1 MEETING OF THE SCIENTIFIC REVIEW PANEL 2 ON TOXIC AIR CONTAMINANTS 3 CALIFORNIA AIR RESOURCES BOARD 4 5 6 7 8 9 10 11 12 13 TRANSCRIPT OF PROCEEDINGS 1200 University Avenue 14 Riverside, California Wednesday, November 11, 1998 15 9:00 A.M. 16 17 18 19 20 21 22 23 REPORTED BY: Katherine Gale, 24 CSR 9793 Our File No. 1-50626 25 1 MEMBERS PRESENT: 2 Dr. John Froines, Chairman 3 Dr. Craig Byus 4 Dr. Gary Friedman 5 Dr. Anthony Fucaloro 6 Dr. Stanton Glantz 7 Dr. Peter S. Kennedy 8 Dr. James Seibert 9 10 REPRESENTING THE CALIFORNIA AIR RESOURCES BOARD: 11 MR. WILLIAM LOCKETT, Deputy Ombudsman, Northern California 12 MR. PETER MATHEWS, Office of Ombudsman 13 14 REPRESENTING THE OFFICE OF ENVIRONMENTAL HEALTH HAZARD ASSESSMENT: 15 DR. GEORGE ALEXEEFF, Deputy Director of 16 Scientific Affairs 17 REPRESENTING THE DEPARTMENT OF PESTICIDE REGULATION: 18 Mr. Paul Gosselin, Assistant Director 19 Mr. Tareq Formoli, Associate Environmental Research Scientist 20 Dr. Ruby Reed, Staff Toxicologist 21 Mr. Kevin Kelly, Associate Environmental 22 Research Specialist 23 24 25 BARNEY, UNGERMANN & ASSOCIATES 1-888-326-5900 1 PROCEEDINGS 2 * * * * * 3 DR. FROINES: I guess we'll call this 4 meeting to order and thank Jim Seiber for replacing 5 me last month while I was busy with MTBE which is now 6 complete. 7 And so we're going to change the agenda 8 a little bit. What we'd like to do is to start out 9 talking about the workshop. And the reason for 10 changing the agenda slightly is just because Stan and 11 Kennedy and Peter aren't here and that this is that 12 we might be able to dispose of readily, fairly 13 quickly, and then perhaps the others might be here 14 for the substance of discussions. 15 So I wrote a memo which everybody 16 received, and my proposal was that this workshop be 17 similar to the workshop we had at UCLA in March, and 18 that is that it be an SRP workshop in which we work 19 closely with DPR to put it together but it basically 20 be our responsibility to organize; that we would 21 define the agenda and that we would define the 22 speakers in collaboration with DPR. But this would 23 be a -- in a second -- a second scientific workshop 24 sponsored by the SRP. And I don't know if there was 25 discussion about that at the meeting. 3 BARNEY, UNGERMANN & ASSOCIATES 1-888-326-5900 1 DR. SEIBER: Well, I think our 2 supposition from the beginning was that -- as I 3 recall, was that it would be a joint undertaking. 4 And that's why I think the -- it's introduced by both 5 the ARB and the SRP panel chair. 6 So I guess the thing we would need to 7 probably discuss or consider is whether it's only -- 8 you know, what involvement of the two parties as it 9 takes place. 10 And we've asked DPR to come up and step 11 up to the plate, so to speak, and prepare a draft 12 which we have. And personally I think it's a 13 workable draft, and I think it can accomplish what 14 you mentioned, John: the involvement of SRP and the 15 selection of the exact experts and specific topics to 16 be addressed. 17 DR. FROINES: I think that the one 18 thing that -- this is a strange room, isn't it? It's 19 too big so that you feel like you're talking in this 20 vacuum. 21 DR. FUCALORO: We should invite some 22 students in. 23 DR. FROINES: Yeah. 24 DR. FUCALORO: In today's environment 25 they'd get half a class credit. 4 BARNEY, UNGERMANN & ASSOCIATES 1-888-326-5900 1 DR. FROINES: We should have all the 2 environmental policy student's here -- right? -- so 3 they can see how it really works in the real world. 4 DR. FUCALORO: If this is the real 5 world. 6 DR. FROINES: That's right. If this is 7 the real world, we're all in deep trouble. 8 Anyway, the one thing I think is clear 9 to me -- and I don't know how others feel -- but that 10 Bill Lockett and I have gone around and around 11 talking about when the meeting should occur. 12 And everybody on this panel is busy. 13 And the one thing we want to do is have a 14 well-organized meeting. And so Bill was talking 15 about a January 15th day. And I would actually 16 propose that we have it in February and we use 17 December and January to organize the meeting, and 18 that way we would be able to do a really good job at 19 doing it. 20 And I think otherwise we're going to 21 have to plunge right in right now and put an awful 22 lot of our time into meeting this January 15th 23 deadline. And I frankly think that that would be 24 premature. And it would not be as good a workshop, I 25 think. 5 BARNEY, UNGERMANN & ASSOCIATES 1-888-326-5900 1 So I would argue for some time in 2 February that we can work out mutually with Paul and 3 others at DPR and that we try and get everybody from 4 the panel. 5 DR. SEIBER: Well, I certainly agree 6 with that. Particularly if we're going to get some 7 top-notch experts from elsewhere in, it's essential 8 we give them enough lead time. 9 Also this is a dialogue opportunity. 10 The chemical companies and people with all different 11 backgrounds would want to come and participate. So 12 we need to give them time to think about it too. 13 DR. FROINES: So nobody disagrees? 14 That's okay with you, Paul? 15 MR. GOSSELIN: Yes. 16 DR. FROINES: Do you want to sit up 17 front just so you have a feeling of warmth and 18 closeness, congeniality as it were? 19 DR. SEIBER: We thought maybe you could 20 move your chair in the middle here. 21 DR. FROINES: Might be a little too 22 friendly. 23 Anyway, the second issue about the 24 workshop is that I do think this is a good start. My 25 sense is that one of the things that would be most 6 BARNEY, UNGERMANN & ASSOCIATES 1-888-326-5900 1 valuable is we need to look at the list of pesticides 2 that we anticipate coming before us over the next 3 year and add to that any other pesticides of 4 particular relevance. 5 For example, just to pick my favorite, 6 I don't know if you had a list of 12, whether Telone 7 would be on it, but there's some interesting science. 8 And Telone's role relative to what happens with 9 methyl bromide, it's clearly going to go up or down. 10 And so there are some other pesticides that may have 11 constant -- may be of some significance that we want 12 to think about. 13 So if we try and define a list of 14 pesticides that could come before this panel over a 15 period of time, we should then look at those and try 16 and define what are the underlying scientific issues 17 that this panel should be knowledgeable about in 18 order to address them. 19 This is a -- this is -- we have 20 historically dealt principally with carcinogenesis, 21 with their toxics. And so we're in a different 22 ballgame now. We're dealing with non-cancer 23 endpoints. We're dealing with neurotoxicity. We're 24 dealing with clearly different approaches to 25 evaluation. 7 BARNEY, UNGERMANN & ASSOCIATES 1-888-326-5900 1 And it seems to me that we need to 2 probably, as a subcommittee, define what are the key 3 scientific questions that need to be addressed 4 ranging from the mechanisms of delayed neuropathies 5 and that kind of issue to how one deals with plasma 6 cholinesterase to -- but even those are stated in the 7 practical context. We need an underlying mechanistic 8 basis. So one of the issues is to what degree do we 9 understand mechanism which, therefore, can drive our 10 understanding of health effects and dose response. 11 So it seems to me we need to define the 12 pesticides, we need to define the underlying 13 scientific issues, and then we need to define who are 14 the best people to speak to those issues. So it's in 15 a sense a tier of three, it seems to me. And then we 16 can try and get them here and see where it goes from 17 there. So that's the kind of approach that I would 18 think would be useful. 19 DR. SEIBER: Yeah, John, one thing we 20 talked about -- and I don't know whether we reached a 21 resolution -- maybe we did in our own minds -- was we 22 could separate the fumigants from all the other 23 pesticides and maybe think about having two 24 workshops: just kind of a general pesticide-in-air 25 workshop in February and then a more specific one 8 BARNEY, UNGERMANN & ASSOCIATES 1-888-326-5900 1 just on fumigants because they are, as you indicated, 2 loaded with issues and may require more time than a 3 one-day workshop. 4 DR. FROINES: Well, let's take that a 5 step further. Maybe what we want to do is to have 6 this body in a sense convene at a series of workshops 7 over time on the issues of pesticides in California 8 because it is such a major issue. 9 And we can see as a way to -- as a way 10 to not always focus on the narrow regulatory issues 11 but to try and look at the science underlying it that 12 would facilitate making good regulatory decisions. 13 MR. GOSSELIN: Yeah, I think with the 14 discussions my staff have had on trying to develop 15 the workshop, the draft before you now for the topics 16 will cover some general scientific -- compelling 17 scientific issues that will cover a number of the 18 pesticides that are coming before us. 19 But what we also got into was that not 20 all the topics that we're facing can be covered in a 21 one-day workshop. And we're looking at maybe having 22 a follow-up one in six months. 23 And you know, the whole issue that 24 covers all of them is how do you design -- one of the 25 issues is how do you design the appropriate 9 BARNEY, UNGERMANN & ASSOCIATES 1-888-326-5900 1 monitoring program to characterize exposure. 2 From that, that doesn't even get 3 into -- and this is a major issue with the fumigants: 4 How do you take that data and model it to create 5 buffer zones and to evaluate on exposures. That, I 6 think, is going to be an important topic for maybe a 7 subsequent workshop. 8 But the whole issue on cholinesterase 9 inhibition and those issues that will cover the whole 10 range of pesticides does need a large amount of time. 11 DR. FROINES: Well, I think you're 12 right. I mean, it seems to me that -- I think I 13 understand a lot of the toxicology of these 14 compounds. 15 I think the exposure issues are really 16 quite difficult and challenging, and so one could 17 argue that we're going to need to put a fair emphasis 18 into how does one address these questions, especially 19 because theoretically we're dealing with air toxics 20 as opposed to occupational exposures. 21 Occupational exposure assessment is 22 difficult enough because you have multiple exposures 23 to pesticides, and people don't know how to do that 24 very effectively. 25 But here we're dealing with a cast of 10 BARNEY, UNGERMANN & ASSOCIATES 1-888-326-5900 1 very -- a very different situation where we're 2 dealing with an ambient of concentrations, and 3 they're important issues. 4 So I would agree. I think we -- I 5 think we ought to signal the exposure as one of the 6 key areas. Certainly the health effects endpoint is 7 another. 8 And I think what we want to do -- my 9 only criticism of this is I think the panel does need 10 to know -- have some information as background and -- 11 but I think we want to avoid it being too much 12 government in a sense of describing what we do and 13 how things are done and so on and so forth. 14 But we've all been -- you know, we're 15 getting older, so we've been through a million 16 meetings like that where a whole bunch of people go 17 up and say stuff that put you to sleep, and that's 18 what we want to avoid, it seems to me. 19 DR. SEIBER: The only exception I would 20 add to that is this Food Quality Protection Act has 21 really turned things around, and now pesticides in 22 air and residues in food and water, they're all 23 looked at together. And in the past we used to be 24 able to partition them out and address each medium 25 separately. 11 BARNEY, UNGERMANN & ASSOCIATES 1-888-326-5900 1 So I hope we can have kind of -- and I 2 thought somebody like Steve Johnson could come and 3 give the current thinking in Washington, which is 4 changing literally from week to week, on how to 5 implement that act. That would be important, new 6 information. 7 MR. GOSSELIN: But I think for the 8 major scientific topics that were laid out, I think 9 we were originally having an idea of having sort of a 10 panel of experts with different perspectives to -- 11 instead of getting into sort of that straightforward 12 presentation but get into a dialogue on the different 13 sides and points of view on those issues, which I 14 think is what you're talking about. 15 And I think that's what we're looking 16 for, those broader topics to actually have it maybe 17 designed that way, to elicit some comments and some 18 thought and dialogue. 19 DR. FROINES: And there's a lot going 20 on right now. You know, people are -- you know, 21 people are looking at interindividual variability 22 much different than they have in the past, and that's 23 going to become a major issue. 24 You know, here's this paper in nature, 25 math -- "Mice lacking serum peroxinaser, susceptible 12 BARNEY, UNGERMANN & ASSOCIATES 1-888-326-5900 1 organophosphate toxicity." So genetic polymorphisms 2 and molecular biology is now a part of what we're 3 talking about. 4 And so when we're looking at sensitive 5 individuals, sensitive populations, all that becomes 6 important. And so we need to bring it to the level 7 at which some of the science is beginning to operate 8 at. 9 And because it has clear significance, 10 especially when we're trying to look cross species. 11 And so we need to do a good job with the 12 toxicokinetics, and then various genetic issues 13 become even more important given different potential 14 polymorphisms and various metabolizing enzymes. 15 So it seems to me that we probably need 16 a small group which, I guess, should be Jim and me 17 and Craig. I read the transcript. I know who talked 18 the most. So if you talk the most, you get to be 19 part of the committee; right? And if Gary or Tony 20 wants to be on the subcommittee, they can volunteer. 21 DR. FUCALORO: Or not. 22 DR. FROINES: Or not. 23 DR. FRIEDMAN: I don't feel I have the 24 expertise in that area. 25 DR. FUCALORO: I mean, that really is 13 BARNEY, UNGERMANN & ASSOCIATES 1-888-326-5900 1 not my area. Right. 2 DR. FROINES: I think this is a tough 3 one for us because we've been taught by George back 4 there for all these years so we trust him, and we 5 listen to him in a decent way. Now we're trying to 6 deal with delayed neuropathies in hens. 7 DR. FUCALORO: In hens? 8 DR. FROINES: Yeah. And we've got to 9 figure out how to deal with that. 10 DR. BYUS: Yeah, I have actually in 11 front of me the list I got some -- a while ago on 12 what the potential pesticides that would be presented 13 to us in the next year, theoretically. 14 And if you could -- which ones of these 15 have not -- I think we're pretty good on the cancer 16 endpoints in terms of health. As you said, we've got 17 a pretty good experience with that. 18 But it's the non-cancer endpoints, 19 especially if they are at all unusual -- even the 20 usual non-cancer endpoints -- that you might 21 highlight for us. 22 Tell us which one of these -- without 23 us seeing all the documents which ones have 24 non-cancer endpoints. Is it clearer or is it some -- 25 you know, does it require some interpretation in the 14 BARNEY, UNGERMANN & ASSOCIATES 1-888-326-5900 1 level of calculating NOELs and LOELs, whatever. 2 And you're the experts at it. And if 3 you could -- on the front end, this is what I think 4 you're saying, John: If you can identify those 5 difficult areas for us initially, then we could have 6 some other -- some people come and speak to us about 7 it, it might save everybody a lot of time and 8 actually make a much better analysis. 9 I mean, can you do that, Paul, or is 10 that difficult to do or not? 11 MR. GOSSELIN: Yeah, I think from the 12 dozen or more risk assessments we've gone through and 13 completed, there is probably a finite set of 14 compelling endpoints and things that have been 15 driving the risk assessments that we could probably 16 lay out and maybe give some examples. So I think -- 17 I think that's doable. 18 Not -- you know, I think as we go 19 through, in my experience, getting risk assessments 20 in the end, those are the questions that I'll 21 typically ask as to the story behind the story in the 22 risk assessment. 23 But there's a lot that we have from 24 prior risk assessments that we can actually scope out 25 for the workshop that will cover, you know, all the 15 BARNEY, UNGERMANN & ASSOCIATES 1-888-326-5900 1 ones coming up. So I think we can use our prior 2 experience to lay those things out. 3 DR. FROINES: I think Jim Seiber is 4 right. We need to be careful that we schedule it -- 5 we define the issues we want to talk about rather 6 carefully so we don't try to do too much and plan to 7 do a couple more later to cover more ground. 8 DR. FUCALORO: I agree. I think if you 9 do too much, actually, you end up not really being 10 very effective, and I think if you parse out the 11 information in a reasonable rate, I think people can 12 absorb it. 13 DR. SEIBER: And again, one of the 14 purposes of the workshop is to get community 15 involvement. This is their opportunity, people 16 outside the panel and state agencies, to speak up. 17 So we want to make sure we save some time for that. 18 DR. FROINES: Yeah. And I think it 19 would be good to have some industry representatives 20 participate. 21 You know, on Telone there's a nice 22 paper in the latest chemical research in toxicology, 23 but I know that Dow is doing some work on DNA adduct 24 formation. So where you have active research 25 programs going on, it seems to me to be useful to try 16 BARNEY, UNGERMANN & ASSOCIATES 1-888-326-5900 1 to identify. And your folks may be aware of some of 2 the most active work going on that would be helpful. 