balance between the false positives and false 16 negatives? 17 Mary Frankenberry is going to present 18 an approach where we think we can start getting 19 us at providing some types of confidence 20 intervals. 21 The next couple of slides I'm going to 22 show you are ones that we did not provide an

### 202-234-4433 Neal R. Gross & Co., Inc. Page 237 1 example for you yet, and I put it in there 2 because it is definitely something that we are 3 considering and we've done a little bit of 4 testing with. 5 If you've heard of kriging or nearest 6 neighbor approach, you've probably heard it used 7 in geo-spatial analysis. It's been a way to take 8 a look at monitoring points over an area, in 9 other words, monitoring points in space, and fill 10 in, in between those sample points. 11 It's a way, essentially, the way you 12 do it, is you have the points, you analyze them, 13 you look for any correlation between the sampling 14 points, which is what this variogram is one way 15 that it's done, and then, you fill in, by waiting 16 -- the waiting, based on the correlation between 17 the points with the nearest neighbor type 18 approach. 19 And so, most of the time, it's been 20 used for spatial analysis. We've looked at this 21 because I think, that same concept seems like it 22 would also work for temporal analysis, and I have

### 202-234-4433 Neal R. Gross & Co., Inc. Page 238 1 seen -- I have been to some national meetings, 2 where I have seen this approach tried out. 3 We had a couple of people, Jim Hetrick 4 and Jim Wolf in our office, who looked at it and 5 did give it a try, and so, what I want to show 6 you is, very quickly, what they did is, some of 7 their preliminary analysis, they looked at 8 atrazine and they looked at a couple of other 9 pesticides. 10 The basic approach is first doing a 11 visual inspection of the data, and you noted from 12 the atrazine chemographs I showed earlier, that13 you could see the temporal correlation -- auto14 correlation in there. It was evident. 15 They did some variogram analysis and 16 it did -- to quantify the temporal dependence, 17 and what they found is that you did get 18 correlation between measurements that ranged from 19 10 to 60 days apart. 20 The other thing they found is, it 21 wasn't constant from year to year. So, it's not 22 something you can apply to one year -- that you

### 202-234-4433 Neal R. Gross & Co., Inc. Page 239 1 can analyze in one year, and apply year to year. 2 So, it isn't constant from year to 3 year, but it does find a way of pin-pointing that4 auto-correlation and they've done some cross5 validation and what they have -- some of the 6 preliminary analysis is they can do a conditional 7 simulation with -- that can give you an imaging 8 of the time series over years. They can use -- 9 come up with a probabilistic generation of 10 exposures, and do some stochastic simulations, so 11 that we can get some confidence bounds on that. 12 So, in addition to what you're going 13 to hear from Mary and Mike, this is another 14 approach that we're going to be taking a look at. 15 The statistical approaches that I've 16 mentioned, their disadvantages are complex. They 17 take a lot more effort. It's not a quick 18 analysis of your data. 19 But where we need to provide 20 probabilistic distributions or where we need 21 confidence bounds around existing monitoring 22 data, that may be -- we see that as an approach

### 202-234-4433 Neal R. Gross & Co., Inc. Page 240 1 to take. 2 One of the other advantages, they 3 don't necessarily assume that the greatest -- the 4 highest exposure has already been detected, and 5 that's one of the reasons for the confidence 6 intervals on that, and they provide us with some 7 non-subjective way of estimating missing values 8 and the ways to account for temporal correlation. 9 They're more complex. The other issue 10 is, they don't necessarily capture the underlying 11 explanatory variables, or explaining what caused 12 that spike to occur when it did, but they may 13 have a utility in certain instances, particularly 14 when we're looking at needing a confidence bound 15 on our exposure estimates. 16 I've mentioned a little bit about 17 modeling methods and we are getting -- you know, 18 getting into a lot more detailed, involved 19 procedures. WARP, I showed you how we've been 20 using WARP and a lot is, in terms of identifying 21 -- raking watersheds, based on vulnerability and 22 then targeting areas of -- where more monitoring

### 202-234-4433 Neal R. Gross & Co., Inc. Page 241 1 would be needed. 2 But WARP has provided an estimate of 3 selected percentiles, as well as an annual mean, 4 an annual maximum -- and it's provided some 5 moving average concentrations. 6 We look at it as a potential for use. 7 A lot of it, as the authors and developers of 8 WARP have said, it helps us screen areas where we 9 need to have more targeted monitoring. 10 They have -- they do provide some 11 estimates of these various exposure percentiles, 12 with some confidence bounds on there, so, it's 13 something that we may be looking at, as we go 14 forward with this. 15 In a lot of cases, we've used 16 deterministic models to provide ground water -- I 17 mean, surface water exposure estimates. We've 18 used pesticide route zone model, which simulates 19 pesticide run-off from the field and we use exams 20 with exposure analysis modeling system, which 21 simulates the receiving body. 22 And we've used that to provide

### 202-234-4433 Neal R. Gross & Co., Inc. Page 242 1 multiple years of daily concentrations, varying 2 with weather patterns, and so, again, it gives us 3 a way of assessing the effect of different 4 weather patterns, and we've used that in various 5 tiers of our drinking water exposures, exposure 6 estimates. 7 In the 2007 SAP, that we had on 8 atrazine's ecological exposure monitoring 9 programs, Syngenta investigated a potential for 10 using PRZM, to fill in concentrations between 11 measured data from the chemographs. 12 We've looked at that. It probably was 13 a little bit more intense involved and complex 14 than we were planning to go into, but it's 15 something we were considering and have taken a

16 look at. 17 I put this in, we really didn't 18 include this in the paper, but we have seen some 19 attempts to try to use stream-flow as a way to 20 adjust pesticide concentrations in between 21 monitoring events. 22 I've seen as many chemographs where it

### 202-234-4433 Neal R. Gross & Co., Inc. Page 243 1 didn't work, as where it did. There are -- it's 2 not -- what we quickly learn is, it's not just 3 the flow, but it is also the flow in relating to 4 the timing of the planting, the timing of the 5 rain fall events, all those together.

