### 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

+ + + + + WEDNESDAY, APRIL 28, 2010

+ + + + +

The Panel convened at 8:30 a.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 TABLE OF CONTENTS Opening of Meeting and Introductions. . . . . .4 Charge to Panel - Question 1.2. . . . . . . . .6

Charge to Panel - Question 1.3. . . . . . . . 62

Charge to Panel - Question 1.4. . . . . . . . 96

Charge to Panel - Question 1.5. . . . . . . .128

Charge to Panel - Question 1.6. . . . . . . .142

Charge to Panel - Question 1.7. . . . . . . .191

Charge to Panel - Question 1.8. . . . . . . .207

Charge to Panel - Question 1.9. . . . . . . .239

Concluding Remarks. . . . . . . . . . . . . .342

### 202-234-4433 Neal R. Gross & Co., Inc. Page 4 1 P-R-O-C-E-E-D-I-N-G-S

2 8:30 a.m. 3 MR. BAILEY: We've got a lot of 4 material to cover over the next two days, and 5 we're anxious to get going. I'm Joe Bailey. 6 I'm serving as the DFO for the meeting, 7 Designated Federal Official. 8 I just wanted to let the panel 9 know that I tried to e-mail the public 10 comments and presentations last night, but 11 some of the e-mails kicked back because they 12 were too big. What a surprise. But I will 13 make a second attempt this afternoon or 14 tonight to get it to everybody, so everybody 15 has all of the presentations electronically. 16 At this point I'll turn it over to 17 Dr. Portier, our Chair for this meeting. 18 Thank you. 19 DR. PORTIER: Good morning. I'm 20 Ken Portier, Chair. This is the -- I guess 21 it's the third day of the FIFRA Scientific 22 Advisory Panel meeting on the re-evaluation of

### 202-234-4433 Neal R. Gross & Co., Inc. Page 5 1 the human health effects of atrazine, review 2 of experimental animals and in vitro studies 3 and drinking water monitoring frequency. 4 We've twice introduced the panel, 5 so I don't think at this point we need to 6 reintroduce the panel. Most everyone in the 7 audience is probably familiar with us now. 8 And we have before us the bulk of our task, we 9 have remaining 12 questions, and two days to 10 do it, 16 hours. So my goal is to average 11 about 50 minutes a session, take a break after 12 two questions, and break at five o'clock this 13 evening. All right. So we're not going to 14 push it like we did yesterday. I realize 15 people have kids -- staff have kids to pick up 16 and -- yes, it's easy to keep people happy. 17 Right? 18 It's unlikely we're going to get 19 to any of the hydrology questions today, which 20 gives that part of the panel time to really 21 delve into that a little bit more. My goal 22 will be to get eight questions done today, 1.2

### 202-234-4433 Neal R. Gross & Co., Inc. Page 6 1 to 1.9. I'll be happy if we do that, but I -- 2 you know, even if we just get through 1.8 I 3 think we'll be doing well. 4 So with that I will ask Dr. Mendez 5 or Dr. Lowit, if they have any opening 6 comments from EPA, or Dr. Cooper? 7 DR. MENDEZ: We don't have any 8 opening remarks at this time. And Dr. Cooper 9 will start reading Charge Question 1.2. 10 DR. PORTIER: Thank you. 11 DR. COOPER: I didn't know I was 12 going to do this. So the Charge Question 13 1.2 -- in Charge Question 1.2, based on an 14 evaluation of the studies examining the mode 15 of action at atrazine on neuroendocrine 16 function, Section 3.2 of the draft issue 17 paper, the Agency has preliminarily concluded 18 that atrazine affects both the HPG axis and 19 the HPA axis. 20 With respect to the temporal 21 concordance, recent studies show that atrazine 22 induces a rapid, within minutes, increase in

### 202-234-4433 Neal R. Gross & Co., Inc. Page 7 1 ACTH and adrenal cortical hormones, 2 corticosterone and progesterone, in both male 3 and female rats, Fraites, et al., 2009; Laws, 4 et al., 2009; and Pruett, et al., 2009, while 5 changes in the HPG axis, such as suppression 6 of the LH surge, may take up to two to three 7 days, Cooper, et al., 2009. That should be 8 2000, by the way. 9 (Laughter.) 10 DR. COOPER: Note the mistake in 11 that, please, so I'm not on the griddle to 12 produce a paper last year. 13 This sequence of HPA alterations 14 followed by HPG changes indicates that the 15 suppression of the surge may be, in part, 16 mediated by activation of the HPA axis, i.e. 17 a corticosterone suppression of the GnRH and 18 LH release. In addition, with respect to the 19 dose-response concordance, atrazine-induced 20 increases in ACTH, corticosterone and adrenal 21 progesterone are seen following a single dose 22 of atrazine, 50 milligrams per kilogram.

### 202-234-4433 Neal R. Gross & Co., Inc. Page 8 1 In contrast, the HPG is not 2 altered by following a single dose up to 200 3 milligrams per kilogram. However, when 4 treated for multiple days, the dose necessary 5 to alter the HPA axis is lower than or equal 6 to the one needed to affect the HPG axis. 7 Charge Question 1.2, please 8 comment on the Agency's preliminary hypothesis 9 for the mode of action involving atrazine's 10 alteration of both the HPA and the HPG axes. 11 Does the document adequately and clearly 12 describe the hypothesis in the context of a 13 toxicity pathway, i.e. cellular responses 14 that, when sufficiently perturbed, are 15 expected to result in adverse health effects? 16 Does the document clearly describe the data 17 used to test the proposed hypotheses? To what 18 extent do the available data establish key 19 events in the proposed mode of action 20 hypothesis? And what are the strengths and 21 limitations of the data available on this 22 hypothesis?

### 202-234-4433 Neal R. Gross & Co., Inc. Page 9 1 Please include in your comments a 2 discussion of the Agency's interpretation of 3 the data linking the initial perturbations in 4 the HPA axis to the changes in the HPG axis.

5 Is there more? 6 DR. MENDEZ: Yes, there's more.

7 Hold on. 8 DR. COOPER: Long question. 9 Please comment on the evidence that the 10 initial perturbations in the HPA axis may lead 11 to impairments in reproductive function and/or 12 developmental consequences. Which events 13 is/are viewed as critical in leading to health 14 consequences? Are there data on other 15 substances that would inform this question? 16 DR. PORTIER: Thank you. We've 17 kind of spread out the panel a little bit

18 more. 19 So, Dr. O'Byrne, you've got a 20 little of room. You ready to kick us off

21 here? 22 DR. O'BYRNE: Thank you. Thank

### 202-234-4433 Neal R. Gross & Co., Inc. Page 10 1 you very much. 2 I think the EPA's preliminary 3 hypothesis for activation of atrazine's mode 4 of activation -- mode of action involving 5 alteration of both the HPA and the HPG axes is 6 adequately described and scientifically sound 7 based on the experimental data that's 8 available. 9 The details of the toxicity 10 pathway, however, is very, very limited, and 11 the mechanisms of action of atrazine on the 12 perturbation of the HPG I'll describe in a 13 minute. The mechanisms of action on the HPA 14 perhaps should be moved into questions 1.3 and 15 1.4 because there's some overlap there. 16 But the key question of the causal 17 link between the activation of the HPA and the 18 subsequent suppression of the HPG axis is far, 19 far from conclusive. Nevertheless, I think 20 the available data provides a reasonable case 21 for the Agency to put forward that preliminary 22 hypothesis.

### 202-234-4433 Neal R. Gross & Co., Inc. Page 11 1 Now I don't wish to review the 2 post data, post-2003 data on the HPA and HPG 3 axes. I'm very mindful of the Chair's comment 4 at the beginning of this that we shouldn't 5 repeat what other people have said or what we 6 say ourselves, otherwise we'll be chopped off 7 in mid-sentence. So that's a great advantage

8 to me. 9 (Laughter.) 10 DR. O'BYRNE: But nevertheless, I 11 think Dr. Handa's additional information 12 yesterday was particularly helpful. And of 13 course you'll remember that. I would like to 14 make a very brief comment about the 15 interaction between the HPA and HPG axes, just 16 in case there are people in the audience that

17 are new. 18 It is extremely well-established 19 that there's an inverse relationship between 20 the HPA and the HPG axes, which has led to the 21 hypothesis that activation of the HPA results 22 in a suppression of the HPG. This is not

### 202-234-4433 Neal R. Gross & Co., Inc. Page 12 1 rocket science, and this is particularly true 2 in response to stressful stimuli. And in 3 clinical scenarios as well. For example, in 4 Cushing's disease there is a beautiful inverse 5 relationship between circulating levels of 6 cortisol and the degree of reproductive 7 suppression in terms of normal menstrual cycle 8 in women, oligo, and complete amenorrhea. 9 So this physiological correlate of 10 the inverse relationship, coupled with the new 11 evidence that atrazine activates the HP axis, 12 has obviously led the Agency to this 13 preliminary hypothesis that the mode of action 14 of atrazine involves an alteration of both of 15 these critical axes. And the influence is 16 sequential rather than some parallel fashion, 17 so that changes in the adrenal steroid 18 hormones are driving the deleterious effects 19 on the reproductive axis. So I just wanted to 20 give you that brief summary. 21 Now my major comments relating to 22 atrazine. There's clear evidence that there's

### 202-234-4433 Neal R. Gross & Co., Inc. Page 13 1 a transient increase in corticosterone, and 2 we've seen evidence of that with rapid 3 increase and return to baseline within six 4 hours. Whether this is measured after a 5 single injection, or exposure, or after a 28- 6 day exposure and the final administration 7 results in an indistinguishable rise and fall 8 in corticosterone. 9 Now there's ample evidence that 10 increases in -- acute increases in 11 corticosterone, cortisol depending on the 12 species, do not, and I mean do not affect the 13 pulsatile release of LH. And this is in a 14 huge range of species, from rats all the way 15 up to humans. There is, however, one 16 exception and that is the sheep. And here, 17 physiological stress levels of cortisol, or 18 cort, results in a rapid decrease in LH pulse 19 amplitude. And this happens within 30 to 60 20 minutes. 21 And this is a pituitary 22 phenomenon, where there's a reduction in

### 202-234-4433 Neal R. Gross & Co., Inc. Page 14 1 pituitary sensitivity to GnRH, the tropic 2 stimulus. But there is very clear, clear 3 evidence that atrazine does not have this 4 pituitary effect, and I think that data is 5 quite solid and unambiguous. And in the 6 sheep, incidentally, it also has an acute 7 effect on pulse frequency, and we don't really 8 need to go into that. 9 Now, in contrast to these -- the 10 lack of evidence of an acute effect of 11 corticol, corticosterone, on LH pulse 12 frequency, evidence concerning the effects of 13 acute stress, or cort, on the surge release of 14 LH is less consistent. However, chronic 15 levels of these hormones, their effects on the 16 surge generating mechanism are quite 17 consistent. 18 And I'd like to just talk to you a 19 little bit about the data that is available. 20 And in the context of the rat, it's actually 21 pretty meager. But, nevertheless, back in the 22 late `70s, Baldwin and his colleagues showed

### 202-234-4433 Neal R. Gross & Co., Inc. Page 15 1 that a single injection of dexamethasone or 2 cortisol at two to eight hours after the 3 administration of estradiol benzoate did not 4 block or affect the LH surge in rats. So 5 that's fairly conclusive that acute increases 6 in glucocorticoids do not suppress the LH 7 surge in this species. 8 However, if he takes a chronic 9 approach and implants a capsule where you get 10 chronic elevated levels of cortisol, then you 11 disturb the cycles for weeks and you 12 completely block the pre-ovalutory -- the 13 spontaneous pre-ovalutory gonadotropin surge. 14 So clearly chronic is a good example of 15 chronic cortisol having an effect. 16 Then in the mid `90s there was 17 another study where somebody restrained rats 18 for various time points, zero, one, and two 19 hours before the estimated time of the onset 20 of the spontaneous surge, and continued that 21 restraint until lights went out, which 22 basically means after the surge is over. And

### 202-234-4433 Neal R. Gross & Co., Inc. Page 16 1 in those rats 50 percent had no surge and 50 2 percent had an attenuation, or a decrease in 3 amplitude. So here we have two rat studies 4 that actually conflict in some ways. But you 5 can sit here and debate the reasons why that 6 may be the case. 7 I'd like to describe just a couple 8 of experiments that have been carried out in 9 the sheep, and there's been a very interesting 10 flurry of activity very, very recently in the 11 sheep, which has been initiated by one of your 12 great physiologists, Fred Cosh, who actually 13 should be here rather than me. Perhaps Joe 14 was less convincing and persuasive with Fred 15 Cosh. I don't know. But, well, maybe he's 16 enjoying his retirement. 17 But he really has spurred the 18 sheep people interaction around the globe. 19 And, in particular, Harry Dobson in Liverpool 20 in the UK, and what she's done is that she's 21 acutely activated the HP axis in her ewes with 22 insulin-induced hypoglycemia. And she's done

### 202-234-4433 Neal R. Gross & Co., Inc. Page 17 1 this at 30 and 32 hours after withdrawal of 2 progesterone. What the sheep guys do is they 3 have their sheep, they put an implant of 4 progesterone in and then they pull it out, and 5 then 48 hours later you have a spontaneous LH 6 surge. And this is synchronizing the surges 7 so to -- it facilitates their experimental 8 design. 9 So she induced hypoglycemia, and 10 very close to the surge. It decreased 11 circulating levels of estrogen significantly, 12 but not markedly. And this resulted in a 13 delay of the LH surge by nine hours. What 14 Fred Cosh has done, and this was published 15 this year, Fred Cosh has also done an 16 experiment, but instead of using a single 17 acute stress, he's used a series of acute 18 stresses, and these are psychological 19 stresses. And he's exposed his ewes to thee 20 psychological stresses at 12 to 18 hours, 24 21 to 30 hours, and then 36 to 42 hours after 22 that progesterone implant is pulled out.

### 202-234-4433 Neal R. Gross & Co., Inc. Page 18 1 Remember, the surge occurs at 48 hours. 2 And that repeated acute stress 3 paradigm, and he had a whole range of these, 4 I've just described one of them, had 5 absolutely no effect on the LH surge. It 6 occurred on time, normal amplitude. So here 7 we have two sheep people had papers published 8 this year that also are very, very different. 9 But what Fred did is, if he 10 administered physiological levels of cort, 11 corticosterone, for 42 hours, then he delayed 12 the LH surge by 10 hours, just like Harry 13 Dobson. And there's also a reduction in 14 amplitude. But you've got to remember that 15 the sheep is quite unusual in this context of 16 amplitude modulation in response to 17 physiological levels of cort. 18 I think I'd also like to remind 19 the panel that there isn't a shred of evidence 20 that the GnRH surge generating mechanism in 21 the rat, or indeed the sheep, bears any 22 resemblance to a human or primate, and I think

### 202-234-4433 Neal R. Gross & Co., Inc. Page 19 1 that's actually very important. And we can 2 discuss that if people think that's necessary. 3 So how does atrazine fit into all 4 of this? Well, although there is clear 5 evidence that sustained or chronic levels of 6 glucocorticoids suppress the pulse generator, 7 and I hope that's fairly clear, in a wide 8 range of species, from rats right up to 9 humans, there is a lack of evidence that 10 atrazine causes a sustained increase in 11 corticosterone. 12 Indeed, if you look at the data 13 that was presented in the last couple of days 14 from Pruett published in 2009, daily exposures 15 to astronomical levels of atrazine, we're 16 talking about 150 milligrams per kilogram per 17 day given intraperitoneally, resulted in a 18 transient increase in cort that was no 19 different from that from a single injection. 20 So up and down within six hours. 21 Dr. Handa showed us yesterday that 22 50 milligrams per kilogram increased

### 202-234-4433 Neal R. Gross & Co., Inc. Page 20 1 corticosterone for less than an hour in the 2 rat. The other study was in the mouse. So 3 the notion that a three-day protocol of 4 exposure to 50 milligrams could result in a 5 complete blockade of the LH surge, I think is 6 unlikely. And then the sort of clinch was 7 yesterday again, when Dr. Handa showed us that 8 adrenalectomy didn't block the surge 9 induced -- the blockade of the surge induced 10 by atrazine. So I think that really does make 11 one appreciate that the glucocorticoids 12 perhaps are not involved. 13 With respect to the health 14 consequences, it's my considered opinion that 15 there is little evidence, perhaps no evidence, 16 of adversity because the concentrations that 17 have been used in the various experiments that 18 I've reviewed draw no comparison whatsoever to 19 what we would expect humans, or indeed 20 wildlife, to be exposed to. 21 This may -- it may be very 22 different for amphibians. I mean these guys

### 202-234-4433 Neal R. Gross & Co., Inc. Page 21 1 live in the water. They're like a blancmange; 2 they absorb everything through their skin, and 3 very readily. And I think this was elegantly 4 portrayed yesterday by Pastoor's comments. 5 That's my opinion. 6 I think there is a dire need for 7 new data, particularly experiments involving 8 environmentally relevant doses of atrazine, 9 given chronically, via an oral route, and I 10 don't mean by gavage, I mean in their drinking 11 water. And it astonishes me and some of my 12 other colleagues here that nobody's actually 13 looked at the effect of such administration of 14 low levels that one would expect animals to be 15 exposed to, and looking at the effects on 16 corticosterone release, basal corticosterone 17 release. It's not been done, and that is 18 absolutely mind blowing. That's the first 19 experiment that I would have done, and in 20 those same animals you could have looked at 21 various physiological reproductive parameters. 22 And I think the comment that Dr.

### 202-234-4433 Neal R. Gross & Co., Inc. Page 22 1 Gilliom made yesterday about concurrence is 2 very, very well taken. And he simply added to 3 the bottle of water. So that's easy. Now Dr. 4 Mendez described key additional experiments 5 and data that's going to come out in spring 6 and summer of 2010. Well, spring's here and 7 it feels like summer's here as well, to me, 8 coming from London. But, you know, some of 9 those are critical and I'm wondering when 10 they're going to come. 11 But I cannot impress the 12 importance of looking at brain expression of 13 critical neuropeptides. I mean the fact that 14 nobody's bothered to look at CRF and 15 vasopressin expression is again astonishing. 16 Looking at GnRH levels by microdialysis is 17 something that I think should be done, and 18 there's somebody sitting around this table who 19 is an expert in this, and this is not a 20 trivial technique, as very few people can do 21 it properly. And you've got somebody in your 22 presence who can do this beautifully. So

### 202-234-4433 Neal R. Gross & Co., Inc. Page 23 1 people should take advantage of that. 2 And the catecholamines. I mean 3 one can't escape from those. And then 4 kisspeptin, I mean Dr. Mendez mentioned this 5 in her slides. Kisspeptin's been around for 6 something like seven years. It's the new 7 thing on the block in terms of for the 8 reproductive physiologists, and it's the 9 driving force to the GnRH neurons. And, 10 again, nobody's bothered, as far as we can 11 tell, to look at the expression of kisspeptin 12 in response to this herbicide. And these are 13 very simple and easy experiments to do, and 14 would give us a huge amount of information 15 that would make us -- make it easier for us to 16 give an informed decision. 17 So I think that's all I wish to 18 comment in my response. 19 DR. PORTIER: Thank you.

20 Dr. Bucher.

21 DR. BUCHER: Thanks. 22 John Bucher. So, in general, I

### 202-234-4433 Neal R. Gross & Co., Inc. Page 24 1 thought that the document adequately 2 established the interrelationships between 3 disruption of the HPG axis and the resulting 4 phenotypic effects including reproduction, 5 development, immune endpoints, and cancer in 6 experimental animals. There's a general 7 consistency in dose, response, and timing that 8 are required to satisfy a mode of action, and 9 the document does a reasonable job of 10 interpreting the recent literature in the 11 context of the proposed MOA. 12 In my opinion, more could have 13 been said about the biological plausibility 14 and support for cross-species applicability 15 that the literature on the HPA axis and stress 16 research in general that you just heard about 17 brings to the proposed MOA. Although I'm not 18 an expert at all in this area, the human 19 relevance of using disruption of the LH surge 20 and the benchmark dose calculation is, in my 21 mind, strengthened by the extensive 22 documentation of effects of various types of

### 202-234-4433 Neal R. Gross & Co., Inc. Page 25 1 stress acting through the HPG axis to affect 2 human reproductive health. 3 That said, I don't believe that 4 figure 3, which is the schematic of the 5 proposed MOA on page 30 of the white paper, 6 does a good job of capturing the key events in 7 the proposed MOA. The problem is that it goes 8 into too much detail in trying to describe 9 what are, in essence, redundant mechanisms 10 that are typically involved maintaining 11 homeostasis. 12 This also relates to the question 13 of whether there's a clear toxicity pathway 14 described in the document. Although Dr. 15 Cooper, on Monday, said he was leaning towards 16 the right side of the house through the HPA 17 axis as representing a direct or possibly a 18 linear pathway for atrazine's biological

19 effects. 20 I don't think that these highly 21 dynamic mechanisms really lend themselves to 22 the toxicity pathway concept. For example, LH

### 202-234-4433 Neal R. Gross & Co., Inc. Page 26 1 secretion is directly sensitive to 2 gonadotropin-releasing hormone, but also 3 indirectly to gonadotropin-inhibiting hormone, 4 ACTH, corticosterone, corticotropin-releasing 5 hormone, and possibly progesterone. 6 It is not clear why, to me yet, 7 why the data on temporal relationships between 8 the stimulation of the HPA axis and the 9 disruption of the HPG axis are what they are. 10 I think it may be more useful to scale back 11 your expectations for making all of the data 12 fit within a coherent framework. Toxicity 13 pathways most likely are not linear, but 14 rather are webs with nodes that represent 15 convergent points, or points of greatest 16 sensitivity. Figure 3, to me, is really a web 17 with LH pulse suppression as a sensitive node. 18 Despite this, I think the Agency's 19 on solid ground in using disruption of the LH 20 release and other biological endpoints that 21 have been directly associated with it as 22 measurable key events. This endpoint is the

### 202-234-4433 Neal R. Gross & Co., Inc. Page 27 1 most sensitive in terms of the atrazine 2 chronic dosing studies and it's been plausibly 3 linked to the phenotypic outcomes of interest. 4 As with the application of other 5 MOAs to specific situations, if you look 6 closely at how well the MOA fits specific data 7 sets, you'll see weaknesses in fits to the 8 model. But as we've all heard many times, all 9 models are wrong, but some are useful. I 10 think in this case the disruption of the HPG 11 axis is useful and the Agency should move 12 forward with it as a point of departure until 13 something clearly better comes along. 14 That concludes my comments. 15 DR. PORTIER: Thank you.

16 Dr. Akana? 17 DR. AKANA: What I'll do is just 18 add what has not been covered already, and I 19 concur with quite a number of the points. In 20 my opinion, the hypothesis, like many, is a 21 maturing hypothesis, and I don't think it's 22 quite developed to the point where it should

### 202-234-4433 Neal R. Gross & Co., Inc. Page 28 1 be aggressively pursued at this point.

2 Now what do I mean? One of the 3 points of the hypothesis is that there is a 4 central action of atrazine, and here is where 5 I think some important spotty sets of data are 6 missing. And when we talk about central 7 action, we're not talking about the brain, and 8 the type of evidence we've had so far is, 9 again, a little bit lighter on what you find 10 in the brain. 11 I think it's very promising that

12 we heard some of the cFos data and some of the 13 gonadotropin -- excuse me, the GnRH brain 14 data, but I think it's absolutely critical 15 that in the same kinds of animals they also 16 look at CRF and ABP in those brain sections. 17 And if they also layer in there with cFos, you 18 can get some sort of temporal sense of which 19 one is reacting first. So that part, I think, 20 is critical.

21 Now when we talk about the 22 activation of HPA system, there's the

### 202-234-4433 Neal R. Gross & Co., Inc. Page 29 1 hypothalamus, so that is relatively untouched. 2 The data on pituitary, POMC type of 3 production, that's also very lightly touched. 4 But what most concerns me when you talk about 5 activation of the HPA system; it is a feedback 6 system, a negative feedback system. And the 7 very preliminary data that we've have, which 8 is really exciting, that Dr. Handa talked 9 about with the adrenalectomy, is the direction 10 I think the studies need to go. 11 What we've seen are some really 12 lovely datasets on characterizing the response 13 to the HPA to atrazine in terms of ACTH and 14 corticosterone. And the data sets are 15 strongest with a single injection, a single 16 acute injection. The time frame and the dose 17 response and the time domains are very nice 18 for saying that atrazine stimulates the HPA 19 system with a single acute injection. 20 Now, the other fun thing about the 21 HPA system is with one of the outputs, just 22 one of them, which is corticosterone. As we

### 202-234-4433 Neal R. Gross & Co., Inc. Page 30 1 all remember, corticosterone is also a 2 glucocorticoid, and that is a hidden partner 3 in the hypothesis that must be addressed. 4 Because it's a glucocorticoid, you're changing 5 metabolism. Okay. In the framework of an 6 acute response, that is actually not a major, 7 major concern. 8 But as soon as you move into a 9 chronic model, a chronic model of atrazine, 10 you enter a whole new type of dynamic. What 11 has been emerging in the last 10 years is in 12 the stress system, when you move into repeated 13 or chronic stress, you have a different brain. 14 Okay. CRF and PVN, that one is pretty well 15 recognized, but CRF is found in other cell 16 bodies, cell brain nuclides in the brain. 17 It's a distributed system, it's responsive to 18 stress, they interact. There are neural 19 connections that are proven, and they have 20 major, major outputs. 21 So you have CRF and PVN, but you 22 also have it in BNST, in the central nucleus

### 202-234-4433 Neal R. Gross & Co., Inc. Page 31 1 of amygdala, you have in the prefrontal 2 cortex. And when it's activated in a stress 3 circuit, what you get is actually positive 4 feedback of corticosterone onto those systems, 5 and it drives other behaviors. So you have a 6 different kind of animal, which -- with 7 chronic stress, and it might help make some of 8 the data in the repeated atrazine application 9 much more coherent when you are sensitive to

10 that.

11 Now when we talk about 12 glucocorticoids and the metabolism, this is 13 one of my areas of energy balance, you are 14 feeding into the reproductive system. The 15 reproductive system is sensitive to energy 16 substrate flows. So I would urge a more -- a 17 larger picture taken with the data, that you 18 look not only on the HPA and the LH surge, but 19 in the framework of what kind of energy peak 20 the animal is. For instance, atrazine very 21 often reduces body weight. 22 And now, in terms of the animal

### 202-234-4433 Neal R. Gross & Co., Inc. Page 32 1 and negative energy balance, this is critical 2 how it nuances some of the LH surge and also 3 the HPA. So what I'm saying is, I think the 4 hypothesis needs to evolve to address the 5 acute response somewhat separately from the 6 chronic response. 7 That was my major point. I also 8 would like to table the toxicity pathway to 9 the next charge question. I think the key 10 events are still somewhat murky, therefore, in 11 this change because we don't know precisely 12 what's happening, the atrazine action, as it 13 kicks off in the hypothalamus. 14 Now the idea that it works 15 primarily on the HPA is perhaps conditioned, 16 because the literature shows there is, again, 17 a very strong interaction in the chronic state

18 between the HPA and the HPG. And there's some 19 very nice models of where HPA and HPG axes are 20 rendered independent of each other by 21 controlling both the corticosterone level and, 22 in the male rat, the testosterone level.

### 202-234-4433 Neal R. Gross & Co., Inc. Page 33 1 And here I'm thinking of a model 2 of Victor Viau, and I think that is a fabulous 3 template to consider how to interpret atrazine 4 action when you have independent control of 5 each axis. So overall, I think the strength 6 of the hypothesis is mostly in acute 7 injection -- in acute atrazine exposure. I 8 think it's much more limited in the chronic 9 state, and I think there are many tools that10 can -- that are in place already and well11 established that can be used to tackle those 12 problems, and I would urge the panel to 13 encourage those be employed. 14 And I'll stop there. Thank you. 15 DR. PORTIER: Thank you. 16 Dr. Fenner-Crisp? 17 DR. FENNER-CRISP: Given what's 18 already been said, I don't want to repeat any 19 of that. I support most of the comments made. 20 I'd like to focus mine on exposure root and 21 its relevance in dose concordance. I can 22 appreciate that in the laboratory setting one

### 202-234-4433 Neal R. Gross & Co., Inc. Page 34 1 wants to do experiments that see something, 2 and that generally can explain why higher 3 doses are used, at least in the first round. 4 But I also would appreciate, as Dr. O'Bryne's 5 comment, one wants to ultimately understand 6 what may or may not be happening at human 7 exposure relevant levels. 8 The body of literature in vivo 9 show studies by several routes, oral gavage, 10 some sub-Q, some IP, and one would have to try 11 to understand what difference does that make 12 in the results in comparing them across those 13 studies with respect to pharmacokinetics. 14 Would you be seeing different patterns of 15 percentages of rate and percentages of 16 metabolic formation, and conjugation, the17 whole ADME scheme, depending upon the route18 specific application?

19 And how does that affect the

20 results that one sees and how does one take 21 that into account when trying to do a dose 22 concordance across these varying routes of

### 202-234-4433 Neal R. Gross & Co., Inc. Page 35 1 exposure, trying to compare and understand 2 their relationship, particularly when trying 3 to understand where, how, if the HPA axis 4 disturbances impinge on the HPG. 5 The Agency mentioned somewhere in 6 the white paper that they plan to do benchmark 7 dose analysis somewhere along the way when 8 they get to the hazard characterization. It 9 may be useful to do that sooner rather than 10 later to get a better understanding of dose 11 concordance in hazard identification. 12 And I am assuming that one's going13 to apply somebody's, not the Agency's, pre14 existing PBPK model to expand on that 15 understanding. That would be a recommendation

16 that I would offer. 17 I think that it may come to the 18 point where some of the studies that have been 19 done, and offer some kind of results, may have 20 to be redone by more relevant routes of 21 exposure to confirm or not those particular 22 findings, if at a point in time they are

### 202-234-4433 Neal R. Gross & Co., Inc. Page 36 1 thought of as being critical to the 2 understanding of the pathways, and an integral 3 part in doing the risk assessment. 4 DR. PORTIER: Thank you. 5 DR. SELVAGE: Okay. Thanks. 6 My response is -- it kind of 7 segues into the next question as well, so I'll 8 keep this part pretty limited. I agree with 9 most of what's been said. I think Dr. O'Byrne 10 did a really nice job of describing, you know, 11 a lot of concerns that I think are valid. You 12 know, I guess I'll just add that, you know, I 13 do think the document does describe the 14 hypothesis well; I think that's clear. 15 However, I don't think there's 16 nearly enough data yet to, you know, draw the 17 conclusion that the EPA is leaning towards, in 18 that it's the HPA axis disruption that's 19 affecting the HPG function. You know, I would 20 say that, you know, in thinking about this 21 from a CNS perspective, you have -- there's a 22 lot of overlap between the HPA and the HPG

### 202-234-4433 Neal R. Gross & Co., Inc. Page 37 1 axis at the level of the CNS in terms of, you 2 know, receptors for gonadal hormones being 3 present in areas that are going to affect HPA 4 axis function, and vice versa. So I think, 5 you know, it's going to be important to look

6 at that. 7 Also, a lot of stimuli that are 8 going to affect the HPA axis are also going to 9 affect the HPG axis is what I'm trying to get 10 at here, so, you know, perturbations of a lot 11 of neurotransmitter systems that are going to 12 affect the HPA axis are also going to affect 13 the HPG axis, you know, and they might be 14 doing this -- affecting each axis separately. 15 So I think, you know, you could be having some 16 other central action affecting both of these 17 systems. So I think it's really important to 18 look at what's going on at the level of the 19 brain in much more depth. 20 Also, I need to concur with Dr. 21 O'Bryne on the need for more cort 22 measurements, basal cort measurements, in

### 202-234-4433 Neal R. Gross & Co., Inc. Page 38 1 particular, and to my mind this is especially 2 important in the chronic studies because all

3 the cort measurements that we've seen have 4 been after atrazine in the chronic studies. 5 You know, there's certainly a possibility 6 that, for one thing, the circadian rhythm of 7 cort could possibly be disrupted by atrazine. 8 Also, you know, it seems possible 9 to me that you have up-regulation of the HPA 10 axis in general in these females. It's 11 certainly a possibility. I think that needs 12 to be tested, for instance, give atrazine, you 13 know, chronically then stop the atrazine and 14 on the next day give another stressor and see 15 how their response compares to, you know, 16 animals that haven't received atrazine, I 17 think, if you want to see if you're getting an 18 up-regulation in general of the HPA axis. 19 I think there's, you know, some 20 possibilities with, you know, the proposed 21 mechanisms of action, for instance the 22 phosphodiesterase inhibitors, the increased

### 202-234-4433 Neal R. Gross & Co., Inc. Page 39 1 cyclic AMP, and cyclic AMP for instance is -- 2 cyclic AMP pathways are involved in the -- 3 stimulating the transcription of CRF. So I 4 think looking at those areas will be 5 important. 6 Other than that, I think a lot of 7 this will just feed into the next question. 8 You know, I think there's a good -- you have 9 a good starting point, but I think a lot more 10 needs to be done to draw a firm conclusion. 11 Right now the conclusions are being based on 12 correlations, and obviously correlation 13 doesn't mean causation. So I think at that 14 point we could probably go on to the next 15 question and let -- well, after other comment. 16 DR. PORTIER: Thank you. At this 17 point we'll open it up to comments from anyone 18 on the panel. 19 Dr. Krishnan. Was it -- oh, Dr.

20 Akana. 21 DR. AKANA: I wanted to reinforce 22 a point that Daniel made, is that in a lot of

### 202-234-4433 Neal R. Gross & Co., Inc. Page 40 1 the timing of samples taken, it's like 15 2 minutes or 30 minutes, and I totally 3 appreciate why that's done, particularly if 4 it's a terminal sample. But ACTH actually has 5 a much, much faster time dynamic than 6 steroids. It's up and down, so in terms of 7 like restraint, it responds in under two 8 minutes, and in our hands it's down in like 15 9 minutes. It's fast. But what it does 10 stimulate, of course, is a longer, slower and 11 sustained rise in corticosterone. 12 So in the experiments we see, 13 particularly with cannulated animals, the 14 opportunity to take samples that are sensitive 15 around the peaks and falls of where you're 16 going to find ACTH separate from 17 corticosterone are just wide open and can be 18 taken to advantage. 19 And then I'll take this point to 20 say that the urine collection and measurement 21 of corticosterone, to my mind, is a fabulous 22 tool. And what it brings to mind also is to

### 202-234-4433 Neal R. Gross & Co., Inc. Page 41 1 recall that corticosterone is carried by a 2 binding protein. When you measure 3 corticosterone you're actually, in most cases, 4 measuring total. But the bioactive portion, 5 of course, is free. So you have to 6 reinterpret this, particularly in a chronic 7 state where the binding protein will decrease. 8 And the urine samples are 9 fabulous, again, because they give you an 10 integrated measure, but you're measuring free 11 corticosterone, the bioactive fraction being 12 seen. So there's a lot of rich possibilities 13 in the kinds of data that are coming out, but 14 they could be tweaked, be a bit more 15 sensitive. 16 DR. PORTIER: Dr. Krishnan, and 17 then Dr. Hayton. 18 DR. KRISHNAN: I just wanted to -- 19 to O'Bryne's comment in relation to those two 20 slides yesterday. You saw some of the 21 magnitude of difference between the NOAEL 22 water concentration sources and the monitored

### 202-234-4433 Neal R. Gross & Co., Inc. Page 42 1 concentrations. I think that's what you were 2 referring to at some point. 3 Just look at the last one, or the 4 one to the right-most comparison, which was 5 the chronic one. There was a factor of about 6 6,000-something, where the NOAEL is all the 7 way up there, NOAEL water concentration, 8 monitored community water concentration was 9 here, and the factor was about 6,000- 10 something, 6,200 or 500, whatever. 11 The classification I was trying to 12 get when you all walked out on me at the end 13 for the session there -- 14 (Laughter.)

15 DR. KRISHNAN -- was that the 16 expected factor, or the target factor is 17 5,000. That's what wasn't on the figure. The 18 difference was being shown as 6,000-something. 19 But the expected or the target factor in the 20 risk assessment was about 5,000. That was my 21 comment yesterday. 22 Because of the uncertainty factor

### 202-234-4433 Neal R. Gross & Co., Inc. Page 43 1 on the source contribution that's accounted 2 for in the NOAEL to bring it down to a human 3 relevant concentration. So that would make a 4 difference. Because down below is what 5 actually the humans are consuming as water 6 concentration. Up there is you take the dose 7 given to the animal and then try to solubilize 8 them in the water that can be consumed. 9 So, you know, that -- I just 10 wanted to clarify that. So I'm trying to -- 11 DR. LOWIT: Kannan? Dr. Krishnan?

12 DR. KRISHNAN: Yes. 13 DR. LOWIT: We had some questions 14 about Dr. Pastoor's slides also, about the 15 differences in some of the numbers. But 16 the -- but one thing that I know to be true is 17 that the -- whether -- the magnitude of the 18 totality of the uncertainty factors is not 19 5,000, and that's the value that I think that 20 you're quoting. It's either 300 or 1,000 -- 21 DR. KRISHNAN: Okay. Well, the -- 22 DR. LOWIT -- depending on the --

### 202-234-4433 Neal R. Gross & Co., Inc. Page 44 1 DR. KRISHNAN -- 5,000 I quoted is 2 based on what he presented. He said 1,000 was 3 the factor involved in that particular 4 assessment, including a 10 for children. And 5 then he said 20 percent was included as a 6 source contribution. That was presented 7 during his talk, and then there was some other

8 comments -- 9 DR. LOWIT: Yes, and --

10 DR. KRISHNAN -- that came after.

11 DR. LOWIT -- too bad Dr. Pastoor 12 couldn't clarify those numbers with the 13 microphone on, because I think some of the 14 numbers he was quoting, I think they were 15 getting mixed up, and there was some 16 differences in between the OW and the 17 Pesticides Office procedures that got blended 18 in that conversation. It's really confusing. 19 DR. KRISHNAN: Yes. No, so I just 20 wanted to, you know, keep in that mind. I 21 didn't want that to be one of the driving 22 forces of our discussion, or how you view

### 202-234-4433 Neal R. Gross & Co., Inc. Page 45 1 things. 2 The other thing is that the focus 3 on the toxicity pathway is based on the 4 National Academy of Sciences recommendations, 5 and is unquestionably on a solid footing the 6 way the Agency has put it together. But one 7 of the things that worries me a bit is that I 8 hope there -- the assessments won't take us 9 down a pathway of establishing no observable 10 perturbation effect level without, you know, 11 regard to the no observable address effect

12 level. 13 So I think at some point as this 14 matures along, that relationship has to be 15 strengthened and clearly presented, such as a 16 like an AUC of an LH surge works in an 17 organism level effect or something, so that 18 the perturbation levels for specific pathways 19 that are chosen, even though, you know, some 20 are blurred along the line with respect to the 21 outcome in the animals. 22 As long as those are chosen for a

### 202-234-4433 Neal R. Gross & Co., Inc. Page 46 1 benchmark, those analyses or other kind, with 2 particular reference to, or in relationship to 3 the organism that will affect. I think that 4 will be reasonable. I just wanted to add that

5 comment. 6 DR. PORTIER: Dr. Hayton? 7 DR. HAYTON: I have a question for 8 the discussion, and I'm trying to understand. 9 I know we can measure perturbations in the 10 HPA/HPG axis signals, at what point do you 11 think those constitute an adverse health 12 effect? I mean me speaking into this 13 microphone, my corticosterone probably is 14 going up, but is -- 15 (Laughter.) 16 DR. HAYTON -- is that an adverse 17 health effect? And it seems to me there's not 18 much linkage between all those signals and 19 adverse health. And I ask this because it's 20 important for a later question, so maybe it 21 gets addressed in later questions too, but any 22 perspective on that?

