### 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

+ + + + + TUESDAY, APRIL 27, 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

C-O-N-T-E-N-T-S

Opening Remarks and Introductions . . . . . . .4

EPA Presentation: Use of Bootstrapping

Methods . . . . . . . . . . . . . . . . 11 Mary Frankenberry

EPA Presentation: Artificial Neural

Networks. . . . . . . . . . . . . . . . 35 Mike Messner

EPA Summary - Nelson Thurman. . . . . . . . . 69

Public Comments . . . . . . . . . . . . . . . 96

Charge Questions . . . . . . . . . . . . . .340

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

2 8:31 a.m. 3 MR. BAILEY: Let's get started 4 here this morning. My name is Joe Bailey 5 again. I'm serving as the designated federal 6 official for the meeting. This is the 7 Reevaluation of the Human Health Effects of 8 Atrazine. 9 I just want to make a couple of 10 quick comments. EPA's presentations from 11 yesterday are in the docket, so if anybody 12 wants to see them, they're there. 13 We will have a public comment 14 session this morning. And I would ask anybody 15 who has electronic copy of their comments to 16 e-mail them to me. I will get them -- I'll 17 give you the e-mail at break or sometime if 18 you do need that. 19 And the final reminder is just to 20 please state your name when you're making 21 comments so that we can get the name recorded 22 into the audio and written transcript.

### 202-234-4433 Neal R. Gross & Co., Inc. Page 5 1 And I think that's all I have to 2 announce this morning. And I'll turn the 3 meeting over to Ken Portier. Thank you.

4 SESSION CHAIR PORTIER: Good 5 morning. Welcome to day two of this EPA SAP 6 meeting on Reevaluation of Human Health 7 Effects of Atrazine: Review of Experimental 8 Animal and In Vitro Studies and Drinking Water 9 Monitoring Frequency. 10 We're continuing the presentation 11 from day one. But as we normally do with the 12 panel on the second day we're going to go 13 around and introduce everyone from the panel. 14 I'm Ken Portier, the director of statistics at 15 the American Cancer Society national home 16 office in Atlanta. I'm a bio-statistician, a 17 member of the permanent panel. And we'll 18 start with John.

19 DR. BUCHER: John Bucher. I'm the 20 associate director of the National Toxicology 21 Program. I'm a toxicologist and a member of 22 the permanent panel.

### 202-234-4433 Neal R. Gross & Co., Inc. Page 6 1 DR. SCHLENK: Dan Schlenk, 2 professor of aquatic ecotoxicology, Department 3 of Environmental Sciences, University of 4 California, Riverside, and a member of the 5 permanent panel. 6 DR. CHAMBERS: I'm Jan Chambers, a 7 professor in the College of Veterinary 8 Medicine at Mississippi State University. I'm 9 a pesticide toxicologist and a member of the 10 permanent panel. 11 DR. LEBLANC: I'm Gerry LeBlanc. 12 I'm head of the Department of Environmental 13 and Molecular Toxicology, North Carolina State 14 University. And I'm a permanent panel member. 15 DR. HOLLADAY: I'm Steve Holladay. 16 I'm a professor at University of Georgia 17 College of Veterinary Medicine. I'm head of 18 Anatomy and Radiology Department. I'm an 19 immunotoxicologist, first time on the panel. 20 DR. REGAL: Jean Regal, University 21 of Minnesota Medical School, Duluth -- 22 immunotoxicology.

### 202-234-4433 Neal R. Gross & Co., Inc. Page 7 1 DR. WILLIAMS: Carmen Williams, 2 National Institute of Environmental Health 3 Sciences, and I'm a reproductive endocrine and 4 fertility specialist and reproductive tract 5 biologist. 6 DR. DELCLOS: Barry Delclos from 7 the FDA, National Center for Toxicological 8 Research, toxicologist. 9 DR. HORTON: Teresa Horton, 10 Department of Neurobiology and Physiology, 11 Northwestern University, Evanston, Illinois, 12 reproductive neuroendocrinology, maternal 13 fetal interactions and development of the 14 reproductive system and neuroendrocine system.

15 DR. AKANA: Susan Akana from the 16 University of California, San Francisco. I'm 17 a research physiologist with a specialty in 18 the stress axis and its interaction with 19 energy balance. 20 DR. O'BYRNE: I'm Kevin O'Byrne 21 from King's College London, the Department of 22 Anatomy and Human Sciences. And I'm a

### 202-234-4433 Neal R. Gross & Co., Inc. Page 8 1 reproductive physiologist. 2 DR. SELVAGE: Dan Selvage, Idaho 3 State University. I study stress and gonadal 4 hormones. I'm banished to the corner over

5 here.

6 SESSION CHAIR PORTIER: Dr. 7 Gilliom? 8 DR. GILLIOM: Bob Gilliom, U.S. 9 Geological Survey. And I am director of 10 pesticide studies for the National Water 11 Quality Assessment Program. 12 DR. COUPE: Richard Coupe, U.S. 13 Geological Survey. 14 DR. YOUNG: Linda Young, 15 Department of Statistics, University of 16 Florida. 17 DR. LEE: Herbert Lee, University 18 of California, Santa Cruz, Department of 19 Applied Mathematics and Statistics. 20 DR. REED: Nu-may Ruby Reed, 21 California Environmental Protection Agency. 22 I do pesticide risk assessment and risk

### 202-234-4433 Neal R. Gross & Co., Inc. Page 9 1 assessment issues.2 DR. FENNER-CRISP: Penny Fenner3 Crisp, private consultant, Charlottesville, 4 Virginia. My area of interest is toxicology 5 and risk assessment. 6 DR. GREENWOOD: Richard Greenwood 7 from University of Portsmouth in the U.K. I'm 8 a toxicologist, pesticides and environment. 9 DR. KRISHNAN: Kannan Krishnan, 10 professor and director of the Toxicology 11 Research Center of the University of Montreal, 12 Canada. My expertise is in pharmacokinetics 13 and risk assessment methods. 14 DR. HAYTON: William Hayton from 15 the College of Pharmacy at The Ohio State 16 University., professor of pharmacy. And my 17 area is pharmacokinetics. 18 CHAIR HEERINGA: Steve Heeringa, 19 the University of Michigan. I'm a 20 statistician for the Institute for Social 21 Research and I'm currently the Chair of the 22 FIFRA Science Advisory Panel.

### 202-234-4433 Neal R. Gross & Co., Inc. Page 10 1 SESSION CHAIR PORTIER: Thank you. 2 Dr. Selvage, I think after we do the public 3 comments we're going to move you around and 4 kind of give you a little room. We added two 5 more members since yesterday so -- as if it 6 wasn't tight enough. 7 Just to give you a little idea of 8 how we readjusted the agenda, we're going to 9 spend the first period this morning before the 10 break on the remaining EPA presentation. 11 Following the break we have six 12 groups of public commenters that have asked to 13 spend time. You have some documents added to 14 what was already in the docket. We'll take a 15 look at those during the break. I doubt if 16 we'll get through all the public commenters.

17 We have about three hours of 18 public comment, so we'll do two hours of that19 before lunch. We'll take an hour, hour-and20 fifteen-minute lunch, and then we'll come back 21 for public comments. And then we'll start on 22 the questions.

### 202-234-4433 Neal R. Gross & Co., Inc. Page 11 1 And even though we -- our agenda 2 says we'll stop at 5:00 we'll probably push it 3 a little bit to 5:30 -- maybe a quarter to 4 6:00 today to kind of capture a little bit of 5 the time we've lost. 6 And, with that, I'm going to turn 7 it over to Mr. Thurman to continue the -- 8 introducing the speakers for the water part. 9 MR. THURMAN: Okay. Where we're 10 going to go next is we presented two examples 11 in the white paper for you. And Mary 12 Frankenberry is going to give a presentation 13 on the use of bootstrapping methods to 14 evaluate how well different sampling frequency 15 estimate time average concentrations over 16 time. And then Mike Messner is going to talk 17 about how an application of artificial neural 18 networks to simulate pesticide concentration 19 patterns and how that might be applied. So 20 I'm going to turn this over to Mary. 21 MS. FRANKENBERRY: Thank you, 22 Nelson. As Nelson said, we'll be looking --

### 202-234-4433 Neal R. Gross & Co., Inc. Page 12 1 I'll be looking this morning at evaluating 2 sampling strategies for estimating maximum 3 concentrations of different durations. 4 And as we also said yesterday, we 5 talked about recent work by Crawford and 6 others that have evaluated the performance of 7 different sampling strategies for estimating8 the upper percentiles of true values -- so9 called true chemograph profiles -- and we'll 10 get into that a little more. 11 In the white paper that OPP did we 12 carried out two methods that were variations 13 on the Crawford bootstrapping approach, and 14 one of which I'll be presenting today. 15 Crawford's work created synthetic 16 true chemographs using linear interpolation to 17 augment less than daily sampling up to 365-day 18 profiles. OPP, however, chose three -- I'm 19 sorry -- 30 community water system where 20 Crawford looked at Heidelberg data. We chose 21 these CWS data. They were normally sampled 22 weekly or biweekly and augmented again to 365

### 202-234-4433 Neal R. Gross & Co., Inc. Page 13 1 days linearly. 2 The systems that we chose were 3 taken to be representative of most of the 4 systems -- AMP systems over the five years. 5 So they included some low, medium, and high 6 concentration systems. 7 While earlier work looked at the 8 upper percentiles of a single day 9 concentration, OPP is concerned with the 10 maximum value of several different durations 11 ranging from probably single day values all 12 the way up 90-day averages at the current 13 time. Similar to earlier methods, OPP looked 14 at the performance of different sampling 15 strategies for computing estimates of true 16 values for these maximum running averages. 17 Sampling was carried out using the 18 interpolated systems according to schedules 19 which ranged from quarterly sampling to 20 sampling every four days. We actually did put 21 in also a seasonal daily strategy where we 22 sampled every day during the season of April

### 202-234-4433 Neal R. Gross & Co., Inc. Page 14 1 through August. I think it was biweekly 2 beginning and ends of the year. 3 Each sampling strategy was 4 implemented with replacement over 4,500 times 5 following a random start. Each resample was 6 interpolated to 365 days, and then the maximum 7 single day, maximum three-day, and so on 8 average of each run was compiled with the 9 range and percentiles of these maximum values 10 reported. And we took this range of maximum 11 values and presented it against the true value 12 for each chemograph and the tables that will

13 follow. 14 This is just a matrix of our 15 sampling strategies versus the concentration 16 durations that we looked at. On the left 17 you'll see the sampling intervals going from 18 daily down to quarterly. I put in single days 19 up to 90-day averages here. But we also 20 looked at 14-day averages, I think 28- or 30- 21 day averages, 60-day averages as well. 22 Okay. Chemograph number 21 is

### 202-234-4433 Neal R. Gross & Co., Inc. Page 15 1 something -- well, I'll present some numbers 2 on that. But just to show you what it looks 3 like, it's an example of our middle group of 4 systems. It rises to its peak and then 5 declines somewhat slowly over the course of 6 several weeks. If you look at the notches on 7 the graph in the peak there those represent 8 weekly samples. So you'll see that the -- 9 from beginning to end of this peak that's 10 somewhere along the order of five to six

11 weeks.

12 These are tables of the numbers

13 that we ran for them. You can see the true 14 value for single daily -- a single day value15 sampled at either four-day intervals, seven16 day intervals, or 14-day intervals. The true 17 single day value for this chemograph was

18 31.25. 19 On the right-hand column here we 20 show how many times we actually captured that 21 mean in all of these 4- to 5,000 samples. And 22 actually it's kind of what you'd expect for

### 202-234-4433 Neal R. Gross & Co., Inc. Page 16 1 sampling every four days. We might catch it 2 once in four days or 25 percent of the time, 3 sampling every seven days about 14 percent of 4 the time, sampling every two weeks about 7 5 percent of the time.

6 If we look at the mean returns or 7 the mean runs on these resamples we see that 8 we were 4 to 5 percent lower than the true 9 value for sampling every four days. If we 10 sampled every seven days we were 7 to 8 11 percent lower on average, every two weeks 14 12 to 15 percent lower on average. We also show 13 the lowest runs, and they run from 11 up to 27 14 percent underestimating. But, clearly, the 15 performance is best if the sampling is more 16 frequent than less frequent. 17 That was the first graph -- or 18 table represented single day values. These 19 are seven-day average concentrations -- 20 maximum seven-day average concentrations for 21 the same chemograph. You can see that the 22 performance is a little better when we go from

### 202-234-4433 Neal R. Gross & Co., Inc. Page 17 1 looking at a single-day peak to a seven-day 2 average. On average we get between 2 and 3 3 percent below, between 5 and 6 percent below, 4 or between 13 and 14 percent below. 5 And up at the top we have 6 captured -- the top runs capture the maximum 7 fairly well. We're also starting to 8 overestimate it just a little bit as this9 average gets a little longer than the single10 day or the three-day average. 11 Just to summarize the results for 12 this, which really are consistent with the 13 results for all of the other systems, it 14 appears that accuracy, as you might expect, is 15 best for strategies which employ the most 16 frequent sampling. Accuracy generally seems 17 to improve for longer-term averages, that is, 18 seven days, 30 days, 90 days, over the shorter 19 term averages of single days or three days for 20 instance. 21 Here I'm going to show two other 22 peaks that are representative of two other

### 202-234-4433 Neal R. Gross & Co., Inc. Page 18 1 types of chemographs that we saw among those 2 that we looked at. Number 4 represents a 3 single narrow peak that is created and then 4 declined again in the course of two weeks. 5 And the values here go from a little bit over 6 zero up to 73 parts per billion. And this is 7 down close to 10.7 -- I think 11 parts per 8 billion one week later. And that -- those 9 differences are important when we look at how 10 well we do with sampling. 11 Next graph is simply typical of a 12 series of broad -- one broader series of 13 extended peaks -- and we have a number of 14 those. So we looked at examples of all of 15 these in the exercise that we ran. 16 Okay. This is a busy table -- and 17 I apologize. I took some things out of it 18 actually that you may find yourselves asking

19 about later. But these are the results for 20 the three-day average concentrations sampled 21 at four-day intervals. That's -- everything 22 was done in that manner.

### 202-234-4433 Neal R. Gross & Co., Inc. Page 19 1 This group at the top is the group 2 of thin, skinny peaks and the performance for 3 them. That's the average performance for four 4 of them if you look at the mean returns. 5 Middle group is the -- some middle medium 6 broad peaks. Bottom are the broad peaks. And 7 if you look at our mean returns we go from a 8 most underestimating by 9 percent, 4 percent, 9 and then down to less than 2 percent. We do 10 much better with the broad peaks. If you look 11 at the right-hand -- these two columns at the 12 90 -- 99.9 -- we've estimated the maximum with 13 virtually no error there. 14 Okay. Next slide. That was the 15 three-day averages sampled every four days. 16 This is three-day averages sampled daily 17 during the season, 14 days during the rest of 18 the year. And you can see the performance has 19 gotten even better as you might expect for 20 this kind of sampling. We're looking at, you 21 know, 2 to 3 percent underestimating in the 22 least performing group, 1 percent in the

### 202-234-4433 Neal R. Gross & Co., Inc. Page 20 1 middle group, and less than 1 percent 2 recaptured on mean returns here. The lowest 3 returns are -- have a little more 4 underestimation, but they're not too bad. 5 Up at the top again at least 50 6 percent of the time in 50 percent of the runs 7 we capture the maximum with no error, and 8 sometimes even higher -- 60 percent or more. 9 The final graph here is the -- 10 looks at 90-days averages for sampling every 11 seven days during the season, 14 days during 12 the remainder of the year. This is pretty 13 much the way the current AMP program is run

14 now. 15 And if we look at the mean 16 returns, again -- and in all of these the mean 17 and the median were very similar. So you can 18 call it either way if you want to look at 19 middle values and say half the time we're 20 higher than these, half the time we do less 21 well, all of these are less than 1 percent of 22 the true value here and we still capture the

### 202-234-4433 Neal R. Gross & Co., Inc. Page 21 1 maximum a large percentage of the time. 2 In terms of what we think these 3 indicate, well, as expected an end point with 4 a shorter duration will require more frequent 5 sampling than one with a longer duration to 6 capture corresponding monitoring values with 7 similar accuracy. 8 We think it also shows that the 9 current sampling scheme of weekly and biweekly 10 monitoring appears to perform adequately for 11 estimating 90-day averages with reasonable to 12 good accuracy. 13 Seasonally targeted sampling 14 strategies generally seem to perform better 15 than allocating samples equally throughout the 16 year. Sampling strategies appear to perform 17 differently according to the shape of the 18 chemograph, and because of this it might be 19 useful -- may not be practical. We're 20 considering it might be useful to examine the 21 shape properties of annual profiles and the 22 subset of systems with the highest peaks over

### 202-234-4433 Neal R. Gross & Co., Inc. Page 22 1 the years -- across the years. 2 And here we're looking at -- I 3 think Nelson might have shown this yesterday. 4 This table looks at these individual peaks, 5 not averages, above arbitrary cutoffs of 12 6 parts per billion, 20, 30 parts per billion. 7 To the right are the CWSes where these peaks 8 were found -- 12, 20, 30. And, of course, 9 these 30 and 20 are nested in the systems that 10 are over 12. And as -- of course, as we go 11 from lower to higher concentration we see 12 fewer systems involved.

13 We also have seen that across the 14 years many of these systems are the same; they 15 repeat. There are some different ones each 16 year, but there are some that are consistently 17 among the higher ones each -- from year to 18 year. 19 The other thing to point out is 20 that sample sizes here on the left -- they're 21 in the thousands year by year. Across year 22 they're in the tens of thousands. But when we

### 202-234-4433 Neal R. Gross & Co., Inc. Page 23 1 get to the individual system where we need to 2 do our risk assessments, it's system by system 3 year by year. What we're dealing with terms 4 of sample sizes here are 30 to 35 samples. 5 And that's I think something to keep in mind. 6 So, as a result, what we're asking 7 the Agency for certainly is feedback on 8 looking at the population of systems from year 9 to year. Can we do something with this 10 exercise we've just done? Is there anything 11 practical to do, and especially logistically? 12 But, frankly, our biggest concern 13 in terms of doing our assessments is on the 14 individual system level where we need to look 15 at missing values that result from less than 16 daily sampling. 17 So, by way of summary, results of 18 this preliminary exercise agree with Crawford 19 and others in pointing to smart sampling 20 strategies that can target both spatial and 21 temporal patterns among the CWSes. We think 22 that more intense seasonal sampling among

### 202-234-4433 Neal R. Gross & Co., Inc. Page 24 1 perhaps some of the higher concentration 2 systems in vulnerable areas might be a good 3 allocation of sampling resources and we'll be 4 seeking your feedback on that. 5 And Mike now will be talking about 6 a modeling approach to all of this if you 7 have -- after your questions. 8 SESSION CHAIR PORTIER: Questions? 9 Dr. Young? 10 DR. YOUNG: We saw each other up 11 in the hall, so I'll start kind of where I 12 left off. You know the probability of hitting 13 a peak is almost zero so -- as you go through 14 here. So you -- as you say, everything is as 15 you'd expect it. You're always 16 underestimating that maximum value. But there 17 are a whole host of literature on like extreme 18 value theory. Have you -- is there a reason 19 why you guys don't want to go that way? 20 MS. FRANKENBERRY: No. I think we 21 just haven't gotten to it. But I think that 22 what we did see -- and this is that -- while

### 202-234-4433 Neal R. Gross & Co., Inc. Page 25 1 we did not underestimate it on all of them the 2 highest runs did catch it. And they caught it 3 in percentages that you might expect. But 4 that's the next step. And that's a good 5 suggestion we're waiting to hear about. 6 MR. THURMAN: And, Dr. Young, 7 if -- in the report and such, if you could 8 provide us -- recommend some of those 9 literature we'd be happy to look at them. 10 DR. YOUNG: I just was -- you 11 know, just for information, I was wondering if 12 you guys had already looked at it and there 13 was a reason you were throwing it aside. 14 MS. FRANKENBERRY: No. This is 15 very preliminary -- 16 DR. YOUNG: Okay. 17 MS. FRANKENBERRY: -- and it's 18 mostly descriptive statistics as you see. 19 DR. YOUNG: Okay. Thanks.

20 SESSION CHAIR PORTIER: Dr. Lee? 21 DR. LEE: One minor concern on 22 what you did is, in developing your, quote,

### 202-234-4433 Neal R. Gross & Co., Inc. Page 26 1 true data sets you took the actual 2 observations and then interpolated them. If 3 you have a seven-day average -- you only have 4 observations every seven days on the water 5 sources that have very sharp peaks, like 6 number 4 that you presented and number 22 on 7 the white paper, you may be missing the actual 8 peak. And then the analysis you're doing -- 9 MS. FRANKENBERRY: To begin 10 with -- 11 DR. LEE: To begin with your 12 actual data may be missing the peak and 13 then -- so then this sort of analysis may be 14 further underestimating the actual truth --

15 MS. FRANKENBERRY: No. We 16 realized -- 17 DR. LEE: -- and that might be a

18 concern. 19 MS. FRANKENBERRY: -- that and this 20 was the best we could do in this kind of 21 thing. 22 SESSION CHAIR PORTIER: Yes, Dr.

### 202-234-4433 Neal R. Gross & Co., Inc. Page 27 1 Gilliom? 2 DR. GILLIOM: Well, I concur with 3 that last point, which it sounds like you guys 4 are already realizing that. But it could 5 have -- it's kind of the known/unknown problem 6 that -- was it Rumsfeld brought up. But 7 it's -- it's one -- it can really bias what 8 you end up with. 9 The other -- I guess a part of -- 10 kind of a question more than anything is the 11 implication of the range of time frames you 12 guys are investigating is that on your 13 radar -- and I think the implication of what 14 you want to have us on the radar for giving 15 you comment is that it's possible their very 16 short-term estimates should be within what 17 we're looking at. 18 So this may be a simple point, but 19 the implication is is it's possible that the 20 biological arguments are going to say short 21 term closure is important and we may need to 22 include in our design a way to pick up a daily

### 202-234-4433 Neal R. Gross & Co., Inc. Page 28 1 or one-week maximum type of thing. So that's 2 important for us to know. 3 MR. THURMAN: And that's exactly 4 why we're here. 5 DR. GILLIOM: Yes. Okay. And 6 then I guess related to that -- actually, you 7 know, I think -- I've got a couple of 8 questions related that I think are better to 9 come after we hear the stochastic. So I'll 10 defer and pass it on. 11 DR. COUPE: Richard Coupe. I just 12 wondered if the way the data are presented 13 here with the sharp peaks, medium peaks kind 14 of organizes itself along basin size or 15 intensity of agriculture within the basin. 16 MS. FRANKENBERRY: Along what? 17 I'm sorry. 18 DR COUPE: Along the lines of -- 19 so are these organized -- do they fall into 20 basin size, so sharper peaks, smaller basins, 21 or more intense -- 22 MS. FRANKENBERRY: Yes. I think

### 202-234-4433 Neal R. Gross & Co., Inc. Page 29 1 Crawford found that and we didn't go on to 2 look at that. But I'm sure that probably is

3 the case. 4 DR. COUPE: Yes. And his data you 5 looked at you saw that you could get better 6 statistics on the larger basins because they 7 had slower changing. 8 MS. FRANKENBERRY: Right. 9 MR. THURMAN: This is Nelson 10 Thurman. I just want to add, you know, as 11 we've done that analysis and found the trends 12 based on that I think there are some 13 general -- not just basin size but reservoir 14 versus stream intake. So I think those are 15 things we're looking at as ways of grouping

16 them. 17 DR. COUPE: Sure. I mean, there's 18 an awful lot to become interested in that. 19 And also in Crawford's day, you know, although 20 he went from different sizes they all had the 21 same percentage agriculture. In general 22 that's not true the larger the basin the less

### 202-234-4433 Neal R. Gross & Co., Inc. Page 30 1 agriculture you have. So you won't have the 2 same kind of distribution as you might have 3 with a smaller basin. Thank you. 4 SESSION CHAIR PORTIER: This is 5 Ken Portier. It's clear -- I just wanted to 6 clarify that it's clear that you feel like you 7 have enough information to be able to actually 8 stratify these -- the CWSes based on expected 9 profile or the variability of the profile 10 which you didn't take into account in the 11 simulation yet. Right? 12 But there is that feeling that you 13 might be able to say these are very variable, 14 these are ones that have one peak a year and 15 it's very consistent. We don't know when that 16 peak's going to occur. That's going to depend 17 on climate and agricultural practice. But we 18 usually expect one versus this one that could 19 have two or three or some years it's -- right? 20 So there's the opportunity for differential 21 sampling -- clearly differential sampling

22 there.

### 202-234-4433 Neal R. Gross & Co., Inc. Page 31 1 Any additional questions? Dr. 2 Krishnan? 3 DR. KRISHNAN: I just wonder if 4 you had calculated the areas under the curve. 5 Or like, you know, I see the rolling averages 6 doing a particular period, but have you done 7 area-under-the-curve calculations even -- the 8 same one applies to the presentation of 9 yesterday; you know, taking the points, 10 calculating the area under the curve as well 11 as the interpolated or the modeled ones, 12 because the error on the basis of the area 13 under the curve may not be the same as what we 14 were talking about here. 15 And eventually AUC could also be 16 the more relevant one depending on the -- you 17 know, how we're going to proceed further. 18 MR. THURMAN: This is Nelson 19 Thurman. I just wanted to add on that, I 20 think that's something we've considered, but 21 I think this is also going to be where the 22 toxicologists have to come into play with the

### 202-234-4433 Neal R. Gross & Co., Inc. Page 32 1 exposure folks to answer the questions, and an 2 area under the curve type exposure equivalent. 3 I mean, can we do it in that regard? And I 4 think that's one of the reasons why we've got 5 a diverse group here.

6 SESSION CHAIR PORTIER: Dr. 7 Heeringa? 8 CHAIR HEERINGA: I'd like just to 9 second that point. I think that's something 10 that I struggled with a little bit yesterday 11 afternoon, and I think it's going to be an 12 issue. Clearly, if we're down to daily 13 averages or even three-day averages, it may 14 not make that much of a difference. But if 15 you go out to longer periods that profile -- 16 that profile, which again, area under the 17 curve may not even capture the profile because 18 you could have several profiles that generate 19 the same integral. 20 But I think that's something for 21 us to keep in mind. And is it really acute 22 exposures? Is it sort of medium-term semi-

### 202-234-4433 Neal R. Gross & Co., Inc. Page 33 1 acute exposures? Or is it longer term -- 90 2 day -- maybe even 90 days isn't chronic, but 3 it's more exemplary of a long-term exposure 4 through the water system. So I think that's 5 important for us to keep in mind over the next 6 two days. 7 SESSION CHAIR PORTIER: Any 8 additional questions? 9 (No response.)

10 SESSION CHAIR PORTIER: Doesn't 11 look like it. We can move on to the next 12 presentation. 13 Okay. Dr. Akana? 14 DR. AKANA: I just have a minor 15 question. In my mind what I imagine visually 16 is you have a map of the United States. And 17 on it we saw the blue map with the blue dots. 18 Okay. 19 If you take that map -- okay -- 20 and overlay it on the map with rainfall and on 21 top of that another map with basin, reservoir 22 size, and running water, can you factor an

### 202-234-4433 Neal R. Gross & Co., Inc. Page 34 1 algorithm through 3D -- through the 3D map? 2 MR. THURMAN: Actually, the blue 3 you saw took into account use, rainfall, 4 watershed size -- it took into account a 5 number of those factors which is how we got to 6 that map in the first place. So, yes, it can

7 be done. 8 DR. AKANA: So you have a massive 9 algorithm that just percolates everything 10 through.11 MR. THURMAN: It was a regression12 based analysis, but it did take into account 13 the factors that on a national scale were 14 driving exposures. What we've learned in the 15 separate monitoring study I mentioned, the 16 ecological exposure monitoring study, is that 17 there are also localized factors that start 18 helping to explain the differences we're 19 seeing in exposures even within that most 20 vulnerable area. So those are things that 21 we're looking at and exploring. 22 Separately from this but will tie

### 202-234-4433 Neal R. Gross & Co., Inc. Page 35 1 into this in terms of how can we zoom in maybe 2 in a corn belt scale and take into account 3 those additional local factors. 4 SESSION CHAIR PORTIER: Susan, the 5 panel looked at that. Was it October or 6 December last year? We went through a lot of 7 that on the ecological one. If you can look 8 at the SAP minutes on that you'll see that 9 it -- actually it's another level above what 10 you were talking about that they've actually

11 done. 12 MR. THURMAN: It was actually May 13 of last year. 14 SESSION CHAIR PORTIER: Was it 15 May? 16 MR. THURMAN: So it's been almost 17 a year. 18 SESSION CHAIR PORTIER: Time 19 flies. It seems like I was here yesterday. 20 MR. MESSNER: My name's Michael 21 Messner. I'm a statistician in the Office of 22 Groundwater and Drinking Water. And I'm going

### 202-234-4433 Neal R. Gross & Co., Inc. Page 36 1 to speak about one use of a -- of artificial 2 neural network modeling. I'm going to 3 describe the mathematical formula of this 4 particular kind of artificial neural network 5 model. Then I'm going to show how it can be 6 fit to some atrazine occurrence data. 7 Then I'm going to show how this 8 model can be used to simulate different -- not 9 just different patterns but different levels 10 of atrazine occurrence to assess the 11 performance of some strategies -- in other 12 words, combinations of monitoring plans and 13 decisions based on the monitoring data. 14 Finally, I'll provide a table with some pros 15 and cons of the artificial neural network 16 modeling. 17 My presentation's going to differ 18 from Mary's in two ways. One is the kind of 19 model that I'm using -- the neural network 20 model. The other way though is the way the 21 model's used to assess performance. And I'm 22 kind of wishing I had a pros and cons table on

### 202-234-4433 Neal R. Gross & Co., Inc. Page 37 1 this. I think it's maybe something you're 2 going to be struggling with. 3 And that is where Mary described 4 how the use of statistics and the probability 5 that a statistic would capture a true 6 parameter value -- a true percentile -- my 7 focus is going to be on the decision making 8 using the data to decide that we have a 9 positive or a negative -- sort of like do we 10 put a star on one of those bar charts you 11 looked at yesterday. So my focus is the 12 assessing the probabilities of false positives 13 and false negative. So that's a different way 14 of looking at performance. 15 This is one flavor of artificial 16 neural network model. The ugly looking 17 equation here at the top describes a moving 18 average of log concentration values. The 19 first term here on the right, b0, is an 20 intercept that sets the baseline occurrence -- 21 that is, before any of the other fractions 22 here begin to take effect.

### 202-234-4433 Neal R. Gross & Co., Inc. Page 38 1 Each fraction is called a node. 2 And a node can describe either an increase or 3 a decrease in the atrazine concentration. So 4 if you take the first fraction here and let it 5 describe an increase and then later on a 6 second fraction describes a decrease, together 7 they describe a peak in occurrence. So this 8 particular formula with four of these 9 fractions or nodes can very easily describe a 10 double peak during a source water's year of 11 atrazine occurrence. 12 So with -- if one can understand 13 what these different parameter values mean, 14 one can construct a formula here that will 15 mimic atrazine occurrence. And then with 16 particular values for these 12 parameters here 17 and also with the precision parameter that 18 describes how the measured values can depart 19 from the moving average. We can calculate the 20 log likelihood. I guess you could think of it 21 either as the likelihood of the data given the 22 parameters or the likelihood of the parameters

### 202-234-4433 Neal R. Gross & Co., Inc. Page 39 1 given the data. 2 But with that in hand, there are 3 number of programs -- a number of algorithms 4 one could use then to optimize that -- to 5 maximize the log likelihood and find the best 6 fitting parameter values. 7 All of these routines requires 8 though that you first have a decent initial 9 value. So this just shows how I went about 10 finding initial values for atrazine data from 11 the Maumee River in 1998. I think this -- was 12 this an ecological data set that you provided? 13 Heidelberg? Ambient water. Okay. 14 There are a lot of daily 15 measurement values here in the middle part of 16 the year. These out here I think are every

17 two weeks or so. 18 So the way I went about fitting 19 this was first to say, okay, I'm going to let 20 the intercept -- the b0 term -- be this value 21 here. And then I wanted to have an increase 22 occur at this time of the year. I wanted the

### 202-234-4433 Neal R. Gross & Co., Inc. Page 40 1 increase to be just so big and so fast that it 2 sort of fit the data. I'm just doing this 3 using my eyeball. Okay? And to my eye that 4 looks like an awfully good fit. 5 Next I attacked the parameters in 6 the second node and adjusted those until they 7 kind of fit this downturn here. Then I added 8 the parameters for the third node so that I 9 had this increase occurring at that time of 10 the year. And finally the fourth node 11 described this decrease bringing the atrazine 12 level back down. Now, that's not perfect. 13 That's just an eyeball kind of fit to the data 14 which gave me some initial values for those 15 algorithms to do their thing. 16 This is the result. This is a 17 maximum likelihood model. It's actually a

18 three-node model rather than a four-node 19 model. And you can see that it does a very, 20 very nice job of following the data. 21 The way the three-node model 22 works -- it's a little harder to understand

### 202-234-4433 Neal R. Gross & Co., Inc. Page 41 1 the parameters in the three-node model. The 2 first node causes this increase here. The 3 third node causes this increase here. And the 4 second node actually causes the decrease that 5 you see spanning the time from here to about 6 here. So there's just one node that's sort of 7 describing both of those drops in atrazine 8 concentration. 9 I like this model because it 10 provided -- in terms of log likelihood it 11 provided this sort of the same quality of fit 12 as the four-node model with fewer parameters. 13 And the appearance is a little nicer. There 14 was something funny going on in here with the 15 four-node model. So this was a nice maximum 16 likelihood model. 17 How do I go backwards? Okay. One 18 thing a little bit odd here is there are 19 couple of periods of time where there's a 20 string of four or five values -- maybe more 21 than four or five -- in a row that appear 22 either above or below the curve. And I was

### 202-234-4433 Neal R. Gross & Co., Inc. Page 42 1 concerned that maybe that's a little more than 2 would occur by chance if each day's value was

3 sort of a -- had random error about the curve. 4 So I looked at the residuals and I 5 also looked at something called an 6 autocorrelation function. This figure here 7 plots the autocorrelation function. This is 8 called a correlogram, and you can there's a 9 sort of a cosine -- dampened cosine shape to 10 this that is characteristic of what's known as 11 an AR2 model. So I wanted to build in this 12 kind of autocorrelation. 13 This isn't the way one day's 14 concentration is dependent on the previous 15 day's so much as it is the way one day's 16 departure from expected is related to the 17 previous day's departure from expected. 18 So if you think of that artificial 19 neural network, the smooth curve, as 20 describing the expected log concentrations on 21 different days, what I'm talking about here 22 are the departures from that curve -- that

### 202-234-4433 Neal R. Gross & Co., Inc. Page 43 1 there's still some autocorrelation going on 2 from day to day that you can't explain with -- 3 you know, as ugly as that model is it still 4 doesn't quite account for everything that we 5 might want to account for.

6 So I found that of all the AR 7 models, AR2 did turn out to be the best 8 fitting. These two parameters here tell how 9 a day's departure from the expected value -- 10 that is, from this equation -- are related to 11 the previous day and two days previous. So 12 today's departure would be -- 38 percent of it 13 would be -- or .38 times yesterday's departure 14 plus about .2 times two days' ago departure 15 would be added to some random error for today 16 to produce today's departure from expected. 17 So with those two additional parameters we can 18 explain this additional autocorrelation

19 feature of the data. 20 Okay. So given those model 21 parameters we can drive some summary 22 statistics. We can calculate the mean, the

### 202-234-4433 Neal R. Gross & Co., Inc. Page 44 1 median, we can calculate other percentiles of 2 interest if those are things that you care

3 about. 4 But what if we're concerned about 5 making decision errors when the occurrence is 6 either much higher or much lower than is given 7 by that particular model? Now, this is -- I'm 8 just going to pause right here. One thing we 9 could do with the parameter values is we could 10 estimate the concentrations on days where we 11 don't have data -- we could do things like 12 that. We could provide credible intervals, 13 say, for those concentrations. We could 14 provide credible intervals for these things, 15 the mean concentration, the median 16 concentration. 17 But the interest here -- I'm not 18 going to go down that path. Rather, I'm going 19 to be talking about how to use this particular 20 model to study how different monitoring 21 strategies behave. So if we just accept that 22 this model is true and that we care about

### 202-234-4433 Neal R. Gross & Co., Inc. Page 45 1 occurrence when it behaves this way, we're 2 going -- I'm going to use this model to 3 evaluate how different monitoring strategies 4 behave. Okay? 5 I sense the statisticians in the 6 group might want to see uncertainty intervals 7 about the parameter estimates -- Markov chain 8 Monte Carlo samples. But, I'm sorry, but 9 you're not going to see those things. 10 If we take the model with those 11 parameter values and simply add a constant to 12 that intercept term we preserve the shape of 13 the occurrence pattern and we just -- we 14 simply are changing the scale of it. 15 If the constant that we add is 16 negative then the result is a lower overall 17 level of occurrence. If K is positive then 18 adding it will increase all of the 19 concentration values. The mean, the median, 20 and other percentiles of interest are all 21 going to change by the same factor. 22 The error structure remains the

### 202-234-4433 Neal R. Gross & Co., Inc. Page 46 1 same. The shape of the occurrence 2 distribution also remains the same. The only 3 thing that we're doing is changing the overall

4 occurrence level. 5 This next figure shows two 6 simulations, both with the same random number 7 seed but with different intercept values. And 8 you can see they're identical except for the 9 scaling of the vertical axis. I've drawn a 10 red line here at the 99th percentile given 11 this model. And in one case here on the right 12 the 99th percentile is 10, and on the left 13 it's 25. So there's a factor of two and a 14 half difference. Each point here on the left 15 is two and a half times as high as each point 16 on the right. 17 So if decision makers were 18 concerned about making a negative decision, 19 say, failing to take action given this kind of 20 occurrence pattern, we could simulate with 21 this model -- simulate many years of 22 occurrence to estimate the false negative

### 202-234-4433 Neal R. Gross & Co., Inc. Page 47 1 rate. Similarly, if the decision makers 2 consider this to be a low occurrence pattern 3 and level we could simulate a year of 4 occurrence like this many, many times to 5 estimate the probability of the false 6 positive. 7 We could do this, say, 10,000 8 times if we wanted to get good estimates of 9 those error rates. And we could repeat this 10 using different levels of our trigger or our 11 critical value to see how the probabilities of 12 those decision errors depend on the decision

13 rule. 14 This figure shows how the 15 probabilities of false positives and false 16 negatives play against each other as the 17 critical value for determining a positive is 18 increased from zero here to some high value. 19 If we set the critical value very high this 20 could be like a -- this value could be a limit 21 for, say, the maximum measured value or the 22 sample mean or the second highest -- whatever

### 202-234-4433 Neal R. Gross & Co., Inc. Page 48 1 your test statistic is. 2 If it's high -- if your critical 3 value is high you'll be controlling the false 4 positive rate fairly well, but the price 5 you'll pay is a higher false negative error 6 rate. If you lower the critical value you'll 7 find that you increase the false positive rate 8 while decreasing the false negative rate. 9 Now, this curve sort of shows 10 there's a sweet spot in the middle around 11 about 10 percent. If you could tolerate 10 12 percent false positive and false negative 13 errors you might like a critical value here in 14 the middle. I don't want to suggest that 15 that's where the answer should be. It may be 16 that when you think about consequences of 17 decision errors you may be much more concerned 18 with one kind of an error than another, and 19 that -- what appears to be a sweet spot in the 20 middle might not be acceptable. 21 But my message here is that we can 22 use these kinds of models and these kinds of

### 202-234-4433 Neal R. Gross & Co., Inc. Page 49 1 simulations to get an understanding of how a 2 strategy in a decision rule can perform so 3 that a strategy can be selected with open 4 eyes -- with an understanding of what these 5 error probabilities are. 6 So what often happens is that we 7 can't find a spot where we can craft a 8 decision rule that satisfies both constraints 9 for false positives and false negatives. This 10 almost always happens in my experience. We 11 find that decision makers can't tolerate the 12 idea of errors of any sort and they'll 13 initially want very small probabilities of 14 false positives and false negatives. And we 15 find that we can't achieve that without, say, 16 millions and millions of samples. 17 And so some back and forth is 18 required asking decision makers, well, what 19 can you really live with and what can really 20 be afforded in terms of sampling. Maybe we 21 can afford hundreds of samples or maybe we can 22 afford to challenge thousands of rats in a

### 202-234-4433 Neal R. Gross & Co., Inc. Page 50 1 dose response study. But it's normal to have 2 this back and forth to arrive at a design that 3 one can live with. 4 So, in summary, artificial neural 5 network models are one kind of artificial 6 neural network model, but it's showing you it

7 can be used -- I'm sure there are others. 8 There are also other time series models that 9 can be used to characterize these occurrence 10 patterns and simulate occurrence patterns that 11 are of concern to decision makers -- simulate 12 low occurrence patterns, low levels for which 13 there's concern for the false positive, also 14 simulate high levels where there's concern for 15 the false negative. 16 We can simulate high variability 17 patterns and low variability patterns -- 18 simulate levels and patterns that are of 19 concern to the decision makers and use this to 20 assess candidate monitoring strategies for 21 their ability to satisfy the requirements for 22 false positive and false negative error rates.

### 202-234-4433 Neal R. Gross & Co., Inc. Page 51 1 Here I've listed some of the 2 advantages and disadvantages of the artificial 3 neural network models. At the top on 4 disadvantage I listed the complexities. It 5 can be difficult to understand the parameters. 6 A key advantage is that they can be very 7 flexible and they seem to do a nice job of 8 representing realistic occurrence patterns for 9 atrazine.

10 I've left some blanks here. You 11 all can read these yourselves. I'm sure you 12 have -- you can think of additional pros and 13 cons for this type of modeling. And I'll just 14 stop there and leave those blanks and 15 encourage you to add to those lists. 16 SESSION CHAIR PORTIER: So, Dr. 17 Lee, first question. 18 DR. LEE: I think this was a very 19 nice use of neural networks. Let me start 20 with a technical question. Did you look at 21 the autocorrelation plot for the four-node 22 network that you fit?

### 202-234-4433 Neal R. Gross & Co., Inc. Page 52 1 DR. MESSNER: I don't think I did. 2 DR. LEE: Because I suspect there 3 will be much less autocorrelation there -- 4 possibly none or close enough to none. The 5 four-node one -- I think this is the first 6 time I've had to try to convince someone to 7 use more nodes. Usually it's going the other 8 direction, trying to convince someone they're 9 using way too many nodes and it's not going to 10 predict well. 11 Particularly in this case where 12 you're trying to look for potentially a peak 13 or a very short-term average. The three-node14 model is smoothing a lot more than the four15 node model. And I suspect you'll get better 16 results if you look at the four-node model in 17 this case rather than the three-node model. 18 It's going to fit much more tightly. 19 And one of the things is that sort 20 of the shape of a peak that you can 21 estimate -- the more nodes you use the more 22 variability you can get in different types of

### 202-234-4433 Neal R. Gross & Co., Inc. Page 53 1 shape of peaks you can fit. And so by 2 restricting yourself to three nodes you're 3 forcing a more particular shape of peak that 4 doesn't quite fit the data as much. And for 5 sort of a longer term average that's fine, but 6 if you're looking at a very short-term average 7 or a peak that's going to make a bigger 8 difference. And so I suspect you can get even 9 better results here with a four-node network. 10 And I can put some additional comments in the 11 minutes about model selection there. 12 DR. MESSNER: In the paper I 13 describe another data set that I modeled using 14 a two-node model. And interestingly I found 15 that an AR1 model fit quite well for that even 16 though it has fewer nodes than this.

17 SESSION CHAIR PORTIER: Dr. 18 Heeringa? 19 CHAIR HEERINGA: Thank you for 20 that presentation. One question for you and 21 then one for Nelson. In these models is there 22 any way to incorporate prior -- I know it's in

### 202-234-4433 Neal R. Gross & Co., Inc. Page 54 1 your notes -- prior year information? In 2 other words, if we assume that these community 3 water systems had a response profile that was 4 dependent on intake and volume of water and 5 sources of water I would expect if peaks occur 6 they would subside with some type of profile 7 that may be unique to that water system. If 8 you had data like that how would you factor 9 that into this model? 10 DR. MESSNER: What I'd really like 11 to have first is an expert that I could sort 12 of interview. I would wonder is it -- do you 13 really expect only one peak? Would you expect 14 two peaks? How many peaks would you expect in 15 a year? I imagine that would depend on things 16 like rainfall, and I think it would be very 17 difficult to interview an expert and extract 18 from that expert prior knowledge about these 19 things. 20 But I suppose you could do it. 21 And if you had many years of data also for 22 that particular source water you could perhaps

### 202-234-4433 Neal R. Gross & Co., Inc. Page 55 1 roll all that together. This sort of speaks 2 to my third disadvantage here, year-to-year 3 variability. That's a lot of parameters, and 4 the hierarchal structure -- it would be really 5 fun to try, but I think it would be very 6 difficult. What's your feeling on that, Dr.

7 Lee?

8 DR. LEE: Neural networks are 9 really not the best model to try to 10 incorporate the year-to-year variability. It 11 probably could be done, but it would be really 12 difficult. I think you'd probably find better 13 success with like the kriging-type approach 14 that's also discussed in there or some other

15 sorts of models. 16 CHAIR HEERINGA: Second question

17 was for Nelson. I -- what data do we have 18 available? We know for a select set of 19 community water systems that we have the 20 registrant's data that's been provided as 21 being provided for the 90-day average. And 22 are there other sources in terms of the

### 202-234-4433 Neal R. Gross & Co., Inc. Page 56 1 national water quality programs that produce 2 periodic or annualized estimates of atrazine 3 concentration for community water systems, 4 say, in atrazine use areas? What data could 5 we expect to have across the various sources? 6 MR. THURMAN: Well, NAWQA hasn't 7 really focused on community water systems. 8 They focus on ambient waters, some of which 9 are similar to what you would see in community 10 water systems. They focused on flowing water. 11 So for streams they have places where they 12 have monitored years to year-to-year that you 13 can start to get that. 14 This particular data set that we 15 have now on the community water systems, which 16 is a range from 130 to 150-some systems -- 17 several of those we've got probably at least 18 five years of data that we can start looking

19 at. 20 Now, some of those systems have 21 been monitored historically back years longer

22 before that that we could also take a look at.

### 202-234-4433 Neal R. Gross & Co., Inc. Page 57 1 Some of it would be going back to -- you know, 2 part of the challenge is -- we've also in some 3 of these areas we now have the ability to 4 getting at land use patterns that change year 5 to year over the watersheds, probably more in 6 some of the more recent years than in previous 7 years. So we can start taking a look at that.

8 The one data set that comes to 9 mind that has a whole lot of years of history 10 is the Heidelberg University data set. That 11 is something that we're also going to take a

12 look at. 13 SESSION CHAIR PORTIER: I've got 14 the next question -- Ken Portier. Can you 15 slide back to your best-fitting ANN model 16 picture? I just had a couple of questions on 17 the best fit. So if we're interested in the 18 maximum annual concentration -- right? -- your 19 model underestimates that. And that was one 20 of the reasons you do a -- what is it? -- 21 k0 -- or b0 shift. If you shift it up you 22 could do a better job -- that one -- do a

### 202-234-4433 Neal R. Gross & Co., Inc. Page 58 1 better job of estimating that overall maximum. 2 Right? 3 DR. MESSNER: I don't think I'd 4 put it that way. The reason I was adjusting 5 that intercept was to be able to simulate

6 occurrence levels that are of concern to the 7 decision makers, not to provide a better 8 estimate of the maximum. 9 With -- so if we think of a year 10 as being -- say, this data set is being -- if 11 we could measure every day of the year we

12 would have 365 measurements -- some of them 13 may be missing here -- we could use this model 14 to estimate some missing values -- some 15 concentrations on days that weren't measured. 16 So that's something that could be done 17 pretty -- it would be pretty straightforward 18 using this model, but it wasn't what I was 19 interested in. 20 SESSION CHAIR PORTIER: I guess I 21 see a lot of uses for the model. If you're 22 moving b0 up and down what does that do to the

### 202-234-4433 Neal R. Gross & Co., Inc. Page 59 1 lowest level? Does that shift the whole 2 profile down? 3 DR. MESSNER: Yes. Everything is 4 increased by the same factor.

5 SESSION CHAIR PORTIER: Because 6 your model fits well where there's stuff 7 happening. But if you look on both tails at 8 the BDL levels you're not fitting very well at 9 all -- right? -- because you don't put very 10 much weight on the winter -- I guess it would 11 be the winter time periods -- right? -- 12 where -- I mean, if you look at this point 13 over here you've got a whole bunch of -- you 14 know, three or four levels of zero -- 15 right? -- close to -- below detection limit or 16 near detection limit data that the model 17 doesn't fit very well. 18 DR. MESSNER: Right. Of course, 19 we're not terribly concerned about how --

20 SESSION CHAIR PORTIER: Concerned

21 about those. 22 DR. MESSNER: -- high those values

### 202-234-4433 Neal R. Gross & Co., Inc. Page 60 1 might be. But the likelihoods actually are 2 fairly decent for those sensitized -- 3 SESSION CHAIR PORTIER: And it's on 4 a low scale and they're very small. The other 5 thing is your 99th percentile line -- does 6 that take into account these BDL values here?