3 Who will be the lead for DPR to work 4 with us? 5 MR. GOSSELIN: On setting up the 6 workshop? Lisa Ross is still the staff lead. 7 DR. FROINES: So that's the person we'd 8 call? 9 MR. GOSSELIN: Uh-huh. 10 DR. FROINES: Because we're going to 11 get down to the nitty-gritty fairly soon, I hope, 12 where we're not just talking in loft terms about 13 mechanisms. 14 MR. GOSSELIN: Yeah. And I would -- I 15 mean, we'll -- you know, we're looking to have this 16 set up and get going as quick as we can all get it 17 together. 18 But I think the draft outline here 19 today, especially the discussion on cholinesterase 20 inhibition and the monitoring design are two 21 compelling issues that will cover a large number of 22 the pesticide issues that are going to come before 23 us. So it might be a good starting point. But I -- 24 a lot of people brought up other issues as important 25 issues that I think could be the topic for future 17 BARNEY, UNGERMANN & ASSOCIATES 1-888-326-5900 1 workshops. 2 DR. FROINES: Well, there's a lot of 3 different issues. My understanding -- because I've 4 read the transcript, not having been there -- but 5 with organophosphates, you also have to worry not 6 only about the traditional delayed neuropathies that 7 represent axonal damage, but you also have to be 8 concerned with neurobehavioral changes and other 9 chronic, long-term changes that are quite different 10 than what you think of with organophosphate acute 11 toxicity. And I think that in the long run we have 12 to pay attention to that. 13 Because when we're looking at 14 long-term, more irreversible, in a sense, effects as 15 derived from chronic toxicity that are in some cases 16 neural behavioral and some cases have their own 17 well -- reasonably defined histopathology, that -- so 18 I think that the issues with organophosphates, we 19 would do damage to ourselves if we only saw it in the 20 sort of traditional organophosphate mechanistic view 21 because that's relatively reasonably straightforward. 22 And so the question is -- because one 23 of the problems has always been, you know, even with 24 the delay neuropathy mechanistic work that people 25 like Richardson did 20 years ago on neurotoxic 18 BARNEY, UNGERMANN & ASSOCIATES 1-888-326-5900 1 esterase and what's happened since then, it's still 2 more complicated than what people have said it looks 3 like. 4 And so all I'm saying is that I think 5 it's important for us to look at the science 6 because -- as opposed to the simple whether or not 7 you can correlate a serum level with a brain level of 8 cholinesterase. 9 MR. GOSSELIN: Yeah, I think I -- if 10 this is consistent with what you're saying, that I'd 11 see this workshop as not just a snapshot of the way 12 we've been doing things. 13 I think there has to be an explanation 14 and rationale why we've done certain things the way 15 we've done them to date so everyone can understand 16 our policies. 17 But I think we all know that science 18 and understanding and knowledge is progressing and 19 how that interfaces -- and as Dr. Seiber said, with 20 EPA, it's sort of on the edge of that -- how that 21 interfaces with regulatory agencies is, you know, 22 another compelling issue. How we absorb changes in 23 science and knowledge into a regulatory program is 24 very important. 25 So I see this is really trying to lay 19 BARNEY, UNGERMANN & ASSOCIATES 1-888-326-5900 1 out where a lot of the advances and new knowledge on 2 these issues, sort of the -- where things may go for 3 the future. 4 DR. FROINES: We're currently doing 5 work on two things: We're looking at 6 styrene-butadiene interactions, and we're looking at 7 hexane-methyl ethyl ketone interactions, so we're 8 doing a lot of PBK modeling and looking at those 9 actual interactions between chemicals. 10 And so I think one of the areas that I 11 think is weak in your documents a little bit is 12 discussion of toxicokinetics. There are very few, if 13 any, KM values and B maxes any place in the 14 documents. 15 And it seems to me that these issues 16 about cross-species extrapolation require a good 17 sense of toxicokinetics, and so that's one area that 18 maybe not in the context of this workshop but we 19 certainly need to think about it in the long term. 20 Because it -- I think it's -- Craig and 21 I were talking about it last night, and I think he 22 would agree that the issues of clearance and just 23 basic protein biochemistry is -- needs more 24 attention. And we need -- so we need to bring 25 ourselves up to speed so that the panel is really 20 BARNEY, UNGERMANN & ASSOCIATES 1-888-326-5900 1 comfortable with those kinds of discussions. 2 DR. BYUS: Yeah, my -- I mean, clearly 3 we've identified the serum cholinesterase issue, but 4 we did it after we looked at all the documents. So 5 my question is can we identify those issues until 6 we -- do we have to wait until we see all the 7 documents, or can we do it ahead of time. 8 And it would be better if we could do 9 it ahead of time and deal with those issues in a 10 workshop rather than try and deal with them after. 11 But I think we need to rely on you -- I mean, "you" 12 in the global sense -- to help us identify them on 13 the front end before actually we sit and review all 14 the documents. Is that -- that's the way I look at 15 it in terms of the health effectors, anyway; other 16 than the ones we've already identified. 17 DR. SEIBER: Yeah, I think that if we 18 framed the question right to the outside experts what 19 are the forefront leading edge issues. And many of 20 these experts go to the meetings in Washington with 21 their EPA, SAP group, so they could bring that back. 22 And I think it's a question of 23 informing the process so we know what's going on, we 24 know where science is going, we're regulatory so we 25 can make the best decisions we can with what's on 21 BARNEY, UNGERMANN & ASSOCIATES 1-888-326-5900 1 that list of pesticides. Unfortunately in one day we 2 can't cover everything, so it's more a question of 3 where you draw the line. 4 DR. FROINES: I do think we're talking 5 about a series of workshops. It doesn't even have to 6 include all the SRP members. If they're not 7 interested in something, they don't have to attend. 8 But there are enough scientific issues that if we're 9 going to be spending most of our time -- George has 10 sort of quit bringing things to us, and we can spend 11 all our time on pesticides -- then we'll see about 12 that. But I think it could be fun, frankly. 13 DR. FUCALORO: We have an agenda for 14 the next workshop before us, and what you're 15 discussing is a series of workshops which I agree is 16 a good idea. 17 I think you need some sort of task 18 force to set up the agendas for those. I think 19 that's something that needs to be done next. Don't 20 you? 21 DR. FROINES: Yeah. 22 So I think one of the things we should 23 do is we have a group of three right now who we have 24 identified. We can see if when Dr. Paul Blanc and 25 Peter Witschi are back if they want to participate. 22 BARNEY, UNGERMANN & ASSOCIATES 1-888-326-5900 1 We might even ask people outside who we 2 know who are doing work in the area to be a part of 3 the team if there was somebody we can identify, and 4 then the representatives from DPR and presumably 5 somebody from OEHHA. 6 And so it seems to me we would want to 7 have an ongoing series of meetings who -- boy, we're 8 bringing out everybody here in Riverside. You bring 9 the circus to town, everybody comes out. 10 UNIDENTIFIED SPEAKER: Absolutely. 11 DR. FROINES: Dave Eastman's over 12 there, and Paul Craner just came in. Goodness. We 13 should have these meetings in these outlying places 14 more. We get to see our old friends. 15 DR. FUCALORO: Some of us don't 16 consider Riverside an outside city. I happen to, but 17 some of us don't. 18 DR. FROINES: What the hell were we 19 talking about? 20 DR. FUCALORO: We were talking about 21 setting up -- I mean, I think I was setting a task 22 force or a plan in order to establish agendas for 23 future workshops and, therefore, cover the -- cover 24 the areas we wish to cover, many of which were 25 discussed here today. 23 BARNEY, UNGERMANN & ASSOCIATES 1-888-326-5900 1 DR. FROINES: I think we should set out 2 a plan, and I think we should set out a timetable, 3 because this one has kind of drifted along for -- 4 since before -- since, what, summertime -- since 5 June -- since before June, and now we're into a new 6 year. 7 So I think what we do is we set up 8 subject areas that we want to pursue and then we set 9 up times and then we work and we stick with the 10 times. 11 DR. SEIBER: Well, the way I understand 12 the conversation, we'll have a task force with SRP 13 ideas on what could go into the workshop but will 14 continue to work through the DPR staff. 15 DR. FROINES: Right. 16 DR. SEIBER: And I think that's kind of 17 important. I think DPR needs to, so to speak, learn 18 how to do the workshops also because obviously we're 19 not going to do the detail work. And I'm happy that 20 Paul has designated a person who can work with us 21 who's had some experience in meeting organization 22 already so -- 23 DR. FROINES: In fact, what happened 24 with the workshop we did in March, we identified 25 speakers and then Bill Lockett -- I think Bill called 24 BARNEY, UNGERMANN & ASSOCIATES 1-888-326-5900 1 everybody to get them to come. I don't remember my 2 calling people. 3 Didn't you do the legwork on the 4 speakers for the diesel workshop? 5 MR. LOCKETT: Yes. 6 DR. FROINES: Yeah. So I think 7 absolutely. We need that. But we need the exchange 8 to not be -- it needs to be an equal intellectual 9 exchange as well as an equal work so it's not seen as 10 staff and SRP at all. 11 DR. BYUS: I think we should basically 12 get together with your lead toxicologists on these 13 documents and sit down for some small period of time 14 and hopefully, you know, have them just say what are 15 the issues and where are the gaps and do it for each 16 one of the things that's going to come along and then 17 who are the people we might get to bring in and talk 18 about it. Can we -- I mean, could that be done in a 19 relatively short period of time? Like a day? 20 MR. GOSSELIN: Yeah, for the ones 21 coming up? 22 DR. BYUS: For the ones coming up. 23 MR. GOSSELIN: It depends on how far 24 along those documents are but, yeah, there's no 25 problem doing that. And I think, again, from what 25 BARNEY, UNGERMANN & ASSOCIATES 1-888-326-5900 1 issues -- I mean, for the ones that aren't done, we 2 probably would have a good idea of the realm of what 3 we've seen historically. You know, we would probably 4 cover most of the topics -- I mean, we might get 5 surprised with a new, compelling issue but -- 6 MR. BYUS: Yeah, of course. 7 MR. GOSSELIN: Right. But I don't 8 think that's a problem. 9 DR. BYUS: That's the way I think we 10 should do it, though. I mean, does that seem 11 reasonable? 12 DR. FROINES: I think we have to have a 13 lot of back and forth between meetings. But you 14 know, I think what we should do is every time we have 15 a meeting, since pesticide issues are going to be 16 coming up fairly regularly, is we try to set aside a 17 breakfast or after the meeting or the night before or 18 something like that where we have actually had a -- 19 or try to have, if it can be fit into everybody's 20 schedules, a working group meeting at the SRP 21 meeting. 22 DR. BYUS: That's a good -- great idea. 23 DR. SEIBER: But if we can keep the 24 pressure on this one so we can -- you know, even 25 February isn't that far off with the holidays, so I 26 BARNEY, UNGERMANN & ASSOCIATES 1-888-326-5900 1 think we're going to have to bring this first one to 2 closure as soon as we can. 3 MR. GOSSELIN: And I think even -- 4 DR. FROINES: The danger is that you 5 have a meeting like this and everybody talks and is 6 enthusiastic, and then you finish this meeting, and 7 you say, "I'm glad that's over," and then you go on 8 to your normal work, and things slip by the wayside. 9 So I think that's the message, what you see the 10 danger is. 11 MR. GOSSELIN: How soon would we be 12 able to lock in a date in February? 13 DR. FROINES: I think it's up to Bill 14 to find when the panel's available. 15 MR. LOCKETT: We'll need to poll the 16 panel and figure out a date in February that will 17 work. 18 DR. FROINES: There's a lot of snow on 19 the mountains, so it's going to be difficult. 20 DR. SEIBER: We could have this meeting 21 at Squaw Valley. That's a possibility. 22 DR. FUCALORO: Or Miami. 23 DR. FROINES: Well, is there anything 24 else that we need to -- I think that one thing we 25 need to do is I think it would be good to have -- 27 BARNEY, UNGERMANN & ASSOCIATES 1-888-326-5900 1 we've agreed that it would be good to have some 2 industry representatives, not to lobby us but to talk 3 about science that's going on; and clearly the other 4 point is other members of the community who have an 5 interest in pesticide issues we need to identify as 6 well. 7 The Food Quality Protection Act seems 8 to me to be really important because it's changing -- 9 may change everything. 10 DR. SEIBER: Yeah, I think the -- just 11 taking the aggregate exposure part of the Food 12 Quality Protection Act, just that one part where you 13 look at total exposures, as I mentioned, we didn't 14 have to worry so much about that in the past. And 15 now that's right at the essence of what -- where the 16 regulatory action is moving and rightfully so. I 17 mean, it only makes sense. You've got to add all the 18 exposures from all the media. 19 But what it means for pesticides in air 20 as toxic air contaminants is you don't just do that 21 in a vacuum. You've got to link it up with food and 22 water and the other exposure routes. 23 And where we used to be able to talk 24 about outdoor versus indoor and we kind of said, 25 well, we're not so worried about indoor air because 28 BARNEY, UNGERMANN & ASSOCIATES 1-888-326-5900 1 that's not the mandate that we live under, well, you 2 can't do that anymore. I mean, you never could in 3 the past, but we kind of artificially did. But you 4 just can't do that. 5 DR. FROINES: Well, let's move on. 6 There was something I wanted to say but -- oh, 7 George, who is a point person for us to talk with 8 about this workshop issue? 9 DR. ALEXEEFF: George Alexeeff with 10 OEHHA. 11 Well, you could start with me, and I 12 could point to you depending on the specific 13 individual. If we're talking about organophosphate 14 mechanism action, we have the individual here, one of 15 the staff people here. If we're talking a little 16 more global pesticide questions, it might be a 17 different individual. 18 But we would get one of the members of 19 our pesticide section that would be knowledgeable on 20 the specific experts on the issues depending upon how 21 specific the workshop was set up. 22 So -- so if there's -- you could start 23 with me, and I could just point to you depending upon 24 the specificity or the area of the pesticide 25 toxicology. 29 BARNEY, UNGERMANN & ASSOCIATES 1-888-326-5900 1 DR. FROINES: You know, one thing, 2 looking in the back and seeing my Ph.D. student 3 Lupita Chapa here, is one of the issues that we're 4 dealing with in thorium in Mexico is we don't deal 5 with -- we don't have the luxury of studying DEF and 6 then studying methyl parathion because, you know, 7 down there everybody's exposed to eight or ten 8 pesticides. 9 So we have to deal with the question of 10 how do you deal with everybody from antibiotics on 11 the one hand to methamidophos to residual DDT in the 12 soil. So we have a very complicated exposure 13 pattern. And actually, that undoubtedly occurs here 14 too. 15 And so one of the questions becomes at 16 some point we have to bite the bullet and take on the 17 multiple exposure issue. I don't think we can leave 18 it aside. It is what happens. And health effects 19 derive not from single chemicals. They derive from 20 combinations of chemicals. 21 I just reviewed a paper for Witschi 22 on -- what the hell was it? -- diazanon and methyl 23 parathion. So at some point I think it's important 24 that we do that. 25 And so at some point it would be 30 BARNEY, UNGERMANN & ASSOCIATES 1-888-326-5900 1 interesting for us to learn from you something about 2 the mixtures of exposures to pesticides that actually 3 occur in your experience and something about the 4 temporal characteristics of that as well. 5 MR. GOSSELIN: Yeah. I think even the 6 work and struggle that EPA is going through with FQPA 7 and actually some of the panels that put together to 8 try to investigate this might -- might be helpful. 9 Because EPA is trying to formulate some 10 policies on that, and it's -- even among 11 organophosphates it's a pretty complicated task on 12 how to go about doing that. And that might be a 13 topic for future discussion, for a future workshop. 14 DR. FROINES: I want to say one thing. 15 It seems to me that this panel gets $100 every time 16 it meets, and it's made up of all very busy people. 17 And Bill Lockett would like us to work full time for 18 these issues, and there's a constant battle with 19 that. 20 And what I'm saying is it may be that 21 because I have some interest in pesticides that I'm 22 more willing to put time in outside of the normal 23 role to work on some of these things, and Seiber 24 probably has the same commitment because of his 25 interests, and maybe Craig does. But Gary has a very 31 BARNEY, UNGERMANN & ASSOCIATES 1-888-326-5900 1 different agenda, and I -- Tony, you know, may have 2 his own agenda, clearly has his own agenda. 