### 202-234-4433 Neal R. Gross & Co., Inc. Page 47 1 DR. PORTIER: Dr. O'Byrne? 2 DR. O'BYRNE: I think acute 3 effects are not important. I think there's 4 ample evidence of that. But chronic elevated 5 levels are putting you at risk, and there's 6 huge amounts of clinical data for that in both 7 men and women in terms of infertility and the 8 inverse relationship. 9 However, whatever method you use 10 to reduce those stress levels, whether it's 11 cognitive behavioral therapy, talking to women 12 and just giving them a nice environment to 13 relieve their tensions, et cetera within -- 14 for example, within fertility clinics, you can 15 restore fertility quite easily. I mean, 16 again, there's some magnificent data coming 17 out of the US from Sarah Berger's lab where 18 you can get an 80 percent restoration of 19 normal fertility through a short course of 20 cognitive behavioral therapy. I mean it's 21 just mind-blowingly astonishing data. So 22 chronic levels, yes, are a problem.

### 202-234-4433 Neal R. Gross & Co., Inc. Page 48 1 DR. PORTIER: Dr. Regal had her 2 hand up, and then Dr. Selvage, and then Dr. 3 Williams. 4 DR. REGAL: Just a quick comment 5 in terms of Dr. Pruett's data where he showed 6 that there were alterations in immune system 7 function that correlate -- or immune system 8 parameters that correlated with area under the 9 corticosterone curve. So that under his 10 situations where he was dosing the animals, 11 there was some function change. 12 DR. SELVAGE: Dr. Selvage. I 13 concur with that. I just wanted to add that, 14 you know, it definitely is the chronic 15 activation of the HPA axis that you want to 16 worry about, and there's just a huge laundry 17 list of problems associated with that, 18 including immune system dysfunction, also 19 reproductive dysfunction, psychological 20 disorders, et cetera. So I think that is what 21 we should be mostly concerned about, if we're 22 going to be concerned.

### 202-234-4433 Neal R. Gross & Co., Inc. Page 49 1 DR. PORTIER: I think Dr. Lowit 2 wanted to slip in before Dr. Williams. 3 DR. LOWIT: Yes, we have -- Ralph 4 and Dr. Cooper and I were just, I think at the 5 same time, having the same question, and it 6 may not go here. As I've scanned the 7 questions, it may actually go in 1.9, but I'm 8 going to ask it anyway because it's relevant 9 to the discussion. 10 The discussants are talking about 11 acute and chronic. Where do you turn the -- 12 where does -- you turn from acute to chronic, 13 and keeping in mind what our needs are here, 14 to define some temporal window to establish 15 regulatory limits. So what do we mean as 16 chronic, and when we go from a whole bunch of 17 acutes to something that becomes chronic? 18 DR. PORTIER: So we'll keep that 19 question in mind, as Dr. Williams come in. 20 DR. WILLIAMS: I just would like 21 to ask for clarification on the discussion 22 with Dr. Krishnan and Dr. Lowit. I didn't

### 202-234-4433 Neal R. Gross & Co., Inc. Page 50 1 understand what you were getting at terms of 2 the 5,000 and 1,000, and what do you really 3 mean, like for the more lay person in that? 4 Do you mean that the doses used are even 5 higher than they ought to be, or should the 6 relevant doses be lower, or what -- 7 DR. LOWIT: Well, if you remember 8 from Dr. Pastoor's series of slides, what he 9 was doing in those slides was to compare the 10 atrazine in drinking water monitor levels that 11 Syngenta has calculated with their box and 12 whisker plots across different durations. So 13 basically what Dr. Pastoor was trying to do in 14 a couple of slides was to put everything that 15 we're talking about in a risk assessment 16 context, in bullet form that was quick. 17 And it's -- there's enough nuance 18 in the differences there that there's life 19 stage, there's time, there's different 20 offices. He had things on there that come 21 from the Pesticides Office and from the Water 22 Office, and so it was a blend of a lot of

### 202-234-4433 Neal R. Gross & Co., Inc. Page 51 1 different things on one slide, and he just 2 didn't have time to really go through and 3 explain what all of the columns were. And so 4 in the haste, it just got really quick, 5 because everyone was tired. 6 So what he was doing in that 7 series of slides, and I don't want to speak 8 for him, but I think this is what he was 9 doing, was to compare different aspects of 10 what goes into a risk assessment to the water 11 monitoring data as a reality check, as a 12 reality check to see how the doses in the 13 animal studies compare to what humans get in 14 the water, and actually US water monitoring, 15 and to -- I believe his point was to show that 16 the magnitude between what's in the animal 17 studies that's used as that line in the sand 18 versus what's in the monitoring data are 19 pretty large differences in there. 20 But what got lost in the speed was 21 the nuance of how the uncertainty factors are 22 used, how the conversation from a milligram to

### 202-234-4433 Neal R. Gross & Co., Inc. Page 52 1 a kilogram to a ppm is done across different 2 life stages. So I think that's where a lot of 3 the confusion has been of how some of those 4 numbers were derived. 5 DR. WILLIAMS: So if you take sort 6 of the number of the animal exposure that's 7 closest to some adverse affect in any life 8 stage in humans, is there anything that's 9 closer than something like 100,000 that he was 10 talking about? Like at what point are we -- 11 like how far off are the animal studies -- 12 DR. LOWIT: Oh, it's much

13 closer -- 14 DR. WILLIAMS -- from any possible 15 risk to humans?

16 DR. MENDEZ: It's closer to 17 100,000 -- 18 DR. LOWIT: Nelson Thurman's going 19 to come up here. 20 DR. MENDEZ: If you could just 21 give us a second. But I just wanted to add to 22 what Dr. Lowit was saying in terms of the

### 202-234-4433 Neal R. Gross & Co., Inc. Page 53 1 uncertainty factors. When the Office of 2 Pesticide Programs calculated drinking water 3 level of comparison, we consider the body 4 weight of the individual drinking, for adults, 5 two liters of water. The Office of Water does 6 it slightly different with a 20 percent 7 contribution coming from the water. So that's 8 where the difference between the health 9 advisory levels and the DWLOCs come in. 10 DR. LOWIT: And it's further 11 complicated by the MCL comes from a fairly old 12 dog study whereas all the Pesticides Office 13 work comes from the mode of action that you've 14 heard quite a bit about. Not the HPA part but 15 the HPG part. 16 DR. PORTIER: Instead of kind of 17 going off on this, Carmen, maybe at the break 18 we'll sit down and let you explain how they 19 kind of use uncertainty factors and clarify 20 it. But I think most of the panel probably 21 understands this? No? Okay. I just wanted

22 to double check.

### 202-234-4433 Neal R. Gross & Co., Inc. Page 54 1 (Laughter.)

2 DR. PORTIER: So we'll take two of 3 you because -- no, I know Ken Delclos knows 4 this. Okay. Well, then I stand corrected. 5 Continue. 6 DR. LOWIT: It might actually make 7 more sense if we want to either have Dr. 8 Pastoor explain it himself, or alternatively 9 a group of us from the Agency can, at the 10 break, throw a slide together of what some of 11 the pieces are -- 12 DR. PORTIER: Why don't we do

13 that. 14 DR. LOWIT -- if that would help?

15 DR. PORTIER: Dr. Horton? 16 DR. HORTON: No, all we're really 17 trying to get is a sense -- we don't need a 18 detail, we're just trying to get a sense of

19 how close we are to safe versus unsafe as we 20 go -- as we look at those box and whiskers 21 relative to what --

22 DR. LOWIT: That's not a two-word

### 202-234-4433 Neal R. Gross & Co., Inc. Page 55 1 answer. It's -- 2 DR. HORTON: Okay. Okay. 3 (Laughter.) 4 DR. PORTIER: I'm going to ask Dr. 5 Greenwood to step here for a minute, because 6 he's usually pretty good at explaining stuff.

7 DR. GREENWOOD: I don't want to 8 try and explain, I think we need to get 9 this -- I think it is important because we've 10 already heard about, from several people, 11 about the importance of pharmacokinetics, and 12 that's something the three of us here have 13 been discussing on and off looking at the 14 papers. 15 It's not straightforward to 16 interpret them, and I think it is important 17 that everybody understands the relevance of 18 the levels in the water compared with the 19 probable or possible adding under the curve in 20 the plasma. We want to try and relate what 21 levels of dose given to the animals gives you 22 those areas and what sort of concentrations in

### 202-234-4433 Neal R. Gross & Co., Inc. Page 56 1 the water are giving what sort of exposure in 2 the gut to humans. So in order to sort this 3 out, I think we all need to be clear about 4 what's going on here. 5 DR. PORTIER: My question is, is 6 this the question to be doing it on? 7 DR. LOWIT: That's for, I think, 8 for you to judge as the Chair. But if it's 9 going to cause at least certain numbers of the 10 panel to struggle through the responses to 11 some of the questions, I think at the break 12 we -- that, you know, that the Agency takes, 13 you know, an extra five minutes and we throw 14 something together to help you understand a 15 little bit more of the risk assessment 16 process. But otherwise, I think the better 17 place in 1.9, but that may be tomorrow. 18 DR. PORTIER: No, I think we 19 should do it today, but I'm just trying to 20 figure out whether in this question, which 21 has, you know, six very specific questions, 22 we're king of getting side-tracked, and I

### 202-234-4433 Neal R. Gross & Co., Inc. Page 57 1 don't want to get too side-tracked on that. 2 Dr. Krishnan. 3 DR. KRISHNAN: I think one of the 4 reasons for the side-track being whether the 5 doses we are talking about are really out of 6 whack or is there any relevance at all, 7 because with some of the thousands of factors 8 we saw, I think that's where we got a bit

9 confused. 10 If I can take you all -- I'll only 11 take two seconds -- page number 5 of Pastoor's 12 presentation, if we can get back to that, 13 that's where the factor is. Well, if you can 14 find that, and we can --

15 DR. PORTIER: That's what I was 16 thinking, if EPA could bring that up after the 17 break, we'll have a 10 minute presentation by 18 EPA so they can clarify that. How about that? 19 DR. LOWIT: Yes, we may have to 20 make our own version of that one, because we 21 weren't sure about some of what was -- it was 22 just a confusing presentation. We just have

### 202-234-4433 Neal R. Gross & Co., Inc. Page 58 1 our own version, if that's okay? 2 DR. PORTIER: That's fine. 3 DR. LOWIT: I hope Nelson's going 4 help. 5 DR. PORTIER: Okay. So we'll come 6 back to that and, you know, we'll clarify that 7 definitely today, before lunch. 8 Okay. So if we can get back to 9 these questions. Where are we? Dr. Akana. 10 DR. AKANA: So, when you talk

11 about what are the health concerns of acute 12 and chronic for a single administration of 13 atrazine that's not pharmacological, in the 14 adult I don't think there are major health 15 consequences to a single exposure. In the 16 adult. And then later in the session we'll be 17 talking about doses given to prenatal or 18 gestational or pubertal animals, and that's a 19 whole different ball of wax. 20 In terms of the chronic measures, 21 the problem with looking at what are the 22 health outcomes on chronic exposure is you

### 202-234-4433 Neal R. Gross & Co., Inc. Page 59 1 have a wealth of endpoints to look at, all 2 with different time domains. So you could 3 pick one, any one. You could pick 4 reproductive, immune, body weight, which is 5 one of my favorite cheap endpoints, and what 6 I would imagine is, will you hypothetically 7 want that water exposure chart that we've 8 talked about, and floating above it you want

9 outcomes. 10 What is the first -- what are the 11 responses of the animals to the LOAEL? You 12 know, how major are we talking about, a 13 thousand-fold response in the animal, you 14 know, what's our concern here. So while we 15 construct the water one, what we've one day 16 want to work towards is a hypothetical outcome 17 box and whisker diagram floating right above

18 the water. 19 DR. PORTIER: Dr. Selvage. 20 DR. SELVAGE: Yes, I just wanted 21 to make a couple of comments regarding this 22 issue, one being atrazine -- personally I'm

### 202-234-4433 Neal R. Gross & Co., Inc. Page 60 1 not so concerned about atrazine levels in the 2 plasma, per se. You know, this is stuff 3 that's going to get into tissues, you know, 4 I'll get -- it gets into the brain, et cetera. 5 And if I remember correctly, it hangs out in 6 the brain for some time. I don't think it 7 gets metabolized in the brain very quickly, so 8 I think we need to be concerned about levels 9 in the brain, et cetera. I think that's 10 important when you're talking about this 11 issue.

12 The other comment I wanted to make 13 regarding chronic versus just acute HPA 14 activation is we almost have to have two 15 discussions, one concerning males and one 16 concerning females because of the lack -- 17 supposed lack of habituation you see in

18 females. 19 DR. PORTIER: Any additional 20 comments on this? This is really good. The 21 problem with the first question is we always 22 want to put everything under the first

### 202-234-4433 Neal R. Gross & Co., Inc. Page 61 1 question, and I'm trying to avoid that. I 2 think -- you know, I've heard a lot of good 3 comments from this. 4 Dr. O'Byrne, did you get good 5 notes on this? You think you're going to be 6 able to write up this first one? 7 DR. O'BYRNE: I'll borrow yours.

8 DR. PORTIER: I don't have -- I 9 have three of these -- oh, right yes. Yes, I 10 was going through your six questions; I think 11 they've answered -- we have answers to your 12 six components of this first question. It 13 seems that there is some agreement, 14 concurrence with the hypothesis, but there's 15 things around it that the panel wants to fill 16 in with your model. I guess that would be a 17 fair thing to say.

18 Anna? 19 DR. LOWIT: I think we'll sort of 20 hold back any other clarification questions 21 till we hear the next couple of questions 22 because I think combined we may have a

### 202-234-4433 Neal R. Gross & Co., Inc. Page 62 1 clarification or two. 2 DR. PORTIER: Okay. With that I 3 think we'll move on to Question 1.3, which is 4 another multi-part question. 5 DR. LOWIT: And, Joe, if you could 6 come do your -- 7 DR. PORTIER: Magic.

8 DR. LOWIT: But I'll read from the 9 paper copy, I guess. 10 DR. PORTIER: By the way, I take 11 responsibility for asking the Agency to read 12 the full questions before the panel because 13 the questions are not one question, they're 14 multi-part questions with conditions said at 15 the beginning, and I wanted to make sure we 16 all saw those and were aware of it as we began 17 our discussion. Sometimes we simplify the 18 questions, but this was not a good case for 19 simplifying the questions. 20 DR. LOWIT: The Agency has 21 preliminarily concluded that atrazine directly 22 targets cells within the HPA axis, Section 3.2

### 202-234-4433 Neal R. Gross & Co., Inc. Page 63 1 and 3.3.2.3 of the draft issue paper -- I 2 don't know if I got all that or not -- and the 3 increased activity of the adrenal axis does 4 not reflect non-specific stress. Evidence for 5 this conclusion is based on the following 6 observations: 7 Bullet number 1, several studies 8 report increased adrenocorticotropic hormone, 9 ACTH, and corticosterone levels immediately 10 following a single explore to atrazine and its 11 two metabolites -- I won't say the whole 12 names -- DIA and DEA, but not DACT. This data 13 comes from the Laws, et al., Fraites, et al., 14 and Pruett, et al., studies. 15 A single intravenous 16 administration of DEA in vivo also causes an 17 immediate increase in ACTH and adrenal hormone18 release indicating that a chlorotriazine19 induced GI streass is not driving the hormonal 20 response. The adrenal corticosterone response 21 to continued oral exposure to atrazine did not 22 habituate in rats or mice. And that comes

### 202-234-4433 Neal R. Gross & Co., Inc. Page 64 1 from the Fraites, Laws, and Pruett papers. 2 Also, although atrazine induced a 3 rapid increase in ACTH, prolactin secretes was 4 not affected in the same animals. This is 5 unusual in that an increase in both ACTH and 6 prolactin are typically observed in response 7 to a number of physiological and psychological

8 stressors.

9 Please comment on the extent to 10 which the available evidence supports the 11 preliminary conclusion that atrazine and its 12 intermediate metabolites, DIA and DEA, induce 13 changes in the HPA axis as a result of a 14 direct action on the HPA tissue, and such 15 tissue -- such changes are not due to a 16 generalized or non-specific stress response.

17 Are there data on other substances that would 18 support this conclusion? 19 DR. PORTIER: Dr. Selvage? 20 DR. SELVAGE: Okay. That's really 21 almost a one-part question, when you think 22 about that way.

### 202-234-4433 Neal R. Gross & Co., Inc. Page 65 1 We can be optimistic. Let's see, 2 first I wanted to just give a preliminary 3 couple of remarks. I'm going to -- for my 4 answer I stuck to a mechanism of action. I'm 5 not really considering dose so much, because 6 the doses are obviously very, very high for 7 this. 8 Another thing I wanted to say, and 9 this is just my own personal view, is the term 10 non-specific stressor, generalized stressor. 11 You know, there's certainly stressors that 12 activate the HPA axis a number of ways, but I 13 think for each stressor, I think that there 14 are fairly specific, for instance, neuro 15 pathways, that can be activated, and can be 16 delineated with lots and lots and lots of 17 work. So I think that I'm just not a big fan 18 of the non-specific stressor. However, I do 19 realize that gets used a lot, so I just wanted 20 to say that. 21 Okay. And so then to get on to 22 the question about whether there's a direct

### 202-234-4433 Neal R. Gross & Co., Inc. Page 66 1 action on HPA axis tissues, once again, with 2 the HPA axis, in response to a wide variety of 3 homeostatic challenges, you know, just about 4 any homeostatic challenge you can throw, an 5 animal you can get an HPA axis response. So 6 to determine a specific action, per se, is not 7 easy, especially a specific action on HPA 8 tissues, because there could be multiple 9 actions on specific HPA tissues than actions 10 on other tissues that in turn affect the HPA 11 axis. 12 So I guess the short answer to 13 this is, you know, I don't think there's 14 enough data yet. We need more information 15 regarding atrazine's affects at a variety of 16 levels. So, and also interpretation of the 17 results presented so far is a little bit 18 difficult for me because we've got -- we're 19 using different strains of animals and 20 different species. 21 So we've got evidence in mice and 22 we've got evidence in, well, now, with Dr.

### 202-234-4433 Neal R. Gross & Co., Inc. Page 67 1 Handa's work, three different -- at least 2 three different strains of rats, and different 3 strains of rats all will response differently 4 to the same stressor and, you know, even the 5 vendor you get your rats from can affect how 6 they're going to respond to a stressor. 7 So it's difficult to kind of make 8 a -- you know, take all this information and 9 think that it all really, you know, fits 10 together in a cohesive manner with all these 11 different animals. On the other hand, you've 12 got a bunch of different animals and your 13 getting a similar response. So that's also a 14 positive. 15 So I guess -- let me see, once 16 again, you know, I guess it's possible with 17 the information available that the HPA 18 disruption by atrazine could be due to a 19 direct affect on HPA tissues. The evidence 20 that's been giving the supporting evidence, 21 first of all, is simply that atrazine 22 activates the HPA axis when given

### 202-234-4433 Neal R. Gross & Co., Inc. Page 68 1 peripherally, you know, and that's obviously 2 an important finding. 3 Also, other stressors such as 4 restrain stress, were able to cause prolactin 5 release, whereas atrazine administration did 6 not cause prolactin release, and that's given 7 as supporting evidence.

8 Also the fact that sub9 diaphragmatic vagotomy didn't block the HPA 10 axis response to atrazine at least rules out 11 gut irritation as the means of activating the 12 HPA axis, and then we have the information 13 that when we give, I believe it was DIA was 14 given IV, you're still able to activate the 15 HPA axis. Some other information I would say 16 would, you know, at least preliminary support, 17 looking into this hypothesis, is that atrazine 18 can get into the brain and can have affects at 19 the brain. 20 Having said that, I just think 21 there's not enough evidence to really say that 22 atrazine is acting directly at HPA tissues,

### 202-234-4433 Neal R. Gross & Co., Inc. Page 69 1 although you can't say it is either. And 2 with -- for instance you've got this 3 habituation of the cort response that did not 4 seem to occur, but you got -- there's 5 habituation of the ACTH response, which to me 6 makes me wonder is something going on at the 7 level of the adrenal gland, and there's some 8 information, I believe in amphibians and fish, 9 that actually -- and I believe this was 10 discounted by the EPA, probably for good 11 reason, but those two studies showed actually 12 a decrease in cort synthesis in those species. 13 So if that's actually true, the 14 you probably are working at the hypothalamic 15 level to activate the HPA axis, or, you know, 16 or some other level and not directly at the 17 adrenal gland. However, more information is

18 needed. 19 So, you know, I think there's a 20 lot of alternative hypotheses that need to be 21 investigated. The first one, which I've 22 already brought up, is I think you might have

### 202-234-4433 Neal R. Gross & Co., Inc. Page 70 1 an overall increase in HPA responsiveness 2 that's been to stressors in general in these 3 chronic HPA -- in these chronic atrazine 4 administration studies, which, once again, 5 brings us back to why it's important to get 6 baseline cort measurements and other time 7 points for cort. 8 Also, in the studies where we're 9 looking at chronic atrazine administration 10 over four days, or Pruett's study over 28 11 days, there were no measurements made in 12 between. And you can get alterations, you 13 know, in the HPA axis over time that we just 14 might not have seen. 15 And I think you can't really do 16 this so easily in mice, but in rats you can 17 certainly put in an IV catheter and keep it 18 patent for a decent amount of time, and you 19 could be making these measurements. So I 20 think that's something that could, and should, 21 be done. So, you know, you put in an IV 22 catheter and you indicate many draw blood

### 202-234-4433 Neal R. Gross & Co., Inc. Page 71 1 draws. I mean they're not going to stay 2 patent forever, but you can still do that and 3 it'd be helpful. 4 So there's also, you know, just 5 many other parameters that I think atrazine 6 could be affecting that could activate the HPA 7 axis. You know, you could get physiological 8 changes in the periphery that I don't think 9 have been examined. I did see one paper that 10 indicated atrazine actually caused 11 hypotension, a decrease in blood pressure. A 12 decrease in blood pressure activates the HPA 13 axis. I think that would need to be examined. 14 Let's see, also I think 15 sympathetic activation, activation of both 16 central catacombing noradrenergic system needs 17 to be examined more thoroughly, and also we 18 need to look at, in these animals, and you 19 could do this if you have an IV catheter in 20 place, at least -- it's a little tough, but 21 you want to look at norepinephrine and 22 norepinephrine secretion in the periphery,

### 202-234-4433 Neal R. Gross & Co., Inc. Page 72 1 because that can cause a lot of the affects 2 that have recorded, especially the immune 3 system affects.

4 What else do I have here. Once 5 again, I think it's important to look at more 6 central mechanisms, as Dr. Akana said, CRF, 7 vasopression, once again norephinephrine. 8 Also I think looking at the affects for PDE, 9 phosphodiesterase inhibitor, inhibition could 10 be looked at more thoroughly in the pituitary, 11 as well as in the brain because, you know, a 12 cyclic AMP, when you're increasing cyclic AMP,13 you know, if you're doing this fairly non14 specifically, you could just be, you know, 15 causing a myriad of effects we haven't seen. 16 So those are my main comments 17 regarding the specific action there. You 18 know, I think other people will add a lot more 19 to this. In terms of evidence for other 20 substances, simazine was tested, which is like 21 some of the atrazine, and that had lesser, I 22 believe, activation the HPA axis, but it did

### 202-234-4433 Neal R. Gross & Co., Inc. Page 73 1 activate the HPA axis acutely. Was that done 2 chronically? I don't -- simazine? It was 3 just -- okay, it was acute. Okay. But it did 4 have an affect, you know. 5 Also, there's other, you know, 6 molecules like atrazine that can get into all 7 sorts of different tissues, you know. It's 8 obviously a different molecule and probably 9 will get in more tissues. But ethanol, for 10 instance, the number of way that agents like 11 that can activate the HPA axis are legion. So 12 I just think it's way too early to draw a 13 conclusion that you're directly affecting HPA 14 tissues. So give Dr. Cooper a lot more money

15 to do --

16 DR. PORTIER: Dr. Akana. 17 DR. AKANA: First off, in the HPA 18 world, if you're interested in an agent that 19 stimulates ACTH and you want to know if it's 20 non-specific, the answer is there's, in my 21 world, no such thing as non-specific stress. 22 You have uncontrolled stress, you have

### 202-234-4433 Neal R. Gross & Co., Inc. Page 74 1 parameters coming that you don't know about. 2 So in the HPA world, half the experiment is 3 controlling your situation to exquisite, 4 immaculate basal levels. 5 And so in both acute injection and 6 in chronic, it is really important to know you 7 have your animal in a basal condition. And in 8 many cases, that's corticosterone. Now I know 9 that's an inhibition against sampling from 10 animals if you don't have a catheter in, but 11 if you look at the literature, if you really, 12 really need to know, you can measure it in 13 urine, you can measure it in fecal boli, if 14 you really have to, which you can. 15 So I think what I can say is that 16 in response to acute injection, does atrazine 17 stimulate ACTH, I go for that. Yes, it 18 definitely does. And the more recent studies, 19 to me, are much more credible because they

20 show a wonderful control of basal ACTH and 21 corticosterone as an initial condition. And 22 that's critical in my book.

### 202-234-4433 Neal R. Gross & Co., Inc. Page 75 1 Let's see, on the question of 2 gastric distress, I don't think it's quite 3 definitive yet that the response to atrazine 4 is not in the gut; we have one nice vagotomy 5 experiment. But in the feeding world there's 6 an exquisitely simple experiment, is because 7 rats, and I believe mice, cannot vomit. If 8 they are given something to eat or gavage, 9 they can't get rid of it. So what they can do 10 is they run and will eat inert clay, kaolin. 11 And you can measure this. So you provide in 12 the cage a source of kaolin, and you measure13 how much they eat. And it's very old14 fashioned and very simple. 15 And in the feeding world they have 16 many, many, many measures for measuring the 17 gastric distress, and a lot of them are 18 behavioral. And I think the atrazine studies 19 may be ready to look at different kinds of 20 behaviors as very sensitive indicators of what 21 kind of actions they're getting. 22 I looked in my time, I didn't see,

### 202-234-4433 Neal R. Gross & Co., Inc. Page 76 1 what are any affects of -- on behavior with 2 atrazine administration? 3 DR. COOPER: I'd just add one 4 quick point. Michell Hotchkiss, working in 5 Dr. Law's lab, has done the pica studies, 6 and -- right. So we have that data, it just 7 hasn't been submitted yet. 8 DR. AKANA: Oh, that will be 9 really useful. 10 DR. COOPER: And I guess without 11 giving the specifics in general, it turns out 12 that you see no change in pica behavior, no 13 increase in inert -- 14 DR. AKANA: You see no change. 15 That's promising. Thank you. 16 That also reminds me that in very 17 old traditional studies with chronic stress, 18 at the end of the experiment they would 19 examine the gut for ulcers, you know, very 20 classic, very old, and very direct in this 21 particular kind of study with gavage. 22 Now when we come to the question

### 202-234-4433 Neal R. Gross & Co., Inc. Page 77 1 of habituation, this is a very interesting 2 nugget in this study, and it raises some 3 possibilities. First of all, in the 4 male/female difference, we'll remember that 5 females have a lot more of the binding protein 6 CBG. So this may be obscuring some of the 7 responses we see. I would love to know what 8 is the actual free corticosterone response in

9 those females. 10 And then immediately the second 11 thing is, I'm intensely interested in those 12 adrenals, and I think it's ready for studies 13 of adrenal sensitivity, both in vivo and in 14 vitro to be initiated. And that might help 15 clarify what's the male/female difference. 16 And then in my particular world, 17 when we talk about habituation and the HPA 18 system, there is one particular brain nuclei, 19 the peri-ventricular thalamus -- excuse me -- 20 that's correct, the peri-ventricular thalamus 21 of the hypothalamus and I wonder if there's 22 some special susceptibility in the female.

### 202-234-4433 Neal R. Gross & Co., Inc. Page 78 1 And then on the concern about 2 prolactin, from -- I'm to a prolactin expert, 3 but from my review of the literature, the 4 prolactin response is not always obligate with 5 a stress response. And also, depending on 6 whether it's a predicable or non-predictable 7 stress, that's GeneQuant. 8 And also the time course can vary 9 from that which you find with corticosterone. 10 So depending on when you sample, you may miss 11 a prolactin response. There's also a diurnal 12 difference in the timing of prolactin in 13 response to, say, restrained stress. So the 14 prolactin divergence, per se, do not concern 15 me at this time. And, oh, the last point 16 which may be of interest is that the prolactin 17 response can be very dependent on the dopamine 18 total for the animal. So that's something to 19 just flag in the back of your mind. 20 DR. PORTIER: Dr. O'Byrne --

21 LeBlanc? 22 DR. O'BYRNE: I also agree, this

### 202-234-4433 Neal R. Gross & Co., Inc. Page 79 1 business about non-specific stress really does 2 muddy the water and should be discontinued. 3 Adding uncontrollable stress muddies it just 4 as much, in my mind. I mean people who work5 in the stress world are plagued by sub6 clinical stresses, which have a nasty habit of 7 summating and synergizing and screwing up your 8 experiments. So stress is a stress, and it 9 depends on your ability to detect it. 10 In terms of the dynamics of ACTH 11 and cort release in response to atrazine seem 12 pretty normal to me. The business about the 13 ACTH not being maintained and cort being 14 maintained doesn't necessarily surprise me, 15 but from -- the HPA axis is not my baby. But 16 I do recall being confused by the literature, 17 graphs showing that ACTH doesn't always 18 increase. 19 So I think there are changes in 20 sensitivity to the -- of the adrenal level, 21 and I think this is an amazingly dynamic 22 system. So you don't necessarily always need

### 202-234-4433 Neal R. Gross & Co., Inc. Page 80 1 the brain to get the same degree, I think, of 2 cort response. It's a very sensible system. 3 We can switch over to a semi-automatic, 4 peripheral system, I think, in the context of 5 chronic, ongoing, or repeated stresses.

6 In term of the tools that could be 7 applied, we've got CRF1 and CRF2, not counting 8 mice. They should be used in these sorts of 9 experiments so you can get -- you know, 10 differentiate the involvement of the receptor 11 sub-types. And even if you don't want to use, 12 not counting mice -- and I have problems with 13 them, they're not as clean as people think 14 they are -- there are amazingly selective CRF1 15 and CRF2 receptor antagonists, which are 16 extremely selective, extremely potent, and

17 those are tools that should be used. 18 In the context of prolactin, I 19 don't know anything about prolactin, to be 20 honest. But it does seem a little puzzling to 21 me. But trying to do some work last night, I 22 discovered an amazing paper in 1990 -- I can't

### 202-234-4433 Neal R. Gross & Co., Inc. Page 81 1 remember where it was published -- 2 Neuropeptides, which is, you know, a 3 reasonable journal. 4 But CGRP, given intraperitoneally5 and subcutaneously, blocks the prolactin6 induced -- the stress -- that blocks the 7 progesterone increase in response to stress --

8 I can't remember what the stress was -- 9 thermal stress and injection stress. And 10 that's quite interesting because I did a bit 11 of work on CGRP, which is quite potent in 12 terms of stimulating the HPA axis and 13 inhibiting the HPG axis. That's what we 14 discovered. This is calcitonin gene-related 15 peptide. 16 I mean the work didn't go any 17 further, we just beautifully described it, and 18 it fitted within the stress arena. But it was 19 quite interesting to discover this paper, that 20 it blocks the prolactin response. 21 And I think Susan's comments about 22 the dopamine system in the brain controlling

### 202-234-4433 Neal R. Gross & Co., Inc. Page 82 1 prolactin, there is a paper from Garla in 2 1990 -- unfortunately it's in Life Science, 3 which is a pretty awful journal, so I'm not 4 quite sure whether it'd be worth quoting -- 5 but there they talk about the increases and 6 decreases in prolactin in response to 7 different stresses. So I think there's very 8 old literature on this discordance, which 9 perhaps shouldn't be of great surprise, that's

10 what I read. 11 DR. COOPER: One of the things 12 that we find consistently within the 13 hypothalamus, especially when we looked in the 14 mediobasal region when we did our 15 catecholamine work, and it's published data, 16 is that we do see the one thing that hangs in 17 there as the dose goes down is an increase in 18 dopamine, and these are, again, acute 19 exposures. 20 This is in contrast to the 21 neurotox papers that you saw that implied 22 there was dopamimetic neurotoxicity. We see

### 202-234-4433 Neal R. Gross & Co., Inc. Page 83 1 within the mediobasal hypothalamus an increase 2 in dopamine concentration in DOPAC, both of 3 which, of course, you know will inhibit 4 prolactin. And in our 2000 paper you saw 5 post-dependent decrease in serum prolactin in 6 estrogren-primed animals. And the other thing 7 about that is that seemed to be a brain effect 8 because of certain dynamics between how much 9 dopamine -- I'm sorry, how much prolactin was 10 present in the pituitary of those animals. So 11 what you're saying is consistent with that.

12 DR. PORTIER: Dr. LeBlanc. 13 DR. LeBLANC: I agree that there's 14 an accumulating body of evidence that would 15 indicate indeed that atrazine is affecting the 16 HPA axis in a manner that's independent of a 17 generalized stress response. But I think the 18 key word in the statement we have on the board 19 there is preliminary, preliminary conclusion 20 and I hope that's emphasized by EPA. And I 21 think we've heard that from everyone has 22 spoken, the evidence is accumulating, but as

### 202-234-4433 Neal R. Gross & Co., Inc. Page 84 1 there are only -- I don't think we can 2 conclude at this point that that is indeed the 3 case. We need more information. 4 And I think it's important to 5 recognize that in terms of a generalized 6 stress response, it's not driven only by ACTH, 7 and the EPA had addressed that and they've 8 looked at the prolactin response and they use 9 that as part of their evidence, and I think 10 that's good. But there are certainly other 11 hormones that should be considered. 12 And one has, thyroxine, we've 13 heard at least two studies with which 14 thyroxine levels have been evaluated, and 15 typically thyroxine levels are increased with 16 a generalized stress response. However, the 17 studies that we were exposed to, thyroxine was 18 either not affected or decreased. So, again, 19 that would argue against a generalized stress 20 response. 21 Another hormone is growth hormone. 22 It's typically decreased in stress response,

### 202-234-4433 Neal R. Gross & Co., Inc. Page 85 1 and I don't think anyone's looked at growth 2 hormone, but it might be something to consider 3 as additional evidence as to whether or not 4 we're looking at a generalized stress 5 response. And I think another interesting 6 aspect with respect to growth hormone, in the 7 rat at least, is that it -- growth hormone 8 regulates sex-specific cytochrome P450s in the 9 liver of the rat that could impact 10 corticosterone metabolism. 11 I'm not sure that they would 12 affect atrazine metabolism, but could affect 13 corticosterone metabolism. So it may be a 14 very -- it may provide some additional 15 linkage, or explanation that relates to the 16 sexual -- sex differences that we see in some 17 of the atrazine responses like habituation. 18 Everything else I have here I 19 think has been covered. I'm not going to be 20 repetitive. One other point, I think it's 21 important also to recognize that there could 22 be complexity here that we're not recognizing,

### 202-234-4433 Neal R. Gross & Co., Inc. Page 86 1 and maybe I can best explain it with an 2 example. Perhaps atrazine is indeed eliciting 3 a generalized stress response, but over and 4 above that it's impacting TSH levels, which 5 are impacting thyroxine levels. 6 And so we're saying, oh, look at 7 this profile, we're not seeing a generalized 8 stress response. But maybe we are, but in 9 addition we're seeing something else. As Dr. 10 Bucher said earlier, toxicity pathways are 11 rarely linear, typically they're webs, there 12 are many things going on. So there could be 13 additional layers here that we're really not 14 considering; we're sort of taking the easiest 15 path in trying to explain it in that manner. 16 But I think we need to recognize that there 17 could be multiple things happening. And I 18 think I'll stop there. 19 DR. PORTIER: Additional comments 20 from the panel? Dr. Selvage? 21 DR. SELVAGE: Yes, I just wanted 22 to add a couple of things. First of all, I

### 202-234-4433 Neal R. Gross & Co., Inc. Page 87 1 realize it's extremely easy to sit here and 2 conjecture and, you know, dream up 3 experiments, and it's much more difficult to 4 actually do them. So I want to take -- I want 5 to make sure that gets said because we could 6 probably sit here all day and come up with 10 7 years of work. But -- 8 DR. PORTIER: If you didn't do 9 that, you would be a unique panel. 10 DR. SELVAGE: The other thing 11 that -- I just wanted to add one more thing 12 that might be worth looking at, but the 13 problem with having different strains of 14 animals confuses the matter a little, is that 15 it looks like with this smaller -- obviously 16 in different strains of animals, but with the 17 smaller dose of atrazine, you got, I think it 18 was 75 mgs per kg, you got at least double the 19 ACTH response in females versus 100 mgs per kg 20 in males, so. 21 And you're measuring the 22 measurements in the chronic studies, and in

### 202-234-4433 Neal R. Gross & Co., Inc. Page 88 1 the acute studies, the females were done on 2 proestrus at a time when, relatively speaking, 3 estradiol levels are going to be higher. So 4 they might -- that's thought to be -- 5 estradiol is thought to increase HPA activity, 6 so I think it might be worth looking at 7 central sex differences as well as adrenal sex 8 differences in response -- HPA responses to 9 atrazine. 10 DR. PORTIER: Any additional 11 questions? Dr. Akana? 12 DR. AKANA: I agree that looking 13 at a stress response to atrazine is really 14 hard because you're looking at a web, an 15 ensemble of responses. So a general 16 philosophy is to look at the temporal pattern, 17 see which one changes first. And then a 18 second general strategy, which many labs do, 19 is you take down one system at a time. And 20 then if you're really clear -- for instance 21 adrenalectomy and corticosterone replacement. 22 And then if you get really bold, you do two at

### 202-234-4433 Neal R. Gross & Co., Inc. Page 89 1 the same time. So there are some approaches 2 that might be yielding. 3 DR. PORTIER: Anna, you had -- Dr. 4 Lowit? 5 DR. LOWIT: Yes, I was just going 6 to take the opening from Dr. Selvage to -- 7 it's fascinating to sit here and listen. I'm 8 learning a lot about the stress response and 9 the HPA that I don't know if I ever really 10 wanted to know or not, but I'll soak it all 11 in. 12 Just to I guess push back a little 13 bit to -- as you're thinking about the 14 comments and writing the report, about what 15 our -- what the purpose of this is, and about 16 the value, the added value of understanding 17 every tiny detail of a mechanism when, at the 18 end of the day, the Agency needs to come up 19 with a scientifically supportable risk

20 assessment. 21 And what that means is that we're 22 going to need to derive a series of values

### 202-234-4433 Neal R. Gross & Co., Inc. Page 90 1 that are protective of human health. And the 2 value of -- the added value of understanding 3 every component of that web that we keep 4 hearing about in that need. So I just ask you 5 to put that in the back of your mind as you

6 make these comments. 7 DR. PORTIER: Dr. Selvage? 8 DR. SELVAGE: Yes, that's why I 9 prefaced this by saying I wasn't taking dose 10 into account, so.