7 DR. MESSNER: Yes. When I use 8 this model to estimate a 99th percentile or a 9 95th percentile I'm --

10 SESSION CHAIR PORTIER: 11 Integrating? 12 DR. MESSNER: -- integrating and 13 summing over the 365 days of the year. And so 14 it's not the percentile for this particular 15 year, it's actually a percentile for the 16 model. So if I could simulate 10,000 years 17 the percentile for that simulation, let's say, 18 would be very, very, very, very close to what 19 I get by integrating and summing across the 20 days of the year for the model.

21 SESSION CHAIR PORTIER: You talked 22 about credible intervals. Is it possible with

### 202-234-4433 Neal R. Gross & Co., Inc. Page 61 1 this model to establish a credible interval of 2 time above a certain threshold? So if I were 3 to pick this curve and say I want to know the 4 time above zero -- log -- whatever -- on this

5 scale -- 6 DR. MESSNER: Right. So -- 7 SESSION CHAIR PORTIER: -- can you 8 estimate that time period -- how many weeks, 9 how many days -- 10 DR. MESSNER: So, if like you were 11 to tell me that we want to know what fraction 12 of the time the levels above ten parts per 13 billion? 14 SESSION CHAIR PORTIER: Right.

15 DR. MESSNER: Yes. I could tell 16 you what percent of the time with this model 17 I'd expect the concentration to be above that 18 level. And, again, we're talking about 19 percent of the days.

20 SESSION CHAIR PORTIER: Yes. 21 Because -- I mean, one of the things we heard 22 yesterday is they may not be the maximum

### 202-234-4433 Neal R. Gross & Co., Inc. Page 62 1 concentration. They may be how many days a 2 person is exposed above a certain threshold. 3 So if I'm drinking the water and I'm drinking 4 it for four weeks at above 10 parts per 5 mission that may cause the health effect. And 6 so I'd want to know for this site what's the 7 probability it's going to be more than ten 8 weeks or more than five weeks. That's turning 9 the model backwards. It's the inverse -- 10 DR. MESSNER: Yes. Estimating the 11 percent of days above a level is very easy to 12 do. What's difficult to do and requires 13 simulation is estimating how many years -- 14 during how many years one would have, say, 15 consecutive days above a level. That's -- 16 SESSION CHAIR PORTIER: But it can

17 be done. 18 DR. MESSNER: -- something that can

19 be done -- 20 SESSION CHAIR PORTIER: It may be 21 difficult --

22 DR. MESSNER: -- but --

### 202-234-4433 Neal R. Gross & Co., Inc. Page 63 1 SESSION CHAIR PORTIER: Yes. 2 DR. MESSNER: -- you know, I sort 3 of cringe at the thought of programming that.

4 SESSION CHAIR PORTIER: Dr. 5 Gilliom. 6 DR. GILLIOM: As you've applied it 7 for evaluating sample strategies the value of 8 any of these interpolation models basically 9 producing an estimate of the true population 10 is -- it depends on how well it estimates 11 truth basically. 12 And when you have a really dense 13 data set, like almost every day like the 14 Heidelberg data, you're probably -- I mean, 15 frankly, you're probably better off just 16 connecting the dots because you've actually 17 then included these maximums that we're 18 worried about. You don't have to worry about 19 smoothing distorting things or anything. 20 And then, on the other hand, if 21 you apply the same method to sparser data then 22 you've got a severe problem with whether you

### 202-234-4433 Neal R. Gross & Co., Inc. Page 64 1 can replicate truth because you're missing so 2 many true events. So you're kind of in a fix

3 there. 4 So I think ironically for dense 5 data sets you can use the method to get a 6 pretty good quantitative tool for producing 7 test data sets for evaluating sample 8 strategies. And then, on the other hand, when 9 you get to all the more normal circumstances 10 we have it's got the problem of not being able 11 to fill things in because it's not related to 12 predictor variables that have connection to 13 what's really going on in the field, like used 14 patterns and precipitation events and all that 15 which are what's really creating the extreme

16 events. 17 So I guess what I'd like to see in 18 the direction of thinking when we're looking 19 at how to simulate reality for the purpose of 20 these sampling experiments is to get an 21 approach that takes into account the maximum 22 we can about cause and effect variables that

### 202-234-4433 Neal R. Gross & Co., Inc. Page 65 1 actually simulate the type of distributions we 2 expect in reality. 3 And I think that direction would 4 give us a better foundation for defending how 5 it is and give you more reality in what the 6 concentrations are and incorporate error 7 better and yield a better sampling design. 8 SESSION CHAIR PORTIER: This is Ken 9 Portier. Kind of like filling in the blanks 10 with knowledge rather than just kind of 11 interpolating or smoothing is really what 12 you're talking about. Linda -- Dr. Young? 13 DR. YOUNG: Yes. Just kind of a 14 follow up on the whole discussion I think 15 because this what's bothering -- this is -- 16 what's been bothering me is kind of in the 17 same realm. How many -- you're heavily 18 relying on getting a very dense data set to do 19 this -- right? -- to really get a good fit for 20 your ANN model. Right? 21 DR. MESSNER: I'll say yes. There 22 are many parameters here and it takes a lot of

### 202-234-4433 Neal R. Gross & Co., Inc. Page 66 1 data to get good estimates when you have so 2 many parameters. But, on the other hand, 3 personally what I'm concerned with is trying 4 to model something that causes concern for the 5 decision maker -- something realistic such 6 that if this were the true case -- if you 7 really had a system that behaved like this 8 you'd be concerned about either false 9 positives or false negatives. 10 So I like it to be realistic, but 11 I'm finding I don't care so terribly much 12 about explaining a particular data set and 13 making predictions for a particular stream. 14 DR. YOUNG: So the key seems to be 15 to be able to get -- if that's the philosophy 16 then to get a series of what seems to be a 17 range of profiles that you might want to do. 18 And then -- and if you do that then you

19 have -- then I'm not sure the value of the 20 model. I mean, once I begin to do that the

21 connect the dots does seem to be a reasonable 22 thing.

### 202-234-4433 Neal R. Gross & Co., Inc. Page 67 1 So I -- so at one point I thought 2 you were going to try to do this for each 3 community water system. But you're not. 4 You're just going to look at a range of these 5 types of things. Right? 6 DR. MESSNER: Perhaps. 7 DR. YOUNG: Okay. I'm just trying 8 to get where you're coming from. 9 SESSION CHAIR PORTIER: This is Ken 10 Portier. I was thinking the same thing as Dr. 11 Young was and realizing you have 13 plus three 12 parameters -- what is that? -- 16 parameters 13 and the average data set has 36 data points, 14 many of which are in the no-detect winter 15 range. Right? So you're down to almost a 16 data point per parameter.17 And you're trying to fit a two18 point autocorrelation structure, and you start 19 getting missing values and you just can't -- 20 so the model, while nice mathematically -- we 21 love it, and it's pretty. When you've got a 22 lot of data, it's nice. When you have -- you

### 202-234-4433 Neal R. Gross & Co., Inc. Page 68 1 start getting missing data and low counts, 2 you're starting to have faith rather than

3 data. 4 Yes, Dr. Lee. 5 DR. LEE: If I could actually just 6 respond to that briefly. Known networks have 7 a particular structure such that the effective 8 number of parameters tend to be smaller than 9 the actual number of parameters. So you don't 10 necessarily need quite the same multiplier of 11 data points to parameters as you would in, 12 say, a standard regression model. 13 And you can get fairly -- I mean, 14 you wouldn't need, say, this dense a data set 15 to get a fit like this. Just sort of 16 eyeballing it, guessing -- certainly I think 17 if you had a quarter as many data points, you 18 could still get it pretty much the same fit. 19 I don't know how the fit would change beyond

20 that. 21 DR. YOUNG: But the point would be 22 that you'd probably miss some of those peaks,

### 202-234-4433 Neal R. Gross & Co., Inc. Page 69 1 which is really what you want. So as soon as 2 you start doing that, yes, the fit's good to 3 what you saw, but you didn't see what you

4 wanted to see. 5 SESSION CHAIR PORTIER: Well, I 6 think the statisticians have had their fun

7 here. 8 Mr. Thurman, we'll send it back to 9 you for a summary. 10 MR. THURMAN: Okay. Actually, I 11 was having fun too. All right. What I'm 12 going to try to do is bring this back to -- 13 all right -- what are we going to do with this 14 stuff. As Anna Lowit said yesterday, when the 15 rubber hits the road how are we going to use 16 this, so that when you folks are commenting on 17 our questions you kind of know where we're 18 coming from and where we're hoping to go on

19 that. 20 Let's start with what we know and, 21 hopefully, I can even fill in some of the 22 holes or questions that maybe didn't answer as

### 202-234-4433 Neal R. Gross & Co., Inc. Page 70 1 well. Earlier -- we know pesticide 2 concentrations in water varies both spatially 3 and temporally. We're operating under the 4 feeling that the variability you're going to 5 see spatially and temporally outweigh the 6 other variability you'll see in sampling and 7 analytical. 8 And there may be -- I mean, I 9 think in general we believe that's true. If 10 there are more exceptions to that then, 11 General, I'm sure the USGS folks who have a 12 lot more experience in that are going to tell 13 us that and we can take that into account. 14 But that's where we're operating right now. 15 We have -- and particularly for 16 those of you who have been on the SAP a year 17 ago and then those two years before that, 18 we've been doing a lot with the ecological 19 exposure monitoring wrapping our minds around 20 the spatial variability and how do we capture 21 that and how do we use that to particularly 22 focus on the areas where we think there's

### 202-234-4433 Neal R. Gross & Co., Inc. Page 71 1 going to be more exposure concerns. 2 For this particular drinking water 3 assessment with atrazine we're zooming in on 4 community water systems that happen to be in 5 those areas that spatially are having a high 6 exposure history. And so we're looking at the 7 temporal pattern -- how do we get at the 8 temporal pattern. 9 And, now, we know when you start 10 looking at timing and frequency of sampling it 11 has to take into account that temporal 12 pattern. But it also needs to keep in mind 13 what is our exposure duration of concern. We 14 have a monitoring data set that for these 15 community water systems that took weekly 16 samples during the use season to characterize 17 a 90-day exposure. And that's -- and we think 18 that's been working pretty well for what we're 19 doing. 20 If we end up with a shorter 21 duration of exposure how well does that data 22 work for us? How well can we use it? What --

### 202-234-4433 Neal R. Gross & Co., Inc. Page 72 1 how can we characterize the uncertainty we 2 have in that -- and if we do it to the point 3 where we don't have to have additional more 4 frequent monitoring, or do we need to go to 5 that approach. That's a question we're 6 wrestling with in that regard. 7 You heard in Mary Frankenberry's 8 presentation that obviously shape of the 9 exposure chemograph influences that. And we 10 are looking at ways that can we bend the 11 community water system based on whether it's 12 a flowing water body or a reservoir, and even 13 within that it's a -- you know, how big is the 14 basin size, how big is the use -- how great is 15 the use within that basin size. So we're 16 going to be taking a look at that in ways 17 that -- once again, it's helping us be smarter 18 in where -- in how we're going to do. 19 And the complexity of the approach 20 is going to depend on the quality of the 21 monitoring data. When I first started doing 22 this work we were really criticized as you

### 202-234-4433 Neal R. Gross & Co., Inc. Page 73 1 guys are using deterministic models that 2 aren't real that generate exposures that don't 3 really happen. We did it for screening 4 purposes. 5 I would argue that when you've got 6 monitoring data that -- of any sample 7 frequency and when you're trying to interpret 8 that you're applying a model to interpret that 9 monitoring data. And some of the models can 10 be fairly simplistic; some of them are going 11 to be more complex. 12 All of them are going to have some 13 degree of wrongness in terms of estimating 14 your exposure. To the extent that we can 15 characterize the uncertainty in that that 16 helps us when we're making our decisions on

17 the assessment. 18 So you're going to see a question 19 I have later is how simple is -- when it 20 simple good enough. That's what we're taking 21 a look at -- you know, when can we live with 22 that and when do we need to go more complex.

### 202-234-4433 Neal R. Gross & Co., Inc. Page 74 1 So here's what we plan to do. And 2 I think I want to emphasize a few things. And 3 Dr. Lee and others pointed this out. 4 Whenever -- and particularly in the paper we 5 started looking at the community water systems 6 to start taking a look at how we might apply 7 this. And, once again, this wasn't the 8 drinking water exposure assessment itself.

9 It's let's look at methods that we can use to 10 apply to interpret that exposure assessment. 11 And so, you know, we're already 12 starting out with a data set that's weekly 13 sampling. And when I gave you my presentation 14 and I started saying, well, let's try -- I 15 want to try to illustrate what this means. 16 The first thing I did is I looked at that 17 weekly -- that data -- interpolated weekly 18 data set and said, All right, now if I show 19 you an example of weekly sampling then I've 20 got the same data set you have there.

21 So I went back to use what we had 22 the monitoring on the ecological exposure data

### 202-234-4433 Neal R. Gross & Co., Inc. Page 75 1 set which is much more robust in sampling 2 frequency to illustrate that point. We know 3 that for the most part those are going to 4 occur farther up in the watershed. We tend to 5 expect higher concentrations from those 6 particular sites than we're going to find in 7 community water systems further downstream. 8 But it still gives us an idea of how can we 9 put together an approach that we can then 10 apply to the community water systems. 11 So we're going to take a look at 12 robust monitoring data sets. The Heidelberg 13 University has a lot of intensive sampling in 14 a number of streams in varying -- with varying 15 basins that we'll be able to look at. We're 16 going to be looking at several of the 17 ecological exposure monitoring sites that had 18 more intensive sampling. And the idea is to 19 evaluate the approach that we will then apply 20 to how well is the community water system data 21 working. 22 We're going to take a look at

### 202-234-4433 Neal R. Gross & Co., Inc. Page 76 1 sampling these data sets at different 2 intervals. We'll use anywhere from three, 3 seven, 14, 30-day sampling. So some of the 4 discussions you've had before is how well do 5 some of these models perform when you have 6 less frequent monitoring, when your chemograph 7 shape from the monitoring data isn't as well 8 defined. So we're going to be taking a look

9 at that. 10 We're going to use -- then use as 11 the approaches that we described in Section 12 5.4 of our white paper we presented here any 13 other things that you folks think maybe we 14 need to take a look at in doing that 15 evaluation. And we're going to see to use 16 that to evaluate how well these different 17 approaches estimate exposures between sampling 18 points and generate exposures for varying 19 rolling average periods. 20 Right now for atrazine we're 21 working with a 90-day exposure period -- is 22 our exposure period of concern. We may end up

### 202-234-4433 Neal R. Gross & Co., Inc. Page 77 1 looking at a shorter duration of exposure. 2 Now we don't know yet -- this is part of what 3 we'll be hearing in this SAP and probably 4 continuing into September. If we have a much 5 shorter duration how well can we use the 6 existing weekly monitoring data. That's one 7 of the things we're trying to evaluate out of

8 that. 9 So when ultimately we come up with 10 an exposure duration of concern we can say, 11 all right, this is what we need to do to 12 provide your exposure estimates on that with 13 whatever confidence bounds we need to place on

14 that. 15 And so our ultimate focus is on 16 taking into account the spatial, temporal, 17 and, in particular in this case, the temporal 18 nature of the pesticide concentrations to 19 answer those two questions you see at the 20 bottom -- how frequently does sampling need to 21 be in order to adequately characterize various 22 exposure durations with a specified confidence

### 202-234-4433 Neal R. Gross & Co., Inc. Page 78 1 interval and how much can we derive from 2 existing less frequent sampling. 3 We're applying this to the 4 atrazine in community water system data. We 5 think this type of question we wrestle with 6 with other pesticides as well. And, to be 7 honest with you, we wrestle with it not just 8 for drinking water exposures but for 9 ecological exposures. And so these are things 10 that -- we're focusing on atrazine but have 11 applications beyond atrazine. And so we're 12 aware of that and we see the value of this not 13 just for atrazine but going beyond. 14 We have four questions that you 15 will be getting to later in the week. I tried 16 to simplify these into two main issues for you 17 to look at. Given the nature of the temporal 18 patterns, in this case atrazine in surface 19 water, but pesticide currents in general -- 20 how do we best develop the confidence bounds 21 and exposure estimates for monitoring data of 22 different sampling frequencies.

### 202-234-4433 Neal R. Gross & Co., Inc. Page 79 1 Now, a converse of this would be 2 if you're designing a monitoring study to 3 provide exposure estimates with -- for certain 4 duration how frequently do you have to sample 5 to give a level of confidence. So that's 6 where a couple of our questions are coming

7 from on that. 8 We presented approaches to you 9 that are common in literature. We've already 10 heard a couple of suggestions that we haven't 11 looked at yet and we may want to look at. And 12 so the questions we want you to -- as you look 13 at those approaches or any others what are the 14 advantages and disadvantages in -- for 15 estimating pesticide concentrations for either 16 short or moderate or long duration of 17 exposure. 18 And it comes down to that 19 question. When is simple good enough and when 20 do we need to look at more complex methods? 21 And I think -- yes, you've heard enough of me. 22 SESSION CHAIR PORTIER: Dr. Young?

### 202-234-4433 Neal R. Gross & Co., Inc. Page 80 1 DR. YOUNG: So you know in 2 designing a study there's often this tradeoff 3 in what we'd like and what we can actually do. 4 Okay? So how much -- is there room for 5 tradeoff in one day would be good but we can't 6 really do that as well as what we would need 7 to to actually talk about one-day maximum. So 8 seven day -- is that part of this discussion 9 or not? You understand my question? 10 MR. THURMAN: I think I do, but 11 I'm going to respond to you. And if I'm wrong 12 you can say, No, that's not what I meant. I 13 think -- you know, for a lot of it we know 14 we're not going to get sampling, for the most 15 part, if it's intense enough to give you daily 16 peak. And we know that you're going to need 17 less frequent sampling. 18 And so I think there are tradeoffs 19 there. And this is where to the extent that 20 through an uncertainty analysis or through 21 supplemental modeling can we at least get an 22 idea of what that peak is given what we have?

### 202-234-4433 Neal R. Gross & Co., Inc. Page 81 1 I'm not sure if that's what you're talking 2 about and I may be off -- 3 DR. YOUNG: Yes. And so what if 4 the answer's no? I mean, just what if. I'm 5 not saying it will be, but what if it's no? 6 Does -- is there room for discussion of 7 broadening that to get -- so that at least 8 you're getting what you say you're getting?

9 MR. THURMAN: And that becomes a 10 conversation not just with us on the exposure 11 end but the folks in the tox end and our risk 12 managers as well. I mean, so I think

13 that's -- 14 DR. LOWIT: That's basically what 15 I was going to add to this. I said from the 16 beginning yesterday this is really a rubber 17 meets the road analysis, and you're asking a 18 rubber meets the road question of a reality. 19 What is the real situation of daily sampling 20 throughout the Midwest in every water system 21 is not going to happen. 22 So the first question is: is what

### 202-234-4433 Neal R. Gross & Co., Inc. Page 82 1 Syngenta is doing right now enough if it -- 2 and what is the relevant confidence in that 3 and uncertainty in that. If the degree of 4 uncertainty is very high is there a way to get 5 a handle on that and how will more frequent 6 sampling improve that? The balance comes in 7 with the hazard assessment piece, the risk 8 managers, the cost -- all of that goes into 9 the decision process. 10 So the degree to which it's 11 possible to fully understand all those 12 components you can make a more full discussion 13 of the pros and the cons of a lot of 14 monitoring, smaller amounts of monitoring -- 15 and then when you blend that with the hazard 16 assessment to come to the closest to ideal 17 that we possibly can. So the degree to 18 which -- I guess I don't really have anything

19 else. 20 MR. THURMAN: No, but this is -- 21 honestly this is why we're here. And this is 22 what -- we want -- scientifically how far can

### 202-234-4433 Neal R. Gross & Co., Inc. Page 83 1 we go -- how far can we take this. And your 2 feedback will then lead us to whatever 3 discussion we need to do in terms of -- Okay, 4 we can only go this far -- how do we deal with 5 that. And we want your honest feedback on 6 that so when we have that discussion we know 7 where we can go.

8 SESSION CHAIR PORTIER: Dr. 9 Heeringa?

10 CHAIR HEERINGA: I asked about data 11 earlier, Nelson. The other part in designing 12 any statistical process costs and technologies 13 come into play here. And I'm not sure I 14 understand -- and maybe it would be helpful 15 for the panel to understand -- where the costs 16 enter in these water samples. Are they in the 17 labor to physically visit the site each day or 18 each sampling point, pick the water sample and 19 transport it? Is it in the assay? 20 The reason I ask is that, you 21 know, one strategy which is hinted at here is 22 for more intensive sampling during periods of

### 202-234-4433 Neal R. Gross & Co., Inc. Page 84 1 sort of high runoff and after application. 2 And that's just intuitive from a lot of 3 statistical arguments. 4 But the cost of doing that -- I 5 mean, is it the assay? Is it the physical 6 labor -- you know, the assistance to do this 7 collection? Do you have a sense of where that

8 cost structure -- how that breaks down?

9 MR. THURMAN: I'm sure the USGS 10 and Syngenta as well can give you a much 11 better -- but I know there is a substantial 12 cost in physically going out, visiting the 13 site, taking the sample, transporting it back. 14 So there is a substantial cost involved in 15 doing that in that regard. 16 CHAIR HEERINGA: Hopefully we can 17 hear from them. And the other thing I think 18 when we looked at the ecological side, in 19 addition to the point sampling -- the time 20 specific sampling -- there are integrated 21 samplers too, are there not?

22 MR. THURMAN: That's correct.

### 202-234-4433 Neal R. Gross & Co., Inc. Page 85 1 CHAIR HEERINGA: And from a 2 statistical standpoint the ability to sort of 3 integrate concentration over a period of time, 4 while it doesn't give you the profile it at 5 least gives you the mass. And that might be 6 actually useful in estimation. And I don't 7 think Dr. Lee and Dr. Young have been thinking 8 about this, but I think it would be useful if 9 we can have a little description of what those 10 measurement technologies and what those costs 11 look like as we think about this process. 12 MR. THURMAN: Yes, that's correct. 13 And I know that the technology is improving in 14 water sampling in general and that there are 15 auto-samplers that will take sips over time, 16 and so you can get an integrated sample over 17 a time period. 18 Some of them will do this for a 19 number of periods. The samples will be stored 20 so that it reduces the number of trips you 21 have to make. So I -- and I think as Syngenta 22 has continued with the ecological monitoring

### 202-234-4433 Neal R. Gross & Co., Inc. Page 86 1 they've gone more toward these because it 2 does -- there is a savings involved in that.

3 SESSION CHAIR PORTIER: Dr. 4 Gilliom?

5 DR. GILLIOM: I have a few 6 thoughts on those other things I can bring out 7 later, but not now I don't think. On the -- 8 an issue we haven't talked about that I think 9 I'm interested in in having the biological 10 side of the panel understand, but also 11 understand from EPA how we might need to 12 factor this into sampling design evaluation, 13 is the whole area of co-occurrence with other 14 contaminants and mixtures. 15 It's kind of unrealistic in these 16 agricultural systems to isolate out one 17 chemical like atrazine and its degradants in 18 terms of exposure. And so if we're looking at 19 the sampling design problems and there's going 20 to be a need to even take the simplest case of 21 combining it with simazine which is part of 22 the total chlorinated triazine group it has

### 202-234-4433 Neal R. Gross & Co., Inc. Page 87 1 different seasonal patterns than atrazine. 2 And those are changing, in fact, as cropping 3 patterns change and GMO crops come in and 4 herbicide use patterns change. 5 So one of the things I was 6 thinking about as we look at our charge, which 7 is really to help give you guys a roadmap to 8 a decision making process for coming up with 9 monitoring we're not given a specific target 10 like we need the five-day moving average or 11 the one day. Ours is -- our charge is more -- 12 given these circumstances what process should 13 we follow as an agency to come up with an 14 approach. 15 Well, you have more to deal with 16 than just atrazine, of course. And some of 17 the specific toxicological related studies 18 maybe we're talking about this week are 19 specific to atrazine. But then in the next 20 panel, which is also relevant to the 21 monitoring design problem, you're going to be 22 talking about the epidemiological studies more

### 202-234-4433 Neal R. Gross & Co., Inc. Page 88 1 in there. 2 And there's going to be a lot more 3 issues come up about how to separate out the 4 potential co-occurrence effects -- just simple 5 ones like there's nitrate in atrazine -- does 6 that interact to have a different concern than 7 just atrazine alone or does atrazine with 8 fungicides or whatever. 9 And the point being is that when 10 we look at the sampling design needs for that 11 it may totally change how we look at what 12 knobs are really -- need to be turned to get 13 the right frequency and the right moving 14 average values through the year. So we may 15 look at atrazine and say, Well, if we know we 16 need a seven-day moving average for atrazine 17 we can dial that right into a three-month 18 period and come up with a really efficient 19 design. 20 We could even go into the sampling 21 tricks. We could do some -- since we're 22 moving average sampling composite sampling and

### 202-234-4433 Neal R. Gross & Co., Inc. Page 89 1 use amino assays that are cheap and screen and 2 then analyze. But if the problem goes beyond 3 atrazine and it has to be captured in the same 4 monitoring thing then it changes how we 5 approach it. 6 So I guess it's a concern I have 7 to the process of how we give guidance on 8 monitoring design, but it's also kind of a 9 question of the rest of you looking at the 10 biology as we go through this how comfortable 11 are we with limiting the scope to atrazine 12 with making these kinds of decision. 13 MR. THURMAN: I just -- I want to 14 add one thing to what you were saying, Bob. 15 When we're looking at community water system 16 monitoring they actually measure for total 17 chlorotriazines. And some of the figures 18 we've seen labeled atrazine -- and we do have 19 the atrazine measurements as well as simazine 20 measurements, but we also have total 21 chlorotriazines, and that's ultimately what 22 the drinking water assessment will be based

### 202-234-4433 Neal R. Gross & Co., Inc. Page 90 1 on. 2 But you made some other points 3 that -- but as long as everyone knows we do 4 have -- for the drinking water exposure we are 5 considering total chlorotriazines. 6 DR. GILLIOM: I guess just one 7 follow up that I lose track of once in a while 8 too is that this monitoring design and purpose 9 is in supplement to the regular Safe Drinking 10 Water Act monitoring. So it's -- people may 11 not always realize that, that you have every 12 system being done quarterly just for the 13 regulated compound atrazine, and then you have 14 this special program layered onto it that's 15 required by FIFRA that Steve explained 16 yesterday what the trigger points are and 17 everything. 18 So I'm assuming that that is still 19 the conceptual model you're moving ahead with. 20 There's kind of a double monitoring plan. 21 MR. THURMAN: That is correct. 22 SESSION CHAIR PORTIER: Very good.

### 202-234-4433 Neal R. Gross & Co., Inc. Page 91 1 Dr. Coupe? 2 DR. COUPE: Yes. Thank you. Hey, 3 I was just curious. I heard two of you 4 mention already that daily sampling is off the 5 table or whatever, but why would that be if 6 you can't answer the question as to what's the 7 cost of the collection or what-not? What if 8 human health says, you know, you need to 9 collect daily and that's what has to be. No 10 offense to the statisticians, but it's a 11 model, and all models are wrong -- some are 12 useful maybe. 13 DR. BRADBURY: Sometimes. Always 14 useful but how you interpret them. This is 15 Steve Bradbury speaking. I would suggest you 16 don't constrain yourself in terms of sampling 17 design frequency, different scenarios of how 18 you may have embedded sampling within a 19 different sampling design. Do what you think 20 is right in terms of the scientific 21 perspectives that we should consider. 22 At some point we'll have to decide

### 202-234-4433 Neal R. Gross & Co., Inc. Page 92 1 how to implement the scientific perspectives 2 that you raise or you offer to us. I wouldn't 3 constrain yourself. I think Dr. Lowit though 4 made a good point yesterday when we were 5 talking about some of the toxicology, and it 6 would apply to the sampling design too. 7 As you describe different 8 approaches that we should consider we would 9 respectfully request you also be very clear on 10 what it is -- what's the question that you 11 think we should have and that we should come 12 up with an answer for and perspectives on how 13 good an answer can be with different 14 approaches.

15 Because we also want to ensure 16 that we're focusing on issues that we need to 17 get resolved -- a resolution to. And with all 18 due respect to my previous history, as well as 19 my colleagues in the room, we're talking about 20 issues here that aren't in a research mode. 21 We will learn things and will contribute to 22 research, but we'd also like a focus on what

### 202-234-4433 Neal R. Gross & Co., Inc. Page 93 1 are the issues that we can take on tomorrow, 2 six months from now, 12 months from now which 3 will certainly contribute to the broad 4 scientific knowledge, but ought to focus on 5 real decisions that we have to be making in 6 real time. 7 And we'll never know everything. 8 And so it's how to make informed decisions 9 with what we do know. And some of Nelson's 10 comments and Anna's comments on helping us 11 think about uncertainty and variability 12 interpretation will be critical. 13 But the bottom line is don't 14 constrain yourself in terms of where you need 15 to go, but offer some insights into the 16 perspectives in terms of the range of options 17 that you may consider. 18 SESSION CHAIR PORTIER: Okay. I 19 think we're ready for the overall summary and 20 conclusion. Dr. Lowit. 21 DR. LOWIT: I don't have a slide 22 and I won't say much. I thought it just would

### 202-234-4433 Neal R. Gross & Co., Inc. Page 94 1 make sense to go back to where we started. 2 Last fall a group of us sat in 3 front of the permanent panel and announced we 4 were doing this reevaluation and we would come 5 to the SAP several times in 2010. And we told 6 you yesterday we're going to add another one 7 in 2011 -- that our initial hope had been in 8 September of this year to have a harmonized9 weight of the evidence across cancer/non10 cancer. But our colleagues at NCI are not 11 going to have their agricultural health study 12 reconsideration done in time, so we're going 13 to separate the cancer. 14 So we still have the exact same 15 two goals today that we did back last fall -- 16 that we have two pretty practical questions. 17 And the first one has to do with drinking 18 water monitoring frequency required of 19 Syngenta. And the second one is a basic 20 question -- do we need to reopen the human 21 health risk assessment. 22 And we're doing a lot on two major

### 202-234-4433 Neal R. Gross & Co., Inc. Page 95 1 fronts that you've heard a lot about. The 2 hazard assessment component -- we're in the 3 sort of mid -- a snapshot on time on the 4 update of the literature review of the hazard 5 assessment. And the new data since the last 6 risk assessment suggests that the HPA axis 7 happens on a -- maybe on a shorter temporal 8 scale than does the data that supported the 9 2003 risk assessment. 10 And so as we think about that HPA 11 data and its temporality and how you would 12 take that and think about linking key events 13 across that pathway of toxicity -- how to link 14 those together to -- across time and across 15 dose to think about the relationship of one to

16 the other and how to translate that -- the 17 temporal component of that into the drinking 18 water frequency, which we've talked a lot 19 about this morning and I won't reiterate. 20 And part of that hazard assessment 21 is to rethink things like the points of 22 departure, the uncertainty factors, the --

### 202-234-4433 Neal R. Gross & Co., Inc. Page 96 1 whether it's a rolling average or some other 2 dose metric. So we're really looking forward 3 to the discussion over the next few days. I 4 guess that's -- do you have anything else? I 5 think that's it. 6 SESSION CHAIR PORTIER: Very well. 7 I think at this point we'll take a 15-minute

8 break. I have 10:08. We'll return at 10:25.

9 MR. BAILEY: If I could ask all 10 the people who are making public comments to 11 please come up here and check with us so we 12 can get your files loaded into the laptop 13 ready to go. Thanks. 14 (Whereupon, the above-entitled

15 matter went off the record at 10:09 a.m. and 16 resumed at 10:27 a.m.) 17 SESSION CHAIR PORTIER: Okay. 18 Let's begin. Before lunch we're going to have 19 presentations first by the Triazine Network 20 with a Mr. White, Laura Knoth, and Richard 21 Fawcett. And following that we're going to 22 have beginnings of the presentation from

### 202-234-4433 Neal R. Gross & Co., Inc. Page 97 1 Syngenta of crop protection. So we'll start 2 with Mr. White. 3 MR. WHITE: Thank you, Mr. 4 Chairman, members of the Committee. My name 5 is Jere White. I live in east central Kansas. 6 I'm the executive director of the Kansas Corn 7 Growers Association and also Kansas Grain 8 Sorghum Producers. And if you're not from the 9 Midwest you probably have no idea what grain 10 sorghum is. But it's a grain crop actually 11 similar to corn in some ways and, yet, very 12 different. I'm here on behalf of Kansas

13 farmers. 14 I also serve as chairman of the 15 Triazine Network. The network was formed in 16 1995 as a response by the grower community to 17 the EPA announcement of a special review and 18 the reregistration efforts. 19 We represent over 30 commodities 20 in over 40 states. Most of our members are 21 organizations like my own, but also includes 22 many individuals farmers. Network membership

### 202-234-4433 Neal R. Gross & Co., Inc. Page 98 1 encompasses farm groups literally from border 2 to border and sea to sea -- in fact, some 3 across some seas. We have an executive 4 committee that's formed from states like 5 Kansas, Missouri, Florida, California, and 6 Hawaii. 7 We certainly are a very diverse 8 group focused on a single outcome. And our 9 objective has always been to ensure that EPA 10 understands the value and the utility of 11 atrazine. We also have assumed that role with 12 the registrants because, as you can imagine a 13 long process like this, it's not only 14 important that the people regulating the 15 product understand its value it's important 16 that the people that are producing the 17 product -- and I might add an off-patent 18 product -- understand the value to farmers. 19 And so we've engaged on all points on that. 20 But the fact is that atrazine has 21 been the foundation of our weed control 22 programs for 50 years now. We know the

### 202-234-4433 Neal R. Gross & Co., Inc. Page 99 1 product well. We know how to steward atrazine 2 in a way that provides safety for ourselves in 3 the environment. And that's the environment 4 that we live and farm in. 5 I'm going to turn over comments 6 now to Laura Knoth. Laura is the executive 7 director of Kentucky Corn Growers, and then 8 she'll pass the baton to Dr. Fawcett, and then 9 I'll wrap up. Laura? 10 MS. KNOTH: Thank you. Thanks, 11 Jere. Mr. Chairman and members of the panel, 12 as Jere said, my name is Laura Knoth. I'm the 13 executive director for the Kentucky Corn 14 Growers and Kentucky Small Grain Growers in 15 Kentucky. 16 I grew up on a Kentucky farm that 17 I still own and operate there today. 18 Graduated the University of Kentucky with an 19 agriculture degree, natural resources major. 20 I started my career as an environmental 21 consultant and then came home to agriculture. 22 I wanted to just talk today about

### 202-234-4433 Neal R. Gross & Co., Inc. Page 100 1 stewardship and conservation as it relates to 2 atrazine. And please pardon nervousness. 3 This is obviously my first advisory panel. 4 It's because American agriculture 5 and American farmers are dependent upon the 6 integrity of their soil and other natural 7 resources for their livelihood that they work 8 to protect and improve the land. As a result 9 significant benefits to society have been 10 achieved and improvements and efficiencies 11 will continue to lessen the environmental 12 impacts of food production. 13 Crops cannot be produced without 14 disturbing the soil in some way. Tillage is 15 the farmer's way of preparing the ground for 16 planting, for breaking it up and smoothing it 17 out. Tillage also helps control weeds and 18 aerates the soil. Yet there are consequences 19 to tillage: Rain and wind carry loosened soil 20 off of the fields, adding silt to the 21 waterways and particulate matter in the air. 22 Old school cultivating with a moldboard plow

### 202-234-4433 Neal R. Gross & Co., Inc. Page 101 1 had even greater impacts on soil and water. 2 In today's agriculture when 3 tillage is necessary farmers have adapted from 4 the historical tillage practices of intensive 5 soil disruptive for weed control to simpler 6 practices, such as conservation tillage, which 7 minimizes soil disturbance. 8 By leaving the crop residue on the 9 field for cover and eliminating additional 10 trips across the field for tilling farmers are 11 better able to protect the soil from water and 12 wind erosion. It conserves moisture, reduces 13 runoff, and improves the wildlife habitat, and 14 it limits our output as farmers of labor, 15 fuel, and machinery to produce a crop. 16 Several crop production systems 17 fall under the heading of conservation 18 tillage, including no till, ridge till, low 19 till, and minimum till. But common to all of 20 these is a crop mulch covering left on the 21 ground to provide a protective cover to the 22 soil between the seasons. And it improves the

### 202-234-4433 Neal R. Gross & Co., Inc. Page 102 1 soil fertility by maintaining that nutrient 2 rich organic matter on the field. 3 Conservation tillage allows 4 organic matter to build up in the soil, 5 absorbing carbon dioxide, and reducing a 6 significant amount of greenhouse gas. Just 7 like our lawns and gardens, compost and mulch 8 are good things in agriculture. 9 As a result of increasing adoption 10 of conservation tillage and other soil 11 conservation practices soil erosion from U.S. 12 crop land has steadily declined. A natural 13 resources inventory report from 2007 published 14 by the Natural Resources Conservation Service 15 states that soil erosion resulting from 16 rainfall and runoff declined 42 percent 17 between 1982 and 2003. And, likewise, soil 18 erosion from high winds declined 44 percent 19 during that same time frame. 20 In 2008 atrazine was applied to 21 over 650 percent of the conservation and no 22 till corn acres. As America's original

### 202-234-4433 Neal R. Gross & Co., Inc. Page 103 1 stewards of the environment growers value 2 atrazine for its capability with conservation 3 tillage. 4 The ability of atrazine to move 5 off the surface crop residue of the top soil 6 to where the weeds germinate -- it moves down 7 into the soil as well as the length of that 8 weed control that makes atrazine the tool of 9 choice for no till farmers and adopters of 10 other conservation tillage practices. 11 Effective weed control -- it's not 12 a luxury. It's a necessity in conservation 13 tillage systems. So without herbicide use no 14 till agriculture becomes impossible. And 15 that -- you know, that causes additional 16 increased erosion estimated to be over 300 17 billion pounds of soil annually. 18 Much of this soil erosion would 19 enter waterways. Sediment is the largest 20 contaminate of surface water by weight and 21 volume. And it's identified by the states as 22 the leading pollution problem in rivers and

### 202-234-4433 Neal R. Gross & Co., Inc. Page 104 1 streams and the fourth leading problem in 2 lakes. Sediment in surface water is largely 3 a result of soil erosion, which is influenced 4 by soil properties, and for agriculture the 5 production practices that farmers choose. 6 Farmers and industries have 7 heavily invested in research on BMPs for 8 pesticides, including atrazine. Stewardship 9 requirements on the label for atrazine are 10 unique. And they are not typical with other 11 pesticides. BMPs effective in reducing runoff 12 of atrazine into surface water, including 13 those conservation tillage practices, buffer 14 strips, vegetative filter strips, terraces, 15 contour planning, post-emergence application, 16 and mechanical incorporation. 17 It should be noted that atrazine 18 BMPs and stewardship provide benefits, not 19 just for atrazine but for a variety of other 20 concerns, including nutrients and other 21 pesticides. BMPs and other stewardship 22 efforts used by farmers often depend on site

### 202-234-4433 Neal R. Gross & Co., Inc. Page 105 1 specific conditions. And on our farms 2 stewardship is -- occurs every day. It's an 3 important part of continuing to be able to

4 farm. 5 I want to thank the panel for its 6 deliberations this week. As I said, this is 7 my first SAP and I have to say the volume of 8 science put in front of you all seems 9 staggering. So good luck on your 10 deliberations. I wish you well. At this time 11 I'll turn it over to Dr. Fawcett. 12 DR. FAWCETT: Thank you, Laura. 13 My name is Richard Fawcett, and I'm here 14 appearing on behalf of the Triazine Network. 15 My background is as a weed 16 scientist and also working in water quality. 17 I've done a lot of work in developing best 18 management practices and being involved in 19 educational efforts to try to get those on the

20 land. 21 I appreciate the opportunity to 22 share some information about atrazine use with

### 202-234-4433 Neal R. Gross & Co., Inc. Page 106 1 this SAP panel that has a very important task. 2 And it's very important to weigh carefully, 3 because atrazine remains a very important tool 4 to American agriculture. 5 It may seem surprising a product 6 that's been around for 50 years is so widely 7 used. But the reason it's so widely used is 8 that it works so well. It works better than 9 alternatives or, maybe better said, it makes 10 alternatives work better. 11 It's interesting when a new 12 herbicide active ingredient for corn is 13 registered and hits the market the first thing 14 that usually happens is it is marketed with a 15 combination of atrazine as a prepackaged 16 product or labeled as a tank mix in 17 combination with atrazine because usually a 18 relatively low rate of atrazine improves that 19 product; controls weeds maybe missed by the 20 alternative herbicide.

21 We've heard about the 22 environmental benefits that atrazine's

### 202-234-4433 Neal R. Gross & Co., Inc. Page 107 1 important and with conservation tillage. 2 Atrazine is also an essential tool in 3 herbicide resistance management that has 4 become so important as herbicide tolerant 5 crops have been planted over such a large 6 acreage. 7 We scientists routinely recommend 8 to farmers that they do not use the same 9 herbicide mode of action alone year after year 10 after year because that brings on weed -- 11 herbicide resistant weeds. And atrazine is 12 very often in corn. That alternative mode of 13 action is used to manage weed resistance. 14 I've been involved in several 15 analyses of very large databases to exam the 16 hypothesis that there is a yield benefit from 17 using atrazine. I'd like to briefly share a 18 little bit of that with you. There are 19 actually two ten-year analyses over a 20-year 20 period where we used the research report of 21 the North Central Weed Science Society as a 22 source of studies.

### 202-234-4433 Neal R. Gross & Co., Inc. Page 108 1 The North Central Weed Science 2 Society published the research report as an 3 outlet for universities for their annual 4 progress report. And it's by far the largest 5 published source of the herbicide efficacy 6 trials. 7 In comparing treatments that 8 either had atrazine or atrazine alternatives 9 we haven't -- be very careful that they were 10 logical comparisons or fair comparisons. The 11 treatments had to have -- they had to control 12 both broadleaves and grass and so usually had 13 to have at least two active ingredients. They 14 had to be registered for use at the time of 15 the analysis -- they have been experimental 16 when the study was done. They had to be used 17 as registered rates. So there's a lot of 18 criteria that the studies and treatments had

19 to meet. 20 But over the period of 1986 to 21 `95, the first analysis that was done in 22 response to the special review for atrazine --

### 202-234-4433 Neal R. Gross & Co., Inc. Page 109 1 over that time period atrazine -- treatments 2 containing atrazine yielded 6.3 bushels or 5.9 3 percent higher than alternatives -- treatments 4 without atrazine. 5 After ten years had passed to see 6 whether that benefit still remained we went 7 back to that research report, used the same 8 methods, and analyzed another ten years of 9 data from -- see you get the years -- I guess 10 it would be '96 to 2005. During that time 11 period the atrazine treatments yielded 5.4 12 bushels or 4.6 percent higher -- very similar 13 benefit despite the introduction of many new 14 herbicide active ingredients, new technologies 15 like herbicide tolerant crops -- that benefit 16 was really rather surprisingly constant. And 17 there were 236 studies and 5,811 treatments in 18 those analyses -- very, very large database. 19 Well, after 62 years of 20 publication the North Central Weed Science 21 Society terminated their publication of the 22 research report in 2006 for budgetary reasons.

### 202-234-4433 Neal R. Gross & Co., Inc. Page 110 1 And so in order to look at the most recent 2 years and do a similar analysis we had to come 3 up with a different way of getting studies. 4 We started by contacting all the 5 states that traditionally submitted studies to 6 the research report. And this is, again, 7 north center -- primarily corn belt. And we 8 got studies directly from them, often from 9 websites, sometimes directly from the 10 universities. 11 But to try to go on a broader 12 scale to get more data and actually to look at 13 regions outside the corn belt we also utilized 14 an electronic database, so it's Syngenta crop 15 protection have that contain mainly university 16 studies but also some company-sponsored 17 studies. 18 We actually analyzed those 19 separately -- took out the Syngenta studies 20 and we was -- actually there was less benefit 21 in the Syngenta studies than the university 22 studies. So we used the entire database. We

### 202-234-4433 Neal R. Gross & Co., Inc. Page 111 1 wanted to make sure there wasn't any bias 2 there. We used the entire database. 3 For the three years 2006 to 2008 4 there were 310 qualifying studies of 4,293 5 treatments -- a huge stack data -- very large 6 analysis. There were 24 U.S. universities in 7 22 states that represent all the major corn 8 growing regions that did over 80 percent of 9 the studies. So for that three-year time 10 period corn yielded an average 5.3 bushels or 11 3.5 percent higher -- again, a very similar 12 benefit that remains despite all the new 13 technologies. And these -- all these were 14 statistics that we analyzed. They were15 significant by t-test and Wilcoxton signed16 rank test. 17 Thus, despite the introduction of 18 many new herbicide active ingredients, new 19 technologies like herbicide tolerant crops, 20 the benefit of atrazine remains. It's the 21 most -- it's also cost effective. When you 22 consider both the lower cost and the yield

### 202-234-4433 Neal R. Gross & Co., Inc. Page 112 1 increase the benefit from atrazine remains 2 over $30 per acre. 3 But besides just an economic 4 benefit we've heard about the environmental 5 benefits from the conservation tillage. And 6 one thing I am concerned about is when you 7 survey farmers and ask them if they're 8 considering to go to conservation tillage what 9 their biggest worry is, is always weed 10 control. They're worried that if they give up 11 that tried and true tillage method that they

12 won't be able to control weeds. 13 If atrazine were not available I'm 14 afraid we would backslide. Some of the 15 farmers that are in conservation tillage would 16 start doing more tillage. Some of the farmers 17 considering that shift would not make that 18 shift. 19 Atrazine remains a valuable tool 20 in agriculture, producing both economic and 21 environmental benefits. With that I'd like to 22 shift it back to Jere White and have him make

### 202-234-4433 Neal R. Gross & Co., Inc. Page 113 1 some closing comments. 2 MR. WHITE: Thanks, Dick. As of 3 now we've participated in every SAP concerning 4 atrazine since the beginning of this special 5 review in 1994. We missed the 1988 -- 6 obviously special review was not in place, but 7 I must say my total of SAPs regarding atrazine 8 was somewhat higher than what was reported to 9 the panel yesterday. And I hope my wife 10 doesn't read the report because I've told her 11 I've been going to these SAPs in 2007, and I 12 don't think any of those were on the list. 13 But, regardless, we do want the 14 panel to know that although we see the value 15 and we understand the benefits and we've 16 shared them with EPA and actually EPA I think 17 has incorporated a lot of our work into their 18 analysis of benefits of the product.

19 We also understand that there are 20 other issues. And we certainly do not 21 casually dismiss activists' claims of harm 22 from the use of atrazine, but we do insist

### 202-234-4433 Neal R. Gross & Co., Inc. Page 114 1 that sound scientific weight of evidence 2 prevail on regard to regulatory action further 3 lending its use. 4 In the course of time in my career 5 that I've been involved with atrazine we've 6 seen significant changes in labeled use rate. 7 There is stewardship incorporated into the 8 labels, and, quite frankly, agriculture has 9 adapted and the product has maintained its

10 value. 11 Obviously there are issues we need 12 to be concerned. We're the primary handlers 13 of the product. Our kids and our grandkids 14 are a part of our farms, they're a part of our 15 land, they're a part of our lives. And we 16 need safe tools in our toolbox. And we 17 believe atrazine because of our experience and 18 simply -- you know, to put it -- simply put, 19 because of our participation in now 16 years 20 of scientific review we believe atrazine to be 21 one of the safest tools that we have in our 22 toolbox. That's important to us.

### 202-234-4433 Neal R. Gross & Co., Inc. Page 115 1 Personally, I do understand the 2 implications of cancer. I buried my father a 3 few years ago after he lost his fight with 4 prostate cancer. Don't take it lightly. 5 Cancer strikes unique fear in all of us, and 6 certainly I'm not exception. 7 I've also had experience with 8 birth defects. My first grandchild was born 9 still because he suffered severe developmental 10 birth defects. And so, you know, even though 11 there was no implications of pesticide 12 exposure or anything like that in that case 13 it's -- we understand what these tragedies in 14 life are. And if they were going to affect 15 anyone we would expect them to affect 16 ourselves and our families. And we do not 17 take it lightly at all. 18 If we believed that these were 19 scientifically weight of evidence issues that 20 we should be considering or that we believed 21 we wouldn't be here today. We don't believe

22 that.

### 202-234-4433 Neal R. Gross & Co., Inc. Page 116 1 And, quite frankly, the EPA did 2 not believe it until the New York Times and 3 Huffington Post supplied their version of the 4 peer review to an NRDC report last summer. 5 And that report was taken on by certain 6 political appointees at EPA. 7 And you can simply go back to what 8 EPA was posting on its own website in July of 9 last year. Upon reregistration in 2006 EPA 10 determined that triazine herbicides post no 11 harm that would result in the general U.S. 12 population, infants, children, or other, 13 including consumers. 14 I know this process did not begin 15 a year ago, as was inferred yesterday, to take 16 a look at the new reports and the new science 17 that's out there. We're not opposed to that 18 obviously. If there's legitimate concerns 19 that surface they could surface at any time. 20 You could finish a review one day. The next 21 day you could have issues. But there is a 22 certain amount of process that certainly comes

### 202-234-4433 Neal R. Gross & Co., Inc. Page 117 1 under question at this point. 2 From the growers' standpoints our 3 growers often ask when is enough enough. You 4 know, take the case of water. Atrazine 5 certainly has the most comprehensive database 6 of any pesticide. Is it enough? I mean, the 7 discussions this morning -- at some point 8 people involved in science and policy have to 9 make determinations. But, certainly, when you 10 look at the substantial data on atrazine 11 compared to anything else that you look at out 12 there -- and I would argue any contaminant the 13 water system looks at -- the database is 14 certainly more robust. 15 When you further consider that the 16 levels of concern have multiple safety 17 factors -- tremendous safety factors backed by 18 decades of scientific review there seems to be 19 little doubt that the robust data -- and since 20 conservative safety factors provide confidence 21 for farmers, for regulators, and for

22 consumers.