6 Some folks at the USDA's ARS research 7 center and -- in Missouri, Columbia, Missouri, 8 have looking at an index of trying to couple flow 9 adjustments with the timing of planning of rain 10 fall events, and we're keeping an eye on that, 11 because that offers some promise, that we might

12 be able to use that. 13 At this point, I'm finishing my 14 presentation, and I'll open it for questions, 15 then, we will move on to the next one or two of 16 the next two examples. I'll let you folks figure

17 that. 18 SESSION CHAIR PORTIER: Likely, one. 19 Questions? Yes, Dr. Krishnan? 20 DR. KRISHNAN: I have two clarifying 21 questions. First one is, in the graphs you 22 showed, it was atrazine, but was that like, a

### 202-234-4433 Neal R. Gross & Co., Inc. Page 244 1 total, in terms of including also the other 2 duration products, or do such figures exist for 3 other duration products? 4 MR. THRUMAN: In that particular -- 5 this particular illustrations, it was atrazine 6 only. 7 One thing I just want to clarify, 8 we're not -- at this point, we're not really 9 doing -- presenting a drinking water exposure 10 assessment. We're using whatever available data 11 we have, to try to come up with approaches that 12 we'd use to analyze, that we would then apply to 13 the drinking water exposure assessment. 14 The monitoring data that we got from 15 Syngenta on community water systems is total 16 chlorotriazines. So, that would be what we would 17 be focusing on, in that regard. 18 DR. KRISHNAN: Okay, my second one, in 19 your initial slide, you refer to the 90 day 20 rolling average, probably you or someone else can 21 answer, as well, and you refer to the time frame 22 of concern being the major reason for the choice

### 202-234-4433 Neal R. Gross & Co., Inc. Page 245 1 of 90 days. 2 I have seen some justification along 3 those lines, as well. I'm wondering if we could 4 get some further clarification on the choice of 5 the 90 days, as to what went into that thinking? 6 Is it based on the tox studies, during which -- 7 DR. AKANA: I guess, I'll answer a 8 question, and I'm not asking, just to make sure 9 that we're on the same page. 10 The 90 day rolling average was what 11 was used in the 2003 risk assessment. So, one of 12 the major points on the table for 13 reconsideration, as part of this analysis, is in 14 a pretty straight forward question, is the 90 day 15 still the right time frame, and that, hopefully, 16 will get a lot of conversation over the next few 17 days. 18 So, it's absolutely on the table, to 19 move that 90 days shorter or longer, for that 20 matter, depending on, you know, where the data

21 move. 22 At that time, the 90 day rolling

### 202-234-4433 Neal R. Gross & Co., Inc. Page 246 1 average was selected by a match to the toxicology 2 data, specifically, the LH data, specifically, a 3 six month rat study. I don't know the exact 4 author, if you really want to see it, but that's 5 my -- 6 DR. KRISHNAN: No, I think we're on the 7 same page. At least, I understand, that's what I 8 wanted to make sure, because 90 days, typically, 9 in rodent studies, represents about a tenth of 10 the life time, which is not what corresponds to 11 what's typically the sub-chronic. 12 On the equivalent human, typically, 13 it's a tenth of a duration -- a life time is 14 considered to be about seven years. That's what 15 people normally use. That's why I tried to see, 16 but this clarification helps -- would help in 17 other discussions. 18 DR. AKANA: It was done as an equal 19 matching of the days, on an effect, the 90 days 20 or short than the six months. So, that was a 21 quite conservative choice on the Agency's part.

22 SESSION CHAIR PORTIER: Dr. Lee?

### 202-234-4433 Neal R. Gross & Co., Inc. Page 247 1 DR. LEE: I have a question and a 2 comment. First, the question, do we know about 3 the measurement error uncertainty, in taking 4 these samples, from the water streams, and 5 they're sort of presented up here, as stated 6 points without any error. 7 Presumably, if you sent several people 8 to the same stream and had them all take a sample 9 and then go analyze them in separate labs, you'd 10 get different answers. 11 MR. THURMAN: First of all, we probably 12 can get a little bit of that information. They 13 have -- they did do some fill-blanks and such. 14 I think the question you ask is 15 complex in all kinds of different ways, because 16 it does -- what you saw were daily chemographs, 17 but they were basically sampling, for the most 18 part, taken in one day, one time -- one incident 19 a day, dipping graph sampling. 20 Now, a few of those actually were 21 auto-samplers that sift at intervals, and then 22 what you have for a daily is a 24-hour average

### 202-234-4433 Neal R. Gross & Co., Inc. Page 248 1 over that. 2 You still have sampling taking one 3 point, across the stream. So, you will get some 4 variation in that. We don't really have that 5 characterized in this particular study. 6 DR. LEE: That could be a useful thing 7 to know a little bit more about, if you're trying 8 to make any sort of confidence interval. That's 9 going to be critical for your intervals. 10 MR. THURMAN: Yes, that's true. Now, 11 what I will say is that for the community water 12 systems, it comes from the -- they have -- 13 they've sample both source water and the treated 14 water. We're focusing on the source water. It 15 comes from the intake. 16 So, what you see is what is integrated 17 at that intake, which takes some of that 18 variability out. You still have a temporal 19 variability that you're going to get in that. 20 In fact, sometimes, what we'll see is 21 monitoring data is, where they've paired the 22 source water with the treated water is, that

### 202-234-4433 Neal R. Gross & Co., Inc. Page 249 1 sometimes, you'll see treated water with higher 2 concentrations than source water because it's 3 differences in time, and so, it's part of the 4 variability that's -- 5 DR. LEE: That's natural variability.