3 DR. FUCALORO: Several of them. 4 DR. FROINES: Several of them. And so 5 it may be that we will see different levels of 6 participation, and we should be willing to accept 7 that. 8 Because when we have workshops, we're 9 not necessarily always dealing with a quorum 10 situation. So I think we do have to acknowledge that 11 some people on the panel may or may not be as active 12 in participation as others and accept that, although 13 when we actually make regulatory decisions we're 14 going to have to have everybody knowledgeable. 15 But if in fact Craig learns more about 16 plasma cholinesterase and there's communication with 17 Gary or -- I'm not trying to exclude you -- I'm 18 simply trying to be realistic about people's time -- 19 that it will be a learning process and it will have 20 broad -- 21 DR. FRIEDMAN: I think, you know, 22 people like me, I probably will benefit more from 23 such a workshop because there's a lot I would learn 24 from that. 25 I thought you were going to say that 32 BARNEY, UNGERMANN & ASSOCIATES 1-888-326-5900 1 you should get $200. 2 DR. FROINES: Well, I think we should 3 do that because I'm on the carcinogen identification 4 committee, and it's more lucrative to be on that 5 committee. So that there needs to be an issue of 6 equity. But now that we've had an election, we'll 7 get -- those things will get straightened out, I'm 8 sure. 9 DR. SEIBER: Let me just try a 10 suggestion now since we've had some good ideas here 11 in discussion. And I don't know how -- what level of 12 specificity you want to get into it now, but it seems 13 since we're all focused in now on the workshop 14 agenda, what if we added in under environment 15 monitoring and fate a discussion of aggregate and 16 cumulative exposure in the latest thinking. I know 17 that in itself is huge. But just to bring the key 18 issues out. 19 DR. BYUS: I think that would be 20 wonderful. 21 DR. SEIBER: And then under the 22 endpoints we talked -- John brought up the 23 neurological effects of not just -- well, I guess 24 organophosphates but also other pesticides. 25 And when I read this draft agenda over, 33 BARNEY, UNGERMANN & ASSOCIATES 1-888-326-5900 1 I thought we ought to be able to cover in three hours 2 more than just cholinesterase. That seemed like it 3 was too heavily loaded on cholinesterase and maybe if 4 we had another topic in there. 5 DR. BYUS: Maybe like the mechanism of 6 the delay in neurotoxicity I think is something that 7 is not particularly clear. 8 DR. FROINES: That's not so simple to 9 cover in three hours. It's a lot. 10 DR. BYUS: It is. Well, as a 11 possibility. 12 DR. FROINES: There are different 13 levels of it too. 14 DR. BYUS: Right. 15 DR. FROINES: Because you have the 16 issue of what it is and all of that and the 17 mechanistic detail. And then you have using hens for 18 testing and then what do you do about the 19 toxicokinetics of hens. So I mean, you can bite off 20 a lot of pieces on that subject. So we have got to 21 be careful that we don't, you know, get too spread. 22 So we're done on this one, aren't we? 23 Probably more than done. 24 DR. SEIBER: What's going to happen 25 next? Are we going to get this group together by 34 BARNEY, UNGERMANN & ASSOCIATES 1-888-326-5900 1 telephone or something like that and maybe with OEHHA 2 and DPR people also? 3 DR. FROINES: I'd propose that probably 4 it makes most sense, given that he's in Riverside, 5 I'm in L.A., you're in Sacramento, and he's somewhere 6 between Nevada and Davis, that we have a conference 7 call next week. And we'll work it out when that will 8 be. And we start -- and I would even argue that we 9 set up a series of regular conference calls so that 10 we -- so we don't let the thing drop. 11 That's what I think the biggest -- 12 putting on workshops like diesel was very easy 13 because we knew all the players and we said, well, 14 it's going to be boom, boom, boom boom, boom, and 15 that's it. And we just called them, and they came. 16 Here we don't necessarily know all the players, and I 17 don't think any of us do. We all know pieces of it. 18 So I think we need to have a regular 19 process of -- to keep this stuff going. Otherwise 20 it's going to have a tendency to drift the way it's 21 been drifting. Even though Jim's been trying to push 22 it along and everybody's tried to deal with it, it's 23 still drifting. 24 MR. GOSSELIN: And I think because we 25 haven't done this workshop before and a lot of these 35 BARNEY, UNGERMANN & ASSOCIATES 1-888-326-5900 1 topics may be very broad and we are looking at a 2 series that to get something going that we know is 3 achievable even if it may seem that the topics aren't 4 going to cover three hours, I -- my own personal 5 perspective, I'd like to get a nice meeting we have 6 that's solid to build from rather than something that 7 we overload, have it be muddled, and everyone feeling 8 frustrated that we haven't accomplished much. 9 DR. FROINES: Based upon what we've 10 said today, you know what might be very useful for 11 you to do is after this meeting is to go back and 12 have a meeting in Sacramento and have your -- the 13 people who are the most technical people in DPR, for 14 them to sit down and come up with a list of what they 15 consider some of the most important and interesting 16 and topical scientific issues or scientific/policy 17 but by and large scientific issues, and then we can 18 see the benefit of that input. 19 And I don't think people need to 20 necessarily get their heads locked into a regulatory 21 framework. Looking at what are underlying issues 22 that help us define dose response from mechanism and 23 what are some of the questions associated with that 24 would be very useful to have as a starting point for 25 trying to come out with we may end up picking two or 36 BARNEY, UNGERMANN & ASSOCIATES 1-888-326-5900 1 three things and say let's just go with that. But 2 having it be an intellectual exercise and not just 3 show and tell is what we're really after. 4 So we'll set up the meeting. Bill can 5 set up the meeting for sometime next week. 6 DR. ALEXEEFF: George Alexeeff. 7 If I could just make a side comment 8 since we seem to be starting with the last item on 9 the agenda, and that has to do with the next coming 10 meeting in December. 11 One of the items on the proposed agenda 12 is our acute methodology for risk assessment, 13 methodology for doing acute risk assessment, and so 14 that will work out very well with the issues being 15 discussed with DPR because we will be trying to 16 present at least, you know, our sort of framework on 17 how we evaluate acute non-cancer endpoints. 18 So I think this year -- it looks like 19 the agenda for this year will be a lot of evaluation 20 of non-cancer endpoints, both the acute and the 21 chronic, which would be, I think, rather 22 scientifically interesting and challenging for the 23 committees. 24 DR. FROINES: George, how long do you 25 think that's going to take? 37 BARNEY, UNGERMANN & ASSOCIATES 1-888-326-5900 1 DR. ALEXEEFF: Well, the leads on the 2 document are Dr. Seiber and Glantz. And they had 3 asked us to -- since it's a different approach, we're 4 concerned about -- mostly about the methodology, 5 although we have 50 substances where we've 6 implemented the methodology. 7 They wanted the presentation to be 8 loaded with examples of the methods. So kind of go 9 through the method, like here's this method we're 10 discussing, and to give an example of how it actually 11 works and what the issues and uncertainties and 12 problems with that method are. Because every method 13 we come up with has its shortcomings. It's not a 14 perfect, ideal situation. But we work with the data 15 that we have. 16 So it's going to be kind of a lot of 17 examples and explanations of things that the way we 18 use the data and the way we give those examples. So 19 that itself will take, you know, at least an hour or 20 two just discussing the issues and the methods. 21 And then there obviously will be 22 questions about the specific chemicals and how maybe 23 those methods were applied to those chemicals. So 24 like, for example, one issue that comes up and it 25 comes up also for the pesticide documents is using 38 BARNEY, UNGERMANN & ASSOCIATES 1-888-326-5900 1 the developmental or reproductive study and trying to 2 determine whether it has acute application or 3 acute -- you know, for acute exposure. 4 And that's an important issue, and you 5 can see how we've tried to do that. That itself can 6 go on for a reasonable length of discussion. So but 7 there's going to be a number of those, probably ten 8 issues like that. 9 DR. FROINES: You're like my wife. 10 DR. ALEXEEFF: I'm sorry -- or thank 11 you. 12 DR. FROINES: You're like my wife. I 13 ask her a question, and then she answers it whichever 14 way she chooses to, which has nothing to do with the 15 question I asked most of the time. She has her own 16 agenda, and she pursues her agenda. 17 DR. FUCALORO: That's the definition of 18 a politician. Maybe a wife, too, but certainly a 19 politician. 20 DR. FROINES: So George, help me out 21 here. Give me a time. 22 DR. ALEXEEFF: My sense of what will 23 happen is it will take at least a half a day. You 24 know, we're talking like three hours. And I have a 25 feeling it will roll over to another meeting, the 39 BARNEY, UNGERMANN & ASSOCIATES 1-888-326-5900 1 subsequent meeting. 2 DR. FROINES: So we're at a half a day. 3 The reason I'm -- because I think we can finalize our 4 agenda for the next meeting right now. That's half a 5 day. We'll finish methyl parathion, and we'll have 6 an update on the workshop. And I think we just did 7 the -- unless somebody has anything else to say, I 8 think we just did the agenda. 9 MR. GOSSELIN: Yeah. We also are going 10 to present molinate. 11 DR. FROINES: After George said all 12 that? 13 MR. GOSSELIN: I said -- 14 DR. ALEXEEFF: Why do you think I said 15 it first? 16 MR. GOSSELIN: We're prepared and 17 willing. But I know that will take a couple hours. 18 DR. SEIBER: Yeah, I know a little bit 19 about the molinate issues, and that's an important 20 one. We want to make sure we save plenty of time. 21 But on the other hand what George mentioned, as we 22 get away from this hypnotism on cancer as the only 23 endpoint out there, I think this is just really 24 important stuff. And so they're both important. 25 We've got to spend time on them. 40 BARNEY, UNGERMANN & ASSOCIATES 1-888-326-5900 1 DR. FROINES: Well, Paul, we have to do 2 methyl parathion. We have to have a -- what we 3 should say is a five- to ten-minute update on the 4 workshop so we don't bog down on it. 5 We've got George who wants half a day, 6 but it sounds like it will take a week if we gave it 7 to him. And then we have molinate. And that's too 8 much for one day. 9 (Off the record.) 10 MR. FROINES: Maybe what we can do with 11 molinate -- first, is Paul's not here, but does Paul 12 have an early draft? Do you have an early draft of 13 the document? 14 MR. GOSSELIN: Yeah. Actually, we have 15 had at least one conference call and some written 16 comments on some issues. So what -- I think what you 17 were leading to is if we'll continue to work with the 18 leads on molinate and maybe at that meeting not have 19 a full presentation but a synopsis presentation of 20 the overheads. 21 And actually, we'll have completed the 22 public comment period, so we could probably provide 23 some of the background preliminary information and 24 work out a lot of the issues with the leads prior to 25 that meeting. 41 BARNEY, UNGERMANN & ASSOCIATES 1-888-326-5900 1 MR. FROINES: What we did with diesel 2 last October is we weren't prepared to discuss it and 3 there were still changes being made by George and his 4 staff. 5 So what George did is they came and we 6 spent part of the day -- basically it was an 7 informational presentation. And then at two 8 subsequent meetings we took up diesel in detail. 9 I think that -- unless anybody 10 disagrees, that seems to me to have been a useful way 11 of doing it. And so if what you did was made a 12 preliminary presentation, we could get feedback -- 13 the panel could get feedback from the leads to hear 14 what their concerns are, and then we can take it up 15 at the next meeting in some detail. 16 MR. GOSSELIN: Right. 17 MR. FROINES: Does that make sense? 18 DR. ALEXEEFF: If I may add, that may 19 be what also happens with the acute document as well. 20 I mean, I think it will go over probably to the 21 following, subsequent meeting. And that's just my 22 thought. 23 Because there's potentially 50 24 substances that people might want to -- after we've 25 discussed the technical issues -- may want to look at 42 BARNEY, UNGERMANN & ASSOCIATES 1-888-326-5900 1 again. 2 We can just -- we're open to any sort 3 of format. But I think for that sort of thing we're 4 approaching a new -- considering new methodology. I 5 think two meetings is very likely also for that 6 document as well. 7 DR. FROINES: Well, the one thing -- 8 Bill, the one thing that's becoming clear in this 9 meeting and I think has been becoming clear for the 10 last year, in fact, is that we are -- we went -- for 11 those in the audience who don't know, we went for, 12 what, 18 months without a meeting at one point. 13 There were some political problems going on that had 14 to be resolved. 15 But now it looks like we're going to be 16 meeting monthly on an -- on an indefinite basis. 17 That's the feeling I'm getting. And with the 18 workshops you may actually have more. So we're 19 talking about quite a heavy workload. Everybody 20 needs to be aware of that, I think. 21 DR. ALEXEEFF: Well, just in terms of 22 the OEHHA documents, what we see for the year are 23 essentially three documents. But each document is 24 very complex and has a lot of issues. But that's 25 what we're expecting to bring to the panel, just 43 BARNEY, UNGERMANN & ASSOCIATES 1-888-326-5900 1 those three. 2 DR. FROINES: Are they expecting to 3 bring any chemicals to the panel? 4 DR. ALEXEEFF: Those three documents 5 I'm referring to are methodology documents with -- I 6 mean, it will cover a total of over 170 chemicals 7 between the documents. 8 But it's mostly the methodology used 9 and then the application of that methodology as 10 opposed to an in-depth discussion of a single 11 chemical or a couple chemicals. So it will be a 12 little bit different. 13 DR. FROINES: Well, we're not going to 14 get an MTBE or diesel or some more traditional 15 compound? 16 DR. ALEXEEFF: MTBE is probably the 17 other substance that could come before the panel from 18 us. It will probably be very similar to the other 19 MTBE documents that our department is developing. We 20 have already developed three documents in MTBE. 21 And so it's very likely after the CIC 22 meeting in December and the reproductive meeting in 23 December -- those are our departmental meetings on -- 24 with science panels -- that we may then be developing 25 an air document on MTBE. 44 BARNEY, UNGERMANN & ASSOCIATES 1-888-326-5900 1 So that could come. But that will take 2 some time and probably won't be available -- we're 3 talking until later in the year, next year, calendar 4 year. 5 DR. SEIBER: Well, that raises the 6 whole question of we saw a prioritization list -- oh, 7 I don't know, maybe in the springtime -- that had 8 styrene and MTBE and a lot of different things on it. 9 I think it would be kind of nice to have an update on 10 it. Because I had the impression that maybe styrene 11 would be coming along this year. 12 DR. ALEXEEFF: We're also starting to 13 work on styrene, but I think that one's going to be a 14 little long and difficult document to prepare, so I 15 don't think it will be ready this year. It might be. 16 DR. FROINES: But the panel is -- this 17 discussion is such that I think it's pretty clear 18 that we're going to be working on a relatively 19 ongoing basis for the next period of time. 20 DR. ALEXEEFF: I mean, the other 21 substance that has come up and in part because of 22 DPR's work has to do with crystalline silica. That's 23 another substance that will be -- that ARB has asked 24 us or notified us that they will be requesting us to 25 prepare a document on that as well. 45 BARNEY, UNGERMANN & ASSOCIATES 1-888-326-5900 1 And then the other one was PAHs and 2 nitro PAH documents and looking at how to consider 3 the more multiple issues involved with genotoxicity 4 and such. So those are the -- that's pretty much the 5 summary of the documents that we see in the horizon 6 over the next year that the staff will be working on. 7 DR. FROINES: Well, I can suggest a 8 couple more I think that you should put in your -- 9 the back of your head. One is aldehydes as a generic 10 group because they're very reactive and they're 11 important. 12 And for example, you know that HEI had 13 an RFA out last year about aldehydes so that they're 14 certainly -- at the national level they're concerned 15 about that as a class of compounds. 16 And then related to the PAH aldehyde 17 issue is those compounds that produce oxidative 18 stress. Reactive oxygen species -- quinones, for 19 example -- are the ones that we're interested in. 20 But the whole issue of electron 21 transfer reaction, electron stress, oxidative stress, 22 all of that seems to me -- and all of that, again, is 23 related to mobile sources to a large degree. 24 And it seems to me that we have -- if 25 you sort of say what are the most important air toxic 46 BARNEY, UNGERMANN & ASSOCIATES 1-888-326-5900 1 compounds, it's not just looking at your isolated 2 individual carcinogen spewing out of some factory. 