### 202-234-4433 Neal R. Gross & Co., Inc. Page 118 1 Mark Twain wrote in Life on the 2 Mississippi that there is something 3 fascinating about science. One gets such 4 wholesale returns of conjecture of such 5 trifling investment of fact. EPA, in fact, 6 has a process designed to avoid absence of 7 fact, and that's what this process is. 8 This week, however, you have 123 9 studies in front of you for your deliberations 10 and have less than a month to review them. 11 For stakeholders the charge questions were 12 only released on the evening of the 8th, 13 allowing a mere eleven working days to develop 14 a response. 15 To have a re-review of atrazine 16 and stated two-thirds of the way through the 17 normal pesticide registration process when it 18 was scheduled for a 2013 registration review 19 is contrary to the process established under 20 FIFRA and not based on sound science. 21 I must give each of you special 22 thanks. You are being asked to review two

### 202-234-4433 Neal R. Gross & Co., Inc. Page 119 1 completely separate disciplines in this SAP: 2 toxicology on many fronts and drinking water 3 monitoring; requiring unusually wide span of 4 research expertise. And though the average 5 number of studies submitted for SAP review -- 6 the average per session numbers around 15 -- 7 the EPA has generously provided you with 123. 8 Actually I think the number is slightly higher

9 than that. 10 And while that might just be a 11 sign of EPA's confidence in the scientific 12 capabilities of the panel -- and I'm sure it 13 is -- given the short time frame involved, it 14 does not -- it certainly does bring into 15 question the agency's definition of open and 16 transparent and inviting stakeholder 17 participation. 18 Regulators, government bodies, and 19 organizations around the world, including the 20 U.K. in 2000, Canada in 2004, WHO and FAO in 21 2007, Australia in 2008, and most recently the 22 state of Minnesota have recently given

### 202-234-4433 Neal R. Gross & Co., Inc. Page 120 1 atrazine favorable reviews. 2 And despite activists' lies to the 3 contrary, no country has ever banned atrazine 4 for health concerns, none, including the 5 European Union. EU regulations do restrict 6 the use of any pesticide that has a potential 7 to occur in groundwater at amounts greater 8 than one part per billion -- or .1 part per 9 billion, but that is a political not a 10 scientific standard. 11 While EU farmers do not currently 12 use atrazine, they use a similar triazine 13 herbicide with nearly the same safety profile: 14 terbuthylazine. But you don't hear that when 15 you read the reports or look at the news 16 articles; not because the reporters don't

17 know -- because I've told them -- but because 18 it doesn't fit into their story. 19 The continuous restatement of this 20 activist propaganda has taken on its own life 21 and has been declared as fact; probably be 22 declared as fact again before the day's over

### 202-234-4433 Neal R. Gross & Co., Inc. Page 121 1 with, yet it is a falsehood. 2 Extensive monitoring show the 3 levels of atrazine in raw and finished water 4 is steadily decreasing due to a number of 5 factors, including label changes that occurred 6 in the early nineties and stewardship 7 activities on the farm which you've just heard

8 about. 9 But atrazine is one of many 10 regulated chemicals that are present in safe 11 water -- in safe amounts in our drinking 12 water. We know that it's safe because of the 13 extensive scientific body of research 14 available to us. Other chemicals like 15 fluoride added to drinking water to protect 16 our teeth and the byproducts of chlorination 17 trihalomethanes are also in our drinking 18 water, but they're there to do important jobs 19 like kill dangerous pathogens such as E. Coli. 20 They're present in water and they're present 21 in safe amounts. However, most of these other 22 contaminants do not have the same massive body

### 202-234-4433 Neal R. Gross & Co., Inc. Page 122 1 of science supporting their safe presence in 2 water as atrazine does. 3 On December 20, 2008, the 4 President-elect Obama said in his weekly 5 address, it's about ensuring facts and 6 evidence are never twisted or obscured by 7 politics or ideology. For more than 50 years 8 atrazine use has been conservatively regulated 9 and approved for use in agriculture by EPA and 10 its predecessor agencies through both 11 Democratic and Republication administrations. 12 For instance, one of the most 13 significant determinations made in the past 14 two decades regarding atrazine that atrazine 15 was not likely to be a carcinogen actually 16 occurred during the Clinton administration. 17 The current politically driven, second 18 guessing of previous EPA and SAP decisions 19 suggest twisting and obscuring at levels that 20 should make a politician blush. 21 We would argue that those 22 decisions were not made in some black box. We

### 202-234-4433 Neal R. Gross & Co., Inc. Page 123 1 are confident that the past -- that when the 2 dust settles the scientists who have been 3 working diligently for years -- many of you in 4 this room have been a part of many SAPs -- and 5 in this room today both have the agency and 6 the SAPs will be vindicated for their past 7 regulatory decisions. 8 And make no mistake about it. We 9 believe that the reviews that have been 10 done -- while we might not have agreed with 11 every turn or twist that EPA, the agency, and 12 their SAPs have made in the past collectively 13 we think it has been a very solid, very deep 14 process. It's not something that the agency 15 under any administration has taken lightly. 16 It's not something that the 17 SAPs -- the previous SAPs have taken lightly. 18 And, again, many of you have been involved in 19 those. And to suggest that somehow a SAP 20 process under a different administration was 21 somehow lacking I think is a disservice to 22 people that have dedicated a lot of their time

### 202-234-4433 Neal R. Gross & Co., Inc. Page 124 1 and effort to this project. 2 But, having said that, we 3 certainly will roll up our sleeves. We'll be 4 back in September and we certainly look 5 forward to working with all parties as the 6 process continues. Thank you. 7 SESSION CHAIR PORTIER: Thank you. 8 Any questions from the panel? Yes, Dr. Regal. 9 DR. REGAL: Just is there any 10 number out there in terms of corn yields with 11 no herbicide versus corn yields with 12 herbicide? 13 DR. FAWCETT: I can't give you a 14 firm number. But just from looking at -- it 15 depends on how many weeds you have in a field. 16 Some fields have a lot of weeds; some have 17 less. Typically in our research plots we 18 always have controls without any herbicide. 19 They may not yield anything. They may be 20 20 bushels compared to 200 bushels for a 21 herbicide. But if you have a field that's 22 relatively clean it might yield 100 bushels.

### 202-234-4433 Neal R. Gross & Co., Inc. Page 125 1 It just depends on how many weeds are there.

2 SESSION CHAIR PORTIER: Dr. 3 Gilliom? 4 DR. GILLIOM: So is it reasonable 5 to assume given the continued need for 6 atrazine that the use should still remain 7 pretty constant in the corn belt total? 8 MR. WHITE: You know, we would 9 argue that the use has -- you know, certainly 10 it's changed in the 15, 16 years since the 11 special review was initiated. The use today 12 is really tied -- you know, if you go back 30 13 years ago atrazine might have been the main 14 component of weed control, and label grades 15 would have reflected it. They would have been 16 very high. 17 Today it's more of a component in 18 a mixture of new chemistries. But as Dr. 19 Fawcett said the really issue is even some of 20 the most popular new chemistries like 21 glyphosate quickly found problems with weed 22 resistance. And so you have to have some

### 202-234-4433 Neal R. Gross & Co., Inc. Page 126 1 alternative. And the reality is, is that, you 2 know, it's surprising to us. But the utility 3 and the need for atrazine today, although it's 4 in a different fashion, is probably just as 5 profound as it was 20 years ago or 30 years 6 ago. But it's different. 7 DR. FAWCETT: I'll just quickly 8 give an example from Iowa. Today in Iowa I 9 think atrazine's actually used on more acres 10 today than it was 20, 30 years ago. It's used11 at lower rates, different ways, some post12 emergence and combinations. So the 13 environmental load is actually less, but it's 14 just as important, if maybe not more 15 important, than it was 20 or 30 years ago. 16 MR. WHITE: And I guess the other 17 point I'd add, in conservation tillage it is 18 absolutely critical.

19 SESSION CHAIR PORTIER: Dr.

20 Horton?

21 DR. HORTON: Yes. I have a 22 question. One of the things we're going to be

### 202-234-4433 Neal R. Gross & Co., Inc. Page 127 1 considering on the biology panel is that the 2 health effects may occur at many different 3 levels and different stages of development. 4 We may be looking at fetal periods, perinatal, 5 pubertal, adult, cancer, neurotoxicity. 6 And so in your statement you 7 commented that the European Union safety 8 review said atrazine would not harm humans. 9 Could you comment on what specific human 10 health effects the European Union evaluated -- 11 what stages of development, which health 12 effects they were evaluating? 13 MR. WHITE: In fairness I probably 14 would need to go back and take a look at all 15 that. You know, I'm sure that those reviews 16 did not include some of the newer stuff that 17 this panel and future panels will be taking a

18 look at. 19 But I do believe that it certainly 20 included some of the things that we are 21 looking at and probably the Syngenta folks 22 might be better equipped. But I'd be happy to

### 202-234-4433 Neal R. Gross & Co., Inc. Page 128 1 go back and specifically give a list of those 2 things that were reviewed. I don't know it 3 off the top of my head.

4 SESSION CHAIR PORTIER: Dr. 5 O'Byrne? 6 DR. O'BYRNE: Kevin O'Byrne. I 7 don't think any sane person would say that 8 there is not a requirement for herbicides, and 9 I get a sense that as the commitment to reduce 10 the amount of usage globally -- perhaps 11 globally. 12 But I have a simple question. The 13 application of these herbicides, are they 14 coordinated with weather forecasts and things 15 like that by the farmers? 16 MR. WHITE: Well, certainly one of 17 the BMPs that we encourage farmers to utilize 18 is if it looks like a significant rainfall 19 event's on the horizon, you don't go out and 20 spray the field. But having said that, you 21 know, Mother Nature is somewhat fickle 22 sometimes, and so you don't always know when

### 202-234-4433 Neal R. Gross & Co., Inc. Page 129 1 those will occur. 2 And having been involved in other 3 water issues in my state, I can tell you that 4 in spite of your best modeling, in spite of 5 your best efforts, there will be, you know, 6 acts of nature that will fall out of your 7 parameters. You know, I think farmers do a 8 much more precise job today. I mean, you 9 know, a lot of herbicide goes down using 10 satellites to drive the sprayer, not farmers. 11 You know, the issues like over-applying 12 because of overlaps that were very common 13 were -- you know, a couple of decades ago are

14 somewhat unheard of on the most modern farms. 15 One of the challenges, though, is 16 that as a society we like the notion of small, 17 what we call family farms in this country. 18 It's not -- you know, it's kind of a romantic 19 notion. But the bottom line is is that most 20 of the very smallest of farmers are the ones 21 doing the poorest job of applying herbicides 22 and things like that because they're using the

### 202-234-4433 Neal R. Gross & Co., Inc. Page 130 1 economies of scale. They're not using GPS to 2 help them put the product where it needs to 3 be. They're probably using a sprayer that 4 they bought at a sale that had been used by 5 another farmer that might represent technology 6 that's 20 or 30 years old. 7 So there's -- it's like new cars. 8 It takes a long time for the transportation 9 system to cycle through. It does the same on 10 farms. But everyone's about efficiency. And 11 the most efficient use of a herbicide is to 12 use the least amount that you need. But if 13 you use less than the least amount that you 14 need you've done a disservice because you 15 improve the chances for resistance, you've 16 spent money and you get no benefit. 17 And there are levels -- you know, 18 you could go back -- with atrazine you can go 19 back as the labeled rate was reduced in the 20 nineties, you saw weed control come off the 21 label for different weeds just simply because 22 it wasn't efficacious anymore.

### 202-234-4433 Neal R. Gross & Co., Inc. Page 131 1 SESSION CHAIR PORTIER: Dr.

2 LeBlanc? 3 MR. WHITE: I don't know if I

4 rambled too much on that. 5 DR. LEBLANC: You mentioned that 6 atrazine was banned in the U.K. not for health 7 concerns but because levels in drinking water 8 exceeded a somewhat arbitrary limit. 9 MR. WHITE: No. Actually I said 10 it was not banned in the U.K. It's use was 11 discontinued. 12 DR. LEBLANC: Okay.

13 MR. WHITE: And not because the 14 levels in drinking water -- because of 15 detections in groundwater. 16 DR. LEBLANC: Detection in 17 groundwater. And the -- and you also 18 mentioned that an alternative, or a 19 substitute, triazine is used in place of 20 atrazine. 21 MR. WHITE: Yes, terbuthylazine.

22 DR. LEBLANC: So I assume that

### 202-234-4433 Neal R. Gross & Co., Inc. Page 132 1 levels of that herbicide are not found in 2 excess of that limit in groundwater?

3 MR. WHITE: I would assume that 4 they've not detected it in groundwater at that 5 level. So that it's a concern but, you know, 6 again, it's a very similar product. You know, 7 I'm not familiar with terbuthylazine because, 8 in fact, we don't have it registered in the 9 United States. 10 DR. LEBLANC: I'm not familiar 11 with it either.

12 MR. WHITE: Yes. 13 DR. LEBLANC: And perhaps I'm 14 going above your level of understanding and 15 expertise. 16 MR. WHITE: Well, other than my -- 17 my understanding is that the tox and actually 18 the compound is very similar, as are the other 19 triazines. 20 DR. LEBLANC: I just wonder if 21 its -- presumably its levels are lower than 22 the limit I think you said was 0.1 parts per

### 202-234-4433 Neal R. Gross & Co., Inc. Page 133 1 billion. 2 MR. WHITE: 0.1 parts, yes. 3 DR. LEBLANC: Is it because it 4 degrades more rapidly or that is -- is it used 5 effectively as a lesser concentration? 6 MR. WHITE: I don't think that 7 would be the case, but there's probably people 8 in the room that can answer that better than

9 I can. 10 SESSION CHAIR PORTIER: I think we 11 want to stop at this point. I really want to 12 get on to some of the other commentors. And 13 I appreciate the Triazine Network being 14 represented. I've heard you many times, and 15 it's always good to be reminded of where this 16 product fits into agricultural practice and 17 its key component. Thank you very much. 18 The next group that's up is the 19 Syngenta. Syngenta has seven presenters. And 20 they're going to begin their presentation and 21 we'll stop at some good point for lunch and 22 then they'll finish after lunch.

### 202-234-4433 Neal R. Gross & Co., Inc. Page 134 1 Joe, I don't even see seven chairs 2 there so you're going to have to pick and 3 choose who gets to sit at the table. And I 4 guess first up is Dr. Simpkins. Is that 5 first? Or who's your lead on this. You are. 6 Syngenta has provided a large packet of 7 material to the panel and to the online 8 archive. 9 DR. BRECKENRIDGE: Mr. Chairman, 10 I'm Charles Breckenridge. I'm a senior 11 toxicology fellow with Syngenta. I've been 12 responsible for the safety assessment of the 13 product since about 1994. 14 Today we have invited our 15 colleagues who assist us with the 16 interpretation of the endocrine effects of17 atrazine. And we're going to be making multi18 part presentation. The other two Syngenta 19 presenters are, in fact, going to address the 20 water questions and so they'll come up later. 21 To give you an orientation of the 22 sequence of speakers today, and also, Mr.

### 202-234-4433 Neal R. Gross & Co., Inc. Page 135 1 Chairman, just to inquire how you wish to 2 proceed, we have diverse topics that we are 3 going to be talking about and we have 4 approximately in this section 90 minutes of 5 presentation. I trust that it's most 6 convenient to ask questions after each 7 subsection. So if you choose to do that that 8 would be fine. 9 SESSION CHAIR PORTIER: With10 questions we may only be able to get two11 thirds of that. So we'll --

12 DR. BRECKENRIDGE: Sure. It's as 13 you choose. So the first topics -- two topics 14 deal with one of the charge questions, the 15 cancer mode of action, and whether or not it 16 still pertains. 17 The first speaker will be Dr. Jim 18 Swenberg from North Carolina in Chapel Hill. 19 He will be dealing with the framework analysis 20 as it was conducted and presented to the SAP 21 in 2000 and refreshing our memories about the 22 conclusions reached at that time and the

### 202-234-4433 Neal R. Gross & Co., Inc. Page 136 1 implications of any new research on that 2 topic. 3 Dr. James Simpkins from the 4 University of North Texas will then address 5 the question of aromatase and whether or not 6 atrazine is a -- first off, the evidence that 7 it induces aromatase in vitro and the 8 relevance of those observations to the whole 9 animal. As you know, aromatase is a 10 significant enzyme in the conversion of 11 testosterone to estrogen. 12 And any time you would have 13 another mode of action that would lead to the 14 production of estrogen one would be concerned 15 that perhaps that mechanism would be operative 16 in humans. And so Syngenta initiated a 17 program of research with Dr. Simpkins more 18 than three years ago to investigate those 19 studies and try to understand exactly the 20 relevancy of those observations in vitro to 21 the human. And we'll be summarizing about 22 three years of research on that.

### 202-234-4433 Neal R. Gross & Co., Inc. Page 137 1 You have in your packet three 2 papers that were submitted by us at the 3 beginning of the year. These are the papers 4 by Yee et. al. These have not yet actually 5 gone to publication. We've been adding new 6 data to them and we will be publishing those 7 shortly. 8 Finally, I'm going to round up the 9 section where we're making a transition from 10 discussion of the cancer mode of actions and 11 the potential mechanisms to a discussion of 12 the endocrine effects of atrazine relative to 13 non-cancer end points. So that's the bridge 14 section there. It will be very short.

15 We then turn to our Dr. Robert 16 Handa. And when we ended the more animal 17 descriptive toxicology around about the 2000 18 SAP, we turned our attention to the question 19 about the GnRH pulse generator and exactly 20 what were the mechanisms whereby atrazine was 21 affecting that system. 22 Dr. Handa will be summarizing that

### 202-234-4433 Neal R. Gross & Co., Inc. Page 138 1 program of research which also is being 2 carried out over about three years. There are 3 several publications, and those by Foradori 4 et. al. are the ones that are in your packet. 5 But more importantly for us today, we're going

6 to share some of the new research that we have 7 conducted and for studies that are still 8 ongoing. 9 Finally, when we come out of that 10 particular section we're going to turn our 11 attention to the question of the toxicologic 12 consequences of effects on the endocrine 13 system, especially as it pertains to the HPA 14 axis.

15 We're fortunate that Dr. Steve 16 Pruett has agreed to come and speak about his 17 research -- and this is not Syngenta funded 18 research -- that he began in 2003 looking at 19 the relationship between the area under the 20 curve exposure to corticosterone induced by 21 atrazine and immune system responses. 22 In addition to that, Dr. Pruett is

### 202-234-4433 Neal R. Gross & Co., Inc. Page 139 1 advising us on studies that we have ongoing 2 relative to the question of the 3 immunotoxicologic potential of atrazine and 4 we'll share preliminary results of those 5 investigations -- or at least their study 6 designs. We have committed to the agency we 7 will submit those two studies to the agency by 8 about end of July. 9 And, incidentally, those studies 10 were conceptualized and initiated in December 11 of last year and in February I believe of this 12 year. So we're working on a fairly fast track 13 here to try to get data that is meaningful to 14 the questions that are in front of this group. 15 So, with that, I'll turn it over 16 to Dr. Swenberg. 17 DR. SWENBERG: Thank you very 18 much, Charles. And it's a pleasure to be here 19 with the SAP as a former member of this 20 organization. 21 And what I'd like to do today is 22 talk to you about -- since many of the members

### 202-234-4433 Neal R. Gross & Co., Inc. Page 140 1 this is your first SAP on atrazine -- bring 2 you up to date on kind of where we are in 3 understanding the carcinogenic potential of 4 this very important compound. 5 So this slide just gives you an 6 overview of how comprehensive the 7 carcinogenicity database is on atrazine. 8 There have been three different mouse cancer 9 bioassays in males and females. All of these 10 are negative at all sites. 11 There has been a series of Sprague 12 Dawley cancer bioassays. Four of these have 13 been in female Sprague Dawleys and they are a 14 single site, single sex, single tumor type 15 positive. Ovariectomized females were also 16 evaluated, and they are negative at all sites. 17 Sprague Dawley males are negative at all 18 sites. And the Fischer 344 rat, male and 19 females, are negative at all sites. 20 Next please. So what I'd like to 21 do is -- you may or may not be familiar with 22 the international program for chemical safety

### 202-234-4433 Neal R. Gross & Co., Inc. Page 141 1 and the EPA framework for evaluating 2 mechanistic data. This way of examining data 3 came about -- it started at a meeting in 4 Hanover, Germany in 1997, and one of your 5 panel members, Dr. Fenner-Crisp, and myself 6 were at that meeting. 7 It then evolved into more 8 intensive study. A number of publications 9 have come out on it, and, most importantly to 10 you, it is part of the 2005 cancer risk 11 assessment guidelines of the EPA. So we'll 12 walk through these different bullets as they 13 pertain to atrazine. 14 Next please. So the first 15 thing -- go back please. The first thing one 16 does in this framework approach -- and it was 17 brought about to increase the transparency of 18 how decisions are made -- is to postulate the 19 mode of action after a thorough review of, you 20 know, the literature and the findings. 21 And so the postulated mode of 22 action for atrazine is that it causes an

### 202-234-4433 Neal R. Gross & Co., Inc. Page 142 1 increase in mammary tumors by a species, 2 strain, and sex specific mode of action that 3 is the result of prolonged exposure to 4 endogenous estrogen. 5 Next please. So we want to then 6 examine the key events that are driving this 7 phenomenon. So as you heard yesterday from 8 Dr. Cooper, and we'll expand upon today, 9 atrazine inhibits the LH surge in female 10 Sprague Dawley and, as he showed, Wistar rats. 11 The Sprague Dawley rat is well 12 known that its reproductive senescence is 13 characterized by constant estrus. And chronic 14 exposure to atrazine promotes early 15 reproductive senescence in female Sprague 16 Dawley rats. This results in prolonged 17 exposure to endogenous estrogen. 18 So we want to evaluate these key 19 events. According to the framework we'll be 20 looking at dose response relationships, 21 temporal relationships evaluating the 22 strength, the consistency, and the specificity

### 202-234-4433 Neal R. Gross & Co., Inc. Page 143 1 of this association, as well as the biological 2 plausibility and coherence of the results. 3 Next please. So this is a 4 slide -- I think Ralph also showed this 5 yesterday. This is a very high dose cancer 6 bioassay that was done. And one of the things 7 you'll notice -- in the blue are the 8 controls -- that the Sprague Dawley female 9 rats has a very high background incidence of 10 mammary tumors, but that with exposure to 11 atrazine what we're doing is we are decreasing 12 the latency time, i.e. the curve shifts to the 13 left as we're looking at that screen, and we 14 have an increase in incidence. These are the 15 hallmarks of a dose response in 16 carcinogenicity. 17 Next please. I think that Dr. 18 Cooper also showed one of these slides. Now, 19 this slide is very interesting. So he 20 explained how he used vaginal smears to 21 characterize the estrus cycle of the rat. 22 What this slide represents is on the y-axis

### 202-234-4433 Neal R. Gross & Co., Inc. Page 144 1 there are 90 individual lines of animal data. 2 These are the 90 animals that were in this 3 study. This is the six-month period of time. 4 And what you see is this starting 5 of these red lines, and the red lines 6 represent persistent estrus. And what's 7 unusual about the Sprague Dawley rat is that 8 this is a control animal that this early 9 senescence, i.e. persistent estrus, starts 10 very early in their life. It's -- this is 11 about a 90-day into the study where we start 12 seeing this. That's markedly in contrast to 13 most other strains. 14 Next please. Now, if you expose 15 these rats to 400 parts per billion of 16 atrazine for six months and you're doing the 17 same thing -- this is actually the same study 18 now -- these are the 400 PPM atrazine 19 animals -- and you can readily appreciate that 20 the increase in reproductive senescence and 21 the persistent estrus has clearly increased. 22 Next please. This is shown more

### 202-234-4433 Neal R. Gross & Co., Inc. Page 145 1 easily with a -- over on the y-axis we have 2 percent of days in estrus. And you can see 3 the controls are running around between 40 and 4 45 percent, and in a dose-related manner it's 5 going up to 65 percent. So this is the 6 evidence for chronic exposure to endogenous 7 estrogen. 8 Next please. Now, the mechanism 9 for this is this inhibition of the LH surge 10 that Dr. Cooper spoke of yesterday. And what 11 you can see -- it's probably most easily seen 12 in this repeat sample group -- that you have 13 a complete inhibition of the LH surge at high 14 doses. These are the same high doses that 15 result in the increase in mammary cancer. So 16 this shows the dose response relationship for 17 this key event. 18 Next please. Here is a comparison 19 of two bioassays, a second Sprague Dawley 20 bioassay and a Fischer 344 bioassay. These 21 are the female animals. And you see the much 22 higher incidence of the mammary cancer in the

### 202-234-4433 Neal R. Gross & Co., Inc. Page 1461 Sprague Dawleys and that there is a dose2 related increase. And now we're up to a 80 3 percent incidence in the control animals -- 4 just showing you how susceptible these animals 5 are. The Fischer rat on the other hand has a 6 much lower background of mammary cancer and 7 there is no dose response relationship. 8 Next please. If one looks then at 9 the percent of days in estrus you also see a 10 very striking difference. We have the 11 increase and dose response relationship in the 12 Sprague Dawleys in days in constant estrus 13 compared to the Fischer rat where this effect 14 just does not happen. In fact, the amount of 15 estrogen days decreases with increasing age. 16 Next please. This is then 17 compared across the board for the Sprague 18 Dawley rat, the Fischer rat, and the human. 19 So you can see I spoke about when senescence 20 starts. You can see that the Sprague stands 21 out here at 30 to 40 percent of the life span, 22 whereas the Fischer rat and the human are more

### 202-234-4433 Neal R. Gross & Co., Inc. Page 147 1 in the 60 to 70 percent range. 2 The principal cause of senescence 3 in the Fischer -- or the in Sprague Dawley rat 4 is this lack of the LH surge and the lack 5 of -- so it's a hypothalamic failure rather 6 than an ovarian failure. 7 In the Fischer rat we also have 8 hypothalamic failure, but now it's not for LH 9 release, it's for controlling prolactin 10 surges. And in the human it's depletion of 11 ovarian follicles that drive reproductive

12 senescence. 13 So if we look at the LH surge 14 capacity the Sprague Dawley loses this, the 15 Fischer rat maintains it, and the human 16 maintains it. Estrogen and progesterone 17 ratios are elevated and prolonged in the 18 Sprague Dawley, they're reduced in the 19 Fischer, and they're reduced in the human. 20 The predominant cyclic pattern is 21 one of persistence estrus in the Sprague 22 Dawley rat, pseudopregnancy episodes in the

### 202-234-4433 Neal R. Gross & Co., Inc. Page 148 1 Fischer rat, and menopause in the human. 2 Prolactin secretion is persistency elevated. 3 It's -- in the Sprague, it's episodically 4 elevated in the Fischer, and it's reduced in 5 women. And prolactin dependence is high in 6 the Sprague Dawley, medium in the Fischer, and 7 non-existent in the women. 8 Next please. So pulling this all 9 together one can look at the human relevance 10 of this. The LH surge suppression does not 11 increase estrogen exposure in humans. The 12 ovary, not the hypothalamus, drives 13 reproductive senescence in humans, and 14 reproductive aging in human results in 15 estrogen deprivation, not increased exposure 16 to estrogen. 17 Next please. So the next part of 18 the framework mode of action analysis is to 19 consider are there other potential modes of 20 action that we need to be examining? And 21 three of them that have continually been 22 evaluated are shown here. Is the compound

### 202-234-4433 Neal R. Gross & Co., Inc. Page 149 1 genotoxic, is it estrogenic, and does it 2 affect aromatase? Many of these issues on the 3 hormonal milieu were covered also by Dr. 4 Cooper yesterday. 5 Next please. So the next two 6 slides will just give you the large number of 7 in vitro studies that have been conducted on 8 atrazine for genotoxic potential. And they 9 cover virtually all of the types of assays 10 that are normally done for hazard I.D. You'll 11 notice that they're predominantly negative 12 with very few positive studies. 13 Next slide. You also see it in 14 this slide. This is the status of the data in 15 the year 2000. 16 Next please. So the weight of 17 evidence in the year 2000 strongly indicated 18 that atrazine is not genotoxic. This is 19 derived from two reviews by David Brusick in 20 1994 and again in 2000. Again, in 2000 Dr. 21 Andrew Kligerman from the Research Triangle 22 Park EPA did sister chromatid exchange in

### 202-234-4433 Neal R. Gross & Co., Inc. Page 150 1 chromosome analysis studies. They were 2 negative. 3 And there are a number of studies

4 that have been done between 2000 and the 5 present time that were in your package. And 6 these also do not change the weight of 7 evidence. So atrazine is not genotoxic and we 8 can put away that mode of action. 9 Next please. The second was the 10 estrogenic potential of atrazine, and, there 11 again, have been a wide number of screening 12 studies that have been -- that have evaluated 13 this as well as some of the traditional 14 reproductive toxicology studies. They are all 15 negative. So estrogen is not -- or I should 16 say atrazine is not estrogenic. 17 Next slide. But we still do have 18 uncertainties. This is the last step in a 19 framework mode of action. So the mode of 20 action underlying the tumor response in the 21 Sprague Dawley females is very well 22 understood. However, the precise targets

### 202-234-4433 Neal R. Gross & Co., Inc. Page 151 1 still have more to be known. 2 Since the 2000 review Dr. Handa's 3 laboratory has started to work on this, and he 4 is primarily focused on the HPG and the HPA 5 targets that Dr. Cooper also talked about 6 yesterday. And he will speak later on on this 7 new research so that you are brought right up

8 to date on where we're at. 9 Furthermore, the significance of 10 the in vitro induction of aromatase was

11 unknown. There has been research now on 12 amphibians and on fish that has been 13 conducted, and it did not show any evidence 14 for functional consequences in vivo. 15 Furthermore, Dr. Simpkins will 16 bring you up to date on his laboratory's 17 efforts to assess the mechanisms -- the in 18 vitro mechanisms and to explore why we're not 19 seeing these effects in vitro, again, to bring 20 you up to the very latest point. 21 Next please. So one can use the 22 cancer risk assessment guidelines, go through

### 202-234-4433 Neal R. Gross & Co., Inc. Page 152 1 the human evidence, the animal evidence, the 2 mode of action, and the human relevance of 3 that mode of action, and you see the checks in 4 these boxes that is -- this was based back in 5 the year 2000 -- it has not changed. 6 Next please. So, in conclusion, 7 the mode of action underlying the increased 8 risk and incidence of mammary tumors to a 9 female Sprague Dawley rat is very well 10 characterized. The key events that are 11 leading to this carcinogenic response have 12 been elucidated and are dose dependent and 13 temporally consistent. 14 The mode of action has been 15 determined to not be relevant to humans. And 16 plausible alternative modes have been 17 experimentally discounted.

18 The U.S. EPA concluded that 19 atrazine is not likely to be carcinogenic in 20 humans. And other international groups, 21 including IARC, Australia, the EU, and the WHO 22 have reached similar conclusions. New

### 202-234-4433 Neal R. Gross & Co., Inc. Page 153 1 research that has been conducted since 2000 2 has strengthened the confidence in this 3 conclusion. 4 Now, I'd like to end with one last 5 thing that came up yesterday. Could we have 6 the next slide? There was a question raised 7 about polycystic ovary syndrome in women. 8 This was a major focus in the 2000 SAP 9 assessment of atrazine. And Dr. John Marshall 10 from the University of Virginia, who is a 11 recognized expert on PCOS, put together this 12 slide and gave a presentation. 13 So you can see the comparison here 14 of atrazine versus PCOS. Atrazine has reduced 15 LH secretion. PCOS is associated with 16 elevated LH secretion. Atrazine has decreased 17 LH pulse amplitude. PCOS has increased LH 18 pulse amplitude. There is no change in 19 pituitary sensitivity to GNRP -- or H I should 20 say -- whereas in PCOS there is increased 21 pituitary sensitivity. 22 There is -- it is correlated with

### 202-234-4433 Neal R. Gross & Co., Inc. Page 154 1 weight loss -- atrazine exposure is -- in the 2 rat, whereas PCOS is commonly correlated with 3 both obesity and diabetes. Androgen levels 4 are decreased or unchanged with atrazine. 5 They are markedly increased in PCOS. They are 6 not associated with endometrial cancer in 7 atrazine. PCOS has an increased association 8 with endometrial cancer. 9 Atrazine is associated, as you 10 heard, with mammary tumors. PCOS does not 11 have any association with breast cancer. 12 Atrazine induces reproductive senescence. 13 PCOS does not resemble menopause. And the 14 neuroendocrinology of atrazine is well 15 understood. It is not well understood for

16 PCOS. 17 Last slide please. So this is 18 just a quote out of the 2000 SAP on atrazine 19 cancer classification meeting. Further, if 20 this and this relied -- or was -- if you went 21 back to the previous sentence was associated 22 with LH -- flattening of the LH response --

### 202-234-4433 Neal R. Gross & Co., Inc. Page 155 1 occurred in humans. It could not result in 2 PCOS since this condition is associated with

3 elevated LH. 4 Therefore, the conclusion that 5 there could be a potential for human cancer 6 from elevated estrogen levels if atrazine had 7 effects on conserved hypothalamic mechanisms 8 in humans similar to those in Sprague Dawley 9 rats is at odds with the arguments and other 10 conclusions of the agency draft assessment. 11 So I hope this is helpful to the 12 discussions on PCOS. Thank you very much. 13 SESSION CHAIR PORTIER: I think at 14 this point we'll open it up to a couple of 15 questions. Is there some? Dr. Holladay. 16 DR. HOLLADAY: Nice overview. 17 Thank you. One of your slides indicated there 18 were no functional differences found in fish 19 exposed to atrazine. I think there was a 20 review in EHP, or Environmental Health21 Perspectives, in `10 -- 2010. There's a meta22 analysis of the literature available that

### 202-234-4433 Neal R. Gross & Co., Inc. Page 156 1 suggested something like 30 out of 40 immune 2 end points were suppressed in freshwater fish 3 with atrazine exposure. Are you aware of why 4 that might be the case what these guys found 5 as compared to what you were suggesting? 6 DR. BRECKENRIDGE: Yes, sir. 7 Charles Breckenridge from Syngenta. I'll 8 respond first with respect to the statements 9 on Cloath and Tanguay. Those comments were 10 pertaining to reproductive effects on 11 aromatase specifically as a mechanism whereby 12 a sex reversal could be accounted for by 13 atrazine exposure. 14 And, in fact, this panel in 15 earlier times has reviewed the Cloath work, 16 and the evidence suggests that there's no 17 evidence of aromatase modification in those 18 animals. In regard to immunotoxicity in 19 native species, I think that would be more 20 appropriate at another SAP rather than here 21 because today we're going to be mainly 22 focusing on the endocrine mechanism. So if I

### 202-234-4433 Neal R. Gross & Co., Inc. Page 157 1 could ask to defer any kind of a detailed 2 discussion on that, sir, I'd appreciate it.

3 SESSION CHAIR PORTIER: Dr. Reed? 4 DR. REED: I have two questions. 5 One is in your slide 14. So you line up the 6 Sprague Dawley and Fischer 344 and then women. 7 Since the mice bioassay also indicated 8 negative response for mammary gland tumors, 9 could you line up mice -- adding another 10 column for mice in this schematic of things, 11 or is it not -- 12 DR. SWENBERG: I don't believe 13 those studies have been conducted because of 14 the negative bioassay, but certainly it could 15 be looked at. But the mouse doesn't go into 16 the same reproductive senescence that the 17 Sprague Dawley female does. 18 DR. REED: Right. That's what I 19 was asking about -- if you could line them up 20 together with that. 21 DR. SWENBERG: Yes. I don't think 22 that's been attempted --

### 202-234-4433 Neal R. Gross & Co., Inc. Page 158 1 DR. REED: Mode of action -- 2 DR. SWENBERG: -- but it's a good 3 suggestion. 4 DR. REED: Okay. My next question 5 is that in the agency's issue paper there are 6 two studies of Fukamachi 2004 and Ueda 2005 7 that allude to the possibility of promotional 8 potential. Would you care to comment on that? 9 I mean, I understand that there's a lot of, 10 you know, issues about the study design and 11 also the interpretation of the data. 12 But given that it -- what the 13 author is saying has merit, meaning that 14 there's a possibility of promotional 15 potential, how would that fit into the mode of 16 action scheme? 17 DR. SWENBERG: Yes. This -- these 18 two papers -- I've gone through them several 19 times. They are very complex. So if the 20 first paper, which is -- has the transgenic 21 animals being used, I have not yet been able 22 to find, you know, what are the numbers of

### 202-234-4433 Neal R. Gross & Co., Inc. Page 159 1 copies of the transgene in different animals 2 and different cells. You'll remember this was 3 an issue with the TGAC mouse -- transgenic

4 mouse. 5 So I'm having a difficult time 6 understanding it. The statistical analyses

7 that were done are somewhat unusual. The 8 model's quite unusual. If we go to the second 9 paper where they use the fairly standard DMBA 10 breast cancer induction model -- I am familiar 11 with that model. 12 Again, the data are really 13 difficult to interpret. There is some 14 suggestion of a high dose effect there. But 15 what the mechanism is I don't think we 16 really -- I mean, those animals were 17 ovariectomized. So it's not a mechanism 18 that's similar to what we're seeing in these 19 bioassays. 20 But they do deserve further 21 consideration of all of the work that's been 22 published related to genotoxicity and

### 202-234-4433 Neal R. Gross & Co., Inc. Page 160 1 promotion and that. Those are very 2 interesting papers and provocative papers. 3 But I've been working in carcinogenicity 4 research for more years than I'd like to -- 5 going back to before 1970 -- let's put it that 6 way -- including promotion and initiation 7 promotion studies, and I can't fully interpret 8 those studies.

9 SESSION CHAIR PORTIER: Dr. 10 Williams. 11 DR. WILLIAMS: I just wanted to 12 clarify. You said in on one of your --

13 SESSION CHAIR PORTIER: Pull the 14 mike closer. 15 DR. WILLIAMS: Sorry -- LH 16 suppression does not increase estrogen 17 exposure in humans. What it looked like you 18 were really saying was that PCOS is associated 19 with elevated LH levels. But if you actually 20 suppress LH is there any experimental evidence 21 to say that in humans, or maybe in primates, 22 that suppression of LH does not increase

### 202-234-4433 Neal R. Gross & Co., Inc. Page 161 1 estrogen exposure? 2 DR. SWENBERG: I'm going to turn 3 that over to Dr. Simpkins. He's an expert in 4 this area.

5 DR. HANDA: I'm not sure I 6 understand the question completely. But since 7 estrogen is driven by LH changes with age -- 8 and I'm assuming you mean changes with age in 9 at menopause there's decrease -- 10 DR. WILLIAMS: No. I'm actually 11 not talking about menopause at all. So if you 12 think about younger women who are 13 anovulatory -- sometimes PCOS related but 14 sometimes for reasons that we can't -- 15 DR. HANDA: Hypothalamic 16 amenorrhea or something like that.17 DR. WILLIAMS: Or simply oligo18 ovulatory for, you know, unexplained reasons. 19 That type of women -- is there any evidence 20 that their failure to ovulate potentially a 21 slight disregulation of LH, as opposed to 22 complete ovarian failure where you don't --

### 202-234-4433 Neal R. Gross & Co., Inc. Page 162 1 you know, obviously estrogen has left. 2 DR. HANDA: Usually those are 3 associated -- for example, hypothalamic 4 amenorrhea will be associated with a decrease 5 in LH, and, as a result, there's no 6 corresponding increases in estrogen. 7 DR. WILLIAMS: But, again, so 8 complete hypothalamic amenorrhea is -- you 9 know, is again a complete failure. What about 10 oligomenorrhea -- women who periodically don't 11 ovulate? Where -- you know, here we're 12 talking about this potentially intermittent 13 suppression of LH release related to 14 intermittent high levels of atrazine. 15 So if you see this happening how 16 can you say that that would not necessarily 17 increase estrogen exposure? Is there any 18 evidence for that? 19 DR. HANDA: As far as I know, no. 20 SESSION CHAIR PORTIER: Okay. I 21 think we'll move on to the next presentation. 22 DR. SIMPKINS: I'm Jim Simpkins

### 202-234-4433 Neal R. Gross & Co., Inc. Page 163 1 from the University of North Texas Health 2 Science Center. And I think I can do this. 3 We will in the next few minutes 4 try to sort out the observation that in 5 certain transformed cell lines exposure to 6 relatively high doses of atrazine induce 7 expression of aromatase, enhanced aromatase 8 activity. Whereas that observation is not 9 made in vivo. The answer to that is we 10 believe embedded in the metabolism of atrazine 11 with exposure, certainly to mammals, and 12 likely to every species. 13 Atrazine is a relatively short 14 lived compound after dosing. It is converted 15 to the chlorotriazines which are shown in the 16 green area on that slide. Those 17 chlorotriazines, as well as atrazine itself, 18 are then conjugated as part of the process of 19 their elimination. What is also shown on that 20 slide is the percent of those metabolites that 21 are present in the urine. This happens to be 22 in humans, but the numbers are very similar in

### 202-234-4433 Neal R. Gross & Co., Inc. Page 164 1 primates as well as in rodents. Where the 2 dominant form are the conjugated triazine and 3 triazine metabolites. Ammeline and 4 hydroxytriazine are plant metabolites shown

5 here and here. 6 The point I will make is that we 7 have an opportunity with cell lines to ask 8 questions that simply cannot be asked in vivo 9 because cell lines are not good at 10 metabolizing atrazine so when we put atrazine 11 in, we should, at the end of our studies have 12 predominantly atrazine with very little 13 metabolism occurring. 14 Now what I will show you are what 15 I think are the most comprehensive studies 16 done to date. For concentration and duration 17 assessment of the effects of atrazine, and a 18 variety of its metabolites, in an H295R cell, 19 this is an adrenal cortical tumor cell line 20 that was shown by Sanderson to be responsive 21 to atrazine with increased expression in 22 activity of aromatase. So we wanted to take

### 202-234-4433 Neal R. Gross & Co., Inc. Page 165 1 a careful look at that cell line. I will also 2 point out to you that the data you see, will 3 see, were presented in one of the manuscripts 4 that Dr. Breckenridge refers to. The data you 5 will see is essentially identical to data that 6 we have in a placental tumor cell line which 7 also responds to atrazine. So you will see 8 part of the data but I think, as you will 9 agree, it is an extensive data set. 10 What is shown here is aromatase 11 messenger RNA levels in H295R cells that were 12 treated from as short as a quarter of an hour 13 to 72 hours at four doses, 0.100 nanomolar, 1 14 micromolar, 10 micromolar. As you can see15 atrazine causes a consistent two- to three16 fold increase in expression of aromatase 17 messenger RNA that begins at about two hours 18 and persists through 72 hours. 19 So with this high concentration of 20 atrazine in a cell type that cannot metabolize 21 you can induce, you can demonstrate a highly 22 reliable consistent induction of aromatase.

### 202-234-4433 Neal R. Gross & Co., Inc. Page 166 1 If we look at two of the chlorinated 2 metabolites, the desethyl and desisopropyl 3 forms of atrazine, we see a modest response 4 that is delayed relative to atrazine and is 5 reduced in amplitude. You can notice, this is 6 for both of those metabolites this is less 7 than a two-fold induction of the message. 8 In contrast to that, 9 hydroxyatrazine, ammeline, and 10 diaminochlorotriazine are negative at all 11 times and all doses, short of a sporadic hit 12 here or there, but I will point out to you 13 that for each of these metabolites there are 14 essentially 44 samples, so we're not surprised 15 that we get an occasional hit. Statistically 16 we ought to see that happen occasionally. But 17 we don't think these small occasional hits are 18 significant. So these metabolites appear to 19 be inactive.

20 We also then looked at two model 21 conjugates of atrazine -- that is, the 22 glutathione and the mercapturate form of

### 202-234-4433 Neal R. Gross & Co., Inc. Page 167 1 atrazine, keeping in mind that the atrazine is 2 the active, and we wanted to know when they're 3 conjugated does atrazine lose its activity. 4 Not only is atrazine negative when 5 it's conjugated, there appears to be a 6 reduction in aromatase message, at least at 7 the 24-hour sampling point. So these 8 metabolites, which are the predominant form 9 soon after administration of atrazine, are not 10 inducing aromatase in this cell line. 11 The doubling that we saw in 12 message is very consistent with measurements 13 of activity conducted by Dr. Sanderson, as 14 well as with an increase in this case estrone 15 concentrations in the media. And his 16 metabolite response is very similar to that 17 which we see. Two of the chlorometabolites 18 show an increase in activity of aromatase, 19 whereas the hydroxymetabolites are completely 20 negative. So we think there's good 21 concordance in the data sets to date. 22 So this message increase is

### 202-234-4433 Neal R. Gross & Co., Inc. Page 168 1 consistent with activity increase, and all of 2 them are happening at or around ten micromolar 3 atrazine in vitro. And we've identified those 4 metabolites which are inactive in vitro, and 5 those are the predominant metabolites that 6 show up when atrazine exposure occurs in vivo. 7 An additional question we asked 8 was the extent to which the induction of 9 expression of aromatase could be secondary to 10 cytotoxic effects of atrazine or its 11 metabolites. And we undertook these series of 12 studies because we had been studying nervous 13 tissue, and it's very clear that chemical or 14 physical insults to brain cells result in 15 expression of aromatase, and that's probably 16 part of a protective mechanism there.

17 So -- but before we do that I want 18 to make a comment about all of these in vitro 19 studies -- and it is for you the panel just a 20 word of caution. Atrazine is very insoluble. 21 What's shown here are photomicrograms of 22 atrazine at 3 micromolar, 10, and 30

### 202-234-4433 Neal R. Gross & Co., Inc. Page 169 1 micromolar in culture. And in many of the 2 documents that you've had to read folks are 3 using in vitro exposures up in this range. 4 In PBS we see atrazine come out of 5 solutions somewhere between 1 and 3 6 micromolar. That's shown in these slides as 7 the dark aggregates. Those aggregates are 8 larger in number and in size at higher 9 concentrations of atrazine. And at 30 10 micromolars you can see they're completely 11 covering the cells in this dish. If you 12 solubilize in DMSO you can enhance the 13 solubility of atrazine. But I'll point out to 14 you, at 30 micromolar we start seeing atrazine 15 come out of solution. So keep that in mind in 16 interpreting data. 17 Despite those aggregates, when we 18 look at solubility using any of three methods 19 at times ranging from a few minutes all the 20 way out to 72 hours -- and what's shown here 21 is representative data at 24 hours -- even at 22 extraordinarily high concentrations -- in this

### 202-234-4433 Neal R. Gross & Co., Inc. Page 170 1 case up to 300 micromolar -- in which cells 2 are literally coated with atrazine we get no 3 toxicity. 4 And we don't see toxicity for this 5 which is a cell viability assay. We don't see 6 it if we look at assays that require 7 functioning mitochondria to report the health 8 of cells. We don't see it if we look at 9 production of reactive-oxygen species. We get 10 a straight line over an extraordinarily wide 11 range of atrazine concentrations. 12 We see no toxicity with any of the 13 metabolites that I showed you in the previous 14 slides at any of the times we assessed. And 15 we see no interaction between atrazine and, in 16 this case, three known cytotoxic agents, 17 glutamate, succinate dehydrogenase inhibitor, 18 NPA, and then exogenous administration of 19 hydrogen peroxide. 20 So atrazine is neither protecting 21 these cells nor enhancing the toxicity of 22 known insults. So atrazine and its

### 202-234-4433 Neal R. Gross & Co., Inc. Page 171 1 metabolites are not cytotoxic in the cell 2 lines, and they don't potentiate toxicity of 3 other agents. 4 We then turn our attention to 5 potential effects of triazines on 6 phosphodiesterases. And we did that because 7 in the literature there were a number of hints 8 that atrazine may be interacting with the 9 breakdown of cyclic AMP, which is one of the 10 jobs of phosphodiesterases. 11 For example, dating way back to 12 1997 there's a report that a high single dose 13 of atrazine increase cyclic AMP levels in 14 livers of rats. Leroux reported on a series 15 of chemicals that he had synthesized using 16 atrazine as a scaffold for the purpose of 17 producing phosphodiesterase for inhibitors and 18 showed very good evidence that he could 19 improve the phosphodiesterase-4 inhibiting 20 activity of atrazine. 21 Sanderson reported in 2002 that 22 there was a strong correlation between

### 202-234-4433 Neal R. Gross & Co., Inc. Page 172 1 atrazine's effects on cyclic AMP 2 concentrations and their ability to induce 3 expression of aromatase. And then in 2004 4 Roberge reported that atrazine inhibited 5 phosphodiesterase using a bovine liver 6 preparation. And there's a great deal of data 7 from a variety of sources indicating that 8 cyclic AMP is critical to aromatase gene 9 expression. 10 So what we set about doing was 11 asking the question, does atrazine or any of 12 the metabolites that I showed you interfere 13 with phosphodiesterase activity and thereby 14 increase cyclic AMP and then signal to 15 aromatase through this PKA CREB 16 phosphorylation pathway. 17 And then I'll finish by showing 18 you data that resulted from us identifying the 19 phosphodiesterases in H295R cells as well as 20 in the JEG3 cells and then designing and using 21 small inhibitory RNAs to knock down message 22 levels for those species and the effects that

### 202-234-4433 Neal R. Gross & Co., Inc. Page 173 1 that has on the atrazine signaling. 2 These are all results for atrazine 3 inhibition of phosphodiesterase activity. 4 IBMX is a well-described phosphodiesterase 5 inhibitor that has an IC50 value of about two 6 micromolar. Atrazine does indeed repeatedly 7 reduce phosphodiesterase activity. It's about 8 20-fold less potent than IBMX. 9 And then the other metabolites 10 that we assessed really had very little 11 activity in this assay. Their IC50s, if we 12 could calculate them, were in the millimolar 13 or molar range, which means that they are very 14 ineffective PDE inhibitors. 15 We then designed primer pairs to 16 ask questions about what species of 17 phosphodiesterase is made by the H295R cells, 18 and we did the same with the JEG3 cells 19 because both of those cell types essentially 20 showed the same time course and magnitude of 21 aromatase induction in response to atrazine. 22 We made the assumption that, that

### 202-234-4433 Neal R. Gross & Co., Inc. Page 174 1 being the case, the two cell lines should show 2 comparable phosphodiesterases, and we could 3 use those to identify the site of action of 4 atrazine. And it turns out four 5 phosphodiesterases were picked up by our 6 primer pairs in both of those cell types. 7 But only two of those were present 8 in the same relative concentration -- and that 9 is the PDE4D and the PDE8. We then built 10 siRNA constructs to knock down those species,

11 and these are those data. 12 The siRNAs for PDE4 reduced PDE4D 13 levels by about 50 percent. The siRNAs for 14 PDE8 reduced levels by about 60 percent. In 15 both cases reducing levels of these 16 phosphodiesterases essentially blocked the 17 ability of aromatase to induce -- excuse me -- 18 of atrazine to induce aromatase expression, 19 suggesting that these PDE4s were indeed 20 mediating the ability of atrazine to induce 21 expression of aromatase. 22 What we haven't yet done, because

### 202-234-4433 Neal R. Gross & Co., Inc. Page 175 1 this is an ongoing set of studies, is 2 transfected into these cells scrambled forms 3 of the siRNA to make sure that we're not doing 4 something else to the cells that's off target. 5 Those things will be done and hopefully will 6 be reported to you this summer. 7 So let me finish and conclude. 8 The in vitro-in vivo dichotomy and the effects 9 of atrazine on aromatase we believe are 10 because atrazine is very rapidly metabolized 11 in vivo with the formation of essentially 12 inactive or weakly active chlorotriazines as 13 well as conjugates, and, therefore, atrazine 14 doesn't stay around long enough to induce 15 aromatase expression. 16 That's in contrast to what we 17 believe is happening in cell types where the 18 triazine that we put in is either not 19 metabolized or only metabolized very slowly, 20 is able to stay around and, likely through a 21 PDE inhibition, able to increase expression of

22 aromatase.