11 DR. PORTIER: Dr. Reed. 12 DR. REED: Well, I was going to 13 say this to Question 1.9, but I think this is 14 a good place. I'm not going into 1.9, but I 15 think this a good place to just, you know, 16 bring out some of the endpoints. So at the 17 very tail end of this hypothesis, the 18 endpoints that we're seeing in animal studies, 19 in dogs, there's cardiopathy, there atrial 20 fibrillation in rats, and these are sort of 21 the endpoints that comes out as, 22 quote/unquote, more or less more sensitive

### 202-234-4433 Neal R. Gross & Co., Inc. Page 91 1 than other endpoints. Rats, extra-medullary 2 hematopoiesis in the spleen, renal effects, 3 neuropathy, just throw out some of the 4 endpoints and see if you can connect the dots 5 at the very end. 6 DR. PORTIER: Any additional 7 comments? Dr. Lowit. 8 DR. LOWIT: We don't want to get 9 into Question 1.9 here. I didn't mean to do 10 that with my comment, it's just the opening 11 was there and I felt like it needed to be 12 said. But our desire with -- the last 13 atrazine risk assessment really set a strong 14 standard by using an LH endpoint. As a 15 precursor event, we are far removed from any 16 of these more serious outcomes, and we plan to 17 follow that same approach. The ultimate 18 question is, what does that place in the 19 precursor events, to be a precursor to all 20 these other outcomes that may come up. 21 DR. PORTIER: I'm not seeing a lot 22 of additional questions, so I think we'll ask

### 202-234-4433 Neal R. Gross & Co., Inc. Page 92 1 EPA if they got out of this what they were 2 looking for. 3 I mean, you know, my take on this 4 is that they don't like this non-specific 5 stress term and they really kind of have 6 explored -- like you said, they've explored 7 the stress question quite a bit trying to put 8 your experiments in a -- 9 DR. COOPER: If I could just make 10 one comment, final comment. Yes, I think 11 these have been extremely helpful. I think 12 that some of the directions that have been 13 suggested this morning are already being 14 pursued. We're one lab, three PIs, and we 15 published the first paper on the adrenal 16 access in November or December, I forget 17 exactly when it came out. So this is 18 relatively new to us. We're not experts in 19 HPA by any means. 20 The connection was there in the 21 literature. We continue to be confused by the 22 acute versus chronic outcomes, and the onus is

### 202-234-4433 Neal R. Gross & Co., Inc. Page 93 1 on us, and I think others, to looking into the 2 connections, if they are there. We can't 3 ignore them. They're big flags that at least 4 in the endocrine world are important to us. 5 So all this has been helpful. 6 The suggestions about knock out 7 specific receptor blockers for CRF, 8 measurements of CRF, AVP, these things are 9 hitched into. And I have one technician, and 10 these ladies behind me have one each too, so 11 if we had the world enough and time enough, we 12 may have been able to address those things. 13 But this is useful. 14 And we see this as not our 15 research, per se, it's a research area that 16 there's a lot of very well-qualified labs 17 around. It's an extremely interesting series 18 of events that occur, and the more we can 19 enlist the basic scientists in these kinds of 20 questions, the happier we are. 21 One other thing about dose, I 22 think we constantly are dealing with the

### 202-234-4433 Neal R. Gross & Co., Inc. Page 94 1 issues of dose and route of administration of 2 those kinds of things. They're not foreign to 3 us, but sometimes the restraints of the 4 question put us -- so we're looking at little 5 parts of the bigger picture and you see these, 6 and of course those are all very good comments 7 that we've received about that, and we 8 appreciate them.

9 DR. PORTIER: Let's take a break 10 until 10:30. 11 (Whereupon, the above-entitled

12 mater went off the record at 10:14 a.m. and 13 resumed at 10:33 a.m.) 14 DR. PORTIER: So, Dr. Lowit, I was 15 trying to summarize Question 1.3 and kind of 16 looking over my notes, and I get the feeling 17 that Dr. LeBlanc's comments were probably the 18 most pertinent ones in saying there's an 19 accumulating body of evidence, but it's 20 preliminary and there's need for more 21 information. 22 And we got a lot of suggestions of

### 202-234-4433 Neal R. Gross & Co., Inc. Page 95 1 where the additional data, addition 2 information will come from. And I've talked 3 to the panel members, and the -- kind of the 4 details on that additional information that 5 they'd like to see and the stress-related 6 impacts, that that's all going to be put in 7 the report. 8 And I do think there's a general 9 acknowledgment of what EPA's trying to 10 accomplish with this in terms of their need 11 for a risk assessment. And you're going to 12 see some of that. It may extend then to 13 academic research needs, but there's -- I 14 think there's a good recognition of where you 15 need to go with this. 16 DR. LOWIT: I think some of these 17 issue will -- what I'll call the collision 18 between the risk assessment world and the 19 academic world will probably reappear in 20 Question 1.9, so I think I'll hold back sort 21 of pushing any more around that, because the 22 question is when is enough enough.

### 202-234-4433 Neal R. Gross & Co., Inc. Page 96 1 DR. PORTIER: And I'm making kind 2 of a list of issues as they come up here 3 that'll come back up again in 1.9 where we 4 starting looking at issues like acute versus 5 chronic definition, how do we look at that, 6 and health effects and how do we define those 7 health effects. And so we'll just kind of8 keep track of those and that'll be our catch9 all question. 10 So with that we're going to move 11 on to Question 1.4. 12 DR. LOWIT: We threw together a 13 quick slide to sort of do the -- but we have 14 to either switch the video thing, or get it to 15 John's computer. It's on my machine. 16 DR. PORTIER: That's okay. It'll 17 just a second. 18 (Pause.)

19 DR. PORTIER: Now we took a break 20 and everybody destressed and got their cort 21 levels low, now don't -- you know, don't raise 22 it just yet.

### 202-234-4433 Neal R. Gross & Co., Inc. Page 97 1 DR. LOWIT: Except Nelson and I, 2 because we've been sitting here doing this. 3 Okay. So this is not what Dr. 4 Pastoor showed, you know, thinking where are 5 those little box and whisker plots and where 6 are the margins of difference. Intentionally 7 not there. We, as a team, as an agency across 8 three offices, came into this meeting focused 9 entirely on science, and focused entirely on 10 a lot of very difficult science that may or 11 may not have a lot of impact on what is 12 already a very complicated risk assessment. 13 And so you may, after seeing Dr. 14 Pastoor slide, notice there's a vast crevasse 15 where our documents to you don't talk about 16 this stuff, and that's, in many ways, 17 intentionally. We want this meeting to be 18 about science and to be about the science that 19 informs our decisions, not necessarily about 20 the decisions that we haven't made and haven't 21 figured out how to make yet. That's why 22 you're here to help us, guide -- to guide us

### 202-234-4433 Neal R. Gross & Co., Inc. Page 98 1 to make the right ones. 2 So you haven't heard us talk about 3 points of departure, except for I think two 4 bullets in Liz's slide yesterday. We haven't 5 talked about uncertainty factors, we haven't 6 talked about margins of exposure, we haven't 7 talked about RfDs, we haven't talked about any 8 of that because we want this to be about 9 science and it's very complicated all by 10 itself. 11 And when you bring in a lot of 12 very complicated policy on top of the science, 13 it gets confused. And so we want this meeting 14 to be about science and about the science that 15 will help us to go in different directions to 16 inform the decisions that we have to make. 17 So what we're getting back to is 18 not what you -- I don't think what you've 19 asked for, but I think it's what you really

20 need. 21 And that may be a little 22 patronizing on my part. I apologize for that.

### 202-234-4433 Neal R. Gross & Co., Inc. Page 99 1 Oh, piddle. That came out in not the right 2 way. I'm sorry about that. 3 Oh, well, it's too late now, it's 4 on the record. And my slide just went away. 5 So what is worth taking a minute 6 to talk about is what it is that we need. 7 Okay. We, at the end for the day -- what 8 happened to the computer? 9 DR. PORTIER: I think when you 10 close it, it -- 11 (Pause.) 12 DR. LOWIT: Okay. Don't touch.

13 DR. PORTIER: Don't stress. 14 DR. LOWIT: Don't stress. Right. 15 I'll check my cort levels. 16 This would be acute or chronic, I 17 don't know. It was atrazine, it's both I 18 guess. What we need at the end of the day is 19 science had informed some difficult decisions, 20 and one of the most important ones we have to 21 make this choice about is what we call the 22 point of departure. And what that is is a

### 202-234-4433 Neal R. Gross & Co., Inc. Page 100 1 value that we'll select, or a series of values 2 for that matter, that represent whether it's 3 a NOEL or LOEL or a benchmark dose, hopefully 4 for precursor event and mode of action for 5 atrazine that represents a level by which we 6 can -- act as a starting point to create a 7 risk assessment that's safe for human health. 8 And those can get very 9 complicated, especially for something like 10 this, because duration is an issue, and we've 11 heard a lot about acute versus chronic, and I 12 think the grayness between acute and chronic 13 I think is probably more important to us 14 than -- as much as anything right this second 15 because we need a -- we will need a certain 16 amount of clarity around the relationship 17 between the HPA and HPG and the clarity of 18 those key events to get a handle on how often 19 we need to monitor and water. So whether it's 20 days or weeks or months or years, that kind of 21 resolution is important to us. 22 Life stage is also important,

### 202-234-4433 Neal R. Gross & Co., Inc. Page 101 1 whether it's adults, it's pregnant females, 2 it's newborns, it's in utero, it's postnatal, 3 it's perinatal, it's pubertal for lack of a -- 4 it's a route. We look at point of departure 5 by route. I think for atrazine route is less 6 important because we're really in this 7 analysis looking at oral exposure and drinking

8 water. But for a lot of other assessments we 9 think about things in other routes. 10 The other pieces that we need will 11 be, since we'll be determining a point of 12 departure from animal data, we'll have to 13 extrapolate from animals to humans and that's 14 how you will go from one of those steps that 15 Dr. Pastoor talked about, one of those orders 16 of magnitude to go from the animal value down 17 to a human equivalent value. There are 18 different ways of doing that. The standard 19 way is to divide by 10. There are more 20 sophisticated approaches it can be upon. 21 From that point we go what we 22 think of as the average human to a sensitive

### 202-234-4433 Neal R. Gross & Co., Inc. Page 102 1 human, and standard procedure will be to 2 divide by another 10. There are also most 3 sophisticated ways of doing that, that could 4 be anything from something smaller to 5 something far larger. 6 Specific to the Pesticides Office, 7 since we work under the Food Quality 8 Protection Act, Congress mandates that we add 9 a 10X factor for the protection of infants and 10 kids, and that value is only removed with 11 sufficient data on hazard and exposure. 12 And so the default window of 13 uncertainties is 1,000. It can be bigger or 14 it can smaller depending on the situation, 15 depending on what science informs the animal 16 to human, the human sensitivity, or the FQPA. 17 So you may start with a default of 1,000, 18 bigger or smaller, depending on the science. 19 Drinking water, Dr. Pastoor had a 20 series of box and whisker plots, and I believe 21 there quite a bit of comments from Dr. Young 22 wondering about the differences in the --

### 202-234-4433 Neal R. Gross & Co., Inc. Page 103 1 looking at the totality of the data set versus 2 individual sites. And I think our message 3 tomorrow will be very clear that we assess 4 risk to individuals at individual sites 5 because every site has its own atrazine level 6 and we have to make sure that the people in 7 those sites are protected as individuals. 8 DR. THURMAN: And this is Nelson 9 Thurman. Just to give you an idea of how we 10 do the drinking water component part of it, 11 because we know we have to -- the temporal and 12 spatial variability we talked to you about, we

13 have to account for that. We know we're not 14 going to get coverage everywhere, over all

15 dates. 16 So what we end up doing is 17 focusing on what we think are the most 18 vulnerable areas, or the most vulnerable 19 systems. A lot of times that's done based on 20 something like a WARP model, something like -- 21 based on our best information we have based on 22 the relative -- on the crops being grown, the

### 202-234-4433 Neal R. Gross & Co., Inc. Page 104 1 relative vulnerability of the sites, the 2 weather patterns. Sometimes in the case of 3 atrazine, it's based on the fact that we do 4 have Safe Drinking Water Act monitoring over 5 time that tells us -- helps us zoom in on 6 where we think the most vulnerable systems are 7 going to be. 8 The goal is, if we can protect 9 those systems, we're protecting the less 10 vulnerable systems. We don't go into this 11 saying that all systems are in trouble. We 12 know that there -- that we're zooming in on 13 the most vulnerable, and the idea is that's a 14 sensitive sup-population for us, and so we

15 want to make sure that we're safe on that

16 level.

17 We also need to account for that 18 temporal variability over time. And we need

19 to be able to match that to the hazard 20 assessment. So that's what we try to do. A 21 lot of cases we use deterministic models

22 because that's the one we have. In the case

### 202-234-4433 Neal R. Gross & Co., Inc. Page 105 1 of atrazine we do have a wealth of monitoring 2 data. With that sampling, as I pointed out 3 yesterday, even interpreting monitoring data 4 is a model.

5 And so we need to account for what 6 kind of uncertainty do we get in those 7 sampling frequencies so that we make sure that 8 we're not saying, This is safe, whenever the 9 actual exposures would be greater. That's our 10 biggest concern in that regard, so, and that's 11 why the questions we have before you on 12 drinking water, the intent is for you to help 13 us figure how best to quantify that 14 uncertainty in sampling frequencies and how we 15 deal with if that duration exposure changes so 16 that we can then go back and determine on 17 those individual systems are they safe or do 18 we have things we need to do. 19 DR. LOWIT: Okay. So just to sort 20 of close this out, and how those -- how all 21 these pieces are matched, it gets very tedious 22 and complicated very quickly, particularly as

### 202-234-4433 Neal R. Gross & Co., Inc. Page 106 1 you think about multiple durations and 2 multiple life stages and many different CWSs, 3 of different levels all over the country 4 that -- how those values will be matched. 5 That you'll match the points of 6 departure from the appropriate duration from 7 the most sensitive life stage, to the -- from 8 the right routes, to individuals that match 9 those profiles in that drinking water area. 10 So if it's an infant, you'll match it an 11 infant water consumption; if it's a adult, you 12 match it to the adult consumption, and that's 13 done for every individual CWS. And as Nelson 14 mentioned, across the country the amount of 15 atrazine in the water varies greatly. 16 So to try to bullet what those 17 values and those margins of exposure are in 18 three bullets is -- doesn't necessarily 19 provide the fullness and the robustness of 20 what the risk picture looks like, because it 21 varies a great deal across the country. 22 Oh, and the last point is that

### 202-234-4433 Neal R. Gross & Co., Inc. Page 107 1 it's less important to think about those 2 margins of exposure for the 2003 risk 3 assessment because we've gone into this 4 analysis with a clean slate. That's the last 5 risk assessment. We're going into this with 6 a clean slate to ensure that everyone around 7 the country is protected. 8 DR. WILLIAMS: I think -- yes, 9 that was pretty much what I needed, not what 10 I asked for. The only question I have is how 11 do you -- back to Dr. O'Bryne's question -- 12 that the very low doses that were going down 13 from these what seem to be considered kind of 14 high-dose treatments of rats and so forth, how 15 do we know that these low-dose exposures 16 themselves do no have long term chronic 17 effect. Has that been looked at, is it being 18 looked at, or is that just out of the realm of 19 this handle and shouldn't be considered? 20 DR. LOWIT: Well, to the extent 21 there is -- there are chronic long term rat 22 studies, and certainly the mammary tumors were

### 202-234-4433 Neal R. Gross & Co., Inc. Page 108 1 a topic that Syngenta covered quite a bit 2 yesterday, so there is -- there are a series 3 of chronic studies in rats. There is the 4 standard, what we'll call the guideline set of 5 different kinds of toxicities, developmental, 6 repro, cancer, different durations, that sort 7 of thing. 8 There is also what we're -- one of 9 the things that we will do in the September 10 meeting is to bring in the epidemiology from 11 the human epidemiology literature that has its 12 own challenges. But we'll provide a more full 13 picture of the totality of the toxicity 14 profile I think. 15 DR. PORTIER: Dr. Young? 16 DR. YOUNG: Given the nature of 17 these sites and the fact that they're likely 18 to be spread out, does it -- spatial 19 correlation, and I know the emphasis here is 20 temporal, but isn't one of the reasons is the 21 sites are likely so far apart that spatial 22 correlation is questionable?

### 202-234-4433 Neal R. Gross & Co., Inc. Page 109 1 DR. THURMAN: Yes. You know, 2 that's a question -- it depends on what scale 3 you're looking at, but, yes, I think that 4 spatial correlation on a localized scale is 5 going to be very questionable. I think in 6 general we can identify areas where there's a 7 higher likelihood of high exposures, and 8 that's something we've learned a lot more 9 about as a result of the eco-monitoring that 10 I think we're just starting to say these are 11 things we can starting at those. But more of 12 a -- in classic geospatial sense, that 13 correlation is not as -- it's not going to be 14 easy to find, if it exists. 15 DR. YOUNG: Yes, because the 16 higher levels are likely a change of mean and 17 not necessarily reflective of a correlation 18 structure once they get that far apart. 19 DR. PORTIER: Thank you very much. 20 I think we need to move on to 21 Question 1.4. 22 DR. LOWIT: Dr. Cooper can read.

### 202-234-4433 Neal R. Gross & Co., Inc. Page 110 1 DR. COOPER: This must be another 2 bad question. 3 DR. PORTIER: And actually it 4 doesn't even look like a question, it's just 5 please comment. 6 DR. COOPER: Yes. Charge Question 7 1.4, based on a review of in vitro studies 8 evaluating the effects of atrazine on estrogen 9 production, the Agency has preliminarily 10 concluded that atrazine does not have a direct 11 effect on the catalytic activity of aromatase. 12 However, with continued exposure, atrazine can 13 cause increased estrone and estradiol 14 production the H295R and JEG-3 cell lines, 15 Sanderson, et al., 2000; Laville 2006; Higley, 16 et al., 2010. 17 These changes in estrogen 18 production have been associated with increased 19 cyclic AMP, and CYP19, and message RNA, 20 Sanderson, et al., 2000, 2001, that are part 21 of a complex mode of action through which 22 atrazine up-regulates the gene expression of

### 202-234-4433 Neal R. Gross & Co., Inc. Page 111 1 aromatase and possibly other enzymes within 2 the steroidogenic pathway, Section 3.3.2.3 and 3 Figure 3, Arrow 7 on the draft issue paper.

4 Wow. 5 The hypothesis that atrazine 6 alters multiple steroids is supported by the 7 increased testosterone concentrations in H295R 8 cells following exposure to atrazine, Higley, 9 et al., 2010, and in vitro studies 10 demonstrating that atrazine affects a number 11 of signal transduction pathways and/or 12 transcription factors in a variety of cells 13 Suzawa and Ingraham 2008; Albanito, et al.,

14 2008. 15 Up-regulation of the expression of 16 a group of major steroidogenic genes has been 17 observed in JEG-3 cells, Susaw and Ingraham, 18 2008. In vivo, there is little evidence that 19 atrazine alters aromatase, per se, Modic 2004, 20 and the evidence associating atrazine exposure 21 to increases in serum estrogens appears to be 22 related to a general increase in gonadal and

### 202-234-4433 Neal R. Gross & Co., Inc. Page 112 1 adrenal progesterone and androstenedione, 2 Modic 2004; Laws 2009. 3 Where is the question mark?

4 Please comment on the extent that 5 the available data do or do not support the 6 Agency's preliminary conclusion that atrazine 7 has a general stimulatory effect on 8 steroidogenesis, as opposed to a direct effect

9 on aromatase. 10 DR. PORTIER: Dr. LeBlanc, your

11 comments. 12 DR. LeBLANC: Thank you. 13 I really don't like reading 14 verbatim to an audience, but I have a lot of 15 factual information here, so I am going to 16 read, and please bear with me. But the enzyme 17 aromatase is a product of the CYP19 gene and 18 it's responsible for the aromatization of19 androgenic C19 steroids to estrogens, 17-beta20 estradiol, estrone, et cetera. 21 Aromatase is expressed in various 22 tissues in both males and females. Gonadal

### 202-234-4433 Neal R. Gross & Co., Inc. Page 113 1 expression of aromatase is largely responsible 2 for elevated plasma levels of estradiol and 3 related estrogenic hormones in reproductively 4 mature females. Aromatase is also expressed 5 in other tissues, however, including bone, 6 brain, placenta, and others, in males, 7 immature animals. In reproductively senescent 8 females, plasma estrogen levels were likely 9 the product of aromatase activity in these 10 other tissues. 11 Aromatase gene expression in these 12 different tissues is under different 13 regulatory controls. The tissue-specific 14 regulation stems from the existence of 15 multiple promoter regions on the gene, the 16 CYP19 gene, that control the expression and 17 the differential production of estrogens in 18 response to different stimulatory factors, 19 hormones, et cetera. 20 In the ovary, aromatase is under 21 the regulatory control of gonadotropin 22 follicle stimulating hormone, FSH. FSH is

### 202-234-4433 Neal R. Gross & Co., Inc. Page 114 1 produced by the pituitary gland, it stimulates 2 a signal transduction cascade within the 3 ovary, the granulosa cells, resulting in 4 intra-cellular elevation of cyclic AMP levels. 5 The elevated cyclic AMP levels then stimulate 6 the association of the transcription factors 7 SF1 and CREB to their adjacent response 8 elements resulting in stimulation of the CYP19 9 gene expression. 10 So in this situation we have two 11 adjacent response elements and there are two 12 factors that are involved, SF1 and CREB. CREB 13 is phosphorylated and apparently both of these 14 transcription factors need to bind, and in 15 doing so then recruit other players that 16 stimulate transcription of the aromatase gene. 17 Adipose aromatase appears to be 18 under the joint regulatory control of 19 cytokines, including TNF-alpha, IL-6, IL-11, 20 it's under the influence of glucocorticoid 21 hormones, as well as the transcription factor 22 SP1. So there are multiple players in

### 202-234-4433 Neal R. Gross & Co., Inc. Page 115 1 regulating the expression of aromatase in the 2 adipose tissue. The cytokines stimulate 3 transduction pathways within the adipose sites 4 that result in the interaction of the 5 transcription factor STAT3 and possibly others 6 with their response elements. 7 Glucocorticoid hormones will bind 8 to their glucocorticoid receptors and bind -- 9 this complex then binds to the glucocorticoid 10 response element to regulate gene 11 transcription. The glucocorticoid receptor -- 12 I'm sorry, SP1, which is activated by a 13 phosphorylation event, also binds to a 14 response element within the motor region of 15 CYP gene to regulate gene transcription. 16 Together these transcriptional 17 regulators stimulate aromatase activity in the 18 adipose tissue, and, again, these factors 19 don't seem to function independently in 20 regulating transcription, but seem to 21 cooperate in the regulation of transcription 22 in adipose tissue. Thus, chemicals that

### 202-234-4433 Neal R. Gross & Co., Inc. Page 116 1 modulate any of these pathways could 2 potentially impact aromatase expression. 3 Finally, in the placenta, 4 aromatase appears again to be under multiple 5 regulatory controls, and there's much less 6 known about the regulation of aromatase in the 7 placenta, but perhaps most relevant to our 8 discussions is that ligands to the retinoid X 9 receptor, RXR, appear to be involved. And 10 accordingly, compounds such as retinoids, 11 fatty acids, as well as some xenobiotics could 12 influence aromatase activity via this 13 regulatory pathway. 14 Now we know that atrazine has been 15 shown to elevate aromatase activity in 16 cultured cells, and at issue here is whether 17 or not this is a specific affect of atrazine 18 on aromatase, or some generalized affect on 19 steroidogenesis. In terms of atrazine 20 directly impacting the catalytic activity of 21 the aromatase enzyme, I'm aware of no 22 precedent for this in the literature. I'm

### 202-234-4433 Neal R. Gross & Co., Inc. Page 117 1 furthermore not familiar with any precedent of 2 the aromatase enzyme being susceptible to 3 allosteric interactions, et cetera, that would 4 result in some direct increase in catalytic 5 activity through interacting with a ligand. 6 As discussed above, there are 7 multiple regulatory elements through which 8 atrazine could impact the expression of the 9 CYP19 gene, and the greatest evidence that 10 exists is interaction involving the cyclic AMP 11 SF1 pathway. Atrazine has been shown to 12 increase cyclic AMP levels in cells, and it 13 has also been shown to activate SF1 via 14 increased phosphorylation. 15 There is one paper that indicates 16 that atrazine actually binds to SF1 and 17 activates, but that's been discounted in at 18 least one other paper, and I think the 19 argument against that is rather good. So I 20 don't argue that SF1 may be activated, but I 21 don't think it's through direct interaction 22 with the atrazine. I think it's through

### 202-234-4433 Neal R. Gross & Co., Inc. Page 118 1 perhaps a phosphorylation event. 2 Now, at it turns out, SF1 is not 3 a -- the signaling pathway is not a specific 4 regulatory process for aromatase. SF1 is 5 recognized as generally stimulating 6 steroidogenesis in cells, and so it may very 7 well be that this effect of atrazine on the 8 SF1 signaling pathway is indeed a general 9 effect on the steroidogenic pathway and not 10 specifically on aromatase. And I say that 11 with caution because I'm not trying to imply 12 that it's a non-specific effect. It is a 13 specific effect but involves multiple player 14 in steroidogenesis. 15 So the conclusion can be made that 16 atrazine's effects on aromatase gene 17 expression represents a generalized effect on 18 steroidogenesis, probably mediated by SF1 and 19 cyclic AMP. Potential interactions of 20 atrazine via other known regulatory sites, 21 however, must be evaluated. There are a lot 22 of potential regulatory pathways through which

### 202-234-4433 Neal R. Gross & Co., Inc. Page 119 1 atrazine could be acting, and they haven't 2 received a lot of attention. And I think we 3 need to consider that. 4 For example, the glucocorticoid 5 hormone pathway. It has been evaluated with 6 respect to whether or not atrazine binds to 7 glucocorticoid receptor, and the evidence 8 indicates that it doesn't. However, we do 9 know that atrazine stimulates glucocorticoid 10 levels, so in that respect we could be 11 inducing endogenous glucocorticoid levels with 12 atrazine treatment that is resulting in a 13 stimulation of aromatase via the 14 glucocorticoid hormone pathway that can't be 15 excluded at this point. 16 SP1 was another transcription 17 factor involved, and I could find no evidence 18 that atrazine has an effect on SP1. The 19 information simply isn't out there to make a 20 judgment one way or another. The same thing 21 for RXR. I identified RXR as a potential 22 target for atrazine, but at this point in

### 202-234-4433 Neal R. Gross & Co., Inc. Page 120 1 time, as best that I can determine, there's no 2 evidence to indicate whether or not atrazine 3 is binding and activating the RXR. 4 So in conclusion, there's 5 significant evidence that atrazine has the 6 potential to regular gonadal CYP19 expression 7 through the stimulation of the cyclic AMP SF1 8 signaling pathway. This effect would be 9 expected to be common to most sterogenic 10 pathways along the hypothalamic, pituitary, 11 adrenal, or gonadal axis. It functions on

12 both axes. 13 It's also plausible that atrazine 14 stimulates adipose CYP19 expression through 15 its activation of the HPA axis resulting from 16 the increased glucocorticoid levels that we 17 see with atrazine treatment. And that's all. 18 DR. PORTIER: Thank you. 19 Associate discussant Dr. Delclos.

20 DR. DELCLOS: I won't have that 21 much to say. I think that, as indicated in 22 the document, as Dr. LeBlanc has said, there's

### 202-234-4433 Neal R. Gross & Co., Inc. Page 121 1 clear evidence that the ATR do not directly 2 interact with aromatase, but that the enzyme 3 is induced after longer term exposure in 4 several cell lines in vitro. And one thing 5 that struck me in reading the literature, and 6 was pointed out in the public comments 7 yesterday in the Syngenta, is that most of 8 these in vitro studies take -- do not take 9 into account the metabolism and the 10 relationship of -- they use atrazine, they 11 don't take into the account the metabolic 12 capabilities of the -- in the animal and what 13 happens and it seems like the metabolites are 14 really the major players after atrazine gets 15 in the body. 16 But that being said, there are a 17 couple of studies that did use the metabolites 18 and they found that the major metabolite, 19 DACT, is not active, but the two 20 monodealkylated metabolites, DIA and DEA, are 21 active, although they may be a little less 22 potent than ATR itself. So there is some

### 202-234-4433 Neal R. Gross & Co., Inc. Page 122 1 relevance of these in vitro activation studies 2 perhaps. 3 But there is little evidence in 4 the rodent studies, or there's no direct 5 evidence in the rodent studies that aromatase 6 is being elevated in vivo. The only evidence 7 that's been used to support that is the 8 pattern of hormone stimulation and reduction 9 in the testosterone elevation of estradiol and 10 estrone. The studies that have directly 11 looked at aromatase elevation, the Modic 12 thesis that was presented, and the rest, and 13 the Sanderson abstract, showed no evidence 14 that gonadal aromatase is induced in vivo 15 after atrazine exposure. 16 Several possible other 17 explanations for the elevation of estradiol 18 and estrone have been presented, including 19 increase for the aromatizable androgenic 20 substrates effects on metabolism of the 21 estradiol, or induction of adipose aromatase, 22 and I think that hasn't been worked out.

### 202-234-4433 Neal R. Gross & Co., Inc. Page 123 1 But there is some evidence from 2 the in vitro studies, the study by Higley that 3 was cited, that there is a general activation. 4 And as Dr. LeBlanc talked -- said, there are 5 multiple pathways that have been proposed to 6 be affected by atrazine or its metabolites 7 that may support a general induction of 8 steroid synthesis. 9 So I think that there is no -- to 10 summarize, there is no existing evidence in 11 the rodent studies that there's an elevation 12 in vivo, and there is supporting evidence that 13 there's a general increase in steroidogenesis, 14 so I think the hypothesis is supported, 15 although it's not definitively proven; there's 16 still work to be done in that regard. 17 DR. PORTIER: Thank you.

18 Dr. Horton? 19 DR. HORTON: Thank you. 20 Just a reminder that when you're 21 talking about steroidogenesis in vivo, and 22 particularly when you're talking about the

### 202-234-4433 Neal R. Gross & Co., Inc. Page 124 1 ovary and testes, you're talking about a very 2 complex organ. Steroidogenesis in the ovary 3 is a two-cell process that requires the 4 interaction between the fecal and granulosis 5 cell, and you have to have enzymes in two 6 different cells working together. You also 7 require the interaction between two 8 gonadotropin in order to make the ovary work 9 properly, and those two gonadotropin must be 10 secreted in sequence in order to have the 11 ovary work properly in its cyclic fashion. 12 And what I've not heard discussed 13 is the role of atrazine or any impact of 14 atrazine on the secretion of follicle 15 stimulating hormone. I've heard a great deal 16 of discussion of the role of atrazine on the 17 secretion of luteinizing hormone. So what's 18 missing from this discussion is the potential 19 impact of the set up of the ovary and its 20 preparation for steroidogenesis by follicle 21 stimulating hormone, because in an ovary that 22 is not prepared properly, it will not respond

### 202-234-4433 Neal R. Gross & Co., Inc. Page 125 1 to luteinizing hormone in the appropriate way. 2 So I would encourage any studies 3 to -- in the future to also examine the levels 4 of follicle stimulating hormone. Thank you. 5 DR. PORTIER: Dr. Williams. 6 DR. COOPER: Can I just make one

7 comment?

8 DR. PORTIER: Sure.

9 DR. COOPER: FSH has been looked 10 at in the ovariectomized estrogen primed 11 female and in the male, and there hasn't been 12 really any change noted in that they're 13 relatively short term treatments. That's just 14 the background that somehow slipped. I 15 apologize you didn't see that. 16 DR. PORTIER: That was Dr. Cooper,

17 EPA. 18 Dr. Williams? 19 DR. WILLIAMS: I would say I don't 20 have anything to add to what's already come 21 out. I agree with the comments that have been

22 made.

### 202-234-4433 Neal R. Gross & Co., Inc. Page 126 1 DR. PORTIER: Dr. Schlenk?

2 DR. SCHLENK: Yes. One of the 3 things we've dealt with a lot with -- in terms 4 of pesticide metabolism, is that with drug 5 interactions, oftentimes when you see issues 6 related to clearance, it's not necessarily 7 induction of pathways, it's actually 8 inhibition of pathways. They tend to be more 9 thermodynamically sort of, you know, favored, 10 if you will. 11 One of the things I didn't see in 12 the White Paper, and has not been mentioned 13 all that much, are the inhibition of catabolic 14 pathways that atrazine may actually take -- 15 have some impairment on. And I know I think 16 we talked earlier, CYP3A is actually inhibited 17 fairly potently by atrazine, at least in about 18 a one to two micromolar, and I've got a 19 reference to throw in the report. 20 But one could argue that the 21 enhancement of the steroid levels perhaps 22 would be due to inhibition of catabolism

### 202-234-4433 Neal R. Gross & Co., Inc. Page 127 1 perhaps, of steroid -- rather than looking at 2 the steroidogenic pathway, but actually 3 looking at the catabolic pathway that actually 4 keeps the levels high. And honestly, 5 thermodynamically that would make a little bit 6 more sense perhaps. But it may be, again, a 7 minor pathway outside of what the hormonal -- 8 luteinizing hormone issue is related to that. 9 Just something to consider. 10 DR. PORTIER: Additional comments? 11 (No response.) 12 DR. PORTIER: I won't even attempt 13 to summarize this. I'm assuming Dr. LeBlanc's 14 got it all down and, well, his comments were 15 pretty clear, if you could follow it. Which 16 I'm sure Dr. Cooper could; maybe not the rest

17 of us. 18 I think the general conclusion was 19 that -- let's see if I can -- clear evidence 20 it's not direct. That's what I got out of 21 this. There's a lot of evidence for indirect, 22 but not a lot of evidence for direct effects.

### 202-234-4433 Neal R. Gross & Co., Inc. Page 128 1 Okay. Why don't we move on to 2 Question 1.5 then. 3 DR. COOPER: Charge Question 1.5, 4 a series of studies evaluating the effect of 5 either peripubertal or gestational exposure to 6 atrazine in the male rat indicate that 7 atrazine decreases testosterone concentrations 8 and may lower androgen dependent tissue 9 weights, but that it has little effect on 10 basal LH secretion in the male. This response 11 generally occurs at doses of 50 milligrams per 12 kilogram and above. 13 In contrast, atrazine in vitro has 14 been found to consistently increase steroid 15 hormone production. Thus, there is an 16 apparent discrepancy between the in vivo and 17 in vitro data. However, our understanding of 18 the interplay between the adrenal and the 19 gonadal axis may provide an explanation -- 20 period. An explanation. 21 (Laughter.) 22 DR. COOPER: At the doses used in

### 202-234-4433 Neal R. Gross & Co., Inc. Page 129 1 the in vivo studies, atrazine induces an 2 activation of the adrenal axis, increased ACTH 3 and corticosterone, and the increase in 4 corticosterone does not habituate, i.e. it 5 does not lessen with repeated dosing. There 6 are a number of studies in the literature 7 demonstrating that prolonged corticosterone 8 stimulation will impair testosterone 9 production by a direct action on 10 steroidogenesis in Leydig cells. 11 Therefore, in vivo effects of 12 testosterone synthesis are likely the result 13 of an adrenal hormone-mediated down-regulation 14 of the HPG axis through corticotropin 15 releasing hormone, CRH modulation, or GnRH 16 pulsatility, or directly in the testes through 17 a glucocorticoid receptor-mediated change in 18 steroidogenesis. 19 Please comment on the degree to 20 which the proposed mode of action, Figure 3 of 21 the draft issue paper, provides a biologically 22 plausible explanation for the decrease in

### 202-234-4433 Neal R. Gross & Co., Inc. Page 130 1 serum testicular testosterone identified in 2 the in vivo studies. Please comment on the 3 extent that the available data do or do not 4 support this hypothesis. 5 DR. PORTIER: Dr. Delclos is the 6 lead discussant. 7 DR. DELCLOS: Okay. Well, the 8 white paper reviews several studies in which 9 testosterone levels are replaced by exposure 10 to atrazine during the peripubertal or 11 gestational period, and at least one study 12 where exposure to commercial formulation 13 involving atrazine in inerts in adults reduced 14 testosterone, and there was generally no 15 consistent corresponding effect on LH, 16 although there was evidence of a decreasing 17 trend in at least one study, the Stoker study. 18 There was no direct assessment of 19 the HPA axis in these studies, but the 20 proposed MOA involving HPA axis is certainly 21 plausible, given the known suppressive effect 22 of corticosterone and corticosterol -- or

### 202-234-4433 Neal R. Gross & Co., Inc. Page 131 1 cortisol on the HPG axis at all levels, and 2 the clear evidence that, from other studies, 3 that atrazine can stimulate the HPA axis at 4 levels at which the testosterone reduction has 5 been reported. So there is suggestive 6 evidence supporting this MOA. 7 But there are a few issues. As I 8 said on the first day in my question, I'm 9 intrigued by this fact that the major 10 metabolite, DACT, affects puberty, which is a 11 sensitive short term endpoint, but does not 12 affect, or only weakly affects, the HPA axis. 13 And the pubertal delay can occur at levels 14 below those at which ACH, cortisol increase, 15 the corticosterone increases have been 16 demonstrated. Presumably this affect on the 17 HPG axis is important in this delay in the -- 18 in puberty in the males. 19 And at least in the one -- in the 20 study of the male, the PK study by Ross, which 21 is the only one that I'm aware of that looked 22 at specific metabolites in various tissues,

### 202-234-4433 Neal R. Gross & Co., Inc. Page 132 1 but they did find high persistent levels of 2 DACT in the brain. So I think this is just 3 something that could be -- should be further

4 evaluated. 5 The other issue was the Rosenberg 6 study which indicated that prenatal exposure 7 led to a lasting affect on testosterone and 8 delayed preputial separation, and there was no 9 data on the HPA axis provided from that 10 exposure, but where expected activation in the 11 dam was likely. 12 I'm not really too aware of the 13 effects of activation of HPA axis on puberty. 14 I know that there's at least one study looking 15 at I think dexamethasone to the dam indicating 16 that puberty can be delayed, and there was a 17 paper last year from Richard Sharp's lab in 18 which he was -- looked at the affect of 19 dexamethasone on dibutyl -- interaction with 20 dibutyl phthalate in reduction of 21 testosterone, and he had indicated that there

22 was no effect of dexamethasone on the --

### 202-234-4433 Neal R. Gross & Co., Inc. Page 133 1 directly on the testosterone levels. There 2 was a decreased birth weight in the 3 neonatal -- in the pups, but that it greatly 4 enhanced the ability of dibutyl phthalate to 5 reduce testosterone synthesis. 6 So, again, this is -- these are 7 just the, as I say, the proposed mode of 8 action is plausible, but I think it needs to 9 be further evaluated in these -- particularly 10 in the pubertal exposures and the gestational 11 exposure.