6 MR. THURMAN: Yes. 7 DR. LEE: You can't get rid of it. The 8 question is just can we quantify it a little 9 better, and it's not that you need to sample it 10 everywhere, but if you had some sort of global 11 idea of what it might be like, that would be 12 really helpful. 13 MR. THURMAN: I know we have a couple 14 of USGS folks on the Panel, who hopefully, can 15 provide some words of wisdom to help us figure

16 that out. 17 That's one we've wrestled with,

18 because we do know that -- 19 DR. LEE: I figured it's something you 20 must have looked at before, but I didn't see 21 anything about it in the white paper. 22 The other comment I want to make is,

### 202-234-4433 Neal R. Gross & Co., Inc. Page 250 1 I think that the kriging Gaussian process type 2 approach has a lot of potential here. I'm glad 3 to see you folks are looking at it. 4 I did want to comment, that you talked 5 about some variogram analysis, and they've 6 noticed that it varies a lot from year to year. 7 It's actually a very noisy process to try and 8 analyze a variogram, and I'd expect that even if 9 you sort of just took repeated samples, you'd get 10 very different variograms within the same year. 11 And so, there is a lot more possibly 12 going on there, and it may be that it actually 13 doesn't change that much year to year, and you're 14 just looking at variability, sampling 15 variability. 16 MR. THURMAN: Well, I will say that 17 their initial analysis was with a limited data 18 set. We were going -- we're going to be looking 19 at a lot -- hopefully, a lot more data -- sets of

20 data. 21 So, hopefully, some of that will start 22 shining in, but I appreciate that.

### 202-234-4433 Neal R. Gross & Co., Inc. Page 251 1 SESSION CHAIR PORTIER: I had a 2 question, it was just a clarification. The 3 hydrographs we're seeing here are for the raw 4 water is raw water at the intake, or is this from 5 the ecological studies that we -- 6 MR. THURMAN: The ones I showed you 7 were illustration of ecology studies, and the 8 reason I showed you that is because -- and you 9 see in the paper, we showed some of the 10 chemographs with the drinking water, but those 11 are weekly samples. 12 So, what I wanted to do, to try to -- 13 particularly, when I started illustrating, you 14 know, let's take seven day samples, I realized, 15 that's not going to work for those -- you know, 16 for those chemographs we generated before. 17 So, that's why I went to the 18 ecological exposure monitoring, because it did 19 have daily variations. 20 SESSION CHAIR PORTIER: I was thinking 21 about intake water coming from -- well, we have a 22 dendritic system, right, and you're up here, at

### 202-234-4433 Neal R. Gross & Co., Inc. Page 252 1 the ecological studies were high up here, level 2 one, level two streams, and rarely do community 3 water systems draw from that level. They're 4 drawing three, four and five, right? 5 MR. THURMAN: Yes, that's true, 6 although, as we've looked at this, I have found - 7 - I have come across looking at maps and 8 analyzing particularly, some of the monitoring 9 sites and where it goes, I've found community 10 water system intakes up in those same areas, and

11 some of -- 12 So, it can happen. We know that those 13 are typically higher up in the watershed than 14 what you're going to see farther down. I 15 selected those because while they're farther up 16 stream, they do show the shape of the chemographs 17 that you're likely to see, even farther down

18 stream.

19 SESSION CHAIR PORTIER: That's the 20 confirmation. Dr. Young? 21 DR. YOUNG: I just have a basic 22 question. I don't -- I think I'm missing some big

### 202-234-4433 Neal R. Gross & Co., Inc. Page 253 1 idea, because you talk about false positives and 2 false negatives. So, then that -- I'm not 3 clearly, exactly what you're trying to estimate, 4 because if you get a value, it could have 5 measurement error, but it may -- what if it's 6 right on, but you take another value and it's 7 right -- no measurement error, but you get 8 different values? 9 Are you trying to estimate the mean 10 for the area, a quartile? You see, I don't see 11 what the foundation is for false positive and 12 false negative. 13 MR. THURMAN: I think that's one where 14 I think Mike Messner will be able to illustrate 15 it a little bit better in his presentation, than

16 what -- 17 What we're looking at is, and just to 18 try to give you -- which I don't know if it will 19 help you or not, we get exposures -- monitoring 20 sample -- data samples, say, weekly, and we've 21 got to come up with an estimate of a duration -- 22 of an exposure for a duration that's say, one

### 202-234-4433 Neal R. Gross & Co., Inc. Page 254 1 month. 2 And so, if we take those weekly 3 samples, there's various approaches that you can 4 take. I mean, if you assume that the same 5 concentration for the next -- for a seven day 6 period until your next sampling and average -- 7 and use that to average those together, to come 8 up with a one month sample, there are times when 9 you may have hit, where if the one sampling point 10 happened to hit your peak, and you carry that out 11 seven days, when in fact, it drops pretty12 rapidly, you're going to end up with an over13 estimate of that monthly average. 14 There are other times when you may be 15 an under -- under-estimating, because you don't 16 hit that peak. So, that's what I'm -- 17 DR. YOUNG: I think, let me see if I 18 have it. So, what you're trying to estimate is 19 the average for the temporal scale of interest?