### 202-234-4433 Neal R. Gross & Co., Inc. Page 176 1 And, finally, I would point out 2 that in the in vitro system these effects of 3 the triazines happen at very high 4 concentrations. Thank you. 5 SESSION CHAIR PORTIER: Thank you. 6 We'll open it up for some questions. Dr.

7 Schlenk? 8 DR. SCHLENK: I'm actually really 9 intrigued by your conjugate data because I 10 guess I wouldn't have expected the conjugates 11 to cross the cell membrane and get into the 12 cells. But, yet, the glutathione conjugate 13 does appear to actually impair transcription. 14 I'm just curious what your thoughts are in 15 particularly the glutathione conjugate and how 16 that may actually be impairing. 17 DR. SIMPKINS: Yes. Keep in mind 18 in all of our study -- in vitro studies we do 19 these assessments with I think -- with 0.01 20 percent DMSO, which is probably affecting 21 solubility of membrane and maybe enhancing the 22 movement of the conjugates into the cells. I

### 202-234-4433 Neal R. Gross & Co., Inc. Page 177 1 don't know. 2 DR. GREENWOOD: Richard Greenwood. 3 You in your figures say that I think it was 85 4 percent was conjugated to glutathione and 15 5 percent not. Which -- what's the source of 6 the data? Because it's sort of flipped on 7 that in quite a few of the rodents. That is 8 where I think it's more or less exactly the

9 converse. 10 DR. BRECKENRIDGE: Okay. There 11 are several sources of the data. In fact, 12 there are regulatory studies in radiolabeled 13 compounds in regard to metabolism in rodents. 14 And so when Dr. Simpkins mentioned there was 15 a concordance between rodents and primates and 16 humans, there is approximately -- and it's 17 fairly well described, at least in our data 18 and others -- that the chlorals represent only 19 about a maximum 15 percent, and the rest are 20 conjugates. 21 I'm sorry. I don't know the 22 discrepancy between information you have and

### 202-234-4433 Neal R. Gross & Co., Inc. Page 178 1 what we understand. But that's roughly the 2 situation. The rates of metabolism and the 3 elimination kinetics are described in some 4 rodent studies. We have done primate studies 5 and we intend to do actually a much more 6 thorough characterization of that on a shorter 7 time scale given the concerns about short time 8 frame events, especially as it relates to the 9 HPA axis. 10 So to some extent we're going to 11 come back with some pharmacokinetic data that 12 gives a proper description of the early time 13 events in the biotransformations using 14 specific analyte techniques to get at all the 15 metabolites that are pertinent I think to the 16 toxicities we're discussing here. So perhaps 17 if you'd give us a chance at the next 18 occasion, we'll have a lot more data on that.

19 SESSION CHAIR PORTIER: Dr. 20 Williams? 21 DR. WILLIAMS: I just have a short 22 question about the different

### 202-234-4433 Neal R. Gross & Co., Inc. Page 179 1 phosphodiestrases. Is there any evidence that 2 atrazine affects various PDEs differently? So 3 you looked at 4 and 8, but what about PDE3 or 4 others that are more prevalent function in 5 other tissues?

6 DR. SIMPKINS: We have not 7 assessed specific interaction of atrazine 8 on -- to date on any of the specific 9 phosphodiesterases, some of which, as you 10 know, are cloned and the proteins are 11 available. So those studies are doable -- we 12 just don't have the data on them. 13 The data that I showed is a liver 14 homogenate phosphodiesterase preparation. So 15 atrazine could be affecting any of a number of 16 phosphodiesterases. The other thing you would 17 note is that the maximum suppression produced 18 by atrazine, as well as IBMX, is only about a 19 60, 65 percent reduction in phosphodiesterase 20 activities. So there are other 21 phosphodiesterases that appear to be resistant 22 to both of those compounds.

### 202-234-4433 Neal R. Gross & Co., Inc. Page 180 1 SESSION CHAIR PORTIER: Dr.

2 Chambers?

3 DR. CHAMBERS: Back to Dr. 4 Schlenk's question, is it possible in your 5 system that those conjugates were being 6 hydrolyzed?

7 DR. BRECKENRIDGE: Just as a 8 further comment on the aspect of the uptake of 9 chemicals into the cells, we are actually 10 going to do a metabolite profiling in the 11 media and intracellularly with these H295R 12 cells just so we can ascertain whether any 13 biotransformations are occurring. 14 And, secondly, we want to know 15 what the component of, lets say, 16 bioconcentration due to the DMSO is. 17 Obviously we're interested in biological 18 processes under physiological conditions and 19 not these kinds of model systems that are used 20 for other purposes. So we have those 21 investigations in plan as well. 22 DR. SELVAGE: Dan Selvage. I just

### 202-234-4433 Neal R. Gross & Co., Inc. Page 181 1 had a question about the PDEs of 4B and 4D? 2 Perhaps you can help me out here. Do you know 3 their expression levels in the pituitary or 4 hypothalamus? I thought 4B was in the 5 pituitary but I'm not 100 percent sure on

6 that.

7 DR. SIMPKINS: I don't know 8 relative expression levels of the various 9 subtypes in all the tissues. I don't know 10 about the pituitary. 11 DR. DELCLOS: I'm not sure this is 12 the appropriate place for the question. But 13 since you mentioned pharmacokinetic studies 14 and you mentioned -- you were discussing the 15 solubility issue, I'm wondering if this is -- 16 are there pharmacokinetic studies being done 17 closer to levels of human exposure? 18 There's some things that strike me 19 as unusual about the pharmacokinetic data, 20 either if there's double peak of absorption in 21 the mouse and rat or with the flat level of 22 atrazine appearing over time. And I'm

### 202-234-4433 Neal R. Gross & Co., Inc. Page 182 1 wondering if solubility in the gut has 2 something to do with this, these higher dose

3 levels. 4 DR. BRECKENRIDGE: Okay. Thank 5 you very much. We are going to do really a 6 study design prep work after this meeting, and 7 we're going to kick those studies off so that 8 we're welcoming any suggestions that would 9 inform risk characterization as far as 10 biotransformation over short time periods, 11 including lower doses. And actually I think 12 Dr. Swenberg is -- low doses are near and dear 13 to his heart. And we tend to want to do 14 studies in relative -- in meaningful dose 15 ranges, both for animal modeling as well as 16 human risk characterization. So we'll 17 certainly take that into consideration, sir.

18 SESSION CHAIR PORTIER: For the

19 record that was Dr. Delclos asked the 20 question. Any additional comments? 21 This is probably a good point to 22 break for lunch, but I -- but if you want to

### 202-234-4433 Neal R. Gross & Co., Inc. Page 183 1 have a closing remarks on this section, 2 because I know your transition. I looked3 through your slides and it's more of the non4 cancer stuff. 5 DR. BRECKENRIDGE: I don't think 6 we need to make a closing statement. I'll 7 make an introductory statement for the next 8 two parts then when we return. Thank you very 9 much, sir.

10 SESSION CHAIR PORTIER: So the 11 panel's been sucking this all in. We need 12 biological material to keep going. So we'll 13 break until -- I have 12:02. We'll break till

14 1:15. We'll reconvene at 1:15. 15 (Whereupon, the meeting adjourned, 16 to reconvene this same day, April 27, 2010, at 17 1:15 p.m.)

18

19

20

21

22

### 202-234-4433 Neal R. Gross & Co., Inc. Page 184 1 A F T E R N O O N S E S S I O N 2 1:15 p.m. 3 SESSION CHAIR PORTIER: So, Dr. 4 Breckenridge, I guess we'll continue with 5 your -- what was it? -- transition from cancer

6 to non-cancer. 7 DR. BRECKENRIDGE: Thank you very 8 much, Mr. Chairman. So the next sections deal 9 with the toxicologic consequences of the 10 endocrine effects of atrazine, especially as 11 it relates to non-cancer end points. 12 And the first thing we want to 13 talk about is -- you will recall in November 14 we postulated that there was a dose duration 15 phenomenon relative to the responsiveness of 16 the GnRH system to atrazine's effects. And 17 this exhibit -- it appeared in handouts. 18 Short duration studies of Dr. 19 Cooper referred to these the other day, and 20 these are his data. Single day or three day 21 leads to no effect levels on the LH surge 22 suppression. In our own hands we have shown

### 202-234-4433 Neal R. Gross & Co., Inc. Page 185 1 that for five days we get effects as low as 50 2 milligrams per KG. Longer duration studies of 3 the no effect levels progressively get lower

4 and lower. 5 The Stoker 2000 is an important 6 study, and it didn't specifically measure LH 7 in this particular study, but it measured the 8 time to I believe vaginal opening, which is 9 presumed to be attributed to some effect on 10 pulsatile GnRH release. 11 And then the Morseth study is the 12 six-month study that Dr. Swenberg was speaking 13 of earlier where we measured LH in female 14 Sprague Dawley rats after they had been 15 treated for six months. 16 We recognize that there's an 17 interaction between duration of treatment and 18 sensitivity to the chemical. And so we wanted 19 to postulate or try to separate those 20 components. 21 This slide is a recapitulation of 22 similar kind of characterization, so that the

### 202-234-4433 Neal R. Gross & Co., Inc. Page 186 1 shorter duration types of studies that usually 2 set short duration toxicologic end points for 3 the purpose of risk assessment tend to have 4 higher no effect levels. Not all of the 5 responses on this slide are relating to the LH 6 effect, so that there's information here about 7 pregnancy loss and so on. 8 But quite a number of them 9 actually are relating presumably to effects on 10 the LH pulsatile release. And so you go from 11 shorter duration early in life time at no 12 effect levels to older animals that are, in 13 the case of the female Sprague Dawley rat, 14 particularly sensitive. 15 Next slide. So we designed a 16 study that would try -- would ask the question 17 as to whether or not the young animal is more 18 sensitive than the older animal relative to 19 the effects on -- atrazine's effects on LH. 20 And for this study we had two cohorts of 21 animals. The first cohort called Cohort 1 the 22 dams were treated from the point of conception

### 202-234-4433 Neal R. Gross & Co., Inc. Page 187 1 all the way through end of lactation. The 2 pups were receiving atrazine in their milk3 through the mother at that time. And post4 lactationally we started gavaging the pups 5 with the appropriate dose. 6 These cohorts run for different 7 durations of time. And the first time that we 8 were interested in assessing them was five 9 days after vaginal opening. And this was the 10 earliest time that we thought we could 11 challenge the system to find out if the LH 12 surge would be suppressed. 13 So that subgroup is the group that 14 we are looking at today. And this subgroup 15 is -- they were treated identical except the 16 dams were not exposed and the pups only were 17 treated post-lactationally. So we can assess 18 whether something's special about continuous 19 treatment versus a short-term treatment. This 20 study is still ongoing and you see we have 21 sacrifices coming out in the middle to late

22 June.

### 202-234-4433 Neal R. Gross & Co., Inc. Page 188 1 And these animals who will then 2 have additional 90 days of treatment -- again, 3 we'll assess the LH surge. And at that point 4 we're going to have a recovery subgroup just 5 to see -- or test the hypothesis of 6 reversability, which you'll hear about later

7 from Dr. Handa. 8 And, likewise, we get a window on 9 whether the vulnerability at this time is, in 10 fact, due to continuous treatment or due to, 11 in fact, the age of the animal. So the intent 12 is to try to separate out those factors that 13 are, let's say, a buildup of effect or a 14 deterioration of a function as a function of 15 dose duration versus a simple vulnerability 16 change as the animals age. Obviously we have 17 the hypothesis that it's a vulnerability 18 change that has actually occurred. 19 Next slide. And today we are 20 providing you the information on this. And we 21 have committed to the agency to provide the 22 full report by the end of July.

### 202-234-4433 Neal R. Gross & Co., Inc. Page 189 1 Next slide. This is more cut-down 2 version of that particular schema focusing 3 just on the animals that we're going to talk 4 about today. So we're going to be discussing 5 Cohort 1 animals, subgroup A. But, in fact, 6 for certain metrics we're going to give data 7 for group A, B, and C. At this point in age 8 they're all identical. Some of those animals 9 continue on and are dosed for additional 10 duration of time. 11 And in addition to that we were 12 interested in putting in a control group that 13 would show, in fact, that laboratory and this 14 process of treatment and so on could detect LH 15 surge suppression. So we took animals that 16 were 12 weeks of age and dosed them for five 17 days at 100 mgs per kg. We selected that does 18 because we wanted to make sure we were going 19 to get an LH effect. It would have been 20 tidier if we'd have used 50 mgs per kg because 21 that is the high dose in this study. But, 22 nevertheless, we wanted to prove that, in

### 202-234-4433 Neal R. Gross & Co., Inc. Page 190 1 fact, in this lab and in this operation we 2 could actually elaborate an effect of atrazine 3 treatment on the LH surge. 4 Next slide. So the first results 5 are from that first cohort of animals that are 6 only treated when they're 12 -- approximately 7 12 weeks of age, and they're given five days 8 of atrazine treatment. They're 9 ovariectomized, and LH surge is induced by the 10 implantation of an estrogen pellet. 11 The light cycles are set such that 12 we can sample them and get appropriate blood 13 and measure LH. And what we see is, in fact, 14 there is and has been described many times the 15 LH suppression of atrazine at 100 mgs per kg 16 as measured by both mean peak height and area

17 under the curve. 18 Next slide. The animals that were 19 treated either throughout entirely from 20 conception to the point of LH effect at 21 termination were unaffected by atrazine at any 22 dose up to 50 mgs per kg. And, likewise, the

### 202-234-4433 Neal R. Gross & Co., Inc. Page 191 1 cohort that was only exposed from end of 2 lactation to onset of sexual maturation were 3 unaffected by atrazine treatment at that age. 4 The statistics are shown below giving area 5 under the curve and peak height. 6 Next slide. Now, because we took 7 these animals to sexual maturity we were 8 smearing -- or looking for vaginal opening -- 9 onset of sexual maturation. That was the 10 entry into the cohort effectively -- they had 11 to reach that end point. So effectively we 12 knew what the vaginal opening dates were or 13 duration to. 14 And these are the three subgroups 15 in Cohort 1, and this is the combination of 16 the subgroups. And we can see that while we 17 have an LH surge suppression -- or we don't 18 have an effect of atrazine on the LH surge 19 suppression we do have an effect in these 20 young animals on the presumed pulsatile LH 21 release that's attributed to regulating sexual 22 maturation -- or at least vaginal opening.

### 202-234-4433 Neal R. Gross & Co., Inc. Page 192 1 So we observe that there's an 2 effective treatment, and the no-effect is 25 3 mgs per kg in this study. That's 4 approximately equivalent to what had been 5 reported previously by Laws et al., Ashby et 6 al. So there's several studies. And we 7 weren't terribly surprised by this result, but 8 it is confirmation of what had been given

9 before. 10 Next slide. As one nuance around 11 this is this is the cohort that were actually 12 treated for the inception onward and that 13 difference was statistically significant. 14 This difference was not and we don't 15 understand why that is. It's trending up, but 16 it's not increased enough to be significant. 17 So that's just a piece of 18 information that -- next slide. Okay. That 19 is addressing the question of age dependent 20 sensitivity to this particular system, perhaps 21 elaborated by both the LH surge mechanism and 22 the pulsatile LH mechanism. Dr. Handa will

### 202-234-4433 Neal R. Gross & Co., Inc. Page 193 1 have considerable more to say about those 2 processes and the effects of atrazine on them. 3 So, with that, I would stop and 4 maybe if there's any quick questions I could 5 take them. But perhaps we could put them all 6 together after the next piece if that's 7 suitable.

8 SESSION CHAIR PORTIER: Dr.

9 Chambers? 10 DR. CHAMBERS: This is real quick. 11 Just on the dosing, the dams were given those 12 doses and then the pups were given the very

13 same doses?

14 DR. BRECKENRIDGE: That's correct. 15 DR. CHAMBERS: Okay. 16 SESSION CHAIR PORTIER: Okay. Dr.

17 Handa. 18 DR. HANDA: Okay. Good afternoon. 19 My name is Bob Handa. I'm a professor in the 20 Department of Basic Medical Sciences at the 21 University of Arizona, College of Medicine. 22 Today what I'd like to do is spend

### 202-234-4433 Neal R. Gross & Co., Inc. Page 194 1 a little time telling you about some of the 2 studies that are ongoing in my lab regarding 3 the examination of the mechanisms that might 4 underlie atrazine suppression of LH secretory 5 patterns. I think Dr. Breckenridge showed you 6 a number of these questions that we'll try and 7 answer today regarding the LH -- the 8 hypothalamic-pituitary-gonadal axis and its 9 regulation or its modification by atrazine 10 exposure. 11 What I'd like to do today is spend 12 a brief period of time addressing these first 13 six questions. I want to thank Ralph Cooper 14 for introducing the topic. This will allow me 15 to go a little faster here. 16 And then bulk of my time today 17 will be spent hopefully addressing these lower 18 two questions, and that is whether atrazine 19 alters the secretion of other hormones, most20 notably those involved in the hypothalamic21 pituitary-adrenal axis, and whether these 22 changes in the HPG axis that we see following

### 202-234-4433 Neal R. Gross & Co., Inc. Page 195 1 atrazine administration are secondary to the 2 changes in the HPA axis. 3 So you've seen this type of data 4 before showing that atrazine can reduce the 5 hormonal induced LH surge in a female rat -- 6 rodent. This is data taken from Wistar 7 females -- young adult Wistar females. And on 8 the left side you can see that, in fact, under 9 hormonal stimulation there's an increase in LH 10 that occurs in the afternoon. And when 11 atrazine is administered by gavage at three 12 different doses, 5100 and 200 milligrams per 13 kilogram, we can obliterate that LH surge. 14 We went one step forward. And, 15 again, just to verify that this, in fact, 16 might be due to effects generated at the GnRH 17 neuron, or above the pituitary, we asked the 18 question as to whether these effects are 19 mediated by changes in pituitary sensitivity

20 to GnRH. 21 But these data show that, in fact, 22 if we take estrogen treated ovariectomized

### 202-234-4433 Neal R. Gross & Co., Inc. Page 196 1 female rats and we obliterate their endogenous 2 GnRH by passive immunization that we can then 3 have them respond to a synthetic GnRH agonist, 4 D-ALA-6 GnRH, and, in fact, there's no 5 difference in the response to following 6 several different doses of atrazine. 7 So these results suggest that the 8 pituitary sensitivity to GnRH has not changed 9 and that the effects we see on the HPG axis 10 are actually due to changes in hypothalamic 11 function. 12 Now, to address this we used a 13 GnRH EGFP transgenic rat model -- and in this 14 rat model has been engineered such that GnRH 15 neurons express enhanced green fluorescent 16 protein which allows you to visualize these 17 neurons in situ. We can couple this 18 immunocytochemistry for a protein called cFos, 19 and cFos is commonly used to demonstrate 20 neuronal activity. When neurons are active 21 cFos is expressed within the nucleus. And 22 what we have known for several years now is

### 202-234-4433 Neal R. Gross & Co., Inc. Page 197 1 that during the LH surge that GnRH neurons 2 express cFos during the LH surge but not 3 before and not after the LH surge. 4 So we embarked on an experiment to 5 determine if cFos was expressed in GnRH 6 neurons and if atrazine modified that 7 expression of cFos. What you can see is the 8 panel on the right -- is that during the LH 9 surge you get about 75 percent of GnRH neurons 10 that express cFos indicating that their 11 active, and that at high doses of atrazine, 12 doses that inhibit the LH surge, you actually 13 see a much reduced activation of GnRH neurons, 14 suggesting that GnRH neurons -- changes in 15 GnRH neuron activity may, in fact, underlie 16 the deficits in LH secretion that we see in 17 those animals treated with atrazine. 18 Now, based on these findings we 19 also hypothesized that perhaps GnRH neurons 20 might be altered in terms of their ability to 21 produce GnRH. As a result, we examined GnRH 22 mRNA as shown in this slide as well as other

### 202-234-4433 Neal R. Gross & Co., Inc. Page 198 1 primary transcript for GnRH. And as this 2 slide shows we found no evidence that there 3 are alterations in GnRH synthesis or 4 expression. 5 Also, we counted the number of 6 cells using in situ hybridization, as well as 7 following immunocytochemistry, and found no 8 changes in GnRH expression throughout the rat 9 brain. 10 As a result of these studies we 11 hypothesized that the GnRH neuronal system may 12 be, in fact, not altered by GnRH and that -- 13 or may not be altered by atrazine and, as a 14 result of the response of the GnRH system to 15 estrogen, may, in fact, recovery following 16 cessation of atrazine treatment. 17 So in this study we examined the 18 ability to induce an LH surge in animals that 19 were tested two days and four days after the 20 cessation of atrazine treatment which occurred 21 for four days prior. What you can see, again, 22 is that when tested immediately at the end of

### 202-234-4433 Neal R. Gross & Co., Inc. Page 199 1 those four daily gavages with atrazine that 2 you can see a decrease in the peak of the LH 3 surge, and that's coupled with a decrease in 4 the activity of GnRH neurons as measured by 5 Fos expression -- that within two days after 6 the termination of treatment that the peak of 7 the LH surge begins to recover, and it's 8 normal by four days following cessation of 9 treatment, and that the same occurs in the 10 activity of GnRH neurons. 11 These data suggest then that the 12 inhibition of GnRH and the LH surge is 13 transient and is very rapidly recovered 14 following the loss of exposure to atrazine. 15 We also examined pulsatile hormone 16 secretion -- and Dr. Cooper mentioned this 17 briefly yesterday. In the absence of hormone 18 administration LH and GnRH are released in a 19 pulsatile fashion. And they are coupled in 20 time such that each quanta of GnRH that's 21 released from the hypothalamus initiates a 22 small pulse of LH in response.

### 202-234-4433 Neal R. Gross & Co., Inc. Page 200 1 This pulsatile pattern of LH and 2 GnRH are of physiological importance. If GnRH 3 is released in a constant fashion it very 4 quickly loses the ability to drive LH 5 secretion. 6 So in these data you can see that, 7 in fact, if we sample quickly enough we can 8 identify discrete increases in LH secretion 9 with a pulse period of about 30 minutes. And 10 if we treat animals with atrazine ultimately 11 what we see is something that looks like this 12 where the number of pulses in a sampling 13 session is dramatically reduced. And when we 14 do see those pulses they're much larger. This 15 suggests that there is a disruption of the 16 GnRH pulse generator, and that's a very17 important component of the hypothalamic18 pituitary-gonadal axis. 19 Now, just to show you that this 20 is -- my last slide showed you pulses of LH. 21 Just to show you that the same changes occur 22 in regard to GnRH secretion we began to

### 202-234-4433 Neal R. Gross & Co., Inc. Page 201 1 examine GnRH release in an ex vivo system 2 where hypothalamic slices were peri-fused with 3 media, and the results are shown here. 4 Animals were treated with 200 milligrams per 5 kilogram atrazine for four days. 6 The hypothalami were removed. 7 They were put into the superfusion chamber and 8 then we examined pulsatile GnRH release from 9 these hypothalami. And what you can see is 10 hypothalami taken from control animals have 11 normal looking pulses of GnRH, which, again, 12 occur about every 30 minutes. And hypothalami 13 taken from animals that were treated with 200 14 milligrams per kilogram atrazine you can see 15 that the GnRH pulses are dramatically reduced 16 in frequency, and when they do show up they're 17 dramatically elevated in amplitude. 18 As a result we see no real change 19 in mean GnRH levels or area under the curve. 20 It's really just the dynamics of the system. 21 Peak amplitude is increased and the number of 22 peaks is reduced by atrazine.

### 202-234-4433 Neal R. Gross & Co., Inc. Page 202 1 Okay. So I want to change gears 2 just a little bit. I think those data 3 indicate that there are dramatic effects of 4 atrazine on the hypothalamic-pituitary-gonadal 5 axis, both in terms of pulsatile hormone 6 secretion, as well as the generation of the 7 pre-ovulatory surge of LH. 8 And we embarked on a series of 9 studies -- I'll tell you a little bit about 10 this one. Looking for change -- potential 11 changes in endocrine and immunological 12 function within male Sprague Dawley rats the 13 design of the experiment looks like this where 14 we have animals that were treated with three 15 different doses of atrazine -- 6.5, 25, and 16 100 milligrams per kilogram per day for either 17 1, 7, 14, or 28 days. The animals at 28 days 18 will be taken for an examination of 19 immunological function by Steve Pruett. 20 We were able to take these animals 21 on 1, 7, and 14, and that's the data I'll 22 report to you today. We have not yet analyzed

### 202-234-4433 Neal R. Gross & Co., Inc. Page 203 1 these -- the blood from these animals at 28 2 days. 3 So the design of the experiment 4 then was to treat the animals with atrazine or 5 a vehicle control and then to sacrifice them 6 30 minutes after the end of gavage and examine 7 the influence of that atrazine -- acute 8 treatment of atrazine on a number of different

9 hormones. 10 Now, I have to tell you a little 11 bit about our approach to measuring these 12 hormones. We use classical antibody based 13 approaches to measure hormones such as 14 corticosterone, prolactin, and progesterone, 15 as well as ACTH. I won't report the data on 16 ACTH -- we don't have it yet. 17 We also used a different 18 approach -- liquid chromatography tandem mass 19 spectrometry was used to measure the serum 20 estrogens -- estrone, estradiol, and 21 estriol -- as well as the androgens -- 22 androstenedione, testosterone, and

### 202-234-4433 Neal R. Gross & Co., Inc. Page 204 1 dihydrotestoterone -- and we have not yet 2 obtained the data on aldosterone levels. 3 Now, why would we want to use the 4 LCMS to measure steroid hormones? I think 5 there's been recently a controversy regarding 6 the ability to measure estrogens and androgens 7 using antibody based approaches. There's some 8 evidence that there's very low fidelity in the 9 different assays that are used to measure 10 these hormones, particularly when you get to 11 low levels. And by low levels we mean about 12 100 picograms or less. We also used 13 deuterated steroids as internal standards so 14 that we could identify exactly where peaks of 15 these hormones ended up on the chromatograms. 16 Let me just briefly describe the 17 biosynthesis of steroid hormones so you can 18 which of these hormones we began to examine. 19 All steroid hormones are derived from a common 20 precursor, and that precursor is cholesterol, 21 which is taken up into steroid synthesizing 22 tissues. It's then transferred into the

### 202-234-4433 Neal R. Gross & Co., Inc. Page 205 1 mitochondria by this steroidogenic acute 2 regulatory protein, and then it's acted upon 3 by a number of enzymes. The rate limiting 4 enzyme is P450 side chain cleavage. And, as 5 a result, you can see that then flows downhill 6 depending on the presence of these different 7 enzymes in different tissues. 8 But what you can immediately see 9 here is these hormones that are -- these 10 steroids that are indicated in green are the 11 progestins, and they actually give rise to all 12 the other steroid hormones -- the 13 mineralocorticoids, such as aldosterone, the 14 glucocorticoids, such as cortisol, the 15 androgens, such as androstenedione, 16 testosterone, and DHT, which are the 17 predominant androgens found in the rat. And 18 androgens give rise to the estrogens -- 19 estrone, estradiol, and estriol -- which are 20 the predominant estrogens also found in the

21 rat. 22 So we measure plasma levels of

### 202-234-4433 Neal R. Gross & Co., Inc. Page 206 1 progesterone, of aldosterone, of 2 corticosterone, androstenedione, testosterone, 3 dihydrotestosterone, estrone, estradiol, and 4 estriol. 5 And I'll show you the results of 6 these studies. I should first tell you a 7 little bit about some of the other results 8 from this series of studies. Again, animals 9 were kept on atrazine at least three doses for 10 up to 28 days, and this is the result of 11 results showing changes in body weight. I 12 think someone from the panel asks whether 13 atrazine alters body weight, and what you can 14 see here is at the highest dose -- 100 15 milligrams per kilogram -- per day there's a 16 significant decrease in body weight. The 17 changes that you see at the 6.5 and the 25 18 milligram per kilogram dose did not reach 19 significance.

20 Someone else also asked whether 21 there are effects of atrazine on adrenal 22 weight yesterday, and we will report now that

### 202-234-4433 Neal R. Gross & Co., Inc. Page 207 1 there was no effect of atrazine at any one of 2 the three doses on adrenal weight, whether 3 calculated on absolute adrenal weight or an 4 adrenal weight to body weight ratio. 5 What we find if we look at some of 6 these hormones -- for example, 7 corticosterone -- we find that, in fact, 8 following the initial treatment with atrazine, 9 we see a very dramatic increase in 10 corticosterone. Again, this is 30 minutes 11 after gavage, and we see that there is a dose12 response curve. We have not yet found the no13 effect level because 6.5 milligrams per 14 kilogram effectively increases corticosterone, 15 but albeit not to the degree seen following 16 100 milligrams per kilogram. 17 Of interest is the fact that after 18 seven daily doses of atrazine we see no 19 increase in corticosterone in these animals. 20 And this is maintained throughout day 14 -- or 21 14 daily doses -- suggesting that the response 22 of these animals -- of male Sprague Dawley

### 202-234-4433 Neal R. Gross & Co., Inc. Page 208 1 rats to atrazine is habituated somewhere 2 between the first and the seventh day of

3 treatment. 4 We continue on. We can measure 5 progesterone, and progesterone is another 6 hormone -- steroid hormone of adrenal origin 7 in the male. Progesterone is largely secreted 8 in response to ACTH administration. And what 9 you can see is the same thing that happens for 10 corticosterone also occurs for progesterone. 11 Within 30 minutes after the first injection of 12 atrazine, we see dramatic increases in 13 progesterone, which are lost by the seventh 14 and the fourteenth exposure to atrazine. 15 Interestingly, there are no 16 changes in prolactin to response to atrazine 17 administration at any of the doses for any of 18 the time periods. And this suggests that the 19 effects of atrazine on corticosterone and 20 progesterone are not a generalized stress 21 response because in most instances prolactin 22 rises following a stressor.

### 202-234-4433 Neal R. Gross & Co., Inc. Page 209 1 We also examined the androgens, as 2 I indicated, using LCMS. These are the 3 results shown here. We find no effect of 4 atrazine at 1 or 7 or 14 days of treatment at 5 any of the doses on plasma levels of 6 androstenedione, testosterone or 7 dihydrotestosterone. There is a trend for the 8 longest time point examined -- 14 days -- and 9 the highest dose -- 100 milligrams per 10 kilogram -- to reduce androstenedione levels. 11 But these did not reach significance. 12 Similarly, we also measured the 13 estrogens -- estradiol, estrone, and estriol. 14 And what we report now is that for all the 15 groups there was a substantial number of them 16 below assay sensitivity -- more than 50 17 percent in every group. And as a result we 18 have to report that the average values are 19 below assay sensitivity. 20 The sensitivity of this assay is 21 very low in terms of milligram -- or picograms 22 per ML. For estradiol and estrone it's 2

### 202-234-4433 Neal R. Gross & Co., Inc. Page 210 1 picograms per ML. For estriol it's 10 2 picograms per ML. And for the rodent that's 3 at the very low physiological end of the

4 scale. 5 These chromatograms then show

6 standards for each of these hormones -- and 7 you can see it's very selective in terms of 8 what we're measuring. And so we have an assay 9 that is very specific and very sensitive, and 10 we aren't measuring changes in any of the 11 estrogens. This assay was originally 12 developed by Steve Soldin at Georgetown 13 University to measure low levels of estrogens 14 and androgens. 15 So this suggests that, in fact, 16 there are some changes in response to atrazine 17 in the male. To be honest, we have not yet 18 run as extensive an experiment in females. 19 This is a little bit harder to address just 20 because of the cyclicity of females. But, 21 nonetheless, I'll try and piece together the 22 results of several different studies to

### 202-234-4433 Neal R. Gross & Co., Inc. Page 211 1 demonstrate to you that, in fact, there may be 2 similar changes that occur in females. 3 So in this study we examined the 4 acute response of the components of the HPA 5 axis, particularly corticosterone on -- 6 following atrazine administration at two 7 different doses of 50 and 200 milligrams per 8 kilogram -- and what we see, in fact, in 9 females -- ovariectomized females that we find 10 a very rapid increase in corticosterone that 11 peaks within 20 minutes. And at the highest 12 dose these levels of corticosterone are 13 actually maintained elevated for up to 12 14 hours. So this is a very unusual type of 15 corticosterone response in that it's extended 16 for a long period of time. At lower doses, 17 the response is much briefer, and we get a 18 peak which rapidly drops down to the levels of

19 the controls. You can also see here that 20 gavage by itself causes an increase in 21 corticosterone. 22 Results taken from a different

### 202-234-4433 Neal R. Gross & Co., Inc. Page 212 1 study in which animals were exposed to five 2 daily doses of atrazine at the 100 milligram 3 per kilogram dose show that, in fact, after 4 five daily doses, we seem to find also that 5 there's an increase in corticosterone. In 6 particularly, these animals were also measured 7 for LH responses to estrogen, and we find no 8 LH surge in response to estrogen. 9 And, lastly, in this series of 10 slides, I want to introduce some studies 11 performed by Dr. Pruett who will address these 12 in more detail shortly in that he used female 13 mice -- not rats. These animals were 14 administered atrazine for up to 28 days. They 15 were administered in a different route -- 16 intraperitoneally. But what you can see if 17 after a single exposure to atrazine that 18 there's a dramatic rise in corticosterone -- 19 the levels in mice are much greater than those 20 achieved in rats -- and that this is 21 maintained for over four hours and that 28 22 days later -- after 28 daily exposures to

### 202-234-4433 Neal R. Gross & Co., Inc. Page 213 1 atrazine you find the same effect is present, 2 suggesting that in females there's very little 3 habituation to atrazine exposure in that 4 corticosterone responds in a similar fashion 5 through at least four weeks. 6 Okay. So this begs the question 7 as to whether or not the product of the HPA 8 axis -- that is corticosterone -- can 9 influence the HPG axis. And we know from a 10 number of studies that corticosterone and 11 perhaps CRH can negatively impact the 12 hypothalamic-pituitary-gonadal axis. 13 So we asked the question as to 14 whether or not if we disrupted this axis, 15 particularly if we adrenalectomized the 16 animals, whether this would affect the ability17 of atrazine to disrupt the hypothalamic18 pituitary-gonadal axis. 19 The design of the study was to 20 adrenalectomize or sham adrenalectomize these 21 animals and then begin treatment with 200 or 22 50 milligrams per kilogram atrazine. And at

### 202-234-4433 Neal R. Gross & Co., Inc. Page 214 1 the end, initially we examined these animals 2 for pulsatile hormone secretion. We used a in 3 dwelling right atrial cannula to collect 4 samples every five minutes for a three-hour 5 period. If you remember from our previous 6 results, atrazine normally decreases the 7 frequency of these pulses and increases the 8 amplitude of these pulses. 9 These are the results of this 10 study in which in the sham animals, again, you 11 can see following exposure to -- well, 12 following exposure to atrazine at these two 13 doses you see a decrease in pulse frequency 14 coupled with an increase in pulse amplitude. 15 And if we remove the adrenals you see no 16 effects of atrazine on those hormonal changes, 17 suggesting that pulsatile LH is driven by 18 changes in corticosterone levels. 19 Of course, we also examined the 20 hormonal induced surge of LH and asked the 21 question as to whether adrenalectomy can block 22 the effects of atrazine on the estrogen

### 202-234-4433 Neal R. Gross & Co., Inc. Page 215 1 induced LH surge. And remember that atrazine 2 very potently inhibits the LH surge.

3 These are the results of that 4 study. We can induce an LH surge with 5 estrogen and progesterone. That treatment 6 with atrazine reduces the peak amplitude and 7 the area under the curve of LH secretion, and 8 that in the adrenalectomized animals those 9 effects of atrazine are identical, suggesting 10 that for the LH surge generation that adrenal 11 secretions are not responsible for the 12 inhibition seen by atrazine treatment. 13 Okay. So let me summarize very 14 quickly here. What we know is that atrazine 15 increases corticosterone and progesterone 16 secretion within 30 minutes after a single 17 treatment. But this disappears by 7 or 14 18 days in male Sprague Dawley rats. That in 19 females, atrazine also increases 20 corticosterone following a single dose and 21 that this -- these levels may remain elevated 22 for a long period of time and that females do

### 202-234-4433 Neal R. Gross & Co., Inc. Page 216 1 not seem to habituate to this effect as do

2 males. 3 We find no effect of atrazine on 4 prolactin, on any of the androgens measured, 5 or on any of the estrogens measured. And this 6 suggests that changes in vitro -- reported in 7 in vitro studies showing increases in 8 aromatase may not actually correspond to 9 physiological changes in hormone levels. 10 And, lastly, we show that 11 adrenalectomy blocks the effects of atrazine 12 on the LH pulses, but doesn't block the 13 effects of atrazine on the LH surge. And this 14 suggests that the effects of corticosterone on 15 the HPG axis may not come into play in terms 16 of the loss of cyclicity seen in these animals 17 with age. 18 So some key points I want you to 19 remember when driving home tonight, and that 20 is that high doses of atrazine can inhibit the 21 HPG axis -- I know you're all going to be 22 thinking about this on the way home -- and

### 202-234-4433 Neal R. Gross & Co., Inc. Page 217 1 that the effects on the HPG axis are reversed 2 following cessation of treatment, that the 3 effects of atrazine on the HPG axis are 4 secondary, perhaps to changes in HPA axis 5 activity in that adrenalectomy can block the 6 effects of atrazine on pulsatile hormone 7 secretions but not on the LH surge. 8 And the fact is that at this point 9 in time we find no effects of atrazine on 10 circulating androgen or estrogen levels in 11 male rats using LCMS. 12 So some of the things that we're 13 approaching in terms of identifying how this 14 might work, we are testing the ability of 15 atrazine to activate CFR neurons or the 16 hypothalamic centers -- neurons involved in 17 regulating the HPA axis. We can passively 18 immunoneutralize HCTH and get HCTH out of the 19 picture, and that will tell us whether 20 atrazine can effectively activate the adrenal 21 directly. 22 And we also want to determine

### 202-234-4433 Neal R. Gross & Co., Inc. Page 218 1 whether the effects of atrazine we see on 2 hormone secretion are differences between our

3 measurements and those of other labs are due 4 to methodological considerations, and so we're 5 going to measure using antibody based assays 6 as well as LCMS assay to measure these 7 changes. Are there any questions?

8 SESSION CHAIR PORTIER: Yes. Dr.

9 Horton? 10 DR. HORTON: Thank you. Theresa 11 Horton, Northwestern University. In the 12 female estrocycle or menstrual cycle, 13 whichever group of species you want to 14 consider, there's a switch between a period of 15 negative feedback and positive feedback. And 16 it appears that what you have delineated in 17 your work here is potentially a need to focus 18 on those two separate components of the cycle 19 independently, and that the HPA axis 20 components may be, in fact, impacting the 21 negative feedback components, if that is 22 influencing the pulsatile secretion. Would

### 202-234-4433 Neal R. Gross & Co., Inc. Page 219 1 you agree with that?

2 DR. HANDA: I'm not sure -- 3 DR. HORTON: Or suggest --

4 DR. HANDA: I'm not sure I would 5 agree with that completely. The pulses that 6 we measured in terms of pulsatile LH 7 secretion, of course, were measured in the 8 absence of negative feedback. 9 DR. HORTON: Right. 10 DR. HANDA: That's the only way we 11 can actually see that. 12 DR. HORTON: Okay. 13 DR. HANDA: Okay. So we don't 14 really know if, in fact, there's a change in 15 sensitivity to estrogen negative feedback. We

16 have to address that --

17 DR. HORTON: That's true. 18 DR. HANDA: -- by actually looking 19 at the ability of estrogen to inhibit those 20 pulses and then we will be able to answer

21 that. 22 DR. HORTON: Okay. And the second

### 202-234-4433 Neal R. Gross & Co., Inc. Page 220 1 part to that is then the LH surge mechanism is 2 a positive feedback mechanism. And since 3 there's ample evidence that there is something 4 altering that positive surge mechanism it 5 appears the potential of that needs to be 6 investigated independently and maybe a 7 component of impacts that may be part of 8 modification of the HPG regulatory mechanisms. 9 DR. HANDA: And I agree with that 10 completely. 11 DR. HORTON: Okay. 12 DR. HANDA: I think we are looking 13 at two different, although related, mechanisms 14 driving LH and GnRH neural activities -- 15 DR. HORTON: Okay. 16 DR. HANDA: -- and that just 17 because we influence one doesn't necessarily 18 say that we can influence the other. 19 DR. HORTON: Okay. Thank you. 20 DR. HANDA: So it appears that 21 corticosterone may -- the system may be much 22 more sensitive to corticosterone when we

### 202-234-4433 Neal R. Gross & Co., Inc. Page 221 1 measure pulsatile hormone secretion. 2 DR. HORTON: Thank you.

3 SESSION CHAIR PORTIER: Dr. 4 Selvage? 5 DR. SELVAGE: Yes. That was very 6 nice. You addressed a lot of the questions 7 that I've been asking myself in the past 8 couple of weeks here. I just had a couple of 9 questions, and you went pretty fast so if I 10 just missed something forgive me. 11 So in your chronic studies when 12 you gave atrazine chronically, did you ever 13 measure cort levels, you know, like, say, 14 prior to the atrazine application? 15 DR. HANDA: No, we didn't. 16 DR. SELVAGE: Okay. 17 DR. HANDA: No, we didn't. All 18 the analyses were done as compared to the 19 vehicle treated control at the same time. 20 DR. SELVAGE: Okay. I think that

21 would be a useful measure.

22 DR. HANDA: It would add a number

### 202-234-4433 Neal R. Gross & Co., Inc. Page 222 1 of animals to the group --

2 DR. SELVAGE: Yes. 3 DR. HANDA: -- and so, you know, in 4 order to save some animal -- 5 DR. SELVAGE: Okay. 6 DR. HANDA: -- life we -- 7 DR. SELVAGE: And just a technical 8 question, in your ex vivo GnRH studies what 9 was the media that you dissolved the atrazine 10 in? You know, I've been thinking, well, you 11 can shoot this stuff in ICV or whatever, but 12 you'd probably get a -- you know, a vehicle 13 effect if you tried to do that. 14 DR. HANDA: Right. 15 DR. SELVAGE: So what media did 16 you use for that? 17 DR. HANDA: So that was using 18 artificial CSF. Again, that was all in 19 vitro -- 20 DR. SELVAGE: Right. 21 DR. HANDA: -- that tissue was

22 taken out.

### 202-234-4433 Neal R. Gross & Co., Inc. Page 223 1 DR. SELVAGE: Right. 2 DR. HANDA: We made sagittal 3 slices and then placed them into the 4 superfusion chambers and ran artificial CSF 5 over the top of that, either containing -- 6 well, in this case there was nothing else in 7 that CSF. So the atrazine exposure became -- 8 came earlier than the examination of pulses. 9 Okay? 10 DR. SELVAGE: That's it for now. 11 DR. HANDA: Okay. Thank you.

12 SESSION CHAIR PORTIER: Dr.

13 LeBlanc? 14 DR. LEBLANC: That was a very nice 15 presentation. So one of the take-home 16 messages that that I got from it was that 17 males habituate and females don't with respect 18 to corticosteroid -- or atrazine treatment 19 with respect to corticosteroid levels. It 20 wasn't obvious to me as to why. Is there an 21 obvious mechanism there or reason? 22 DR. HANDA: I don't think there's

### 202-234-4433 Neal R. Gross & Co., Inc. Page 224 1 an obvious mechanism. Obviously sex 2 differences in stress responses have been 3 explored for years and years. And one of the 4 things that has come about if you look at the 5 literature is that there are some sex 6 differences in habituation to a stressor. 7 And, again, females don't necessarily 8 habituate as fast as males. That's stressor 9 specific. It usually involved estrogen and 10 testosterone being onboard. In this case 11 we're using a very different system so we 12 can't really say why males may habituate and

13 females won't.

14 DR. LEBLANC: At least at face 15 value, it seems that there's some lack of 16 concordance between what we saw just now and 17 some of the studies we were exposed to 18 yesterday -- things like testosterone levels 19 being affected or not being affected, 20 estradiol levels being affected or not being

21 affected. 22 And, again, I guess my question's

### 202-234-4433 Neal R. Gross & Co., Inc. Page 225 1 a general one. Have you -- is it obvious to 2 you why we see these inconsistencies? Is 3 it -- if I look more closely at the dosages, 4 would that explain it or the sex differences 5 or the duration of exposure? 6 DR. HANDA: What we believe is 7 that when measuring -- and I should go back to 8 a couple of recent reports, one by the College 9 of American Pathologists, where they did a 10 test and submitted samples to a number of 11 different companies for measuring estrogen, 12 testosterone by antibody based assays. They 13 left it up to the companies. 14 They found a variation within what 15 those companies produced using different 16 antibodies of up to ninefold from the lowest 17 to the highest, the idea being that when you 18 use the antibody to measure something you're 19 really dependent on the specificity and the 20 sensitivity of that antibody to detect it. 21 And there have been some reports 22 that antibodies may -- especially steroid

### 202-234-4433 Neal R. Gross & Co., Inc. Page 226 1 antibodies because they're directed against a 2 very small molecule -- that they may interact 3 with something that we call a matrix. Okay? 4 And that's really a fancy word for something 5 in the assay tube. And as a result we don't 6 necessarily get the exact right levels, 7 especially when we're looking at low levels. 8 But, again, we're going to test 9 that by trying to directly compare our 10 measurements using LCMS versus an antibody 11 based approach.

12 SESSION CHAIR PORTIER: Dr. Schlenk 13 and then Dr. Regal.

14 DR. SCHLENK: Yes. Just to follow 15 up on Jerry's comment there. Am I right in 16 terms of your slide saying that you didn't 17 detect any estrogen in any group in the

18 controls? 19 DR. HANDA: The majority of 20 animals had levels below detectability. We 21 did detect some.