12 DR. PORTIER: Dr. LeBlanc? 13 DR. LeBLANC: Ample evidence 14 indicates that atrazine stimulates the 15 hypothalamic-pituitary-adrenal axis resulting 16 in increased production of adrenal 17 corticosteroids and progesterone. Induction 18 of HPA axis is well known to suppress the HPG 19 axis predominantly through the inhibition of 20 hypothalamic GnRH and/or the secretion of 21 gonadotropin inhibiting hormone resulting in 22 the suppression of LH from the pituitary.

### 202-234-4433 Neal R. Gross & Co., Inc. Page 134 1 And I find this proposed mechanism 2 for the suppressive action of atrazine on 3 testosterone production largely plausible. 4 There are issues that I still struggle with, 5 and I'll try and communicate right now. One 6 is that -- well, we had this issue of 7 discrepancy between in vitro and in vivo 8 observations, and it seems to me that the 9 weight of the evidence is indicating that in 10 vitro we're looking at the perturbation of the 11 axis, and that's perfectly plausible. 12 And it appears that in vitro we're 13 seeing effects, at least on aromatase, via 14 some direct regulatory pathway within the 15 cells. And right now SF1, cyclic AMP seems to 16 be the -- there's the most evidence for and 17 interaction at that level. However, and so 18 the presumption would be that both of these 19 processes would take place in vivo, but I 20 suppose the effects on the axes perhaps 21 predominate and so we're not seeing the 22 induction of aromatase in vivo, or it might be

### 202-234-4433 Neal R. Gross & Co., Inc. Page 135 1 a consequence of pharmacokinetics of atrazine. 2 I certainly don't know the answer to that. 3 However, the pituitary also is 4 regulated by SF signaling, specifically LH 5 production -- SF1 signaling. I'm sorry. And 6 so if we accept the premise that SF1 is having 7 a stimulatory affect, it certainly raises 8 issues as to why we're not seeing a 9 stimulatory effect of the activation of SF1 at 10 the level for the pituitary, which would 11 result in an enhanced steroidogenesis. I'm

12 not sure. 13 The other thing I struggle with is 14 if we're looking at an overall -- let me think 15 about this. I'm going to stop there. I'm 16 going to get myself too deep into a hole here 17 that I'm not going to be able to get out of -- 18 (Laughter.) 19 DR. LeBLANC -- and I don't think 20 I'll contribute anything of significance. So 21 I'll stop there. 22 DR. PORTIER: Dr. O'Byrne.

### 202-234-4433 Neal R. Gross & Co., Inc. Page 136 1 DR. O'BYRNE: I just have one 2 comment to make. In the context of decreasing 3 luteinizing hormone, I see it time and time 4 again, it's difficult to see a reduction in 5 gonadal intact animals. That doesn't mean to 6 say there isn't a decrease because it's below 7 the detection of the assay, and that is 8 something that really has to be taken on 9 board. So when people say there's no 10 decrease, I don't believe it. And that's all. 11 DR. PORTIER: Dr. Selvage?

12 DR. SELVAGE: From what I've 13 heard, I don't think I can really add much 14 more to this. So I will pass. 15 DR. PORTIER: Dr. Williams. 16 DR. WILLIAMS: The only thing I 17 would add is the -- in thinking about kind of 18 peripubertal or gestational exposures, what 19 really hasn't come out -- we've talked about 20 direct effects, but thinking about kind of 21 epigenetic changes that are going to later 22 impact on many different systems.

### 202-234-4433 Neal R. Gross & Co., Inc. Page 137 1 So, you know, the cell culture 2 evidence I think it's pretty straightforward 3 and easier to interpret. But the in vivo data 4 I think is going to take a lot of mechanistic 5 examination before we can really clearly put 6 a story together, which I think is what Dr. 7 LeBlanc was getting at. But it's going to be 8 really complicated. And if you, you know, 9 directly answer the questions here, you know, 10 there's a general stimulatory effect. I mean 11 that seems rather superficial when you 12 consider what might really be going on from a 13 neuroendocrine standpoint. 14 DR. PORTIER: Additional comments 15 from the panel? 16 (No response.)

17 DR. PORTIER: So what I read from 18 this is that the -- the mechanism of action is 19 plausible, all right, but really needs more -- 20 at least the in vivo is plausible but needs 21 more explanation, and the in vitro stuff is 22 what it is. I mean you believe the in vitro

### 202-234-4433 Neal R. Gross & Co., Inc. Page 138 1 stuff, but the in vivo, more mechanistic 2 information to really be able to interpret why 3 it tends to conflict. Is that a clear 4 summary? 5 (No response.) 6 DR. PORTIER: Additional comments? 7 (No response.)

8 DR. PORTIER: I'm not sure that 9 helps, but -- 10 (Laughter.) 11 DR. PORTIER: I want to give Dr. 12 LeBlanc a few more minutes to think through 13 this. I can just see the wheels turning. 14 He's thinking, Well, maybe I'll get this 15 figured out by lunch. 16 I don't think we're going to get 17 much more from the panel on this. 18 Dr. Lowit? 19 DR. LOWIT: Even with the lack of 20 clarity I think we heard what we were looking

21 for.

22 DR. PORTIER: Dr. LeBlanc.

### 202-234-4433 Neal R. Gross & Co., Inc. Page 139 1 DR. LeBLANC: Just one comment. I 2 think one of the reasons, at least one of the 3 reasons that I struggle with this, and I'm not 4 as close to the data as Dr. Cooper is, but it 5 seems to me, with respect to steroid hormone 6 levels, depending upon which study you're 7 looking at, different things happen. 8 Sometimes things go up, sometimes things go 9 down, sometimes they don't change. And so, 10 you know, I don't think we can explain that 11 right now, but it's also hard to come up with 12 a biologically plausible explanation for 13 what's going on. 14 I mean, does the weight of the 15 data indicate that testosterone is going down?

16 DR. COOPER: There's several 17 different studies and several different dosing 18 regimens, but as the background paragraph said 19 in this thing -- it did a good job of 20 capturing that anyway, I think -- is that the 21 studies that have been done generally imply 22 there's a decrease in T, but they're, you

### 202-234-4433 Neal R. Gross & Co., Inc. Page 140 1 know, they're in vivo, longer dosing, and 2 that's that disconnect between the in vitro 3 and the in vivo studies. 4 I will add that there is evidence 5 that there's an increase in testosterone in 6 Leydig cell preparations. And that was 7 done -- increase in testosterone production --

8 DR. LeBLANC: In the cells but not 9 in the plasma? 10 DR. COOPER: In vitro, the -- 11 DR. LeBLANC: Oh, in vitro. 12 DR. COOPER -- in purified Leydig 13 cell preparation, which is another -- those 14 studies were done as a part of the EPA's 15 Endocrine Disruptance Screening Testing 16 Program's development of the H295R cells, 17 whereas background work that was done in 18 those -- this isn't published, so we couldn't 19 lay it out there, but I think for 20 clarification the studies that have been done, 21 they were comparing directly Leydig cells 22 against H295R to see how representative the

### 202-234-4433 Neal R. Gross & Co., Inc. Page 141 1 295R were of the "real thing," rat Leydig

2 cells.

3 And the data that has been 4 obtained so far -- and, again, these are 5 different labs that ran these studies -- 6 showed that -- and they were looking at the 7 production of testosterone and estradiol -- 8 that not only did estradiol or estrone, 9 whichever your measurement -- your 10 estrogen you wanted to measure, were increased 11 in response to atrazine. Again, going back to 12 the Sanderson work and one of the primary 13 reasons they selected that cell line, but also 14 the testosterone increased. 15 And the Higley paper points to 16 that H295R data, and as a part of the 17 supporting validation of that assay, the 18 Leydig cells were compared, and in the Leydig 19 cells they saw increased T. That's the in 20 vitro evidence that it's increased 21 steroidogenesis more than just estradiol, and 22 in addition other hormones were looked at and

### 202-234-4433 Neal R. Gross & Co., Inc. Page 142 1 they were up. 2 And then there's this acute 3 increase in testosterone that you'll almost 4 always see when you look in vivo, but the 5 chronic it's always decreased, and that's 6 what's the disconnect that we were seeking 7 guidance on, which we probably confused you

8 more than we're confused. 9 DR. PORTIER: I don't think we saw 10 any additional insight. That's -- if I 11 could -- if I heard that. 12 Any additional comments? 13 (No response.) 14 DR. PORTIER: I'm going to leave 15 this question open because I really do see the 16 wheels turning. I suspect he'll come back 17 from lunch with a light bulb over his head. 18 Why don't we -- we're going to 19 move on to the next question, 1.6. I don't 20 think we'll finish it before we break for 21 lunch, but we can begin the discussion on that 22 question. And it may take us 15 minutes just

### 202-234-4433 Neal R. Gross & Co., Inc. Page 143 1 to read the question. 2 DR. LOWIT: We're going to do a 3 quick musical chairs. 4 DR. PORTIER: Bringing in the 5 neurotox expert. Right? 6 DR. LICCIONE: I was hoping Ralph 7 Cooper would read this because he's had a lot 8 of practice today, but I'll try to read slow, 9 I'm not as experienced as he is. 10 Based on a review of the 11 neurotoxicity studies, Section 3.4 of the 12 draft issue paper, the Agency has 13 preliminarily concluded that several recent 14 studies provided further support for the 15 concern that dopaminergic neurotransmission 16 may be affected by atrazine, a concern that 17 was raised by studies prior to 2003. 18 However, the Agency has concluded 19 that several aspects of these studies of the 20 dopaminergic neuronal pathways, in particular 21 the changes noted in the stereological 22 evaluations and the observed changes in

### 202-234-4433 Neal R. Gross & Co., Inc. Page 144 1 behavior, should be considered as preliminary 2 findings. And in my presentation I also 3 emphasize inconclusive. 4 This conclusion is based on the 5 notable limitations identified in the data 6 including, one, a lack of clear dose-response 7 relationships; two, lack of inclusion of 8 suitable positive controls to confirm the 9 competency and reliability of the procedures 10 utilized in examining dopaminergic systems in 11 the brain; three, limited data to corroborate 12 stereological findings; four, limited or no 13 supporting histological and behavioral 14 assessments; and, five, no consideration of 15 the potential role of the HPA axis, for 16 example, alterations in corticosterone. 17 EPA has further determined that 18 two non-dompaminergic neurotoxicity studies, 19 one on brain somatostatinergic systems and the 20 other on neurobehavior in mice, also have 21 significant limitations. For example, the 22 lack of details on the source and purity of

### 202-234-4433 Neal R. Gross & Co., Inc. Page 145 1 atrazine; the age and body weights of the 2 mice; poor quality of the amino cupric silver 3 staining photomicrographs; limited 4 presentation of the reverse-transcriptase 5 polymerase chain results; lack of data to 6 corroborate the conclusion of neuronal 7 degeneration; reference citations did not 8 support statements made in the text; no 9 explanation of biological plausibility of the10 alterations in somatostatinergic receptor sub11 types; inappropriate statistical evaluation of 12 data, litter versus the pup; discrepancies in 13 the number of pups examined for behavioral 14 endpoints; and lack of objective and validated 15 behavioral tests. Please comment on these 16 preliminary conclusions regarding the 17 neurotoxicity findings. 18 Okay. The Agency has 19 preliminarily concluded that the available 20 studies indicate that the neurotoxicity 21 endpoints examined are not more sensitive than 22 those evaluated for neuroendocrine function

### 202-234-4433 Neal R. Gross & Co., Inc. Page 146 1 following atrazine exposure. For example, 2 attenuation of the LH surge and estrous cycle 3 disruptions in female Sprague-Dawley rats 4 which form the basis for the current chronic

5 RfD. 6 In addition, the Agency has 7 concluded that there is no association between 8 atrazine exposure and development of9 Parkinson's disease on the basis of non10 specificity of effects on brain dopaminergic 11 system, lack of histological and behavioral 12 features characteristic of Parkinson's 13 disease, and results of epidemiological 14 studies. Please comment on this preliminary 15 conclusion. 16 DR. PORTIER: Thank you. 17 So, Dr. Horton, it looks like we 18 have two comments we're looking for. And turn 19 on your mike, please. 20 DR. HORTON: Let's see if I 21 managed to respond to both of those. Okay. 22 In response to the first comment, the Agency

### 202-234-4433 Neal R. Gross & Co., Inc. Page 147 1 provides information in Section 3.4 of the 2 white paper and the presentation given on 3 Monday, that there reason for concern that 4 dopaminergic transmission may be affected by 5 atrazine, as shown by studies conducted prior 6 to 2003. The Agency then reviews two more 7 recent studies, Belloni, et al., and Coban and 8 Filipov 2007, which provide additional data 9 reaching similar conclusions. 10 In addition to previous 11 suggestions that atrazine may negatively 12 impact dopamine transmission, the Coban and 13 Filipov study also suggests that serotonergic 14 systems may be involved. Additional studies 15 were presented suggesting that atrazine may 16 also influence somatostatinergic systems as 17 well as other neuropeptides. Any alteration 18 in these neural pathways may ramify through 19 many homeostatic, neurobehavioral, and 20 metabolic systems, as mentioned in the 21 response to Question 1.2. 22 Although each study individually

### 202-234-4433 Neal R. Gross & Co., Inc. Page 148 1 suffers from technical errors and problems 2 with reporting and should be considered 3 preliminary as is consistent with your 4 conclusions -- or the conclusions of the 5 Agency, when considered in total, the emerging 6 body of evidence suggest an area of concern 7 that requires further investigation into the 8 neurotoxicity and neuroendocrine effects of 9 atrazine across all stages of a life span in 10 environmentally relevant doses. 11 These areas of concern include the 12 prenatal/perinatal periods and effects in 13 adulthood on a wide range of neurotransmitter 14 systems should also include the oft neglected, 15 but nevertheless important glia, and bring 16 regions other than those defined by a strictly 17 Parkinson's disease model. Research should be 18 conducted with consideration to the fact that 19 there are critical periods during development, 20 both prenatal and postnatal, including during 21 the adolescent period -- see work by Cheryl 22 Sisk and others, and I'll provide a list of

### 202-234-4433 Neal R. Gross & Co., Inc. Page 149 1 references -- when transient exposure to 2 chemicals can have permanent organizational 3 effects on the nervous system. 4 Additionally, cumulative exposures 5 to steroids and/or stress is proposed to have 6 cumulative or allostatic affects on health, 7 and I can provide references. There's a 8 recent reference that has just appeared in the 9 general Hormones and Behavior by Bruce McEwan 10 and John Wingfield. That has just appeared in 11 Hormones and Behavior 2010.

12 Of concern to human health and 13 well-being is the suggestion that atrazine may 14 affect numerous regions and neurotransmitter 15 systems. Careful wording must be used when 16 reporting these new developments. Use of the 17 phrase non-specific, as with a non-specific or 18 non-Parkinsonian model, conveys a sense of 19 unimportance. In contrast, the possibility 20 that multiple neurotransmitter systems are 21 involved, in fact, should shift our focus on 22 the mode of action.

### 202-234-4433 Neal R. Gross & Co., Inc. Page 150 1 The early studies were focused on 2 a model fo Parkinson's Disease. The realities 3 of current research funding mechanisms often 4 force researchers to squeeze their work into 5 the context of one disease model or another, 6 whether the square peg fits in the round hole 7 or not. With the emergence of more research, 8 the peg may not fit, and appears not to fit 9 the Parkinson's disease model, but now needs 10 a new hole of its own. 11 The emerging preliminary data do 12 suggest a plausible link and basis for 13 additional studies related to the new mode of 14 action for atrazine proposed in the Agency's 15 white paper. Additional research is needed to 16 determine the size and shape of the new peg 17 and the new hole, including studies 18 specifically designed to evaluate the changes 19 in neurotransmitter and neuropeptide systems 20 in -- concerned in the context of the broader 21 mechanism of action proposed in the white 22 paper.

### 202-234-4433 Neal R. Gross & Co., Inc. Page 151 1 For the record, researchers 2 working with animals face increasing 3 limitations on their ability to meet the 4 criteria set forth by the EPA for determining 5 whether data are acceptable. Researchers are 6 under increasing pressure to limit the number 7 of animals used in their work, and one 8 question they must respond to on every animal 9 care and use regulatory form is whether or not 10 an experiment replicates an experiment 11 conducted by their laboratory or any other 12 laboratory or any published study. 13 It is increasingly difficult to 14 get permission to replicate a study that has 15 been done in the past, and to get permission 16 to conduct that study from your institutional 17 review board. Any attempt to replicate 18 results -- or any attempt to replicate results 19 of a previous study must be done in the 20 context of new studies, thereby increasing the 21 complexity of an experiment, thereby often 22 weakening your statistical power.

### 202-234-4433 Neal R. Gross & Co., Inc. Page 152 1 We encourage the EPA to 2 communicate with the National Institutes of 3 Health, the Department of Agriculture, the 4 National Science Foundation, and the American 5 Association for Laboratory Animal Care, the 6 accreditation agency for animal facilities, to 7 the extent possible to make them aware of the 8 EPA's guidelines for acceptable data. Thank 9 you. 10 DR. PORTIER: Thank you.

11 Dr. Chambers.

12 DR. CHAMBERS: Thanks. 13 I think points are well taken, but 14 I think I'm going to take a different tack on 15 answering this question. I think a number of 16 people around the table today have mentioned 17 the dose levels that have been used in a lot 18 of these studies, and I'd just like to 19 reiterate my concern about some of those dose

20 levels too. 21 Necessarily, in academic labs I 22 think we need to go to high doses just to sort

### 202-234-4433 Neal R. Gross & Co., Inc. Page 153 1 of justify that we get some results that we 2 can publish, but that doesn't necessarily do 3 you a whole lot of good in the regulatory 4 arena, and I'd like to emphasize that. 5 Another point along those lines 6 too, is when you start using these 7 astronomical doses that we've seen numerous 8 times in these studies, you pretty much 9 obliterate the metabolism in other sorts of 10 defense mechanisms, and so they're not 11 necessarily realistic. So the mode of action 12 you discover at those high doses may not be 13 anywhere near reality. 14 With respect to your first 15 question there, I think -- I looked at all 16 those studies and I concur with the 17 deficiencies that you identified, and so I 18 don't see that many of them are very useful 19 for risk assessment. They certainly are not 20 designed and not done to the quality that you 21 expect out of the registrants and the other 22 types of studies that are used in the

### 202-234-4433 Neal R. Gross & Co., Inc. Page 154 1 regulatory sense. 2 Just for, I guess, the sake of 3 transparency, I do want to mention that the 4 Filipov studies, and there are three of them, 5 did come out of a center grant that I was in 6 charge of at the time. I did not collaborate 7 on those studies; I had nothing to do with 8 them. As a matter of fact, I did comment on 9 the high doses and did object to those at the 10 time, but they got done anyway. But at any 11 rate, I don't -- I thought maybe I better say 12 that just in case anybody knows where Filipov 13 was at the time that he did those studies. 14 So you identified a number of 15 rather non-specific effects -- oh, I shouldn't 16 use non-specific I guess -- sort of scattered 17 effects, non-dose responses, scattered types 18 of things, and I don't think they really 19 reflect a strong indication of neurotoxicity. 20 Probably the study that is most useful from 21 the standpoint of identifying whether any of 22 these neurotoxic mechanisms on dopamine are

### 202-234-4433 Neal R. Gross & Co., Inc. Page 155 1 any more relevant to your point of departure 2 in risk assessment would be the Rodriguez 3 study, and I still have difficulty with the 4 way they tried to describe dose levels there. 5 And, Ruby, I tried to interpret 6 that the way you did yesterday, too, but I 7 looked again last night, and every time where 8 they talk about the chronic dose levels in the 9 feed, they just say five mgs per kg or ten mgs 10 per kg and don't identify day. And I see in 11 your write-up you identified day, and that's 12 sort of the interpretation. But nevertheless, 13 that is not the way you express chronic doses, 14 and so it was really very difficult to tell 15 what they were being exposed to. 16 They should have described, for 17 something like that, a feeding study, was this 18 put in pellets, was this powdered form, and, 19 you know, did the animals scatter it and did 20 they really understand how they were getting 21 it, is it something they put on cookies, like 22 sometimes we do with feeding studies and so

### 202-234-4433 Neal R. Gross & Co., Inc. Page 156 1 forth? And so I think you're really left with 2 not knowing for sure how they animals were 3 dosed and how consistent that five or ten mgs 4 per kg per day, I presume, was done. 5 I'm concerned -- so that probably 6 is some of the lowest dose data that's in this 7 mix. I'm rather concerned about the 8 stereological results because those have a 9 tremendous amount of overlap in the individual 10 animals between the treated and the control. 11 So I'm not really convinced that there's an 12 effect there. There was a limited number of 13 animals that are presented and the -- again, 14 a tremendous overlap between the controls and 15 treated. So if there's anything there, I 16 really do think that needs some sort of repeat 17 some time along the line.

18 I'm not sure what else to comment 19 on that except, again, these are not data that 20 are consistent enough and well-described 21 enough for you to conclude anything other than 22 that they are preliminary and they have

### 202-234-4433 Neal R. Gross & Co., Inc. Page 157 1 limitations. 2 With respect to the Parkinson's 3 disease question, I think the studies that 4 have implicated Parkinson's disease there are 5 basically an over-interpretation of the 6 results that they've gotten. I'm not 7 convinced that the studies that they've done, 8 because of the behavioral endpoints and that 9 sort of thing, are really suggestive of an 10 implication in Parkinson's disease. That's 11 not to say that that isn't true, but there's 12 nothing in these studies, I think, that really 13 suggests that. 14 So I am in concurrence with your 15 evaluation of those papers that they are 16 preliminary, they're non-conclusive, and they 17 probably do not lead to any suggestion that 18 these effects should supplant the POD that 19 you've already got in place.

20 DR. PORTIER: Dr. Reed. 21 DR. REED: First of all, I want to 22 thank the Agency for putting all the

### 202-234-4433 Neal R. Gross & Co., Inc. Page 158 1 literature paper and its collections in such 2 an organized fashion. It really helped to go 3 in -- you know, the summary, the review 4 they're very helpful to guide me in terms of 5 which particular article that I want to zoom 6 in. I did go and get all the articles, so 7 that helps too. And so that, you know -- what 8 I mean is that we don't have to agree with the 9 review or the interpretation of this study, 10 but the guide is great. 11 Let me see, for the first 12 question, again, my take is going to be 13 slightly different, so that's great. You 14 know, all three of us look at different 15 aspects of the issue. So I also agree that 16 the Agency came to the preliminary conclusion 17 about the findings being preliminary because 18 of limitations. 19 Basically, when I look at 20 neurotoxicity, I am looking at whether CNS, 21 PNS have been affected, and atrogen 22 technically is neurotoxic. I think what was

### 202-234-4433 Neal R. Gross & Co., Inc. Page 159 1 puzzling and what all the studies were going 2 about is trying to connect between mode of 3 action and the manifestation of that, which we 4 are not clear about how many different mode of 5 action or networks involved, and so it's sort 6 of at this stage impossible to connect to the 7 two. And we're going to be seeing a lot of 8 that expression within, you know, our meeting

9 here.

10 I have one comment because I came 11 to the same conclusions as Dr. Chambers that 12 if I were to look at the endpoints, which 13 would have some kind of an impact on risk 14 assessment, it will be the Rodriguez study 15 because of the low, you know, NOEL. And I'm 16 not trying to defame the study at all because 17 I'm not entirely clear about how the dose was 18 decided, I just caught on the fact that it 19 says that they controlled the diet, so I 20 figured that they must have made measurements 21 of the diet in order to control the body 22 weight.

### 202-234-4433 Neal R. Gross & Co., Inc. Page 160 1 I am impressed with the fact that 2 these are fairly recent studies, and so, you 3 know, yesterday I mentioned with the 4 oncogenicity part of our discussion and in my 5 questions, you know, during the presentation, 6 and also I'm just struck by the fact that if 7 something is important, can we perhaps make an 8 effort to contact the author and maybe clarify 9 some of these points? I mean if we think 10 there is value in it, I would encourage the 11 Agency to do that. 12 I notice that one of the authors 13 in the Rodriguez study is actually from the 14 Agency. Am I correct on that? Maybe I 15 wasn't. But -- is it? Okay. Well, in any 16 case, that's what I'm thinking, that if it is 17 possible to contact the office, we might be 18 able to get information if dose is the issue.

19 DR. LICCIONE: I have a comment 20 though about the confidence in the study. I 21 mean I think at face value, as Dr. Chambers 22 mentioned, the stereological results, I have

### 202-234-4433 Neal R. Gross & Co., Inc. Page 161 1 zero confidence in that. And I have a number 2 of problems with the behaviorial assessments. 3 DR. REED: Right. Right. 4 DR. LICCIONE: I believe that in 5 contacting them we would have to address a lot 6 of these limitations -- 7 DR. REED: Right. Right. 8 DR. LICCIONE -- rather -- in 9 addition to clarifying the dosing regimen, 10 which I also had difficulty understanding 11 because they didn't provide the correct 12 information. 13 DR. REED: Right. No, no, I

14 wasn't -- 15 DR. LICCIONE: But I think --

16 DR. PORTIER: That was Dr. Luebke.

17 Dr. Reed? 18 DR. LOWIT: Luccione. 19 DR. PORTIER: Luccione. He got it 20 wrong. 21 Dr. Lowit. 22 Okay. Back to Dr. Reed.

### 202-234-4433 Neal R. Gross & Co., Inc. Page 162 1 DR. REED: No, no, I totally agree 2 with you. I just haven't done with the 3 concept. I'm saying that if it is just a 4 matter of dose, then, you know, we can go and 5 contact, but I think there's some protocol 6 observational issues that we might not be able 7 to resolve is what I was going to say. So 8 that's good. We're all in agreement with each

9 other. 10 In terms of neurotoxicity, I ask 11 myself what kind of an endpoint am I looking 12 for anyway, and it's going to come up in 13 Question 1.9, but what I'm thinking of, and, 14 you know, it's something sort of -- focused me 15 in the sync, it was because I notice that some 16 of the studies, they might not be listed 17 within this group, actually came up with 18 clinical sign kind of effects, and I don't 19 know the reasons behind it, but I think that 20 that might be something, you know, worth 21 looking into in terms of manifestation of 22 neurotoxicity.

### 202-234-4433 Neal R. Gross & Co., Inc. Page 163 1 Let me see. I think I would focus 2 on neurobehavioral and neurodevelopmental, 3 which my understanding is that we don't have 4 something like that. I don't want to be the 5 R2D2 type of person as a risk assessor, but it 6 might be worthwhile for the Agency to, instead 7 of saying that we don't have enough 8 information, these are all preliminary, we 9 don't think the endpoint is going to be more 10 sensitive than what we've been looking at, 11 since we haven't defined that so we cannot 12 make such conclusion, it might be worthwhile 13 to look into the possibility of -- and I think 14 the Agency accumulated a lot of great 15 information, asking a lot of good questions 16 about neurotoxicity, that it might be possible 17 to work together in coming up with a 18 neurodevelopmental study, or even FOB type of 19 study, at least explore that possibility. I 20 think it's good to well characterize it before 21 we throw it away saying it's not as sensitive.

22 DR. CHAMBERS: Let me ask a

### 202-234-4433 Neal R. Gross & Co., Inc. Page 164 1 question since this is a pesticide, was a DNT 2 study conducted on it? No? 3 DR. LOWIT: No, there's no DNT.

4 DR. PORTIER: What does that stand

5 for? 6 DR. LOWIT: Developmental -- 7 DR. CHAMBERS: Developmental 8 neurotoxicity study. 9 DR. LOWIT: Sorry. 10 DR. CHAMBERS: Sorry.

11 DR. REED: Can I make a comment or 12 question? I don't think there's FOB study. 13 Right? Was there? 14 DR. MENDEZ: I don't believe so, 15 but I'm not 100 percent sure -- 16 DR. REED: Acute versus chronic

17 or -- 18 DR. MENDEZ: I don't think that we 19 have an acute neurotoxicity study, if that's 20 what you're asking.

21 DR. REED: And so these are the 22 two, DNT and the neurotoxicity studies is what

### 202-234-4433 Neal R. Gross & Co., Inc. Page 165 1 I'm referring to. 2 DR. LOWIT: I guess I'll go back 3 to one of my comments earlier about the -- 4 particularly the DNT that costs somewhere in 5 the order of 7, 800, up to, you know, upwards 6 of a million dollar study, and many, many, 7 many animals. The value added of that study, 8 given the nature of the totality of the -- 9 what is known about atrazine and that we're 10 really diving down into more precursor events, 11 and DNTs, developmental -- you know, the 12 stuff, the alphabet soup -- developmental 13 neurotoxicity studies are not always the most 14 sensitive studies, and it's, at least my 15 personal opinion, it's highly unlikely that 16 study would give you anything lower than the 17 things that we're talking about for the --

18 related to the hormones. 19 DR. PORTIER: Dr. O'Byrne? 20 DR. O'BYRNE: My understanding is 21 that atrazine has been around for 60 years. 22 Surely there's some clear epidemiology -- epi

### 202-234-4433 Neal R. Gross & Co., Inc. Page 166 1 data because some of these male farmers must 2 be now in their 80s. So is there not a clear 3 guidance from that sort of data, clinical epi 4 data on Parkinson's? 5 DR. LOWIT: I missed the first 6 half of the question. You're asking about --

7 DR. O'BYRNE: It's been around for 8 60 years. Farmers have been spraying it on 9 their crops. And some of those guys now must 10 be in their 80s, so is there is any epi data 11 showing that there's an increased incidence of 12 Parkinson's disease? Do we need animal

13 models? 14 DR. LOWIT: There is -- our 15 epidemiological evaluation is still ongoing, 16 but there is -- atrazine was included as part 17 of the Agricultural Health Study, and there is 18 a relatively recent study on Parkinson's, and 19 atrazine was not one of the pesticides where 20 they saw a positive statistical association 21 with Parkinson's in pesticide applicators. 22 DR. PORTIER: Was it Dr. Horton?

### 202-234-4433 Neal R. Gross & Co., Inc. Page 167 1 Yes. And then Dr. Chambers. 2 DR. HORTON: One of the things I 3 want to make sure that we made clear is the 4 distinction between neurotoxicity and 5 neurodevelopmental effects. Whereas, you 6 know, we have one killing neurons in an acute 7 fashion, whereas exposure at different stages 8 of life altering a developmental program, and 9 I think those are two very different things 10 that have to be examined, which is why, in my 11 statement, I commented that the studies need 12 to be examining factors at different life 13 stages. 14 And I think that is some of what 15 needs to be examined in terms of looking at 16 weight of the evidence. And I think looking 17 at the totality of the evidence, regardless of 18 what you're looking at in terms of the doses 19 and things here, there is some suggestive 20 evidence that points in that direction. 21 The other question I have is for 22 Dr. Liccione -- okay. I'll get it. When you

### 202-234-4433 Neal R. Gross & Co., Inc. Page 168 1 say you discount the stereological data, part 2 of it was you commented on the calibration. 3 Could you comment -- or explain why you 4 discounted it and which specific study? 5 DR. LICCIONE: Okay. The 6 Rodriguez in particular -- 7 DR. HORTON: Okay. 8 DR. LICCIONE -- the stereological 9 showed, as Dr. Chambers said, when you see the 10 overlay from a variability, the stereological 11 results should account for a coefficient of 12 error biological variation to give you a 13 handle of the statistical dispersion. Because 14 stereology is based on random systematic 15 statistical sampling, which is often used in 16 survey sampling, and one has to address those 17 statistical issues in looking at it because 18 stereology has not gained wide acceptance yet 19 because of a lot of problems with methodology 20 and statistical error. 21 DR. CHAMBERS: This is Janet 22 Chambers. I just wanted to make sure that my

### 202-234-4433 Neal R. Gross & Co., Inc. Page 169 1 question wasn't interpreted as a suggestion 2 that DNT be run. I was just thinking that 3 perhaps it was already part of your data sets. 4 But I think sort of following onto 5 that conversation that was going a few minutes 6 ago, I think what you all really need to do is 7 make sure that you're looking at what appears 8 to be most sensitive out there, and not 9 requiring a lot of data that are just probably 10 going to be false leads because they're only 11 go to show effects at higher levels and all. 12 You've got the data sets that you 13 can look at for the most sensitive effects. 14 I think you pretty much decided that the 15 neuroendocrine appears to be the most 16 sensitive effect right now, and going into a 17 bunch of other types of data requirements or 18 data studies that are not related to the very 19 sensitive effects are probably not going to 20 lead to anything very useful. 21 DR. PORTIER: My understanding of 22 the question to the panel though is whether

### 202-234-4433 Neal R. Gross & Co., Inc. Page 170 1 you think the neurobehavioral, neurotox 2 effects are less sensitive than the endocrine. 3 DR. CHAMBERS: And I think I'll 4 try to answer that again, Ken. Based on these 5 particular papers that we saw, I don't see 6 that they are -- there is anything that is 7 more sensitive than the other endpoints that 8 they've used up till -- that you've used up 9 till now. 10 DR. PORTIER: But I think we have 11 some -- actually, I think Dr. Reed was next,

12 and then Dr. Horton. 13 DR. REED: By saying 14 neurodevelopmental effects, I also don't mean 15 the standard -- what I said is that the Agency 16 had gathered a lot of information by now 17 specific to atrazine, but I thought by working 18 together you might be able to come up with a 19 valid -- a study to study the 20 neurodevelopmental effect manifested from -- 21 whether it's, you know, endocrine effects or 22 not, because I think you're going to get a lot

### 202-234-4433 Neal R. Gross & Co., Inc. Page 171 1 of questions further down the road about what 2 happened to the pre- and post -- prenatal and 3 perinatal exposures, and how is that 4 manifested in -- during the development. That 5 was what I -- I didn't mean the standard DNT 6 study either. 7 I'll let Dr. Horton comment, and

8 then I'll come back to the next one. 9 DR. HORTON: Okay. In that 10 context I think all three of us are in 11 agreement in terms of, you know, at the 12 current state of development of the data, the 13 answer to the second question of are the 14 neurotoxicity data more sensitive than the 15 endocrine data. No, because the data are 16 simply not good enough. They're, you know, 17 they're clearly preliminary. That is 18 absolutely clear. They're very preliminary. 19 What the data suggests is that 20 there is a possible mode of action and a 21 plausible reason to suspect that there is 22 something going on that is consistent with the

### 202-234-4433 Neal R. Gross & Co., Inc. Page 172 1 suggested mode of action that has been 2 discussed in context of the other question 3 that is worth additional investigation.

4 DR. PORTIER: Dr. Reed. 5 DR. REED: Okay. So my second 6 part of comment is this, that the endpoint for 7 neuroendocrine aspect has not been clearly 8 defined. I mean it's a mode of action, it's 9 not an endpoint, and when it comes to endpoint 10 for risk assessment, I'm not quite sure yet 11 how that line is going to be drawn in terms of 12 what is the manifestation of that and, you 13 know, and so forth. 14 So given that the information 15 right now is available, they don't look "more 16 sensitive," but that, again, is just looking 17 at the mode of action, not the dose response

18 and not the result of the cascade of events 19 that would come out at the very end in terms 20 of the endpoint. I feel like it's premature 21 for me to say that the neurological endpoints, 22 including the neurodevelopmental and all the

### 202-234-4433 Neal R. Gross & Co., Inc. Page 173 1 other, you know, endpoints put together, is 2 less sensitive. 3 I think that's probably a little 4 bit different -- you know, less sensitive than 5 the neuroendocrine type of endpoint, because 6 if we're looking at either the same or similar 7 mode of action or a different mode of action, 8 we haven't even defined what that endpoint is. 9 So we're saying there's not enough 10 information, you know, from the neurotoxicity 11 part of the database, it's not the same as 12 saying because we don't have that, so it's not 13 going to be more sensitive. Does that make

14 sense? 15 DR. HORTON: I would say this is a 16 case where there's a difference in the 17 statement the data don't support versus there 18 are no data. And in this case the statement 19 is there are no data, not the data don't 20 support. And so it's a need for more data.

21 DR. PORTIER: That was Dr. Horton. 22 That's exactly what I was trying

### 202-234-4433 Neal R. Gross & Co., Inc. Page 174 1 to get. The point is I don't think they're 2 answering your question about which one's 3 better, and they're basically saying, we don't 4 have enough data on the neurotoxin, 5 neurobehavioral endpoints to be able to make 6 that assessment. And Dr. Reed is leaving open 7 the issue that a neurobehavioral endpoint may 8 actually be the key health effect that they 9 may be looking at. 10 DR. REED: Which we don't know at 11 this point.

12 DR. PORTIER: Dr. Chambers. 13 DR. CHAMBERS: But I don't think 14 these data sets are suggestive enough to say 15 that you really need to launch a big effort to 16 look for that at this point. I mean there's 17 a little bit of stuff that's low dose in what 18 we looked at, and it really is not showing a 19 good dose response curve on the neurochemistry 20 or the behavior or any of the endpoints that 21 were looked at in stereology, any of that, to 22 suggest that this is -- this has really got a

### 202-234-4433 Neal R. Gross & Co., Inc. Page 175 1 lot of plausibility in terms of displacing 2 what you already know in terms of the most 3 sensitive effect. If I`m getting the sense of 4 what you're asking. 5 DR. PORTIER: I was going to make 6 a suggestion that we leave this question open, 7 take a break, come back right after lunch and 8 continue, kind of -- because I feel like we're 9 kind of going in a little bit of a circle 10 here, no data, can't decide, not enough data 11 to decide if we need to suggest even more 12 research. So we're kind of caught in a loop

13 here. 14 So let's break till 1:15. We'll

15 reconvene at 1:15. 16 (Whereupon, the above-entitled 17 matter went off the record at 12:04 p.m. and 18 resumed at 1:16 p.m.)

19

20

21

22

### 202-234-4433 Neal R. Gross & Co., Inc. Page 176 1 A-F-T-E-R-N-O-O-N S-E-S-S-I-O-N 2 1:16 p.m. 3 DR. PORTIER: Before we get 4 started, we need to kind of close off Question 5 1.5, and I just wanted to look over at Dr. 6 LeBlanc and see if he'd had a brainstorm over 7 lunch and whether he wanted to revisit it. If 8 not, we'll close it off. 9 DR. LeBLANC: Well, I can say that 10 in the hour I had during lunch, I thought 11 about it definitively, I've worked out the 12 mode of action, all the intricacies -- 13 (Laughter.)