20 MR. THURMAN: That's correct. 21 DR. YOUNG: Okay.

22 MR. THURMAN: That's correct.

### 202-234-4433 Neal R. Gross & Co., Inc. Page 255 1 SESSION CHAIR PORTIER: Dr. Hayton, 2 from the Ohio State University joined us. He 3 wasn't here when we started, and he's got a 4 question, and -- 5 DR. HAYTON: Well, a couple of 6 questions. One is, what -- you're talking -- 7 these chemographs, what happens to that in the 8 pipe? I mean, when I open my faucet, am I -- you 9 know, if I took a sample out of my kitchen sink, 10 once a week, would it look like what you're 11 showing us, or does that get modulated in the 12 distribution? 13 MR. THURMAN: It gets modulated. There 14 are a number of factors that go into that. It 15 goes through a treatment system. Depending on 16 the type of treatment that the community water 17 system has, you may have some non or all of the 18 atrazine removed, depending on the treatment 19 system. 20 Because you're going into collecting 21 and holding tags of processing tags and moving 22 through, it does get -- tend to get modulated as

### 202-234-4433 Neal R. Gross & Co., Inc. Page 256 1 you go through what's exposed. 2 However, I will point out that EPA's 3 goal is to protect the source water. So, we're 4 focusing on how do we protect the source water? 5 We need to generate exposure estimates 6 that are going to reflect drinking water for 7 human health, at the same time. If you look at 8 the reasonable certainty of no harm, if we can 9 get the source water concentration lower than our 10 levels of concern, we can be certain that the 11 treated water is going to -- 12 DR. HAYTON: So, there's a margin of 13 safety there, and then finally, what -- it wasn't 14 clear to me, exactly how do you use those 15 concentrations? I mean, obviously, protecting 16 public health, but how -- does a bell go off 17 somewhere, when the atrazine concentration spikes 18 and the whole water system shuts down, or what 19 happens? 20 MR. THURMAN: What we do is, we have a 21 dietary exposure assessment and Dr. Lowit will 22 probably be able to answer a little better than I

### 202-234-4433 Neal R. Gross & Co., Inc. Page 257 1 do, but you basically, you take your drinking 2 water exposure estimate, with the average for 3 whatever duration of concern it is, couple that 4 with your dietary exposure and in cases where you 5 do have residential exposure, you couple those 6 together. 7 Atrazine, the dominant route of 8 exposure, and maybe the only real route of 9 exposure for atrazine is from the drinking water. 10 So, we don't really have exposure in food that we 11 would expect, and while there may be some long 12 use in some areas, for the most part, we don't 13 have residential exposure, that we look. 14 So, essentially, we are looking, in 15 this case, at concentration in drinking water, 16 but for other pesticides, it's coupled with the 17 dietary exposure. 18 DR. HAYTON: But if you think it's too 19 high, do you -- you know, what's the next step? 20 SESSION CHAIR PORTIER: I think Dr. 21 Bradbury can answer that. 22 DR. BRADBURY: So, just let me touch on

### 202-234-4433 Neal R. Gross & Co., Inc. Page 258 1 your question and reaffirm that the conditions of 2 the re-registration in 2003 are designed to 3 protect the source water. 4 So, the monitoring analysis that 5 you're going to hear about from the team, 6 combined with whatever you decided the 7 appropriate exposure window is, if we need to 8 change it, the whole construct of the regulatory 9 decision is that people are drinking the raw 10 water, not the finished water, and their goal is 11 to ensure protection of the source water, because 12 5th RED, we can protect the source water. 13 Safe Drinking Water Act, we use 14 technology, if necessary, to get the 15 concentration down to a safe level. Our approach 16 is, we should be protecting the source water 17 through a regulatory decisions. 18 Now, the conditions of re-registration 19 in 2003 have this monitoring program in place in 20 the community water systems, and if we get a 21 level above our level of concern, we're aware of 22 it quickly and I believe in our condition of re-

### 202-234-4433 Neal R. Gross & Co., Inc. Page 259 1 registration, if in two -- let me back up. 2 The community water system is 3 monitored for five years. So, if it goes into 4 the program, it's monitored for five years. If 5 during the course of the five years, it never 6 exceeds the level of concern, then it can get out 7 of the monitoring program, but it could always 8 come back in again, if it's safe drinking water 9 sampling regime, which is once every quarter, 10 starts to approach the three part per billion MCL 11 and then it goes back into the sampling program. 12 So, it's an ongoing monitoring 13 program. But five years in a row, you don't 14 exceed a rolling 90 day average, then you -- it 15 comes out of the monitoring program. 16 If it hasn't exceeded in two years, 17 so, one year, it exceeds, it exceeds the next 18 year, then atrazine is off-labeled in that 19 drinking water schedule and it can't be used in

20 that watershed. 21 So, we do have a bell that goes off 22 and the bell that goes off is, you can't use

### 202-234-4433 Neal R. Gross & Co., Inc. Page 260 1 atrazine in that drinking watershed, if you

2 exceed the level of concern. 3 Some of the dialog we'll have on the 4 science is, is that 90 day rolling average 5 changing, as we look at the toxicology? Do you 6 have a monitoring program in place, if exposure 7 window is variable? How should your frequency of 8 sampling vary? 9 SESSION CHAIR PORTIER: Well, a bell 10 has gone off. It's 6:02 p.m. by my ruling and we 11 have about an hour's worth of presentation by 12 EPA, that we're going to put off, I'm sorry, 13 Mary, until tomorrow morning. 14 Well, I'll looked at your slides, and 15 the statisticians over here could probably stand 16 it, I'm sure this whole Panel would -- would fall

17 off. 18 We're going to pick up in the morning. 19 This will impact the public presenters, in the 20 sense that they're going to be moved back another 21 hour. If there are presenters for which this is 22 going to cause a problem, please, let myself or

### 202-234-4433 Neal R. Gross & Co., Inc. Page 261 1 Joe Bailey know. We'll try to schedule you a 2 little earlier. I know some people don't stay 3 for all of this discussion. 4 We start again tomorrow morning at 5 8:30 a.m., on time, with EPA's continued 6 presentation on the water. 7 (Whereupon, the above-entitled matter 8 concluded at approximately 6:05 p.m.)