22 DR. SCHLENK: Even the controls.

### 202-234-4433 Neal R. Gross & Co., Inc. Page 227 1 DR. HANDA: Even in the controls. 2 And the idea is that circulating estrogen 3 levels are not very high in males. They are 4 in females -- well, in rats the highest level, 5 physiological levels are in about the 50 6 picogram per ml range and basal levels are in 7 the 10 to 15 picogram range for estradiol, 8 which means in males they're going to be way 9 down there in the 2 picogram range -- very 10 difficult to detect. 11 DR. SCHLENK: Okay. Because, I 12 mean, if I compare slide 13 -- I mean, they're 13 in the 20 to 40 picogram per ml range, and 14 you're saying there's that much discrepancy 15 between an RIA and your LCMS method? 16 DR. HANDA: I mean, basically 17 there's that much discrepancy between RIAs. 18 Okay. So if you examine different places that 19 use different assays -- different 20 antibodies --

21 DR. SCHLENK: Sure. 22 DR. HANDA: -- to detect estrogen

### 202-234-4433 Neal R. Gross & Co., Inc. Page 228 1 levels sometimes you'll see a 10 and sometimes 2 you'll see an 80. And even if it's the same 3 sample -- 4 DR. SCHLENK: Well, I understand

5 that. That's -- 6 DR. HANDA: -- it's got much 7 variation. 8 DR. SCHLENK: That's a pretty 9 small variation I would think as opposed to a 10 tenfold difference. That seems pretty 11 dramatic actually, I mean, particularly when 12 you're not seeing any estrogen in a -- 13 DR. HANDA: And, again, I can only 14 say, again, we measured estrogen levels in 15 those females that we showed following -- up 16 to 12 hours of increases following 17 corticosterone. And, again, we see no 18 detectable estrogen -- estradiol levels in 19 those animals. 20 DR. BRECKENRIDGE: Mr. Chairman, I 21 submit that this is an experimental question 22 that we'll elucidate, and we'll do it by

### 202-234-4433 Neal R. Gross & Co., Inc. Page 229 1 making comparisons between the two 2 methodologies and then we'll come back. Thank 3 you. 4 SESSION CHAIR PORTIER: Dr. Regal 5 and Dr. O'Byrne.

6 DR. REGAL: Just back to that 7 habituation thing for a second, you know that 8 male rats habituate but female mice don't. 9 You don't know about -- so you've got two 10 species in there too. Right? 11 DR. HANDA: Exactly. And that was 12 the caveat with the study. We piecemealed 13 together evidence from a number of different 14 studies. We know that five days of treatment 15 in rats -- they still show a response. But 16 that's not inconsistent with the data we 17 showed in the male because we only looked at

18 seven. 19 DR. O'BYRNE: I was about to say a 20 mouse is not a small rat. But can I ask you 21 a question about Fos. It's a very powerful 22 tool. And you showed complete obliteration of

### 202-234-4433 Neal R. Gross & Co., Inc. Page 230 1 the LH surge with your 50 milligram dose, but 2 very little -- well, you don't show 3 significant tenuation of the Fos activation. 4 How do you account for that?

5 DR. HANDA: So we don't know for 6 sure. And the idea with the Fos is we're 7 taking a snapshot of Fos expression at one 8 particular time. Okay?

9 DR. O'BYRNE: Of course. 10 DR. HANDA: Which was 1700 hours, 11 which is what we estimated beforehand about 12 the peak of the LH surge. Now, when the LH 13 surge is reduced in amplitude, but perhaps not 14 all the way, sometimes it shifted -- 15 oftentimes we see it shifted in time. Okay? 16 So the induction of Fos expression in GnRH 17 neurons is time locked so that it doesn't just 18 pop on in all neurons. It slowly creeps up on 19 all those neurons and you kind of see a wave 20 of Fos expression occurring through the 21 population of GnRH neurons. If we miss the 22 peak we're going to hit something that's not

### 202-234-4433 Neal R. Gross & Co., Inc. Page 231 1 necessarily as robust. 2 DR. O'BYRNE: So delay in the 3 surges is reasonable, and there's evidence for

4 that as well. 5 DR. HANDA: In fact, every time 6 we've measured the presence of an LH surge but 7 reduce in size that surge is delayed in onset. 8 The samples I showed you today -- it was 9 basically obliterated so you couldn't tell

10 that.

11 DR. O'BYRNE: I have one other 12 question relating to the adrenalectomy. I 13 mean, I'm fascinated that you can't block the 14 effects of the surge. What do you think is 15 going on there? 16 DR. HANDA: We were very surprised 17 when that happened. I don't know. We have no 18 idea -- 19 DR. O'BYRNE: So it's quite 20 critical, isn't it? 21 DR. HANDA: It is. It is. And so 22 we are very happy when we saw that there was

### 202-234-4433 Neal R. Gross & Co., Inc. Page 232 1 a decrease of the obliteration of the effect 2 on LH pulses. We expected to see a 3 decrease -- or prevention of the inhibition of 4 the LH surge following adrenalectomy -- didn't 5 show up. And so we're scratching our heads 6 and we've got to go back and figure out why 7 that is. 8 DR. O'BYRNE: You're not only one.

9 SESSION CHAIR PORTIER: Last two 10 questions and then we'll move on. Let me 11 start with -- actually let's do Dr. Akana. 12 You had one already. 13 DR. AKANA: On your reversal with 14 the removal of atrazine did you measure 15 corticosterone in those animals? 16 DR. HANDA: Unfortunately we 17 didn't -- 18 DR. AKANA: Okay. 19 DR. HANDA: -- because it was 20 much earlier on before we began to explore the 21 contribution of corticosterone. 22 DR. AKANA: And Part B, on your

### 202-234-4433 Neal R. Gross & Co., Inc. Page 233 1 long body weight studies where you had the 2 per-fed controls -- okay, so these are running 3 28 days -- have you started considering to 4 measure leptin or to measure nasal-anal length 5 to see what kind of growth you are getting in 6 the two different -- the control food 7 restricted and the high dose?

8 DR. HANDA: That's an excellent 9 idea. I think we should consider that. 10 DR. SELVAGE: Dan Selvage again. 11 Just one question. Hopefully I'm not going 12 off on too much of a tangent. But considering 13 your expertise in HPA and HPG axes, do you 14 think there could be a disruption of the 15 neuradrenergic -- central neuradrenergic 16 system going on that could explain both of

17 these effects? 18 DR. HANDA: That's a possibility. 19 That's been suggested before actually by Dr. 20 Cooper in terms of some of the data that he's 21 been able to garnish over the last ten years. 22 And so I would not want to misinterpret his

### 202-234-4433 Neal R. Gross & Co., Inc. Page 234 1 data. I guess I'd have to ask him more 2 specifically after this. 3 SESSION CHAIR PORTIER: I think at 4 this point we'll move on and forewarn Dr. 5 Pruett that he's going to face a lot of 6 questions. Linda, do you have a quick 7 question? I kept -- I thought I kept seeing 8 something but I -- 9 DR. YOUNG: No. I just -- I'm 10 really surprised that some of these results 11 aren't significant. So I was just questioning 12 kind of what's -- whether you powered your 13 study and what kind of numbers you had in your 14 treatment groups along the way. 15 DR. HANDA: Which experiment 16 are -- in particular are you referring to? 17 DR. YOUNG: This is one. I mean, 18 over time when it -- the two lines are 19 consistently below the control you would think 20 you'd be picking up significance for most 21 analyses, yes. 22 DR. BRECKENRIDGE: Okay. So

### 202-234-4433 Neal R. Gross & Co., Inc. Page 235 1 that's about a 5-1/2 percent reduction in gain 2 on those ten animals in the group when you 3 start to -- I mean, we're not discounting that 4 those are probably treatment-related effects. 5 But it's a statistical detection phenomenon. 6 And so that's typical -- that statistical 7 significance with that kind of -- and on body 8 weight reaches levels when you start to get 9 around 8, 9 percent reduction. 10 And that's -- clearly is a trend 11 there that indicates there's a compound effect 12 on body weight. It's interesting that they 13 don't discriminate between each other at 25 or 14 6.5 mgs per kg. And so there's other 15 possibilities. 16 Mr. Chairman, if I could, I just 17 want to kind of give a segue now to the 18 immunotox presentation. So we've been 19 spending a lot of time describing 20 endocrinological characterization. And the 21 immunotox area is a somewhat unique advantage 22 to actually do a translational research from

### 202-234-4433 Neal R. Gross & Co., Inc. Page 236 1 end point measurement into -- things really 2 matter for the well-being of the animal or the 3 human. And this is systems impacts and

4 adverse effect outcome. 5 So Dr. Pruett is especially in 6 that topic, and I think you'll see a 7 connection between the work on the cort 8 systems and the immune system response. 9 DR. HANDA: We need Joseph Bailey 10 here to to unlock the computer. 11 DR. YOUNG: It's just that it 12 makes me question what methods you used in the 13 analysis. If you have something with that 14 many time points straight that's consistently 15 below, to not pick that up indicates that -- 16 it makes me question statistical methodology. 17 So just for a comment. 18 DR. BRECKENRIDGE: Thank you. 19 We'll look at that very carefully. I should 20 say that most of this data has come in over21 the last days, so that it's not exactly well22 examined at this point. Thank you.

### 202-234-4433 Neal R. Gross & Co., Inc. Page 237 1 DR. PRUETT: Ready? Okay. Thank 2 you very much for the opportunity to speak to 3 you today. I want to thank Dr. Bob Luebke for 4 setting the stage for this presentation. He 5 gave us a very nice overview yesterday of the 6 effects of atrazine on immunological 7 parameters. 8 I'm not going to try to reiterate 9 all of that, but I would like to focus on a -- 10 narrow down just a little on one of the 11 components of that, particularly because it 12 also ties into the discussion that we've just 13 been having about endocrine effects of 14 atrazine. 15 I should also tell you that these 16 studies were not done on behalf of Syngenta.17 These were studies that were from an NIH18 sponsored grant, and then also one of the 19 experiments I'll show is from a project with 20 Pfizer. 21 And really the basis for those 22 studies -- the reason for those studies is

### 202-234-4433 Neal R. Gross & Co., Inc. Page 238 1 that, quite often, when chemicals are being 2 tested for safety near the maximum tolerated 3 dose there's often a non-specific stress 4 response associated with that. And the exact 5 quantitative contribution of that response to 6 immunological end points had not been 7 investigated previously. And that's really 8 what this -- these experiments were designed 9 to do. But it turns out I think they do have 10 something to say about the questions at hand 11 today with regard to atrazine. 12 You've seen the diagram of the HPA 13 axis, so I won't go into that again. Suffice 14 it to say that corticosterone, in addition to 15 feeding back and controlling that axis and 16 also contributing to effects in the HPG axis, 17 also affects the immune system at both the 18 organ, cellular, and functional levels. 19 I've indicated a couple of 20 parameters by underlining them that I will 21 mention again as we go through some data. 22 Natural killer cell function and antibodies --

### 202-234-4433 Neal R. Gross & Co., Inc. Page 239 1 both of those have been selected. In fact,

2 those are two of the ones that have been 3 identified by EPA and FDA in their guidance 4 documents as functional immunological 5 parameters that would be useful in evaluating 6 immunotoxicity. 7 First, the approach that we've 8 taken has been a little different than what 9 most investigations have done in terms of 10 evaluating, not single time points of the 11 corticosterone level, but rather looking at

12 the area under the curve.

13 And the value of that can be 14 illustrated in these graphs. You can see that 15 we've dosed mice with 100, 200, and 300 16 milligrams per kilogram, single dose, and then 17 we follow them over a period of hours and 18 measure corticosterone in the blood. 19 And what you can see is that, if 20 you look at the hour one values, they are 21 between 8- and 900 for all three dosages. 22 That -- if that was the only information you

### 202-234-4433 Neal R. Gross & Co., Inc. Page 240 1 had you would conclude that corticosterone is 2 affected very, very similarly by all three 3 doses and that there was not really a dose 4 response pattern. And, therefore, if you saw 5 a dose response in immunological effects you 6 would assume that it wasn't glucocorticoid

7 related. 8 However, if you measure area under 9 the curve -- and you can see those values up 10 at the top of each graph -- those are very 11 nicely dose dependent. And we have graphed 12 those and they are for a number of different 13 stressors over a considerable time period. 14 So one of the interesting 15 parameters that we've evaluated is the 16 expression of the major histocompatibility 17 complex class 2 protein on spleen cells. This 18 protein is involved in presenting foreign 19 antigens to T cells and it's a critical 20 component, both of the antibody response and 21 the T cell mediated acquired immune response. 22 And it turns out to be one of the most

### 202-234-4433 Neal R. Gross & Co., Inc. Page 241 1 sensitive parameters in terms of the effects 2 of glucocorticoids. 3 What you can see on these graphs 4 is that at 100, 200, and 300 milligrams per 5 kilogram on the left, if we plot those data in 6 terms of corticosterone area under the curve 7 instead of using the milligram per kilogram 8 dosage you can see that the effects of 9 exogenous corticosterone, which are indicated 10 by the dotted line, and restraint stress, 11 those effects are quite similar to the effects 12 that we see on an equivalent area under the 13 corticosterone concentration versus time curve 14 as we see with atrazine. Those values -- or 15 the elevations and the slopes of those lines 16 are not significantly different.

17 If we look at dose values and 18 compare one-day and 28-day exposures, we also 19 see there that there is really no difference 20 in the corticosterone production one day as 21 compared to 28 days. So, as has already been 22 mentioned, no sign of habituation in these

### 202-234-4433 Neal R. Gross & Co., Inc. Page 242 1 female mice in this particular study. 2 I'd also point out that the low 3 dose at the 28-day -- in the 28-day group is 4 37.5 milligrams per kilogram, and if we just 5 did a simple -- ANOVA comparing the doses in 6 either of these studies we find that that 7 difference between the control and the low 8 dose is not significant. And, in fact, it 9 doesn't get significant until we get to about 10 100 milligrams per kilogram. And that's 11 generally the case in -- for all of the 12 immunological parameters that we've measured. 13 This is the most sensitive immunological 14 parameter that we've measured in this series 15 of studies. 16 Natural killer cells I mentioned 17 are an important parameter in determining 18 overall immunotoxicity, and they are also 19 decreased in a linear manner predictable by 20 area under the corticosterone concentration 21 versus time curve, and also quite similarly to 22 the effects of corticosterone, exogenous

### 202-234-4433 Neal R. Gross & Co., Inc. Page 243 1 corticosterone, and restraint, which were 2 designed to give similar area under the curve

3 values. 4 This is an experiment where we're 5 changing gears a bit and looking at male 6 Sprague Dawley rats. And this is a project 7 that I did with Pfizer. And the idea here was 8 that new guidance documents indicated that the 9 FDA would no longer take investigators' word 10 for it that thymus decreases and other things 11 that are typical -- other changes typical of 12 stress responses are due to a non-specific 13 stress response. They indicated that from now 14 on there would need to be evidence of a stress 15 response along with those immunological 16 changes to make the case that there was, in 17 fact, a stress response causing those 18 immunological effects. 19 So one of the easy ways to measure 20 a stress response, rather than bleeding, to 21 get blood values for corticosterone is to take 22 urine samples. And what we found is that a

### 202-234-4433 Neal R. Gross & Co., Inc. Page 244 1 six-hour urine sample from zero to six hours 2 after dosing gives a very nice indication of 3 the excess corticosterone produced during that 4 period of time. 5 I think it's very analogous to

6 area under the curve and we do have data on 7 that. I don't have a slide here with me 8 today. But we have compared area under the 9 curve and urinary glucocorticoids and they do 10 have a nice correlation. 11 So in this particular experiment

12 we've evaluated several stressors. The 13 experiments labeled 20 and 25 involve atrazine 14 at quite high doses. But what you can see 15 here is that they decrease lymphocyte 16 differential and stressors in general -- 17 glucocorticoids in general have this effect. 18 But you can see that the relationship is quite 19 similar for all the different stressors and 20 that the urine corticosterone values seem to 21 be quite predictive of that effect.

22 And there are several other

### 202-234-4433 Neal R. Gross & Co., Inc. Page 245 1 parameters. In the interest of time I don't

2 have those shown. But there are several other 3 parameters with similar relationships. 4 So you've seen this before. This 5 is a study that is in progress that Syngenta 6 has commissioned. And the last column under 7 28 days will be used for evaluation of dose 8 response relationship in the -- in terms of 9 immunological effects. 10 And we have some groups in 11 there -- the NK assay anti-asialo GM1 and the 12 AFC assay cyclophosphamide. Those are 13 positive control groups where we should 14 definitely see an effect just to make sure 15 that the assay's working properly, and we 16 should be able to get a much better idea than 17 we have now about the dose response pattern. 18 As already mentioned, these 19 animals will also be used to evaluate 20 endocrine effects, and we will take urine 21 samples from these animals to evaluate 22 corticosterone. So those results, the plan is

### 202-234-4433 Neal R. Gross & Co., Inc. Page 246 1 to report those in July. 2 And similarly, one of the areas 3 where there is some uncertainty because the 4 two major studies didn't reach quite the same 5 conclusion is the effects of atrazine on 6 development of the immune system. And a 7 developmental study was already planned when 8 I came -- when I became involved in this 9 process. And it became clear that we could 10 probably get some useful immunological 11 information from this study as well. 12 Now, the ovariectomy, admittedly, 13 may have some effects on immune system 14 parameters, but the parameters that I've been 15 talking about typically are not drastically 16 affected in adult animals by ovariectomy. And 17 I think this would give us some useful 18 information. So we would check urine 19 corticosterone shortly before the ovariectomy 20 in both the animals that are exposed 21 throughout gestation and early development, 22 and then we would do the same thing for

### 202-234-4433 Neal R. Gross & Co., Inc. Page 247 1 animals on the -- in Cohort 2 that are exposed 2 for a lesser period of time.

3 Then we would measure 4 immunological parameters, both immediately 5 after that at the time indicated on the chart 6 there for blood collection, and then we would

7 also let them recover for three weeks and then 8 also evaluate immunological parameters at that 9 time. 10 I believe we can evaluate not 11 perhaps exactly the same parameters that were 12 evaluated in the Rooney and Rowe studies, but 13 we can evaluate parameters that are very 14 comparable that should give us a similar 15 answer -- like instead of the -- we can do 16 mixed lymphocyte culture, which should give us 17 an idea of the T cell -- specific T cell 18 response, even though that different assay was 19 done in those investigations, as well as we 20 can measure all of the typical immunological 21 basal data that was measured in both of those 22 studies. And that, again, should be available

### 202-234-4433 Neal R. Gross & Co., Inc. Page 248 1 in July. 2 To summarize, high doses of 3 atrazine increase circulating levels of 4 corticosterone in rodents. Elevated 5 corticosterone levels have been reported for 6 atrazine doses associated with immunological 7 effects. The effects of the immune system may 8 be caused by elevated corticosterone levels -- 9 the effects of atrazine on the immune system. 10 Urinary corticosterone at zero to 11 six hours and area under the plasma 12 corticosterone concentration versus time curve 13 are good predictors of immune system effects. 14 And studies in progress should provide us a 15 description of the dose response relationship 16 for the urinary corticosterone levels and 17 immunological changes, and also should give us 18 some more information about developmental 19 effects of atrazine exposure in terms of dose 20 response. 21 And I'd be glad to address any 22 questions that you might have.

### 202-234-4433 Neal R. Gross & Co., Inc. Page 249 1 SESSION CHAIR PORTIER: Dr. Regal. 2 DR. REGAL: Yes. So are you 3 planning on looking at the male and female 4 offspring? 5 DR. PRUETT: I think if you go to

6 those -- back to those --

7 DR. BRECKENRIDGE: I can address 8 that quickly. Charles Breckenridge. So we're 9 only carrying the females because originally 10 that was designed as a study to look at the 11 impact on LH mechanisms. So that's all we 12 have running in that study.

13 DR. REGAL: Yes. Because the 14 other two studies in the literature saw the 15 primary effects in the males. 16 DR. PRUETT: Right.

17 DR. BRECKENRIDGE: We understand 18 that. And we may have to go back. 19 DR. REGAL: And then is -- how -- 20 so 111-day old rat -- most of the other 21 studies also use slightly younger animals. 22 Right?

### 202-234-4433 Neal R. Gross & Co., Inc. Page 250 1 DR. BRECKENRIDGE: Yes. 2 DR. REGAL: Okay.

3 DR. BRECKENRIDGE: Yes. Yes. 4 This won't be an exact replica of either of 5 those studies -- absolutely. 6 DR. REGAL: Okay. 7 DR. BRECKENRIDGE: No, it won't. 8 And that -- and it may be necessary to do an 9 additional study to clarify what's still 10 uncertain.

11 SESSION CHAIR PORTIER: Dr. Akana? 12 DR. AKANA: Is the urine 13 collection -- is it a nighttime or a light 14 time collection? What time of the day in the 15 cycle? 16 DR. BRECKENRIDGE: Yes, the urine 17 will be collected during the interval of time 18 from lights on for six hours. And it 19 coincides with the time when dose is 20 administered actually.

21 DR. PRUETT: We've evaluated other 22 times, and we've also evaluated longer

### 202-234-4433 Neal R. Gross & Co., Inc. Page 251 1 collection times -- zero to 24 hours. And 2 zero to 6 gives us the least noise in the 3 system -- less error within groups. So that's 4 the basis for that. 5 DR. AKANA: That probably also 6 gives you the least urine volume. 7 DR. PRUETT: Yes, it does. Yes. 8 That's right. We do adjust. We also -- we do 9 an adjustment for creatinine, which should 10 account for differences in urine output. And 11 that also does help to decrease the 12 variability in the numbers.

13 SESSION CHAIR PORTIER: Dr. 14 Selvage?

15 DR. SELVAGE: I have 16 catecholamines on the brain. But some of 17 these -- some of the results you've seen, like 18 with NK cells in the spleen, could that be 19 explained by catecholamine action at the level 20 of the spleen? 21 DR. PRUETT: Yes. Some portion of 22 the effects of these stressors is almost

### 202-234-4433 Neal R. Gross & Co., Inc. Page 252 1 certainly due to catecholamines. There are 2 some data that I didn't show you where the 3 effects of the chemicals and restraint stress 4 depart considerably from the effect of 5 exogenous corticosterone. Now, exogenous 6 corticosterone -- there isn't a big 7 catecholamine response because the only stress 8 there is brief handling to do the dosing. 9 The others -- the chemicals 10 themselves where the restraint induce is a 11 major catecholamine response -- and for some 12 parameters we see that all the chemicals and 13 the restraint track much closer to each other 14 than they do to corticosterone, suggesting 15 that probably it's catecholamines or some 16 other stress mediator that is driving that 17 particular effect. 18 Most of these we didn't -- we ones 19 that I showed you we didn't see that pattern, 20 but we have seen it for other parameters.

21 SESSION CHAIR PORTIER: Dr.

22 LeBlanc?

### 202-234-4433 Neal R. Gross & Co., Inc. Page 253 1 DR. LEBLANC: You showed rather 2 nicely that at these dosages the area under 3 the curve is very informative with respect to 4 corticosterone levels. But these are high 5 dosages. And I was just wondering if you 6 titrated down to levels that are more 7 representative -- the NOEL, the LOEL for 8 atrazine -- whether the peaks might be more 9 informative -- or at least as informative. 10 DR. PRUETT: That is possible. We 11 have done some studies at lower levels and 12 also a number of vehicle studies. And below 13 a certain value -- and it's not far from the 14 lowest value that I showed you up there -- the 15 100 milligram per kilogram -- it's not far 16 from that. We don't see any immunological

17 effects. 18 However, we have not looked at 19 some parameters that some people have reported 20 to be enhanced if there is a very brief stress 21 response. So one example might be cocaine, 22 which induces a very brief, but high

### 202-234-4433 Neal R. Gross & Co., Inc. Page 254 1 amplitude, stress response in rodents. And 2 that actually doesn't cause immuno 3 suppression; it enhances some immunological 4 end points, similarly with certain physical 5 stressors or restraint stress if it's just a 6 very short duration.

7 SESSION CHAIR PORTIER: Dr. Akana? 8 DR. AKANA: Have you carried 9 adrenalectomized animals through this 10 protocol? 11 DR. BRECKENRIDGE: No, we have 12 not. I think it's a rather arduous task to 13 maintain animals for any duration of time. 14 And actually it's the in-dwelling catheters 15 that Dr. Handa uses that permit us to do those 16 kind of experiments because we can provide 17 back saline to those animals.

18 DR. PRUETT: We've done some 19 experiments like that with other chemicals, 20 not atrazine. And for a number of the 21 parameters that I've shown you here, 22 particularly MHC Class 2, the effect

### 202-234-4433 Neal R. Gross & Co., Inc. Page 255 1 completely disappears in the adrenalectomized 2 animals. We've also used glucocorticoid 3 synthesis inhibitor and a glucocorticoid 4 antagonist and we get the same answer using

5 all three methods. 6 SESSION CHAIR PORTIER: Okay. I 7 think we're going to move the token to the 8 other side of the table for a while.

9 DR. BRECKENRIDGE: That's correct. 10 And I had a summary. I'll just give that out 11 in paper copy. 12 And I'm only going to make two 13 comments just making an introduction. Dr. 14 Pastoor is going to present a margin of 15 exposure assessment using NOELs that exist at 16 the present time in the regulation of 17 atrazine. So the acute NOEL is 10 mgs per kg 18 short term, 6.25 in long term, 1.8 mgs per kg. 19 These are obviously subject to a new research 20 when some of these other parameters get 21 investigated. 22 And, just in general, to say that

### 202-234-4433 Neal R. Gross & Co., Inc. Page 256 1 Syngenta's committed to continuing to conduct 2 research to elucidate the mechanisms of 3 actions of atrazine on all aspects of 4 endocrine and impact functions in toxicology. 5 So, with that, I'll ask the 6 colleagues from the other side to come up and 7 we'll abandon the table. Thank you very much 8 for your patience. 9 SESSION CHAIR PORTIER: Before you 10 all leave I think Dr. Bucher's got a quick 11 question. 12 DR. BUCHER: Sorry. I just wanted 13 a quick question. Is this the only study the 14 one that's going on now with the in utero 15 exposure that you know of with atrazine? 16 DR. BRECKENRIDGE: Could you 17 repeat please? 18 DR. BUCHER: You have a study 19 going on with in utero lactational exposure. 20 Is this only one that you're aware of that's 21 been done this way so far? 22 DR. BRECKENRIDGE: I'm the only

### 202-234-4433 Neal R. Gross & Co., Inc. Page 257 1 one that -- I haven't directly involved with 2 conducting so I don't know what others may be 3 doing. I think there could be programs 4 similar to that elsewhere, but I don't know of

5 those.

6 DR. BUCHER: So there's no -- 7 given the neurological effects that have been 8 seen in all of these other studies has any 9 thought been given to neural behavioral 10 studies or assessments of the developing 11 nervous system in these animals? 12 DR. BRECKENRIDGE: We're listening 13 with interest to the discussion of the neural 14 toxicity sections that were brought forward in 15 this meeting in the last few days. And we 16 have been investigating that model for two 17 years for other reasons. We are aware -- 18 brutally aware of its limitations, and so 19 we're reluctant to do those kind of high dose 20 types of experimentations. If we thought 21 there was a need to investigate those kinds of 22 outcomes we would. Thank you.

### 202-234-4433 Neal R. Gross & Co., Inc. Page 258 1 DR. HENDLEY: Okay, thank you, Mr. 2 Chairman. My name is Paul Hendley. I'm a 3 senior Syngenta fellow from the product safety 4 department in Syngenta. My interests are in 5 exposure assessment. And what Dr. Pastoor and 6 I will be talking about over the next few 7 minutes is moving from toxicology into the 8 exposure assessment and leading to talking 9 about the risk assessment part of the 10 challenge to understand that. 11 Okay. We're looking forward to 12 giving the panel some more information that's 13 going to compliment that they've already seen. 14 And the first part of that is going to refer 15 back to the atrazine drinking water monitoring 16 databases and show how they indicate that the 17 current monitoring frequency is sufficient to 18 estimate exposure profiles for the end points 19 and duration.

20 And then we'll move to Dr. Pastoor 21 talking about the margins of safety -- and 22 they're extremely large for the exposures in

### 202-234-4433 Neal R. Gross & Co., Inc. Page 259 1 toxicological end points. And he will go into 2 the issues of some of the thresholds in 3 detail. 4 But I would like to take the 5 opportunity now to talk about a little sort of 6 safety warning because I'm going to use the 7 word peaks and maxima and high centiles. But 8 the important thing to bear in mind when I'm 9 saying that is the drinking water supply is 10 indicated as safe. No finished drinking water 11 samples have ever exceeded 100 parts per 12 billion, which is the one-day HAL. And Dr. 13 Pastoor will go into the background of that. 14 In the atrazine monitoring program 15 with high frequency, no system has had a 16 finished water annual average greater than 3 17 parts per billion of atrazine from 2006 to 18 2009, which is the current MCL or MCLG as the 19 running annual average. And also, no 90-day 20 rolling average has exceeded the drinking 21 water level of -- I always want to say 22 concern, and, of course, it isn't -- it's

### 202-234-4433 Neal R. Gross & Co., Inc. Page 260 1 comparison -- of 37.5 parts per billion total 2 chlorotriazines in rural finished water in the 3 atrazine monitoring program. So that's the 4 background against which we're going to talk 5 about peaks and maxima. 6 So the two features of my talk are 7 about the atrazine monitoring programs and the 8 magnitude, the focus, and the frequency that 9 has produced a massive database, and then 10 some of the analyses that have been done on 11 that database that have indicated the 12 trends -- and they're trending downwards -- 13 the confidence with which we understand the 14 peak values and the high centiles, and some 15 sampling performance of some alternative and 16 additional sampling designs to those that 17 you've seen already from EPA. 18 But I think the keynote word for 19 my presentation is going to be database 20 because when I sum up I'm going to use the 21 word exceptional for this database. And I 22 hope by then you'll realize why I'm absolutely

### 202-234-4433 Neal R. Gross & Co., Inc. Page 261 1 certain that's the right word to use in how it 2 provides a unique resource for actually 3 answering some of the questions that the panel 4 has been challenged with. 5 So the magnitude of the surface 6 water programs is where I'd like to start. 7 There's essentially two types of surface 8 water, non-drinking water and drinking water. 9 Let's deal with the non-drinking water first. 10 And by that I'm talking about all water 11 bodies -- streams, rivers, lakes -- not 12 associated with drinking water finished 13 analyses. 14 There's about 180,000 atrazine 15 analyses in that database. Probably one of 16 the best and most consistent databases, 17 particularly because it analyzes multiple 18 compounds, is the NAWQA program that Dr. 19 Gilliom supervises. 20 You've heard about the Heidelberg 21 College program -- we'll come back to it 22 briefly. That is characterized by superb

### 202-234-4433 Neal R. Gross & Co., Inc. Page 262 1 daily information, so very relevant to sample 2 frequency work. 3 The ecomonitoring program many of 4 you know quite well from several presentations 5 in the past. And, in addition, there's a 6 massive database on over 100,000 analyses on 7 other non-drinking water. 8 However, the rest of the 9 presentation is going to be on the topic of 10 drinking water -- community water systems that 11 are using surface water as sources. And 12 there's going to be three sets of acronyms 13 that we'll use extensively. The Safe Drinking 14 Water Act program, which is a program managed 15 by the states -- and we will keep calling it 16 SDWA from now on -- and the Syngenta managed 17 voluntary monitoring program, which we will be 18 calling VMP, and the Syngenta managed atrazine 19 monitoring program, AMP. 20 So what do I mean by that? The 21 SDWA program has been running since 1993, and 22 it's a regulatory compliance program that's

### 202-234-4433 Neal R. Gross & Co., Inc. Page 263 1 roughly 90 regulated compounds -- atrazine is 2 one of them. And the 12,000 community water 3 systems on surface water have to meet 4 compliance. 5 Typically sampling for atrazine is 6 up to four samples per year, and that has led 7 to the accumulation of 50,000 or so samples 8 since 1993. And that's coming from 4,400 9 community water systems. The SDWA program 10 only looks at finished water. 11 So the next part of the program is 12 the Syngenta voluntary monitoring program. 13 And that little icon has appeared at the top 14 of the pyramid for a reason -- because the 15 community water systems that move into the 16 voluntary program are moved in because this 17 ran from `93 to 2003 are those with a 18 significant history of atrazine detections. 19 And 132 community water systems 20 eventually became part of the voluntary 21 monitoring program, covering ten states. And 22 the voluntary monitoring program typically

### 202-234-4433 Neal R. Gross & Co., Inc. Page 264 1 used 26 to 30 samples a year. And those 2 samples were stratified towards the peak 3 runoff time in the growing season. 4 Now, in addition to finished 5 water, sort of -- let's say 26 raw samples and 6 26 finished samples taken a year. And that 7 has accumulated a database of over 22,500 8 finished water samples. 9 The second program is the atrazine 10 monitoring program, and that was mandated in 11 2003. The way it was set up was it had to 12 capture all the community water systems with 13 annual average atrazine concentrations in 14 excess of 1.6 parts per billion, which is half 15 of this MCL level. 16 But that was going back to 1997, 17 so it looked back over the records for the 18 last six years to pull in all the community 19 water systems that had a history of 20 atrazine -- interesting atrazine residues -- 21 and that's why we also have an icon at the top 22 of the pyramid. We're focusing in on those

### 202-234-4433 Neal R. Gross & Co., Inc. Page 265 1 sites of most interest. 2 In the end, 152 community water 3 systems are in that database from ten states. 4 The sampling frequency is higher than the 5 voluntary program. The timing is very 6 similar. And, again, you have a full set of 7 raw and finished samples. And that's amassed 8 about 26,500 finished water samples. 9 Some people find this format 10 easier to look at, and I think it deals 11 directly with the word Dr. Gilliom used early, 12 which was density of sampling. What this 13 shows is a -- the time course from zero to 365 14 days. And what it shows is for each day 15 within the entire SDWA database how many 16 measurements there are in the database. 17 And because atrazine runoff is 18 stochastic -- it's due to the timing of 19 rainfall application, complex interrelated 20 factors. What we see here is how well we've 21 sampled that universe of possible actions. We 22 also happen to see that apparently in the

### 202-234-4433 Neal R. Gross & Co., Inc. Page 266 1 Midwest, sampling on Christmas Day and New 2 Year's Day are not popular activities. 3 In addition to the SDWA 4 distribution we see the same thing for the VMP 5 and AMP. And what you can see here is April 6 1 to July 31 is -- if you like the growing 7 season when we know you're likely to get 8 higher residues -- higher runoff occurring -- 9 and you can see how VMP, AMP selectively 10 samples from that period. 11 But think about the total sum of 12 the database. If you think of that, say, 13 April 15 you have around 200 -- well, 150 14 samples to 250 samples perhaps. And, again, 15 you add in the AMP samples, the amount of data 16 and information in our database is really 17 quite remarkable. 18 So that gives us a database of 19 enormous magnitude. It's focused on sites of 20 interest and it has high frequency monitoring 21 data. So Dr. Heeringa used the phrase "prior 22 information." This is a pool of prior

### 202-234-4433 Neal R. Gross & Co., Inc. Page 267 1 information of some considerable power. And 2 it also perhaps also ought to be in the list 3 of what do we know now, which is a question 4 that Dr. Thurman asked in one of his slides. 5 So the first thing we did with the

6 database was we looked at trends. And what we 7 have here -- what are we doing from now is 8 giving you a one-page summary, a very short 9 introduction and some conclusions, and you 10 will see the reference, in fact, up in the top 11 left-hand corner here. That is on the 12 docket -- that report -- but with just too 13 detail and too little time to go through it in 14 detail I'm afraid. 15 So what we see here is across the 16 period 1994 to 2006 there is a downward trend 17 in time weighted annual mean concentrations of 18 atrazine. And there's two lines on there 19 because the sites where the raw annual mean 20 greater than 3 at some point within that 21 historical database are actually seen to be 22 trending downwards at a faster trend than

### 202-234-4433 Neal R. Gross & Co., Inc. Page 268 1 those without such a history. 2 And that's encouraging. And one 3 of the reasons to note is that across the top 4 line here you see the total atrazine use in 5 millions of pounds. And that hasn't changed 6 significantly over the 1994 to 2006 period.

7 So the decrease and the trend downwards 8 largely reflects activities by the growers, 9 improvements in stewardship for atrazine use. 10 In addition to this for the annual 11 mean is a similar and somewhat steeper trend 12 for the high centile peak values. And USGS 13 also reported a similar trend in their NAWQA 14 decadal review. 15 The second thing we did with the 16 database was look at both peak and high 17 centile atrazine drinking water 18 concentrations. And here obviously with 19 sample sizes in the order of 50,000 data 20 points they're large enough to estimate the 21 high centile population measurements with 22 extreme confidence.

### 202-234-4433 Neal R. Gross & Co., Inc. Page 269 1 And what this table does is 2 summarize those measurements. The actual 3 confidence limits are in the detailed report. 4 And Dr. Mosquin from RTI International is with 5 us on the table should you have any questions 6 on the detail of this piece of work. Dr. 7 Mosquin is down there. 8 On the top line you can see the 9 SDWA data. And what you have is a 99.9th 10 centile value of 6.7 parts per billion from 11 our 4,400 community water systems. For the 12 VMP, AMP we have 22.7 ppb as the 99.9th 13 centile. 14 Interestingly, if you take from 15 SDWA the data corresponding to those community 16 water systems in VMP and AMP you see that the 17 99.9th centile moves from the 6.7 of the total 18 population to 17 parts per billion. In other 19 words, SDWA sampling across the years does a 20 good job of capturing the community water 21 systems with a history of higher atrazine

22 occurrence.

### 202-234-4433 Neal R. Gross & Co., Inc. Page 270 1 The panel also asked the question 2 earlier about sourcing for community water 3 systems. So what was done here was the 4 database was broken down into subsets, the 5 first of which is community water systems 6 using static water bodies as the source. 7 There's 134 -- about two-thirds of that 8 population in the VMP and AMP. And there, the 9 99.9th centile and the 99th are higher than 10 the whole population, and correspondingly the 11 flowing water subset, the high centile values 12 are lower. In other words, the static water 13 bodies actually tend to have higher residue 14 patents, and that is unsurprising when you 15 think about the hydrology. 16 Additionally on here, and 17 unsurprisingly as well, is when you look at 18 the April to July period, you come out with 19 centile estimates that are considerably higher 20 than the whole population. 21 Okay. That led us to the question 22 before -- some of the questions before the

### 202-234-4433 Neal R. Gross & Co., Inc. Page 271 1 panel about sampling frequency and confidence 2 intervals. What I'm going to do now is show 3 three more approaches in addition to those 4 you've seen from EPA. 5 The first of those deals with the 6 longer term exposures -- the 90-day exposures. 7 And in all these cases again I'm going to give 8 a very brief summary. The reference -- or the 9 handout material you have will provide details 10 should you want more, or, indeed, our experts 11 around the table with us. 12 So in this approach we used raw 13 water from 400 community water systems from 14 the AMP program from 2003 to 2006, and we15 looked at four sampling frequencies. Thirty16 five samples a year stratified to the runoff 17 season, 17, nine and six. We looked at both 18 the full data set and the flowing water/static 19 water subsets -- either source subsets. We 20 simulated a set of samples, calculated the 21 maximum 90-day rolling averages, and compared 22 the predictions with the measured values.

### 202-234-4433 Neal R. Gross & Co., Inc. Page 272 1 The conclusions from that work are 2 for the 90-day rolling averages maxima both 3 the AMP schedule of 35 samples a year and the 4 17 samples per year approach are almost 5 indistinguishable. And what's more the static 6 water systems' lower frequency sampling is 7 effective. 8 But I think to answer a thought 9 that was almost voiced by the panel, the 10 correct -- I think it was -- the correct sort 11 of suitable frequency for community water 12 systems can be a sign based on history and 13 knowledge about the source water, the atrazine 14 trends, flows, et cetera. 15 The next two approaches deal with 16 the question of the confidence associated with 17 various sampling approaches if shorter 18 exposures become of interest. And the first 19 of these -- and here Dr. Sielken from Sielken 20 Associates is on the table with us to answer 21 any questions -- the approach was using 202 22 community water system finished water profiles

### 202-234-4433 Neal R. Gross & Co., Inc. Page 273 1 which were up to eleven years in duration. 2 Each of those was linear 3 interpolated across the entire length of the 4 multi-year profile. And then fixed sampling 5 intervals -- two day intervals, three day 6 intervals, four day intervals -- were applied. 7 And the sampled maxima from those samples were 8 compared with the observed peak maxima for the 9 entire community water system profile. 10 The combined ratios of those 11 comparisons for each of the 202 individual 12 profile analyses were built into a 13 distribution. And that led to conclusions 14 across all the community water systems. And 15 I'll give you the example for the seven-day 16 frequency. And you can be 95 percent 17 confident that the sampled maximum from your 18 seven-day sampling profile is greater than or 19 equal to 78 percent of the maximum. 20 You can turn that around into what 21 you could call a performance factor and say, 22 if I multiply my sampled value by 1.28, which

### 202-234-4433 Neal R. Gross & Co., Inc. Page 274 1 is the reciprocal of .78 or 78 percent, you 2 would be confident that you were trying to 3 estimate -- managing to estimate the observed 4 maxima. 5 Similar conclusions are in the 6 handout for various intervals and time 7 weighted periods. And the approach was also 8 applied to daily data sets -- and I'll come to 9 how that's helpful in a moment. 10 The second and last experiment I'm 11 going to tell you about also deals with the 12 question of the shorter exposure periods and 13 sampling frequency. In this case, rather than 14 using the power of the history from the VMP 15 and database what was used were the daily data 16 sets that are available, where true daily day 17 after day after day samples were taken. 18 And I'll just sort of briefly 19 dwell on these because there is one very late 20 breaking item, as Dr. Breckenridge sort of 21 mentioned. Data always seem to come in at the 22 last minute. And a few weeks ago we became

### 202-234-4433 Neal R. Gross & Co., Inc. Page 275 1 aware of a community water system in Missouri 2 between 1993 and 2000 took -- well, I think 3 five years with more than 300 samples. 4 This is truly a valuable resource. 5 If you really want to understanding drinking 6 water variability you want to deal with 7 measurements made in drinking water. This was 8 something we were unaware of until very 9 recently. This is a community water system 10 that samples the Missouri River. It's a big 11 system. So that's the most relevant one we

12 have. 13 The Heidelberg College data set 14 you've heard about from EPA. The key point I 15 want to make is that there are four watersheds 16 and they vary in area between about 34 square 17 miles and 6,300. And somebody mentioned basin 18 area earlier. And so this is a very 19 convenient set for understanding some of the 20 implications of basin area -- all of these 21 heavily agricultural 60 to 80 percent raw 22 crop.

### 202-234-4433 Neal R. Gross & Co., Inc. Page 276 1 But the important think to note is 2 both Heidelberg College and the eco programs 3 are raw water. They're not drinking water. 4 So the last group of data is the 5 eco program data. And, remember, for those 6 who haven't spent many hours on this these are 7 very small streams -- some of them are six 8 feet wide -- but certainly they're all very 9 small on small watersheds -- typically nine 10 to -- well, up to 100 square miles is the very

11 most.

12 We looked at 2009 data taken 13 daily -- composite samples actually -- ten 14 sites. And in addition, of course, there are 15 some ongoing programs -- there will be 30-plus 16 sites of daily data coming in in 2010. I

17 won't dwell more on that. 18 But I will raise a point that a 19 panel member made yesterday. And the question 20 was are there drinking water community water 21 systems in some of these upstream small 22 watersheds? And the answer is yes there is.

### 202-234-4433 Neal R. Gross & Co., Inc. Page 277 1 But there's a twist because the community 2 water system's job is to provide a continuous 3 supply to their customers. So if you have a 4 very small stream that's prone to drying up or 5 going very low you have to do something about 6 it. And what you can see on this diagram is 7 a watershed that's actually coming down 8 here -- there's a creek -- doesn't look unlike

9 some of the eco creeks. 10 But what they do is they pump from 11 this creek, typically not in the worst runoff 12 events because they don't want to put sediment 13 and stuff in there, and they pump into a 30 14 mega gallon kind of settling reservoir -- 15 that's million gallons. And then they pump it 16 into a 90 mega gallon storage reservoir. 17 That's actually got 150 days of supply for 18 that community water system in there. 19 And so the raw water that actually 20 feeds the treatment plant comes from this 21 storage reservoir. It doesn't come from the 22 creek. Now, the reason why I raise that is

### 202-234-4433 Neal R. Gross & Co., Inc. Page 278 1 because in May 2006 -- May 23 actually -- was 2 a residue reported that 227 parts per billion 3 in the creek. On the same day the raw water 4 that was going into the plant was .09 parts 5 per billion. And then the finished water that 6 came out was .05 parts per billion. 7 In your handout there are two high 8 numbers. One of them is this 227 as raw water 9 feeding a community water system. This is in 10 the white paper -- sorry -- from the EPA. And 11 so the value that is of 227 is a true value 12 for the creek. It is not relevant for what is 13 going into the plant. And, in fact, another 14 value -- 73 ppb -- was reported in 2008. And 15 that is also in the database. It's got a 16 different CWS code number in the EPA white 17 paper. And that was also not representative 18 by about the same ratio of the true raw water 19 that's actually feeding the plant. 20 So the important thing to realize 21 is these what are called side channel 22 reservoirs have no watershed of their own.

### 202-234-4433 Neal R. Gross & Co., Inc. Page 279 1 There's no water drains in there barring 2 actual rainfall. You've got to pump water 3 uphill to get them in there. 4 So looking at our daily data set 5 the same sort of simulation approach that Dr. 6 Frankenberry discussed generated simulated 7 sampling ranges including the every seven days 8 AMP ranging. And then it compared the 9 simulated data with the true values -- the 10 full daily data set -- and estimated the 11 ratios between the true and the simulated

12 values. 13 And these, again, are sampling 14 performance factors -- and Dr. Mosquin 15 actually did this work and so, again, he can 16 answer the questions on this. And those 17 performance factors for estimating maximum 18 daily values from seven day in season sampling 19 programs range for the community water system 20 between 1.2 and 1.8 and for the Heidelberg 21 College set of watersheds -- there's four,

22 remember -- between 1.1 and 2.6. But I'll

### 202-234-4433 Neal R. Gross & Co., Inc. Page 280 1 hasten to point out that's not drinking water, 2 so its relevance has to be carefully 3 considered. 4 And, again, for the eco programs, 5 which I believe are representative merely of 6 understanding how extremely flashy systems 7 behave and really have very little relevance 8 to drinking water, the range was 2.1 to 2.6.

9 So what can we conclude about 10 sampling frequency and confidence? The data 11 support lower frequencies than current AMP 12 programs, but 90 day for the longer averaging 13 periods, community water systems characterized 14 by static source water require fewer samples 15 than flowing, and you can use knowledge -- 16 prior knowledge to come up with suitable 17 frequencies for sampling such watersheds. 18 The huge available monitoring 19 database address current SAP questions, and 20 the daily data sets are very important to help 21 us kind of validate our thinking about 22 sampling frequency.

### 202-234-4433 Neal R. Gross & Co., Inc. Page 281 1 We used two complimentary sampling 2 performance estimation approaches. One was 3 the one from the VMP data looking down at the 4 entire profiles across history, sampling many 5 years, many circumstances. The other was 6 working up from true daily measured data sets. 7 Both of those gave similar results for the 8 daily data sets that are available. And those 9 two converged to suggest that sampling 10 performance factors for estimating maximum 11 daily values from seven-day sampling regimes 12 range between 1.1 and 2.6. 13 And why is that a useful number? 14 Well, it's consistent with the 3X sampling 15 uncertainty factor that's already in the 16 drinking water level of comparison. So the 17 numbers are coming out and, again, making 18 sense within the context of the existing risk 19 assessment process. And Dr. Pastoor will 20 mention that later. 21 Additionally, in turning very 22 briefly to the modeling questions, a variable

### 202-234-4433 Neal R. Gross & Co., Inc. Page 282 1 data permit confident analyses of sampling 2 uncertainty. Direct analysis of relevant data 3 sets that have historical relevance are 4 true -- feasible. And so I would suggest that 5 developing models to interpolate between less 6 frequent samples may be unnecessary given the 7 unique qualities of the atrazine database. 8 I would also suggest -- just 9 popping back to the first point on community 10 water systems, I would submit to the panel 11 that considering the source of the community 12 water systems may be an easier way of 13 classifying than worrying about peak shape, 14 but I think both need to be examined 15 carefully. 16 So, in wrapping up, we have a 17 truly exceptional database of monitoring that 18 provides very effective way of getting into 19 some of the questions being asked due to its 20 temporal and spatial coverage. It gives us 21 high certainty that 99.9th centile can be 22 determined and other high centile values, and

### 202-234-4433 Neal R. Gross & Co., Inc. Page 283 1 we can understand trends that are declining. 2 The current seven-day regime being 3 used in AMP is sufficient for estimating 4 short, intermediate, and long-term exposures 5 with high confidence using some of the 6 approaches we've show you. No additional 7 uncertainty factor is needed based on sampling 8 performance. 9 We recommend that you should use 10 finished drinking water for all aspects of 11 human exposure assessment, and we would also 12 suggest that the data available -- the 13 relevant data available, and full use of that 14 is preferable to developing models. 15 And, with that, after questions I 16 will turn you over to Dr. Pastoor.

17 SESSION CHAIR PORTIER: Panel? 18 Questions? Dr. Horton. 19 DR. HORTON: I have a question for 20 you. I'm a neuroendocrinologist so I'm going 21 to ask you some naive question regarding 22 hydrology. Most of what I've heard regard

### 202-234-4433 Neal R. Gross & Co., Inc. Page 284 1 surface water runoff -- what is done regarding 2 sampling of deeper water supplies -- aquifers, 3 wells, and such things? 4 DR. HENDLEY: Okay. Very good 5 question. There are approximately 212,000 6 ground water samples also from the SDWA 7 program. So from that database plus some very 8 focused studies done on both community water 9 systems on drinking water, as well as rural 10 wells, which are the smaller wells that maybe 11 an individual family may use, there was a12 great deal of work done between the mid13 nineties and the early 2000s. 14 EPA reviewed all of the water data 15 in roughly 2002. They concluded that the 16 exposure through groundwater was limited. And 17 then they actually -- that's -- they then 18 moved towards these programs on surface water. 19 So the data show that surface water is what to

20 concentrate on. 21 As I pointed out, none of the 22 surface water samples are exceeding the health

### 202-234-4433 Neal R. Gross & Co., Inc. Page 285 1 standard. Groundwater residues are so much 2 lower than surface water residues that EPA 3 judged surface water to be the focus.