3 I mean, I think that the mobile source 4 issue around reactive oxygen compounds is really 5 important and certainly aldehydes, it is important, 6 especially with the oxygenates where you are 7 generating formaldehyde and acid aldehyde and then 8 peroxy acetyl nitrate and the others. 9 And so it seems to me that we need to 10 identify those compounds not just -- you know, we got 11 a list where we had this compound, a sole tone 12 compound, that's been banned for 20 years on 13 somebody's list. 14 And so we really ought to say what are 15 the really most important compounds and let's go 16 ahead and talk to the panel about that and you can go 17 to work on it. 18 DR. ALEXEEFF: Uh-huh. 19 DR. SEIBER: But one thing -- this 20 document that we're going to take up, this is really 21 loaded with information. We -- this is a here and 22 now. It's done. It's ready to go. This is the 23 acute reference exposure levels for airborne 24 toxicants. I think it's extremely important. 25 So all things are coming along, but 47 BARNEY, UNGERMANN & ASSOCIATES 1-888-326-5900 1 this one here deserves a lot of attention because 2 there's some good work here. And I think it's kind 3 of unique to California. So this is what we're 4 looking for. 5 DR. FROINES: I'd like to see -- you 6 know, if you take PAN, for example, the data on PAN 7 is very limited. It's genotoxic. There's evidence 8 of carcinogenicity. There's evidence of lung 9 effects. 10 We know that if you use ethanol, you 11 start to get a lot of PAN because you have a lot of 12 acid aldehyde in an environment like L.A. where you 13 have a lot of nitrogen oxides and so on and so forth. 14 The data on PAN is really deficient 15 from a regulatory standpoint. You would want more 16 before you labeled it as a toxic air contaminant. So 17 one of the things, it seems to me, George, is to be 18 thinking about as you look at reactive oxygen 19 compounds is to also develop a list that says, 20 "Research needs to be done in these areas, and here 21 is the kinds of research we think needs to be done," 22 and DPR the same way to create out of a regulatory 23 process, to create a research agenda at the same time 24 to fill gaps and that -- so that the regulatory 25 process doesn't always have to be quite as -- so 48 BARNEY, UNGERMANN & ASSOCIATES 1-888-326-5900 1 like, you know, like a civil engineer, a linear 2 process. 3 DR. ALEXEEFF: And if I may plug the 4 document again that Dr. Seiber was raising, there's 5 actually one thing different with this document. We 6 do have a research need section in there. 7 So we can look at that, how we can work 8 that kind of section, so that we -- because it just 9 seemed to us we knew where all the data gaps are. It 10 was important just to outline them there in general. 11 The outline is there as to where a lot of research as 12 to go for the acute toxicity arena makes sense. 13 DR. FROINES: I think one of the things 14 I'd like to see coming out of the DPR interaction is 15 more a sense in the academic community of what our 16 research -- some of the research issues that you 17 think are particularly important and would be helpful 18 as we move forward to actually build this linkage 19 between the government regulatory agencies and the 20 academics in California who are doing research in 21 these areas. That -- those linkages haven't been 22 extended enough and I think could be. 23 So should we move on? Yes. It's good 24 to have that discussion. We won't have it again. 25 MR. FRIEDMAN: It seems like it took 49 BARNEY, UNGERMANN & ASSOCIATES 1-888-326-5900 1 quite a long time. 2 DR. FROINES: Let's move on to DEF. 3 MR. GOSSELIN: Thank you. 4 Since the last meeting, we went through 5 and we did post DEF out for another round of public 6 comments. 7 One thing you should also take a look 8 at is we started a process of actually posting our 9 documents even for comment period on our Internet 10 home page. And we're looking to enhance that and 11 actually have it cross-linked with ARB's SRP page 12 which I think in the future will be real helpful to 13 people coming in looking for the agenda schedule and 14 documents. 15 So we did go out. We had opened up the 16 comment period, sent a notice out to the interested 17 party list for DEF, and went through that. I don't 18 believe we got any comments back during that process. 19 But the one thing that we did go 20 through is we did send to you a summary list of the 21 changes that were brought up at the last meeting to 22 the document, and they're bulleted as sort of a frame 23 of reference, and we faxed out to you the actual 24 change of the text to the original document that 25 would make it easier to see where we inserted it. 50 BARNEY, UNGERMANN & ASSOCIATES 1-888-326-5900 1 And today we have the sort of revised document that 2 incorporates those changes. 3 DR. FROINES: Is that this document 4 (indicating)? 5 MR. GOSSELIN: What's the date on that? 6 DR. FROINES: November '98. 7 MR. GOSSELIN: That should be it, 8 right. 9 So that document has the changes that 10 were faxed out to you a week or two ago. So I don't 11 know if you wanted me to go through each one of those 12 changes or if there were questions on that. 13 The other thing is we've been working 14 with ARB and the panel on the draft findings which 15 you have the latest copy of. Those reflect comments 16 that were submitted in over the past couple weeks. 17 DR. FRIEDMAN: I have a question about 18 the findings. Is this an appropriate time? 19 MR. GOSSELIN: Uh-huh. 20 DR. FRIEDMAN: I'm not clear on the 21 logic and the reasoning that lead to this being 22 labeled as a "toxic air contaminant." You know, I'm 23 convinced that it's a poison. I wouldn't want to eat 24 it or have anyone else eat it or breathe it, but I'm 25 just wondering if we're not stretching a bit to meet 51 BARNEY, UNGERMANN & ASSOCIATES 1-888-326-5900 1 this definition. 2 The margin of exposure, you know, for 3 the acute effects was very high so that it seems like 4 it wasn't labeled as a toxic air contaminant based on 5 that but rather on the carcinogenic effect or the 6 carcinogenic risk. 7 And in order to be labeled as a toxic 8 air contaminant, it needs to be -- cause one cancer 9 case out of ten million people, as I understand it, 10 one-tenth of the -- of the significant exposure. 11 So -- and in order to meet that 12 criteria, it seemed like you had to say that the 13 exposure lasted a lifetime. And no -- I don't 14 believe that this -- anyone has ever been exposed to 15 this substance for a full lifetime. 16 So I'm just wondering -- I'd like to 17 understand better how one comes up with the 18 conclusion that this is a "toxic air contaminant" by 19 the definition that's given in here. 20 DR. FROINES: But there's a -- can I 21 interrupt, Paul, before you get started? Because I 22 think there's a prior issue that we would -- it would 23 be nice to have Stan here since he'll be very -- I 24 was going to say articulate but I think outspoken. 25 Outspoken may be the more accurate way of describing 52 BARNEY, UNGERMANN & ASSOCIATES 1-888-326-5900 1 it. 2 We have to make a decision separate 3 from Paul. In the past we have declared compounds 4 as -- we have recommended that compounds be declared 5 toxic air contaminants based on no quantitative 6 estimate of exposure or risk. 7 We have made -- risk assessments have 8 been made in documents, but there hasn't been a 9 bright line for us. We've never had a bright line. 10 With a compound that's carcinogenic we've said it's a 11 toxic air contaminant irrespective of what the bright 12 line of 10 to the minus 5, or 10 to the minus 6, or 13 10 to the minus 7. 14 So the actual use of the risk 15 assessment for purposes of defining a substance as a 16 toxic air contaminant has never occurred for this 17 panel. 18 We have made the decision based on the 19 general -- the very general definition that we all 20 are aware of. And so the -- we have to decide 21 whether we want to recommend as a panel that 22 something be declared a toxic air contaminant or 23 whether we want to accept the language that is 24 basically in this report. 25 It says, "We agree with the science and 53 BARNEY, UNGERMANN & ASSOCIATES 1-888-326-5900 1 recommend that the director initiate regulatory steps 2 to list DEF as a toxic air contaminant," and that's 3 different. They are different ways of doing it. 4 DR. FRIEDMAN: Well, it's obvious this 5 is a toxic substance, so why did we go through -- I 6 mean, is it just a no-brainer? I mean, why did we go 7 through all these calculations and measurements and 8 so on if it's -- you know, nobody denies that this is 9 a toxic substance and, yes, some of it gets into the 10 air. So why did we go through all of this? 11 DR. FROINES: Well, because this panel 12 has historically disagreed with DPR on this issue. 13 It's been a fundamental disagreement since the early 14 '80s. And we've argued -- and now it's not quite as 15 contentious an argument, but there are -- but we have 16 disagreed. 17 And there is a court case under the 18 Toxic Substances Control Act where a judge in 19 Washington on an EPA where industry argued to take 20 into account exposure. 21 The judge overruled that and said that 22 a rattlesnake in a bottle is toxic whether it's in 23 the bottle or not and so that whether or not the 24 rattlesnake was out of the bottle doesn't define 25 whether the substance is toxic or not. 54 BARNEY, UNGERMANN & ASSOCIATES 1-888-326-5900 1 So that's the disagreement we've had 2 historically with DPR, that DPR uses their estimated 3 exposures as a way of calculating their MOEs and then 4 the MOE is 7,000 times above some number. 5 And so we're all safe as long as that 6 estimate of exposure is correct or that it doesn't 7 get used more or that something doesn't happen that 8 makes that estimate of exposure turn out to be not 9 correct. 10 And some of our -- some of the 11 disagreements has to do with concerns about that 12 exposure. So the issue for us is in essence to do it 13 our traditional way or to basically pursue it the way 14 DPR would prefer to do it. 15 DR. FRIEDMAN: Well, is what I see in 16 this document our traditional way or not? 17 DR. FROINES: Not really. 18 DR. FRIEDMAN: Because this document is 19 supposed to be coming from us, not from them. 20 DR. FROINES: So it's -- yeah. 21 DR. FRIEDMAN: How would you word, 22 then -- speaking for the panel, how would you word 23 the conclusion that this should be labeled as a 24 "toxic air contaminant"? 25 DR. FROINES: Well, you can take out 55 BARNEY, UNGERMANN & ASSOCIATES 1-888-326-5900 1 any one of our older documents and read it. I think 2 at the end of our older documents we say the SRP 3 finds the evidence is compelling and recommends that 4 diesel will be declared a toxic air contaminant. 5 DR. FRIEDMAN: Not because it can cause 6 cancer in a certain number of people. If it can 7 cause cancer in 100 million people, it's still a 8 toxic air contaminant? In one in 100 million? 9 DR. FROINES: Right. 10 And that's been the basis of the 11 disagreement. And that's -- and there are different 12 levels of -- this document -- I don't see any -- oh, 13 yeah, they are. They've put the MOEs in the document 14 as our findings. It's up to this panel. 15 DR. SEIBER: I don't know. I have a 16 problem with this discussion. One reason we asked 17 DPR to assemble this table, which is in the executive 18 summary, which has got all the chemicals that we've 19 ever declared as toxic air contaminants with DEF in 20 its appropriate ranking, was to kind of help put 21 things in perspective. And it's pretty clear it's 22 kind of in the middle on a potency basis. 23 The difference is -- and this is what 24 we're talking about now -- is the exposure. I don't 25 have another table like this with the -- to compare 56 BARNEY, UNGERMANN & ASSOCIATES 1-888-326-5900 1 the exposures. 2 My guess is the DEF exposure will be 3 lower than let's say for ethylene -- inorganic lead 4 or ethylene dichloride -- or benzene. I don't know 5 that for a fact because I didn't go back. 6 And that means a lot to me when I'm 7 trying to consider whether this is a problem or not. 8 The exposure is almost off the chart. I mean, there 9 is exposure, but it is very low. Then it shouldn't 10 be -- you know, on a relative basis it's not the kind 11 of threat that some of these other chemicals are. So 12 is that our business or not? 13 And I'm not sure I understand this 14 discussion about exposure levels. I think they are 15 very important. And of course, part of our document 16 is on exposure levels, so how can we -- how do we 17 deal with that on the final conclusion? 18 DR. FUCALORO: You know, I'd like to 19 make an observation, someone who's not been on the 20 panel for very long. I've read a while back the law 21 which controls the designation of TACs, and it 22 occurred to me that the hurdle is very low, that they 23 use the word "may pose a threat" -- I'm not quoting 24 exactly -- it's just my recollection -- to human 25 health. 57 BARNEY, UNGERMANN & ASSOCIATES 1-888-326-5900 1 It seems to me almost any chemical you 2 choose could fit that definition. I mean, it seems 3 to me -- I'm not sure we've ever turned down -- I am 4 not sure. Did you ever turn down a chemical that 5 came before us as a TAC to be designated? 6 So I think the key to it has to be the 7 priority list. And that priority list -- and as I 8 recall, the criteria used in -- I think it's OEHHA 9 includes not only toxicity but also exposure. And so 10 you have a combination of those two. 11 Whether or not it makes sense, I have 12 no basis for judging that because I don't have 13 experience in the area. But I assume people in OEHHA 14 have an enormous amount of experience. And to work 15 out a balance between toxicity and exposure to decide 16 which one comes before us. 17 Now, what is the value of doing that if 18 in fact we know the endpoint; that is to say that 19 they probably will be designated a TAC. It seems to 20 me that the reason we would do that is to get the 21 best scientific information available to show how 22 dangerous that chemical is, that substance is, 23 exposure and inherent toxicity, so that mitigation 24 can proceed from there. 25 So I think that's what we're doing 58 BARNEY, UNGERMANN & ASSOCIATES 1-888-326-5900 1 here. The fact that -- I too was struck by the fact 2 that the conclusion in supposedly our document has us 3 recommending designation as a TAC, and when I look at 4 the data, I say jeez, I mean, this doesn't seem to be 5 a big problem. I mean, a combination of toxicity and 6 exposure. But I don't know. 7 It seems the law -- and Bill could help 8 us on this -- the law almost forces us to designate 9 these things TACs given the low hurdles in that 10 regard. 11 MR. LOCKETT: It seems to me that what 12 the panel is about is deciding whether the report 13 represents the best current science. It also seems 14 to me that the panel is responsible for its own 15 findings as to what it wants to state about that 16 science. 17 I think historically the 1807 process 18 as practiced by the resources board is that the board 19 looked at the matter in two phases: risk assessment 20 and risk management. And to progress to the risk 21 management phase a risk assessment report needed to 22 be created, developed, approved by the SRP -- 23 DR. FUCALORO: Mitigation. 24 MR. LOCKETT: -- go to the board, and 25 the board would say, yes, we agree this is the 59 BARNEY, UNGERMANN & ASSOCIATES 1-888-326-5900 1 current science, yes, we declare under law this is a 2 toxic air contaminant, and that began then the risk 3 management phase. 4 DR. FUCALORO: Right. And risk 5 management would be mitigation in that regard. I 6 used the word "mitigation," but I know there's 7 assessment and management. 8 DR. FROINES: No, but I think the point 9 he's trying to make -- the point he's making is that 10 the determination of whether something represents a 11 problem is a risk management issue. 12 MR. LOCKETT: Yes. And there have been 13 cases where the risk assessment has been completed 14 but then because of the actions that have already 15 taken place, no formal risk management process was 16 undertaken. 17 DR. FUCALORO: I understand that. But 18 it still might be designated as a TAC. 19 MR. LOCKETT: Oh, yes. 20 DR. FUCALORO: Exactly my point. But 21 the question I think Dr. Friedman was -- or the issue 22 Dr. Friedman was bringing up was the actual 23 designation or the recommendation that something be 24 designated a TAC, in this case DEF. And I guess my 25 observation is that almost anything brought before us 60 BARNEY, UNGERMANN & ASSOCIATES 1-888-326-5900 1 would fit the definition of a TAC. 2 MR. LOCKETT: Correct. In part because 3 of prioritization. 4 DR. FUCALORO: But it's important for 5 us to carry out this process so that we can get the 6 best science available as to what -- to do the best 7 risk assessment. I use different words, but that's 8 the -- that's the same term. So that people 9 following us based upon this designation can do the 10 best risk management mitigation. 11 MR. LOCKETT: Correct. 12 DR. FUCALORO: I think I understand it 13 in those terms. 