14 DR. LeBLANC -- but for the sake 15 of staying on schedule, I won't speak. 16 DR. PORTIER: It'll be in the 17 report. Okay. So I'll assume that Question 18 1.5 is closed now. But I just wanted to leave 19 that open just in case. 20 And we still have before us 21 Question 1.6. And my reason for leaving it 22 open is still trying to get to this second

### 202-234-4433 Neal R. Gross & Co., Inc. Page 177 1 comment question, which is the more 2 sensitive -- are the neurotoxicity endpoints 3 examined are more sensitive than those 4 elevated for neuroendocrine function. And I 5 realize that there's lack of data and the two 6 studies that we looked at, or the studies that 7 we've looked at, have serious limitations. 8 But the question -- I think the 9 question behind the question here from EPA is 10 is this something they need to go and continue 11 to get data on because it is likely to be more 12 sensitive, or is it something they need to go 13 get data on because it'll round out the issue, 14 or is it not something they need to go get 15 data on. I guess those are the three -- yes,

16 Dr. Horton. 17 DR. HORTON: Okay. So you gave me 18 a multiple-choice question. I think the 19 answer to your question is B. And if B was 20 that there -- no, it's not to just round it 21 out, but it may -- getting more data -- no, 22 it's actually all of the above, which wasn't

### 202-234-4433 Neal R. Gross & Co., Inc. Page 178 1 on your list. 2 The choices were, because the 3 data -- the current data are insufficient to 4 give us an answer to anything, if we have more 5 data will it just round out our understanding 6 of the mechanism of action of atrazine, will 7 the provision of more data give us a better 8 understanding of a more sensitive endpoint, 9 and will it tell us whether there's a more 10 sensitive endpoint. 11 And all of those things are true 12 because it is possible and more relevant here 13 to your regulatory and risk assessment, it's 14 possible that if there are developmental 15 effects, that those could be assessed at an 16 earlier stage and recognized at an earlier 17 point in an experiment and be more focused and 18 with greater, shall we say, gain in an assay 19 system, making for greater statistical power. 20 If you're looking at -- particularly if you 21 could put them into a neurobehavioral context 22 where you can do multiple studies or multiple

### 202-234-4433 Neal R. Gross & Co., Inc. Page 179 1 measurements on an animal in a behavioral

2 screen. 3 As have been done by many of the 4 NIH cores that are doing behavioral screening 5 cores for the neurogenomics screens, the 6 mutagenesis screens where they're looking for 7 point mutations in response to chemical 8 mutagens, and they have batteries of 9 behavioral endpoint, circadian rhythms 10 endpoints, whole panels of neurobehavioral 11 tests that they put the same animals through 12 at different developmental stages, and we do 13 this at Northwestern in our neurobehavioral 14 core, of Rotarod tests and grip tests and the 15 same animal will be put through 15 different 16 types of tests to screen them for various 17 anomalies. 18 And so you could put them through 19 essentially a high-output screening test to 20 look for a variety of things. And so if you 21 can set up a screening program for that, you 22 might be able to pick up a behavioral anomaly

### 202-234-4433 Neal R. Gross & Co., Inc. Page 180 1 on the same animal at a fairly efficient cost 2 and with a great deal of power. 3 DR. PORTIER: So, but what's the 4 expectation that that effect is going to occur 5 at a dose, say, lower than an endocrine 6 impact? And so that's one part of it. The 7 other part of it is the difference between 8 objective and subjective measurements. Right? 9 And a lot of the neurobehavioral stuff is 10 relatively subjective. 11 I know they're improving the 12 methodology, but a lot of it, you know, you 13 need many more animals -- they're not 14 sacrificed, that's good -- many more animals 15 to come up with that good definitive finding 16 of a small behavioral change. At least the 17 stuff that I've seen in the years we've been 18 before here, whereas a lot of people like the 19 objective measurements. Now you did mention 20 some, you know, like genomic screens and 21 stuff, those are more objective measures. 22 Right? The kind of repeatability is pretty

### 202-234-4433 Neal R. Gross & Co., Inc. Page 181 1 high. 2 DR. HORTON: Well, I would say the 3 kind of behavioral testing that I'm thinking 4 of are things like circadian rhythms where 5 you've got the animals on a running wheel, and 6 I would counter by saying some of the weakness 7 in the endocrine studies is that unless you're 8 doing pulsatile bleeding for some of these 9 endocrine measures, you're going to miss 10 changes. And that is very labor intensive for 11 what you're doing with the animals. 12 Many more of these behavioral 13 tests are automated using motion sensor boxes, 14 light detector, behavior -- oh, infrared 15 boxes, there are a great deal more 16 automation -- automated systems going into 17 these to do high through-put screening of 18 behaviors for these -- that have been 19 developed for the neurogenomic studies because 20 of the -- what I'm thinking of specifically 21 are the ENU genomic screening systems. So -- 22 DR. PORTIER: I think this is

### 202-234-4433 Neal R. Gross & Co., Inc. Page 182 1 good. 2 DR. HORTON -- in terms of looking 3 at low doses, I think many -- mainly it's 4 because many of the developmental effects may 5 be sensitive to lower doses than adult 6 response, and you just don't know what you're 7 going to pick up when you start looking at the 8 low doses because those experiments haven't 9 been done yet. 10 DR. PORTIER: I have a follow-up 11 question for the Agency. If atrazine were 12 newly registered today, and hadn't been around 13 for 50 years, would a neurodevelopmental or a 14 neurotox battery be required of the registrant 15 as part of the standard package? I mean would 16 we have had something like that in the 17 standard packet? 18 DR. MENDEZ: Elizabeth Mendez,

19 EPA. 20 Within the last two years the new 21 CFR, the new Code of Federal Regulations, we 22 have a new set of guidelines, and under those

### 202-234-4433 Neal R. Gross & Co., Inc. Page 183 1 conditions an acute neurotox would have been 2 required. A DNT is still not, and a 3 subchronic as well. So an acute adult 4 neurotox and a subchronic neurotox would have 5 been required. A DNT is still a tier two 6 test, and DNT is the developmental neurotox.

7 DR. PORTIER: Dr. Chambers. 8 DR. CHAMBERS: There are plenty of 9 objective measures in behavioral tests, so 10 that's -- it's not all fuzzy subjective stuff. 11 With all due respect, I'm going to disagree 12 with you. I know that resources and time and 13 everything is really limited, and I don't 14 really see anything in the data sets that we 15 were provided with that suggest that doing 16 some extensive developmental neurotoxicity, 17 not DNT testing, but any kind of extensive 18 developmental neurotoxicity testing would 19 really be a wise use of time and resources 20 right now considering the much more extensive 21 database you have already presented to us on 22 the neuroendocrine effects.

### 202-234-4433 Neal R. Gross & Co., Inc. Page 184 1 So I don't think there's really 2 anything suggestive in those particular papers 3 that were given to us that suggest a very 4 extensive array of neurotoxicity testing is 5 done. I'm just a little bit afraid that it 6 might be nothing more than a fishing 7 expedition and that you would not find 8 anything at lower doses that would, again, 9 displace the neuroendocrine effects as the 10 most sensitive effect right now.

11 DR. PORTIER: And so there's the 12 other issue though is the developmental versus 13 adult. All right. I mean part of what I hear 14 Dr. Horton saying is developmental 15 neurobehavioral and so the question is whether 16 the endocrine data and endpoints are 17 sufficient at the developmental stage. I 18 mean, you know what I'm kind of saying? 19 Because most of the studies we've looked at 20 are adult animal studies. Right? 21 DR. CHAMBERS: Well, a couple of 22 these -- this is Jan Chambers again -- a

### 202-234-4433 Neal R. Gross & Co., Inc. Page 185 1 couple of these were early treatments, but 2 they were not well-powered for the 3 statisticians, they were not well-conducted, 4 you know, not standard types of tests and all. 5 So, again, the data are not good in terms of 6 dose responses and so forth. So, again, you 7 know, in my mind, I didn't see anything that 8 really suggested that we should rush right out 9 and expand these types of studies. 10 DR. PORTIER: I guess it's my 11 understanding there'll be more data coming on 12 some of that as well. Right? Some of the -- 13 DR. MENDEZ: That is correct. We 14 have more data coming in within this week.

15 DR. PORTIER: Dr. Horton. 16 DR. HORTON: Yes, well, one of the 17 areas where we disagree is over the quality of 18 the data. And I guess the metaphor here is 19 whether you are feeling the elephant in the 20 room or not. And while each individual study 21 is not of high quality, when you look at each 22 of these individual studies, I'm feeling an

### 202-234-4433 Neal R. Gross & Co., Inc. Page 186 1 elephant in the room that suggests that there 2 may be something going on in terms of the 3 effect on the nervous system.

4 And each of the nervous -- the 5 neural systems that is impacted or suggested 6 to have -- to be influenced by atrazine in 7 these systems, the dopamine system, the 8 serotonin system, the -- what do we have in 9 here, the somatostatin system -- not so much 10 the somatostatin because that is influencing 11 growth hormone, but it feeds back in there 12 someplace, but primarily serotonin and the 13 dopamine systems. And as you look at how 14 widespread those areas are, when you think of 15 their impact on cognition, when you think on 16 their impact on affect and attention. 17 You need to consider not just what 18 impact they may have on reproductive function, 19 on the HPA axis, you need to consider what 20 impact they have on mental disorders, 21 schizophrenia, affective disorders, executive 22 function disorders. There's a wide range of

### 202-234-4433 Neal R. Gross & Co., Inc. Page 187 1 issues. 2 You need to consider the 3 relationship between estrogens and their 4 inter-relationship with insulin signaling and 5 metabolic disorders. We're walking into 6 potentially a broad range of effects. There 7 are insulin receptors in the brain. Anybody 8 who had physiology or biology 20 years ago 9 probably thinks of glucose and insulin, 10 insulin not having an effect in the brain, and 11 glucose uptake being constant in the brain. 12 Well, that's true, but there are 13 insulin receptors in the brain, and those 14 insulin receptors are interacting with 15 estrogens, and they're influencing the 16 signaling in the brain. So as I feel this 17 elephant in the room, and I feel the dopamine 18 system potentially being influenced, I think 19 we need to look at this. 20 And when I look at graphs that, 21 yes, they have small sample sizes, and the 22 data were collected by stereology, which may

### 202-234-4433 Neal R. Gross & Co., Inc. Page 188 1 or may not have wide acceptance, but the 2 stereology is a relatively new and highly 3 sophisticated method for collecting data. It 4 requires exceptionally expensive confocal 5 microscopes, which are on the order of tens of 6 thousands of dollars. It requires 7 considerable training in using that microscope 8 to analyze the micrographs. These are not 9 simple techniques. 10 Or I consider that journal editors 11 consistently require people to cut down the 12 amount of images that they put into papers. 13 I'm not disillusioned or concerned when 14 there's not a micrograph in a paper. But when 15 I do see that an author has given me not just 16 the bar graph and the standard error of the 17 mean, but they have given me the scattergram 18 that includes every individual point for the 19 animal so that I can compare the distributions 20 for myself and look at the overlap and see 21 what those data look like, and know what that 22 elephant in the room feels like.

### 202-234-4433 Neal R. Gross & Co., Inc. Page 189 1 I'm willing to think that we do 2 have an elephant in the room, and I think we 3 need to accept that we have an elephant in the 4 room. And I think we need to evaluate the 5 effects of atrazine on the brain in multiple 6 situations. Thank you. 7 DR. PORTIER: I think what I'm 8 going to recommend to Dr. Horton and Dr. 9 Chambers and Dr. Reed is when we put this 10 together, we don't necessarily need consensus, 11 but we need all of these arguments kind of 12 filled out. And I think you've done that. So 13 I'm not worried about coming to consensus on 14 this one. I pushed, but it's clear that we're 15 not going to get the panel to agree on this. 16 And I get the feeling Dr. Horton's 17 on one side, Dr. Chambers is kind of on the 18 other, and Dr. Reed's kind of in the middle. 19 So we'll be looking at Dr. Reed to kind of 20 build that transition between the two. 21 Any additional comments on this 22 question?

### 202-234-4433 Neal R. Gross & Co., Inc. Page 190 1 DR. REED: I was asked if I'm 2 ambivalent. No, I'm not ambivalent for being 3 in the middle. Yes, but I think, you know, my

4 comments were -- 5 DR. PORTIER: No, I think of you 6 more as cautious and unwilling to give up on 7 these potential health effects -- 8 DR. REED: Right. Right. 9 DR. PORTIER -- as a potential 10 point of departure. 11 DR. REED: Right. And the concern 12 was really just based on the mode of action, 13 as we've been talking about these two or three 14 days, and in addition there might be, you 15 know, other sidebar on the mode of action 16 which is not completely deciphered, but I am 17 concerned about developmental type of effect 18 with in utero exposure, perinatal exposure, 19 and the sensitivity issue in that I think it

20 needs to be addressed. 21 DR. PORTIER: And it will be. 22 Yes, Dr. Lowit.

### 202-234-4433 Neal R. Gross & Co., Inc. Page 191 1 DR. LOWIT: I would, unless Dr. 2 Cooper has something -- or Dr. Mendez had 3 something to add, I would, I guess, follow 4 your line of thinking to have the report 5 represent the variety of opinions, and I guess 6 putting a happy face on coming back two or 7 three more times. 8 We do have the September meeting, 9 and I'm not aware that anything new will come 10 up on this issue, but we may be able to, when 11 we have a newer set of points of departure and 12 a fuller evaluation of the life stage effects, 13 this may become -- there'll be more clarity 14 with a more full analysis around the 15 relationship of all these, and we can make a 16 more robust description, I think. 17 DR. PORTIER: Okay. I think we'll 18 close out on this question. That ends 19 Question 1.6, and we're going to move on to 20 Question 1.7. 21 DR. COOPER: I'll read this 22 question. I'll keep the ball moving anyway.

### 202-234-4433 Neal R. Gross & Co., Inc. Page 192 1 Charge Question 1.7, based on a 2 review of two studies of the potential effects 3 of atrazine on the prostate, Section 3.3.2.2 4 of the draft issue paper, the Agency has 5 concluded that the results of the Rayner, et 6 al., study 2007 -- the Rayner, et al., 2007 7 study of pregnant rats treated during 8 gestation support previous observations, 9 Stoker, et al., 1999, that atrazine treatment 10 to the rat dam either perinatally or early 11 postnatally can increase prostate weights due 12 to an increase in inflammatory infiltrate in 13 the male offspring. 14 This effect on the offspring was 15 shown to be due to a suppression of prolactin 16 in the atrazine exposed dams during 17 lactation -- which I might add is in contrast 18 to the Stoker paper where it was done 19 postnatally -- and is consistent with the mode 20 of action of atrazine on neuroendocrine 21 function. 22 The Agency also preliminarily

### 202-234-4433 Neal R. Gross & Co., Inc. Page 193 1 concluded that further research is needed to 2 provide more convincing evidence that 3 atrazine-mediated suppression of prostate 4 cancer in the probasin/stroke SV40T antigen 5 transgenic rat, androgen-dependent prostate 6 cancer rodent model, may possibly be due to7 caloric restriction rather than endocrine8 related as postulated by Kandori, et al.,

9 2005.

10 Please comment on these 11 preliminary conclusion regarding the recent 12 prostate findings. Please comment on the 13 extent to which available data support the 14 proposed mode of action for prostatitis, and 15 the appropriateness of the rodent model in the

16 context of human health. 17 DR. PORTIER: Dr. Williams. 18 DR. WILLIAMS: So this question 19 gives us some questions about studies that we 20 really haven't talked about at all yet, so I'm 21 just going to briefly review the two studies 22 in question and then answer these.

### 202-234-4433 Neal R. Gross & Co., Inc. Page 194 1 So the Stoker, et al., `99 paper 2 demonstrated that postpartum administration on 3 day 1 to 4 postpartum of doses between 6 and 4 50 milligrams per kilogram per day of atrazine 5 to lactating rat dams dramatically, or in the6 higher doses completely, inhibited suckling7 induced prolactin release in the dams, and 8 that it also caused an increased incidence of 9 lateral prostate inflammation in the male 10 offspring at four months of age. 11 They observed the same effect 12 after treating dams with bromocryptine, which 13 is a dopamine agonist that inhibits prolactin 14 release. And this effect was reversed by the15 administration of prolactin to the atrazine16 treated dams. So they basically saw an effect 17 and they also reversed the effect, and so it 18 was a really very nice study in that way. 19 The proposed mechanism to explain 20 these results was that prolactin is important 21 for neonatal brain development, and lack of 22 neonatal prolactin exposure from getting

### 202-234-4433 Neal R. Gross & Co., Inc. Page 195 1 prolactin in the milk leads to a failure of 2 dopaminergic system development -- again, 3 we're talking about this sort of neonatal 4 effect on the brain here -- and eventual 5 hyperprolactinemia in the adult male. 6 The study didn't actually 7 demonstrate hyperprolactinemia, this was based 8 on previous work where that had been shown, 9 that hyperprolactinemia can occur at about the 10 one month old male after this kind of an 11 exposure. And the prolactin levels were only 12 measured at four months of age, and at this 13 time there was no further hyperprolactinemia, 14 so they were different from controls at that 15 point. But the proposed mechanism was that 16 there was this period of hyperprolactinemia 17 that led to prostatitis. 18 So the newer studies, Rayner, et 19 al., in 2007, examined whether treating rat 20 dams with 100 milligrams per kilogram per day 21 of atrazine during late gestation, in day 15 22 to 19, had adverse effects on prostate

### 202-234-4433 Neal R. Gross & Co., Inc. Page 196 1 development of the male offspring at either 2 four or seven months of age. And in this case 3 they actually used a cross-fostering design to 4 distinguish between direct effects of prenatal 5 exposure of the atrazine that's given during 6 gestation, or was if effects of the prenatal 7 exposure to atrazine on the mom with milk, and 8 so the cross-fostering design was used. And 9 so they basically took pups from controls and 10 had them suckling from the previously 11 atrazine-treated animals, and then they also 12 some atrazine -- animals from atrazine-treated 13 dams that were moved over to control animals. 14 So it was a really nice cross-fostering study 15 in that way. 16 So this study demonstrated a lot 17 of similar things, that they -- suckling from 18 an atrazine-exposed dam resulted in an 19 increased incidence of prostatitis, whether or 20 not the male was exposed prenatally to 21 atrazine. So it looks like it's a postnatal 22 effect that is the sensitive time, not

### 202-234-4433 Neal R. Gross & Co., Inc. Page 197 1 prenatal. And that was consistent with the 2 Stoker findings where they only treated 3 postnatally and got the effect. Here if the 4 pup didn't suckle from the atrazine-treated 5 mom, there was no effect. So if they went 6 over to the controls, they did not have the 7 prostatitis. 8 So regarding the proposed mode of 9 action, the Stoker results demonstrate a clear 10 connection between diminished maternal 11 prolactin levels and prostatitis in the male 12 offspring. However, the proposal that the 13 prostatitis was due to hyperprolactinemia in 14 the male offspring wasn't tested in these 15 studies, as I mentioned. The prolactin levels 16 were only measured at termination of the 17 experiments at 120 days of age and were no 18 different from controls at that time. They 19 clearly could have been elevated earlier on, 20 and that just wasn't measured here. 21 One way to test that question 22 would be to follow prolactin levels and

### 202-234-4433 Neal R. Gross & Co., Inc. Page 198 1 document that indeed they are elevated during 2 some time of the peripubertal period, or 3 potentially blocking hyperprolactinemia at 4 that time by administering bromocryptine to 5 see if that's actually the mechanism to 6 explain the prostatitis because there's also 7 the possibility that there were atrazine 8 metabolites or something in the milk that the 9 pups were exposed to, and that these 10 metabolites might have affected the brains 11 directly or done something else that led to 12 the prostatitis later. 13 The reason that this matters is 14 because it would be important to know if it's 15 something in the milk that's a problem or 16 something not in the milk that's the problem 17 if we're going to think about human health 18 effects later. For example, if the problem 19 was related to diminished prolactin levels in 20 the milk, then maybe we ought to be worrying 21 about the effects on human health of failure 22 to breast feed, which is true of about 30

### 202-234-4433 Neal R. Gross & Co., Inc. Page 199 1 percent of women in the United States. 2 On the other hand, if it's 3 something due to having atrazine metabolites 4 or something else in the breast milk, we need 5 to worry about the 70 percent of women who are 6 breast feeding. And so, kind of getting back 7 at is it really important to figure out the 8 mechanism in this particular case, it may be 9 because it'll affect how we're going to think 10 about the exposures to the pups. 11 So now I'd like to move on to the 12 Kandori findings where the Kandori paper, 13 looking at prostate cancer and the 14 probasin/SV40T antigen-transgenic rat, the 15 paper basically supported the idea that 16 atrazine-mediated suppression of prostate 17 cancer in this model was due solely to caloric 18 restriction and not -- and was not an 19 endocrine-related outcome. 20 And I think that's an important 21 question given that there is a lot of 22 literature where, at least in the high-dose

### 202-234-4433 Neal R. Gross & Co., Inc. Page 200 1 atrazine studies, there is clearly a caloric 2 restriction effect, where given high enough 3 doses, animals will lose weight and maybe the 4 weigh loss could end up explaining findings

5 later. 6 Unfortunately, there's a lot of 7 problems with this particular study, and so I 8 think at the end the Agency's conclusion that 9 it's leading you to uncertain findings is 10 generous at best. And there were four 11 problems that I'll outline. One is that the 12 atrazine dose that was administered is very 13 uncertain in these studies. They were using 14 dietary administration, they had two rats per 15 cage, they don't really know what each rat 16 got. And the diets, when they went back and 17 measured what the diets actually had in them, 18 they didn't have in them what they thought 19 they had put in them in the first place, and 20 so the intake couldn't really be calculated. 21 The testosterone levels that they 22 saw in these rats were not different, even

### 202-234-4433 Neal R. Gross & Co., Inc. Page 201 1 though they had similar doses, where in other 2 studies testosterone levels were different in 3 the atrazine-treated animals. But the 4 atrazine dosing might have been so variable 5 that you couldn't find results. The

6 testosterone levels had standard error bars 7 that were basically as large as the bars 8 themselves. And so it was just a lot of 9 variability, it was so hard to make a 10 conclusion. 11 The caloric restriction group 12 themselves had highly variable testosterone 13 measurements, and so was it caloric 14 restriction and other issues with that, or was 15 it something to do with the testosterone. 16 It's really not clear. And then at the end of 17 the day this was a model where 100 percent of 18 the animals have adenocarcinoma or other -- or 19 intraepithelial neoplasia in the prostates at 20 15 weeks of age. These were looked at 13 21 weeks of age, and indeed pretty much 100 22 percent of the animals had the problem.

### 202-234-4433 Neal R. Gross & Co., Inc. Page 202 1 What they showed was that with 2 either the atrazine or the dietary restriction 3 and caloric intake there was a very, very 4 slight decreased if you measure the number of 5 epithelial cells as a ratio of epithelial 6 cells to total prostate size. And it was a 7 very small change and it was not a change in 8 overall levels of cancer at all. And given 9 that they only did these measurements on 10 literally two slices through the prostate and 11 they didn't do serial sections that encompass 12 the entire prostate, the findings were so 13 minimal that I'm not real enthusiastic that 14 another person doing the exact same study 15 would come up with the same results. 16 So interesting idea, potentially 17 could complicate studies if you have to think 18 about caloric restriction, but I'm not sure 19 that this particular study should be given 20 really any weight in terms of what the EPA 21 decides to do. 22 So regarding the appropriateness

### 202-234-4433 Neal R. Gross & Co., Inc. Page 203 1 of a rodent-model in the context of human 2 health, there really is a consistent finding 3 in both rats and humans of an association 4 between prostate inflammation and 5 proliferative inflammatory atrophy lesions, 6 prostate hypertrophy, intraepithelial 7 neoplasia, and cancer. And there's enough 8 findings in human literature in that regard 9 that there's actually been clinical trials 10 looking at non-steroidal anti-inflammatory 11 agents for the attenuation or treatment of 12 prostate cancer. 13 So the link is really strong in 14 the human literature, and certainly it seems 15 to be just as strong where prostatitis is seen 16 in association with prostate neoplasias in 17 rats. So there's a lot of similarities to the 18 two systems, and I think that that says that 19 it's a reasonable model. 20 In terms of thinking about 21 prolactin exposure -- sorry, loss of prolactin 22 exposure and effects through lactation, I

### 202-234-4433 Neal R. Gross & Co., Inc. Page 204 1 think we need to know a lot more about the 2 mechanism before you can say that's a

3 reasonable model. 4 DR. PORTIER: Thank you.

5 Dr. Delclos? 6 DR. DELCLOS: I'm in agreement 7 with those comments, and I really have nothing

8 further to add.

9 DR. PORTIER: Dr. Horton. 10 DR. HORTON: I'm in agreement, and 11 I have nothing to add. 12 DR. PORTIER: Somebody else, 13 please? Dr. Heeringa agrees. 14 Dr. Cooper. 15 DR. COOPER: Just to follow up one 16 thing. There's, again, the time line's a 17 blur, but I don't believe this was post-2003. 18 We had a graduate student working in my lab 19 who essentially followed through on that. The 20 hypothesis that was being examined, it was 21 based on Crowley's work earlier on, was that 22 if you inhibit prolactin, tubular and

### 202-234-4433 Neal R. Gross & Co., Inc. Page 205 1 fundibular dopaminergic neurons won't mature. 2 And that was based on a number of different 3 studies where they showed if they're not 4 there, they don't get momma's prolactin. 5 And so what Chris Langdale did, 6 and this is his thesis work, which is through 7 NC State tox department, he showed that the -- 8 he looked at the dopaminergic neurons' 9 developing, and indeed there was a delay. 10 Where the change occurred most dramatically in 11 terms of prolactin regulation was between 12 PND27 and 35, peripubertal change. And it 13 occurred only at that time, and that matched 14 very well back with some of those -- Judy 15 Ramelay's work looking at maturation of 16 prolactin regulation. 17 So there was some mechanistic -- 18 again, these are piecemeal things, but I think 19 they're supportive of that, or point in the 20 direction that there may be impairment in that 21 titis system based on that kind of exposure. 22 And whether that is an impact -- these neurons

### 202-234-4433 Neal R. Gross & Co., Inc. Page 206 1 grow -- they mature up to birth and then they 2 require the mother's prolactin, so whether the 3 preterm treatment is going to influence her 4 ability to release prolactin and then that's 5 something that I don't believe has been 6 followed through, 7 So, no, we didn't measure both 8 before and after birth, but mechanistically 9 anyway it's -- the data that Chris Langdale 10 had was consistent with that dopaminergic 11 hypothesis. I think it speaks somewhat to 12 this do we see developmental effects. I 13 believe we've looked for developmental effects 14 that maybe looking under the light, but 15 they're there.

16 DR. PORTIER: Dr. Horton.

17 DR. HORTON: Dr. Horton. I was 18 just going to comment, but Dr. Cooper said it 19 for me, is that what he just said about the 20 prolactin changes in these developing males 21 points to a developmental effect of the 22 atrazine on the dopamine neurotransmitter

### 202-234-4433 Neal R. Gross & Co., Inc. Page 207 1 system, which is relevant to Question 1.6. 2 DR. PORTIER: I don't see any 3 additional comments, and I can't really 4 summarize her summary, which was pretty good. 5 So we'll make sure that's in the report. 6 Okay. Gosh, I was thinking we 7 might not get to the hydrology today. So take 8 your time reading Question 1.8. 9 DR. LUEBKE: Okay. On to Question 10 Number 1.8. Based on data obtained in studies 11 to assess the effects of atrazine on the 12 immune system following developmental and 13 adult exposure, as well as in vitro 14 mechanistic studies, EPA concluded that 15 atrazine has the potential to affect the 16 immune system. However, the Agency has also 17 concluded that underlying mechanisms of 18 atrazine-mediated immunotoxicity -- you'd 19 think I could say that word by now -- and its 20 relevance to potential adverse health effects 21 in humans are still not thoroughly understood. 22 It is well established that products of the

### 202-234-4433 Neal R. Gross & Co., Inc. Page 208 1 endocrine system modify immune function. 2 However, adult rodent studies have not 3 determine whether immune system effects are 4 caused by direct effects of atrazine and/or 5 its metabolites, or whether they are the 6 result of modulated endocrine hormone 7 production, which in turn affects immune

8 cells. 9 Two published studies indicating 10 that exposure to atrazine during immune system 11 development may result in altered immune 12 functions in offspring. Although no 13 conclusions were drawn on the potentially -- 14 on the potential adversity of these effects 15 because immunosuppression was observed in one 16 study and immunoenhancement was observed in

17 the other. 18 Please comment on the potential 19 explanations for the disparate findings 20 reporter by Rooney, et al., and Rowe, et al. 21 Many immunotoxicologists consider 22 immunomodulation -- i.e., suppression or

### 202-234-4433 Neal R. Gross & Co., Inc. Page 209 1 enhancement of immune function -- as a 2 potentially adverse alteration of homeostasis 3 because both have been associated with disease 4 states. Thus, while the results of Rooney, et 5 al., and Rowe, et al., may appear to be 6 contradictory, together the data indicate 7 unintended immunomodulation at approximately 8 the same dose in two species.

9 Please comment on the effects of 10 gestational atrazine exposure as 11 immunomodulation when describing the 12 immunotoxicological outcome of developmental 13 immunotox study -- immunotoxicity studies. 14 Appendix -- shall I keep going? 15 Okay. Appendix B of the draft 16 issue papers describes experiments conducted 17 by EPA scientists on the potential 18 developmental immunotoxicity of atrazine. The 19 results for the experiments provide 20 conflicting results. Additional studies did 21 not provide a suitable explanation of the 22 differences. The Agency believes both sets of

### 202-234-4433 Neal R. Gross & Co., Inc. Page 210 1 data are of high quality. However, in the 2 context of hazard assessment, such differences 3 are difficult to interpret. Please comment on 4 the information contained in Appendix B and 5 provide suggestions for interpreting such data 6 as part of the atrazine re-evaluation. 7 Oh. Oh, okay. Here we go. We're 8 having so much fun. 9 The available data -- this is a 10 long question too -- the available data do not 11 indicate that atrazine-induced immunotoxicity 12 is a more sensitive endpoint than the 13 atrazine-induced effects on neuroendocrine 14 function, e.g. attenuation of LH surge and 15 estrous cycle disruption which form the basis16 for the current chronic RfD in female Sprague17 Dawley rats. Please comment on the degree to 18 which these preliminary conclusions are 19 supported by the available data. 20 DR. PORTIER: Dr. Holladay.

21 DR. HOLLADAY: The text for that 22 question was longer than any others. We ought

### 202-234-4433 Neal R. Gross & Co., Inc. Page 211 1 to petition for a higher per diem or something

2 for that. 3 Ken, we talked as a group about 4 addressing each sub-question, I think there 5 were four in here, one at a time and maybe it 6 being more functional if we did it that way. 7 The first of those is the Appendix 8 B question, which Dr. Luebke covered very well 9 the day before yesterday, I think it was. So 10 I'll just review that very briefly. These are 11 the Rooney, et al., studies where the 12 hypothesis that atrazine may cause 13 developmental immunotoxicity through 14 disruption on prolactin or thyroid hormones 15 was tested in Sprague-Dawley rats using a dose 16 of 35 milligrams per kilogram per day by oral 17 gavage. This is from gestation day 10 through 18 postnatal day 23, I think it was. And they 19 chose that dose to be just above the NOEL for 20 delayed onset of puberty in female offspring. 21 They had separate groups exposed 22 to bromocryptine and to propylthiouracil to

### 202-234-4433 Neal R. Gross & Co., Inc. Page 212 1 produce hypoprolactinemia and hypothyroidism 2 respectively. Neither of those two groups 3 caused immunosuppression in the offspring. 4 The experiments were replicated twice. The 5 offspring did show immunosuppression at about 6 eight to nine or ten weeks of age. The 7 atrazine decreased the primary antibody 8 response to sheep red blood cells and 9 decreased the delayed type hypersensitivity 10 response in adult male, but not female, 11 offspring. 12 I think these tests were probably 13 chosen or selected in part from the National 14 Toxicology Programs Risk Assessment for 15 Immunotoxicity and positive data would predict 16 a positive response also in challenge assays 17 if we were to proceed that way. So it's a 18 good testing, good experimental design. I 19 read the papers, I put in the graphs. The 20 suppression looked real and I think it was at 21 about 56 to 59 percent of the control level. 22 You can ask questions were p-

### 202-234-4433 Neal R. Gross & Co., Inc. Page 213 1 values -- was chance playing a role in this 2 one time out of 20, will p-value let you down 3 just because of the level we set? I don't 4 think that's the case, but with one chance out 5 of 20, and then in a replicate experiment 6 multiplying that it shouldn't occur more than 7 one time out of 400 twice in a row on you for 8 one assay, and then we've got the DTH as a 9 second assay that did the same thing, the 10 experimental design looked good, the data

11 looked real. The authors concluded that 12 developmental exposure to atrazine caused a 13 gender-specific suppression of immune function 14 in the adults that didn't appear to be through 15 prolactin or thyroid hormone, the mechanism. 16 So that's an overview for the 17 studies. The difficulty that we were asked to 18 consider came from the further repeat of these 19 studies when the lab was moved from old EPA 20 facility to the new one across the lake from 21 NIEHS, and then didn't replicate for the 22 investigators in spite of same protocol, same

### 202-234-4433 Neal R. Gross & Co., Inc. Page 214 1 lab people doing the assays. So 35 milligrams 2 per kilogram per day was the high dose 3 selected in the repeat study, the same as the 4 first study. Lower doses of 17-1/2 and 3-1/2 5 milligrams per kilogram per day were used. 6 This was an attempt to establish a dose 7 response for the effect observed. End data 8 were negative.9 Second experiments used Sprague10 Dawley, Long-Evans, and Wistar rats to look 11 for a strain effect. Strain differences data 12 were, again, negative. The assays were 13 conducted only in males given the results in 14 the first set of experiments. So the 15 investigators concluded that some unknown 16 environmental factor was probably behind the 17 difference in response. They have a high 18 level of confidence in the technical soundness 19 of the published studies. 20 From my review of those, I see no 21 reason to think otherwise and agree with this 22 unknown environmental factor. I think it was

### 202-234-4433 Neal R. Gross & Co., Inc. Page 215 1 Dr. Akana who suggested that vibration in a 2 new facility or something like that could play

3 a role. I know last week someone from the lab 4 came to my office with those conical 5 centrifuge test tubes we hold our cells in, 6 the orange-topped ones, and said these were 7 from the last two batches we'd gotten. 8 Opened one and he said, smell it, 9 and I smelled it. I said, I don't really smell 10 anything. He said, Okay. Opened the next 11 one, he said, smell this one. It smelled like 12 a plastics factory or a new car or a carpet. 13 And he said, I've never smelled that in these 14 before, but I'm afraid that could skew our 15 data, whatever these things are emitting could 16 be harmful to ourselves, and he was concerned 17 enough he called the vendor, who said, Yes, 18 we've outsourced our production to Mexico. 19 Don't know what the difference 20 was, but sometimes there are little things 21 that do this to us that cause differences like 22 this. Unknown environmental factor was a good

### 202-234-4433 Neal R. Gross & Co., Inc. Page 216 1 disclaimer, I think, for that, and we get 2 caught in it now and then. So my conclusion 3 is there's no reason to doubt the results of 4 either study in this case, and I think the 5 original study was conducted appropriately and 6 the results should be accepted as real under 7 the conditions of that study. 8 DR. PORTIER: Okay. Done with the 9 first part. 10 DR. REGAL: Right. So with regard 11 to the Rooney study -- 12 DR. PORTIER: Dr. Regal. 13 DR. REGAL: With regard to the 14 Rooney study, everything looks very sound in 15 terms of methods, techniques, design, and, you 16 know, clearly a critical parameter has not yet 17 been defined to explain why it can't be 18 replicated in another status.

19 DR. PORTIER: Dr. Bucher.

20 DR. BUCHER: So I'm not an 21 immunotoxicologist, but I do have the pleasure 22 of having attracted Andy Rooney to our program

### 202-234-4433 Neal R. Gross & Co., Inc. Page 217 1 from EPA, so I talked to him about these 2 studies, and I just wanted to have a 3 placeholder in case the discussion went off in 4 an area where he would have disagreed with 5 some of those conclusions, but he agreed with 6 everything that has been said about those two 7 studies -- and that they were, in fact, 8 excellent studies and just for some reason 9 didn't repeat. So I agree with those

10 comments. 11 DR. HOLLADAY: All right. So 12 Holladay back. Now the second question we're 13 asked to address was the dichotomy, if you 14 will, between the Rooney, et al., results 2003 15 and Rowe, et al., 2006. The difference 16 between these studies on one reported 17 postnatal immune suppression, one reported 18 enhanced immune responses. These are in the 19 adult offspring after the developmental 20 exposure. 21 I think the most important thing 22 to consider between these two studies is that

### 202-234-4433 Neal R. Gross & Co., Inc. Page 218 1 there were many differences between 2 experimental design. The Luebke lab used the 3 Sprague-Dawley rat and out-bred animal; the 4 Rowe, et al., studies, which is John Barnett's 5 lab in West Virginia, another internationally 6 recognized laboratory, both the laboratories 7 are of that stature, used Balb/c mice. So 8 we've got different experimental animals. The 9 Balb/c mouse is a T helper 2 skewed mouse 10 which is skewed towards enhanced antibody 11 production. So that's one difference that's 12 important. 13 Exposure route is also important. 14 The Sprague-Dawley rat study is oral gavage, 15 which provides a bolus or spike exposure of 16 the atrazine to the pregnant animals. The 17 Barnett lab used implants that provided a 18 lower level time release. The doses were 19 comparable. The Rowe, et al., studies 20 calculated their dose varied from about 35 to 21 23 milligrams per kilogram per day atrazine. 22 This is in the mice, again, from gestation day

### 202-234-4433 Neal R. Gross & Co., Inc. Page 219 1 10 to 12, so this is a shorter exposure as

2 well. 3 So both studies were well 4 designed, in my mind, robust, used statistical 5 power analyses to calculate the needed N. The 6 Barnett study used N of 11 group size, which 7 is larger than I've tended to use in a study 8 like this. 9 So the results are seemingly 10 different, but when we consider the endpoints 11 evaluated, when we consider the models, I'm 12 not sure they are -- well, it's not worrisome 13 to me that they're different. I commented the 14 other day to that we're seeing more results of 15 this sort, even within strains where we see 16 both immune suppression and immune enhancement 17 coexisting in the same animals. 18 It was kind of a paradox when we 19 first realized this was happening, but it 20 does. DTH, delayed-type hypersensitivity, or 21 T cell response might be depressed, while 22 other T cell activities are skewed or

### 202-234-4433 Neal R. Gross & Co., Inc. Page 220 1 enhanced. 2 So we've got genetically different 3 animals and one is showing a depressed T cell 4 response, the DTH response in the rat study, 5 and others showing an enhanced response in the 6 mouse study, the MLR or proliferation, T cell 7 proliferation outcome, and the cytotoxic T 8 lymphocyte activity and other T cell activity, 9 as well as enhanced antibody production. So 10 different results but very different models, 11 results not inconsistent with literature in 12 other mouse models with different chemicals. 13 So as the Charge Questions 14 indicated, there are seemingly different 15 results, but in my opinion these should, at 16 this time, be both considered as observations 17 that represent true outcomes for the models 18 and experimental systems used. 19 DR. REGAL: Jean Regal. I 20 definitely agree, I just have a couple of 21 differences to add for the record in terms of 22 the end result. They were looking at eight

### 202-234-4433 Neal R. Gross & Co., Inc. Page 221 1 week old rats and 12 week old Balb/c mice as 2 to their timing, and I have no reason to think 3 that those are different in terms of being 4 post -- past sexual maturity. They used two 5 different vehicles, time-release pellets 6 versus methylcellulose gavage. Again, no 7 reason to believe there would be a difference. 8 One question I would have for 9 people who think about atrazine metabolism is 10 would the metabolism differ depending on the 11 route of administration, i.e. one gavage 12 versus sub-Q administration? Could some of 13 the metabolites be, you know, causing an 14 immunoenhancement versus some an 15 immunosuppression? So I guess I'll be 16 looking -- and any comments people have on 17 that would be appreciated. 18 And the only other -- one other 19 thing in terms of the rat study, there was a 20 very small decrease in weight of the seven day 21 old rats, and with the Balb/c mice there was 22 no weights at birth so the very small chance

### 202-234-4433 Neal R. Gross & Co., Inc. Page 222 1 that any of this might be -- have been done to 2 intrauterine growth restriction rather than an 3 effect of atrazine. 4 DR. BUCHER: So I have nothing 5 really to add. I do agree that while it would 6 have been nice if these changes would have 7 gone in the same direction, it doesn't 8 necessarily detract from the fact that they 9 are real effects, so. 10 DR. PORTIER: Well, why don't we 11 open up and see if there's any metabolism

12 comments. 13 Dr. Hayton. 14 DR. HAYTON: Yes, I seem to 15 remember the McMullin 2007 paper which was a 16 physiologically-based PK modeling study, and 17 it's far from definitive, but the kinetics 18 suggested that there was a very substantial 19 pre-systemic elimination for the oral route. 20 And so that I think more than -- something 21 more than 60 percent of the atrazine was 22 converted to metabolites pre-systemically.