4 SESSION CHAIR PORTIER: Dr. 5 Gilliom.

6 DR. GILLIOM: On the -- on that 7 trend analysis graph, which was slide eight, 8 is -- I wasn't able to catch up totally on the 9 background documents so I apologize for that. 10 But how was the -- was the trend analysis that 11 Syngenta did based on the aggregated data or 12 was it a site-by-site analysis that this is 13 summarizing? 14 DR. HENDLEY: This is summarizing 15 the data from 103 water -- raw water bodies 16 from 96 community water systems. And I think 17 it was -- there were two communities we looked 18 at. One was a population with I think more 19 than nine years of continuous data and the 20 other was a population with more than five 21 years of continuous data. 22 And so those were looked at within

### 202-234-4433 Neal R. Gross & Co., Inc. Page 286 1 the categories, as we said, of source water 2 type and also the, if you like, the low 3 series, the ones with history never exceeding 4 three ppb, and ones with the high, higher than 5 three ppb. So those community water system 6 data sets were looked at in various clusters. 7 DR. GILLIOM: So the lines on the 8 graph are kind of a generalization of that? 9 DR. HENDLEY: They are absolutely 10 a generalization. If you saw the original 11 graphics you would all have screamed and run 12 out of the room because they are a series of 13 distributions for each of the years of the 14 data within the year. And you really can't 15 explain them in a 20-minute presentation. 16 However, I would commend you to 17 have a look at the report, because it's very 18 relevant to some of the work that you and 19 Recio have done. 20 DR. GILLIOM: Yes. Because you -- 21 I mean, you guys are -- I haven't caught up to 22 the fact of trying to resolve the differences.

### 202-234-4433 Neal R. Gross & Co., Inc. Page 287 1 But you're aware that that's a different 2 result than what that work shows for the large 3 rivers? 4 DR. HENDLEY: I think that was 5 actually why you probably wanted to talk to

6 Dr. Chen.

7 DR. GILLIOM: Yes.

8 DR. HENDLEY: I would defer to Dr. 9 Herschel and Dr. Chen who are both in the 10 room. And perhaps after this session it will 11 be best if you spoke to them about that. 12 DR. GILLIOM: Okay. And one other 13 just while I have the mike here. On the slide 14 12 where you did the comparison for the 90-day 15 exposures, was -- am I correct in 16 understanding that this was done by 17 essentially resampling distributions from the 18 AMP data which was on the order of 30 to 35 19 samples a year?

20 DR. HENDLEY: Correct. 21 DR. GILLIOM: So I guess -- and 22 the only point, which was the same point we

### 202-234-4433 Neal R. Gross & Co., Inc. Page 288 1 talked about some with the EPA simulated data 2 experiments, was that -- and it's mostly 3 relevant to shorter-term occurrences. But you 4 don't have -- in the original data set used to 5 build the relations, you don't have the 6 highest peak from more frequent sampling. In 7 other words, it's limited by the original

8 data. 9 DR. HENDLEY: I think that's an 10 accurate statement. Of course, this analysis 11 was looking at the success against the 90-day 12 rolling average end points. 13 DR. GILLIOM: True enough. It's 14 just that some of the 90-day ones can be 15 pretty affected by relatively short-term

16 runoff events and so forth. That would be the 17 only -- 18 DR. HENDLEY: But, again, this is 19 over 440 community water system years. So 20 it's sampled pretty thoroughly across time. 21 DR. GILLIOM: With all the sites 22 aggregated, you mean, or you mean --

### 202-234-4433 Neal R. Gross & Co., Inc. Page 289 1 DR. HENDLEY: I'm just trying

2 to -- 3 DR. GILLIOM: I was getting a 4 little confused at some points in here where 5 we had aggregated across sites -- kind of

6 the -- 7 DR. HENDLEY: Right. 8 DR. GILLIOM: -- grand data set, 9 because it's a mixture of approaches that 10 makes a difference. Because some of these 11 questions are being targeted to the most 12 vulnerable systems, so it's more that 13 individual system versus the global. 14 DR. HENDLEY: I think the point -- 15 well, one of the points here is, of course, 16 the AMP programs are already the most 17 vulnerable systems. 18 DR. GILLIOM: Right. 19 DR. HENDLEY: So, you know, the 20 entire analysis was on the most vulnerable 21 systems. 22 DR. GILLIOM: Right.

### 202-234-4433 Neal R. Gross & Co., Inc. Page 290 1 SESSION CHAIR PORTIER: Dr. Young? 2 DR. YOUNG: But just to follow up, 3 if I understand correctly you took these and 4 you did just linear interpolations. So any 5 peaks that were missed are still missed. And 6 so, in fact, it's a very great smoothing. And 7 so -- and then things are aggregated, so we're 8 losing things over space and time. And then 9 to draw conclusions like that seems just very 10 counter-intuitive. So -- 11 DR. MOSQUIN: Paul Mosquin, RTI. 12 There's two different approaches used. One 13 uses the linear interpolation. And when the 14 linear interpolation was used that was for 15 data sets that were, let's say, essentially -- 16 had a large number of observations relative to 17 the others -- the Heidelberg, the ECHO and the 18 St. Louis. So there was less interpolation, 19 let's say, than you would if you'd used a VMP 20 or an AMP site. 21 For -- in the case of aggregation 22 the interpolation, if you will, was by a

### 202-234-4433 Neal R. Gross & Co., Inc. Page 291 1 weighting, which is a constant value weighting 2 over a particular interval centered on the 3 measurement, which is then a finite population 4 approach. So they are separate techniques in

5 that sense.

6 DR. SIELKEN: Can I add to that 7 response a little bit? This is Bob Sielken. 8 When we did the analysis looking at the CWSes 9 it is true that we used the available 10 realistic data, interpolated it linearly 11 stepwise and it didn't make much difference 12 which we did to create a test profile for the 13 202 CWSes over about 1,400 years. So we had 14 a large CWS/year combination.

15 So we took those real data set -- 16 realistic data set for year-to-year 17 variability that was discussed earlier -- took 18 those as tests to see how well our performance 19 would do -- not necessarily how well they 20 would have captured some unknown maximum. But 21 when we went back and sampled those profiles 22 whatever scheme we used -- would it have

### 202-234-4433 Neal R. Gross & Co., Inc. Page 292 1 captured what was known to be there. 2 So they're really just used as 3 test cases when we're going back to those 202 4 CWSes. And, you know, we got really good 5 performance. Paul Hendley mentioned that, you 6 know, you got at the 95 percent confidence 7 limit -- the ratio of the sample max to the 8 true profile max in your test case was 78 9 percent. And that was at one day. We got -- 10 we did the analysis for three-day rollings and 11 seven-day and ten-day and others. And we 12 could show that -- of course, the level of 13 performance improved. So there were none of 14 those that were really bad even looking at the 15 short durations down to one day. 16 The follow up to that is is that 17 in addition to using those representatives

18 test cases based on real data we went to the 19 Heidelberg, the Missouri, and then looked at 20 partitioning the data sets. And we found that 21 in all of those separate analysis, which were 22 closer to having a raw database that was

### 202-234-4433 Neal R. Gross & Co., Inc. Page 293 1 nearly daily sampling, that we got the same 2 sort of performance. 3 And I think that that's really 4 germane to the question about what about short 5 durations. And in that analysis we show that 6 even down to one day your current sampling 7 plan is really on top of things.

8 DR. YOUNG: But the -- I need to 9 do some more reading on it because there's a 10 logical disconnect here. The things that you 11 see -- if you sample every fourth day and your 12 peaks occur in between you're going to miss 13 something. It -- that's just a fact. You 14 know, you can't get away -- that if you want 15 short time scales you've got to sample on 16 short time scales. 17 So -- now, that's a fact. It's 18 just -- it doesn't matter whether you're in 19 space or time. If you want fine resolution 20 you've got to sample at that fine resolution. 21 Now, I can't quite -- haven't quite figured 22 out what's happening here, but that fact

### 202-234-4433 Neal R. Gross & Co., Inc. Page 294 1 can't -- it's just solid. So help me 2 understand why all of a sudden this is going

3 to work when I know that last fact's a fact. 4 DR. HENDLEY: I'll make out, 5 though, is I think that's why I'm happy that 6 we had the two-pronged approach working 7 upwards from true daily data, which addresses 8 your question, as well as downwards from the 9 extent of data collected across many years and 10 many sites. 11 Dr. Mosquin? 12 DR. MOSQUIN: Thank you. Yes, 13 certainty at a given site you're not going to 14 capture all the peaks if you sample 15 intermittently. The argument for the 16 weighting approach is -- relies on a belief 17 that the sites are comparable in some manner 18 so that for some sites you do sample the peak. 19 For other sites you don't. And yet because 20 there are enough sites that are of comparable 21 nature the times when you do sample the peaks 22 the weight is going to contribute that site's

### 202-234-4433 Neal R. Gross & Co., Inc. Page 295 1 maximum a certain number of days. 2 DR. YOUNG: But aren't you then -- 3 I mean, that seems to me to be changing the 4 question, because aren't -- I mean, and maybe 5 I need guidance here. I just don't know. I 6 don't think we're trying to find the peak of 7 the whole population. Aren't we trying to 8 think about each site and what we can say 9 about a site? Or are we just kind of talking

10 about for all of those blue dots out there? 11 I mean, because that's -- I mean, you're 12 looking at all blue dots. 13 DR. MOSQUIN: Right. That's -- 14 DR. YOUNG: And I thought we 15 wanted to be able to draw inferences at 16 locations. And those are two very different 17 questions. 18 DR. MOSQUIN: Right. So you 19 might -- I mean, that's why the two analyses 20 are performed. And one way to view it perhaps 21 in terms of the -- you know, the finite 22 population methods is that you ultimately

### 202-234-4433 Neal R. Gross & Co., Inc. Page 296 1 arrive at estimates that might represent, say, 2 your prior belief for sites of this kind in 3 terms of centiles. 4 DR. SIELKEN: I'd like to add two 5 things here. One is that in the profile that 6 you're sampling from those data are related to 7 each other. I mean, if you have admittedly a 8 peak that went up in a minute and came back 9 down by the end of the day you'd probably miss 10 it even with daily sampling. 11 But you've got a profile where 12 yesterday is a little bit related to the day 13 before and today is a little bit related to 14 yesterday and tomorrow will have this relation 15 over days. So that's one point -- that this 16 data is related and not isolated from each

17 other. 18 The second point regards to this 19 aggregation point -- really what we did was -- 20 when we were, say, talking about the 202 CWSes 21 was we tested the procedure individually on a 22 CWS, got an answer, and then said, well,

### 202-234-4433 Neal R. Gross & Co., Inc. Page 297 1 either put up a table of 202 answers or 2 characterize the distribution of those 3 answers, which you would do in a statistical 4 analysis. You'd look at the performance of 5 your procedure and you'd evaluate it 6 individually and then report the distribution 7 of those performances. And that's all we're 8 doing. 9 DR. YOUNG: Again, I think -- I'd 10 like clarification. Are we going to be 11 looking at locations and want to be able to 12 draw inference at locations or across the

13 whole area? 14 SESSION CHAIR PORTIER: Linda, I 15 think you can save that question. When EPA 16 reads the question to the panel you can ask 17 for clarification again at that time and we'll 18 get staff to come up and clarify it, because 19 I understand what you're talking about. It's 20 a matter of exactly what data you're 21 estimating for the decision role and there's 22 a lot of ways to look at that.

### 202-234-4433 Neal R. Gross & Co., Inc. Page 298 1 I don't want to drag this out for 2 too much longer, but Dr. Horton's been waiting 3 patiently for her question.

4 DR. HORTON: I have another 5 question of just how community water systems 6 are making decisions about how to pump and 7 when to pump. And going back to your slide 8 16, you're showing the model system and you're 9 saying, you know, the communities are not 10 pumping all the time from their sources, but 11 yet they're sampling -- or oftentimes their 12 samples are being taken even when pumping is 13 not occurring. 14 I'm wondering if information from 15 sampling can be used by communities to make 16 decision as to when to pump or not in order to 17 keep their side channel reservoirs cleaner. 18 DR. HENDLEY: I think there's two 19 answers to that. It depends on the community 20 water system. If you're on the Missouri or 21 the Mississippi, you have a constant stream of 22 water that you're pretty confident about, and

### 202-234-4433 Neal R. Gross & Co., Inc. Page 299 1 I understand it's efficient for them to pump 2 continuously under those circumstances. 3 For this type of smaller community 4 water system on a more variable water source 5 my understanding -- and these are individuals. 6 They all have their own characteristics, 7 communities, numbers of people to supply, and 8 jurisdictions within which they work -- but I 9 understand that the reason why they don't like 10 to pump during runoff events is sediment 11 organic matter, as well as synthetic organic 12 chemicals. 13 And so they will try and avoid 14 that where they can. And in fact you could do 15 it by chemical analysis. I think it's an 16 interesting suggestion. The problem is time, 17 because you've got to get that information 18 somehow in real time if you're going to use it 19 in real time. I think with what we know and 20 what they know about runoff they know, and 21 that's why they do tend to avoid peak events. 22 So they're very clever guys.

### 202-234-4433 Neal R. Gross & Co., Inc. Page 300 1 They're good at doing their job. And they 2 minimize their own difficulties. And that's, 3 in fact, why there's this sedimentation 4 reservoir. 5 And we didn't go into it, but 6 there are aspects to do with blending. And I 7 understand from people much more expert than 8 I that there are actually other legislations 9 to do with blending and getting a more sort of 10 homogenous supply in terms of the way their 11 plant's going to work. You know, they don't 12 want peaks going into the plant -- much easier

13 to have a smooth constant set of 14 concentration. So they do their best to 15 simplify things for themselves like all of us. 16 VOICE: Just to add one little 17 thing to that, that points out the difference 18 between using finished water concentrations to 19 characterize the drinking water than it would 20 to take an ambient water out of the creek as 21 a measure of drinking water -- just greatly 22 illustrates that difference.

### 202-234-4433 Neal R. Gross & Co., Inc. Page 301 1 SESSION CHAIR PORTIER: Dr. 2 Heeringa asked for the last question here. 3 CHAIR HEERINGA: I'll do this 4 quickly, and if it doesn't come across, I'll 5 have a side conversation. So getting back to 6 Linda's question, think of the 202 community 7 water systems. I'll start out and I'll take 8 the maximum observed value in that community 9 water system and I'll plot that on -- one to 10 202. There are 202 points and it's 78 percent 11 of the maximum value. I plot that for every 12 community water system, and those are the -- 13 and then I do a bootstrap sample from the 14 observed sample data for each community water 15 system. And I resample according to 16 frequency. So I get a distribution for each 17 of those community water systems. 18 And what you're saying is that in 19 95 out of 100 community water systems that the 20 sample point exceeded that 78 percent of the 21 observed maximum, not that five percent of the 22 generated samples for a community water system

### 202-234-4433 Neal R. Gross & Co., Inc. Page 302 1 exceeded -- 2 DR. HENDLEY: Dr. Sielken will

3 address that. 4 DR. SIELKEN: Thank you, Paul. 5 This is Dr. Sielken. Yes, Dr. Heeringa, you 6 have the example right. You're looking at all 7 202, how they performed, simulated each one, 8 and then you looked to see the -- what you 9 would have expected across that group. And 10 you would have expected in 95 percent of the 11 cases that your sample max would have been 12 bigger than about 80 percent of that. 13 CHAIR HEERINGA: So you're looking 14 along this axis. I think Linda's looking 15 vertically at the distribution of the 16 simulation samples within a community. 17 DR. SIELKEN: Yes. I am looking 18 across the CWS axis. 19 SESSION CHAIR PORTIER: Frigid 20 factor is going up in the audience. We're 21 looking for a break, but we have about 13 22 slides -- right? -- for the last presentation

### 202-234-4433 Neal R. Gross & Co., Inc. Page 303 1 here. 2 DR. PASTOOR: I promise not to be 3 too boring. Okay? All right. Let me just 4 first of all get my slides up here. Just one

5 second here. 6 (Pause.) 7 DR. PASTOOR: All right. 8 Everybody stand up and do calisthenics now. 9 Okay. 10 Tim Pastoor. I'm a toxicologist 11 and principal scientist with Syngenta, and I'm 12 batting cleanup today. And it's my pleasure 13 to try and bring us back to what this all 14 means in context. 15 And, Dr. Portier, you've been 16 mentioning that there seems to be one side of 17 the table over here that gets all excited 18 about things like corticosterone increases, 19 whereas the other side of the table gets 20 excited about, you know, 95th percentile of 21 the 99.9 percentile of confidence. So what my 22 job has been over the last number of weeks is

### 202-234-4433 Neal R. Gross & Co., Inc. Page 304 1 to spent time in both of those rooms, and I 2 think I get a higher place in heaven for that. 3 But the point is is that I was 4 able to sit with the neurobiologists, Dr. 5 Handa and Dr. Simpkins, as well as to sit with 6 Dr. Chen and with Dr. Hendley and also with 7 Bob Sielken, RTI. And, believe me, I've 8 learned more about statistics than I've ever

9 wanted to know. And I know more about 10 neurobiology than I should know. 11 But collectively we're trying to 12 answer a question that I think Anna Lowit -- 13 Dr. Lowit brought up the other day is -- where 14 does the rubber hit the road. And someone 15 else -- I think it was Dr. Hayton -- asked, 16 well, what's coming out of my tap and what 17 does that mean for health? And for me it's a 18 matter of how do you answer your friends and 19 family. And when they say, well, atrazine -- 20 you find it in water -- what does that really

21 mean. 22 So my job is to take the

### 202-234-4433 Neal R. Gross & Co., Inc. Page 305 1 neurobiology and the statistics and bring that 2 together in something that resembles something 3 of a risk assessment. Now, this is a risk 4 characterization, and it's a contextual one. 5 It's not a true risk assessment. It's just a 6 way of giving you some sense of where we are. 7 Now, one of the first things we've 8 got to do is take a look at exposure. I'm 9 going to take a look at exposure and I'm going 10 to bring the toxicology back in again. And in

11 order to do that we have to take a look at all 12 those data points. And Dr. Sielken graciously 13 gave me one example of how we do the linear 14 interpolation to get at how much exposure 15 might occur in a particular CWS or overall 16 anyway. 17 And the first thing you have to do 18 to establish an exposure is take all of these 19 data points and do a linear interpolation. 20 Why would you do that? It's because you now 21 have from these data points -- this is over 22 quite a number of years you can see here on

### 202-234-4433 Neal R. Gross & Co., Inc. Page 306 1 the X axis. You can actually do a linear 2 interpolation and you can begin getting an 3 idea of the 365-day pattern -- or 365-day 4 profile for the atrazine concentrations in 5 each individual CWS. 6 The value to that is that you can 7 then start taking slices of that and saying, 8 well, what's the average concentration that 9 you'd have for 90 days, for 30 days, for 10 10 days, and, of course, you can also take a look 11 at it on the basis of single-day peaks. And 12 you can compare that then to no-effect levels, 13 which is what I'm going to do next. 14 So the real thing here is when you 15 take a look at all the information that we 16 have -- and this is in finished water from the 17 CWSes primarily in the Midwest that have been 18 in this intensive monitoring programs. So 19 these are the CWSes where you'd expect to find 20 atrazine in the first place. And, indeed, 21 that's where we focus our attention. 22 We've got over 40,000 individual

### 202-234-4433 Neal R. Gross & Co., Inc. Page 307 1 data points which are then taken, and we've 2 made this linear interpolation for 365 yearly 3 points. That gives us a half-a-million points 4 to work with from the standpoint of 5 understanding what the distribution of 6 concentrations are in water in the Midwest in 7 finished drinking water. 8 So when we do that you can then 9 take a look at what that shows us. And I like 10 this because this box and whiskers diagram 11 kind of pulls it back from all the stuff that 12 we've been listening to -- well, how much is

13 where. 14 If you take a look at the one-day 15 concentrations and you look at the -- this is 16 the mean right here which is less than 1. You 17 look at the 75th percentile, of course, and 18 99.9th percentile -- you can look at that over 19 these rolling averages as well -- so 10 day, 20 30 day, and 90 day. 21 And you get an idea of what the 22 concentrations actually are in the water

### 202-234-4433 Neal R. Gross & Co., Inc. Page 308 1 supplies that we've been sampling with a large 2 degree of intensity that we've been doing. 3 And you can see here that the -- we know with 4 a significant degree of confidence that the 5 top value there -- 99.9th percentile anyway -- 6 is right around 15. Fifteen drops down as you 7 start averaging your 365-day profile. So you 8 can kind of get an idea of how much atrazine 9 is in the water. 10 Now, that's all well and good, 11 but, again, what does that really mean? What 12 kind of context can we put that in relative to 13 water limits that EPA has already set? And 14 there are actually limits that you can compare 15 that to. Let me give you that so that you can 16 put it in relative context.

17 EPA has two sets of values that 18 have been developed. One is by the Office of 19 Water, and these are health advisory limits. 20 And they're duration specific. You can see 21 here seven-day HAL for adults, one-day HAL for 22 children, and, of course, you've heard already

### 202-234-4433 Neal R. Gross & Co., Inc. Page 309 1 about the three part per billion maximum 2 contaminant limit which is a lifetime health 3 advisory as well. That was established back 4 in 1988. 5 That particular value is based on 6 .5 milligram per kilogram per day no-effect 7 level, a thousandfold uncertainty factor, and 8 also a contribution of 20 percent of water to 9 a dietary contribution. I'll get back to 10 that. But, anyway, that's where that number

11 comes from. 12 And in actuality it is the 13 statutory limit for atrazine. If you look at 14 the SDWA code you'll actually see that the 15 maximum contaminant limit, or the maximum 16 contaminant limit goal of three parts per 17 billion, actually has a statutory statement 18 that surrounds it. And I'll leave it at that, 19 but that's what the official level is that we

20 cannot exceed. But there are other levels 21 that are duration specific. 22 The Office of Pesticide Programs

### 202-234-4433 Neal R. Gross & Co., Inc. Page 310 1 also had what are called drinking water levels 2 of comparison, which are also duration 3 dependent. This is a 90-day DWLOC -- this for 4 infants. We have an annual one here -- 90-day 5 and so forth. So these are duration specific. 6 This particular value here is 7 based on a ten -- I'm sorry -- a 1.8 milligram 8 per kilogram per day study. That was the 9 Morseth study that Dr. Breckenridge referred 10 to. I believe it's also a study that Dr. 11 Mendez referred to as one of the end points of 12 interest.

13 That also has a thousandfold 14 safety factor built into it. Why? There's 15 the typical hundredfold safety factor built 16 in, and then there's an additional tenfold 17 safety factor. That tenfold safety factor 18 that's added onto it is for two reasons -- 19 threefold for uncertainties with a drinking 20 water program and threefold for uncertainties 21 with regard to children. Now, I think we're 22 answering both of those question, but suffice

### 202-234-4433 Neal R. Gross & Co., Inc. Page 311 1 it to say that's the basis for a thousandfold 2 uncertainty factor. So that's 12.5 parts per 3 billion.

4 There's also a value here of 298. 5 That's a one-day drinking water level of 6 comparison that's used by EPA as a way of 7 giving yourself a level to compare against 8 measurements that you would find in community 9 water systems. That value is based on a 10 10 milligram per kilogram no-effect level. It 11 also has a one thousandfold safety factor 12 applied to it. 13 Okay. So what happens when you 14 take what I showed you before on the box and 15 whiskers diagram here? And if we rescale the 16 y-axis now, because we've got to put in those 17 larger values -- so we now have this axis 18 here -- same box and whiskers diagram. But 19 now we're going to put the values in for the 20 one day or the shorter term values. 21 You can see that the information 22 that we've achieved from the water monitoring

### 202-234-4433 Neal R. Gross & Co., Inc. Page 312 1 program in the Midwest has clearly shown that 2 we're well below these levels which already 3 have a one thousandfold safety factor built 4 in. 5 Now, if you take a look at the 6 longer term, which is the 90-day -- here's 7 some values just to give you some context to 8 it -- there is, of course, the seven-year 9 adult health advisory limits, seven-year 10 child, and, of course, the 90-day drinking 11 water level comparison just to give you an 12 idea of where these 90-day rolling average 13 values are falling out relative to EPA's 14 already established comparison levels. That's 15 just to give you some comparison to 16 established levels that EPA can use. 17 The other way as a toxicologist 18 that I can do it -- and you've been hearing a 19 lot of about corticosterone up and down and 20 no-effect levels and dosages at 200 milligram 21 per kilogram, 50, and so forth. I've also 22 mentioned that there's a short term limit for

### 202-234-4433 Neal R. Gross & Co., Inc. Page 313 1 NOEL for 10 and longer term NOELs. 2 How do they all fit together? 3 Well, they fit together in the following way. 4 If you look at the top over here you can see 5 the no-level levels of 10 for short term, 6.25 6 for intermediate, and longer term is the 1.8 7 milligram per kilogram per day. These are 8 values that Dr. Mendez was referring to 9 yesterday and are the values that underpin 10 these limits down here. 11 And I did a calculation just to 12 get an idea of what that means in parts per 13 billion. So what -- if someone were to 14 actually be drinking water that would give 15 them a 10 milligram per kilogram dosage on 16 that particular day what does that convert to? 17 And the conversion factor that I use, which is 18 down here on the bottom, is a 70 kilogram body 19 weight, somebody drinking two liters a day. 20 And what that converts to in this particular 21 case is 350,000 parts per billion. And, 22 likewise, if you look at the lower value for

### 202-234-4433 Neal R. Gross & Co., Inc. Page 314 1 longer term exposure of 1.8 milligrams per 2 kilogram per day -- if you do that same 3 conversion it comes out to 63,000 parts per 4 billion. 5 Why am I doing this? I'm trying 6 to give us a context for a question that 7 actually came up yesterday, which is what's 8 the gap between what we're finding in these 9 water supplies with great confidence and the 10 toxicological testing levels that we're using. 11 What can we say about that? That's why I did 12 these calculations. 13 And I went one step further and I 14 said, Well, what if you compared the gap 15 here -- what kind of levels do you get? If 16 you compare the 99.9th percentile in the case 17 of one day you're dealing with something close 18 to 23,000 fold difference. If you look at the 19 75th percentile the gap is obviously quite a 20 big larger to the tune of 410,000 for one day, 21 69,000 for 90 day. 22 And if you take the mean values

### 202-234-4433 Neal R. Gross & Co., Inc. Page 315 1 and compare that against those no-effect 2 levels you're talking about nearly a 3 millionfold difference between the no-effect

4 level that's seen here and the mean value 5 that's found in the water supplies that we're 6 detecting, which is somewhere less than one 7 part per billion. 8 Likewise, for the longer term 9 value you're still looking at something like 10 150,000 fold difference between the no-effect 11 level and the 50th percentile that's found in 12 the 90-day rolling average. 13 So overall what we can say by this 14 that you've heard from Dr. Hendley, that 15 you've heard from the neurobiologists and so 16 forth, is that with regard to the water 17 monitoring programs it's extraordinary 18 extensive. We've got 100,000 finished 19 drinking water samples to work with, which for 20 the statisticians has been like kids in a 21 candy store with all that data to work with. 22 They've had a great time with it.

### 202-234-4433 Neal R. Gross & Co., Inc. Page 316 1 It's also been focused. We've got 2 50,000 samples from CWSes that have been 3 triggered into the extensive monitoring 4 program, which is based on these criteria of 5 half the MCL. And on top of that it's a 6 frequent program. It's weekly during the 7 planting season when you're likely to find 8 atrazine in the water. 9 On top of that the results are 10 then showing that there's a sufficient 11 database to start making estimates of what you 12 believe to be the highest values. And we can 13 say with certainty what we know they are at 14 the 99.9th percentile because of the extensive

15 database. 16 On top of that, and because of 17 this large database that we're working with, 18 it's our opinion -- and I think Dr. Hendley 19 articulated this -- is that models are really 20 unnecessary. If you've got the data you don't

21 need the models. 22 Finally, I think I'd like to leave

### 202-234-4433 Neal R. Gross & Co., Inc. Page 317 1 us all with this final message here -- that 2 the drinking water is safe. The margins of 3 exposure are very, very large and substantial. 4 And I think that is a good indication that for 5 as much as we want to know a great detail 6 about the mode of action and the levels at 7 which it can occur, we need to put that in a 8 context of exactly what can people be exposed

9 to. 10 And I got to thinking as well the 11 other day when I was talking to Dr. Simpkins 12 about that one slide -- I don't know if you 13 remember that where they saw the atrazine 14 precipitating out in solution. And so I asked 15 our chemist, well, what's the water solubility 16 limit for atrazine? 17 And so I went back to this 18 slide -- and I'm going to leave you with this 19 last slide here. And I said, well, what's the 20 water solubility limit if I were to look at it 21 on this scale. And that's what the atrazine 22 water solubility limit is; it's about 33,000

### 202-234-4433 Neal R. Gross & Co., Inc. Page 318 1 parts per billion. 2 And I sat there and thought about 3 that for a minute, and I thought, you know, 4 the fact of the matter is we're establishing 5 that no one is getting exposed to atrazine in 6 excessive amounts, nor could they because you 7 simply can't get enough atrazine in the water 8 to get that kind of a dose. 9 Now, the last thing I want to 10 leave you with too is that we are still in the 11 process of refining these no-effect levels. 12 We will understand them better and better as 13 we go through the information. And I think 14 when it comes to atrazine there has been a lot 15 of work, not just on the mode of action level, 16 but I believe on the mechanistic level to 17 understand how it works. And we'll get a 18 better idea of what these no-effect levels are 19 and how they compare with these water 20 monitoring limits. 21 So I hope what I've done here 22 today is give us a contextual reference to

### 202-234-4433 Neal R. Gross & Co., Inc. Page 319 1 what we're finding in these toxicology studies 2 relevant to the levels that we're finding in 3 the monitoring program. Okay? And I'll take 4 questions. 5 SESSION CHAIR PORTIER: Questions? 6 Dr. Krishnan? 7 DR. KRISHNAN: I have a couple of 8 questions. Maybe with this slide. Here, this 9 is similar to your slide on page five also 10 where you showed the margin of exposure of 11 about 6,000 at the last set of data -- 12 right? -- 1.8? Maybe -- just to be sure that 13 you mentioned -- would this set of data, the 14 1.8 as the RfD, the uncertainty factor was

15 thousand. 16 DR. PASTOOR: Yes, that's correct. 17 DR. KRISHNAN: And the relative 18 source contribution used was 20 percent as in 19 other risk assessments. So it should be about 20 a 5,000 is the expected margin of safety 21 because we can't just compare those 63,000 22 directly with the water concentration that

### 202-234-4433 Neal R. Gross & Co., Inc. Page 320 1 doesn't have any -- I'm trying to --

2 DR. PASTOOR: Yes.

3 DR. KRISHNAN: -- be sure that I 4 understand it correctly. 5 DR. PASTOOR: You're absolutely 6 correct. And, in fact, I think it's more 7 appropriate to go back to this slide right 8 here. And if, for example, we compare to the 9 12.5 -- just for an example -- this is based 10 on 1.8 milligrams per kilogram per day divided 11 by the 1,000 uncertainty factor and multiplied 12 by the 20 percent contribution of water to the 13 diet. Now, the other 80 percent is considered 14 to be foodborne atrazine. And I should point 15 out there is no atrazine exposure through the

16 food. 17 What EPA has in their document to 18 account for food is actually -- let's see, the 19 number is .000041 milligrams per kilogram per 20 day by food contribution. So the source 21 contribution is actually going to be 100 22 percent water. If you're going to get exposed

### 202-234-4433 Neal R. Gross & Co., Inc. Page 321 1 it will be by this route. Does that answer 2 your question?

3 DR. KRISHNAN: Thanks for the 4 clarification on the reassessing of the water 5 source contribution. But what I wanted to be 6 sure is that the margin of about 6,000 or so 7 that you showed with the last one that 8 compares with an expected margin of 5,000 9 based on the same assessments that you were 10 comparing to that's what I wanted to be sure 11 about -- thousand of uncertainty factor and 12 five for the water source contribution, which

13 would mean -- because there's no benchmark of 14 what is expected, so that's why I'm saying. 15 Because the margin of exposure is usually 16 interpolated based on the applied uncertainty

17 factors to an assessment. So --

18 DR. PASTOOR: That would be true -- 19 well, yes. You're absolutely right. I think 20 we're saying the same thing here unless I'm 21 wrong here. These already have built-in 22 they're uncertainty factors. So you're

### 202-234-4433 Neal R. Gross & Co., Inc. Page 322 1 comparing uncertainty factored levels to the 2 existing concentrations. 3 Let me correct this. This does 4 not have the 20 percent correction here. It's 5 actually built in to the 298. Do I have that 6 one right? 7 DR. KRISHNAN: The 20 percent 8 is -- 9 DR. PASTOOR: Right. Only in the 10 MCL values that are calculated is a 20 percent 11 calculation made for relative source 12 contribution in the health advisories -- the 13 Office of Water calculations that are made. 14 DR. KRISHNAN: Not with these 15 numbers that are presented as the pbbs? 16 DR. PASTOOR: No. This has got 17 a -- this is a 1.8 divided by what the 1,000 18 for the uncertainty factor, and then the 19 according body weight for either an adult or 20 a child. So the adult would be 70 divided by 21 two liters -- 70 kilograms divided by two 22 liters. For the child it's 10 kilograms

### 202-234-4433 Neal R. Gross & Co., Inc. Page 323 1 divided by one liter per day consumption. So 2 sorry for that. 3 SESSION CHAIR PORTIER: I think the 4 rest of us are going to take a break and 5 you're going to keep working on this. 6 DR. PASTOOR: Right.

7 SESSION CHAIR PORTIER: Dr. 8 Breckenridge, do you have any final words? 9 Because after this we're going to switch to 10 the rest of the public commentors. 11 DR. BRECKENRIDGE: No, Mr. 12 Chairman. Thank you very much for your 13 continued patience and the time you spent with 14 us this afternoon. We greatly appreciate the 15 opportunity to share new information. Thank 16 you very much. 17 SESSION CHAIR PORTIER: We're going 18 to take a 15-minute break and reconvene at

19 four o'clock. 20 (Whereupon, the above-entitled 21 matter went off the record at 3:45 p.m. and 22 resumed at 4:02 p.m.)

### 202-234-4433 Neal R. Gross & Co., Inc. Page 324 1 SESSION CHAIR PORTIER: Okay. We 2 have -- yes, I know -- my bell. I left my 3 bell at the other meeting room. We have 4 remaining four public commentors. It will 5 take a little over a half-hour. These are 6 relatively short compared to the two sets of 7 public comments we've heard before. So, Joe, 8 what's the order here? Just like it is?

9 MR. BAILEY: Yes. 10 SESSION CHAIR PORTIER: So I guess 11 the first commentor is Alan Roberson with the 12 American Water Works Association. 13 MR. ROBERSON: Well, my comments 14 start off by saying good morning, but I'll 15 switch that to good afternoon. And while I 16 was in the audience, I made up 60 slides that 17 I'll start off with. 18 (Laughter.) 19 MR. ROBERSON: I do have one thing

20 that's real short. 21 SESSION CHAIR PORTIER: As long as 22 you can do it in the five minutes we've got.

### 202-234-4433 Neal R. Gross & Co., Inc. Page 325 1 MR. ROBERSON: I'll talk really 2 fast. So, anyway, I want to thank EPA and SAP 3 for the opportunity to present the perspective 4 of the American Water Works Association. This 5 is an important issue to us. 6 We're an international non-profit 7 scientific and technical association 8 representing drinking water -- primarily 9 drinking water utilities. So some of the 10 questions I've heard earlier about water 11 utilities I'd be happy to answer. We've got 12 almost 50,000 members, 4,200 member utilities 13 that serve about 80 percent of the water in

14 the U.S. 15 So we're dedicated to safe water 16 and we appreciate the opportunity to comment 17 on the statistical approaches for the drinking 18 water monitoring frequency.

19 Our staff -- me -- and our member 20 utilities -- we're not expert on the health 21 effects issues, and we'll leave those issues 22 to the appropriate experts -- and a lot of

### 202-234-4433 Neal R. Gross & Co., Inc. Page 326 1 those are around the table.

2 We have reached out to some of our 3 members that have statistical expertise to 4 develop these verbal comments. And these 5 comments focus on the drinking water 6 monitoring frequency as opposed to the 7 ecological monitoring. There's two separate 8 issues there and we recognize that.

9 So -- and the other caveat I want 10 to make is that I'm not a statistician but I 11 play one on T.V. I'm an engineer by training 12 so I've had to go out to my members to do 13 this. So these verbal comments mirror our 14 written comments that we submitted to EPA on 15 April seven that are in the docket -- little 16 more detail in those comments. 17 So we've been following the 18 regulatory process for atrazine, simazine, and 19 the other triazines since the MCLs came out in 20 the early nineties. As you know, compliance 21 with the atrazine MCL of three parts per 22 billion is based on annual average of

### 202-234-4433 Neal R. Gross & Co., Inc. Page 327 1 quarterly samples. 2 And one sort of side comment I 3 want to make is that sampling is taken as what 4 is known as the entry point to the 5 distribution system -- so it's the finished 6 water after any treatment. If you hear about 7 raw water samples -- utilities may take those 8 as part of the participation in the Syngenta 9 program or they may be doing that as part of 10 their process control if they're trying to 11 determine how much carbon they might need to 12 add to comply with the MCL. 13 So atrazine and the other triazine 14 herbicides have been a major issue for us and 15 our members for the past 20 years due to this 16 potential to contaminate groundwater and 17 surface water. Over the past 20 years we've 18 written many comments to EPA as part of the 19 atrazine re-registration process. 20 In the past we were concerned 21 about the lack of data to make regulatory 22 decisions. But the recent IRED has been a

### 202-234-4433 Neal R. Gross & Co., Inc. Page 328 1 step in the right direction in requiring the 2 registrants to conduct monitoring in source 3 water. We think that's very important to have 4 that information. And we think those 5 registrant monitoring requirements should be 6 a requirement for any pesticide with the 7 potential to contaminate drinking water. 8 So our past written comments have 9 focused on several issues, but primarily our 10 main concern has been the additional treatment 11 burden that our utility members and ultimately 12 their customers continue to shoulder in order 13 to comply with the current atrazine standard. 14 Many service water utilities 15 installed additional treatment, either 16 granular activated carbon or powdered 17 activated carbon or both, soon after the MCL 18 was finalized in 1991 to comply with the new 19 standard. In fact, I would say from sort of 20 anecdotal evidence most service water 21 utilities now have carbon treatment in one 22 form or another to comply with the atrazine

### 202-234-4433 Neal R. Gross & Co., Inc. Page 329 1 MCL and to address other issues such as taste 2 and odor issues. 3 The registrant and the growers 4 have made some progress in controlling 5 atrazine at the source. And this stewardship, 6 combined with the additional carbon treatment 7 by utilities, have contributed to atrazine 8 violations in community water systems 9 decreasing from 81 in 1995 to three in 2007. 10 And that data came from the EPA's data system. 11 Any potential change in compliance 12 monitoring has implication for our members, 13 particularly the small and medium systems in 14 the Midwest that are subject to the wide 15 variability of atrazine concentrations in 16 their source waters. 17 Without restating the obvious in 18 the extensive literature you've seen the 19 service water utilities get that flush in the 20 runoff, and that depends on a lot of factors 21 such as the application date, the intensity 22 and direction of the rainfall, the type of the

### 202-234-4433 Neal R. Gross & Co., Inc. Page 330 1 watershed, several other factors. In some 2 Midwestern reservoirs the spring flush will 3 remain in the reservoir so that the atrazine 4 levels remain elevated year round. 5 I want to talk a little bit about 6 the economic implications for a required 7 increase in compliance monitoring. For 8 example, assume you have a small service water 9 system in the Midwest that serves 500 10 connections -- that's about 1,500 people. And 11 for this example let's assume an average 12 monthly water bill of $30 a month, so that the 13 total annual revenue for this system would be 14 about $180,000 a year. 15 So the analysis for a single 16 compliance sample using the approved GCMS 17 method costs about $200. And it should be 18 noted that the amino assay analytical method 19 has not been approved for drinking water 20 compliance monitoring. It's good for 21 screening. It's just not sensitive and 22 accurate enough for the compliance monitoring.

### 202-234-4433 Neal R. Gross & Co., Inc. Page 331 1 Assume an additional $100 for sample 2 collection. That gives a total cost of $300 3 for each additional compliance sample. 4 So doubling the samples for this 5 water system from four to eight would increase 6 the monitoring cost by about $1,200 a year. 7 That's about one percent of the revenue for 8 that system. So there's a significant impact 9 for any change in compliance monitoring. And, 10 again, that's for the drinking water side. 11 The ecological from my point of view will be 12 done by the registrant and our utilities would 13 not be involved with that. 14 At the same time, due to this 15 application in right-of-ways and other 16 widespread uses, atrazine is ubiquitous is 17 almost all surface waters and many 18 groundwaters, albeit in low concentrations. 19 In a recent study by USGS out of 4,600 samples 20 only eight were non-detects. In other words, 21 atrazine was detected in 99.8 percent of the 22 USGS samples of potential sources in drinking

### 202-234-4433 Neal R. Gross & Co., Inc. Page 332 1 water. This study did have a relatively low 2 detection limit of .004 parts per billion, and 3 the samples were taken in might be considered

4 vulnerable areas. 5 EPA's recent release of finished 6 water monitoring data from 44 states is part 7 of it's six-year review of drinking water 8 regulations. So EPA's required to go back and 9 look at the drinking water standards every six 10 years. That basically parallels the 11 previously mentioned violation data. 12 Atrazine was detected in 4.23 13 percent of about 161,000 samples. And I'm 14 going to give some ranges of the median, the 15 90th percentile, and the maximum levels from 16 that data set. And that's from each state, so 17 when you see the range it's -- you know, 18 here's the lowest in one state and here's the 19 highest. 20 The median range from .1 to 1.61 21 part per billion, the 90th percentile range 22 from 0.4 to four parts per billion, and the

### 202-234-4433 Neal R. Gross & Co., Inc. Page 333 1 maximum range from .1 to 27 parts per billion. 2 Generally atrazine is found less frequently in 3 finished drinking water as opposed to drinking 4 water sources due to existing carbon treatment 5 to comply with the MCL. 6 So we have four general 7 recommendations for the EPA and the SAP. EPA 8 should use its authority under FIFRA to 9 require environmental monitoring for any 10 pesticide with the potential for being water 11 contamination. EPA should complete this 12 reevaluation of atrazine as soon as possible 13 and to continue to hold to its principles of 14 good science and transparency. 15 EPA should use its toxicological, 16 epidemiological, and cost benefit expertise to 17 develop the appropriate risk management option 18 for drinking water as soon as possible. And 19 the registrants, or the users, should pay for 20 any additional compliance monitoring if needed 21 for water utilities. 22 Finally, I want to comment a

### 202-234-4433 Neal R. Gross & Co., Inc. Page 334 1 little bit on the basis of drinking water 2 monitoring frequency due to the potential 3 implications to compliance monitoring for 4 service water utilities. 5 A two-step process is needed to 6 make the decision if any additional monitoring 7 is necessary. First, EPA needs to determine 8 the appropriate concentration and time frame 9 that protects public health. It is important 10 to decide what criteria are before any attempt 11 to made to define a sampling strategy. 12 To do this some basic decisions 13 need to be made regarding what causes the 14 risks that are being mitigated. Are the risks 15 acute, chronic, sub-chronic, semi-chronic -- 16 there are different words you can use. If 17 chronic then what levels over what duration 18 are implicated in the health end point of

19 concern. 20 These fundamental questions need 21 to be answered, and we are looking at EPA to 22 answer these questions. Then a sampling plan

### 202-234-4433 Neal R. Gross & Co., Inc. Page 335 1 can be developed to meet those objectives. 2 Again, the current atrazine MCL of 3 3 parts per billion in compliance is based on 4 an annual average of quarterly samples. This 5 may or may not be the bright line for shorter 6 term exposures to atrazine. I have seen other 7 numbers mentioned such as 12, 12-1/2, 20, 30, 8 37-1/2 parts per billion and others -- there 9 was a whole list in the previous 10 presentation -- along with time frames of one, 11 seven, 30, and 90 days. 12 At this point we recommend that 13 the EPA make the decision as soon as possible 14 on a bright line for the appropriate 15 concentration and time frame for public health 16 protection noting that the ecological issues 17 may require a different set of criteria. 18 Then once the appropriate 19 concentration and time frame is set the 20 appropriate monitoring strategy can be 21 designed for water utilities, noting that the 22 current framework may or may not be

### 202-234-4433 Neal R. Gross & Co., Inc. Page 336 1 appropriate. 2 We think that the artificial 3 neural network approach developed by EPA is 4 too complex for water utilities and state 5 primacy agencies to use in developing 6 compliance monitoring strategies for specific 7 utilities. 8 It may be useful in evaluating 9 possible sampling structures during the 10 development of alternative rules, but even 11 before this application there are other 12 methods that have been explored, like 13 bootstrap sampling that are as effective and 14 much simpler than the ANN approach. 15 We've developed an approach that 16 focuses on developing a high confidence that 17 a measured value does not exceed specific 18 values established in the regulation, whatever 19 those values might be. 20 This approach found that the 21 number of samples needed to characterize a 22 spring flush and understand its potential

### 202-234-4433 Neal R. Gross & Co., Inc. Page 337 1 impacts on compliance for a specific level of 2 concern -- in this case we used three parts 3 per billion on an annual average because

4 that's what we were -- we knew to be a set 5 value for drinking water. That level of 6 concern is weighted to the mean and the 7 standard deviation of historical data for each 8 site. 9 These potential monitoring 10 requirements can be very succinctly and 11 summarized on the approach shown on the next 12 page -- and that's the graph -- I think it's 13 on the back of what everybody's gotten. 14 The results from this approach 15 suggest that using historical data -- and, 16 again, that's really looking at the mean and 17 standard deviation -- sampling can be designed 18 so that surface water systems that are 19 vulnerable with high means and high 20 variability sample more frequently while 21 systems that have low means and are little 22 variability sample less frequently. And I've

### 202-234-4433 Neal R. Gross & Co., Inc. Page 338 1 given a electronics copy of this spreadsheet 2 on stick drive to EPA staff, and that's 3 available for anyone to use. It's really a -- 4 I think a pretty simply tool that might be 5 effective. 6 So that's the end of my comments. 7 If there are any questions? 8 SESSION CHAIR PORTIER: Any 9 questions from the panel?

10 MR. ROBERSON: Wow.

11 SESSION CHAIR PORTIER: I don't see 12 any. Could be a factor that you're very clear 13 or a factor that we're very tired. 14 MR. ROBERSON: You've had a long 15 day. Okay. 16 SESSION CHAIR PORTIER: I suspect 17 it was clear. 18 MR. ROBERSON: Okay. And I will 19 be around for some of the discussion tomorrow 20 afternoon and Thursday when you start talking 21 about this issue. My toxicological background 22 is pretty thin so I'm going to pass on that

### 202-234-4433 Neal R. Gross & Co., Inc. Page 339 1 tomorrow morning.

2 SESSION CHAIR PORTIER: An 3 opportunity to learn more.

4 MR. ROBERSON: I learned a lot 5 today.

6 SESSION CHAIR PORTIER: The next 7 speaker is Dr. Sass with the National 8 Resources Defense Council. Dr. Sass provided 9 two handouts this morning to the panel. 10 DR. SASS: Thank you very much for 11 your indulgence. I know it's been a really 12 long two days and I know it's not going to get

13 shorter. 14 My name is Jennifer Sass. I'm a 15 scientist with the National Resources Defense 16 Council, which is an environmental non-profit. 17 And I'm in the health program. I'm located 18 here in Washington, D.C., and my background is 19 molecular, developmental, and toxicology. 20 I have two handouts for you. So 21 one is this report. It's an update from a 22 report that we actually did, I think, in

### 202-234-4433 Neal R. Gross & Co., Inc. Page 340 1 August of `09 -- doesn't seem that long ago to 2 me. And we analyzed the data and crunched it 3 and sort of came up with different tables of 4 the individual community water systems as well 5 as drinking water and watershed both from the 6 Syngenta -- I'll call it Syngenta EPA data -- 7 from the monitoring programs that you've been 8 hearing about. 9 So we presented that in a report 10 in August and this is an update of the more 11 recent years from that data set. But the 12 summary of that -- there's some executive 13 summary, but the summary of that is in my

14 comments. 15 My comments, which have also been 16 passed to you -- I'm not going to read all of 17 it obviously; I think it's about 17 pages. 18 But I did respond to the actual charge 19 questions that you've been given and I slotted 20 my answers -- I read those charge questions 21 and tried to answer those and give you what I 22 think are my answers. So feel free to sleep

### 202-234-4433 Neal R. Gross & Co., Inc. Page 341 1 through this presentation, and then when you 2 get to those charge questions you can pop open 3 this handy list and see what Jennifer would 4 have said. 5 And a lot of them -- again, the 6 toxicology is really very expert, and you know 7 that, and you've heard from the experts 8 actually. So in a lot of them, I just say

9 that I don't have an answer for that and I 10 look forward to seeing what you guys come up 11 with. So I haven't stretched myself -- I 12 haven't made up anything -- I haven't 13 stretched myself beyond what I actually can

14 comment on. 15 So question 1.1 -- this is the 16 issue of the carcinogen -- whether -- how to 17 classify it as -- what its potential is to be 18 a human carcinogen. This is something that 19 EPA and I have been going back and forth on 20 since I started this job in 2001, in January. 21 So my answer to this hasn't 22 changed that much, which is that I think

### 202-234-4433 Neal R. Gross & Co., Inc. Page 342 1 classifying it as not likely a human 2 carcinogen, which is what EPA is proposing 3 here, is inconsistent with EPA's cancer 4 guidelines and supplemental, which were 5 published and finalized in `05, and as well 6 with the criteria of the International Agency 7 for Research on Cancer, IARC, which is 8 probably the premier cancer classification 9 body located in France. They've reviewed 10 atrazine twice. And I also say it would be 11 scientific ignorance and dangerous public 12 health policy to classify atrazine in the way 13 that EPA proposes here. 14 I want to read you the IARC 15 guidelines for classifying something as not 16 likely -- that would be a Group 4 for IARC. 17 IARC has evaluated about 900 agents since the 18 mid -- since 1971 -- since the 1970s. And of 19 those only one has ever been categorized as a 20 Group 4, not likely. And that's because the 21 burden of proof required to put something into 22 not likely, to actually know, to be able to

### 202-234-4433 Neal R. Gross & Co., Inc. Page 343 1 state with scientific certainty -- scientific 2 confidence that you know that it's not going 3 to cause human cancer is a threshold that's 4 very hard to meet for the World Health 5 Organization, which is who IARC advises.