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90:13,17 204:18 210:7,10,12 241:1 needing 240:14 needs 35:20 43:2,4

43:7 214:8 negative 145:2 150:18 253:12 negatives 229:3

236:16 253:2 negligible 225:4 neighbor237:6,17 neighbors 223:22

225:15 Neither 182:19 Nelson 31:20 32:4

42:3,6 51:9 neonatal 145:17 neonate 112:17 nerve 85:1 nervous 64:13

67:13 204:11 net50:1 network 51:15

217:2 networks 224:14

236:8 neural 51:15 217:1

236:8 neuroadrenergic 119:3 neurobehavioral 172:2 174:10,14 187:4 190:4 Neurobiology 9:20 neuroendocrine 10:2 56:5 119:8 137:21 160:21 182:4 190:7 194:10 195:1 197:12 200:19 203:19 204:5,10 215:8 neuroendocrinol... 10:1 neurological 3:14 171:11,16 181:5 184:2 neuron 178:7 180:8

209:4 neuronal 174:6 180:19 181:11 182:16 183:11,15 184:15,21 186:4,7 186:11,20,21 187:2 neurons 62:21

63:18,20 172:20 173:9 175:4 177:13 178:2 180:11,20 181:12 182:12,15 186:10 neuropathology 189:21 neuropeptide

56:11 64:10 94:3 neurotox 199:5 neurotoxicity 51:3 190:2 200:9 neurotoxicology 11:19 never 159:21 160:14 259:5 new7:1,2 15:4 16:22 20:3,3 21:18 22:1,4 31:17 33:4 34:3,9 38:14 40:9,9 42:14 43:6,7 49:10,10,13,15 112:14 132:16 147:13 171:3,14 171:19 194:15 196:21 207:8 217:11 229:21 231:3,10 newest 8:12 nice42:7 69:14

79:18 111:4 116:22 night 170:21 nigra 172:20 175:4 183:12 nigrostriatal 172:10 173:4 181:17 182:8 194:2 nine76:21 82:21 107:14,17 114:20 144:6,14 NOAEL48:21 49:2

52:4 57:12 NOAEL-5 205:19 nocturnal 66:13 NOEL 89:19 139:16 noisy 250:7 non 24:21 50:6

53:3 127:22 172:19 209:14 255:17 non-cancer 3:15

24:2,19 38:21 39:5 48:12,15 207:4 non-detectable 169:20 non-dopaminergic 175:3 180:20 non-menopausal 130:10 non-parametric 128:3,14 non-selectivity 183:15 non-specificity 181:10 194:1 non-subjective

240:7 norepinephrine 172:7 175:1 193:22 normal 64:17

73:22 115:13 136:22,22 148:3 168:22 normally 61:22

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22:17 28:3 31:9 68:10 69:21 71:4 72:13 73:7 74:22 76:16 78:3,4 82:9 90:18 100:8 102:20 103:21 106:16 108:19 116:11 118:22 145:2 149:19,20 155:2 158:1,21 169:1 172:19 173:8 175:10 178:2 186:11 188:2,3,9 189:8,9 211:4 212:9 214:19 221:2 227:15 230:18 255:14 numbers 141:13 162:10 163:13 175:3 numerous 44:21 190:5 Nu-may 2:13 8:15 N.W 1:16 O objective 33:3 49:9 189:18 objectives 49:7 observation 85:12 171:2 observational 137:15 138:7 154:16 155:9 156:8 observations 180:16 observe 30:18 observed 54:11 obviously 27:22

92:3 100:1 115:12 138:17 256:15 OB/GYN 62:10 occasional 121:10 occasions 32:21 occur 62:14 69:6

69:13,19 81:22 166:5 228:19 240:12 occurred 59:5 144:6 156:6 occurring 57:15

61:4 64:1 68:13 occurs 55:17 65:17

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13:18 offspring 142:21 147:4 150:22 164:13 169:5 174:2 203:17 off-labeled 259:18 Oh 117:5 124:4

202:14 Ohio 255:2 oil 173:14 Ojeda 117:18 okay 39:10 42:14

43:16 49:6 53:12 79:3 96:10,16 97:3,13,16,21,21 98:3,11,14 100:12 100:15 102:19 103:14 107:9 111:14 114:13,21 115:17 117:6 119:10 120:20 121:1,9,19 123:10 123:15 129:17 133:22 134:12 136:9 166:16 169:22 171:8,19 175:12 181:2 184:3 187:4 190:9 199:20 213:17 215:13 216:3,6,7 217:4,7 228:12,13 244:18 254:21 old 65:7 121:20

213:12 older 126:11 131:19 once 62:1 70:1 115:21 140:18 147:5 149:11 151:9 164:22 205:14 208:9 230:20 231:8 255:10 259:9 ones41:16 107:21 122:15,16 162:15 235:6 236:22 251:6 one-tenth 164:8 one-time 8:10 ongoing 26:10

32:12 34:15 259:12 onset47:13 49:1

65:16 115:21 139:15 202:3 open 15:20 16:2

59:2 163:7 215:21 243:14 255:8 opening 3:3,6 12:22 openness 15:15 OPP29:18 31:12 opportunity 5:8 112:18 133:4 opposite 16:2 oral 173:6 209:5,10

211:13 orally 82:12 ORD 32:9,12 order 218:4 ordered 6:16 organ 137:13,13 organisms 11:11 organization 27:1 organs 140:17 origin 56:11 original 50:11