14 So even though we look at a particular 15 substance like DEF and say, "Well, the cancer potency 16 is very low," but those numbers have to be provided 17 or have to be -- we have to validate those numbers to 18 some extent by saying good science was used to come 19 up with those numbers to give guidance to regulatory 20 agencies on how they might mitigate; in other words, 21 how they might manage the risk. Is that -- 22 DR. FRIEDMAN: Yes. But I'd like to 23 suggest that the placement of this substance on that 24 table is not appropriate. When we've looked at 25 others, it seems reasonable to assume a lifetime 61 BARNEY, UNGERMANN & ASSOCIATES 1-888-326-5900 1 exposure, a many-year exposure. 2 DR. FUCALORO: That's a good point. 3 DR. FRIEDMAN: But here we're assuming 4 a lifetime exposure to calculate this risk when there 5 is no lifetime exposure. So I would think it would 6 fall much lower in this table than it's being put. 7 DR. FUCALORO: That's a good point. 8 DR. FROINES: But I think that there's 9 a little apples and oranges going on here. There's 10 one element which is the unit risk value for DEF 11 irrespective of whether lifetime exposure is above 12 perchloroethylene, above formaldehyde, above 13 chloroform, above acid aldehyde, methyline chloride, 14 and even asbestos. 15 And we can get into lots of arguments 16 about how much asbestos people are exposed to on a 17 day in/day out basis and so on and so forth, but 18 we've never questioned any chemical -- we have never, 19 ever, ever done an analysis of the exposure to the 20 substance and used that as a criteria for defining as 21 a toxic air contaminant. Never. 22 DR. FUCALORO: Really? 23 DR. FROINES: Until today. 24 DR. FRIEDMAN: Well, isn't that how the 25 unit risk is determined, by the measure of how much 62 BARNEY, UNGERMANN & ASSOCIATES 1-888-326-5900 1 exposure people are going to have? 2 DR. FROINES: No. 3 DR. FRIEDMAN: Did I misunderstand how 4 the unit risk is calculated? 5 DR. FROINES: No, you're dealing with a 6 theatrical exposure versus an actual exposure. 7 DR. FUCALORO: Yeah. The unit risk is 8 a number that is purely based upon inherent toxicity. 9 In order to get the danger to the population, you 10 must multiply that by the dose. 11 So what you're concerned about -- a 12 real concern and something we -- all but you 13 missed -- I missed it too -- was that this is 14 unusual. This is a pesticide. People don't normally 15 expose to it over an entire lifetime. 16 But you would take that potency 17 factor -- if you noticed the units are in inverse 18 micrograms per meter cubed, and multiply it by dose 19 which would be in micrograms per meter cubed, and to 20 the first approximation that multiplicant will give 21 you the probability that that would have the effect 22 we think it has. 23 So if you multiply the two together and 24 you come up with .1, that means you'd have a 10 25 percent chance -- 10 percent to the population in 63 BARNEY, UNGERMANN & ASSOCIATES 1-888-326-5900 1 a -- of a million people in a 70-year period would 2 end up with cancer. Now, of course that would be a 3 horror, but normally the numbers are much lower than 4 that, thank God. 5 DR. FRIEDMAN: But that milligrams per 6 kilogram, whatever, isn't that assumed that there's a 7 certain duration? I mean, is that for a millisecond 8 or is that -- 9 DR. FUCALORO: Right. 10 DR. FRIEDMAN: Is that for a 11 millisecond? I think there's a duration that gets 12 built into that. 13 DR. FUCALORO: You're right. 14 DR. FRIEDMAN: And I think the duration 15 they assumed is a lifetime exposure at that level, 16 which is not going to happen. 17 DR. FUCALORO: That's right. 18 DR. FROINES: But that's still not the 19 point. The point is -- 20 DR. FUCALORO: Yeah, you're right about 21 that. 22 DR. FROINES: -- that you calculate the 23 number of cancers that would derive from a certain 24 exposure to a certain population. 25 DR. FRIEDMAN: For a certain length of 64 BARNEY, UNGERMANN & ASSOCIATES 1-888-326-5900 1 time? 2 DR. FROINES: Yes. 3 DR. FUCALORO: Yes. 4 DR. FRIEDMAN: And the length of time 5 they assumed here is a lifetime of exposure. 6 DR. FROINES: But the point is to 7 determine the actual risk to the population, you take 8 into account the timing and magnitude of the 9 exposure. This is a potency value. 10 DR. FRIEDMAN: But there's got to be a 11 time factor. Are you saying that exposure -- this 12 potency -- 13 DR. FROINES: I'm saying if this is -- 14 the unit risk for say diesel exhaust is 3 times 10 to 15 the minus 4, if you assume that -- per microgram per 16 cubic meter -- let's assume we have a microgram per 17 cubic meter -- and you assume that people in L.A. -- 18 there are 20 million, and you multiply 20 million 19 times 3 times 10 to the minus 4, you calculate the 20 number of cancers you would expect for a 70-year 21 lifetime of breathing diesel exhaust. 22 Now, if you go and say people breathe 23 diesel exhaust one time a week for six hours a day, 24 when you do the calculation, you'll come up with a 25 different number of people who will develop cancer. 65 BARNEY, UNGERMANN & ASSOCIATES 1-888-326-5900 1 In other words, you plug in the actual 2 exposures into this value to determine the population 3 size at risk so that this is a -- this is a -- in a 4 sense a slope. This is a risk per microgram per 5 cubic meter, but then you put in the exposure to 6 determine the actual population base risk. 7 DR. FRIEDMAN: There's no duration at 8 all in this unit risk? In other words, that exposure 9 for one second is the same as exposure for a 10 lifetime? 11 DR. FROINES: That's not where you take 12 that into account. 13 DR. FUCALORO: You know, I think you're 14 right. I think what these -- the inherent -- what's 15 implicit in here is ambient concentration which means 16 continuous exposure. Am I correct? That's implicit 17 in this number. 18 But Dr. Friedman is pointing out a 19 point that I really don't know the answer to -- but 20 it's something I missed, and he may be right -- is 21 that for pesticides it may not be the right way to 22 go, that people don't really experience that ambient 23 concentration over their lifetimes. I mean, I -- 24 DR. FROINES: But this is -- come on, 25 guys. Get back to the science. When you -- it 66 BARNEY, UNGERMANN & ASSOCIATES 1-888-326-5900 1 doesn't happen for anything. 2 DR. FUCALORO: True. That's true too. 3 DR. FROINES: It doesn't happen for 4 anything. But you take that into consideration when 5 you calculate the population at risk. And so this is 6 not a -- look it: I think that there is a mistake 7 being made in terms of not understanding what the 8 second step of this process is. 9 Because if the value of the -- if you 10 take the unit risk value and you're exposed one hour 11 per day, 30 days a year to .001, the number of people 12 at risk could be vanishingly small. 13 And the risk manager can say, "Okay. 14 I'm not going to do anything about this." Your 15 risk -- your exposure assessment guides your risk 16 management strategy. The risk -- actual exposures do 17 not guide the risk assessment process. 18 DR. FUCALORO: Yeah, I think -- you 19 know, in a way I think you're assuming I'm 20 disagreeing with you. I'm really not in this regard. 21 I think what he's pointing out and I think's 22 correct -- I don't think there's a disagreement 23 here -- is that with pesticides the exposure's more 24 complex in general. It's complex -- let me say it's 25 complex in general but it's more complex in 67 BARNEY, UNGERMANN & ASSOCIATES 1-888-326-5900 1 particular for pesticides, I would think. 2 This is just a guess because, you know, 3 they spray in the spring. Of course diesel exhaust 4 concentration probably varies seasonally also. But I 5 would guess that pesticides would vary even more 6 seasonally than say diesel exhaust, to use that as an 7 example. 8 DR. FROINES: But Tony, all along 9 Paul Gosselin could give you a very articulate speech 10 in which he said 1807 is not even relevant to 11 pesticides because pesticides are not ambient 12 chemicals in the atmosphere. Therefore, we got put 13 in this law and we shouldn't even be here in the 14 first place. I've heard that argument for the last 15 15 years from DPR. 16 MR. GOSSELIN: That wasn't the 17 argument. 18 DR. FUCALORO: There he goes. Froines' 19 setting up straw men again. 20 MR. GOSSELIN: Part of the argument is 21 that the pesticides to at least something are 22 inherently toxic than they are designed to be so. I 23 think we have fully found that there are some 24 pesticides particularly with fumigants that are in 25 the ambient air. The other side of that is that the 68 BARNEY, UNGERMANN & ASSOCIATES 1-888-326-5900 1 pesticides are regulated, which goes to the argument. 2 All that aside, sort of the argument 3 that we historically had about consideration of 4 exposure wasn't something that necessarily totally 5 came out of just our own institutional preference. 6 It was something that was put into the law. 7 DR. FROINES: Yeah, exactly. 8 MR. GOSSELIN: So the document, the way 9 it's been designed, has been crafted in a way to 10 comply with all the points in the law on how we're 11 supposed to provide this document to you to evaluate. 12 And we also have regulation that's 13 specifically, and that's when I put the draft 14 together, Bill actually provided me with a couple of 15 examples that I tried to craft as closely as possible 16 trying to lead in with what specific statutory and 17 regulatory language we have for pesticides under 18 1807. But Bill's -- 19 DR. FROINES: We've been through that 20 before, and we don't agree on those pathos. 21 MR. GOSSELIN: Right. But Bill's point 22 too, is that what principally is the evaluation of 23 whether this document has taken into account all 24 scientific knowledge to assess the relative risk of 25 this pesticide and to come back with us and present 69 BARNEY, UNGERMANN & ASSOCIATES 1-888-326-5900 1 findings. And it is your findings. So -- 2 DR. FROINES: That's my point. 3 MR. GOSSELIN: Right. So there's no 4 disagreement there. 5 DR. SEIBER: Anyway, let me just add a 6 couple things here. 7 DR. FROINES: Can we just have George? 8 DR. SEIBER: Oh, okay. Go ahead. 9 Excuse me. 10 DR. ALEXEEFF: Let me just -- 11 George Alexeeff to clarify a couple of things. 12 Okay. Dr. Friedman is right and I 13 think it's right over here in the sense that the 14 table that we're referring to is a unit risk per 15 lifetime. And that's simply to normalize all of 16 those numbers so that all the numbers can be compared 17 as to how potent of a carcinogen it is. 18 DR. FUCALORO: Inherent potency. 19 DR. ALEXEEFF: Inherent potency of the 20 chemical. That's issue No. 1. 21 Issue No. 2 now comes to exposure. 22 Now, for the pesticides there is a -- on an annual 23 basis a periodic exposure. They have made an 24 assessment in this document of a certain number of 25 exposures occurring; a certain number of applications 70 BARNEY, UNGERMANN & ASSOCIATES 1-888-326-5900 1 and a certain number of exposures. 2 I think it's three or I forget how many 3 it is throughout the year, and then they've averaged 4 that number throughout the year. So the actual 5 exposure concentration during that time period is 6 higher. They average it over 365 days. Okay. 7 Now, the next assumption that is made 8 is that that community will have those several 9 applications each year for 70 years. So that is 10 where the issue comes in, I think, in part of what 11 your concern is. And this is an issue that comes up 12 whenever we're referring to a more site specific kind 13 of a problem. 14 And you'll see in one of the three 15 documents that we're bringing up this year where we 16 actually come up with -- although we calculate unit 17 risks for 70 years and we actually are evaluating a 18 problem, we could actually consider other time frames 19 in terms of actual potential. 20 Where there's a need for mitigation or 21 management, different time frames can be considered 22 when you actually look at the specific site. I'm not 23 saying that's what DPR does, but I'm just saying that 24 you're right. 25 It's 70 years is the potency, but the 71 BARNEY, UNGERMANN & ASSOCIATES 1-888-326-5900 1 application -- it's not assuming that applications 2 are occurring every day. I think that's the major 3 thing. It's assuming they've only occurred in the 4 normal agriculture use and they're averaged over the 5 years. 6 DR. FUCALORO: And in fact, you have 7 several categories -- I'm just looking at my notes. 8 I have to always read them because you tend to write 9 in abbreviations. AADD: the annual average daily 10 dosage. 11 And that would be useful for these long 12 chronic sorts of things. The acute ones of course 13 you'd be more interested in some of the others: 14 seasonal average, daily dosage, and others of that 15 type. 16 So these organizations make note of the 17 fact that some dosages are important to look at the 18 average over a year and then extend it to 70 years. 19 This is the cancer potency in general so -- 20 DR. FROINES: Jim wanted to comment. 21 DR. SEIBER: Well, I think George 22 pretty much stated what I was going to state. 23 I think DEF's in its right place on 24 this table on a unit risk point of view. But I think 25 what Gary and I and maybe others would like to see is 72 BARNEY, UNGERMANN & ASSOCIATES 1-888-326-5900 1 another column over here which takes the exposure 2 which you multiplied by the unit risk to get the 3 number of somethings in a population on a per million 4 basis. 5 And I think if you did that -- it's not 6 part of this table, but if you did that, you would 7 find that DEF is at the margin at best, and we could 8 probably debate whether it's below the cutoff, you 9 know, off the page, or above. And that would be an 10 interesting discussion. I'd like to have that. 11 But it's not part -- as John points 12 out, the law drives us in a certain way. I disagree 13 with it. I think you've got to look at the whole 14 range -- when you make a recommendation to the board 15 that something ought to be done, you've got to look 16 at the whole slate. 17 Now, actually, our findings have all 18 that in it, but the bottom line, the last one that 19 John's referring to, do we or don't we want to 20 classify this as toxic air contaminant, really comes 21 back to where it is on the unit risk chart. 22 DR. BYUS: No, no. Not at all. 23 DR. FROINES: Never has, never will. 24 DR. BYUS: It has nothing to do with 25 it. Read page 78, paragraph 3. Okay? Page 78, 73 BARNEY, UNGERMANN & ASSOCIATES 1-888-326-5900 1 paragraph 3 explains very nicely in the document, I 2 might add, the calculation of the risk. 3 If you go to the findings, the findings 4 state quite nicely what the overall carcinogenic risk 5 is for the population. And they say, if you read 6 finding No. 31, 7 "For non threshold toxic 8 endpoints one in a million risk 9 typically represents the negligible 10 risk standard. Therefore, according 11 to the criteria established in 12 regulations, pesticides with risks 13 greater than 10 to the minus 7 should 14 be identified as toxic air 15 contaminants." 16 And this is 3.9 to 7 times 10 to the 17 minus 7. So it's just barely over what the threshold 18 is. Okay? And that qualifies the risk for the 19 findings. 20 DR. SEIBER: That's what I said. 21 DR. BYUS: So that's really qualified 22 in the findings. It's qualified. We can put it in 23 there if you'd like. 24 DR. FUCALORO: It's not only qualified, 25 it's quantified. And what Jim is suggesting and -- 74 BARNEY, UNGERMANN & ASSOCIATES 1-888-326-5900 1 DR. BYUS: Is another table. 2 DR. FUCALORO: Well, is another column. 3 And you know, if you do it with a spreadsheet, you 4 can sort them as opposed to unit risk factor or 5 overall risk which would be the unit risk factor 6 multiplied by the dosage. And that would -- and that 7 would, I think, you know -- and this is where 8 reconciliation to all our opinions really is at the 9 heart here. 10 DR. FROINES: No. No. 11 DR. FUCALORO: You don't agree? 12 DR. FROINES: I think an absolutely 13 fundamental issue is being lost here. And it is an 14 issue which -- as having been on this panel for 15 15 years, it is an issue which has been argued and 16 argued and argued vehemently during that entire 17 period of history. 18 And this panel until today has always 19 taken the same position. It has always taken the 20 same position, and that is we do not consider 21 exposure -- actual exposure as a criteria for 22 defining whether a substance is a toxic air 23 contaminant or not. 24 DR. FUCALORO: But that's not what 25 anyone's saying. That's not what I'm saying anyway. 75 BARNEY, UNGERMANN & ASSOCIATES 1-888-326-5900 1 I'm agreeing with you. 2 DR. FROINES: The point is -- my point 3 is let's take Jim's suggestion. And we have a table 4 on the right, and it -- we get down to DEF and we 5 find that the actual risk to the population is 6 vanishingly small. Okay? And in fact if you take a 7 lot of these compounds, you might find that's the 8 case. 9 With DEF it's going to be very small 10 and the numbers are 7,000 below or 3,000 or whatever 11 the actual numbers are. All right. You've got the 12 table. Everybody's happy. You've seen it. 13 It doesn't look very important. One, 14 we don't know if next year somebody goes out and 15 sprays pesticides and they spray a whole hell of a 16 lot of it and the exposure levels go way up and that 17 table is no longer relevant because the exposures are 18 very high. Does that mean that we come back and 19 reconsider that as a toxic air contaminant? No. 20 The reason we have always only based 21 our designation of a toxic air contaminant not on the 22 actual exposures is because the inherent toxicity has 23 been the defining criteria. 