6 On the other hand the EPA doesn't 7 seem to have too much trouble bumping things 8 into that category. And I think that's really 9 poor public health policy for an agency that's 10 charged with protecting public health. 11 Atrazine, as I said, has been 12 twice reviewed by IARC in `91 and again in 13 `99. It's classified as Group 3, unable to 14 determine. And that's based on sufficient 15 evidence of causing cancer in experimental 16 animals, but inadequate evidence in humans. 17 It was downgraded in -- from its 18 1991, from its earlier classification, which 19 was a 2B -- Group 2B, possibly carcinogenic to 20 humans. And that's because in the `99 the 21 second work group felt that the mechanism by 22 which it was causing tumors in animals might

### 202-234-4433 Neal R. Gross & Co., Inc. Page 344 1 not be relevant to humans. Nobody questions, 2 though, that it caused cancer in animals. 3 Okay. Dr. Lorenzo Tomatis, who, I 4 point out here, was probably one of the 5 greatest public health experts of our 6 lifetime, a former director of the IARC, as 7 well as chief of the IARC monograph program, 8 wrote, in referring to the decision to 9 classify atrazine as unable to determine, 10 Group 3, "Evidence of carcinogenicity provided 11 by the results of experimental bioassays 12 appears too often to have been disregarded on 13 the basis of suggested mechanistic hypotheses. 14 Ominous consequences on public health may 15 follow if such hypotheses, once actually 16 tested experimentally, are shown to be 17 incorrect or if they do not account adequately 18 for the wide range of susceptibility that is 19 known to exist in human populations." 20 Atrazine has not been adequately 21 tested in studies covering a full range of 22 human exposures, including pre-birth and early

### 202-234-4433 Neal R. Gross & Co., Inc. Page 345 1 life exposures for its potential to cause 2 cancer in humans and it should not be 3 classified as not likely.

4 I have some more on that but I'm 5 not going to read it to you at this time 6 except to say that we would like EPA to follow 7 the advice of earlier scientific advisory 8 panels in 2000 and in 2003 that reviewed this 9 question. In both those panels the final 10 report recommended that EPA consider all of 11 the relevant science relating to atrazine 12 carcinogenicity including whether hormonal 13 effects in childhood or adolescence may have 14 an impact on cancer occurrence in later years. 15 But, unfortunately, this panel has

16 not been asked to look at all that data and 17 has not been charged, actually, with a full 18 review of data for that question. And so I 19 would suggest that the suggestions of earlier 20 panels be heeded. 21 The regulation of hazardous 22 materials in the U.S. is generally based on

### 202-234-4433 Neal R. Gross & Co., Inc. Page 346 1 the scientific dogma that the dose makes the 2 poison -- the notion that a larger doses are 3 more toxic and that smaller doses are less 4 toxic. This belief leads to the presumption 5 that a chemical is safer at lower doses. And 6 for this reason, and also because testing with 7 low doses is often not done for practical 8 reasons, which you all know, we rarely have 9 reliable toxicity data of potential hazardous 10 effects at very low doses. 11 Moreover, for chemicals that 12 interfere with the development of critical 13 organ systems, such as the immune system, 14 reproductive systems, and the nervous system, 15 there is now a substantial amount of 16 scientific proof than when exposure occurs at 17 the same time as these critical systems are 18 developing during early life stages even 19 transient low dose exposures can cause 20 irreparable harm -- that is, the timing of 21 exposure may be as important or even more 22 important than the dose.

### 202-234-4433 Neal R. Gross & Co., Inc. Page 347 1 For example, pre-birth exposure to 2 mercury at levels so low that you can't detect 3 effects in the pregnant mother could cause 4 improper connections between the brain cells 5 that are forming synapses in her fetus and 6 result in lifelong alterations in brain 7 structures and function. We know that.8 Exposure to endocrine or hormone9 disrupting chemicals such as atrazine during 10 critical windows of development has also been 11 shown to have permanent effects in laboratory 12 animal studies. Some of these effects, such 13 as infertility or cancer, may not be obvious 14 until adulthood even though the exposure 15 occurred during fetal or neonatal life. 16 This phenomenon has been 17 demonstrated for atrazine in laboratory 18 animals, such as amphibians, where short 19 exposures during early development stages have 20 had long-lasting or even permanent 21 irreversible effects on adult behavior and 22 longevity, including increased susceptibility

### 202-234-4433 Neal R. Gross & Co., Inc. Page 348 1 to infection -- the immune tox data -- 2 alternations in survival behavior -- also 3 shown there -- and reduced long-term survival. 4 Some of these data were mentioned by your 5 expert speakers that addressed you yesterday. 6 I know because I was here -- something to 7 consider. 8 Jumping to question 1.4, 9 commenting on the agency's preliminary 10 conclusion regarding the aromatase mechanism, 11 I just want to point out there is data, and I 12 don't want to go through the data -- actually 13 Pia summed it up for you and as well I'm sure 14 some of you know it independently. 15 I just want to point out that 16 atrazine is associated with numerous diverse 17 health end points related to endocrine 18 disruption. For example, it's an endocrine 19 disruptor. It impairs the immune system and 20 it is associated with birth defects. It's 21 associated -- it's been associated in male 22 frogs with eggs in their testes, with impaired

### 202-234-4433 Neal R. Gross & Co., Inc. Page 349 1 sperm production and frogs -- in animals -- 2 sorry -- and in humans and with birth defects 3 in human infant gut wall. 4 Giving the experimental evidence 5 of such diverse outcomes it is unclear to me 6 how EPA can determine with confidence that a 7 particular mechanism of toxicity is not 8 relevant until it has been thoroughly tested 9 in multiple, mutually consistent, adequately 10 powered studies that exclude with reasonable 11 certainty bias, confounding, and chance. And 12 I don't think that bar has been met. 13 A 2010 article published by 14 University of South Florida researchers Rohr 15 and McCoy analyzed the findings of over 125 16 independently published research studies of 17 atrazine effects on freshwater fish and 18 amphibians. Their meta-analysis found that 19 many of the studies reported the same health 20 outcomes, even though the studies were in 21 several different wildlife species and used 22 different research methods.

### 202-234-4433 Neal R. Gross & Co., Inc. Page 350 1 In particular, atrazine affected 2 the hormone system of freshwater fish and 3 amphibians in most studies, including effects 4 such as altered time of metamorphosis -- 5 sometimes it was a delayed and sometimes it 6 was accelerated, it wasn't always the same -- 7 impaired sperm production and abnormal gonadal 8 development. 9 These reports of diverse endocrine 10 disruption effects on atrazine across diverse 11 species and in different independent studies 12 suggests that the mechanisms of toxicity for 13 atrazine are likely also diverse, including 14 several mechanisms of action potentially and 15 possibly including aromatase catalysis. 16 Question 1.6, the agency has also 17 concluded that there's no association between 18 atrazine and the development of Parkinson's 19 disease. You heard their presentations 20 yesterday; I also did. Please comment. 21 So my comment is this. A 22 potential association between atrazine and

### 202-234-4433 Neal R. Gross & Co., Inc. Page 351 1 Parkinson's disease has not yet been tested 2 with multiple, mutually consistent, adequately 3 powered studies covering a full range of human 4 exposures that exclude, with reasonable 5 certainty bias, confounding, and chance to 6 provide individual and pooled estimates of 7 risk in near unity with narrow confidence 8 intervals. It has not been tested, in other

9 words.10 However, a number of well11 conducted studies have reported a 12 statistically significant link between 13 Parkinson's disease and exposure to pesticides 14 generally, and including some herbicides and 15 organochlorines like atrazine. 16 For example, in 2010 a Portuguese 17 team reported that among 86 cases of 18 Parkinson's disease, sex- and age-adjusted 19 logistic regression showed a potential risk 20 factor, included pesticides, herbicides, and 21 insecticides. It's in my comments: The odds 22 ratio is 2.6, and the 95% confidence interval

### 202-234-4433 Neal R. Gross & Co., Inc. Page 352 1 range is 1.17 to 5.86. 2 The 2009 epi study from California 3 reported a correlation between well water 4 possibly contaminated with agriculture5 pesticides, possibly because they used GIS6 based models and state pesticide use reports 7 in order to estimate contamination levels, and 8 Parkinson's disease specifically. 9 Although atrazine was not one of 10 the pesticides that was selected for 11 examination in that study, they did find a 12 high level of possible well water 13 contamination with methomyl -- odds ratio is 14 1.67 -- it was statistically significant -- 15 with chlopyrifos -- and the odds ratio of 16 1.87, again statistically significant -- and 17 propargite -- odds ratio 1.92, again 18 statistically significant -- resulting in 19 approximately 70 to 90 percent increases in 20 relative risk of Parkinson's disease. 21 And more recently a 2010 study 22 published in the Journal of Neurology reported

### 202-234-4433 Neal R. Gross & Co., Inc. Page 353 1 on a correlation between blood serum levels of 2 dieldrin, which is also an organochlorine like 3 atrazine, and Parkinson's disease. I also 4 have the odds ratios here. Atrazine may also 5 be found to have similar health outcomes if it 6 were examined properly. 7 These findings are in agreement 8 with an NIH agriculture health study which 9 reported in 2006 a nearly twofold increase in 10 the risk of Parkinson's among applicators. 11 Incident Parkinson's was associated with 12 cumulative days of pesticide use at 13 enrollment. So the more days that you applied 14 the more your risk went up. And they divided 15 them into quartiles. And when the highest 16 quartile, which was 400-plus days, was 17 compared to the lowest the odds ratio was 2.3, 18 and it was statistically significant for 19 persons applying pesticides. 20 For persons applying pesticides 21 more than half the time the odds ratio is 1.9. 22 While this study reported a link between

### 202-234-4433 Neal R. Gross & Co., Inc. Page 354 1 atrazine and incident Parkinson's it was not 2 significant at the 95th percentile. It 3 probably would have been significant at the 4 90th percentile -- the odds ratio is 1.1 and 5 the confidence sensor was -- spanned .5 to 6 2.2, but they didn't present 90th 7 percentile -- or 90 percent confidence 8 intervals. I wish they did. Moreover, the 9 authors reported a link between the 10 organochlorine lending and also incident 11 Parkinson's -- statistically significant. 12 Unfortunately, there was a low 13 number of cases -- 43 percent with atrazine 14 and 19 cases with lindane. It's -- because 15 it's a prospective epidemiology study they're 16 still following it. And it compromises the 17 statistical power of the study at this point, 18 but they're still following up these 19 applicators and I think there may be things we 20 can learn in future iterations -- future 21 reports. 22 These studies and others provide

### 202-234-4433 Neal R. Gross & Co., Inc. Page 355 1 suggestive evidence, though, that a possible 2 link may exist between atrazine exposure and 3 risk of Parkinson's disease. And therefore, 4 a lack of an association cannot be asserted 5 with scientific confidence.

6 I have some answers to 1.8 on the 7 immune system but I actually don't think I'm 8 going to read them for you today. Oh, except 9 to sum up at the end because I read a little10 bit of the Jason Rohr study -- the meta11 analysis and a few things -- except to sum up, 12 that atrazine has been shown to act 13 synergistically with other chemicals to 14 increase their toxic impairing of the immune 15 system. 16 In a 2009 study when tiger 17 salamander larvae were raised for two weeks in 18 atrazine containing -- or in water containing 19 atrazine at 20 or 200 part per billion or 20 chlorpyrifos at 220 or 200 part per billion, 21 no increase in death was observed. But when 22 the larvae were exposed to the combination of

### 202-234-4433 Neal R. Gross & Co., Inc. Page 356 1 atrazine and chlorpyrifos together there was 2 a significant increase in larval death from 3 increased viral infection and disease, so 4 presumably a compromised immune system. 5 This study suggested the two 6 chemicals acting together can harm immune 7 function, whereas either one alone may not. 8 This is significant because these pesticides 9 are commonly found together. USGS finds them 10 up to seven or more at the time routinely in 11 water bodies, and, as well, because many of 12 the pesticide products, including atrazine, 13 are packaged and sold as mixtures with other 14 pesticides. 15 Question 1.9: I sort of use that 16 question as an opportunity to jump in and say 17 that I think EPA failed to consider a number 18 of important studies that are directly 19 relevant to the understanding of human health 20 risks associated with atrazine, and I've 21 identified some of those. 22 One of them that I think is really

### 202-234-4433 Neal R. Gross & Co., Inc. Page 357 1 important and that was mentioned at the -- by 2 the scientific advisory panel you guys in -- 3 I think February was your last meeting -- is 4 one on poor birth outcomes -- it's a 2009 5 study. It found a significant correlation 6 between prenatal atrazine exposure and reduced 7 birth weight -- reduced body weight at birth. 8 They reviewed over 24,000 babies 9 born in Indiana and localized them to 10 particular water systems. I've summed it up 11 for you with a little more data. I think it 12 should be considered. 13 There's also a 2009 study that 14 analyzed over 30 million births across the 15 U.S. and reported an increased risk of birth 16 defects associated with mothers who became 17 pregnant in April to July, when pesticides are 18 at their highest in the waterways. These 19 ecological epidemiology studies, as you know, 20 are more like hypothesis testing rather than 21 conclusive. 22 But what I think is interesting

### 202-234-4433 Neal R. Gross & Co., Inc. Page 358 1 about this is that in spring when other -- 2 where pesticides may fluctuate in the water 3 and might be considered to be highest, other 4 contaminants wouldn't be expected to fluctuate 5 in spring. So, for example, pharmaceuticals 6 that are in our water, other kinds of 7 endocrine disruptors that are in drinking 8 water -- so you wouldn't be expecting them to 9 have seasonal spikes like pesticides. So I 10 think it's worth looking at. I think it's 11 significant. They found a birth defect in the 12 gut wall of newborn babies associated with 13 early life exposures during this time. 14 The other thing I want to point 15 out -- in digging through the RED, which is 16 the Registration Eligibility Decision that 17 EPA -- EPA's final decision to register 18 atrazine -- is that they actually determined 19 that it was likely that workers and homeowners 20 and their families may be exposed to unsafe 21 levels of atrazine because of lawn uses. For 22 workers, that included farmers who mix, load,

### 202-234-4433 Neal R. Gross & Co., Inc. Page 359 1 and apply the pesticides like atrazine -- this 2 is in atrazine RED -- and I have page numbers

3 and references. 4 What they found -- we know that 5 exposures can occur from accidental spills and 6 splashes onto skin or clothing as well as 7 inhalation and droplets being applied directly 8 to the skin. And EPA noted all that and that 9 exposure can also occur when applicators 10 follow all the label requirements and use 11 protection clothing and equipment, that you 12 can still have exposures.

13 We also know that because we have 14 data showing that farmers have it in their 15 urine when they apply atrazine -- and that's 16 data from CDC researchers -- and I've cited 17 all of those studies. As well, we know that 18 there's been links between atrazine levels in 19 the urine and poor sperm quality in rural men 20 associated with atrazine exposure -- 21 statistically significant. 22 And we also know that if you

### 202-234-4433 Neal R. Gross & Co., Inc. Page 360 1 reduce the amount of atrazine that's being 2 applied then you can actually reduce the 3 amount that's in the urine. So we know that 4 there's a direct correlation if we take action 5 that we can actually protect direct exposures

6 to those workers. 7 And in 2006 in its RED in its 8 final decision EPA acknowledged concerns about 9 these human exposures. EPA classified 10 atrazine as an RUP, or restricted use 11 pesticide. That's because of its hazards to 12 ground and surface water, and it means that 13 only applicators can apply it. 14 But there's an exception for lawn 15 care, turf, and conifer trees and it allows 16 homeowners to apply the chemical themselves. 17 And according to EPA's own assessment in its 18 RED, this exception may lead to unsafe 19 exposures that exceed EPA's own levels of 20 concern for homeowners who apply the products 21 for their lawn. And EPA also expressed 22 concern that children who play on these

### 202-234-4433 Neal R. Gross & Co., Inc. Page 361 1 atrazine-treated lawns may also be at risk for 2 potentially unsafe exposures. So the idea of 3 needing to consider these early life exposures 4 is very relevant. It's very real. 5 We have some recommendations. I 6 used question 2.1 to take advantage of some 7 extra space at the end and make some 8 recommendations. So, first of all, the 9 watershed and monitoring programs of watershed 10 and drinking water -- actually our analysis of 11 EPA's atrazine monitoring program taken from 12 20 watersheds between 2007 and 2008, which is 13 our updated report which I've provided to you, 14 confirms that waters are contaminated. They 15 continue to be contaminated. 16 Actually they did 20 watersheds 17 and they all showed detectable levels of 18 atrazine. 16 had average concentrations above 19 1 part per billion. 1 part per billion is the 20 level that EPA has been determined to show -- 21 is determined to be harmful and plants and 22 wildlife -- aquatic plants and wildlife.

### 202-234-4433 Neal R. Gross & Co., Inc. Page 362 1 18 of the monitored watersheds 2 were intermittently severely contaminated 3 where at least one sample was above 20 -- this 4 is watersheds, not drinking water, remember -- 5 above 20 part per billion. And nine had peaks 6 that were above 50 part per billion. Three 7 had maximums that exceeded 100 part per 8 billion. One, the Big Blue River watershed in 9 Nebraska, had 147 part per billion in May of

10 2008. 11 The drinking water data, which we 12 also analyzed and provided an update, was 13 taken between 2005 and 2008. 80 percent of 14 the samples from 153 drinking water systems 15 contain atrazine -- that's raw and finished -- 16 that's 80 percent of total samples. But of 17 the 153 drinking water systems that were 18 monitored, 100 had peaks in the raw water that 19 exceeded 3 part per billion, and two-thirds of 20 these 100 systems also had peaks that exceeded 21 3 in the finished water. Again, they don't 22 exceed the MCL because it's averaged over a

### 202-234-4433 Neal R. Gross & Co., Inc. Page 363 1 year, but they're spiking. 2 Six had high enough atrazine 3 levels to actually exceed the MCL. But what 4 happens is, the utilities put in all the data, 5 and so when you get a lot more non-detects or 6 low levels of the year, you can average away 7 those peaks. But if they just took the 8 quarterlies it would actually exceed the MCL 9 in the finished tap water. 10 But the problem -- and my 11 recommendations as a scientific advisory panel 12 that you can pass on to the EPA -- is that EPA 13 actually identified 1,172 watersheds that were 14 at high risk. They, however, negotiated a 15 monitoring program with the registrant that 16 would only monitor 40 of the 1,172. So 17 everything you've been hearing about and all 18 the data we've collected and everything that 19 EPA has is on about 4 percent of what EPA 20 recognizes as the high risk watersheds. 21 Okay. So we think that that 22 monitoring program should be broadened. For

### 202-234-4433 Neal R. Gross & Co., Inc. Page 364 1 one thing EPA doesn't have any plan to deal 2 with the other ones. So actually everything 3 they're finding and everything they're telling 4 you that they're taking action on is in that 5 40 and the other, you know, 1,060 are being 6 ignored. And I agree with Alan Roberson that 7 that should be paid for by the registrant. 8 And we also think that the 9 scientific advisory panel could recommend to 10 EPA that they publish the monitoring data so 11 that we don't have to keep doing report 12 updates. And they should publish it in a way 13 that the public can look up their data, like 14 they can on our website now, and they can look 15 up their community water system and see what 16 the numbers are. That shouldn't be our job. 17 Thank you. 18 SESSION CHAIR PORTIER: Any 19 questions from the panel? Yes, Dr. Gilliom. 20 DR. GILLIOM: It's partly a 21 question on protocol. Are the reports that 22 are referenced in Dr. Sass' testimony with

### 202-234-4433 Neal R. Gross & Co., Inc. Page 365 1 your notes -- are those automatically included 2 in the record? And part of this is also 3 intermixed with a question that some of the 4 input we've received is based on the 5 epidemiological type of studies -- more the 6 correlation things and sometimes involving 7 mixtures, which is kind of in this gray area 8 of scope for our panel. So it makes it kind 9 of difficult of how to factor everything in. 10 Is there some guidance from -- is it included

11 in --

12 MR. BAILEY: I don't have the 13 studies. I only have the citations that 14 Jennifer has provided. If you -- I suppose if 15 you want copies of them we could try to get 16 them for you -- work with Jennifer to get 17 copies of them. 18 DR. SASS: I was being polite I 19 guess. I can provide those with you. I think 20 that your rules are that you don't put 21 published manuscripts in the docket because it 22 violates the copyright of the journal. So --

### 202-234-4433 Neal R. Gross & Co., Inc. Page 366 1 but I can e-mail them to you and then you can 2 provide them to the committee I believe. Is

3 that correct? 4 MR. BAILEY: We do provide them on 5 an as-requested basis. 6 DR. SASS: So, tomorrow morning 7 I'll bring our thumb drive with all of the 8 atrazine papers as well as the report. Is 9 that okay with you?

10 SESSION CHAIR PORTIER: And the -- 11 I think as of today the minutes from our 12 February meeting are on the February docket 13 where we discuss a lot of the epidemiology 14 studies, the exploratory correlation studies 15 that the panel reviewed back in February. And 16 I think that -- a draft of that report was 17 provided to the panel. Is that right? I 18 think that's right. Dr. Fenner-Crisp? 19 DR. FENNER-CRISP: The report from 20 the February meeting is in the docket and I 21 downloaded it last night. So it's publicly 22 available.

### 202-234-4433 Neal R. Gross & Co., Inc. Page 367 1 DR. GILLIOM: So just -- did we 2 get that one yet for the panel package or is 3 it just on the docket that I should get it if 4 I want it? 5 MR. BAILEY: Actually, I think 6 that one just came out last week. 7 DR. GILLIOM: Okay. 8 MR. BAILEY: Within the last few 9 days. We can e-mail that -- I can e-mail that 10 to you because it is in the docket -- should 11 be in the docket. 12 SESSION CHAIR PORTIER: I think you 13 have to pull it down because it's a pretty big 14 report. We were having problem e-mailing even 15 the panel members the report. So it's better 16 to go to the docket and download it at that 17 point.

18 DR. FENNER-CRISP: It's 80- 19 something pages -- 82 pages. 20 SESSION CHAIR PORTIER: Yes, it 21 was -- we reviewed it pretty thoroughly. 22 DR. FENNER-CRISP: The other point

### 202-234-4433 Neal R. Gross & Co., Inc. Page 368 1 is, I think we have been asked today, in this 2 panel, to focus on the animal studies and not 3 on the epidemiology at this point in time, 4 because it isn't all available. 5 SESSION CHAIR PORTIER: And I think 6 we'll be ruling on that as the conversation 7 goes along. I'll help say whether this is in 8 the discussion. I mean, again, we're going to 9 have more discussion later on in the year, 10 it's going to come back to epidemiology. So 11 thank you very much. 12 The next public commenter is Scott 13 Slaughter, the Center for Regulatory 14 Effectiveness. And then following him is Jay 15 Vroom of Crop Life America. So maybe the two 16 of you can stage up. 17 I do want to get one question in 18 today. We're going to do one question if it 19 kills me.

20 MR. SLAUGHTER: I'm Scott 21 Slaughter and I'm commenting today on behalf 22 of the Center for Regulatory Effectiveness.

### 202-234-4433 Neal R. Gross & Co., Inc. Page 369 1 I met Dr. Portier in the hall at the beginning 2 of the last break, and he looked at me and 3 said, "Well, you wanted to be last." And I 4 told him it was one of my many errors in 5 judgment. 6 I beg your indulgence for just a 7 few minutes while I talk to you briefly about 8 the quality of the information that EPA's 9 asked you to consider in this SAP. The 10 February minutes of the February -- the 11 minutes of the February atrazine SAP were 12 mentioned just a minute ago. And those 13 minutes state, and I quote, "Like all 14 information considered in risk assessments, 15 the quality and reliability of the information 16 provided by epidemiologic studies needs to be 17 closely scrutinized." 18 That's good advice, and it's not 19 limited to epi studies. It also applies to 20 the other studies which EPA has asked this SAP 21 to review and which EPA is considering for use 22 in a new atrazine risk assessment.

### 202-234-4433 Neal R. Gross & Co., Inc. Page 370 1 There are several regulatory 2 requirements and guidelines that govern EPA's 3 use of these studies. EPA cannot base an 4 atrazine risk assessment on studies that do 5 not meet and comply with these requirements 6 and guidelines. The guidelines and 7 requirements include reproducibility. 8 For example, EPA's information 9 quality guidelines require EPA to "ensure the 10 reproducibility of influential information." 11 An atrazine risk assessment is influential 12 information. 13 As another example, EPA is a 14 member of the international coordinating 15 committee for the validation of analytical 16 methods. We groupies know it as ICCVAM. 17 ICCVAM has established test validation and 18 acceptance criteria which require that -- and 19 I quote -- "the extent of within-test 20 variability and the reproducibility of the 21 test within and among laboratories must have 22 been demonstrated. Data must be provided

### 202-234-4433 Neal R. Gross & Co., Inc. Page 3711 describing the level of inter- and intra2 laboratory reproducibility and how it varies 3 over time. The degree to which biological 4 variability affects the test reproducibility

5 should be addressed." 6 As still another example, EPA's 7 FIFRA data rules state that EPA "will evaluate 8 the conduct of each experiment in terms of 9 whether the study was conducted in conformance 10 with the design, good laboratory practices 11 were observed, and the results were 12 reproducible." 13 As a final example, CRE's comments 14 on the 2002 atrazine risk assessment raised 15 validation issues about some of the test data 16 which EPA wanted to use and which allegedly 17 showed endocrine effects from exposure to 18 atrazine. EPA's response to CRE's comments 19 said, and I quote, "In determining whether 20 data are acceptable the agency considers a 21 number of factors: for example, study design, 22 including sample size, replication, use of

### 202-234-4433 Neal R. Gross & Co., Inc. Page 372 1 appropriate controls, et cetera." 2 In light of these regulatory data 3 quality requirements we ask EPA to answer two 4 questions. First, where is the record 5 demonstrating the reproducibility of the 6 studies the agency wants to use in atrazine 7 risk assessment? Second, where is the record 8 demonstrating that these studies meet EPA's 9 other data quality requirements? 10 EPA has dumped a large number of 11 studies and data on the public and has 12 provided very little time for the public to 13 review and comment on these studies and data. 14 EPA's answers to these two questions would 15 greatly improve the transparency and user 16 friendliness of this proceeding. 17 Thank you. And I'll try to answer 18 any questions you might have. 19 SESSION CHAIR PORTIER: Any panel 20 questions? 21 (No response.) 22 MR. SLAUGHTER: Oh, that's good.

### 202-234-4433 Neal R. Gross & Co., Inc. Page 373 1 Thank you. 2 SESSION CHAIR PORTIER: Thank you, 3 Scott. The last public commenter is Jay

4 Vroom. 5 MR. VROOM: Thank you, Mr. 6 Chairman and members of the panel. My name is 7 Jay Vroom. I'm president of Crop Life 8 America, a trade association that represents 9 virtually all of the manufacturers, discovery 10 firms, distributors, and formulators of crop 11 protection products used by American farmers. 12 I submitted my four-page letter 13 for the staff to put in the record and I'd 14 prefer to summarize if I might. 15 I begin by saying good evening, 16 taking a different temporal approach -- 17 perhaps more optimistic with the notion that 18 some of us may have been contemplating 19 exposing ourselves to water contaminated by 20 alcohol after a day like this. 21 Crop Life does not advocate on 22 behalf of any one individual member company or

### 202-234-4433 Neal R. Gross & Co., Inc. Page 374 1 any one particular product provided by our 2 industry to be a tool for American farmers. 3 We do try to take opportunities like this 4 public comment period to articulate specific 5 thoughts with regard to policy that has a 6 precedent that is important for our members 7 and others in the industry from a policy 8 standpoint and of ultimate impact and 9 importance to our customer, the American

10 farmer. 11 With respect to our understanding 12 at Crop Life of what's before this SAP, I was 13 struck by Dr. Sass's presentation that also 14 mentioned a number of other issues that, from 15 my understanding are not before this 16 committee, but, in fact, are also very 17 important issues. And it just, to me, 18 reinforced the reaction that we had when this 19 administration decided to convene the SAP on 20 these issues particular to atrazine, which we 21 believe have been rather thoroughly examined 22 by the agency and with input from previous

### 202-234-4433 Neal R. Gross & Co., Inc. Page 375 1 SAPs in the past. 2 And our preference, of course, 3 would be that the kinds of resources 4 represented by you on this panel and the 5 support of the agency would be actually 6 attentive to many of those other issues that 7 Dr. Sass referenced. And so, in fact, we 8 believe that this is an unfortunate focus of 9 resource that otherwise could perhaps 10 otherwise be allowed to have you spending time 11 on that range of other issues that are on down 12 the road and in front of us. 13 The one specific issue that I'd 14 like to address here is the importance of 15 focusing on those sources of data that are 16 specific to finished drinking water. That is 17 our understanding as to what the issues are 18 really in front of this SAP with regard to 19 that route of exposure and that particular 20 concern with regard to human health effects 21 and the compound atrazine. 22 And I really think it really gets

### 202-234-4433 Neal R. Gross & Co., Inc. Page 376 1 down to the matter of communication. And I 2 would draw another parallel to activity that 3 EPA has undertaken with regard to the 4 requirement under the Safe Drinking Water Act 5 as well as the Food Quality Protection Act 6 passed by Congress in 1996 and that has to do 7 with the evaluation of endocrine effects and 8 crop protection products and other chemicals 9 that humans may be exposed to. 10 And the parallel that I think is 11 important to draw here is how careful EPA has 12 been to explain what they are doing with 13 regard to the very careful and deliberate 14 science-based stepwise approach to 15 implementing the endocrine disruption 16 provisions in the Safe Drinking Water and Food 17 Quality Protection Acts, and more particularly 18 what they are not doing at particular stages. 19 And I think that's been a model 20 with regard to communication by the agency and 21 their advisors that would serve this SAP 22 working with the agency going forward to be

### 202-234-4433 Neal R. Gross & Co., Inc. Page 377 1 extra careful about how you communicate, what 2 you're doing, what you're considering, and, 3 just as importantly, what is not on the table 4 in front of you. 5 And so, again, I would go back to 6 the core presentation that we wish to 7 emphasize here today with these remarks, which 8 is that -- the matter before this SAP has 9 nothing to do with human consumption of raw

10 water and that the data that should be 11 examined and the risk factors that should be 12 considered by this SAP in providing advice 13 back to the agency have to do with the risk 14 factors associated with the presence of this 15 compound in finished drinking water. 16 The record is clear with regard to 17 Congressional intent. In our view, having to 18 do with the scientific validity of information 19 that comes before and consideration of the 20 agency, that it needs to be science-based, and 21 when it is science-based there are a number of 22 criterion that the law is specific with regard

### 202-234-4433 Neal R. Gross & Co., Inc. Page 378 1 to how the agency should consider it and how 2 it should communicate to the public. 3 And I believe, again, that that 4 kind of consideration with regard to 5 communication is an obligation that the SAP 6 over the years has taken seriously and been 7 effective with. And at the end of the day, 8 with regard to the kinds of risks that are 9 being assessed and advice being given to the 10 agency with regard to exposure in water to 11 human beings with regard to atrazine, it's 12 only around the exposure on finished drinking 13 water and that humans are not intentionally 14 drinking unfinished or raw water provided to 15 them by community water systems. 16 So, once again, I thank you for 17 this opportunity to share that perspective. 18 I would also share with you that having been 19 here for much of today I was struck by how 20 lucky we are as citizens of the United States 21 to have the service of committed volunteers, 22 such as yourselves, with scientific expertise

### 202-234-4433 Neal R. Gross & Co., Inc. Page 379 1 that you represent for the SAP in looking at 2 these kinds of issues, serving not only the 3 interest of the general public but my industry 4 and ultimately the American farmer who uses 5 these tools effectively to conduct modern 6 agriculture and to provide us with a safe and 7 abundant food supply. Thank you very much. 8 SESSION CHAIR PORTIER: Thank you. 9 Any additional questions from panelists? Yes, 10 Dr. Coupe. 11 DR. COUPE: I just had a comment 12 mostly, and it's kind of a little bit of 13 different thinking. I think I was more in 14 line with you last week before I got here and 15 heard the discussion. 16 But now I think I understand why 17 we want to look at surface water as opposed to 18 just concentrating on finished water, now that 19 I'm thinking about it, because the sampling 20 the surface water -- examining the surface 21 water gives us a conservative estimate. And 22 it also shows us, you know, sometimes these

### 202-234-4433 Neal R. Gross & Co., Inc. Page 380 1 treatment plants can fail, and it kind of 2 gives us a backup on how much we need to be 3 careful with. 4 But, additionally, listening to 5 some of the other people I was struck by, why 6 should these treatment plants have to install 7 equipment to take care of something that 8 shouldn't naturally be in there? They do 9 their work looking on -- you know, they're 10 meant to take out chemicals that absorb to 11 sediment and to disinfect. They're not meant 12 to take out water-soluble chemicals.13 So we're applying these water14 soluble chemicals. And there's always a 15 chance that they might get through. I know 16 I'm not a toxicologist, so I can't say what 17 the epidemiological work on it is, but it just 18 seems to me that perhaps we should be looking 19 and continue to look in the surface water, as 20 well as the drinking water. 21 MR. VROOM: Thank you. It should 22 be clear that as an industry we are not

### 202-234-4433 Neal R. Gross & Co., Inc. Page 381 1 opposed to testing of other water besides 2 finished drinking water for certain crop 3 protection products. 4 But in terms of the level of the 5 magnitude of testing that has been reviewed 6 here today by any number of presenters, 7 particularly all those representing the data 8 that Syngenta have produced, we think that 9 that's the right place where that kind of 10 resource has been focused in addition to all 11 of the resources that have been put into, 12 number one, innovating other products that 13 have displaced older compounds, but, number 14 two, also allowing for education on how older 15 compounds like atrazine can be more 16 effectively used by growers and other 17 pesticide users -- that the combination of all 18 of those resources coming together have 19 allowed the kinds of trend lines with regard 20 to reduction of exposure and reduction of risk 21 to occur over time.

22 And there are other reasons to

### 202-234-4433 Neal R. Gross & Co., Inc. Page 382 1 sample water for other considerations, 2 including ecological effects, but the level of 3 resource and intensity of volume of sampling 4 seems to be, you know, completely different in 5 those contexts and ought to be approached that 6 way. 7 Lastly, I would say that it's my 8 understanding that community water systems do 9 filter for a wide range of contaminants and 10 that crop protection products, including 11 atrazine, are only, you know, one category, 12 and there are other soluble chemicals that are

13 out there. 14 We think that, you know, the 15 systems are adequate and are working quite 16 well -- always room for improvement. And, 17 once again, the kind of scientific robustness 18 that a group such as the SAP can bring to 19 thinking through those sorts of considerations 20 in EPA's context here as well as for the 21 Office of Water and the Safe Drinking Water 22 programs continues to, I think, advance the

### 202-234-4433 Neal R. Gross & Co., Inc. Page 383 1 science and the practical safety of our water 2 supply. 3 SESSION CHAIR PORTIER: Thank you. 4 We did receive electronically -- and you have 5 copies of a comment from an M. J. Quinn -- no 6 address, no other information -- recommending 7 banning of atrazine. And you can read this. 8 At this point I'm going to make a 9 last call for any additional public 10 commenters. Anyone wishing to provide a 11 comment before the panel? Going once, going 12 twice. 13 I think at this point I'm going to 14 close the period of public comment and we're 15 going to proceed to the panel discussion. 16 We're about three hours late. I guess that's 17 not too bad. For an important meeting like 18 this, that isn't that bad. 19 So I'm going to invite EPA back up 20 to the front table here to read the first 21 question. For the panel, we're going to begin 22 the discussion. I don't think we're going to

### 202-234-4433 Neal R. Gross & Co., Inc. Page 384 1 probably end the discussion, but we're going 2 to at least spend the next 45 minutes on this 3 topic. When we get to about 4:40 we're going 4 to reconsider how much we've got left and then 5 move on -- 5:40 -- I'm sorry. Yes, 45 more 6 minutes -- 5:40 -- 5:40, 5:45. 7 DR. MENDEZ: Good afternoon. This 8 is Elizabeth Mendez again for the U.S. EPA. 9 I'm going to start reading the charge 10 questions to the FIFRA Scientific Advisory

11 Panel. 12 Charge question 1.0 -- in 2003 the 13 human health risk assessment was based on a 14 mode of action in which exposure to atrazine 15 leads to a reduced release of gonadotropin 16 releasing hormone (GnRH) from the 17 hypothalamus, thereby lessening the afternoon 18 pituitary luteinizing hormone (LH) surge in 19 female Sprague Dawley rats. As a result, the 20 estrous cycle lengthens. This, in turn, leads 21 to increased estrogen levels and an increased 22 incidence of mammary tumors in female Sprague

### 202-234-4433 Neal R. Gross & Co., Inc. Page 385 1 Dawley rats. 2 EPA determined that atrazine's 3 cancer mode of action (i.e., premature 4 reproductive aging) in the Sprague Dawley rat 5 is not likely to be operative in humans (a 6 conclusion consistent with the SAP 7 recommendation in 2000). The agency will be 8 evaluating the cancer classification further 9 as the experimental toxicology data are 10 integrated with the epidemiology data. New 11 experimental toxicology studies (Section 3.6 12 of the draft issue paper) do not suggest a 13 change to the agency's previous conclusion 14 that atrazine is not likely to be carcinogenic

15 to humans. 16 Next please. Although the cancer 17 mode of action may not be operative in humans, 18 it is not unreasonable to assume that atrazine19 might cause adverse effects on hypothalamic20 pituitary function in humans. Thus, the same 21 endocrine perturbations that induce tumors in 22 rats may play a role in at least some

### 202-234-4433 Neal R. Gross & Co., Inc. Page 386 1 reproductive/developmental effects (not 2 associated with reproductive aging) that may

3 be relevant to humans. 4 Accordingly, the agency identified 5 disruption of estrous cyclicity and delays in 6 puberty onset (males and females) occurring as 7 a consequence of disruptions to the 8 hypothalamic-pituitary-gonadal (HPG) axis as 9 the critical end points of concern (Sections 10 2.0 and 3.2 of the draft issue paper). 11 The agency continues to believe 12 that this disruption of the HPG axis is 13 critical to affecting estrous cyclicity and 14 delayed puberty onset. However, as discussed 15 in questions 1.2 through 1.6 below (see figure 16 3 of the draft issue paper), new information 17 has been published that indicates a more 18 expanded understanding of how atrazine may 19 perturb the pathway leading to reproductive

20 effects. 21 These new data indicate that 22 atrazine disrupts the hypothalamic-pituitary-

### 202-234-4433 Neal R. Gross & Co., Inc. Page 387 1 adrenal (HPA) axis altering the central 2 nervous system's control of the pituitary and 3 adrenal which, in turn, disrupts the HPG axis. 4 Furthermore, a hypothesis for a direct effect 5 of atrazine on the adrenal cortex and the 6 gonads which may impact steroidogenesis 7 directly is also supported by the available

8 data. 9 Now we get to the question. With 10 the caveat that the review of the 11 epidemiological literature is still ongoing, 12 please comment on the agency's preliminary 13 conclusion that new experimental data from in 14 vitro and in vivo laboratory animal studies do 15 not support a change in the conclusions from 16 the 2003 risk assessment that atrazine is 17 unlikely to be a human carcinogen.

18 SESSION CHAIR PORTIER: So we start 19 with a big question here. Dr. Fenner-Crisp as 20 the lead discussant. 21 DR. FENNER-CRISP: I could give a 22 very short answer, but now being on a panel,

### 202-234-4433 Neal R. Gross & Co., Inc. Page 388 1 I can't do that. I've got to write a lot, 2 give folks more to read. 3 I'll essentially summarize two 4 documents, and I'll start out with saying, in 5 the 2000 draft risk assessment, MOA thing -- 6 that's this one that went to the 2000 SAP and 7 later finalized in the IRED and RED -- the 8 agency presented its analysis of the human 9 carcinogenic potential of atrazine. Rodent 10 bioassay results revealed no increase in any 11 tumor type in male Sprague Dawley rats or in 12 Fischer 344 rats or CD1 or other mice strains 13 of either sex. However, there was an 14 increased incident and/or early onset of 15 mammary adenomas, carcinomas, fibroadenomas, 16 and pituitary adenomas in the females of 17 Sprague Dawleys. 18 EPA conducted an in-depth analysis 19 of these tumors, particularly the mammary 20 adenomas and carcinomas, which included the 21 development of additional data used to 22 describe possible modes of action by which

### 202-234-4433 Neal R. Gross & Co., Inc. Page 389 1 these tumors arose and presentation and 2 conclusions as to the relevance of the 3 hypothesized modes of action with regard to 4 the chemical's human carcinogenic potential. 5 Based primarily on the work of the 6 ORD researchers, a non-genotoxic mode of 7 action was postulated for effects of atrazine 8 on components of the HPG axis and the 9 development of the mammary and to some extent 10 the pituitary tumors in these -- the strain of

11 female rats. 12 An alternative possible genotoxic 13 mutagenic mode of action was not supported 14 based upon the weight of evidence evaluation 15 of a variety of short-term genotoxicity 16 assays. 17 The figure and the text below 18 taken from the 2000 document present the key 19 postulated events. And I pulled the figure 20 off of page 33 in here and the text that 21 surrounds that particular page. I won't go 22 through the figure but remind folks they don't

### 202-234-4433 Neal R. Gross & Co., Inc. Page 390 1 have that document of what the key events

2 were. 3 Key event one was: atrazine 4 exposure affects either directly or indirectly 5 the hypothalamus, leading to decreased 6 secretion of hypothalamic norepinephrine. 7 The second key event: hypothalamic 8 norepinephrine normally modulates the release 9 of gonadotropin-releasing hormone, but with 10 the decreased norepinephrine, one saw a result 11 in a decreased release of GnRH. 12 Key event three: GnRH is 13 responsible for inducing the pituitary gland 14 to release LH. If you have decreased GnRH, 15 you have decreased LH. We've been hearing 16 this from several parties the last two days. 17 Fourth key event: LH normally 18 provides a signal to the ovaries prompting 19 ovulation, but below some critical level the 20 decreased serum levels of LH are insufficient 21 to stimulate ovulation. 22 The fifth key event essentially

### 202-234-4433 Neal R. Gross & Co., Inc. Page 391 1 describes that the feedback loop has been 2 interrupted and you don't get the normal

3 feedback. 4 Key event six was with the 5 increased -- circulating estrogen acts on the 6 mammary gland to increase the risk of mammary

7 tumors. 8 And the last step in there dealt 9 with the fact that there was not a genotoxic 10 mode of action. 11 As will be discussed at greater 12 length below much of the EPA research 13 conducted since that time has been targeted 14 toward improving the understanding of the 15 nature of the reproductive and developmental 16 effects of atrazine. Pursuit of the 17 characterizations of the mode of mechanisms by 18 which these effects occur has revealed at 19 least one major aspect not identified earlier 20 while characterizing the mammary tumor mode of 21 action. And that's activation of the HPA 22 axis.

### 202-234-4433 Neal R. Gross & Co., Inc. Page 392 1 The key events for this phenomenon 2 have now been described -- and that's on 3 page -- I think it's 33 in the current 4 document -- those four key events. 5 Hypothalamic changes resulting in 6 an increase in CRH release -- 7 DR. KRISHNAN: Which document are 8 you referencing? Is that a white paper or --

9 DR. FENNER-CRISP: The current 10 document, yes, white paper. Key event two: 11 increased release of adrenocorticotropic 12 hormone (ACTH) from the pituitary. Key event 13 three: increased production of the 14 corticosterone and progesterone by the 15 adrenals. And key event four: decrease in GNR 16 release from the hypothalamus as a result of 17 one or more of those key events. So we're 18 seeing a circling back. 19 I've stuck Liz's favorite figure 20 in here because I couldn't find that just 21 shows the key events numbered in anybody's 22 presentation for the HPA. And unfortunately

### 202-234-4433 Neal R. Gross & Co., Inc. Page 393 1 the numbers in your favorite thing don't match 2 up with the four key events, but that's okay. 3 The bottom line here is the 4 convergence of key events two and three in the 5 original mammary tumor mode of action and key 6 event four in the HPA activation pathway 7 component are obvious. Discovery that an 8 additional component or pathway may be in play 9 neither negates nor diminishes the conclusions 10 reached earlier with regard to the 11 characterization of the mammary tumor mode of 12 action, or its relevance to human health risk

13 assessment. 14 Even though I was listening very 15 carefully to the presentations today, I'm not 16 completely satisfied with the answer we got. 17 So I kept in here a statement that says, One 18 aspect that remains unclear is whether 19 atrazine can directly affect the hypothalamus, 20 setting off the cascade of effects, or 21 indirectly through the HPA access or both. 22 That's still unclear, so I'm raising that as

### 202-234-4433 Neal R. Gross & Co., Inc. Page 394 1 something to be -- 2 And then I ask another question to 3 think about. Is it possible to incapacitate 4 the HPA pathway and determine if the HPG axis 5 is impacted in same or different manner? I 6 think some of the discussion studies ongoing 7 today led some light on that possibly. That's

8 what I've done so far. 9 SESSION CHAIR PORTIER: Okay. Dr. 10 Bucher as an associate discussant. 11 DR. BUCHER: So I'm in general 12 agreement with the findings from the recent 13 studies on the interrelationships of the HPA 14 and HPG axes do not fundamentally change the 15 conclusions of the 2003 risk assessment 16 concerning the likelihood that atrazine is or 17 is not a human carcinogen. 18 The critical role of inhibitor of 19 LH surge in suppressing the estrous cycling in 20 the SD rat seems to be supported by the recent 21 literature in the sensitivity of the SD rat to 22 increases in mammary tumors with increases in

### 202-234-4433 Neal R. Gross & Co., Inc. Page 395 1 endogenous estrogens or from treatment with 2 estrogenic substances is well recognized. 3 However, I'd caution that the 4 demonstration of the involvement of the HPA 5 axis and the mammary tumor response of the SD 6 rat may, in the eyes of some, diminish its 7 biological significance as an indicator of 8 disruption of the HPG axis. 9 EPA's clearly not doing this in 10 their background document, and the recent 11 findings that Dr. Handa reported today 12 concerning the maintenance of the suppression 13 of the LH surge in adrenalectomized animals 14 certainly supports the EPA's stance here. But 15 I wouldn't be a bit surprised to see papers 16 begin showing up in the literature 17 hypothesizing that this particular event is 18 maybe just a rat strain specific effect that 19 results from a unique or abnormal sensitivity 20 to a general stress response. 21 I've seen a strong tendency, when 22 interpreting chronic rodent cancer studies, to

### 202-234-4433 Neal R. Gross & Co., Inc. Page 396 1 attribute difficult to explain tumor 2 incidences to, quote-unquote, "differential 3 stress across treatment groups." But, in 4 fact, there's hardly ever any data to back 5 this up. 6 Different routes of exposure do 7 result in different rates of tumors in some 8 sites in control animals. And there is a 9 general perception that the levels of stress 10 to animals might be different or greater in 11 inhalation studies where animals are housed 12 for two years in metal chambers with 13 significant air flows and presumably more 14 noise than, say, in studies where animals were 15 simply held in enclosed polycarbonate cages. 16 And we do see somewhat higher 17 rates of adrenal chromocytomas in control male 18 Fischer rats in our NTP studies in inhalation 19 studies than in dose feed studies. The 20 mammary tumors in female Fischer rats are not 21 different. And, of course, according to the 22 prevailing hypothesis they wouldn't be

### 202-234-4433 Neal R. Gross & Co., Inc. Page 397 1 expected to differ as they don't senesce into 2 a persistent estrous state. 3 Unfortunately we don't have any 4 NTP studies in our database where we're used 5 SD rats in inhalation studies. But a brief 6 review of the SD rat inhalation studies in the 7 literature comparing the mammary tumor rates 8 in control females with the rates that were 9 reported in the controls in the dose feed 10 studies that were done by Syngenta on 11 atrazine, you'll find that the tumor rates are 12 actually very similar. 13 So what's the point of this? 14 Well, again, if considerations of the 15 potential health affects of atrazine are in 16 any way diminished by the perception that the 17 responses seen in the Sprague Dawley rat are 18 because of an enhanced susceptibility of this 19 animal to non-specific stress. And not that 20 EPA is doing this in this current review, but 21 strange things do happen over time. I would 22 simply urge that the agency resist this line

### 202-234-4433 Neal R. Gross & Co., Inc. Page 398 1 of reasoning. 2 But the bottom line is, I don't 3 see anything in the recent information that's 4 come out that would change my perception of 5 the original 2003 conclusion. Thank you.