### 202-234-4433 Neal R. Gross & Co., Inc. Page 223 1 Well, that clearly wouldn't happen following 2 subcutaneous administration. So there 3 definitely could be route of administration 4 differences in metabolite exposure.

5 DR. GREENWOOD: I also came to 6 that sort of conclusion because for -- in 7 rodent studies, the profile for atrazine 8 itself is really a text book case of a 9 picture. It's consistent with a very low rate 10 of absorption and a rapid rate of elimination 11 and the production particularly of the diamino 12 chlorotriazine, which is sort of the end 13 product down that route. 14 The production of it was so rapid 15 that really I can't see any other explanation, 16 other than it was by the enterocytes. And 17 this has been seen for drugs and other things 18 that this happens. 19 And you get similar rates of 20 absorption in 21 humans. You can predict human absorption from 22 the rat pharmacokinetics, but the

### 202-234-4433 Neal R. Gross & Co., Inc. Page 224 1 bioavailability by the two is totally 2 different. So the rate of absorption is 3 similar and highly correlated in humans and 4 rats, but bioavailability by the oral route is 5 different. And the difference comes because 6 of this metabolism differential, metabolism in 7 the gut wall. 8 And it's something that's known, 9 really going back a long way where people used 10 C14-labeled phenols which were administered 11 orally and none of them reached the liver 12 intact, so where people were looking in the 13 hepatic portal vein. So it wouldn't surprise 14 me at all to different species and totally 15 different routes of application if you 16 wouldn't get totally different patterns of 17 detoxification products. 18 But what I would guess is, looking

19 at the -- I don't know whether the others 20 agree -- but looking at the profiles, it just 21 seem that this diamino chlorotriazine seems to 22 be the major detoxification end product. I

### 202-234-4433 Neal R. Gross & Co., Inc. Page 225 1 mean it was something like a hundred-fold 2 different -- higher than any of the other 3 compounds after that 24 hours.

4 DR. PORTIER: Dr. Horton.

5 DR. HORTON: Yes. One comment. 6 Even though we're considering the animals held 7 in a laboratory environment under constant 8 photoperiods and that laboratory mice are not 9 photoperiodic, some strains of laboratory rats 10 still show a photoperiodic response, 11 specifically the Fischer 344. And in other 12 species, specifically the dwarf hamsters, 13 Phodopus sungorus, they have been shown to 14 show photoperiodic dependent changes in their 15 immune response, and specifically the cellular 16 versus the humoral immune responses differ on 17 a seasonal basis. 18 So I'm wondering whether in 19 looking at these data, both the rat strains, 20 you know, Fischers versus Sprague-Dawley and 21 also the photoperiods might need to be taken 22 under consideration.

### 202-234-4433 Neal R. Gross & Co., Inc. Page 226 1 DR. SCHLENK: Yes, just to follow 2 up on the metabolism issues. I know -- I mean 3 as I mentioned earlier, there's some really 4 good evidence to suggest that it's a 3A4 5 substrate, which is actually expressed in 6 fairly high concentrations in the gut, so that 7 would argue for enteral metabolism immediately 8 without a systemic absorption at that point. 9 So there is that, although 10 recombinant proteins, I think the high -- the 11 more efficient catalytic pathways 1A2, which 12 would be more liver-based, but again, I think 13 arguing more for a -- if you do have 3A4 under 14 high KM, high sort of concentration-based 15 doses, then you probably would get the gut 16 metabolism preceding the hepatic. 17 DR. PORTIER: Dr. Luebke, you had

18 wanted to make a comment? 19 DR. LUEBKE: Okay. Well, I just 20 wanted to respond to a couple of things. So 21 photoperiodicity, a fellow that I know who's 22 done thousands and thousands of immunotox

### 202-234-4433 Neal R. Gross & Co., Inc. Page 227 1 studies took all of his mouse data from over 2 the years, just the control data, and he 3 graphed the antibody response and the delay 4 type hypersensitivity response, and what you 5 could see was sort of a nadir in the spring, 6 and as winter came on, it went up. 7 So mice are, indeed, photoperiodic 8 in at least -- you know, over the year. Over 9 the year. I shouldn't say photoperiodic. 10 Okay. So, yes, so there is annual cyclicity 11 in all that that can't be explained by seeing 12 sunlight because these things never see 13 sunlight unless they've just come out of the

14 truck. 15 The other thing that I would like 16 to mention is the issue of metabolism, and I 17 too was concerned with this and I thought that 18 there may be some questions about this because 19 of the different, very different routes of 20 exposure. And so I talked to Mike DeVito, who 21 used to be EPA and is now at NIESH and is 22 something of an expert on pharmacokinetics,

### 202-234-4433 Neal R. Gross & Co., Inc. Page 228 1 and he assured me that there would be massive 2 differences in the amount of atrazine, per se, 3 that was likely to seen by these animals that 4 got the subcutaneous implant, because it's not 5 going through the gut, there is no first pass 6 through the liver, and if -- assuming that it 7 partitions into the blood and goes all over 8 the place, then, yes, there's going to be a 9 big difference. 10 But, now, Ralph and Tammy may have 11 to help me out of a quagmire if I start to dig 12 one here, but it's my understanding that if 13 you look at the parent and the metabolites, 14 that there are differences in the metabolites 15 in their action on the HPG axis and maybe the 16 HPA axis. If we assume that the effects that 17 we saw here are somehow related to that, and 18 not a direct effect of atrazine itself or it's 19 metabolites on the cells themselves, then it 20 would not be beyond the realm of possibility, 21 I think, that if you consider that what we 22 might see there, because of the differences in

### 202-234-4433 Neal R. Gross & Co., Inc. Page 229 1 dosing, might be something that's quantitative 2 and not qualitative, because if atrazine and 3 its metabolites are going to effect HPA to HPG 4 and then drive these different effects that we 5 see, then I don't think that they would 6 necessarily go in opposite directions. 7 And I had hoped that I could come 8 up with some different, you know, explanations 9 because it would be real nice to say, well, 10 yes, it's a metabolite thing and that's why we 11 got enhancement in one and suppression in the 12 other. But I still come back to the original 13 idea here that what we've got were unexpected 14 changes in function, neither of them 15 necessarily good.

16 DR. PORTIER: Dr. Greenwood. 17 DR. GREENWOOD: So I think that 18 sort of differences that you're looking at 19 would be larger in terms of exposure probably 20 to atrazine itself because it would much 21 higher, as I think has been said by the 22 implant. You're still going to get DSET

### 202-234-4433 Neal R. Gross & Co., Inc. Page 230 1 eventually formed as you go round the 2 circulation system, it comes through every 3 tissue eventually, and that's, you know, part

4 of the reason we look at the area under the 5 plasma curve as the opportunity factor for 6 reaching any particular tissue, whether it's 7 a target tissue or an non-target tissue. 8 But I think there are other 9 factors which can come into play as well 10 because if you have a high dose particularly, 11 then you start -- I think someone else alluded 12 to this yesterday -- you start to get 13 differences maybe in -- changes in the 14 glutathione pool, and as that's involved in 15 metabolism of all sorts of other things, then 16 you could start to produce different results.

17 And so I mean I haven't -- I would 18 need to -- really to see the sort of 19 concentrations people are getting from the 20 implants over the period of time compared with 21 the -- what you get by oral gavage. But oral 22 gavage is certainly something which is often

### 202-234-4433 Neal R. Gross & Co., Inc. Page 231 1 very difficult to interpret this sort of 2 absorption because the corn oil or the 3 methylcellulose forms part of the system, it 4 becomes part of the metabolic compartment, and 5 it changes with time. 6 So you get, you know, rapid 7 absorption initially, through for instance the 8 stomach wall, of what's free, and then it 9 takes time for the other stuff, particularly 10 with atrazine, I think, with its properties it 11 seems to stick to things, it takes longer to 12 disperse from the bolus. And so you get a 13 longer -- then a longer term lower level. And 14 if you've got metabolism as it's going through 15 the gut wall, then very little of the atrazine 16 itself is actually a component at very, very 17 low levels, and you won't get that if you've 18 got an implant. You'll have a more consistent 19 and prolonged level of atrazine.

20 DR. PORTIER: Dr. Reed. 21 DR. REED: Any reason to think 22 that male/female differences seen in any of

### 202-234-4433 Neal R. Gross & Co., Inc. Page 232 1 the studies could be explained by metabolism? 2 DR. GREENWOOD: Sorry. I haven't 3 seen that, anyway I've not seen any evidence 4 for such a difference. 5 DR. SCHLENK: This is Dan Schlenk. 6 Yes, as far as I know, I don't think there are 7 any male -- gender differences in 3A4 in rats. 8 I know there are the two -- family two 9 enzymes, but not necessarily the threes which 10 would be more appropriate for this, but. 11 DR. PORTIER: Okay. Back to the 12 question. Dr. Holladay. 13 DR. HOLLADAY: All right. Let's 14 continue. The third question was, Please 15 comment on characterizing the effects of 16 gestational atrazine exposure as 17 immunomodulation. This is rather than as 18 describing them as immunotoxic. And I think, 19 after what we've just said, that's the 20 appropriate descriptor, immunomodulating 21 allowing for both suppression and enhancement 22 of immune function after a developmental

### 202-234-4433 Neal R. Gross & Co., Inc. Page 233 1 exposure. 2 So I agree that's the correct 3 descriptor to use and agree with the Rowe, et 4 al., conclusions in their studies that this 5 potentiation of an immune response is an 6 important outcome, may potentiate diseases 7 such as auto-immune or hypersensitive 8 diseases, suggest the need to evaluate the 9 ability of developmental atrazine to enhance 10 postnatal immune responses in mouse models 11 that are genetically prone to express such 12 responses. So I have to wonder what would 13 happen in a mouse model that was genetically 14 predisposed to auto-immunity for instance. 15 That'd be an interesting question to have

16 answered. 17 So, yes, immune modulation is the 18 correct descriptor for these data. 19 DR. PORTIER: Dr. Regal. 20 DR. REGAL: Yes, I agree, with the 21 immune system, whether you get too much of it 22 or too little of it, it can be an adverse

### 202-234-4433 Neal R. Gross & Co., Inc. Page 234 1 event. 2 DR. BUCHER: This is John Bucher. 3 I also agree with that. 4 DR. PORTIER: Any additional

5 comments? 6 (No response.) 7 DR. PORTIER: It's a long 8 question, but you took it apart and answered 9 it. That's great. 10 Any comments from EPA? Oh, 11 there's one more. I'm sorry. It was a long 12 question. I only thought he had broken it 13 into three, and it's four. 14 DR. HOLLADAY: Maybe the most 15 important part. Do the available data support 16 immunotoxic, or immune system endpoints, or 17 immune modulation as more sensitive than the 18 atrazine-induced effects on neuroendocrine 19 function, the attenuation of the LH surge or 20 estrous cycle disruption. Please comment on 21 the degree to which these conclusions are 22 supported by the available data.

### 202-234-4433 Neal R. Gross & Co., Inc. Page 235 1 And I wrote as my opinion, I agree 2 that the available data indicate that 3 neuroendocrine reproductive effects are more 4 sensitive than immunotoxic or immune 5 modulation effects thus far detected. I 6 support the attenuation of the LH surge with 7 NOEL of 1 point milligrams per kilogram per 8 day as the appropriate point of departure from 9 the available data. 10 I just stress that it should be 11 considered the existing developmental 12 immunotoxicity database is quite limited and 13 further studies would be interesting. I think 14 neurodevelopment -- we could argue for more 15 development of immune system, we could certain 16 argue for more studies. But existing 17 database, I support the current point of 18 departure that we're using. 19 DR. REGAL: And I guess I do to 20 the same extent that -- except with the caveat 21 that with the developmental immunotox studies, 22 we really only looked at one dose, and

### 202-234-4433 Neal R. Gross & Co., Inc. Page 236 1 nobody's gone lower than 35 milligrams per 2 kilogram per day for 14 days, I think, or for 3 20 -- however many days they did it. And so 4 because of the disparate results there, and 5 because of -- to me I always try to remember 6 that in immunology stuff, you're going to see 7 bell-shaped dose response curves where you 8 have nothing with a lot, and nothing with a 9 little, but you get stuff in between. And so 10 we might not have hit those in between doses. 11 I think lower doses should be assessed 12 developmental immunotox-wise. 13 DR. BUCHER: And I agree with 14 those comments. I think that there was an 15 attempt to do a dose response study, but it 16 was not successful. But I think that that 17 certainly would strengthen the database, and 18 it's nice to see developmental studies, and 19 I'd certainly like to see them as well for the 20 neurobehavorial effects. 21 DR. PORTIER: I almost expect Dr. 22 Horton to jump in here. Anyone else on

### 202-234-4433 Neal R. Gross & Co., Inc. Page 237 1 metabolism? No? Yes, Dr. Akana. 2 DR. AKANA: I'd just like an 3 opinion from the metabolism crew on what 4 would -- what happens with atrazine when it's 5 mixed in the diet compared to say the gavage 6 delivery. Would you expect the same concerns 7 about the factions of metabolites of atrazine?

8 DR. PORTIER: Dr. Greenwood. 9 DR. GREENWOOD: Yes, I think that 10 if you've got a more continuous intake then 11 you're still going to get a very low 12 absorption from the diet. I think that the 13 atrazine, because it's very insoluble, it's 14 got to move out of the diet into the water 15 before it can cross -- there are several 16 barriers, there's the mucous layer and there's 17 the understood boundary layer, or the boundary 18 layer of water, not understood layer, the 19 boundary layer of water, and before it reaches 20 the epithelium. 21 And I think the key stage in all 22 of this, if you look at the papers of people

### 202-234-4433 Neal R. Gross & Co., Inc. Page 238 1 like Mike Abraham and so on, seems to be the 2 dissolution. And I guess actually the 3 kinetics of movement out of food will not be 4 too dissimilar from the kinetics of movement 5 out of the material that's used on oral 6 gavage. 7 But having said that, if it's in 8 the diet of course then it tends to be taken 9 over longer periods so you get a more -- 10 rather than an acute exposure, as it were, you 11 get a longer term. 12 DR. PORTIER: Dr. Hayton. 13 DR. HAYTON: Yes, I agree with 14 what Richard Greenwood said. The other thing 15 I think that would happen is that there would 16 be a lower exposure rate because it's coming 17 in the diet continuously. And so to the 18 extent that there are these pre-systemic 19 effects by oral gavage, they could be 20 saturable because you give a fairly large does 21 that gets exposed to that pre-systemic 22 machinery, whereas in the diet it would come

### 202-234-4433 Neal R. Gross & Co., Inc. Page 239 1 in at a much more -- at a lower level and at 2 a continuous rate, so. 3 And also the issue that Dr. 4 Greenwood brought up about glutathione pool 5 depletion, that may not happen extensively 6 either. So there's that possibility. 7 DR. PORTIER: Good question. Any 8 additional comments, questions? 9 (No response.) 10 DR. PORTIER: Okay. I don't see 11 any. I think what we're going to do is go 12 ahead and take a 15 minute break before we 13 jump into the big question of 1.9, and that'll14 avoid anybody falling asleep in the mid15 afternoon slump. Right? So we'll be back at

16 2:45. 17 (Whereupon, the above-entitled 18 matter went off the record at 2:27 p.m. and 19 resumed at 2:50 p.m.) 20 DR. PORTIER: Let's get started. 21 We're going to dive into this last question of 22 Section 1, Question 1.9, which we've broken up

### 202-234-4433 Neal R. Gross & Co., Inc. Page 240 1 into kind of two parts, a risk assessment part 2 and a PK part, and we've got kind of two teams 3 that were assigned to answer those questions. 4 Just to kind of forewarn the 5 panel, we're not going to move on to Question 6 2.1 till tomorrow morning, but there are still 7 some clarification questions that the 8 hydrologists and the statisticians have about 9 the hydrology simulations, we we're going to 10 ask EPA and Syngenta to come back up for about 11 a half hour and see if we can kind of clarify 12 especially what those simulations were all 13 about so that we're really certain what they 14 did, and in hopes that that's going to make it 15 easier to us to answer the questions tomorrow 16 morning if we really know what they did. 17 My goal is to break a little after 18 4:30, early today. So, you know, in 19 compensation for yesterday. So -- I'm a mean 20 kind of person, but I'm very variable. Right? 21 So, Dr. Lowit, are you going to 22 read Question 1.9?

### 202-234-4433 Neal R. Gross & Co., Inc. Page 241 1 DR. LOWIT: Sure. And as you're 2 talking about the next steps and everything 3 else, just a little FYI to the panel, I 4 believe Drs. Cooper, Laws, Stoker and Luebke 5 will be either leaving tonight or first thing 6 in the morning, so you may not see them again, 7 or just for a little bit in the morning -- 8 today at the meeting.

9 DR. PORTIER: That's a threat. 10 Okay. 11 DR. LOWIT: Yes. No. Oh, god. 12 They're going home. I'm just going to stop. 13 I'm just going to stop. 14 So if there are any lingering 15 technical issues that we've -- that are hazard 16 assessment related that we need to rely on 17 their expertise, we're just -- we may want to 18 do that before you cut off today. 19 With that, I will read Charge 20 Question 1.9. After the April 2010 SAP, the 21 Agency will evaluate the weight of the 22 evidence, what we call WOE, or woe, for

### 202-234-4433 Neal R. Gross & Co., Inc. Page 242 1 atrazine -- woe is us -- for atrazine by 2 integrating the experimental toxicology data 3 with the epidemiological studies. As part of 4 this work, the Agency will consider the 5 available data on hormonal changes and 6 functional outcomes that may be used as 7 endpoints for deriving PoDs, and that means -- 8 that's what we mean by points of departure 9 that I talked about earlier -- across 10 different durations of exposure and for 11 different populations including potentially 12 sensitive ones. 13 Important studies evaluating the 14 dose response relationships for hormones 15 involved in the HPA axis are still ongoing. 16 These studies are expected to provide high 17 quality data that can be used to characterize 18 the entire dose response curve. With the 19 caveat that these data are not available now, 20 given the current understanding of atrazine's 21 mode of action, please comment on what would 22 be appropriate endpoints to consider for

### 202-234-4433 Neal R. Gross & Co., Inc. Page 243 1 deriving points of departure in a possible 2 future risk assessment. 3 And the second half, given that 4 the duration of the toxicological concern is 5 a key factor in evaluating the frequency of 6 drinking water monitoring, please include in 7 your response a consideration of the magnitude 8 and duration of changes in key events in the 9 toxicity pathway that are sufficient to 10 perturb normal function and comprise human 11 health. In defining the exposure window of 12 interest, please comment on the toxicokinetic 13 and dynamic considerations with respect to 14 atrazine's effects on the HPA/HPG axis. 15 DR. PORTIER: So you need to roll 16 it back to the first section. And I'll turn 17 it over to Dr. Reed, who has a strategy to 18 answer this question. 19 DR. REED: Right. When you don't 20 have the answer, ask. 21 Well, I thought I would give an 22 introduction. As Dr. Portier had said, that

### 202-234-4433 Neal R. Gross & Co., Inc. Page 244 1 I have a strategy, and he said it was okay. 2 I thought I would give an introduction and 3 maybe, you know, set the stage for input from 4 all areas, that I'm sure you are all storing 5 up this -- you know, something that you 6 couldn't say until now. 7 As we've been looking upstream, I 8 think, up until this point, upstream to the 9 pathway of toxicity to define the mode of 10 action, or actions, this issue question is 11 focusing us downstream to look at the key 12 events to define endpoints. And so by looking 13 downstream a little bit -- and it doesn't have 14 to be far, far downstream, it's really up to 15 you to define, this essentially connects us 16 back to the whole body physiology and systemic 17 toxicity, or systematic toxicity. 18 My definition, and you can all, 19 you know, put in your definition, my 20 definition of endpoint is the adverse health 21 effect that can be defined quantitatively with 22 respect to functional manifestation of

### 202-234-4433 Neal R. Gross & Co., Inc. Page 245 1 toxicological significance, or clinical and 2 disease expression such as age-specific 3 functions that are either compromised, or a 4 functional deficit or over-expression, or 5 perturbation of normal physiological 6 expressions. 7 So after I invite my fellow 8 discussants to go ahead first, as I said, I 9 would like to hear from every endpoint group 10 about what endpoints within your expertise 11 considerations that you would use, you know, 12 for point of departure for risk assessment. 13 We, early on, talked about this may be the 14 time or the place where the rubber meets the 15 road. If it were so, then I'd like us to all, 16 you know, put our heads together and it would 17 be going forward all-wheel drive, not just 18 front- or back-wheel drive. 19 The bruntness of the interest that 20 I expect to come out of this issue would 21 really reflect the complexity of addressing 22 the risk of an endocrine destructor with

### 202-234-4433 Neal R. Gross & Co., Inc. Page 246 1 complex signal pathways, and, you know, their 2 induction, their inhibition, and any other 3 possible mode of action that is non-exclusive, 4 or what was the -- general versus specific to 5 what we're interested in. 6 And instead of a shopping list, I 7 thought when you give your input, it'll be 8 good to keep in mind the sensitivity issue in 9 that risk assessment. We're looking for the 10 most sensitive endpoint with the assumption 11 that if you have taken care of -- or protected 12 against the most sensitive endpoint, then, you 13 know, the rest of this endpoint will not

14 occur. 15 And it would also help, now that, 16 you know, this morning you're heard about how 17 these endpoints are going to be used in risk 18 assessment, that if you have some sense of 19 sensitivity in terms of whether humans are far 20 more sensitive than animals pertaining to the 21 endpoint that you're thinking of, then it 22 would be nice to have that information too.

### 202-234-4433 Neal R. Gross & Co., Inc. Page 247 1 Just as a start off point, you've 2 heard the Agency coming with what they 3 currently have been using, and you have an 4 acute toxicity endpoint, you have the short 5 term, you have the intermediate term, so if 6 you want to give your input in such a -- you 7 know, sort of a duration context, that would 8 be good too. And keep in mind that the 9 pharmacokinetic/pharmacodynamic part will be 10 a separate part that you could put in your 11 input. 12 So with that, I just want to 13 remind you that -- I can't remember, this 14 morning or yesterday -- I think it's this 15 morning; such a long day -- I mentioned that 16 besides the endpoint male and female 17 reproductive and then we talked about hormone 18 surge, I mentioned this morning that in the 19 older risk assessment we were also looking 20 into some sensitive endpoints as expressed in 21 cardio type of effect: atrial fibrillation, 22 extra-medullary hematopoietic -- you know, in

### 202-234-4433 Neal R. Gross & Co., Inc. Page 248 1 spleen, that type of thing, and, you know, it 2 might fit in, it might not fit in, but just 3 put a context of that's what you see in the 4 whole animal study in the past where we just 5 don't have the mode of action, only looking at 6 the endpoints. And so maybe that picture will 7 be changed. 8 So with that, I will pass the -- 9 DR. FENNER-CRISP: I think I've 10 been set up. Long, long ago, far, far away, 11 like over in Crystal City, there once was a 12 time when ATD staff was asked to do a 13 literature search and look for other 14 information in addition to the registration 15 package. They said, what? You want me to do 16 what? And it was really very difficult to 17 have that happen. 18 Obviously some things have changed 19 for the better, and in this particular case, 20 on an aspect of one chemical there are a lot 21 of additional data that have been assembled 22 and reviewed. I think yesterday or the day

### 202-234-4433 Neal R. Gross & Co., Inc. Page 249 1 before, and a couple of times today, though, 2 panel members have expressed some concern 3 about perhaps premature dismissal of some of 4 that information. There was some of that 5 conversation when talking about the 6 neurotoxicity, there was some of that 7 conversation yesterday when talking about some 8 of the cancer genotox data that were part of 9 this review. So I think one needs to be 10 mindful of that. 11 And in a comment today about -- 12 we're really starting from scratch in the 13 reassessment. I interpret that to mean that 14 we're going to take another look at everything 15 we have, not simply all the stuff we've 16 concentrated on for the last few days, which 17 is really just one category, or all related to 18 kind of one category of information. There's 19 a whole lot -- if somebody were to bring in 20 the registrant's submissions and place them in 21 the middle of this four-sided table, the pile 22 of paper would represent a lot of trees and it

### 202-234-4433 Neal R. Gross & Co., Inc. Page 250 1 would probably exceed the height of the table. 2 So you have to be mindful of that. 3 Okay. So one of my comments would 4 be, remember that if one is actually doing a 5 reassessment from scratch, that one needs to 6 at least take a cursory view of all the 7 toxicity data from all the studies that are 8 part of the registration record and all of the 9 supplementary stuff that has been acquired 10 since, and revisit those and reconsider them 11 in the light of any new data that may be 12 available in these other domains, because it 13 might well be that something we didn't know 14 about, endpoints, particular endpoints may 15 have come to light through other work, not 16 necessarily atrazine specific. So that's my 17 first point. 18 In this particular case, we have a 19 number of new data sets and new parameters 20 with the further exploration of the mode of 21 action related to reproductive effects, which 22 also require a revisit, and we've talked about

### 202-234-4433 Neal R. Gross & Co., Inc. Page 251 1 that, of the prior assessment and make 2 decisions on whether or not to use what was 3 previously used in the risk assessment, or 4 whether or not some part of the new 5 information will become the focus of the risk 6 assessment for characterization of point of 7 departure, et cetera. 8 I would offer my opinion that the 9 appropriate endpoints for consideration for 10 deriving PoDs going forward would be the data 11 sets at each key event now characterized in 12 the mode of action. When we once had a set of 13 six or seven for the mammary tumor, and some 14 of those were overlapping with what was 15 thought about with respect to reproductive and 16 developmental toxicity, now there's another 17 whole set of data with -- related to HPA axis. 18 So given the definition of key 19 event, presumably there are data that are 20 amenable to evaluation. They referred early 21 on that this is being done in the context of 22 the IPCS mode of action, human relevance

### 202-234-4433 Neal R. Gross & Co., Inc. Page 252 1 framework, and the Agency's guidelines, which 2 describe a key event as an empirically 3 observable precursor step that is itself a 4 necessary element of the mode of action or 5 biologically-based marker for such an element. 6 Meaning you have empirically generated data 7 that can be modeled or evaluated in some way. 8 So I would submit in this 9 particular, given the apparent importance of 10 this chemical and all of the effort that's 11 been put into its risk assessment, that it's 12 time to do a benchmark dose analysis for 13 everything on this particular chemical, and 14 you're beyond the point where you can just 15 pick NOELs and do things. 16 So I would submit that at this 17 point in time one should be doing BMD analysis 18 on every key event, both sides of this new 19 picture, older picture and newer picture, HPG 20 and HPA. Obviously modeling it to the same 21 value, what do you use BMDL, BMD10, whatever 22 it is, and then compare as you do in the

### 202-234-4433 Neal R. Gross & Co., Inc. Page 253 1 cumulative risk assessment. And from that, 2 that will inform you which one among those 3 data sets, if any, should be the appropriate 4 ones from which to define points of departure 5 and proceed with the risk assessment. 6 One point that's probably more 7 related to our PK folks' comments is that it's 8 been pointed out several times, and I'm 9 looking particularly at the NHEERL data with 10 the parent and the metabolites, that not all 11 four of those substances necessarily do the 12 same thing when tested in the same system. 13 And, in fact, there are some examples where 14 the parent in one or two metabolites may exert 15 a particular effect and the other one doesn't 16 at all. There are a couple of studies that 17 have been pointed out. So how does one 18 account for that when trying to do the risk 19 assessment. I think one needs to be mindful 20 of that on the plus/minus examples. 21 So I'll leave it there and 22 delegate to somebody else to do be the sticky

### 202-234-4433 Neal R. Gross & Co., Inc. Page 254 1 for the moment. 2 DR. PORTIER: Well, before you 3 run, because as I was making notes, you made 4 a lot of references to key events, and I 5 wonder, in your mind, what are the key 6 elements, I guess is the word. 7 DR. FENNER-CRISP: The key -- no, 8 key events. 9 DR. PORTIER: Key events. What 10 are the key events in your mind that they 11 should be looking at, or what are the ones 12 that are going through your mind? 13 DR. FENNER-CRISP: Well, I'm not 14 disagreeing with the characterization for the 15 key events that previously were identified in 16 the early stages of the -- well, the mammary 17 tumor mode of action in the beginning stages 18 of looking at the repro and developmentally

19 effects. 20 So we've got -- I think there are 21 eight in there, but the last one referred to 22 the genotox thing, so it's essentially seven.

### 202-234-4433 Neal R. Gross & Co., Inc. Page 255 1 It's the precursor events plus the endpoint of 2 concern. If you don't have sufficient data to 3 do a dose response analysis for any one of 4 those, you know, it's got -- it's less 5 convincing than if you do. 6 And now and looking on the other 7 side of the -- the other axis, there are four 8 key events. So the question is, are there 9 empirically observable, quantitative measures 10 of those key events that could be looked at as 11 potential data sets for PoD identification. 12 DR. PORTIER: Okay. Dr. Reed. 13 DR. REED: Could I get a 14 clarification out of -- when you mention doing 15 benchmark dose analysis on every key event, 16 and -- were you thinking of treating each 17 benchmark response -- or benchmark dose with 18 the same benchmark response like whatever 19 percent of response, or would you be open to 20 a different interpretation in terms of the 21 significance of that response? 22 DR. FENNER-CRISP: Well, the most

### 202-234-4433 Neal R. Gross & Co., Inc. Page 256 1 useful thing would be to be able to model to 2 the same point so that you can make some 3 comparisons. But sometimes, depending upon 4 the nature of the data, one can't. 5 DR. REED: Okay. 6 DR. LOWIT: If I could just jump 7 in for a second there. I think in this 8 context there are two different but important 9 uses of the benchmark dose techniques. 10 There's -- I think the way that Penny's 11 thinking, in a more -- you do a mode of action 12 framework in a temporal concordance dose 13 response concordance analysis in the same way 14 that we've done for a couple of others, like 15 cadodylic acid I think is a good example, 16 where you take the data from the key events 17 and you select a common response level and you

18 evaluate all of the events at the same 19 response level to look at the pattern of the 20 sensitivity of those endpoints at one common 21 response. 22 But that's a different question of

### 202-234-4433 Neal R. Gross & Co., Inc. Page 257 1 using those data as a regulatory endpoint 2 because then I think you have to bring out a 3 more robust thinking of changes from 4 background or historical changes and the 5 relationship of the biological significance of 6 one key event to the other. So I think you 7 could use the benchmark dose differently in 8 that way.

9 DR. FENNER-CRISP: The reason I 10 offered that suggestion is that it is quite 11 possible and quite likely that the shape of 12 the does response for key event A may not be 13 identical to the dose response curve for B, 14 and looking at NOELs you may think they're in 15 this order, but modeling them they may shift 16 the order, and one has to take that into 17 consideration when moving to the risk

18 assessment. 19 DR. PORTIER: I guess the other 20 presenter is Dr. Krishnan. 21 DR. KRISHNAN: I'm going to be 22 pretty much repeating what I've said, but

### 202-234-4433 Neal R. Gross & Co., Inc. Page 258 1 let's see how much of it is the same and how 2 much is different. 3 Well, with respect to what 4 endpoints to base it on, we've heard a lot of 5 good discussion about the relevant endpoints 6 to be considered in the context of hazard 7 identification pretty much this morning. And 8 then, you know, based on considerations of 9 relevance and mode of action, you'll be 10 looking forward to as to which one of those 11 will go down the path of further analysis. 12 I see kind of two scenarios. I 13 think we already heard some of that. First 14 would be the PoD being derived on the basis of 15 key events, particularly as related to the 16 reproductive function and depicted by picture 17 3, as you alluded to. That's good as long as 18 it's the one MOA, or that set of MOA that 19 determines the critical outcome. And one MOA 20 may not fit all the critical out of a lot of 21 several endpoints we talked about.

22 So for some of the other

### 202-234-4433 Neal R. Gross & Co., Inc. Page 259 1 endpoints, I guess the alternative scenario 2 would be deriving PoDs based on the outcome 3 data itself and not necessarily based on the 4 key events being a part of the mode of action 5 framework that remains to be seen. 6 Technically I don't see us being 7 able to say which endpoints will have a lower 8 PoD, and that's unless these analyses are 9 actually done, because in part of kind of dose 10 measure that's used on the X-axis will also 11 determine -- and might change what one might 12 see as being sensitive or less sensitive based 13 on external dose only. There are examples to 14 that, in fact. 15 The development of PoDs based on 16 biomarker levels or perturbation levels would 17 be relevant as long as the relationship to the 18 functional outcome is established 19 quantitatively. You already heard some 20 response to that effect. So the PoDs are 21 based on, for example, hormone levels, so the 22 consideration of the homeostatic and

### 202-234-4433 Neal R. Gross & Co., Inc. Page 260 1 physiological considerations as a basis of 2 benchmark dose analysis would become important 3 rather than using the traditional 5 percent or 4 10 percent change, which was also kind of 5 unpolished, to induct in the comments before

6 me. 7 In this regard, one thing that I 8 thought would be nice to see varying 9 thicknesses of the arrows, you know, depicting 10 the proposed mode of action in Figure 3, or as 11 you go, as you move forward. In certain cases 12 the thicker arrow, that gives, you know, a 13 stronger weight of evidence whereas the other 14 ones could be weaker, it could be a dotted 15 line thing or it could be a solid, things like

16 that. 17 Or, in other words, for specific 18 toxicity perturbation based, you know, 19 analysis, it would be relevant to identify the 20 availability and competence of the data for 21 each of those critical events, for example, 22 from which the analysis could be done. So the

### 202-234-4433 Neal R. Gross & Co., Inc. Page 261 1 ideal -- the desired data would be one, but 2 what's available might be different. So 3 honoring them in terms of, you know, on the 4 basis of consideration of data availability 5 and their competence, the strength of the 6 relationship to the functional effect for any 7 of the key events that you would get in such 8 an analysis, and also the strength of the 9 model fit, which will be done at the end of 10 the BMD analysis, rather than just basing only 11 on the response modeling. 12 And in considering the PoD 13 derivations, I also think that it's important 14 to give due consideration to the internal dose 15 as the dose measure to replace the 16 administered dose given the fact that there's 17 some possibility of situations where you may 18 have some glutathione depletion or first pass 19 affects influencing the nature of the dose 20 response. 21 And in this regard, without 22 getting too much into the next question, I

### 202-234-4433 Neal R. Gross & Co., Inc. Page 262 1 think the measures of dose in deriving the PoD 2 will have to be somewhat related to the total 3 chlorinated forms, it appears, even though we 4 heard more about the two -- the metabolites, 5 the dealkylated ones that do not affect the 6 hormone levels, whereas some of the other 7 studies from Cooper, et al., that identified 8 the DACT, you know, in some evaluations of 9 both male reproductive functions. So I didn't 10 see the connection between the lack of effect 11 of DACT on the hormone levels, but effect on 12 the whole animal levels. So maybe we ought to 13 look at clarification on that aspect. 14 I just have a couple of sentences 15 to go through. Because in those studies there 16 were -- some atrazine-equal end doses were 17 provided for DACT, as for the other 18 metabolites, which then kind of, you know, 19 leads -- possibly leads us down the path of 20 atrazine-equivalent doses at dose measure, you 21 know, internally, which doesn't just represent 22 the atrazine but as well as the other forms,

### 202-234-4433 Neal R. Gross & Co., Inc. Page 263 1 and there's an equivalence that's derived. 2 I'm not saying that's appropriate, but it does 3 make sense to me when I went through those. 4 In that regard, PBPK models, might 5 be able to provide -- depending on the level 6 of the maturity, they could provide that kind 7 of an appropriate dose measure, because one of 8 the papers did present some of the total 9 chloral forms of the atrazine. 10 So the animal model in itself can 11 provide an improvement of the X-axis in 12 deriving, or getting a better handle on the 13 PoDs. And if there's a human model, that 14 means subsequently, you could, you know, even 15 think of replacing the interspecies factors. 16 So I'm not getting into the risk 17 assessment at all. I'll just stay -- pull 18 back. I'll erase the last word that said -- 19 answering de facto. I'll leave it at that, 20 and if Cooper, et al., can clarify the 21 determination, the equivalences for DACT, I 22 would appreciate it, and whether they see a

### 202-234-4433 Neal R. Gross & Co., Inc. Page 264 1 connection or no between the hormone levels

2 and the hormonal effects. 3 DR. PORTIER: Dr. Cooper. 4 DR. COOPER: That's an interesting 5 question because -- I want to restate it just 6 to make sure I address it properly. If you 7 look at all the data with DACT versus the 8 other metabolites, and you look at the 9 reproductive axis, you look at the effects on 10 LH, we've done a pretty complete assessment in 11 the female on the LH surge with those four 12 different molecules. 13 And what we see, or what we have 14 seen over the years when we were naively 15 dosing equal amount of doses, you know, we 16 thought we were delivering the same number of 17 molecules or whatever, but when we eventually 18 went to look at the internal dose, and we were 19 fortunate enough in some of the more recent 20 studies to have assistance with looking at 21 different -- the four -- the three metabolites 22 plus atrazine in the blood, what found was

### 202-234-4433 Neal R. Gross & Co., Inc. Page 265 1 even though we were naively gavaging with 2 equimolar doses, we were getting considerably 3 different concentrations of the different 4 metabolites in the blood when we dosed. 5 And we've already addressed that, 6 very little atrazine, per se, at least in the 7 time points we looked at. We haven't done, 8 obviously, a complete series -- time series of

9 measurements. 10 But DACT was very high. That's 11 number one. So the internal dose of DACT is 12 very high whether we dose once or four times, 13 and given the DACT was really active, we were 14 sort of surprised that such high 15 concentrations were present. But secondly, 16 the amount of DACT necessary to inhibit the LH 17 surge was higher even yet. So now when we do 18 a dose response, and we don't have this 19 complete, but we have it piecemeal in 20 different studies, that we have an established 21 NOEL separately for DACT, we have some 22 preliminary data it might be around 100, which

### 202-234-4433 Neal R. Gross & Co., Inc. Page 266 1 is surprising or interesting because it's -- 2 in itself, if you dose by itself, it still has 3 on the surge the same type of effect that you 4 see with atrazine, per se, or the other two 5 intermediate metabolites. 6 So my feeling is that that 7 particular metabolite, on the LH itself, is a 8 lot lower. And then if you go to -- but it's 9 still effective and I think that's the point, 10 the sticking point here. You know, in a 11 perfect world, you know, DACT, if you were 12 hypothesizing an adrenal involvement, it 13 shouldn't be active at all, and so on. So 14 that higher dose we see effects. 15 And then of course when you look 16 either in vitro, and this is the thing, it's 17 very interesting about the comparisons is that 18 when you look in vitro and the effects on 19 adrenal, then DACT seems to have very -- even 20 more minimal effects, if you will. So that's 21 the situation. 22 I think what we're dealing with

### 202-234-4433 Neal R. Gross & Co., Inc. Page 267 1 here of course is more than one -- like my 2 mother used to say, more than one way to skin 3 a cat, as that you can effect that surge 4 either directly using DACT, or with some of 5 the other compounds there may be a much 6 broader series of events that take place. So 7 even though it doesn't line itself up nice and 8 neatly, I think we're still dealing with 9 compounds that all eventually will knock down 10 the amount of luteinizing hormone secreted. 11 And did that get at what you're 12 after? In other words, I agree. Additionally 13 though, what I was more interested in was the 14 study of Laws 2003, which was on page 31 and

15 32 of the document.