234:3 originally 25:6

38:10 ossification48:17 outcome 52:21 131:1 133:5 148:1 151:11,16 201:20 205:7 206:13 210:8,13,15 outcomes 27:8 39:7

68:11 69:8 70:18 205:10 210:1 outpouring 55:16 outrageously 229:7 ovarian 56:6 64:17

69:12,15 96:18 116:19 117:9,21 131:21 ovariectomized

60:4 61:8 62:12 64:4,6 80:2 90:9 ovaries 67:21 73:16 133:12 ovary 55:14 56:22

61:9,11 67:16,17 90:2 114:2 117:14 overall 14:11 31:13

38:3 76:2 78:9 174:20 175:8 177:4 186:10 overestimate 187:18 overlapping 192:2 overlook 229:11 overt 145:5 overview44:3 163:18 219:7 overwhelm 104:4 over-stimulation

93:12 ovulate 58:2 66:4 116:12,19 ovulating 91:4,5 ovulation47:2

55:21 56:1 65:5 65:11 66:1,6 90:21 ovulators 56:4 O'Byrne 2:12 9:11

9:11 118:15,16,21 119:10,13,22 120:5,9,13 o'clock 82:21 119:7

216:17 P pace 115:20 199:22 page 3:2 122:15

245:9 246:7 paint215:3 pair 211:14 paired 248:21 panel 1:4,15 3:5

4:5,14,16,22 6:10 6:20,22 7:4,8 11:9 11:14,21 12:8,12 12:15 13:3,5,5 15:2 22:7,15,19 22:22 23:15,21 24:15 30:16,20 31:4 38:3 43:13 46:4,8 47:15,16 48:10 60:14 95:10 126:2 134:18 209:17 215:19 230:5 249:14 260:16 panelists 7:1 Panel's 23:14

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99:12 108:7 participate 15:17 participating 145:10 participation 14:5 14:14,18 15:16 16:8 particular 20:16 57:7 83:22 109:11 131:1 173:3 181:4 181:6 203:7 230:17 231:19 235:9 244:4,5 248:5 particularly 30:20

31:2 41:1 42:10 42:15 142:16 151:2 154:9 163:4 170:3 196:21 225:18 233:8 240:13 251:13 252:8 partners 18:8 parts 53:17 56:8

217:21 220:19,22 pass 199:13 223:12 passed 230:1 pasted 161:15 path 154:19 pathway 34:11

41:6 77:12 79:6 93:18 133:1 181:17 194:3 pathways 26:20

27:7 69:9 78:5 198:5 215:2 patients 171:1 pattern 86:21 115:22 225:7,7 230:4 236:1,9,9 patterns 130:20 131:17 219:19,21 223:16,18 224:2,3 227:12,22 242:2,4 pause 20:6 PBPK 8:1 209:20 PCOS 96:17 118:12 PDF 161:15 peak 59:5,8 60:12

60:17 65:8,16 66:13 116:22 225:16 230:7 232:4,5 234:7,8 235:15 254:10,16 peaks 41:12 55:19

226:2 231:17 peer 13:6,13 14:9 14:11 15:10 23:16 24:14,16 26:9 44:7 45:7 50:15 PENELOPE 2:4 Penny 8:8 30:11 people7:2 15:20

31:10 39:17,18 65:9 91:18 117:16 121:2 125:7 138:5 147:18 168:14 215:21 238:3 246:15 247:7 258:9 261:2 people's 32:3 peptide 61:21 percent 141:11 155:14 182:16 percentages 157:1 percentiles 241:3

241:11 perfect 139:11 167:7 perfectly 62:6 64:9 155:16 perform 135:10 performance 51:13 performed 181:22 191:17 perifusion 61:16 perinatal40:19 103:4 113:12 206:19 period 60:10 61:19

70:7 103:20 112:21 113:12 119:5 122:7 130:6 133:12 144:19 149:4 151:2 154:4 158:6 217:18 222:9,11 226:16 228:11 254:6 periodic 21:3 periodically 18:16 periods 69:11 225:8 peripubertal 103:5 113:8,10 peripubertally

71:22 permanent7:7,13 11:9,14,20 13:4 31:4 46:4 165:16 165:19 persist 87:16 144:14 persisted 86:11 102:1 persistent47:3

66:20 117:15 118:7 141:9 179:5 person 223:20 personal 171:2 personally 96:5 perspective 30:1 perspectives 20:4 pertain 171:21

203:4 perturb 106:2 136:2 perturbation46:17

47:10 136:3 201:8 perturbations

26:21 27:8 pesticide 8:6,11,13

8:17,17 11:18 12:22 15:7 16:13 17:1,11 19:20 20:5 21:2,5 28:11 29:4 30:10,13 70:13 220:1,5 221:14 227:13,21 241:18,19 242:20 pesticides 9:5 11:10 16:11 18:17 18:20 19:2,6,11 20:2 138:19 218:12,16,19 219:19 238:9 257:16 phagocytes 145:8,9 phagocytic 145:7 145:13 157:18 phagocytosis 141:2 pharmacokinetics

8:7 pharmacological 139:19 146:7 Pharmacology 10:16 pharmaco-dyna...