6 SESSION CHAIR PORTIER: Dr. 7 Krishnan? 8 DR. KRISHNAN: In considering the 9 new lab animal studies that the agency's 10 preliminary conclusion is the same as in 2003 11 assessment, which is, atrazine is not likely 12 to be a human carcinogen, this descriptive of 13 "not likely to be a human carcinogen" is 14 appropriate when there's evidence that the 15 mode of action in experimental animals does 16 not operate in humans. 17 The white paper lays -- well, 18 emphasizes the initial reasoning that my 19 colleagues just referred to, which is mammary 20 tumors in female SD rats being a consequence 21 of elevated levels of circulating estrogen and 22 prolactin. And that remains unchanged.

### 202-234-4433 Neal R. Gross & Co., Inc. Page 399 1 So the fundamental question of 2 human relevance still remains. And so 3 basically the new studies included here do not 4 provide any compelling evidence to change the 5 classification of atrazine. 6 There's no new evidence that I see 7 that changes the conclusions regarding 8 atrazine's ability to act as an initiator; 9 that is, evidence of mutagenicity or 10 genotoxicity. And also the new studies on 11 tumor promotion progression, in my opinion, do 12 not provide sufficient strength of evidence to 13 change the classification for atrazine. 14 So I agree with the agency's 15 initial conclusion -- or preliminary 16 conclusion that it still be considered not 17 likely to be carcinogenic to humans. 18 However, one aspect that I think 19 could be of concern is the temporal 20 relationship of the early life exposure in 21 light of the revised cancer guidelines of 22 2005. That doesn't come out very well, and I

### 202-234-4433 Neal R. Gross & Co., Inc. Page 400 1 hope in the -- based on epi studies, the 2 analysis that might be ongoing -- I'm not 3 aware of the details of where those studies 4 are -- and I hope there will be some 5 consideration of time since first exposure, 6 duration of window of exposure, and so on, in 7 such analysis to be able to address whether 8 there's any concern for early-life exposures 9 and their relationship to tumorigenesis or the 10 overall weight of evidence. And that's 11 something that I'll be looking forward in the

12 future work. 13 So the answer is yes. 14 SESSION CHAIR PORTIER: Okay. Dr.

15 Reed.

16 DR. REED: It's true that I also 17 have not heard of any presentation that could 18 support any new mode of action within the 19 framework that we're talking about -- I mean, 20 the HPG and HPA axis. 21 However, I'm not I guess ready to 22 rule out the relevance of the two in vivo

### 202-234-4433 Neal R. Gross & Co., Inc. Page 401 1 studies reviewed by the agency -- the 2 promotional -- possible promotional mechanism 3 of atrazine as presented in the Fukamachi et. 4 al., 2004 and Ueda et. al., 2005 pertaining to 5 mammary gland tumors. 6 I don't disagree with some of the 7 uncertainties and limitations presented by the 8 agency review. But I have a slightly 9 different opinion about these two studies. 10 With the Fukamachi study, it's true that 11 there's uncertainties about the transgenic

12 nature of these rats. 13 But the agency considered this 14 study presented no dose response, and I looked 15 at it and I felt sure -- you know, there's 16 this small sample size, and particularly the 17 high control incidence -- I think it's around 18 about 50 percent -- that could cloud the 19 conclusion coming from this study. 20 But when I look at it, I felt 21 there is an apparent increase with the 22 atrazine treatment in both female and male

### 202-234-4433 Neal R. Gross & Co., Inc. Page 402 1 rats. And I guess I'm a little bit more 2 concerned because it was at the range of 5 and 3 50 milligrams per kilogram. 4 I, frankly, am not as concerned 5 about the high dose being -- the incidence at 6 the high dose being dropped off because it's 7 500 milligrams per kilometer and that could be 8 some kind of a high dose effect that I'm not 9 sure that I'm willing to take it in and to say 10 that there is no dose response. The other 11 study -- the other 2005 study was also very 12 interesting, although the effects are now at 13 50 to 500 milligrams per kilogram. 14 It's -- so looking at these two 15 studies I come with a different -- slightly 16 different conclusion. EPA concluded that 17 these two sets of data suggest that estrogen 18 does not induce mammary gland tumors in 19 transgenic rats or ovariectomized rats treated 20 with a mammary tumor inducer, thus 21 highlighting the importance of ovarian 22 hormones in the development of tumors in the

### 202-234-4433 Neal R. Gross & Co., Inc. Page 403 1 mammary gland. 2 And I would have said that you 3 highlighted the possibility of a promotional 4 potential -- not initiating, but promoting. 5 So, frankly, I'm kind of curious that these 6 two studies were from 2004 and `5, but there's 7 no -- as far as I know no other follow-up 8 studies along the same line of promotion. 9 Nevertheless, I would suggest that 10 the agency expand on the discussion to include 11 the significance of these two datasets on 12 tumor promotion and perhaps look at the data 13 in the context of mode of action and perhaps 14 that house might have a little shed or 15 something. I don't know. 16 Anyway, a possibility of, you 17 know, branching it out that might not, you 18 know, at least partly -- not directly 19 associated with the endogenous estrogen at 20 this point. 21 I would also suggest that, you 22 know, if it is possible that the agency would

### 202-234-4433 Neal R. Gross & Co., Inc. Page 404 1 park these issues until all data for cancer 2 risk assessment is ready next year. At such 3 time, I'm sure these data and any other data 4 fitting within the HPG/HPA mode of action 5 would all come into play together with the epi

6 data. 7 SESSION CHAIR PORTIER: Thank you. 8 At this point we open it up to any comments 9 from anyone on the panel. Anybody want to 10 jump in on this question? Add to it? The 11 promoter issue? Dr. Williams? 12 DR. WILLIAMS: I just wondered 13 what you really mean by not likely. So I 14 thought there were some good points raised by 15 the NRDC person regarding, you know, this 16 other commission specific designations. They 17 have a certain definition of not likely or 18 likely or whatever. What do you really mean 19 by not likely? 20 DR. MENDEZ: Our definition for 21 not likely or unlikely to be carcinogenic to 22 human is when they have a mode of action that

### 202-234-4433 Neal R. Gross & Co., Inc. Page 405 1 we feel it's not appropriate to the human 2 condition. Having said that, let's keep in 3 mind that we're going to be looking at the 4 cancer issue in greater detail in 2011. So 5 let's just kind of keep that in mind.

6 SESSION CHAIR PORTIER: Dr. 7 Krishnan, did you want to comment? 8 DR. KRISHNAN: I'm going to leave 9 it off. No, that's fine. 10 SESSION CHAIR PORTIER: But it -- 11 this is Ken Portier. But the definition means 12 you've looked and you don't see anything 13 rather than not look. One of the implications 14 is, you know, you haven't looked for it. And 15 you can't say it's not likely if you haven't 16 looked for it. And I think what EPA is 17 saying, we've looked for it and we see 18 something; we discount it because it's a 19 mechanism that's not related, therefore, it's 20 something else.

21 DR. MENDEZ: And we have also not 22 only looked at the mode of action, we've also

### 202-234-4433 Neal R. Gross & Co., Inc. Page 406 1 evaluated other potential modes of action and 2 have ruled them out. So it's important to 3 keep in mind that we don't just look at one 4 component and just latch onto that. We then 5 move on to disprove, so to speak, other 6 potential MOAs. 7 DR. LOWIT: And the one piece to 8 add to that. The 2003 SAP on epidemiology and 9 atrazine really dealt with some of the 10 epidemiology data at the time for cancer. And 11 so that finding at that time incorporated both 12 the animal mode of action and the epi data 13 available at the time. And as we move towards 14 what will now be 2011 we'll rethink that whole 15 process again.

16 SESSION CHAIR PORTIER: Dr. 17 Holladay? 18 DR. HOLLADAY: I think we kind of 19 said it, but I want to make sure that I 20 understand. My understanding is that, as 21 least formally, EPA's definition of 22 classification of carcinogens is different

### 202-234-4433 Neal R. Gross & Co., Inc. Page 407 1 than IARC's. And we had an IARC definition 2 read to us earlier, but EPA's definition is

3 not the same. Is that correct? So we're not 4 working under the IARC definition per se? 5 DR. MENDEZ: It's important to 6 point out that in 1999 -- I believe it's 7 1999 -- IARC evaluated this very same mode of 8 action and they consider that it was not 9 likely to be relevant to humans. But in their 10 definitions and in their framework they think 11 about it a little bit different. Having said 12 that, the MOA was actually considered and 13 considered to be believable by the IARC.

14 SESSION CHAIR PORTIER: Dr.

15 LeBlanc? 16 DR. LEBLANC: Considering our 17 increasing understanding of the mode of action 18 of atrazine my -- the only recommendation that 19 I have is that as we reevaluate the 20 epidemiological data that perhaps we're 21 sensitive to cancers that might be more 22 prominent in immunosuppressed individuals, not

### 202-234-4433 Neal R. Gross & Co., Inc. Page 408 1 suggesting that atrazine is going to cause 2 immunosuppression in the population, but that 3 would be consistent with the mode of action 4 and it should be considered. 5 SESSION CHAIR PORTIER: Anyone 6 else wish to join in? The issue of promotion, 7 the issue of initiation -- those are always 8 good ones. I don't see -- Dr. Reed. 9 DR. REED: Would it help if you 10 have a copy of the 2005 cancer risk assessment 11 guideline that has the narratives for -- there 12 is a category called not likely to be 13 carcinogen to humans? Because we can provide 14 the panel with that. And I have a copy of the 15 guidelines so maybe I'll give it to Joe. 16 DR. HORTON: I think it would be 17 helpful.

18 SESSION CHAIR PORTIER: Dr.

19 Horton? 20 DR. HORTON: Yes. I was going to 21 say I think it would be helpful to know 22 exactly which guidelines we're working under

### 202-234-4433 Neal R. Gross & Co., Inc. Page 409 1 if we're defining whether it's carcinogenic or 2 not. And also, if this is going to be

3 evaluated under the 2011 SAP under the 4 carcinogen -- under another set of data what 5 other -- I mean, how is this going to be 6 reevaluated? Could you -- what will happen in 7 2011 if we say -- or make a recommendation now 8 that it may not be? What are the consequences 9 of anything -- any recommendations that we 10 make at this point? 11 DR. LOWIT: Well, I'm actually 12 hearing -- I've heard from the -- from most of 13 the respondents that as the question's worded, 14 what's new since 2003 that would change those 15 conclusions. And I've actually heard a 16 consensus that no one's heard anything that 17 really changes those conclusions. So I'd be 18 surprised if we turn that upside down. 19 But in 2011, we will do some more 20 update to the animal. We'll continue to 21 monitor the literature to see if anything new 22 appears in the animal literature that does

### 202-234-4433 Neal R. Gross & Co., Inc. Page 410 1 turn that upside down. And we will also be 2 bringing the epidemiology with the animal to 3 the degree to which there's a concordance with 4 those conclusions.

5 DR. KRISHNAN: Can I -- 6 SESSION CHAIR PORTIER: Yes, Dr. 7 Krishnan?

8 DR. KRISHNAN: Yes. 9 DR. LOWIT: Yes. So, I mean, the 10 one thing that's important for people to know 11 about the atrazine risk assessment, it is a 12 very dynamic thing. It's -- the agency's 13 constantly monitoring the literature on 14 atrazine. So we'll keep up.

15 SESSION CHAIR PORTIER: Yes. I 16 would also say that all we're doing is 17 recommending to the agency. We're not making 18 any final decisions here. And the agency 19 takes our recommendations and incorporates it 20 with everything else and then moves forward 21 from that. So just because we recommend that 22 that holds doesn't necessarily mean they

### 202-234-4433 Neal R. Gross & Co., Inc. Page 411 1 believe us for the next two or three stages of 2 this. 3 DR. LOWIT: And it is worth adding 4 as -- it is worth adding to this piece that a 5 major component of the decision to separate 6 the cancer 2011 was -- with our colleagues at 7 NCI -- and if you're not aware of the 8 Agricultural Health Study, it's a very large 9 robust study upwards of 90,000 people. And I 10 don't know the exact number of people who are 11 atrazine users, but I think it's upwards of 12 50,000, maybe 60,000. 13 So it's a very large data set and 14 it's a very large robust. So we feel like 15 because of the large size of that it will 16 really play a lot of weight, and it's really 17 worth waiting to make sure that the results 18 are very strong and robust.

19 SESSION CHAIR PORTIER: Dr. 20 Krishnan?

21 DR. KRISHNAN: We talked about the 22 revised guidelines of the EPA and this

### 202-234-4433 Neal R. Gross & Co., Inc. Page 412 1 particular clause of not likely to be 2 carcinogenic. The classical example of the 3 description that they give is that there can 4 be positive results in experimental animals 5 when there's consistent evidence -- consistent 6 and strong evidence that the mode of action in 7 experimental animals do not operate in humans, 8 in which case it can be concluded as not 9 likely. 10 But we can draw essentially a 11 parallel between this and the IARC group. I 12 suggest that we don't mix both of them even in 13 our comments. I don't think it's in our 14 purview. Because in IARC's number 4 you have 15 to have evidence suggesting lack of 16 carcinogenicity in experimental animals and 17 lack of carcinogenicity in humans, which is

18 not the case. 19 So I wouldn't -- but this 20 classification -- the way it's termed is 21 consistent with the criteria that EPA 22 considers. And we haven't really seen any

### 202-234-4433 Neal R. Gross & Co., Inc. Page 413 1 convincing animal data that changed the 2 classification, I don't think. The promoter 3 studies can add to the strength of existing 4 evidence, but I don't see how, by in itself, 5 would suggest the chemical to be a carcinogen 6 as a free-standing evidence of information.

7 SESSION CHAIR PORTIER: Dr. Reed? 8 DR. REED: Well, maybe I didn't 9 make myself clear. Let me try it again. What 10 I think we're looking at is that we have found 11 a mode of action that looked very good to 12 interpret the Sprague Dawley rats data. But 13 I'm not ruling out the possibility that other 14 mode of action which is not initiation, but 15 promotion, might be a part of the oncogenic 16 potential that have been sort of indicated by 17 the two promotional studies. 18 The two promotional studies have 19 some problems, but in my mind they do not 20 deserve, I guess, to be put aside to say that, 21 ah, you know, there's a lot of problem with 22 this; we didn't see any potential or support

### 202-234-4433 Neal R. Gross & Co., Inc. Page 414 1 for initiation. 2 But how about promotion, is what I 3 guess I'm saying. That I'd much rather that 4 we take a better look at these two studies and 5 see if we can or cannot fit these two pieces6 of information into the overall -- this well7 put-together mode of action. And if we cannot 8 then we need to set aside another possibility 9 with a lot of question marks. 10 But I felt that these two studies 11 can be looked at in a slightly different light 12 than the way they have been looked at right 13 now according to their reviews by the agency. 14 So as I say, when I look at the Fukamachi 15 study I didn't feel like it was a clear-cut no 16 dose response. And going from a background 17 control incidence and since these are, you 18 know, transgenic in their prime, that the 19 background is 50 percent. 20 When you get to the atrazine dose 21 the lowest dose of 5 milligrams per kilometer 22 you're seeing 100 percent. And so from 50

### 202-234-4433 Neal R. Gross & Co., Inc. Page 415 1 percent to 100 percent with small sample size 2 you could say that there is no statistical 3 significance. But, you know, how statistics 4 come into play is, you know, kind of not very 5 relevant with the sample size. 6 But I am alarmed that there is a 7 50 percent to 100 percent increase from zero 8 to five. And since you have the 5 milligram 9 per kilogram at 100 percent when you get to a 10 50 milligram per kilogram data of course it's 11 another 100 percent. And so to say that, you 12 know, 50, 100, 100 is no dose response it's a 13 little bit kind of not satisfying to me. 14 And then, you know, the agency 15 review saying that, okay, when you get another 16 tenfold increasing dose it dropped off a 17 little bit. Well, I mean, you might have some 18 high dose effects. So I'm not putting a lot 19 of weight on the lack of quote-unquote, "lack 20 of dose response" at the high dose and the 21 fact that, you know, you have high background. 22 So I'd like to see a little bit

### 202-234-4433 Neal R. Gross & Co., Inc. Page 416 1 more rigor in this discussion. I don't know 2 what is this going to lead to -- whether it's 3 going to fit into the current beautiful house 4 or whether it's going to be a slightly 5 different version or possibility. I just 6 personally like to see a little bit more 7 rigor. 8 And apparently, you know, my take 9 on the promotional -- the two promotional 10 studies will be different from Dr. Krishnan's 11 comments. But maybe I'd like to hear, you 12 know, other people who have looked at these 13 two studies in terms of what they think about 14 whether they fit or not fit or irrelevant or 15 anything of that sort. 16 SESSION CHAIR PORTIER: This is Ken 17 Portier. I make the recommendations that the 18 statisticians are thinking, which is, do the 19 study right. Power it up and do it right. 20 And then we don't have these kinds of 21 uncertainties and interpretation. I mean, I 22 agree, a 50 to 100 percent increase is -- you

### 202-234-4433 Neal R. Gross & Co., Inc. Page 417 1 know, it's a big jump. And the fact that it's 2 not statistically significant tells me it was 3 way underpowered. So why did they do the 4 study? 5 And what you're saying is, they 6 did the study because they had some hypothesis 7 that they really think needed to be looking 8 at, and I wish they would have looked at it 9 with sufficient resources to be able to answer 10 the question the first time around. 11 It comes back to this whole 12 repeatability of information issue. EPA can't 13 look at it because we can't assess the 14 repeatability of the experiment with the 15 sample size and the power that they did. My 16 recommendation would always be do it right, do 17 it right the first time. 18 DR. REED: Well, I mean, as a risk 19 assessors, I mean, you know, I feel like -- a 20 lot of times I feel like -- I don't know -- 21 that robot's name is R2D2? It's always 22 information, information, I need more.

### 202-234-4433 Neal R. Gross & Co., Inc. Page 418 1 But when you look at what's out 2 there and, you know, there's times that you 3 say, well, I feel very comfortable to dismiss 4 this -- you know, it's not there. But in this 5 case I feel like there might be something 6 there and I just can't say go back and do some 7 more study because, you know, the agency is 8 not in the business of going and do some study 9 in that sense. 10 But as a risk assessor I feel like 11 I cannot ignore that kind of information. To 12 say that, well, nobody repeated it and so 13 forth and, you know, it's low powered so let's 14 forget about it.

15 SESSION CHAIR PORTIER: Dr.

16 Horton? 17 DR. HORTON: This is a general 18 comment that I would like to add that tags on 19 with Ruby's, is, I felt that there were many 20 times that I understand the need for looking 21 at the quality of data. But as a practicing 22 scientist, there are two things I run into.

### 202-234-4433 Neal R. Gross & Co., Inc. Page 419 1 One is, molecular biologists don't 2 understand statistics, but having been trained 3 as an ecologist generally I do. And so I beat 4 my head against the wall against this all the 5 time. And the other is that you often just 6 don't get the chance to repeat the study. 7 However, the more that the agency 8 can ask people to go out and repeat the study 9 that's great. But I felt that in the review 10 of many of these papers, many of them were 11 dismissed as not providing information when 12 they were being dismissed on a technical basis 13 of not meeting some criterion when they had 14 passed scientific review. 15 And, in fact, they do suggest 16 something and you have to take into this 17 criterion of what is your risk assessment. So 18 I think -- 19 SESSION CHAIR PORTIER: Anyone 20 else? Having spent a lot of time working both 21 with microbiologists and trying to get them to 22 understand statistics, but also reviewing a

### 202-234-4433 Neal R. Gross & Co., Inc. Page 420 1 lot of these kinds of studies it's very 2 frustrating to -- because, you know, EPA did3 look through the literature, and I think two4 thirds of the studies kind of got laid aside. 5 And the fact that this study got 6 considered tells me that the ones they laid 7 aside were even poorer. And that -- you know, 8 as a scientist that really discourages me 9 because that tells me we're doing a lot of 10 under-powered research that's not answering 11 the questions. It just raises more questions. 12 And I get very frustrated with this though. 13 Linda? 14 DR. YOUNG: I have to agree. And 15 I just wonder if there's some way to go back. 16 Because even the studies that I've seen 17 presented by both EPA and Syngenta here, you 18 look at it, and unless they have about two 19 animals in the group, something's happening

20 there.

21 I'm also concerned about the 22 statistical methods they're using, given the

### 202-234-4433 Neal R. Gross & Co., Inc. Page 4211 study design. I think a lot of this period2 by-period analysis is being done, and that -- 3 when you start out with small numbers you 4 shoot yourself in the foot.

5 SESSION CHAIR PORTIER: Dr. 6 Krishnan? 7 DR. KRISHNAN: I'm going to agree 8 with the statisticians. I'm not going to 9 argue. I just want to get back to your

10 comment. 11 Given the experimental design and 12 the animals models and the lack of dose 13 response, that's what really stuck me. And I 14 see your point. I don't think I mentioned my 15 reading -- it was not a question of dismissing 16 an evidence, you know, that clearly indicates 17 that something is a carcinogen, because I 18 don't see these studies showing that the 19 atrazine in itself is a carcinogen. 20 But there's some questionable 21 evidence of it being a promoter. So what I 22 would suggest is that essentially in the

### 202-234-4433 Neal R. Gross & Co., Inc. Page 422 1 weight of evidence -- in the overall weight of 2 evidence, they do park these animal studies 3 and do reconsider in rating the overall weight 4 of evidence when they develop the narrative. 5 Whether it fits a specific mode of 6 action -- whether it fits this house or not I 7 think, as you alluded to, I think sometimes 8 that the incidence itself sometimes just 9 catches the eyes, rather than whether you can 10 explain it by an MOA or not. I don't think 11 that's -- at least for me that's not a major 12 consideration. 13 So how about recommending that 14 these studies be considered in developing an 15 overall weight of evidence narrative as the 16 other human data and so on come in? All I was 17 saying -- that I would agree, but all I'm not 18 agreeing to is that these studies in itself, 19 you know, take them from the current class and 20 make them a likely carcinogen, which is not

21 the case. 22 DR. REED: Well, that was --

### 202-234-4433 Neal R. Gross & Co., Inc. Page 423 1 DR. KRISHNAN: We are on the same 2 side, maybe not on the same page. 3 DR. REED: Right. Same side of 4 the table? No, that's what I'm saying. I 5 mean, I would recommend that we park this 6 rather than coming with an affirmative as, you 7 know, what I thought what we're saying. 8 Rather than coming with 9 affirmatives, saying, yes, we do not see any 10 evidence. I'm saying -- and that's what I was 11 reading before -- that we park this issue 12 because of this. And I think it's a -- you 13 know, I guess you and I now agree. But that 14 was my recommendation. Let's park it.

15 16 SESSION CHAIR PORTIER: I think we 17 have a good sense of what we're going to do in 18 writing this up. So I think it's kind of -- 19 I'm reading general agreement with the EPA 20 statement and with a caveat -- kind of a 21 minority report that we're going -- that when 22 we write up the report we'll make sure that's

### 202-234-4433 Neal R. Gross & Co., Inc. Page 424 1 in there. Yes. Dr. Reed? 2 DR. REED: Can I make just a very 3 brief comment? I don't think it's reasonable 4 to separate out a chemical whether it is an 5 initiator or, you know, being a promoter would 6 be of less important or less relevant to 7 humans because there's all kinds of initiators 8 out there already. 9 And so if a chemical is a promoter 10 it is a cause for concern in that it could be 11 enhancing or increasing or shortening the 12 latency or whatever of something that is 13 already out there that if initiated that 14 possibly be a tumor. 15 So that's why I'm putting a lot 16 of, you know, credence to also a promoter. 17 And I don't think, in cancer risk assessment 18 guideline, the promoter/initiator has been 19 parted out in a way that promoter is not 20 important. 21 DR. KRISHNAN: No, I guess. But 22 the way you would do an assessment would be

### 202-234-4433 Neal R. Gross & Co., Inc. Page 425 1 different, because in one case you might end 2 up having -- identifying a threshold for 3 promotion, but as for initiation you'd rather 4 to go with a unit risk kind an approach or 5 something. But we're not getting into any of 6 the -- those response modeling. 7 SESSION CHAIR PORTIER: I think at 8 this point I'm going to close this question 9 and close today's session. I want to thank 10 the panel for sitting through all these 11 presentations and being patient, and let you 12 know that 8:30 tomorrow morning we're going to 13 start on question 1.2, and we're going to run 14 through these questions. 15 Thank you very much. 16 (Whereupon, at 5:48 p.m., the 17 above-entitled matter was concluded.)

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67:20 Mathematics 8:19 matrix 14:14 226:3 matter 96:15 100:21 102:2,4 236:2 293:18 297:20 299:11 304:18 318:4 323:21 376:1 377:8 425:17 maturation 191:2,9 191:22 maturity 191:7 Maumee 39:11 max 292:7,8 302:11 maxima 259:7

260:5 272:2 273:7 273:8 274:4 maximize 39:5 maximum 12:2 13:10,16 14:6,7,9 14:10 16:20 17:6 19:12 20:7 21:1 24:16 28:1 40:17 41:15 47:21 57:18 58:1,8 61:22 64:21 80:7 177:19 179:17 238:2 271:21 273:17,19 279:17 281:10 291:20 295:1 301:8,11,21 309:1 309:15,15 332:15 333:1 maximums 63:17

362:7 McCoy 349:15 MCL 259:18

264:15 316:5 322:10 326:21 327:12 328:17 329:1 333:5 335:2 362:22 363:3,8 MCLG 259:18 MCLs 326:19 mean 15:21 16:6,7 19:4,7 20:2,15,16 29:17 32:3 38:13 43:22 44:15 45:19 47:22 59:12 61:21 63:14 66:20 68:13 70:8 81:4,12 84:5 117:6 129:8 158:9 159:16 161:8 190:16 201:19 204:11 227:12,12 227:16 228:11 231:13 234:17 235:3 262:20 267:17,19 268:11 286:21 288:22,22 295:3,4,11,11,19 296:7 304:17,21 307:16 308:11 314:22 315:4 321:13 337:6,16 368:8 400:19 404:13,18 409:5 410:9,22 415:17 416:21 417:18,19 423:5 meaning 158:13 meaningful 139:13 182:14 means 74:15 173:13 227:8 303:14 313:12 337:19,21 360:12 405:11 meant 80:12

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340:16 376:6 419:14 passive 196:2 passively 217:17 Pastoor255:14

258:5,20 259:13 281:19 283:16 303:2,7,10 319:16 320:2,5 321:18 322:9,16 323:6 patents 270:14 path44:18 pathogens 121:19 Pathologists 225:9 pathway95:13 172:16 386:19 393:6,8 394:4 patience 256:8

323:13 patient425:11 patiently 298:3 pattern45:13

46:20 47:2 71:7,8 71:12 147:20 200:1 240:4 245:17 252:19 306:3 patterns 11:19

23:21 36:9 50:10 50:10,12,17,17,18 51:8 57:4 64:14 78:18 87:1,3,4 194:5 Paul 258:2 290:11

292:5 302:4 pause44:8 303:6 pay48:5 333:19 pbbs 322:15 PBS 169:4 PCOS 153:11,14 153:15,17,20 154:2,5,7,10,13 154:16 155:2,12 160:18 161:13 PDE 173:14 175:21 PDEs 179:2 181:1 PDE3 179:3 PDE4 174:12 PDE4D 174:9,12 PDE4s 174:19 PDE8 174:9,14 peak 15:4,7,9 17:1 18:3 24:13 26:8 26:12 30:14 38:7 38:10 52:12,20 53:3,7 54:13 80:16,22 181:20 190:16 191:5 199:2,6 201:21 211:18 215:6 230:12,22 260:14 264:2 268:12,16 273:8 282:13 288:6 294:18 295:6 296:8 299:21 peaks 17:22 18:13 19:2,6,6,10 21:22 22:4,7 26:5 28:13 28:13,20 53:1 54:5,14,14 68:22 201:22 204:14 211:11 253:8 259:7 260:5 290:5 293:12 294:14,21 300:12 306:11 362:5,18,20 363:7 peak's 30:16 peer 116:4 pellet 190:10 PENELOPE 2:4 Penny 9:2 people 90:10 96:10

98:14,16 117:8 123:22 133:7 253:19 265:9 299:7 300:7 317:8 330:10 380:5 410:10 411:9,10 416:12 419:8 percent 16:2,3,5,8 16:11,12,14 17:3 17:3,4 19:8,8,9,21 19:22 20:1,6,6,8 20:21 43:12 48:11 48:12 61:16,19 62:11 102:16,18

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29:21 percentages 25:3 percentile 37:6

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397:16 398:4 percolates 34:9 perfect40:12 perform 21:10,14

21:16 49:2 76:5 performance 12:6 13:14 16:15,22 19:2,3,18 36:11 36:21 37:14 260:15 273:21 279:14,17 281:2 281:10 283:8 291:18 292:5,13 293:2 297:4 performances

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404:15 personally 66:3 115:1 416:6 persons 353:19,20 perspective 325:3 378:17 perspectives 91:21

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401:4 pertains 135:16 138:13 pertinent 178:15 perturb 386:19 perturbations

385:21 per-fed 233:2 pesticide 6:9 8:10

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358:5 pharmacokinetic 178:11 181:13,16 181:19 pharmacokinetics

9:12,17 pharmacy 9:15,16 phenomenon 142:7 184:15 235:5 347:16 392:1 philosophy 66:15 phosphodiesterase 171:17 172:5,13 173:3,4,7,17 179:14,19 phosphodiestera... 171:6,10 172:19 174:2,5,16 179:9 179:16,21 phosphodiestera... 171:19 phosphodiestrases 179:1 phosphorylation 172:16 photomicrograms 168:21 phrase 266:21 physical 84:5 168:14 254:4 physically 83:17

84:12 physiological 180:18 200:2 210:3 216:9 227:5 physiologist7:17

8:1 Physiology7:10 Ph.D 1:17,18,20,21 1:21,22,22,23 2:2 2:2,3,4,5,6,7,8,9 2:10,12,13,14,15 2:16,17,18 Pia 348:13 pick 27:22 61:3

83:18 134:2 236:15 picked 174:5 picking 234:20 picogram 227:6,7,9

227:13 picograms 204:12

209:21 210:1,2 picture 57:16

217:19 piece 82:7 192:17 193:6 210:21 269:6 406:7 411:4 piecemealed

229:12 pieces414:5 pituitary 153:19,21 181:3,5,10 195:17 195:19 196:8 384:18 385:20 387:2 388:16 389:10 390:13 392:12 pituitary-adrenal 194:21 pituitary-gonadal

200:18 213:18 PKA 172:15 place 34:6 77:13 113:6 131:19 181:12 304:2 306:20 381:9 placed 223:3 placental 165:6 places 56:11

227:18 plan74:1 90:20 180:21 245:22 293:7 334:22 364:1 planned 246:7 planning 104:15

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278:4,13,19 300:12 planted 107:5 planting 100:16

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367:13 pulled 389:19 pulling 148:8 pulls 307:11 pulsatile 185:10 186:10 191:20 192:22 199:15,19 200:1 201:8 202:5 214:2,17 217:6 218:22 219:6 221:1 pulse 137:19 153:17,18 199:22 200:9,16 214:13 214:14 pulses 200:12,14,20

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185:21 recaptured 20:2 receive 383:4 received 365:4 receiving 187:2 Recio 286:19 reciprocal 274:1 recognize 185:16

326:8 recognized 153:11

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107:7 283:9 335:12 364:9 410:21 423:5 recommendation

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183:16 323:18 record 96:15

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247:7 recovered 199:13 recovery 188:4

198:15 red46:10 144:5,5

358:15 359:2 360:7,18 388:7 reduce 128:9 173:7

195:4 209:10 231:7 360:1,2 reduced 130:19

147:18,19 148:4 153:14 166:5 174:12,14 197:13 200:13 201:15,22 230:13 348:3 357:6,7 384:15 reduces 85:20

101:12 215:6 reducing 102:5 104:11 174:15 reduction 167:6

179:19 235:1,9 381:20,20 Reed 2:14 8:20,20 157:3,4,18 158:1 158:4 400:15,16 408:8,9 413:7,8 417:18 422:22 423:3 424:1,2 reevaluate407:19 reevaluated409:6 reevaluation 1:6

4:7 5:6 94:4 333:12 refer 258:14 reference 267:10

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375:7 references 359:3 referencing 392:8 referred 184:19

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313:8 344:8 refers 165:4 refining 318:11 reflected 125:15 reflects 268:8 refreshing 135:21 Regal 2:15 6:20,20 124:8,9 226:13 229:4,6 249:1,2 249:13,19 250:2,6 regard 32:3 72:6

84:15 114:2 156:18 177:13 200:22 238:11 283:22 310:21 315:16 374:5 375:18,20 376:3 376:13,20 377:16 377:22 378:4,8,10 378:11 381:19 389:3 393:10 regarding 113:7 122:14 194:2,7 204:5 283:21 284:1 334:13 348:10 399:7 404:15 regardless 113:13 regards 296:18 regime 283:2 regimes 281:11 regions 110:13

111:8 register 358:17 registered 106:13

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184:11 relating 186:5,9

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138:19 145:16 146:7,11 244:18 245:8 248:15 399:20 400:9 relationships

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124:22 163:6,13 288:15 324:6 332:1 release 147:9

162:13 185:10 186:10 191:21 201:1,8 332:5 384:15 390:8,11 390:14 392:6,11 392:16 released 118:12

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325:8 381:7 represents 18:2

143:22 373:8 reproducibility

370:7,10,20 371:2 371:4 372:5 reproducible

371:12 reproductive7:3,4

7:12,14 8:1 142:12,15 144:20 147:11 148:13,14 150:14 154:12 156:10 157:16 346:14 385:4 386:2,19 391:15 reproductive/dev...

386:1 Republication 122:11 request92:9 require 21:4 170:6

280:14 333:9 335:17 370:9,18 required49:18

90:15 94:18 330:6 332:8 342:21 requirement 128:8

328:6 376:4 requirements

50:21 104:9 328:5 337:10 359:10 370:2,5,7 372:3,9 requires 39:7 62:12 requiring 119:3

328:1 reregistration

97:18 116:9 resample 14:5

301:15 resamples 16:7 resampling 287:17 rescale 311:15 research 7:8,17 9:11,21 92:20,22 104:7 107:20 108:2 109:7,22 110:6 119:4 121:13 124:17 136:1,17,22 138:1 138:6,17,18 149:21 151:7,11 153:1 160:4 235:22 255:19 256:2 342:7 349:16,22 391:12 420:10 researchers 349:14

359:16 389:6 resemble 154:13 resembles 305:2 reservoir 29:13

33:21 72:12 277:14,16,21 300:4 330:3 reservoirs 278:22

298:17 330:2 residuals 42:4 residue 101:8

103:5 270:13 278:2 residues 264:20

266:8 285:1,2 resist 397:22 resistance 107:3,13

125:22 130:15 resistant 107:11

179:21 resolution 92:17

293:19,20 resolve 286:22 resolved 92:17 resource 261:2

275:4 375:9 381:10 382:3 resources 24:3

99:19 100:7 102:13,14 339:8 339:15 375:3 381:11,18 417:9 respect92:18 156:8 223:17,19 253:3 374:11 respectfully 92:9 respond 68:6 80:11

156:8 196:3 340:18 respondents

409:13 responds 165:7

213:4 response 33:9 50:1

54:3 97:16 108:22 118:14 142:20 143:15 145:16 146:7,11 150:20 152:11 154:22 157:8 166:3 167:16 173:21 196:5 198:14 199:22 207:12,21 208:8,16,21 210:16 211:4,15 211:17 212:8 229:15 236:8 238:4,5 240:4,5 240:20,21 243:13 243:15,17,20 245:8,17 247:18 248:15,20 252:7 252:11 253:21 254:1 291:7 371:18 372:21 395:5,20 401:14 402:10 414:16 415:12,20 421:13 425:6 responses 138:21

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215:11 390:13 responsive 164:20 responsiveness

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331:7 reversability 188:6 reversal 156:12

232:13 reversed 217:1 review 1:7 2:1 5:7

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123:9 127:15 149:19 414:13 revised 399:21

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327:19 re-review 118:15 RfD 319:14 RIA 227:15 RIAs 227:17 rich 102:2 Richard 2:2,6 8:12

9:6 28:11 96:20 105:13 177:2 ridge 101:18 right22:7 29:8

30:11,19 37:19 44:8 46:11,16 57:18 58:2 59:9 59:11,15,18 61:6 61:14 65:19,20 67:5,15 69:11,13 70:14 74:18 76:20 77:11 82:1 88:13 88:13,17 91:20 151:7 157:18 197:8 214:3 219:9 222:14,20 223:1 226:6,15 229:10 249:16,22 251:8 261:1 289:7,18,22 295:13,18 302:6 302:22 303:3,7 307:16 308:6 319:12 320:7 321:19 322:6,9 323:6 328:1 366:17,18 381:9 414:12 416:19,19 417:16,17 423:3 right-hand 15:19

19:11 right-of-ways

331:15 rigor416:1,7 rise 205:11,18

212:18 rises 15:4 208:22 risk 8:22,22 9:5,13

23:2 81:11 82:7 94:21 95:6,9 141:10 151:22 152:8 182:9,16 186:3 258:9 281:18 305:3,3,5 319:19 333:17 351:7,19 352:20 353:10,14 355:3 357:15 361:1 363:14,20 369:14 369:22 370:4,11 371:14 372:7 377:11,13 381:20 384:13 387:16 388:5 391:6 393:12 394:15 404:2 408:10 410:11 417:18 418:10 419:17 424:17 425:4 risks 334:14,14

356:20 378:8 River 39:11 275:10

362:8 rivers 103:22

261:11 287:3 Riverside 6:4 RNA 165:11,17 RNAs 172:21 road 69:15 81:17

81:18 304:14 375:12 roadmap 87:7 Roberge 172:4 Roberson 324:11

324:13,19 325:1 338:10,14,18 339:4 364:6 Robert2:5 137:15 robot's417:21 robust75:1,12

117:14,19 231:1 411:9,14,18 robustness 382:17 rodent 178:4 195:6

210:2 388:9 395:22 RODENTICIDE 1:4 rodents 164:1

177:7,13,15 248:4 254:1 Rohr 349:14

355:10 role 98:11 297:21

385:22 394:18 roll 55:1 124:3 rolling 31:5 76:19

96:1 259:20 271:21 272:2 288:12 307:19 312:12 315:12 rollings 292:10 romantic 129:18 room 10:4 80:4

81:6 92:19 123:4 123:5 133:8 286:12 287:10 324:3 382:16 rooms 304:1 Rooney 247:12 roughly 178:1

263:1 284:15 round 137:8 330:4 route 212:15 321:1

375:19 routes 396:6 routinely 107:7

356:10 routines 39:7 row41:21 Rowe247:12 RTI 269:4 290:11

304:7 rubber 69:15 81:16

81:18 304:14 Ruby 2:14 8:20 Ruby's418:19 rule47:13 49:2,8

400:22 ruled406:2 rules 336:10

365:20 371:7 ruling 368:6

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47:22 63:7 64:7 73:6 79:4 83:18 84:13 85:16 145:12 190:12 200:7 228:3 244:1 262:1 268:19 292:7 293:11,15 293:20 294:14,18 294:21 301:13,14 301:20 302:11 330:16 331:1,3 337:20,22 362:3 371:22 382:1 401:16 415:1,5 417:15 sampled 12:21 13:22 15:15 16:10 18:20 19:15,16 265:21 273:7,17 273:22 288:20 291:21 samplers 84:21 samples 15:8,21

21:15 23:4 45:8 49:16,21 71:16 83:16 85:19 166:14 214:4 225:10 231:8 243:22 245:21 259:11 263:6,7 264:1,2,5,6,8 265:7,8 266:10,14 266:14,15 271:16 271:20 272:3,4 273:7 274:17 275:3,10 276:13 280:14 282:6 284:6,22 287:19 298:12 301:22 302:16 315:19 316:2 327:1,7 331:4,19,22 332:3 332:13 335:4 336:21 362:14,16 sampling 11:14 12:2,7,17 13:14 13:17,19,20 14:3 14:15,17 16:1,3,4 16:9,15 17:16 18:10 19:20 20:10 21:5,9,13,16 23:16,19,22 24:3 30:21,21 49:20 64:20 65:7 70:6 71:10 74:13,19 75:1,13,18 76:1,3 76:17 77:20 78:2 78:22 80:14,17 81:19 82:6 83:18 83:22 84:19,20 85:14 86:12,19 88:10,20,22,22 91:4,16,18,19 92:6 167:7 200:12 260:15,16 263:5 265:4,12 266:1 269:19 271:1,15 272:6,17 273:4,18 274:13 279:7,13 279:18 280:10,17 280:22 281:1,4,9 281:11,14 282:1 283:7 284:2 288:6 293:1,6 296:6,10 298:11,15 308:1 327:3 334:11,22 336:9,13 337:17 379:19 382:3 San7:16 Sanderson 164:20

167:13 171:21 sane 128:7 Santa 8:18 SAP 1:4,19 5:5

35:8 70:16 77:3 94:5 105:7 106:1 113:3 119:1,5 122:18 123:19 135:20 137:18 139:19 140:1 153:8 154:18 156:20 280:19 325:2 333:7 369:9 369:11,20 374:12 374:19 375:18 376:21 377:8,12 378:5 379:1 382:18 385:6 388:6 406:8 409:3 SAPs 113:7,11

123:4,6,12,17,17 375:1 Sass 339:7,8,10,14

364:22 365:18 366:6 375:7 Sass's 374:13 sat94:2 318:2 satellites 129:10 satisfied 393:16 satisfies 49:8 satisfy 50:21 satisfying415:13 save 222:4 297:15 savings 86:2 saw 18:1 24:10

29:5 33:17 34:3 69:3 130:20 167:11 224:16 231:22 240:4 249:14 286:10 317:13 390:10 saying74:14 81:5

89:14 158:13 160:18 226:16 227:14 259:9 298:9 301:18 306:7 321:14,20 324:14 373:15 388:4 405:17 414:3 415:15 417:5 422:17 423:4,7,9,10 says 11:2 91:8

393:17 scaffold 171:16 scale 34:13 35:2

45:14 60:4 61:5 95:8 110:12 130:1 178:7 210:4 317:21 scales 293:15,16 scaling46:9 scenarios 91:17 schedule 272:3 scheduled 118:18 schedules 13:18 schema 189:2 schematic 157:10 scheme 21:9 158:16 291:22 Schlenk 1:23 6:1,1

176:7,8 226:12,14 226:22 227:11,21 228:4,8 Schlenk's 180:4 school 6:21 100:22 science 2:1 9:22 105:8 107:21 108:1 109:20 116:16 117:8 118:3,20 122:1 163:2 333:14 345:11 383:1 Sciences 6:3 7:3,22

193:20 science-based

376:14 377:20,21 scientific 1:4 91:20

92:1 93:4 114:1 114:20 117:18 119:11 120:10 121:13 325:7 342:11 343:1,1 345:7 346:1,16 355:5 357:2 363:11 364:9 377:18 378:22 382:17 384:10 419:14 scientifically 82:22 115:19 scientist 105:16

303:11 339:15 418:22 420:8 scientists 107:7 123:2 scope 89:11 365:8 Scott 368:12,20

373:3 scrambled 175:2 scratching 232:5 screamed 286:11 screen 89:1 143:13 screening73:3 150:11 330:21 scrutinized 369:17 SD 394:20,21 395:5

397:5,6 398:20 SDWA 262:16,21

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217:7 secretory 194:4 section76:11 135:4 137:9,14 138:10 183:1 385:11 sections 184:8

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10:2 180:22,22 221:4,5,16,20 222:2,5,7,15,20 223:1,10 233:10 233:10 251:14,15 semi 32:22 semi-chronic

334:15 send 69:8 senesce 397:1 senescence 142:12 142:15 144:9,20 146:19 147:2,12 148:13 154:12 157:16 senior 134:10

258:3 sense45:5 84:7

94:1 128:9 281:18 291:5 305:6 418:9 423:17 sensitive 186:14,18

210:9 220:22 241:1 242:13 330:21 407:21 sensitivity 153:19 153:21 185:18 192:20 195:19 196:8 209:16,19 209:20 219:15 225:20 394:21 395:19 sensitized 60:2 sensor 354:5 sentence 154:21 separate 34:15

88:3 94:13 119:1 185:19 188:12 218:18 291:4 292:21 326:7 411:5 424:4 separately 34:22 110:19 September77:4

94:8 124:4 sequence 134:22 series 18:12,12

50:8 66:16 140:11 168:11 171:14 202:8 206:8 212:9 242:14 286:3,12 seriously 378:6 serum 203:19

353:1 390:20 serve 97:14 325:13

376:21 serves 330:9 service 102:14 328:14,20 329:19 330:8 334:4 378:21 serving4:5 379:2 session 1:18,21

4:14 5:4 8:6 10:1 24:8 25:20 26:22 30:4 32:6 33:7,10 35:4,14,18 51:16 53:17 57:13 58:20 59:5,20 60:3,10 60:21 61:7,14,20 62:16,20 63:1,4 65:8 67:9 69:5 79:22 83:8 86:3 90:22 93:18 96:6 96:17 119:6 124:7 125:2 126:19 128:4 131:1 133:10 135:9 155:13 157:3 160:9,13 162:20 176:5 178:19 180:1 182:18 183:10 184:3 193:8,16 200:13 218:8 221:3 223:12 226:12 229:4 232:9 234:3 249:1 250:11 251:13 252:21 254:7 255:6 256:9 283:17 285:4 287:10 290:1 297:14 301:1 302:19 319:5 323:3,7,17 324:1 324:10,21 338:8 338:11,16 339:2,6 364:18 366:10 367:12,20 368:5 372:19 373:2 379:8 383:3 387:18 394:9 398:6 400:14 404:7 405:6,10 406:16 407:14

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393:20 settles 123:2 settling 277:14 seven 15:15 16:3,10 17:18 20:11 26:4 76:3 80:8 133:19 134:1 207:18 229:18 279:7,18 326:15 335:11 356:10 seventh 208:2,13 seven-day 16:19,20 17:1 26:3 88:16 273:15,18 281:11 283:2 292:11 308:21 seven-year 312:8,9 severe 63:22 115:9 severely 362:2 sex 140:14 142:2 156:12 224:1,5 225:4 351:18 388:13 sexual 191:2,7,9,21 sham 213:20

214:10 shape 21:17,21

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71:20 77:1,5 95:7 178:6 186:1,11 272:17 274:12 311:20 335:5 339:13 shorter-term 288:3 shortly 137:7

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291:6,7 296:4 302:2,4,5,17 304:7 305:12 sign 119:11 241:22

272:12 signal 172:14

390:18 signaling 173:1 signed 111:15 significance 151:9

206:19 209:11 234:20 235:7 395:7 403:11 415:3 significant 100:9 102:6 111:15 114:6 122:13 128:18 136:10 166:18 192:13,16 206:16 230:3 234:11 242:8,9 263:18 308:4 331:8 351:12 352:14,16,18 353:18 354:2,3,11 356:2,8 357:5 358:11 359:21 396:13 417:2 significantly 241:16 268:6 silt 100:20 simazine 86:21

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21:7 56:9 97:11 109:12 110:2 111:11 120:12 132:6,18 152:22 155:8 159:18 163:22 167:16 185:22 211:2 213:4 241:11 243:2 244:19 245:3 247:14 257:4 265:6 268:11,13 274:5 281:7 319:9 353:5 397:12 similarly47:1

209:12 240:2 242:21 246:2 254:4 Simpkins 134:4

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73:20 79:19 88:4 128:12 188:15 242:5 simpler 101:5

336:14 simplest 86:20 simplify 78:16

300:15 simplistic 73:10 simply 18:11 45:11

45:14 114:18,18 116:7 130:21 161:17 164:8 318:7 338:4 396:15 397:22 simulate 11:18

36:8 46:20,21

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249:21 401:8 402:15 414:11 416:4 slopes 241:15 slotted 340:19 slower29:7 slowly 15:5 175:19

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382:12 solution 169:15

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376:14 steroid 204:4,17,19

204:21 205:12 208:6 225:22 steroidogenesis

387:6 steroidogenic

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90:15 91:15 138:15 202:19 210:12 Steven 1:17,20 2:8 steward 99:1 stewards 103:1 stewardship 100:1 104:8,18,21 105:2 114:7 121:6 268:9 329:5 stick 338:2 stimulate 390:21 stimulation 195:9 stochastic 28:9 265:18 Stoker 185:5 stop 11:2 51:14 133:11,21 193:3 storage 277:16,21 store 315:21 stored 85:19 story 120:18 straight 170:10

236:14 straightforward

58:17 strain 142:2 389:10

395:18 strains 144:13

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395:21 411:18 412:6 strongly 149:17 struck 374:13

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272:11 280:16 sum 260:20 266:11

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