24 And if you assume on a static basis, on 25 the basis of Jim's study in Fresno and the other 76 BARNEY, UNGERMANN & ASSOCIATES 1-888-326-5900 1 study by Kilgore, that that defines the ambient 2 exposures and we decide whether that that should, 3 therefore, not be a toxic air contaminant, we, in a 4 sense, are buying into the level of science on 5 exposure as it currently exists. And that has never 6 been the policy of this panel. 7 We've said that irrespective of that 8 last column that Jim's talking about -- and I think 9 it's fine -- that we will -- irrespective of that 10 last column we're going to call DEF a toxic air 11 contaminant. 12 DR. FUCALORO: Yeah. And I think the 13 law is clear and says -- and, again, puts a very low 14 hurdle to clear in order to designate something as a 15 TAC, and I think DEF falls well within those 16 parameters. 17 However -- and that's the risk 18 assessment which not only includes inherent 19 toxicity -- in this case a cancer potency factor -- 20 but also dosage. That's the health assessment -- 21 rather risk assessment. 22 Then risk management really needs to 23 know those numbers not only to potency but exposure. 24 They need to know that. And we're validating that 25 also. 77 BARNEY, UNGERMANN & ASSOCIATES 1-888-326-5900 1 Don't forget these reports not only 2 include the publication of -- in the case of cancer, 3 a cancer potency factor, but also dosage -- estimated 4 dosage levels. And that's useful to the people who 5 are responsible for risk management after assessment 6 has been completed. 7 If you misunderstood me in saying that 8 because the dosage is pretty low for DEF that I am 9 suggesting we don't designate it a TAC, you have me 10 wrong on that. 11 Because I think that -- again, I read 12 that law several times because I couldn't believe how 13 low the thresholds were in order to designate 14 something a TAC. 15 And so I think DEF and my guess is 16 almost any darn thing they bring before us will be 17 designated a TAC by the law, within the parameters of 18 the law. And that's the thing I urged at the 19 beginning, is the important thing has to be in the 20 priorities in bringing things to us. That's --- 21 DR. FROINES: Let me just say one more 22 thing about this: Is that we have a policy on the 23 panel that we designate things as toxic air 24 contaminants based on the risk assessment. 25 And Gary's raising a different issue. 78 BARNEY, UNGERMANN & ASSOCIATES 1-888-326-5900 1 Gary is saying that things should be declared -- 2 determined toxic air contaminants based on the 3 existing exposure estimation -- 4 DR. FRIEDMAN: Can I clarify something? 5 DR. FROINES: Let me just finish my 6 thought. 7 And all I'm saying is we can do 8 anything we want. We can change our policy and have 9 the designation be defined by exposure and unit risk. 10 But we've never done that before. So that's what we 11 have to deal with. 12 DR. FRIEDMAN: I just want to say that 13 I would like to thank Craig and others, because I 14 misunderstood what the potency was, and Craig pointed 15 out the definition of oncogenicity and so on on page 16 78. 17 And I didn't think this -- because of 18 my previous misunderstanding, I didn't think that 19 this was -- the measure for DEF was comparable to the 20 others, but I now understand that it is. And so I 21 want -- for the record want to say that I withdraw my 22 previous concern about that. 23 DR. FUCALORO: I move that we expunge 24 the record for the last 15 minutes. 25 DR. SEIBER: I don't think we should 79 BARNEY, UNGERMANN & ASSOCIATES 1-888-326-5900 1 expunge it, because, you know, all this said -- and 2 as I say, it's in the right place. I'm glad they put 3 the table together. But to put things in perspective 4 it's also nice to do the wedding, the marriage, of 5 the exposure and unit risk. 6 Now, the law doesn't tell us we have to 7 do that. No, you're right, it doesn't tell us. And, 8 yes, the DEF usage can go way up. But the fact of 9 the matter with this specific chemical it isn't going 10 to go way up because it's used on one crop and 11 they're not going to expand the acreage, it's just 12 not going to happen. There's 30 years of experience 13 that says that's not going to happen. So it's a 14 little bit different than the other chemicals. 15 MR. FROINES: We're not talking about 16 DEF here. We're talking about a fundamental policy 17 decision on pesticides. Make no mistake about it. 18 You change the way you do things and you're not just 19 talking about DEF. 20 Maybe DEF is the most irrelevant 21 chemical that we'll ever have to worry about, and I 22 tend to think that's probably true. But we have to 23 be careful when we make decisions about what the 24 implications are for other substances where it may 25 not be quite so clear. 80 BARNEY, UNGERMANN & ASSOCIATES 1-888-326-5900 1 So once we go down the slippery slope 2 and say we're going to have this table over here and 3 we're going to decide whether to recommend it as a 4 toxic air contaminant based upon what these numbers 5 multiply out to be, we've made a pretty fundamental 6 policy decision. 7 And I don't think we should -- I 8 personally do not think we should make that decision. 9 I think we should -- I think we should -- Wells can 10 do whatever he pleases because it's his prerogative. 11 But I think -- here's the issue for us: 12 The issue for us is what the panel recommends, what 13 we say. We say DEF should be declared a toxic air 14 contaminant. 15 We could also say but the director may 16 want to take into account issues of exposure. But 17 I'd rather he took that into account rather than our 18 taking it into account. 19 Do you see what I'm saying? 20 DR. FUCALORO: Yeah. But exposure, of 21 course, is part of the document that we receive to 22 approve. Exposure is part of the document and has 23 relevance. 24 Now, again, John, I don't think that 25 that would in any way imaginable to me change a 81 BARNEY, UNGERMANN & ASSOCIATES 1-888-326-5900 1 designation from a TAC to a -- not to be a TAC or 2 vice versa. 3 DR. FROINES: We get exposure documents 4 from ARB, and we never use them. We never use them. 5 We get a full exposure document from ARB. It has 6 never been a basis for determining whether 7 something's a toxic air contaminant. 8 DR. FUCALORO: No, I understand that. 9 But it is a base for mitigation or risk management. 10 And it's our job to look at that and to make sure 11 that the exposure estimate is scientifically 12 reliable. Yeah. 13 DR. FROINES: But the panel has never 14 done the following: The panel has never taken part A 15 from the ARB -- 16 MR. FUCALORO: Right. 17 DR. FROINES: -- and part B and said, 18 "Before we decide to declare this a toxic air 19 contaminant, we're going to multiply by what's in 20 part A by what's in part B." We could do that on 21 every compound that's on this list. 22 DR. FUCALORO: Sure. 23 DR. FROINES: We have never done it. 24 It is not our policy to do so. 25 So if we -- and I'm saying I think we 82 BARNEY, UNGERMANN & ASSOCIATES 1-888-326-5900 1 shouldn't change that policy. And so I think that 2 the issue of whether or not the director decides to 3 use the MOE for his decision making, that's another 4 issue. But for the panel I think we should stay with 5 the policy we have. 6 DR. KENNEDY: Well, I've fumed and 7 stewed over this since my first attendance on this 8 panel. The internal tension here is that we -- we 9 consider these data, we evaluate them, and then we 10 sort of put them aside. And I -- I too have always 11 been uncomfortable about that but figure I'm sort 12 of -- you know, I'm the new kid on the block. So be 13 it. 14 I think what John is saying, you know, 15 represents a very fundamental position of the panel 16 and, you know, I'm willing to accept it and to go 17 along with it. But that doesn't alleviate a lot of 18 my discomfort along the way. I just have to figure 19 out how to live with it. 20 DR. FUCALORO: Well, hearing that no 21 one is prepared to have a panelist revolt, maybe we 22 should move on. 23 DR. FROINES: Maybe we should take a 24 break. Take a break and go back and start over 25 again. 83 BARNEY, UNGERMANN & ASSOCIATES 1-888-326-5900 1 (Recess.) 2 DR. FROINES: One of the issues is that 3 Craig has to leave in about 45 minutes, I think. 4 DR. BYUS: No, no, no. Quicker than 5 that. In about 20 minutes. 6 DR. FROINES: Twenty minutes. 7 DR. BYUS: For an hour. 8 DR. FROINES: So why don't we leave the 9 policy decisions until later and any technical issues 10 that we want to take up with respect to DEF at this 11 point. 12 So Craig, why don't you take the lead. 13 DR. BYUS: All right. I just have -- 14 well, my one issue was the serum cholinesterases 15 value and calculating the NOEL. And that's a larger 16 topic. 17 It's not a problem with methyl 18 parathion, which is also an organophosphate, and 19 we'll get into that later on this afternoon. It's 20 not a problem in that calculation. 21 I don't really think it's a large 22 problem because it doesn't really change the NOELs 23 very much at all and even hardly significantly in the 24 document as it is now. I think it's an important 25 concept, though. I've talked to you about it in some 84 BARNEY, UNGERMANN & ASSOCIATES 1-888-326-5900 1 detail. 2 But I do want to -- you did put in on 3 page -- on your revised documents under "Background, 4 Mechanism of Action," you make this statement at the 5 end dealing with what the function of -- 6 DR. FROINES: What page? 7 DR. BYUS: I don't know what page it's 8 on now. This is the -- gosh, I -- it's the -- this 9 is the changes that were faxed to us. 10 DR. SEIBER: Are you talking about the 11 findings or the actual -- 12 DR. BYUS: The actual document. 13 MR. GOSSELIN: What section? 14 DR. BYUS: I don't know. You sent it 15 to me so -- it says "Background," under "Mechanism of 16 Action." I think it's -- well-- 17 MR. GOSSELIN: I think I got it. 18 DR. BYUS: I don't know exactly where 19 it falls in the new purple one. 20 But the point is it says -- you 21 say, 22 "In addition to plasma it is 23 also" -- this is being the serum 24 cholinesterase -- "is present in the 25 liver, lung, and other organs, 85 BARNEY, UNGERMANN & ASSOCIATES 1-888-326-5900 1 although its physiological function 2 is unknown." 3 I took some issue with that, and I 4 still think that it's -- there are functions for it. 5 And we've discussed -- you know, we can discuss it in 6 terms of metabolism, drugs. There's a large function 7 for it, whether you want to call that physiological 8 or not, I don't know. 9 But my main -- and then you put in a 10 nice little discussion about the atypical genetic 11 variants of plasma cholinesterase. And these people 12 are usually very sensitive to succinylcholine 13 anesthesia, and these people die and go into 14 prolonged apnea. 15 And that was good that you put that in 16 here and actually came up with something I never 17 thought about, whether or not if you are an abnormal 18 pseudo-cholinesterase person, do you then have 19 abnormal sensitivity to organophosphates. That was 20 actually nice to put in here. 21 The thing I disagree with -- and I just 22 want to tell you because I haven't had a chance to 23 see you -- is it says at the end, 24 "It was unlikely that plasma 25 butyrylcholinesterase or erythrocyte 86 BARNEY, UNGERMANN & ASSOCIATES 1-888-326-5900 1 acetylcholinesterase would offer 2 significant protection again paraoxon 3 toxicity." 4 And in a literature search I did it 5 actually does offer protection. I mean, I have a 6 reference here, and it says, 7 "Human butyrylcholinesterase 8 has previously been shown to protect 9 mice, rats, and monkeys against 10 multiple lethal toxic doses of 11 organophosphate and organophosphorous 12 acetylcholinesterase. 13 DR. KENNEDY: That's old stuff. 14 DR. BYUS: Well, yeah, it's old. But 15 it's different than what it says here. I'm just 16 saying that it apparently does protect. I mean, 17 that's not really the point, but this statement in 18 here is wrong. So just delete this last sentence. 19 You say, 20 "The investigators concluded 21 that based on the results with plasma 22 acetylcholinesterase, it was unlikely 23 that plasma butyrylcholinesterase or 24 erythrocyte acetylcholinesterase 25 would offer significant protection 87 BARNEY, UNGERMANN & ASSOCIATES 1-888-326-5900 1 against paraoxon toxicity." 2 MR. GOSSELIN: I think the statement 3 was just parroting back what was out of that paper. 4 DR. BYUS: Right. And I'm telling you 5 from what I've read is that that statement isn't 6 correct. So we might as well make it correct. 7 MR. GOSSELIN: Would you like us to 8 take that sentence out? 9 DR. BYUS: Just delete it. Delete it. 10 And you -- well -- 11 DR. SEIBER: Could I ask you a question 12 about where we are in our discussion? I got a copy 13 of what appears to be a revised set of findings from 14 the DPR group this morning. Is this -- Paul, is 15 this -- 16 MR. GOSSELIN: Yeah, those incorporate 17 the comments you sent in to me. 18 DR. SEIBER: Did you get any, other 19 comments that are incorporated in here? 20 MR. GOSSELIN: Bill Lockett sent in 21 some comments and some issues. I spoke with 22 Dr. Witschi, and he didn't have any other than he 23 thought it was too long, and that was about it. 24 DR. SEIBER: Okay. Well, I guess my 25 suggestion is that we -- unless people have some more 88 BARNEY, UNGERMANN & ASSOCIATES 1-888-326-5900 1 on the actual documents -- which I haven't read these 2 purple ones either, so I don't know. We just got 3 these this morning too. 4 But it seems to me the most important 5 thing is to go back and check out these -- the 6 findings that are recommended for us to look at, 7 because that's really what we've got to come up with. 8 DR. FROINES: Yeah. But before we do 9 that, Craig, are you finished? 10 DR. BYUS: I'm pretty much finished, 11 yes. 12 DR. FROINES: I want to give everybody 13 a chance to deal with the substance before we go to 14 the findings. 15 DR. BYUS: They did make some 16 significant number of changes to the document based 17 upon what people had said and what OEHHA had said, 18 and they faxed us these changes specific -- I mean, I 19 don't know where they fit in but -- so I mean 20 that's -- it's worth considering them, I mean, the 21 fact that they did make these changes in response to 22 the criticism and put them in a document, in a brand 23 new document, very quickly. 24 And I just tried to go over it for 25 consistency, but I have only managed to go through 89 BARNEY, UNGERMANN & ASSOCIATES 1-888-326-5900 1 part of it. But it appears to be a pretty good 2 response to what was stated. 3 DR. SEIBER: And I already said my 4 peace about the table that they put in. I think 5 that's a good addition, and I appreciate your putting 6 that in the document. 7 DR. FROINES: Which table are you 8 referring to? 9 DR. SEIBER: The one with the -- all 10 the unit risks for all the SRP declared TACs. 11 DR. BYUS: My question would be: Is 12 the California Department of Health Sciences -- is 13 George happy with the changes that were made in 14 response to his -- he also prepared a very large, 15 extensive list of criticism or suggestions, and many 16 of them, it appears, were incorporated in here. 17 So are you happy, George? That's what 18 I -- that was my question. 19 DR. ALEXEEFF: Yeah, I also just 20 checked with staff. All of our changes have been 21 incorporated, so we're fine. 22 DR. BYUS: So I think that's it worth 23 to be stated for the record, that all of these 24 changes were incorporated in the new, revised 25 document that's before us, and now we can discuss the 90 BARNEY, UNGERMANN & ASSOCIATES 1-888-326-5900 1 findings or in case anyone else has any except for 2 that one strange thing I found but -- 3 DR. SEIBER: Again, just a quick 4 commentary. I think it's very good that DPR and 5 OEHHA and ARP -- the system seems to be working. I 6 mean, we've had places where it hasn't always worked 7 in the pesticide areas, but I want to state for the 8 record that it appears to me the system is working, 9 and I'm very pleased with it. 10 DR. BYUS: Me too. 11 DR. GLANTZ: I'm just -- 12 DR. FROINES: Peter. 13 I'm going around the room. We'll get 14 to you. 15 DR. GLANTZ: Okay. I don't have a lot 16 to say. 17 DR. FROINES: But it's always so 18 choice. 19 Peter. 20 DR. KENNEDY: No, I'm fine. I think 21 that we've come a long way since that first session, 22 and I'm comfortable. 23 DR. FROINES: Gary. 24 DR. FRIEDMAN: I have nothing to add. 25 DR. FROINES: See. It didn't take long 91 BARNEY, UNGERMANN & ASSOCIATES 1-888-326-5900 1 to get to you. 2 DR. GLANTZ: Okay. Well, actually, I 3 also thought -- I only reviewed the changed things 4 you sent, but those look fine. I only had just one 5 little thing about the executive summary. 6 In all of the other ones that we've 7 done at the end, it said, "Should DEF be listed as a 8 toxic air contaminant," and that got left out. And I 9 think it should say, "Yes." 10 Sort of you can get the OEHHA or the, 11 you know -- I don't know if anybody's got one of the 12 reports from before that we went through with ARP, 13 but you could just copy that last little section and 14 change that to DEF. 15 DR. FROINES: We'll come back to that. 16 We haven't finished that discussion. 17 DR. GLANTZ: And also I think we 18 usually put the table that was put in -- you know, 19 where DEF was listed with the other things, didn't 20 that usually go in the executive summary too? So I 21 suggest that. But it terms of the content of the 22 report I agree with Craig. I think you did a nice 23 job in responding to all the criticisms. 24 DR. FROINES: Wake up. 25 DR. FUCALORO: Oh. Call my name. For 92 BARNEY, UNGERMANN & ASSOCIATES 1-888-326-5900 1 the record, he wasn't asleep he was pondering his 2 notes. 