212:19 phase 59:10 136:13 153:5 PhD 100:9 phenomenon 166:6 phenotype 178:8 phosphodiesterase

78:16 photo 185:3 186:14 photomicrographs 177:17 photo-micrograp... 186:1 physiologist9:17 Physiology 9:21 Ph.D 1:17,17,20,21 1:21,22,22,23 2:2 2:2,3,4,4,5,6,7,8,9 2:11,12,13,14,15 2:16,17 pick 142:7 199:22

260:18 picked 134:6 139:13 pictorial 53:21

212:9 picture 66:5 110:13 117:22 156:10,19 158:10 181:13 182:13,22 206:8 piecemeal 206:10 pin-pointing 239:3 pipe 255:8 pit 105:9 pits 215:8 pituitaries 61:17

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61:18 placenta73:9,17 places 165:15 166:3 plan 33:17 planned 138:3 planning 242:14

243:9 plans46:5 plant46:2 planting 243:4 plastic 198:5 play 27:2 108:13 133:1 197:15,22 201:10 plays 73:10 118:4 198:1 Plaza 1:15 please 5:12 12:12 107:11 111:16 123:17 202:17 260:22 pleased4:10 6:3 plenty 67:15 plotted 60:1 PMD-21 72:1 PMD-42 72:1 PND14 142:20 PND2 142:6 PND62 143:8 PND7 142:9,16 point7:3 12:13,20 26:13 30:11 45:11 58:8 59:14,18 62:3 64:18 67:6 78:8 79:4 81:3 84:21 87:17 88:12 95:9 101:18 102:5 118:16 119:13 121:22 124:9,13 124:14,18 126:7 134:5 155:13 163:3 181:2 189:5 189:20 197:16 208:5 210:9 212:22 213:4,10 215:17 218:9,18 226:8 232:12 234:12,20 243:13 244:8 248:3 254:9 256:2 pointed45:11 156:9 pointer 202:16 pointing 157:12 197:18 points 43:1 46:14 105:16 112:5,7 127:16 141:8 152:7 157:21 172:18 180:12,21 207:9 210:3 233:5 237:8,9,10,12,14 237:17 245:12 247:6 policies 18:18 policy 18:22 19:13

52:18 polycystic 96:18 116:19 117:9,21 polyfollicular 130:14 polymerase 175:14 177:18 184:16 poor 177:20 186:2 popping 93:2 population 88:3 137:1 180:19 223:20,21 populations 37:8 147:3,4 181:12 portal 56:12 Portier 1:17,21 6:4

6:7,8 7:15,19 9:7 11:22 14:7 43:11 43:16 52:1 53:1 53:12 95:9 98:15 105:13 107:10 108:10 110:20 111:16 113:13 118:15 121:21 122:19 123:2 124:22 125:6,14 126:1 127:12 128:18 132:7 134:1 163:6,15 169:15 170:12 171:8 190:9 191:13 192:14 196:8 197:8 199:1 199:15 212:6 213:6 215:13 216:3,6,14 243:18 246:22 251:1,20 252:19 255:1 257:20 260:9 Portsmouth 8:4 position 10:13 positive 177:21 178:5,7 183:4 253:11 positives 229:4

236:15 253:1 possesses 74:21 possibilities 36:8,9 111:2 possibility 45:12 188:20 208:13 possible 95:14 145:20 178:20 189:4 229:6 possibly 181:20 184:21 250:11 post40:19 128:7 postdoctoral 139:4 160:16 postnatal 173:18 174:3,13 206:19 postpone 206:4 postponed 38:18

38:19 Postulating 207:19 post-day 174:12 potassium 180:2 potential 33:14

48:12 162:22 171:22 174:9,22 181:10,19 183:17 187:21 194:19 210:1 211:5 212:20 229:14 241:6 242:9 250:2 potentially 114:7 130:8 223:21 pounds44:18 practice42:21 pre40:19 206:18 precede 91:13

201:11 precision 176:10 176:18 precursors 149:21 predict226:6 predictive 68:7 predictor 159:10 pregnancy 150:20 preliminary 194:20

238:7 239:6 premature 132:2 prep 65:7 preparation 205:1

209:9 prepare 13:20 31:5 prepares 23:3 preparing 13:8,10

34:7 present 1:19 2:1,20

5:11 50:11 71:19 73:7 86:21 109:22 180:21 227:4 236:17 presentation 12:14

34:15 43:12 44:2 53:16 54:3 171:13 215:16 220:14 243:14 253:15 260:11 261:6 presentations 5:19 12:6,8,18 35:12 50:20 51:5 126:3 presented 5:18

46:8 176:3 247:5 presenters 260:19

260:21 presenting 31:10

32:6 171:17 244:9 presently 7:12 presiding 1:18 Presumably 247:7 presumption 100:2 pretty 60:7,16

62:16 83:9 101:19 102:22 122:12 147:11 153:4 156:6 160:9 232:4 245:14 254:11 prevalent 116:21 prevented 162:19 192:10 previous 14:2

32:20 225:5 pre-ovulatory 117:1 primarily 23:22

44:19 46:16 53:10 172:9 187:15 primary 92:12,16 144:9 156:2 primates 146:21 primed 60:5 principles 14:21

29:21 prior 19:7 57:17

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57:1 66:9 83:9,10 90:1 100:3,5,6,10 102:3 103:14 106:11,13,20 201:16 208:4,21 210:12 program 11:14 15:2,7 19:4,4,10 26:16 28:11 29:4 62:18 69:4 120:2 155:6 224:9 258:19 259:4,7,11 259:13,15 260:6 programs 8:11 12:22 30:11,13 242:9 progress 24:16 progressive 182:15 prohibitively

229:11 project 139:11 prolactin47:4,6

48:3 56:18,19 64:15 66:13 70:20 139:17,21 141:17 146:9 169:12 202:5 203:1 proliferate 150:4 proliferative 47:7 prominent76:9 promise 199:21 243:11 promoters 73:15 promotes 113:20 prone 152:16 pronounced 169:6 proper 32:1 126:13 properly 24:13