16 DR. COOPER: Of the female?

17 DR. KRISHNAN: Yes. And for male 18 it was the Stoker 2005 -- 19 DR. COOPER: Right. They both

20 were -- 21 DR. KRISHNAN: -- on page 34. 22 DR. COOPER: -- in Stoker paper

### 202-234-4433 Neal R. Gross & Co., Inc. Page 268 1 she dosed again with 21 days in the male 2 which -- 31, I'm sorry, the female gets -- 31 3 days, that's a month of dosing, daily dosing, 4 so again, even though in that one we had a 5 LOEL th was down in the range of the other 6 metabolites. I think 30 days of dosing is 7 different than the comparisons that I was 8 making with the shorter term. 9 And, Susan, the female, the NOEL 10 for DACT, did you get a NOEL in the female for 11 DACT in the pubertal? I know you compared 12 propazine and one of the other intermediate 13 ones, but not -- she's frantically -- I can 14 tell frantically searching through her 15 document and saying that DACT was also 16 examined and she found that DACT -- 17 DR. PORTIER: Let her speak for

18 herself. 19 DR. COOPER: -- was delayed 20 vaginal opening in these animals at a dose

21 of -- 22 DR. LAWS: I've got --

### 202-234-4433 Neal R. Gross & Co., Inc. Page 269 1 DR. PORTIER: Identify yourself. 2 DR. LAWS: Susan Laws, EPA, and

3 the no effect level for DACT was 16.7 4 milligrams, which was equivalent -- equimolar 5 at the time to atrazine 25. That was the no 6 effect. So probably the LOEL was 50 for DACT. 7 But one for the things that I 8 wanted to mention, in the 2009 papers, 9 although in Laws, et al., it's one dose, 10 but -- and that, in Tables 4 and 5, we had the 11 plasma levels of the parent compound and the 12 metabolites on their dose of atrazine. And 13 that's what Ralph was mentioning early -- and 14 we also have -- when we treated the animals 15 with DIA or DACT, and we see that in the first 16 we have a dose -- I mean a time course from 17 five minutes to three hours, and you can see 18 the progression of atrazine is essentially the 19 same in vivo, and then the progression to the 20 increased amount of DACT. 21 And in Fraites, et al., she doses 22 four days and she saw that DACT was --

### 202-234-4433 Neal R. Gross & Co., Inc. Page 270 1 continued to accumulate. So it may be in the 2 pubertals that DACT does continue to 3 accumulate some in the plasma, which may 4 actually get to a point where it's causing 5 these effects, because the pubertals are a 21- 6 or a 30-day exposure period versus the acute 7 things. 8 DR. PORTIER: So I think what -- 9 Dr. Reed wants to open it up now for anyone 10 else to discuss endpoint. Anyone else? Yes,

11 Dr. Greenwood. 12 DR. GREENWOOD: I just wondered if 13 I could ask a point of clarification. When 14 you looked at the accumulation of diamino 15 chlorotriazine in the plasma, was it free or 16 bound, because if it's bound to the serum 17 albumin covalently, it's not going to be doing 18 a lot metabolically. 19 DR. LAWS: I'm sorry. This was in 20 the plasma, and it's total -- as far as I 21 know, it's in plasma, not serum.

22 DR. PORTIER: Dr. Horton.

### 202-234-4433 Neal R. Gross & Co., Inc. Page 271 1 DR. HORTON: I have a question 2 about the definition of a key event, or maybe 3 I just misheard something between what Dr. 4 Fenner-Crisp and what Dr. Krishnan were 5 saying, because what I understood from what 6 Dr. Fenner-Crisp was saying was that a key 7 event has to be part of the MOA, but what I 8 thought I heard Dr. Krishnan saying was that 9 in looking for points of departures, that some 10 of the key events may not belong to the 11 current mode of action. 12 Were you saying that, while we may 13 see some key events that, you know, aren't 14 necessarily part of a mode of action, or were 15 you simply referring to the breast cancer, or 16 the mammary tumor mode of action, but they may 17 be part of the new mode of action that's the 18 model on page 3? Or what did you actually

19 mean? 20 DR. KRISHNAN: Okay. In terms of 21 the mode of action framework, the picture 3, 22 what I indicated was maybe there are some

### 202-234-4433 Neal R. Gross & Co., Inc. Page 272 1 connections and lines that are -- that could 2 be strengthened and some that can be weakened 3 rather than considering all of them as being 4 equally, you know, supported by the current 5 data, that something they thought could be

6 then. 7 On the other hand, for specific 8 endpoints that are used in assessments, a 9 single mode is not going to -- a single mode 10 of action framework might not end up 11 explaining all of the endpoints and outcomes 12 for which, you know, you're going to base the 13 assessment on. So, you know, it's not like, 14 you know, going through the same mode, the 15 house, and then a lot of the outcomes come 16 through, that probably is not a realistic -- 17 and so in that case -- 18 DR. HORTON: Okay. 19 DR. KRISHNAN: -- they might do 20 some analysis even without going through the 21 detailed mode of action if they don't have -- 22 DR. HORTON: Okay. Dr. Horton

### 202-234-4433 Neal R. Gross & Co., Inc. Page 273 1 again. So in this case now the house has some 2 out buildings, we have a barn and -- okay.

3 DR. PORTIER: And I was -- I've 4 been following that, I'm wondering what you 5 think some of those out buildings might look 6 like, because we've been talking about kind of 7 non-hormonal process, repo/developmental

8 events that are neuro or whatever. 9 DR. HORTON: Okay. In that 10 context, the neuro effects that we were 11 talking about are just in the attic because 12 they're on top of the regulatory system that's 13 part of the HPG/HPA system. And so they are 14 built on top of the regulation of the 15 reproductive and the adrenal system because 16 they are part of the system that regulates 17 that, in the hypothalamus and limbic system. 18 DR. PORTIER: One question. Is it 19 possible to draw a picture of that? I mean or 20 add to the -- add to Figure 2 to really 21 explain what you're trying to get at.

22 DR. HORTON: I can do that.

### 202-234-4433 Neal R. Gross & Co., Inc. Page 274 1 DR. PORTIER: I just -- I'm a 2 visual guy. 3 Yes, Dr. Fenner-Crisp. 4 DR. FENNER-CRISP: Maybe another 5 thing that would clarify what Dr. Krishnan 6 said was, not only might you select from the 7 key events related to the mode or modes of 8 action that have been postulated for 9 reproductive and developmental effects, you 10 may also, by virtue of time and exposure 11 duration choose to select a totally different 12 outcome for which no mode of action analysis 13 has been developed to this point in time. 14 And if you look at the body of 15 data related to this chemical or any other 16 pesticide, there are whole lot of other things 17 that get measured in apical studies for which 18 mode of action analysis may never get 19 developed, like body weight changes in a 20 chronic study, or things like that. 21 So it may be appropriate to go to 22 some of these other data sets by virtue of

### 202-234-4433 Neal R. Gross & Co., Inc. Page 275 1 subpopulation, duration of exposure, et 2 cetera, et cetera, and use that data set as 3 the basis for your point of departure. And 4 you can use any of the stuff we've been 5 mulling over for the last two days. 6 DR. PORTIER: This is Ken Portier. 7 But my understanding is that probably was 8 looked at in the 2003 risk assessment, and 9 ruled out in favor of the LH surge -- 10 DR. FENNER-CRISP: Except that I 11 offer the admonish that there may be things 12 known about some of these other endpoints now 13 that weren't known back then that you may want

14 to take a second look at. 15 DR. PORTIER: Dr. Lowit. 16 DR. LOWIT: With the caveat of 17 what Penny just slapped us on the wrist about, 18 I think at this point we have a little bit of 19 confidence -- I don't want to go too far -- 20 that the precursor events around the hormonal 21 changes are more sensitive than the functional 22 outcomes. I'm not aware of any of the

### 202-234-4433 Neal R. Gross & Co., Inc. Page 276 1 functional outcomes that are more sensitive 2 than are the hormonal changes. And someone 3 kick me if I'm wrong. There are a lot of 4 people behind me that probably know the data. 5 Ralph's arguing yes, so may I -- 6 that's part of what we'll ask ourselves, but 7 I think our driving theory right now, and 8 there's -- we haven't seen anything to get off 9 that train, but if we see something, we will, 10 is that the hormone changes, or the precursor 11 events will be -- we expect them to be more 12 sensitive than the outcome data. 13 DR. PORTIER: Dr. Akana I think 14 was next. And then Dr. Hayton. 15 DR. AKANA: Okay. I'm not 16 positive I've got a grip on the idea, but I'm 17 going to throw out an endpoint, and it's just 18 a theoretical possibility. And that is 19 actually continuous recording of body core 20 temperature. Now normally you think, okay, 21 core temperature, you know, it's core, it 22 doesn't move that much, but actually with the

### 202-234-4433 Neal R. Gross & Co., Inc. Page 277 1 nice little implantable transponders, you can 2 demonstrate beautiful basal circadian rhythms 3 in temperature, which are reproducible. 4 The stats people will love it. It 5 generates hundreds and thousands of points for 6 you. It's got maxima and minima, it can be 7 modeled, it's sensitive to glucocorticoids, 8 it's sensitive to food intake. I don't know 9 the data in females, but I'm hoping it shows 10 beautiful cycles you can follow through. One 11 of the beauties is that you can give -- you 12 know, once the animal recovers, you can give 13 your acute dose and keep continuing, and 14 you're collecting online data. 15 So it's not so great for the 16 immune measures that mostly would catch 17 accrued temperature, but I'm wondering how 18 many people could be happy with that kind of 19 endpoint. Oh, and then it covers catechols. 20 DR. HAYTON: Yes, Bill Hayton. 21 DR. LOWIT: One more quick -- with 22 quite a number of these you'd catch locomotor

### 202-234-4433 Neal R. Gross & Co., Inc. Page 278 1 activity which you can, from the same 2 transmitters, so that can be -- usually home 3 cage is really valuable, or depending on your 4 model it could be other locomotor measures, 5 which also have -- can be verified with photo

6 detectors. 7 DR. COOPER: So let me ask you the 8 question then, if you did this and we have the 9 radiotelemetry and it's accessible to us, how 10 readily accessible, I'm not sure of, and 11 there's some of my colleagues who are looking 12 into some of these approaches, but we have -- 13 I could envision three outcomes, and I'll run 14 them by you and you'll see the dilemma that 15 you're suggesting. 16 The first outcome would be we see 17 a difference, and we see at just about the 18 same dose response that we see -- I'll pick 19 another endpoint, the surge, okay. So we've 20 talked about that. How do I establish a 21 functional link on that one? 22 I mean this is really what we're

### 202-234-4433 Neal R. Gross & Co., Inc. Page 279 1 getting at a little bit. You've got another 2 endpoint that changed. Okay. Granted. And 3 it's a measure one, a repeated one. But we 4 have to establish a functional link. And 5 there's the literature there, I'm sure, 6 there's a literature on everything. 7 But the other one is it comes in 8 at a lower dose. How confident can we be that 9 that's indicative of an adverse outcome 10 functionally linked to delayed vaginal opening 11 or mammary gland tumor development and so on? 12 And then the third one is no difference, I 13 guess, or high dose difference because I doubt 14 that you'll see that if we get involved with 15 any of these measures you can be pretty sure 16 you'll see effects. 17 So I mean the question that we 18 really have to get at is, with what we have 19 now, how can we proceed in terms of taking the 20 best estimate of what the real predictors of 21 adverse outcomes are in the data sets we have? 22 In the previous SAP they agreed that the surge

### 202-234-4433 Neal R. Gross & Co., Inc. Page 280 1 itself was a good key event that could be used 2 at this. We were concerned that the adrenals 3 may offer additional lower doses or something 4 like that. 5 But I would doubt -- if we took 6 Penny's approach, I don't think we'd see a 7 difference in the benchmark because I think 8 they'd probably be pretty -- between the, say, 9 the surge and the ACTH or cort or whatever -- 10 however you want to evaluate that. 11 So, again, I think we're really 12 interested in your comments on which is the 13 better of what we've got right now knowing 14 that we don't have the Cadillac we'd love to

15 have. 16 DR. PORTIER: Dr. Hayton. 17 DR. HAYTON: Thank you. I just -- 18 I'm still puzzled. The question, 1.9, what 19 would be appropriate endpoints to consider. 20 I've been trying to write something down here, 21 and I don't think I've quite heard it yet, but 22 it -- we're talking about HPA/HPG signals.

### 202-234-4433 Neal R. Gross & Co., Inc. Page 281 1 Right? Okay. And then downstream sequelae to 2 those particular signals. Okay. Thank you. 3 DR. PORTIER: So I think the LH 4 surge is still in there. Right? And there's 5 some others on the HPA axis that are cong to 6 come up that we're looking at. And the 7 question is, is there anything beyond that 8 that's in that part of the box. Right? And,

9 Dr. Horton. 10 DR. HORTON: Okay. Two things. 11 One is I think we need to redraw the figure to 12 be able to figure out what some of those key 13 events may be to ask what the endpoints are, 14 because I think that's what you want to know, 15 is what are those endpoints, and those 16 endpoints have to be defined by looking at

17 that box. 18 And with respect to the functional 19 issue of the rhythms data, how you interpret 20 that functional outcome will depend on 21 specifically what characteristics of the 22 rhythms are disrupted and how they changed,

### 202-234-4433 Neal R. Gross & Co., Inc. Page 282 1 because if it's increased activity, you've got 2 one functional outcome; if it's decreased, 3 it's a different issue; if it's a delay in the 4 rhythm, as I've heard some suggestion that 5 there's a delay in the onset of the rise, that 6 means a different thing. So there is actually 7 a lot in terms of the functionality that can 8 be interpreted from looking at changes in 9 circadian rhythms. And those things do have 10 a great deal of impact in terms of looking at 11 metabolism and health outcomes. 12 DR. PORTIER: But what I keep 13 hearing is that the early endocrine things, 14 like LH surge, are going to be precursors to 15 any of those functional -- if you look at 16 Figure 3, the functional -- or further down 17 the line, and I think the argument is that 18 there's going to be less sensitivity to that 19 and to these things that are in the pituitary

20 box -- 21 DR. HORTON: Well, it's -- 22 DR. PORTIER: -- or in the CNS

### 202-234-4433 Neal R. Gross & Co., Inc. Page 283 1 box. 2 DR. HORTON: Yes, except that you 3 can pick up -- no, you can pick up circadian 4 changes in males but you can't -- you're not 5 going to get an LH surge in females, and so 6 therefore if you're concerned about reducing 7 animal care costs and use of animals, you can 8 look in both males and females. The advantage 9 of looking in males is you don't have to worry 10 about a four-day cycle, so you've reduced by 11 a factor of four the number of animals that 12 you're working with. 13 So -- although you do have to deal 14 with some of these issues that seem to be 15 sexually differentiated. And also you can 16 look at different ages. And so you do have 17 some different considerations to take in mind 18 whether you're looking at a circadian marker 19 rather than an endocrine marker. 20 DR. LOWIT: I think there's just 21 one point that I'd like to make before we sort 22 of keep moving, is that what's unique about

### 202-234-4433 Neal R. Gross & Co., Inc. Page 284 1 Question 1.9, that's different from 1.2 up to 2 1.8 is that if you go back from a few days 3 ago, the rubber meets the road analogy, this 4 is where the rubber meets the road, and the 5 Agency has to start making some choices soon. 6 Soon, you know.

7 And so to the extent that we 8 can -- you can, in your mind, as hard as it 9 may be, separate yourself, put yourself in our 10 shoes for a minute, that the Agency has to 11 make some choices very, very soon, before 12 September, in fact. So between -- in the next

13 four months. 14 So the things that we have in 15 front of us, that you have, and the seven to 16 ten things that Liz listed up on her slides a 17 few days ago, are all there is to make those 18 choices from. Okay. With respect to these 19 non-cancer endpoints. And so this is a 20 science question because it's getting at the 21 things to think about as we make those 22 choices, but this is not a research open-ended

### 202-234-4433 Neal R. Gross & Co., Inc. Page 285 1 kind of question. 2 DR. PORTIER: Dr. Fenner-Crisp,

3 and then Dr. -- 4 DR. FENNER-CRISP: Yes, Dr. 5 Krishnan referred to it. One thing that 6 currently doesn't exist, that I'm certain will 7 before you make your decisions, that would 8 have been -- that would be very helpful to 9 have, is the framework analysis prepared in 10 parallel to that which was done for the 11 mammary tumor mode of action. And then one 12 could -- it would speak to all the things that 13 were talked about: about how thick the arrows 14 ought to be from where and where, what's the 15 credibility of the data set, you know, and all 16 of those kinds of things, the temporal 17 relationships, the dose -- you know, all that

18 stuff. 19 Were that to exist, it would be 20 much easier for this panel to answer your 21 question. And I know you will be preparing 22 it.

### 202-234-4433 Neal R. Gross & Co., Inc. Page 286 1 (Laughter.) 2 DR. LOWIT: Thank you. Yes. 3 Absolutely. Probably starting next week 4 actually.

5 DR. FENNER-CRISP: Yes. 6 DR. LOWIT: Our assay is halfway 7 done. All right. But some of the studies 8 that Cooper and company and Syngenta are doing 9 are important in that because they provide 10 some of the causal links, and some of the 11 Handa data from the other day really 12 establishes some causality, and there's a 13 number of dose response studies in there that 14 are driving the doses five and below, which 15 gets out some of the comments. 16 So it was really almost impossible 17 to do a few months ago, but three months from 18 how we'll actually be a lot -- 19 DR. FENNER-CRISP: Well, I 20 appreciate that, and I wouldn't wish to 21 suggest I had an expectation it would exist 22 yet. But the point is that eventually, before

### 202-234-4433 Neal R. Gross & Co., Inc. Page 287 1 you make a final decision, you have to have 2 created that document in order to best present 3 the argument for selecting the things that you 4 select. That's all I'm saying. 5 DR. LOWIT: Yes. And Dr. Portier, 6 I think, speaking for the team, at least in 7 this first part, I think we've heard what 8 we've sort of expected or thought, and I don't 9 want to beat it to death. I think the really 10 interesting part is the second part. 11 DR. PORTIER: I was going to 12 acknowledge Dr. Reed, and then ask her to 13 summarize so we can move on to the second 14 part. 15 DR. REED: That was pretty much 16 why I'd raised my hand. I think we heard 17 enough to move forward. There's certain 18 things that we wouldn't know until, you know, 19 you get into the analysis, and so that's my -- 20 DR. PORTIER: So let's pop up the 21 second part of the question, and I'll turn to 22 Dr. Krishnan to talk about the issue of

### 202-234-4433 Neal R. Gross & Co., Inc. Page 288 1 duration. Right? And some of the PK issues. 2 DR. KRISHNAN: I'm not going to 3 make it interesting, if that's what you're 4 looking for. 5 (Laughter.)

6 DR. KRISHNAN: But I have some 7 able colleagues by my side who might try that. 8 I'll put in some of my thinking, and then I'll 9 leave it up to the colleagues, and then I'll 10 come back with additional comments. 11 The question essentially relates 12 the duration of toxicological concern and the 13 frequency of drinking water monitoring that 14 we've been talking about on and off, you know, 15 at least yesterday. And in defining the 16 exposure window of interest requested, that's 17 the comment on the pharmacokinetic dynamic 18 considerations with respect to the atrazine 19 effects on the HPA screening axis. 20 I think initially as we think 21 about the problem in terms of acute versus 22 chronic, or repeated exposures, you can

### 202-234-4433 Neal R. Gross & Co., Inc. Page 289 1 always, you know, somewhere draw the line of 2 intermediate versus chronic, because often the 3 continued exposures get us to what is called 4 as a steady state. So knowing this 5 characteristic of this chemical, I don't 6 expect to -- at least kinetically I don't 7 expect to see differences between intermediate 8 versus chronic duration. 9 So if we consider acute versus 10 chronic scenarios, normally when we protect 11 against chronic effects, protection against 12 acute effects is automatic, and the vice versa 13 is not true. So then we also saw some of the 14 box and whisker plots that showed increasing 15 space as you went from chronic to acute. 16 I'm not going into any specifics 17 of the effects, critical effects between acute 18 and chronic, but in general terms for acute 19 effects you tend to think of maximal 20 concentration as the driver, maximal 21 concentration internally, not in the plasma or 22 the critical tissue. So it's a question of

### 202-234-4433 Neal R. Gross & Co., Inc. Page 290 1 whether we exceed a threshold maximal 2 concentration, for a C-max, and for how long. 3 That's the question with respect to acute 4 scenarios. 5 Then for repeated exposures of 6 chronic, it's often the inner greater internal 7 exposure, or the average daily exposure. 8 That's usually a useful measure. Those are 9 some for the generalities, even though you can 10 always come up with exceptions. 11 Now, when we think about the 12 frequency for drinking water monitoring and 13 the plots of the water concentrations that we 14 saw, you know, there's peak who appeared for 15 a day or a shorter duration and there was some 16 trials and so on mixed with it. 17 But relating that, or viewing that 18 in the context of toxicological concern 19 requires that we think of the continuum of 20 events, meaning that from the water 21 concentration that we see was on the pictures, 22 the next one that I would think of is the

### 202-234-4433 Neal R. Gross & Co., Inc. Page 291 1 exposure pattern, what is the rate and route 2 of contact. Now it might take just a half a 3 cup of water versus a bottle of water. That's 4 a factor of 10, and then you're talking about 5 the peak and then another -- or differences

6 there. 7 So the exposure -- the rate of 8 uptake and then the route of exposure, whether 9 it's only oral, or dermal and other routes, 10 whether they're relevant or not. In most 11 drinking water scenarios, those are 12 considered. I'm not -- it seems to me that 13 the dermal absorption is much less, but I'm 14 unable to give an quantitative estimate based 15 on permeability coefficient. I don't know if 16 I missed the permeability coefficient. I 17 haven't seen it, but those can be estimated. 18 EPA has some methodologies available. 19 So from there, the exposure 20 pattern, or the uptake pattern, and then we to 21 consider the pharmacokinetics which is the 22 ADME, the initial step of rate of absorption

### 202-234-4433 Neal R. Gross & Co., Inc. Page 292 1 would appear to be the limiting factor, while 2 it's relatively a lower rate of absorption as 3 it seems from some of the papers we have seen. 4 So depending on the quantity and 5 the frequency we take, there's the rate of 6 absorption that takes into -- that gets into 7 the play. That's one of the reasons why I 8 feel that an integrated measure of exposure 9 would be more useful rather than concentrating 10 on any of the individual peaks and trials. 11 And also when you, you know, integrate and use 12 an AUC for -- in this context, either 13 internally or externally, the area under the 14 curve of concentration versus time, that also 15 deletes out any -- possibly deletes out any 16 impacts or concerns about specific peaks, or 17 very sharp duration. 18 Also, we heard some -- in terms of 19 the pharmacodynamics aspects, I have done the 20 environmental concentration, the uptake, 21 pharmacokinetics, even though I haven't gotten 22 into all of the details, which my colleagues

### 202-234-4433 Neal R. Gross & Co., Inc. Page 293 1 will, and then in terms of the 2 pharmacodynamics as well. And Dr. O'Byrne 3 talked about it this morning. I thought you 4 emphasized the importance of the sustained 5 chronic alteration of the precursor levels, 6 especially when you talked about the cortical 7 levels this morning. That's what really 8 determines the impact on the LH surge, if I 9 didn't actually put it. 10 So in total, considering the 11 continuum of those events, I'm coming back to 12 the question of duration of the tox concern 13 versus the frequency of monitoring. My 14 initial take -- even though I can learn from 15 people and change my mind later on, my take is 16 that, you know, monitoring the way we have 17 seen, like a weekly monitoring interval over 18 a three-month period, or a certain period, I 19 think will serve the purpose. 20 Since we haven't seen, or at least 21 I haven't seen a study where it really strikes 22 by saying that while the critical window of

### 202-234-4433 Neal R. Gross & Co., Inc. Page 294 1 exposure is one day, or between day 3 and day 2 4 of -- during a gestation period or 3 something, then it really puts you under the 4 pressure to have to essentially monitor within 5 that kind of a time frame all the time, 6 because you don't know who will be in that 7 time frame and when. 8 Since that doesn't seem to be the 9 case, it appears to me that the area under the 10 curve kind of approach would be sufficient at 11 these intervals, and the Agency's may not be 12 as sensitive to very short term fluctuations. 13 And at some point, some kind of sensitivity 14 analysis might be of use. Now once we do 15 determine a PoD, we already have the dose 16 measure, you can always relate that to 17 essentially water concentrations to these 18 temps. 19 And I've tried to ask the question 20 of what is the most sensitive parameter that 21 really drives my, you know, dose measure that 22 I'm using in a risk assessment, or in a dose

### 202-234-4433 Neal R. Gross & Co., Inc. Page 295 1 response curve for humans. Is it the uptake, 2 my peak, and so forth? So that would also 3 give some -- well, I think will give some 4 added confidence in terms of use of, you know, 5 the area under the curve kind for a measure, 6 even for the environmental concentrations. 7 I think with that I'm going to 8 yield the rest of my time to Dr. Greenwood 9 from the County of Portsmouth in the UK. 10 DR. GREENWOOD: Okay. I just want 11 to address, because I'm sure everybody's read 12 what's in the white paper, but I just want to 13 address what I think are one or two important 14 points that hit me between the eyes when I was 15 reading some of these papers. 16 One of the things that came up was 17 that in rats we get this binding to hemoglobin 18 and to plasma proteins. So if you're looking

19 at -- want to look at the level of free 20 diamino chlorotriazine, because this is the 21 stuff that binds rather than the other 22 metabolites, or atrazine to any great extent,

### 202-234-4433 Neal R. Gross & Co., Inc. Page 296 1 then it's certainly going to have an 2 influence, or should have an influence on the 3 interpretation of the levels that you're 4 measuring in blood. 5 And some of the other studies sort 6 of acknowledge that this happens, and then 7 forgotten about it when they come to interpret 8 the profiles, particularly if you're trying to 9 get a handle on what is a critical exposure of 10 site of action to a particular toxicant, 11 whether it be atrazine or one of the 12 metabolites. And it just seemed that when you 13 look at some of these profiles, that in some 14 of these studies, because they're high dose 15 maybe, I don't know, but because they're high 16 dose we're getting really not very much 17 relatively of the glutathione derivatives 18 which are relatively -- seem to 19 pharmacologically inactive, as you might 20 expect, were compared with the oxidative 21 metabolites of atrazine and atrazine itself. 22 And certainly the diamino

### 202-234-4433 Neal R. Gross & Co., Inc. Page 297 1 chlorotriazine seems to be present in some of 2 these studies at about a factor of 100, more 3 than any of the other metabolites. It really 4 is, after something like 12 hours, is the 5 predominant metabolite. Atrazine seems to be 6 peaking after a very few hours. So this just 7 seemed to be the major metabolite. 8 And what's more, when people 9 started to dose this on its own rather than 10 atrazine just to follow the kinetics of it, 11 it's got a very rapid absorption, and a lower 12 level of elimination. It's got a text book 13 sort of profile for that sort of compound. 14 And it does seem to bind -- because it binds 15 to cysteine, it does seem to expose cysteines. 16 It binds to a wide range of proteins. 17 Now, obviously there's a large 18 volume of albumin in the bolus, predominant -- 19 in the plasma it's the predominant protein and 20 it does bind to one particular cysteine in 21 there. But it also seems to bind, when we 22 flip to the later studies, to a lot of

### 202-234-4433 Neal R. Gross & Co., Inc. Page 298 1 different proteins in, for instance, the 2 pituitary. But, again, there's absolutely -- 3 I have no idea what the toxicological 4 significance of that might be, and how much of 5 the -- like how much of that protein is 6 removed, how quickly it's replaced, if it's 7 just -- is it detected as being non-functional 8 and does it replace. I don't know. 9 So it could be an important 10 factor, not just for the pharmacokinetics, but 11 maybe for -- it appears that this stuff is 12 inside certain tissues, but if it's found in 13 there, then it's not available. But is the 14 binding itself toxicologically significant. 15 And I don't think at the moment anybody has 16 any idea. 17 So I think this diamino 18 chlorotriazine is really something that can't 19 be discounted, mainly because it's in there in 20 such large quantities and because it does bind 21 covalently to any cysteine that's in the right 22 sort of conformation.

### 202-234-4433 Neal R. Gross & Co., Inc. Page 299 1 I think the other things that came 2 across to me, there's a study by Carroll, et 3 al., where they've compared the human and rat, 4 gut and uptake of it, and it did show that 5 the -- I think I said earlier that the 6 absorption is very similar in the two. 7 There's quite a high correlation coefficient, 8 in fact, a coefficient determination of .8. 9 But between the bioavailabilities because of 10 this difference in metabolism in the gut, they 11 R squared value goes down to about .3. 12 So it's -- it think there are 13 species differences, and although you might 14 predict in terms of absorption what goes on, 15 and you'd probably be fairly reasonably 16 accurate going from one species to another, in 17 terms of bioavailability you may be a long way 18 out, and it's the bioavailability of course 19 that's the most important thing that we need 20 to look at. It's no use something being 21 absorbed if it then gets wiped out in the 22 first pass of metabolism.

### 202-234-4433 Neal R. Gross & Co., Inc. Page 300 1 So I think, again, looking at some 2 of the studies, some of the models were 3 dismissed because there weren't data to test 4 them and so on, but I think that the model 5 fitting process gives us some take home 6 lessons, I think, about what are the more 7 sensitive parameters in the model and gives us 8 some idea of what would make a big difference. 9 And in most cases, what seems to make a big 10 difference to the exposure is this metabolism, 11 either in the -- by entry sites or by the 12 liver in the first pass of metabolism. 13 And that's why where we -- when I 14 was asked earlier about implants where you 15 avoid some of that metabolism, I mean 16 eventually it's going to meet those same 17 things because the gut gets a blood supply, it 18 doesn't just have a blood supply taken away to 19 the hepatic portal vein, it also needs an 20 arterial blood supply. All of the tissues 21 come in contact -- once it's in the blood 22 stream, every tissue in the body comes in

### 202-234-4433 Neal R. Gross & Co., Inc. Page 301 1 contact with it, target tissues and non-target 2 tissues. 3 So, again, I think some of these 4 issues need looking at because I think what's 5 important is, when you're looking at trying to 6 get a dose response code, is what is 7 available, what is available for interaction 8 with the site of action, because if it's bound 9 up somewhere, it's not available, it's 10 covalently bound to an albumin. 11 I think I'll leave that there. I 12 think those were the main points that, when 13 people are looking for dose response 14 relationships, they may not always see one, 15 and it could be because you get differential 16 metabolism and you get different 17 pharmacokinetics at high doses and at low 18 doses. And I think one of the other panel 19 members may have something to add to that, so 20 I'll leave it there. 21 DR. HAYTON: Bill Hayton. Just a 22 few comments to summarize my report I'm going

### 202-234-4433 Neal R. Gross & Co., Inc. Page 302 1 to turn in. The first thing is that after 2 oral gavage, that the -- in terms of kinetics, 3 the hormonal perturbation occurs very quickly 4 after atrazine administration. I think it's 5 the Fraites papers shows within in 15 minutes. 6 Even though it's a fairly large dose of 7 atrazine, we know from McMullin's study of 8 kinetics, that probably most of the dose is 9 still in the GI tract, so it seems like it 10 doesn't take all that much atrazine hitting 11 the pre-systemic metabolism machinery and then 12 whatever goes on into the systemic 13 circulation. Right away it triggers hormonal 14 perturbations in the HPA axis. 15 I think another thing that's 16 important about the kinetics is that atrazine 17 and its metabolites are not persistent. They 18 seem to be eliminated fairly quickly. There 19 aren't really good estimates in the rat of 20 half-life of the individuals species, I didn't 21 think, reading the PK papers. But just 22 looking at the overall half-life of

### 202-234-4433 Neal R. Gross & Co., Inc. Page 303 1 radioactivity, something on the order of about 2 10 hours in the rat, if you scale that to a 3 human maybe 24 hours, it would be three- to 4 four-fold longer typically. 5 Anyway, what this means is if you 6 stop -- if a person is exposed to atrazine in 7 drinking water, you get rapid onset of effect 8 on the HPA axis. If you stop administration 9 the effects -- it seems like the direct 10 effects have to go away fairly quickly because 11 of the relatively short half-life. 12 So those are some of the things 13 that I think that we know. If we ask the 14 question what's the lower limit of magnitude 15 and duration of perturbation of that hormone 16 signal that produces functional outcome 17 disturbance, in other words if you say that 18 the signal is just a precursor to a functional 19 outcome, adverse event, I don't think that's 20 been characterized. I don't think we know, 21 you know, how much perturbation of this signal 22 and/or for how long.

### 202-234-4433 Neal R. Gross & Co., Inc. Page 304 1 And this was a question I asked 2 Dr. O'Byrne this morning about, you know, the 3 acute versus the chronic and I think the 4 answer was it's the more chronic exposure is 5 probably the more relevant exposure. But I 6 think that's something we don't know. 7 And then finally, I think the 8 exposure window of interest is not readily 9 definable with the data we have now. Acute 10 perturbation seem to be less relevant than 11 chronic perturbation, and I think without the 12 signal functional outcome relationship being 13 well defined, it seems prudent just to use the

14 lowest observed adverse effect level that 15 perturbs biosignal as the point of departure, 16 or as the endpoint to define that.

17 DR. PORTIER: Dr. Greenwood. 18 DR. GREENWOOD: I'll just pick up 19 on one point. And it's difficult to get a 20 feel from these studies which are using oral 21 gavage because of what Dr. Hayton just said, 22 that a lot of the dose is still actually tied

### 202-234-4433 Neal R. Gross & Co., Inc. Page 305 1 up with the bolus and it comes out slowly, 2 probably in the intestine, over a period of 3 time. I think the whole dose eventually will 4 be absorbed, but -- or most of it, but it's 5 very difficult to try and get a feel for what 6 would be the pharmacokinetics if it was in the 7 drinking water. 8 And the problem is that, you know, 9 if you start thinking about taking in lower 10 levels in the drinking water, then you've got 11 to detect it, and if you dilute that by all 12 the tissues in the body, then you've problems 13 in the detection. And that's a real problem. 14 So it's very difficult to see how you get a 15 more realistic model of drinking water intake 16 because of these problems of level of 17 detection. 18 But at some time -- conceptually I 19 find it difficult to go from what's going on 20 with oral gavage and what would be going on 21 with intake throughout the day at lower levels 22 in drinking water. And I think, you know,

### 202-234-4433 Neal R. Gross & Co., Inc. Page 306 1 you'd probably get a different picture in 2 terms of metabolites and everything else.

3 DR. PORTIER: Dr. Schlenk. 4 DR. SCHLENK: Yes, this is very 5 interesting reading. In terms of the 6 kinetics, I think, particularly since most of 7 the doses are all fairly high dose experiments 8 that are primarily oral, and I think it really 9 lends itself to a PK -- PBPK sort of analysis, 10 I think it's perfect because I think, 11 particularly from the metabolism side, you 12 could argue that there's tremendous 13 differences between high dose oral exposures 14 and low level chronic exposures, just from a 15 KM perspective in terms of 16 the P450s that are involved in metabolism. 17 One thing I would note before I 18 forget, actually I wrote it down, if for the 19 non-cancer endpoints that are going to 20 evaluated for this fall, I assume you're going 21 to have a smoking history on some of the 22 individuals for that. I think that would be

### 202-234-4433 Neal R. Gross & Co., Inc. Page 307 1 a very important endpoint since 1A1 seems to 2 be a fairly important metabolizing enzyme for 3 atrazine. So I think that's going to be 4 obviously induced in smokers, that'S going to 5 be a real, I think a real important sort of 6 issue related to that. So I assume that 7 information will be known in terms of that. 8 But to get to Dr. Greenwood's 9 comparison of the human and the rat, there 10 actually is quite a bit known in terms of 11 metabolism of atrazine in terms of its profile 12 in P450 structure. And those data are 13 actually fairly well characterized between 14 humans and rats, so consequently those data 15 should be readily available for PK analysis in 16 terms of uptake, particularly with low level 17 exposures, because, just to give you an 18 example, if you are giving an oral bolus dose, 19 which we've sort of been hearing about, the 20 P450s that metabolize are going to be 21 completely different because in that sense, 22 again I mentioned this earlier, you're CYP3As

### 202-234-4433 Neal R. Gross & Co., Inc. Page 308 1 are actually going to be more appropriate 2 because they're high KM-based P450s. 3 So consequently your profile is 4 going to be different, and since those are a 5 little bit higher -- more highly expressed in 6 the GI you might not ever see atrazine 7 actually be absorbed to a certain degree in 8 that sense. However, at low level doses, then 9 a different P450 profile takes place. And, 10 again, that's 1A1, which happens to have a 11 higher KM -- I'm sorry, lower KM, higher 12 affinity for atrazine. 13 So, again, I think those 14 differences alone will change plasma 15 concentrations, which when -- eventually will 16 change target organ concentrations in terms of 17 your model. I don't think any of that had 18 been sort of evaluated, at least in the 19 literature that I was provided. 20 So I think those are sort of 21 critical issues in terms of metabolism, and 22 particularly since it seems the metabolites

### 202-234-4433 Neal R. Gross & Co., Inc. Page 309 1 tend to be not as potent in terms of its 2 interaction than the parent compound. So I 3 think figuring out those sort of issues 4 related to the metabolism, at the gut, the 5 level for the gut, as well as the liver, are 6 critical. And then, again, knowing what we do 7 know, the difference between the rat and the 8 human, you should be able to extrapolate that 9 pretty readily, I would think, between those

10 two.

11 DR. PORTIER: Dr. Chambers. 12 DR. CHAMBERS: I think all of 13 these comments have been extremely 14 interesting, and I guess I have the mind set 15 of something that's probably a food 16 contaminant, you're going to get it all as one 17 contaminated apple or something like that. 18 And when Kannan was talking I got to thinking 19 that with the two liters of water that 20 everybody drinks every day, that's distributed 21 pretty well throughout the day as opposed to 22 one big slug.