3 Just a -- just to make me feel 4 comfortable with this, the AADDs were purely 5 one-sixth the SAAD; is that right? That's how they 6 computed; right? Just something like that. 7 MR. GOSSELIN: Yes. 8 DR. FUCALORO: That's all I have. 9 DR. SEIBER: I said my peace out of 10 turn. 11 DR. FROINES: Okay. Well, I wanted to 12 make a couple of comments. One problem -- and it 13 occurs in almost all government reviews of 14 chemicals -- is there's a section where people -- 15 that's called toxicokinetics or pharmacokinetics. 16 And people go through and they take all 17 the studies that have occurred, and they look at 18 absorption, distribution, excretion, metabolism, and 19 they look at it in terms of dermal and inhalation. 20 So you know what I'm talking about. 21 Most of those studies, most of those 22 sections in those reports end up being totally 23 unreadable by any normal human being because what 24 they represent is a series of studies. 25 But what I want to know is if you found 93 BARNEY, UNGERMANN & ASSOCIATES 1-888-326-5900 1 a cancer in the colon, what is the distributional 2 information available on that chemical that gives 3 biological significance to finding cancer in the 4 colon. If somebody's got a C14-labeled study and 5 they haven't found any C14 in the colon, you have to 6 say what's going on here. 7 In other words, the toxicokinetics, 8 whether you're looking at clearance or metabolism or 9 distribution, all those things affect the biological 10 nature of the outcome. I mean, that's not said very 11 well. It affects the health outcome and justifies 12 it. 13 So with MTBE and Maltony finds 14 leukemias and lymphomas and we know that the stuff 15 ends up in the spleen, we actually can say that's 16 relevant toxicokinetics, finding the label in the 17 spleen and thinking that actual spleen was an 18 important source of the leukemia lymphoma, that that 19 was an important use of the toxicokinetics. 20 And I can go through this with your 21 staff, but I think that we want to develop 22 toxicokinetic sections that relate to health 23 endpoints, is my take on it. 24 So when you're in here and you're 25 talking about the difficulty of going from hens to 94 BARNEY, UNGERMANN & ASSOCIATES 1-888-326-5900 1 humans, somebody has to write a thoughtful 2 toxicokinetic section about what we know about hens' 3 toxicokinetics for this compound and try and relate 4 that to what you know about humans. 5 And so I think one of the long-term 6 issues for us has to be that we don't just produce 7 sections that are throwaways, because that's what 8 they turn out to be, and that we actually try and 9 link the information. 10 And you folks should read our 11 toxicokinetic section in there, in the MTBE document, 12 because we have actually made an attempt to have the 13 toxicokinetics be relevant to the health outcomes 14 that we were studying as opposed to these long lists 15 of studies that nobody ever can read and everybody 16 always skips over except for the poor guy who wrote 17 it. 18 My -- the second question -- point I 19 want to make is I think it's gotten made a little bit 20 smaller, but this stuff in here about "Increase cell 21 proliferation due to cytotoxicity can result in 22 promotion of tumors by decreasing the time of elder 23 repair of DNA damage, other genotoxic mechanism" -- 24 there's a whole bunch of rhetoric in here. It's kind 25 of the fashionable rhetoric. 95 BARNEY, UNGERMANN & ASSOCIATES 1-888-326-5900 1 And I could give you an equal number of 2 papers on the relationship between cell cycle 3 apoptosis and genetic events to show that in fact 4 that Emanuel Farber in Toronto has shown that cell 5 proliferation in some cases is the reverse of what 6 you might say in here. 7 So I think we have to be careful to 8 avoid the generally popular rhetorical stuff. 9 Because there's an awful lot of good molecular 10 biology that would actually contradict some of this. 11 And I can be happy to provide references to that. 12 Bob Wineberg from MIT, Robert Wineberg, has been 13 writing very articulately about that. 14 The -- I think that the issue of what I 15 hope we can get to in a few months is to not have you 16 say "Not enough is known about the hen" and then 17 basically it's -- you hand wave it away. 18 I'd rather that we -- if it looks like 19 the -- that, 20 "While the hen feeding study 21 has a 30-fold lower NOEL, there are 22 some uncertainties in using it to 23 establish an inhalation NOEL. 24 "First, a cross-route 25 extrapolation needs to be performed. 96 BARNEY, UNGERMANN & ASSOCIATES 1-888-326-5900 1 Second, we need to have a little 2 experience with quantitative 3 extrapolation from hens to humans." 4 So we have a public health issue here. 5 We have an issue where if you do the work, you get a 6 30-fold lowered NOEL. Well, we better figure out how 7 do we do that, how do we deal with that 8 scientifically. So we take that 9 finding and see where it takes us. Do you know what 10 I'm saying? You can't just wish it away because we 11 don't know quite how to handle the hen 12 toxicokinetics. 13 And I wanted to ask George one -- if he 14 had any position on the notion of doing the risk 15 assessment from the high dose point. And I can't 16 quote you from in here, but the document basically 17 says that, 18 "It was not possible to 19 accurately estimate the oncogenic 20 potency or upper bound on the slope 21 for small intestine adenocarcinomas 22 or alveolar or bronchiolar adenomas 23 because the slope estimate is zero 24 when the tumor incidence is only 25 increased at the high dose." 97 BARNEY, UNGERMANN & ASSOCIATES 1-888-326-5900 1 What would be OEHHA's policy on that 2 issue? 3 DR. ALEXEEFF: Could you let me know 4 what page you're on? 5 DR. FROINES: 74. 6 DR. FUCALORO: For the record, can you 7 tell us what you're referring to on page 74, please? 8 MR. FROINES: This is in section 5 on 9 "Oncogenicity," and there is a "Weight of Evidence" 10 discussion -- 11 DR. FUCALORO: Okay. 12 DR. FROINES: -- and a "Quantitative 13 Assessment." And the statement is: 14 "It was not possible to 15 accurately estimate the oncogenic 16 potency (Q1) or upper bound on the 17 slope (Q star) for small intestine 18 adenocarcinomas and alveolar/ 19 bronchiolar adenomas because of the 20 slope estimate as zero when the tumor 21 incidence is only increased at the 22 high dose." 23 Therefore, they used the 24 hemangiosarcomas to calculate the potency. 25 DR. ALEXEEFF: I guess the question or 98 BARNEY, UNGERMANN & ASSOCIATES 1-888-326-5900 1 I have to make an assumption about understanding the 2 issue of the slope estimate is zero. 3 Is that the Q1 is zero? 4 UNIDENTIFIED SPEAKER: Yes. 5 DR. ALEXEEFF: Is that what we're 6 basically saying? 7 UNIDENTIFIED SPEAKER: Q1 asterisks. 8 DR. ALEXEEFF: Well, generally the 9 procedures that we've used in this program is to rely 10 more heavily -- specifically for this reason on the 11 upper 95 percent confidence bound. 12 Because when we have very few dose 13 levels in any of these studies -- even a great study 14 has three or four dose levels -- when you have so 15 few, the estimate of the slope or the Q1 or the 16 maximum likelihood estimate often can go to zero. 17 It's an unstable calculation. 18 But the upper bound estimate on that 19 slope is a stable calculation. And so for that -- 20 that's what one of the major reasons that we have 21 always emphasized the importance of the upper bound. 22 There have been a number of 23 situations -- I'm trying to think. I think acid 24 aldehyde that came before the panel where one of the 25 comments that was submitted was constantly 99 BARNEY, UNGERMANN & ASSOCIATES 1-888-326-5900 1 questioning why don't we focus more on the Q1 in that 2 calculation. 3 And one of the reasons was because if 4 we changed one animal as to whether they had a tumor 5 or not had a tumor, the MLE would go to zero. And so 6 it simply is a, for some reason, unstable 7 calculation, I guess, in the extrapolation procedure. 8 So I guess our -- I don't think it 9 would ultimately change the result of the actual 10 potency here. In this case we would probably try to 11 see if we could determine upper bound slope. 12 But in a situation like this we would 13 probably choose the tumor site that seemed to be the 14 most stable in our calculations as opposed to 15 choosing one that even though we don't use the Q1, it 16 would be nice if we could, you know -- if it's 17 calculatable based upon the data. 18 DR. FUCALORO: Can I ask a question to 19 follow up on that? The decision to use Q1 asterisk I 20 guess as the upper bound because of this difficulty 21 with Q1, is that based upon -- I mean, you do it. 22 You said you do it. But you are not a trained 23 statistician. 24 But are the statisticians in your 25 office satisfied with that particular procedure? 100 BARNEY, UNGERMANN & ASSOCIATES 1-888-326-5900 1 DR. ALEXEEFF: Yeah, they are very 2 satisfied. And for the most part I think what is 3 interesting is when you look at Q1 and Q1 star in the 4 calculation, what is sort of the range between those 5 two values. 6 Like in this case if you look at for 7 DEF, 9.2 for the Q1, which is the MLE 10 to the minus 8 6 and then 1.6, you can see they're actually very 9 close. The upper bound is not far from the line 10 here. So it's a stable calculation. 11 And you can actually look at a number 12 of these. So if you were obtaining upper bound 13 values that were five- or tenfold different from the 14 maximum likely estimates, then we would worry about 15 what's happening in the calculations. 16 So we don't think we're adding a lot of 17 conservatism in sticking with the upper bound, but 18 it's actually the statistical argument that our 19 statisticians give us that it's more stable to stick 20 with the upper 95% UB. 21 DR. FUCALORO: The reason I ask the 22 question is that very often in use of statistics you 23 can make a lot of mistakes, and that's why I really 24 always want to check with someone who's an expert in 25 the area before we proceed. 101 BARNEY, UNGERMANN & ASSOCIATES 1-888-326-5900 1 DR. FROINES: I just want to make one 2 point about that just in terms of the future. That 3 was very helpful, George, and I don't mean to put you 4 up as a straw person at all, but be careful about the 5 writing being dismissive versus trying to explain the 6 position in a thoughtful way. 7 We all, when we're tired -- it's easier 8 to get rid of things than to carefully define the 9 reasons why you were doing what you were doing, and I 10 think that will just improve the overall quality of 11 the documents. It's a minor point. 12 DR. ALEXEEFF: I think just as a 13 follow-up, one of the -- and I can research this and 14 come back at some point and talk about it. One of 15 the criteria that we use in our calculations is the 16 Chi square fit of the line to the points, and there's 17 some other information that comes out in the 18 analysis. 19 And that's usually what we follow as to 20 whether or not one can actually fit a legitimate line 21 to those points. I don't know what would happen for 22 this particular data set, but that might be one way 23 of looking at it that probably Chi square value would 24 show it's not a good fit so -- 25 DR. FROINES: He just did that for your 102 BARNEY, UNGERMANN & ASSOCIATES 1-888-326-5900 1 benefit. 2 DR. FUCALORO: Listen, I'm -- 3 DR. FROINES: He wanted to show he 4 knows some statistics over there. 5 DR. FUCALORO: Well, he knows more than 6 I do if he knows any. 7 DR. FROINES: Well, let's follow Jim's 8 suggestion, and hopefully we might be able to try to 9 finish this by the time we break, which is to go to 10 the issue of the findings. 11 Jim? 12 DR. SEIBER: Well, we just got the 13 findings today, so we haven't had a chance to really 14 read them in detail. And I read them over, and from 15 my point of view they've incorporated practically all 16 the recommendations I had made in a fax that I sent 17 to Paul, I believe, last week. 18 And there's a few little typographical 19 things that I've picked up in a very quick reading 20 that we can maybe hand to you or something like that. 21 But really, John, aren't these our -- these are our 22 findings at this point now. We make the final 23 changes. We don't have to go back to the DPR. 24 So let me just be a little more 25 specific. Since I was the lead on the environment 103 BARNEY, UNGERMANN & ASSOCIATES 1-888-326-5900 1 fate and exposure part, I'll just comment on that and 2 say that I agree with the points that are written 3 down here in the draft findings with just -- again, a 4 few minor things, one of which was a personal problem 5 I have with No. 3 that says DEF breaks down by photo 6 oxidation. 7 It really isn't proven that it's photo 8 oxidation. That's one of several possible 9 mechanisms. So since we want to make sure our 10 science is as right as we can get it, that's the kind 11 of change that I'll write down and hand to you or to 12 Paul. 13 MR. GOSSELIN: Who actually handles the 14 changes? 15 DR. FUCALORO: A moment, please. 16 If we're asked to approve the findings 17 in this report, I think the best we can do today is 18 provisionally, because we were just handed this 19 thing, and I really -- I think we really require 20 reading through it carefully. 21 Now, we can, I suppose, do something 22 which says if we have no objections by a time 23 certain, maybe a week from now, it just goes forward. 24 But I do -- I'm not prepared to say definitely. I 25 just haven't read it and thought about it. 104 BARNEY, UNGERMANN & ASSOCIATES 1-888-326-5900 1 DR. GLANTZ: Well, these are -- I 2 should say they're pretty similar to -- how are these 3 different from what you sent us a while ago? They 4 look similar to me. 5 MR. GOSSELIN: Actually, it's largely 6 the same with a lot of clean-up and edits. The 7 OEHHA's findings that were presented at the last 8 meeting probably account for 80 percent of the 9 findings. 10 It was actually used as the foundation. 11 The beginning was changed with some of the 12 environmental fate information and then the end with 13 some of the specific references to the statutes was 14 changed, and then the toning and thing was changed. 15 So it was essentially largely OEHHA's findings. 16 DR. FROINES: As a procedural matter 17 what I would suggest based on Tony's comments is that 18 we go through them now to the degree we can before 19 lunch. 20 We then say -- say after lunch we say, 21 "Well, I want more time," and then we say if -- 22 "We'll give you until next Friday to get comments in 23 and after that the barn door closes," essentially. 24 So just so we don't let it drag on. 25 MR. LOCKETT: Mr. Chairman, I just 105 BARNEY, UNGERMANN & ASSOCIATES 1-888-326-5900 1 wanted to add that we're prepared today. We have the 2 revised findings on disk and have a computer here. 3 So as you make changes, we can update them and print 4 them out. 5 DR. FROINES: The findings I have here 6 that are not -- have not incorporated Jim's changes. 7 MR. LOCKETT: Yes. To my understanding 8 is they have. 9 DR. FROINES: Well, I'm looking at a 10 set of findings here that I can tell you don't have 11 the changes. 12 DR. GLANTZ: Well, can I make a 13 suggestion? Why don't we go through and discuss what 14 we have here and then maybe during the break you 15 could make up a kind of red-line strike-out version 16 that makes the changes obvious. 17 Because my sense -- I mean, I didn't 18 memorize them, but I did look at them when you sent 19 them to me, you know, a couple weeks ago, and I 20 didn't see any substantive changes between those and 21 these, at least to the things I cared about. 22 So maybe if you could during lunch make 23 something up that highlights exactly what you changed 24 from what you sent to us a couple weeks ago, that 25 might facilitate things. 106 BARNEY, UNGERMANN & ASSOCIATES 1-888-326-5900 1 DR. FRIEDMAN: I would like to make 2 that as a constructive suggestion for the future that 3 if we could get -- you know, I read the findings on 4 the plane coming down, the previous version, and if I 5 could have just -- I'm sure that there's very little 6 change. If I could have just seen what the changes 7 were when we were handed this, it would have made 8 things much simpler. 9 DR. FUCALORO: You mean a red-line copy 10 which -- 11 DR. FRIEDMAN: Yeah, something which 12 shows what changes or additions were made. 13 DR. GLANTZ: Anyway -- 14 DR. FROINES: There's a document that 15 you apparently don't have -- 16 DR. GLANTZ: We'll pick this up at the 17 door. 18 DR. FROINES: -- and we'll give it to 19 you. 20 DR. GLANTZ: It looks like the same 21 thing. 22 DR. FROINES: Let's go through -- 23 DR. GLANTZ: This is the one at the 24 door. 25 DR. FUCALORO: Which is the latest 107 BARNEY, UNGERMANN & ASSOCIATES 1-888-326-5900 1 version: the one at the door or the one which has at 2 the upper right-hand corner "with Seiber's edits 3 included"? 4 MR. MATHEWS: I wrote that. 5 DR. FUCALORO: What? 6 MR. MATHEWS: I wrote that in for you. 7 DR. FUCALORO: Oh, you wrote that in 8 for me. I see. 9 DR. GLANTZ: Except that's different 10 than the one at the door. Because I picked this one 11 up at the door, and it's different than the one he 12 has. 13 DR. FUCALORO: Is this different? 14 DR. GLANTZ: Yeah. That's your 15 writing. 16 DR. FROINES: Well, I think that what 17 we need, Peter, is we need the most recent DPR draft 18 with Seiber's changes included. And that represents 19 the most recent. 