25:4 198:10 properties 17:7 proportion 151:18 proposal 38:14

227:9 propose 207:8 proposed 3:12

40:11 proposing 38:4 propylthiouracil 140:2 prostate45:21 46:1

69:10 209:8 prostatitis 69:10

70:19 202:4 prostitis 140:1 protect207:1 256:3

256:4 258:3,12 protecting 207:1

256:15 258:16 protection 1:1 8:16 17:12,13,14 20:21 20:22 28:15,20 33:19 258:11 protective 104:5 protein78:21 146:19 protein-synthesis 137:20 protocol 193:12

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30:6 34:9 184:21 188:12 190:5 191:3 219:3,7,16 236:3,14,22 239:19 240:6 241:10,16,22 249:15 provided 175:7 179:17 185:4 186:13,16 230:5 230:12 241:2,4 provides 4:17

220:8 providing 26:7

236:11,19 proving 194:11 proximal 135:19 Pruett 158:22 159:14 Pruett's 81:16 PRZM242:10 pseudo-pregnant

91:3 PTU 140:1 141:15 142:15,22 143:7 143:17 169:21 170:9 pub 121:2 pubertal 69:3

71:18 99:14,15 108:21 109:1 110:9 puberty47:13 49:1

68:19 69:6 108:14 109:13 113:12 139:15 202:3 public4:14 5:8,9

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209:2 211:21 publish 170:18 published 12:2,3

70:5 77:6 78:19 82:5 91:18 171:14 189:20 206:6 publishing 117:20 PubMed49:22 pull 121:20 pulsar 63:7 120:1 123:18 pulsatile46:22

62:11 64:13 119:16,18 209:14 pulse 62:22 121:1,1 121:9,9,13 224:17 pulsed 62:1,1,2 pulses 62:13,20

63:10 64:2 93:22 94:6 119:9,19 120:20 121:6,17 202:22 225:1 pup 140:12 142:2,4 163:13 174:17 187:15 189:1 pups 139:16 140:6 141:13,14,20,21 142:10,13 151:2 168:20 187:7 188:3 189:8 192:5 192:8,10 purchase 51:10 purity 185:19 purpose 36:5 pursue 160:14 put 6:21,22 36:9

40:15 44:8 54:14 67:18 71:13 74:15 76:14 78:13 91:15 103:18 104:1 105:9 120:1,19 151:17 161:3,19 188:13 214:11 222:15 237:1 242:17 260:12 puts 62:17 putting4:15 5:20

35:22 199:10 200:11 puzzling 179:6 P-R-O-C-E-E-D-...

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200:7 ranged 238:18 ranging 82:11 rapid 71:7 92:5

214:14 225:16 rapidly 52:20

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52:14 54:17 55:2 56:9 58:7,9 59:13 65:2 67:7 68:6 69:16 70:10 76:8 79:22 93:19 95:8 109:21 113:20 114:1 115:3,19 117:11 118:11 126:18,19 129:20 130:21 131:1,12 165:6 208:22 211:14 246:3 rate 150:20,21

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179:2 190:17 194:3 rationales 185:7 rats 45:9 47:12,19

56:3 59:20 68:21 79:14 83:11 95:19 96:20 126:20,22 128:21 129:8 137:9 164:4,12,15 164:20 173:15 209:7,13,16 211:10,12 raw251:3,4 258:9 reached 152:4 reaction 175:15

177:18 184:16 reactivity 135:17

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96:16 112:12 116:11,12 141:19 141:21 163:20 244:22 251:8 reasonable 22:1

229:2,5 256:8 reasons 181:8

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109:12 146:19 147:5 174:5,6 179:9,10 180:14 180:15 184:6 185:2,12 receptors 93:9,13

179:16 186:22 recognized48:10 93:17 152:8 recommendations

4:17,20 47:15 230:5 reconsider49:15

207:10 reconsideration

245:13 record 122:1 123:5

124:21 125:12 133:14 216:12 recover 158:6 recovered 143:9

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47:14 59:5 61:2 107:8,17,17 202:10 2000s 29:11 2003 19:15 21:7

22:1 32:16 41:17 44:8 45:20 46:13 46:15,19 48:13 50:3 53:20 70:11 171:15,19 201:7 202:21 203:9 217:13,13 222:4 245:11 258:2,19 2006 19:5 2006/2008 19:3 2007 19:8 81:10 123:13 242:7 2008 19:6 2009 35:18 46:3 99:17 2010 1:13 46:7

206:1,2 2011 25:19,20 26:1

38:19 211:19 212:4 21 52:17 60:15

71:22 86:13 158:14 173:18 174:13 21st27:6 21-day 93:1 217 3:19 23 122:16,17 149:7 24 149:3 24-hour247:22 25 124:1 154:9 155:15 158:3 164:21 250 162:6 26 1:13 122:16 261 3:22 28 62:12 149:10 159:22 28-day 120:18 3 3:15 125:8,12 3:30 125:9 3:33 125:13 30 3:7 137:8 164:21 165:1 300 50:4 58:19 91:2 34 3:8 35 155:14 4 4 3:3 4,300 157:3 43 3:10 433 157:3 45 215:17 5 5th 258:12 5:13 216:12 5:16 216:13 50 63:3,4,6 65:18 89:2,2 90:15 96:9 100:22 102:22 103:3 120:2 121:7 121:15 182:16 226:21 500 156:19 53 3:12 6 6 3:4 153:20 156:22

164:19 6-hydroxydopam...

183:5 6.25 49:2 6:02 260:10 6:05 261:8 60 174:3 238:19 65 174:3 7 7 164:19 7044:17 48:22 75 86:18 103:3 8 8:30 261:5 9 9:00 107:4 9041:16 217:18

222:8,11 228:11 228:12 244:19 245:1,5,10,14,19 245:22 246:8,19 259:14 260:4 90's 165:18