### 202-234-4433 Neal R. Gross & Co., Inc. Page 310 1 And so the -- I guess again the PK 2 considerations need to be done of getting that 3 dose over an extended period of time during 4 the day, and it's not going to be comparable 5 very well at all, I don't think, with some of 6 these gavage studies that you're having to 7 compare the endpoints with. 8 So just keeping all these points 9 into consideration as you do your analysis

10 over the next few months and do the 11 consideration I guess tomorrow on the drinking 12 water frequency and all, a very different 13 exposure pattern with drinking water as 14 opposed to the gavage type studies in the 15 animals.

16 DR. PORTIER: Dr. Reed. 17 DR. REED: Yes, as we're talking 18 about PK I was thinking that it's also 19 important what is the dose metrics that you're 20 going to be using to compare the rats and 21 humans for the endpoints of concern. And I'm 22 hearing in some cases area under the curve, in

### 202-234-4433 Neal R. Gross & Co., Inc. Page 311 1 some cases might be peak, and so it might be, 2 you know, more or less related to the 3 endpoints that you are trying to characterize. 4 And, you know, according to 5 Penny's suggestion that we do endpoints based 6 on the schematic of things for the mode of 7 action, and it might be different from one 8 step to the other, and that's something to

9 look at. 10 DR. PORTIER: Any additionally

11 commenters? No? Dr. Lee. 12 DR. LEE: I just sort of have a 13 question. Reading through this particular 14 question, there's a bunch of it that I don't 15 think has been addressed in this discussion. 16 A lot of good points have been raised, but 17 when we have to answer question 2 tomorrow, we 18 need an idea about what is a duration of 19 interest, or an exposure window of interest. 20 And I'm not sure I've gotten much guidance 21 from this discussion on what sort of exposure 22 windows we should be considering tomorrow.

### 202-234-4433 Neal R. Gross & Co., Inc. Page 312 1 DR. PORTIER: Dr. Krishnan. 2 DR. KRISHNAN: Yes, I think most 3 of our consideration was the duration of 4 toxicological concern versus the frequency of 5 monitoring, so that, you know, the frequency 6 for monitoring somehow doesn't give us any 7 data in terms of relevance to the duration of 8 the toxicological effect concern. But based 9 on the toxicokinetic aspects that we heard, or 10 pharmacokinetic aspects we heard, so we tried 11 to answer it on the basis of pharmacokinetics 12 and some of the effects on precursors that 13 have been discussed. 14 But coming specifically to the 15 exposure window of interest, I think my 16 colleague to the left indicated that there's 17 no specific window that can be defined on the 18 basis of the available data. But I mean when 19 you think of the window of exposure, it 20 depends on the critical tox study though to 21 drive the point of departure assessment. At 22 least that's how I'm looking at it, maybe I

### 202-234-4433 Neal R. Gross & Co., Inc. Page 313 1 can get some clarification or help from the

2 others. 3 If the critical window of exposure 4 of the key studies that end up driving this 5 assessment have any specificity of a two-day 6 window during development or something like 7 that, that's how I see a window of 8 susceptibility and window of critical 9 exposure. And based on the discussions that 10 I have seen, it's more of the sustained effect 11 on the specific precursors that would appear 12 to have a key impact on the outcome. 13 And one of the figures in the 14 document, I thought it was Figure 2, where it 15 showed dose duration relationship as well for 16 effect on the LH surge. I forgot the page 17 number; it was Figure 2, that white paper -- 18 27. Okay. So that one showed a dose duration 19 relationship for the NOEL from almost a single 20 day to about a six-month duration or so, which 21 essentially relates to the key event on LH 22 surge, which relates to the critical outcome.

### 202-234-4433 Neal R. Gross & Co., Inc. Page 314 1 So I mean we are kind of -- well, 2 at least from my perspective, from the studies 3 I have heard and seen, I am not getting any 4 other -- well, I don't have any other input. 5 Maybe we'll see if EPA wants to add some 6 clarification to that. 7 DR. LOWIT: Yes, I'll rephrase 8 maybe what Dr. Lee was thinking in my own 9 words. To go back to one of the things I 10 think Ken had sort of parked, the issue of the 11 duration, the acute versus chronic, I've got 12 open on the white paper, page 29, Table 3, 13 which is the early beginnings of what Penny 14 was mentioning around the temporal concordance 15 table for mode of action analysis. 16 It shows the currently -- or at 17 least as of two months ago, this is changing

18 fast -- the HPA data for ACTH and cort and 19 progesterone, and some GnRH four days, LH 20 across, one day up to 26 weeks, and some 21 cyclicity data from one day up to 26 weeks. 22 And keeping in mind that we're going to have

### 202-234-4433 Neal R. Gross & Co., Inc. Page 315 1 some better dose response to fill in a number 2 of those times. 3 I think it's relevant to think 4 about those durations, everything from that 5 one day cort measure all the way up to the 6 six-month LH endpoint that is the current 7 foundation of the RfD, and pretty anything 8 shorter or in between. It's open for us to 9 pick two days, four days, three and a half, or 10 seven and four-quarters, you know, it's --11 four quarters, that eight -- but three12 quarters, you know, it's pretty much open to

13 choose whatever makes the most sense 14 biologically. 15 And what I haven't heard, and I'm 16 hoping we'll hear in the second half of the 17 question, is the dynamic considerations. 18 We've heard a lot of really good points around 19 the kinetic, but what we haven't talked about 20 in this question are the dynamic 21 considerations, the relationship of the key 22 events, the time required to go from changes

### 202-234-4433 Neal R. Gross & Co., Inc. Page 316 1 in cort to eventually changes in LH, and how 2 you think about those and how that becomes 3 relevant to humans, the translation of the 4 one-day to the four-day to the LH, and then 5 translating that into humans.

6 Those are the factors that I 7 haven't heard in this conversation that get at 8 I think what Dr. Lee is asking about. 9 DR. PORTIER: Dr. Krishnan.

10 DR. REED: Now I recall when I 11 came to the meeting, in reference to your 12 question, Dr. Lee, when I came to the meeting, 13 I said to myself the answer is very simple, 14 monitor every 15 minutes. That's what this

15 table tells me. 16 (Laughter.)

17 DR. KRISHNAN: And then as I went 18 along, as the discussions went along 19 yesterday, I think, before the end of the day, 20 I said, I think three or four days or so seems 21 more reasonable. And then I listened to Dr. 22 O'Byrne and then some of our own discussions,

### 202-234-4433 Neal R. Gross & Co., Inc. Page 317 1 and what I'm convinced is that, you know, the 2 key event essentially relates to a sustained 3 effect and it's all the area under the curve 4 either internally or externally. 5 That's where I stand right now. 6 And then so the duration is simply you just 7 multiply it with the number of days that you 8 want, and that's where I stand. So I wanted 9 to clarify that. 10 DR. PORTIER: Dr. Gilliom, and 11 then Dr. O'Byrne. 12 DR. GILLIOM: So you're getting, 13 you know, a few kind of outside-the-box 14 questions from hydrologists who don't 15 understand anything about, or statisticians, 16 about the toxicology, but we're getting into 17 how you translate the realities of the 18 exposure situation into what's relevant for 19 what ends up being a concentration benchmark. 20 And one of the questions I'm still 21 a little confused about, and it's kind of in 22 two parts, is one, and this might be an EPA

### 202-234-4433 Neal R. Gross & Co., Inc. Page 318 1 question, are we still considering the total 2 chlorinated triazine approach, or are we 3 talking only atrazine as a parent compound? 4 And I haven't heard much further discussion of

5 that. 6 And then second, you know, I think 7 with good reason we're thinking about the 8 actual temporal exposure conditions, both of 9 the variation in the water and the variation 10 of the ingestion that happens. But also what 11 we leave out, and it's probably an impossible 12 question but I've to bring it up, is how 13 comfortable is everyone with the conclusions 14 based on the atrazine functionality models and 15 so forth when you also know it's in the 16 presence of a lot of other contaminants? 17 And I guess maybe it goes to, more 18 than anything, I want some perspective on that 19 because it really affects how we view the 20 monitoring requirements. If it were important 21 to pick up certain coincident occurrences, 22 then they might have different patterns and we

### 202-234-4433 Neal R. Gross & Co., Inc. Page 319 1 would have to know how to factor that in to 2 characterizing that. 3 Now I know it adds probably and 4 impossible level of complexity, but 5 unfortunately it's kind of the reality of 6 what's out there, and that's why I bring it up 7 and look for some reaction. 8 DR. PORTIER: Dr. O'Byrne. Oh, 9 let Dr. Okana go next? 10 DR. AKANA: Akana, Okana, doesn't

11 matter. 12 (Laughter.) 13 DR. AKANA: Yesterday we saw a 14 slide from Dr. Handa that I thought could be 15 very useful here. He had a slide where he 16 withdrew atrazine so the animal -- seeing it 17 and then you saw the recovery. And I was 18 absolutely, first of all, thrilled to see it 19 was not irreversible, but second, if I 20 remember right, it declined in four days. So 21 an off response might be very helpful in 22 figuring out your window of vulnerability and

### 202-234-4433 Neal R. Gross & Co., Inc. Page 320 1 duration.

2 DR. O'BYRNE: In the context of 3 the surge, which seems to be the critical 4 event, it's not like a knee-jerk response. 5 This is a massively complicated neuroendocrine 6 signaling system which starts with a gradual 7 rise in estradiol resulting in cascades of 8 neuropeptide changes in the brain. And this 9 event takes probably a day or two to actually 10 get it to work. 11 It's triggered by a rise in 12 estradiol, and those levels of estradiol have 13 to be elevated at a critical level for many, 14 many hours, not two or three, we're talking in 15 women it's something like a day. Yes? And in 16 the context of rats, and they have a four-day 17 cycle, so the window is much, much shorter. 18 So that's one of the reasons why I caution 19 against comparing women with rats. I mean 20 it's just outrageous at many, many levels. 21 (Laughter.) 22 DR. O'BYRNE: We're talking about

### 202-234-4433 Neal R. Gross & Co., Inc. Page 321 1 neuroendocrinology here. 2 DR. PORTIER: I'm glad to hear 3 that. Glad to hear it. 4 DR. O'BYRNE: So I think in terms 5 of the duration, I think that -- I think it's 6 very difficult for you guys to appreciate the 7 duration in terms of sampling water and things 8 like that. I don't know how you're going to 9 do it, to be honest. 10 But this is an event that takes a 11 long time to kick start, and in some ways it's 12 astonishing that it takes four days of daily 13 atrazine at phenomenally high doses, and I 14 still don't like that, of 50 milligrams per 15 kilo to knock it out, and then there's no dose 16 dependent nature to that, which, I mean I'm 17 beginning to realize may not be terribly 18 surprising, I mean in terms of, you know, you 19 completely knock it out with 50, 200, 300 and 20 probably 1,000. 21 It's just either there or it's 22 not. That's what I see in terms of the

### 202-234-4433 Neal R. Gross & Co., Inc. Page 322 1 ovariectomized estrogen-primed animal, which 2 is a much easier model to deal with because 3 there you've got the response to estradiol is 4 being evaluated. Whereas if you take a 5 spontaneously ovulating rat, the machinery is 6 massively more complicated because you may be 7 interfering with the rise in estradiol, and we 8 don't know the dynamics. If the rise in 9 estradiol is less steep, is not maintained at 10 a certain critical value that may impact 11 markedly. 12 So the ovariectomized rat given 13 exogenous gonadal steroids to induce this 14 event is a much cleaner model, and that's the 15 one that has been used and shown at three days 16 is necessary to knock it out. So I don't know 17 if that's helpful at all. 18 DR. PORTIER: Dr. Lowit.

19 DR. LOWIT: If Ken would let me -- 20 if we can push on that concept a little bit. 21 Let's say theoretically, theoretically, there 22 were some -- there were a data set linking

### 202-234-4433 Neal R. Gross & Co., Inc. Page 323 1 four days of atrazine to LH to the surge, it 2 got down to something short, in the rat, of 3 something as short as four -- three, four, 4 five days. How would you translate that? 5 DR. O'BYRNE: It's already at four 6 days. 7 DR. LOWIT: So how would you 8 translate those rat four days into human days? 9 What sort of scale are we talking about? Are 10 we also on the day scale, are we on the week 11 scale? On a month, because that's a whole 12 cycle? 13 DR. HORTON: Yes, I need a 14 refresher course. What happens to 15 corticosterone or cortisol in the rat when you 16 treated them with atrazine? I'm going to 17 brain dead at the moment.

18 DR. COOPER: Yes. 19 DR. HORTON: Okay. 20 DR. COOPER: When you dose them it 21 increases. 22 DR. HORTON: Okay. Cortico -

### 202-234-4433 Neal R. Gross & Co., Inc. Page 324 1 DR. COOPER: Corticosterone 2 increases. 3 DR. HORTON: Increases. Okay. 4 Because there's a very large body of data from 5 the `80s and `90s from the laboratory of Neena 6 Schwartz on the effect of steroids on LH and 7 FSH secretion that can give you information on 8 the time course of this, and treatment over 9 the course of five to ten days with 10 corticosteroids prior -- or just treatment 11 with corticosteroids can influence the 12 differential secretion of LH and FSH. 13 So that might help inform the 14 studies on the set up of atrazine, and also 15 give you some information on the length of 16 time if atrazine setting up the induction of 17 corticosterone, that if you have an effect of 18 atrazine that is inducing the HPA axis, and 19 then you need the exposure of the HPG axis to 20 the steroids to then have an influence on the 21 HPG axis, kind of what the sequence of events 22 would be. So you need to have that kind of

### 202-234-4433 Neal R. Gross & Co., Inc. Page 325 1 time course. 2 DR. COOPER: Yes, I'm familiar 3 with Neena Schwartz's work. And you're right, 4 but it's really hard to pin down some of those 5 durations, but that's the information I'm 6 getting, that maybe we have more limitations 7 from the basic literature than I thought. 8 Back to this dose though, I think 9 I got -- I want to just restate something with 10 the rise in estradiol. In, you know, in a 11 four-day rat estradiol starts to rise around 12 noontime of the day of diestrus 2 and it 13 continues to increase throughout the evening 14 and into proestrus, and that's where you start 15 to have all the dynamic changes that Dr. 16 O'Byrne was referring to. 17 We've monitored that in intact 18 animals under atrazine. We don't -- again, 19 that's -- a lot of these questions are there 20 and we're trying to get as many answers as we 21 can. And when you dose with atrazine from 22 estrus, diestrus 1, diestrus 2, and proestrus,

### 202-234-4433 Neal R. Gross & Co., Inc. Page 326 1 those four days, that's the exact same model 2 that was published in Fraites's paper, the 3 doses required to decrease the amplitude of 4 the LH surge at 1800 hours, the effective -- 5 the LOEL in that study was 6.25, the NOEL we 6 got was 3 point whatever dose halves are. 7 So I think the notion that the 8 estrogen-primed animal, we started out and we 9 continue to work with the estrogen-primed 10 animal. I personally don't really think the 11 estrogen plus progesterone animal is really 12 useful at tox because of the potent signal 13 that P4 gives the pituitary -- I'm sorry, the 14 hypothalamic-pituitary control. 15 But so the two I like, and these 16 are personal preferences, right, is the 17 estrogen-primed female and the intact animal. 18 Now it takes a tremendous amount of effort to 19 do an intact female period. But because we 20 have unlimited taxpayers' resources, we -- 21 (Laughter.) 22 DR. COOPER: No, I mean it's -- we

### 202-234-4433 Neal R. Gross & Co., Inc. Page 327 1 are -- over the -- you know, if you're frugal 2 enough and you're careful enough, you can 3 follow the animals and you can make -- the one 4 thing you have to do if you're following 5 cycles -- if you're doing an intact animal is, 6 number one, and this is really a problem in 7 tox studies, is to make sure your females are 8 cycling. And that's not always the case in a 9 lot of things we get to review.

10 So we make sure for two weeks that 11 these females show four-day cycles. Then we 12 initiate our treatment and then we follow 13 them, and we kill them -- we have killed them 14 every two hours from 6:00 a.m. in the morning 15 to proestrus throughout -- well, now two hours

16 after dark. So we have now a data set that's 17 quite complete. 18 And where we're now currently 19 picking apart that rise in estradiol, that 20 rise in progesterone which is just as 21 important in the afternoon, and then where -- 22 now, think about this, we're trying to

### 202-234-4433 Neal R. Gross & Co., Inc. Page 328 1 evaluate the normal cycle in the animal, but 2 we're dosing them with a compound that we know 3 at some dose is going to disrupt the cycle, so 4 it gets really dicey to make sure that you're 5 dealing with treatment effects as opposed to 6 throwing out affected animals in this kind of 7 thing. 8 When all that's said and done, we 9 do have a LOEL and a dose response down to a 10 NOEL of 3.125 -- that's the right number -- 11 and then we've looked at estradiol and 12 progesterone, we haven't finished the -- and 13 we're looking at ovulation and all the 14 different things that we can just to make sure 15 that we have that boxed in properly. 16 So I think the notion that we 17 need -- 3.25 and 6 I think are still probably 18 up there in terms of exposure. I'm not going 19 to say they're low doses, but in terms of the 20 literature anyway that's down there around 21 where our -- the current point of departure is 22 of 1.8, I think is the NOEL; that's pretty

### 202-234-4433 Neal R. Gross & Co., Inc. Page 329 1 close. 2 So what we were looking for was a 3 question -- to the answer to this question 4 given that kind of information. It took four 5 days to get there to have an effect on the 6 surge. Is that the kind of exposure that you 7 could say this is -- you know, these things, 8 if you're exposed at some sufficient level for 9 that long, it can be adverse, whether it's 10 through adrenal or direct on the pituitary -- 11 hypothalamic-pituitary axis. So that's one of 12 the questions. 13 And then the other question is, 14 built into that, is if it's a single-day 15 exposure, and I think I've already this 16 answer, if it's single-day and it's adrenal 17 response, which we may end up with the same 18 dose response but it may be meaningless in 19 terms of an adverse outcome, we can't -- an 20 adverse outcome on adrenal, and I think I've 21 heard that from this panel one time, which is 22 good. I think that's good. But you still

### 202-234-4433 Neal R. Gross & Co., Inc. Page 330 1 need an adrenal axis. 2 So I think the question we're 3 getting at is, do you have advice on -- I 4 think I've already heard it, and that one day 5 is probably insufficient right now. So it's 6 not like some other chemicals where we can 7 dose once, wipe out the surge, and it causes 8 problems with ovulation, and it causes 9 problems if the animal becomes pregnant with 10 the embryo development and those kinds of 11 things. 12 So we do have one day exposure. 13 If it was for a reasonable period for time, 14 should you go -- you know, that's the question 15 that we're asking, or seeking advice on. 16 DR. O'BYRNE: Okay. Can I ask you 17 a question. Have you tried one, two and three 18 days, or was it just one and four? 19 DR. COOPER: Not yet.

20 DR. O'BYRNE: You haven't. You

21 haven't done that. 22 DR. COOPER: No, we've done one,

### 202-234-4433 Neal R. Gross & Co., Inc. Page 331 1 two -- oh, yes, we've --

2 DR. O'BYRNE: You have?

3 DR. COOPER: No. We've dosed for 4 one or one, two, three, four, but we haven't 5 had the opportunity yet to -- 6 DR. O'BYRNE: And have you looked 7 at the dynamics of the estrogen change in 8 those animals that were dosed for four days?

9 DR. COOPER: Yes -- have we looked 10 at the entire --

11 DR. O'BYRNE: Yes.

12 DR. COOPER: No. 13 DR. O'BYRNE: On day one, two, 14 three, four? 15 DR. COOPER: Only from 6:00 a.m. 16 on pro to two hours after lights out, every 17 two hours. And we haven't found a change in 18 that hormone. We've seen changes at nine 19 o'clock after we dosed, because we dose 9:00 20 a.m. on proestrus as well, and we see changes 21 in progesterone and cort at 10:00. 22 DR. O'BYRNE: So progesterone is

### 202-234-4433 Neal R. Gross & Co., Inc. Page 332 1 attenuated?

2 DR. COOPER: No. 3 DR. O'BYRNE: It's increased? 4 DR. COOPER: Yes. At that -- it 5 increases at 10:00 and 11:00, drops back down, 6 then you see the afternoon rise, and it goes 7 right up to the same levels that we see in 8 control, you know, 60 milligrams per -- 9 nanograms per millimeter, somewhere around

10 there.

11 DR. O'BYRNE: Because of course 12 that progesterone is probably coming from -- 13 it's going to be coming from the adrenals.

14 DR. COOPER: Yes. And the other 15 thing is that -- and we've looked at uterine 16 growth in those animals and that's one of our 17 key criteria is that you want to make sure 18 that you're uterus, which goes from about 200 19 milligrams to almost a full gram over that 20 day, it really balloons up, you want to make 21 sure that they're responding because you don't 22 want to have an animal who's not showing that

### 202-234-4433 Neal R. Gross & Co., Inc. Page 333 1 kind of rise in estradiol because then she 2 wouldn't be proestrus. That was our 3 assumption. 4 DR. PORTIER: Dr. O'Byrne, is this 5 helping you kind of converge -- 6 DR. O'BYRNE: Yes, I see -- 7 DR. PORTIER: -- on a duration? I 8 mean it's fascinating to watch you guys talk 9 to each other, but I'm trying to figure out if 10 this is helping you converge to this duration 11 question. 12 DR. O'BYRNE: Well, the -- I mean 13 I think the four-day duration seems a 14 reasonable ballpark. The question of how we 15 relate this to the menstrual cycle, that's a 16 really difficult one to appreciate because I 17 think in the rat you only need a very short 18 period of raised estrogen to trigger this 19 surge, but you need it for days. I think it's 20 something like 30 -- no, no, no, for the 21 raised elevation -- the elevated levels of 22 estrogen in women is a day or two, I believe.

### 202-234-4433 Neal R. Gross & Co., Inc. Page 334 1 Yes. So I mean that's just massively 2 different. 3 So if you look at it from that 4 point of view, then you have to -- you know, 5 you can model that you need a much, much 6 longer duration of exposure to interfere with 7 that positive feedback effect of estrogen in 8 women. You've got to couple that with the 9 knowledge that the entire surge generating 10 mechanism in women and primates, higher 11 primates, is just totally different from a 12 rat. You don't even need a brain. 13 (Laughter.)

14 DR. O'BYRNE: You don't even need 15 a brain if you're a woman to have a surge.

16 It's an absolute truth. 17 DR. COOPER: Well, that's -- 18 DR. O'BYRNE: The data is there -- 19 DR. COOPER: -- I'm sorry -- 20 DR. O'BYRNE: The data is there -- 21 DR. COOPER: I understand Nobel, 22 sorry --

### 202-234-4433 Neal R. Gross & Co., Inc. Page 335 1 DR. O'BYRNE: The data is that it 2 would be estrogen -- the estradiol -- the 3 positive feedback effect of estradiol is the 4 pituitary phenomenon. 5 DR. COOPER: It's pituitary, in 6 the monkeys, Nobel's work, but I think there's 7 more than sufficient evidence to show that a 8 lot of chemicals that work essentially to 9 inhibitor or impair the pulsatile release of 10 GnRH and release of LH in humans. And I know 11 the pulse frequency is important, and it's -- 12 just as well in humans. 13 But I think the -- back to the 14 duration question, I think we could scale that 15 up and scale it down, and I think that's part 16 of the issue. You're right.

17 DR. PORTIER: Dr. Schlenk. 18 DR. SCHLENK: Yes, just a simple 19 question. I mean do you know from your ex 20 vivo studies what tissue concentration you 21 need, say in the adrenal glands, to get a 22 cortisol release?

### 202-234-4433 Neal R. Gross & Co., Inc. Page 336 1 DR. COOPER: No, not now. 2 CHAIR HEERINGA: Steve Heeringa. 3 I think you've started to address what was 4 going through my mind, and statistically, 5 statistically, the most pathological case in 6 terms of these chemographs and exposures are 7 these short term surges we see, and we had a 8 couple of examples, the Missouri raw water 9 thing that we see where you have several 10 spikes in atrazine concentration in the raw 11 water supply, and they last for about two or 12 three days. 13 And in terms of thinking about the 14 coincidence of sort of the sampling frequency 15 we'll be talking tomorrow, and the concerns 16 you're talking about, it's the first of June, 17 Thursday, it rains, Sunday morning I make 18 coffee and I get a surge of atrazine in my 19 community water supply, if it happens that 20 fast. I make the same coffee Monday morning 21 and Tuesday morning. By Tuesday morning it's 22 gone, it's back down to a lower level.

### 202-234-4433 Neal R. Gross & Co., Inc. Page 337 1 I think what is the impact of that 2 maybe for me, or for women in the household, 3 et cetera. I think that's the key sort of 4 sampling issue that we need to get at. I 5 think if you're saying that it's sustained 6 concentrations at certain levels over a period 7 of time, the statistical issues will become a 8 lot easier. 9 But it's the -- and most of the 10 chemographs, and Nelson and others could 11 confirm this, that we saw, even in raw water, 12 there maybe are two peaks, two or three peaks 13 per year that are real spikes, and most of 14 them are much more uniform flat. And I assume 15 in finished water it even looks flatter yet, 16 so. But I think you were getting at that when 17 you were talking about this before. 18 DR. PORTIER: Dr. Williams. 19 DR. WILLIAMS: I just have one 20 comment about the female menstrual cycle. It 21 does take a much longer time than the rat to 22 actually create a menstrual cycle, but it's

### 202-234-4433 Neal R. Gross & Co., Inc. Page 338 1 not clear that it would take much longer or 2 potentially any longer at all to disrupt that. 3 So if you have an atrazine spike 4 that's the day before or two days before 5 you're going to have an LH surge, just for 6 that one day, could that be disruptive? Based 7 on all the central effects we've been talking 8 about is that enough to disrupt? It's 9 certainly not enough to create a menstrual 10 cycle, obviously you need the days and the 11 feedback and so forth, but how long does 12 disruption take? 13 DR. O'BYRNE: I think you're 14 perhaps asking the wrong person. I mean there 15 are experts in the US who know a great deal 16 more about the control of the menstrual cycle 17 in women. But I would be very surprised if 18 you perturbed the follicular phase by -- 19 during that two-week period you perturbed it 20 on one particular day, I'd be amazed if it 21 impacted on that follicular phase. I'd be 22 absolutely astonished. It just wouldn't make

### 202-234-4433 Neal R. Gross & Co., Inc. Page 339 1 sense to me. 2 I'm just thinking of my time when 3 I was working with monkeys, you really do have 4 to make a major stressor to perturb the 5 menstrual cycle. I don't think one event 6 would make a jot of difference. And this was 7 in the context of restraining Rhesus monkeys 8 in primate chairs. It didn't disturb the 9 cycle. I think --

10 DR. PORTIER: Dr. Horton. 11 DR. O'BYRNE: -- it's quite -- I 12 think it's quite robust. 13 DR. HORTON: This is where I think 14 when we finally see epidemiological data and 15 kind of the absence of data on the 16 developmental issues comes into play because 17 it's in development that neuroendocrine 18 systems and neurotransmitter systems are much 19 more sensitive, and where exposure for 20 transient -- or exposure to chemicals for 21 transient periods of time can have serious 22 long term effects.

### 202-234-4433 Neal R. Gross & Co., Inc. Page 340 1 And so if you take a hit for a day 2 or two at just the right time of development, 3 and unfortunately because we're talking about 4 humans, we don't have experimental data on it, 5 and we never will have experimental data, and 6 you really can't extract it very well, even 7 from epidemiological data, but certainly 8 looking at rodent data, the work that's been 9 done with steroids, you know, treating them at 10 the right stage of the prenatal period for one 11 day with the right steroid can have major 12 developmental effects. 13 Most of this work was done looking 14 at the effects of sexual differentiation, but 15 we're now finding that different critical 16 periods exist for, say, treating with 17 androgens that results in changes in 18 metabolism later in life resulting in the 19 recapitulation of factors like metabolic 20 syndrome. 21 So I think taking into 22 consideration the possibility that exposure to

### 202-234-4433 Neal R. Gross & Co., Inc. Page 341 1 these pulses or periods for over a few days at 2 the wrong time of fetal development might be 3 important. Also what we haven't seen any data 4 on, and I don't know if this will addressed at 5 some other SAP, might be the -- whether there 6 are any data on impacts on in vitro 7 fertilization, early pregnancy, loss. If Dr. 8 Lowit would like to comment on whether any of 9 that is going to be addressed. 10 DR. PORTIER: Actually, before we 11 get to that, I think the hour's getting late. 12 We long ago wiped out my desire to have the 13 hydrology discussion. 14 What I wanted to suggest is if we 15 can capture some of these unanswered 16 questions, you know, the kind of things that 17 we've been -- we haven't had any answers, but 18 we've had some questions that I think will 19 help EPA to refocus how you think about 20 duration and, you know, some of the issues of 21 women's menstrual cycle, the level needed to 22 impact it, at least in higher primates, the

### 202-234-4433 Neal R. Gross & Co., Inc. Page 342 1 key reproductive and what we know about, if I 2 understood, steroidal impacts on key 3 reproductive and developmental points. 4 You know, if we can kind for ask 5 the right questions, that'll at least help the 6 EPA staff kind of begin to formulate the 7 answer. I don't think we quite have gotten to 8 your -- the answer to your questions, but I 9 don't think Dr. Lowit really expected an 10 answer to the question. 11 If that's agreeable? Any final 12 kind of concluding remarks on this point? 13 Dr. Krishnan. 14 DR. KRISHNAN: Could it be a 15 confusing remark?

16 DR. PORTIER: Huh? 17 DR. KRISHNAN: Could it be a 18 confusing remark rather than a concluding one? 19 (Laughter.)

20 DR. PORTIER: That would be an 21 additional confusing remark. 22 DR. KRISHNAN: Okay. I just want

### 202-234-4433 Neal R. Gross & Co., Inc. Page 343 1 to -- before we -- at least in mind I just 2 wanted to get a clarification. So as we see 3 these various precursors that are being 4 modified, you know, which is listed in Table 5 3 where we've got, you know, a change 6 occurring in 15 minutes in cort level, or over 7 a longer period the effect on LH surge and so 8 on, does that -- well, the way I see it is 9 that the monitoring frequency then has to 10 match with this, with essentially with each 11 one of these key event or precursor, whichever 12 you pick, so your frequency will have to match

13 that somehow.

14 But then not each one of these 15 precursors are going to make it through the 16 risk assessment. Like, you know, maybe the 17 cort level is not going to be used in 18 determining the PoD or something. So I think 19 that's where -- that's what has to get into 20 this equation to determine whether we need to 21 ask this question about these various 22 precursors and the frequency of monitoring.

### 202-234-4433 Neal R. Gross & Co., Inc. Page 344 1 Because if not all of these get 2 to -- get into the process of deriving -- or 3 driving the PoD, then I don't see that being 4 a critical factor in this consideration. I'll 5 leave it at that. 6 DR. PORTIER: Thank you. 7 I'm going to actually leave this 8 question open just in case somebody comes up 9 with a brilliant idea in the morning. There's 10 no reason to close it. But I think at this 11 point we're going to break for the day and 12 begin again tomorrow morning at 8:30 again 13 with kind of just a recapitulation of this, 14 and then we'll go into the discussion. 15 I'd like the hydrology people to 16 hang around for a few minutes here after the 17 meeting so we can talk strategy for tomorrow. 18 Thank you very much. 19 (Whereupon, at 4:51 p.m., the 20 meeting was adjourned, to reconvene at 8:30 21 a.m., Thursday, April 29, 2010.)

22

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54:16 55:2 123:18 123:19 146:17,20 166:22 167:2 168:7 170:12 171:7,9 173:15,21 177:16,17 181:2 182:2 184:14 185:15,16 189:8 204:9,10 206:16 206:17,17 225:4,5 236:22 270:22 271:1 272:18,22 272:22 273:9,22 281:9,10 282:21 283:2 323:13,19 323:22 324:3 339:10,13 Horton's 189:16 Hotchkiss 76:4 Hotel 1:17 hour20:1 176:10

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212:1 hypotension71:11 hypothalamic

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212:1 H295R 110:14 111:7 140:16,22 141:16 I idea 32:14 103:9 104:13 199:15 202:16 229:13 276:16 298:3,16 300:8 311:18 344:9 ideal 261:1 identical 257:13 identification

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36:2 39:2 45:18 65:15 86:10 111:11 115:3 116:1 118:22 120:10 123:5 126:7,8,14 143:20 147:18 226:11 246:1 patronizing98:22 pattern 88:16 122:8 256:19 291:1,20,20 310:13 patterns 34:14 104:2 224:16 318:22 Pause 96:18 99:11 PBPK 35:14 263:4

306:9 PDE72:8 peak 31:19 290:14

291:5 295:2 311:1 peaking 297:6 peaks 40:15 292:10

292:16 337:12,12 peg 150:6,8,16 pellets 155:18

221:5 PENELOPE 2:4 Penny 275:17

314:13 Penny's 256:10

280:6 311:5 people 5:15,16 11:5 11:16 16:18 18:7 19:2 22:20 23:1 55:10 72:18 79:4 80:13 103:6 136:9 152:16 180:18 188:11 214:1 221:9,16 224:9,12 230:19 237:22 276:4 277:4,18 293:15 297:8 301:13 344:15 peptide 81:15 percent 16:1,2 44:5

47:18 53:6 164:15 199:1,5 201:17,22 212:21 222:21 255:19 260:3,4 percentages 34:15

34:15 perfect266:11 306:10 perfectly 134:11 perinatal 101:3 171:3 190:18 perinatally 192:10 period 128:20 130:11 148:21 195:16 198:2 230:20 270:6 293:18,18 294:2 305:2 310:3 326:19 330:13 333:18 337:6 338:19 340:10 343:7 periods 148:12,19

238:9 339:21 340:16 341:1 peripheral 80:4 peripherally 68:1 periphery71:8,22 peripubertal 128:5 130:10 136:18 198:2 205:12 peri-ventricular

77:19,20 permanent 149:2 permeability

291:15,16 permission 151:14 151:15 persistent 132:1

302:17 person 50:3 163:5

202:14 240:20 303:6 338:14 personal 65:9 165:15 326:16 personally 59:22

326:10 perspective 36:21

46:22 306:15 314:2 318:18 persuasive 16:14 pertaining 246:20 pertinent94:18 perturb 243:10 339:4 perturbation 10:12

45:10,18 134:10 245:5 259:16 260:18 302:3 303:15,21 304:10 304:11 perturbations 9:3

9:10 37:10 46:9 302:14 perturbed 8:14

338:18,19 perturbs 304:15 pesticide 53:2 126:4 164:1 166:21 274:16 pesticides 44:17

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244:16 Ph.D 1:18,18,21,21 1:22,22,23,23 2:2 2:2,3,4,5,6,7,8,9 2:10,12,13,14,15 2:16,17,18 pica76:5,12 pick 5:15 59:3,3 179:22 182:7 252:15 278:18 283:3,3 304:18 315:9 318:21 343:12 picking 327:19 picture 31:17 94:5 106:20 108:13 223:9 248:6 252:19,19,19 258:16 271:21 273:19 306:1 pictures 290:21 piddle 99:1 piecemeal 205:18

265:19 pieces 54:11 101:10 105:21 pile 249:21 pin 325:4 PIs 92:14 pituitary 13:21 14:1,4 29:2 72:10 83:10 114:1 120:10 133:22 135:3,10 282:19 298:2 326:13 329:10 335:4,5 PK 131:20 222:16

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292:7 339:16 player 118:13 players 114:15,22 121:14 playing 213:1 Plaza 1:17 please7:11 8:7 9:1

9:9 64:9 110:5 112:4,16 129:19 130:2 145:15 146:14,19 193:10 193:12 204:13 208:18 209:9 210:3,17 232:14 234:20 242:21 243:6,12 pleasure 216:21 plenty 183:8 plots 50:12 97:5 102:20 289:14 290:13 plus 255:1 264:22

326:11 plus/minus 253:20 PND27 205:12 PNS 158:21 PoD 157:18 255:11

258:14 259:8 261:12 262:1 294:15 343:18 344:3 PoDs 242:7 251:10

259:2,15,20 263:13 point4:16 5:5

27:12,22 28:1 32:7 35:18,22 39:9,14,17,22 40:19 42:2 45:13 46:10 51:15 52:10 76:4 78:15 84:2 85:20 99:22 100:6 101:4,11,21 106:22 119:15,22 153:5 155:1 174:1 174:11,16 178:17 179:7 188:18 190:10 195:15 205:19 226:8 235:7,8,17 244:8 245:12 247:1 250:17 251:6 252:14,17 253:6 256:2 266:9,10 270:4,13 274:13 275:3,18 283:21 286:22 294:13 304:15,19 312:21 326:6 328:21 334:4 342:12 344:11 pointed 105:2 121:6 253:8,17 points 15:18 26:15

26:15 27:19 28:3 70:7 98:3 106:5 141:15 152:13 160:9 167:20 191:11 206:21 242:8 243:1 253:4 265:7 271:9 277:5 295:14 301:12 310:8 311:16 315:18 342:3 policy 98:12 polymerase 145:5 POMC 29:2 pool 230:14 239:4 poor 145:2 pop 287:20 populations 242:11 portal 224:13

300:19 Portier 1:18,21

4:17,19,20 6:10 9:16 23:19 27:15 33:15 36:4 39:16 41:16 46:6 47:1 48:1 49:1,18 53:16 54:2,12,15 55:4 56:5,18 57:15 58:2,5 59:19 60:19 61:8 62:2,7,10 64:19 73:16 78:20 83:12 86:19 87:8 88:10 89:3 90:7,11 91:6 91:21 94:9,14 96:1,16,19 99:9 99:13 108:15 109:19 110:3 112:10 120:18 123:17 125:5,8,16 126:1 127:10,12 130:5 133:12 135:22 136:11,15 137:14,17 138:6,8 138:11,22 142:9 142:14 143:4 146:16 152:10 157:20 161:16,19 164:4 165:19 166:22 169:21 170:10 172:4 173:21 174:12 175:5 176:3,16 180:3 181:22 182:10 183:7 184:11 185:10,15 189:7 190:5,9,21 191:17 193:17 204:4,9,12 206:16 207:2 210:20 216:8,12,19 222:10 225:4 226:17 229:16 231:20 232:11 233:19 234:4,7 236:21 237:8 238:12 239:7,10 239:20 241:9 243:15,22 254:2,9 255:12 257:19 264:3 268:17 269:1 270:8,22 273:3,18 274:1 275:6,6,15 276:13 280:16 281:3 282:12,22 285:2

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24:11,17 25:5,7 38:20 123:5 129:20 130:20 133:7 134:1 149:5 150:14,21 193:14 194:19 195:15 197:8 260:10 propylthiouracil

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63:14 64:1 Pruett's 48:5 70:10 psychological 17:18,20 48:19 64:7 pubertal 58:18 101:3 131:13 133:10 268:11 pubertals 270:2,5 puberty 131:10,18 132:13,16 211:20 public4:9 121:6 publish 153:2 published 17:14 18:7 19:14 81:1 82:15 92:15 140:18 151:12 208:9 214:19 326:2 pull 17:4 263:17 pulled 17:22 pulsatile 13:13 181:8 335:9 pulsatility 129:16 pulse 13:18 14:7,11 19:6 26:17 335:11 pulses 341:1 pup 145:12 197:4 pups 133:3 145:13 196:9 198:9 199:10 purified 140:12 purity 144:22 purpose 89:15

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