20 DR. SEIBER: That's what I think I 21 have. 22 DR. FROINES: That's what I have. 23 DR. SEIBER: And John, I -- during the 24 previous discussion, I just sat here and I went back 25 and forth, and I saw that they had in fact made the 108 BARNEY, UNGERMANN & ASSOCIATES 1-888-326-5900 1 changes. At some time my suggestion was vague. I 2 said reword the sentence, and they reworded it. 3 DR. FROINES: Folks, we've got a 4 problem here. We've got to get this -- 5 DR. GLANTZ: Can I make a suggestion? 6 While the staff figures out what the latest version 7 is -- because the one that he has and the one that I 8 have which allegedly are both the latest version are 9 different -- 10 DR. FUCALORO: At least printed 11 differently. 12 DR. GLANTZ: -- why don't we talk about 13 the issues that are raised, because there are a 14 couple of issues in here. And then while we're 15 talking about the things more generally, then the 16 staff can figure out which one we want to actually 17 approve or act on. 18 DR. FROINES: Okay. Does everybody 19 have these with the handwritten comments? 20 DR. GLANTZ: No. 21 MR. MATHEWS: I'm producing them right 22 now. 23 DR. GLANTZ: Okay. 24 DR. FROINES: Okay. Stan, why don't we 25 go ahead with what you have in front of you. 109 BARNEY, UNGERMANN & ASSOCIATES 1-888-326-5900 1 DR. GLANTZ: Okay. Well, I just had 2 one or two issues, one of substance, and it gets back 3 to this NOAEL which I really dislike intensely. 4 The -- I'm very uncomfortable -- I 5 mean, I was very pleased to see that the NOELs were 6 added to the report as we requested last time and 7 that they're in the findings. 8 But to me I'm very squeamish about 9 going along with this idea of a no-observed adverse 10 level -- adverse effect level, because I think that's 11 pretty subjective. 12 And personally I would be a lot more 13 comfortable if we took the NOAELs out of the 14 findings. If they want to leave them in the report 15 for reference, I mean, I just as soon they weren't 16 there too, but I can swallow that. 17 But I mean, that's really a regulatory 18 judgment. And I am uncomfortable with us endorsing a 19 regulatory position. I mean, I'm willing to be 20 talked out of it, but I would be more comfortable if 21 those things were deleted. 22 If you look through the findings, they 23 have the NOAELs in each of the items. It starts 24 around number -- it's like No. 18 through No. 24. 25 And then it keeps going to 25. So that's the one 110 BARNEY, UNGERMANN & ASSOCIATES 1-888-326-5900 1 change that -- the one substantive change that I'd 2 like to suggest. 3 DR. FUCALORO: There is a sentence in 4 there which gives me pause. I guess I don't mind the 5 NOAEL and the NOEL both being reported, but they did 6 say something which implies regulation. It says 7 "report would also provide the basis for risk" -- 8 DR. GLANTZ: What number are you on? 9 DR. FUCALORO: 18. -- "basis for risk 10 management. The inclusion of NOAEL provides the 11 information required for risk mitigation." So you 12 may not like it, but it appears that they're using it 13 for purposes of mitigation. 14 Is that correct? 15 DR. GLANTZ: No, I understand that. 16 But it just seems to me -- I mean, there's a certain 17 amount of subjectivity as we talked about at the last 18 meeting in the -- when you put the A in there. And I 19 just as soon let the risk managers take 20 responsibility for that without pinning it on us, 21 because I'm personally uncomfortable with it. 22 I mean, I think the -- in terms of the 23 risk assessment and the hazard identification the 24 NOEL is the important thing. And if DPR wants to 25 say, "Well, we're willing to set -- we're willing to 111 BARNEY, UNGERMANN & ASSOCIATES 1-888-326-5900 1 accept a certain amount of adverse effects or effects 2 because we don't think they're that important," you 3 know, I think that's up to the regulators to do. 4 But I personally would rather not have 5 them saying, "Well, the SRP said this is the number 6 that you should use." Because I don't know if I 7 agree with that number. 8 DR. SEIBER: Well, I thought the NOEL, 9 NOAEL debate relative to cholinesterase inhibitors 10 was kind of an unsettled area, that there's people 11 that kind of feel on both sides. 12 And the way I understand it -- and I'm 13 not a toxicologist -- is that you can demonstrate an 14 inhibition but you can't show there's any adverse 15 effect associated with that inhibition. And that 16 seems kind of important to me. 17 So I don't know whether I'm ready to 18 just take it out. I think we ought to put it in 19 perspective, but I don't know whether I'd want to 20 just take it out of the document. 21 DR. GLANTZ: I wouldn't take it out of 22 the -- I'm willing to leave it in the document. 23 DR. SEIBER: Or even in the findings. 24 DR. GLANTZ: But I'd rather not have it 25 in the findings. 112 BARNEY, UNGERMANN & ASSOCIATES 1-888-326-5900 1 DR. FRIEDMAN: If the pulse rate goes 2 up two beats per minute, that's an effect, but it's 3 not necessarily an adverse effect. I don't see the 4 problem with leaving in the adverse as a meaningful 5 distinction of what's harmful and what's not. 6 DR. GLANTZ: Well, anyway, what do you 7 think? Or what do the other guys think? I mean, I'm 8 not going to, like, kill myself over this, but it 9 bothers me. 10 DR. FROINES: Well -- 11 DR. FUCALORO: I'm sorry. 12 Clarification from Paul regarding how it's used for 13 mitigation. I mean, we certainly want to be on the 14 record as accepting NOAELs as the best available 15 information if in fact they're used for mitigation. 16 MR. GOSSELIN: I think after the last 17 meeting we went back and Dr. Glantz actually had a 18 couple of comments that enlightened us about sort of 19 where we were both talking maybe past each other 20 about this document providing the best science that's 21 known about assessing the risk of death. 22 And you know, we've been using -- 23 pretty much preparing these documents for risk 24 management purposes as a regulatory agency. But for 25 your purposes to look at the science, the NOEL, in 113 BARNEY, UNGERMANN & ASSOCIATES 1-888-326-5900 1 sort of its purest sense would be the plasma serum 2 level, not the NOEL that we would typically use as a 3 regulatory endpoint. So we felt that it was 4 appropriate to go back and make that distinction 5 between the two. 6 And I think in each case you'll see 7 it -- we do take a look at cholinesterase inhibition 8 on a case-by-case basis. And that's why we made the 9 change here, to reflect that NOAEL would be the level 10 that we would typically regulate from. 11 But the report did have all the 12 sufficient information to derive the NOEL where the 13 lowest effect is seen, and that's in serum. So I 14 don't know if that answers your question. 15 DR. FROINES: I -- here's what I 16 think -- a late entry into the game: The first thing 17 is it would be useful if in the findings we 18 actually -- and I don't see it, but I may -- I may be 19 missing it -- if you defined and said, "For purposes 20 of these findings, the NOEL is defined as blah, blah, 21 blah. For purposes of the findings, the NOAEL is 22 defined as blah, blah, blah." So you say to the 23 reader what it is you are -- what your subsequent 24 numbers are based on. Now -- so that's just a point 25 of clarification. 114 BARNEY, UNGERMANN & ASSOCIATES 1-888-326-5900 1 The question then becomes whether or 2 not the NOAEL, NOEL for plasma cholinesterase is an 3 adverse effect or not. And apparently US EPA, from 4 what Craig says, considers it an adverse effect. 5 MR. GOSSELIN: Actually, they did come 6 out with their policy this week restating that they 7 do use plasma cholinesterase, but they did, in their 8 summary, allude that even though that didn't elicit 9 an adverse effect, because of the potential of other 10 things, that's why they do use it. So they even 11 acknowledge that. It's not -- it's still a very 12 difficult complex. 13 DR. FROINES: I understand. I 14 understand perfectly. 15 Now, the fact of the matter is if one 16 could relate, say, that the serum -- the plasma -- 17 the cholinesterase level with brain cholinesterase 18 level, central nervous system levels, and you had a 19 good sense of the relationship to the one exists, 20 which probably there is one that exists, then you 21 actually have a way to talk about one as a measure of 22 an adverse effect rather than simply a measure of 23 exposure because you think that the central nervous 24 system effects do represent something that may have 25 clinical implications so that what you're really 115 BARNEY, UNGERMANN & ASSOCIATES 1-888-326-5900 1 saying is that the linkage between a biomarker and a 2 health outcome has not been quantitatively defined to 3 everybody's satisfaction. 4 MR. GOSSELIN: I would say even further 5 in this specific instance -- 6 DR. FROINES: I understand. That's all 7 I'm talking about. I'm not talking about 8 organophosphates in general. 9 And so but one could conclude that to 10 the degree that an organophosphate producing an 11 inhibition in blood may have implications for other 12 target organs, that it is a potential marker of 13 adverse effects. 14 Having said all that, it seems to me 15 that one could argue that it isn't simply a NOEL. It 16 is a -- at least a potential NOEL, NOAEL based on 17 improved toxicokinetic understanding of the 18 relationship between and validation of that 19 relationship. 20 Is that fair? 21 MR. GOSSELIN: I believe so. 22 DR. FROINES: Does anybody strongly 23 disagree with that? 24 DR. KENNEDY: I sort of do. I have 25 some concerns about how far this goes. I'm still 116 BARNEY, UNGERMANN & ASSOCIATES 1-888-326-5900 1 chewing on the issue of the hens. Certainly, you 2 know, the transition of information across species is 3 an unknown, is an area of necessary additional 4 research. But on what basis do we make specific 5 recommendations or directives for that sort of 6 activity? 7 I think similarly the -- although this 8 potential exists, it has not been defined 9 experimentally. It's something that we perhaps would 10 like to see, and is it -- is that sort of 11 characterization within our purview? Is it something 12 that we need to include? I don't know the answer, 13 but I -- but I'm a little insecure about doing that. 14 MR. FROINES: I think that it -- the -- 15 at some level we're talking about the validation of a 16 biomarker for some other marker or endpoint. And 17 what's been said is that there is -- DPR saying is 18 that "We think that there is inadequate validation" 19 and the US EPA is saying, "Well, we think it may be 20 somewhat better. But as a policy decision it may not 21 be better, but we're going to use it." So we're 22 talking about angels on the head of a pin here a 23 little bit, I think. 24 MR. GOSSELIN: This again is going to 25 be -- I mean, we acknowledge that this is a real 117 BARNEY, UNGERMANN & ASSOCIATES 1-888-326-5900 1 complicated, important topic and is going to be 2 probably one of the more interesting discussions 3 we're going to schedule for the workshop. 4 But I wouldn't -- on the other side 5 too, I wouldn't categorize our position as an 6 absolute position without viewing what the entire 7 database shows for each compound. 8 DR. FROINES: What happens if we take 9 the NOEL as a NOAEL to your numbers? 10 MR. GOSSELIN: If you take the NO -- 11 DR. FROINES: If you take the NO -- 12 blood cholinesterase, how does it change your 13 numbers? 14 MR. GOSSELIN: I still don't think 15 it -- I think the MOEs is still over a thousand. 16 DR. GLANTZ: Uh-huh. 17 DR. FROINES: Yeah. I don't think I'd 18 necessarily leap that way. But one could take this 19 discussion and write this up in your document and 20 say -- describe what some of the issues are and 21 describe what the outcome would be and say this 22 requires further study or something, further 23 evaluation. 24 DR. GLANTZ: Well, I think -- 25 DR. FROINES: In other words, it's a 118 BARNEY, UNGERMANN & ASSOCIATES 1-888-326-5900 1 compromise. I'm looking for a compromise. 2 DR. GLANTZ: Well, no. The -- and I 3 think that's in the document more or less -- maybe 4 not in exactly those terms, but that's in the 5 document. 6 It's just -- and I'm not proposing that 7 we take it out of the document. I'm happy to leave 8 it there. But I think that there is a -- there's -- 9 there are a bunch of important policy issues, in my 10 view, connected with whether to accept this idea of 11 the NOAEL which I personally am uncomfortable with. 12 And so I would feel more comfortable, 13 as I said, if we didn't put them in the findings and 14 just gave them the NOELs and say that's what we're 15 finding. 16 If the department, then, as a matter of 17 policy, wants to use these other numbers, they're in 18 the report. The differences, I think, are explained 19 in the report. 20 And I mean, it may be that we'll, after 21 the workshop, reach a different comfort level with 22 this. But I just -- I think it's giving the 23 committees this idea of a NOAEL which at least I'm 24 not comfortable with. 25 Because my whole view of the NOEL is by 119 BARNEY, UNGERMANN & ASSOCIATES 1-888-326-5900 1 being cautious and saying no observed effect, you're 2 saying -- you're kind of building in the fact that 3 there may be a lot of things going on that you don't 4 know about. 5 DR. FROINES: But Gary's 100 percent 6 correct. Effects occur in physiologic systems that 7 have no significance whatsoever. 8 DR. GLANTZ: No, I understand that. I 9 understand that. But also there are things where 10 you -- where you see small changes that people think 11 are no big deal that later they decide are a big 12 deal. And the -- and especially when you're talking 13 on a population basis. 14 And so to me the conservative approach 15 is to say we're going to say where we can't find 16 anything. And there may be something we're missing, 17 but at least everything we've looked at we can't find 18 anything. 19 And that's a fairly clear endpoint. 20 And we're not being forced to make a judgment about 21 is this change in heart rate or is this change in 22 blood pressure or is this change in cholinesterase 23 inhibition of biological importance. Because I just 24 feel very uncomfortable making that judgment. 25 DR. FROINES: Well, I would be willing 120 BARNEY, UNGERMANN & ASSOCIATES 1-888-326-5900 1 to make -- to go out on a limb on one level. It 2 seems to me -- 3 DR. GLANTZ: It won't affect the 4 overall conclusions of the report. 5 DR. FROINES: Somebody's coming in with 6 a 40 percent inhibition of blood cholinesterase and 7 one says that's like somebody's blood pressure going 8 up two points. 9 I'd say he's smoking dope. Because I 10 suspect -- significant inhibition of blood 11 cholinesterase, something else is happening 12 psychologically that's not good. 13 MR. GOSSELIN: We discussed at the last 14 meeting we do as a regulatory threshold require 15 cholinesterase monitoring of work as using these 16 compounds and other compounds. 17 And if their cholinesterase is 18 depressed typically more than 20 percent, it prompts 19 and sets up a red flag that they're pulled out of 20 that work environment, and it prompts an 21 investigation as to what's going on. So we don't and 22 we haven't historically dismissed depression of blood 23 cholinesterase depression as a biomarker. 24 DR. GLANTZ: Yeah. But, see, I -- I 25 think that's fine, but I see that as sort of a 121 BARNEY, UNGERMANN & ASSOCIATES 1-888-326-5900 1 different question. And that is a question of like 2 when you're given the stuff and you're out there in 3 the regulatory situation having to operationalize 4 this, you know, you might say, "Well, we're going to 5 make a -- we're going to do a risk benefit analysis 6 and be a little bit less cautious than saying no 7 effect and we'll say it will have a little effect 8 before we trigger an investigation." But I see that 9 as sort of a different -- that's a regulatory 10 question. 11 DR. FROINES: Paul, what's your NOAEL 12 based on? 13 MR. GOSSELIN: Actually, it's written 14 in here. 15 DR. FROINES: Yeah, I know. But I'm 16 not looking -- 17 MR. GOSSELIN: It's clinical signs: 18 "impaired retinal function, hematological changes, 19 adverse adrenal changes: increased weight, fatty 20 droplets." 21 DR. FROINES: See, I agree with you, 22 Stan, to a certain degree. I think it's fine to 23 leave the NOAEL in the document, but I think we do 24 have to differentiate from the fact that those are 25 not subtle adverse effects. They're not looking at 122 BARNEY, UNGERMANN & ASSOCIATES 1-888-326-5900 1 enzyme inhibitions, for example. They actually 2 represent clinical findings. 3 So -- and so most of us would argue 4 that something is probably happening in between 5 nothing and those adverse effects just listed. And 6 it would be nice to know what they were because then 7 you can be more protective if you could identify 8 them. 9 So I think that having the NOEL values 10 in is really quite important especially if you define 11 what the NOEL value is and what the NOAEL values are. 12 And hopefully we can improve on that over time. 13 So in some ways I would just like to 14 make sure everything's out there and clear in our 15 findings and in the executive summary and then we 16 don't necessarily have to take out the NOAELs so long 17 as people know what it is. 18 DR. SEIBER: You said you would add 19 something, a definition or something, to put it in 20 perspective. 21 DR. FROINES: I just said they should 22 put something in that would say that "NOAEL for the 23 purposes of DEF is blah, blah, blah, blah, blah. And 24 the purposes of -- the NOEL for purposes of DEF is 25 blah, blah, blah, blah, blah." 123 BARNEY, UNGERMANN & ASSOCIATES 1-888-326-5900 1 And then you've got -- everybody who 2 reads it knows what you're talking about. And the 3 reader says -- can look at it and say, "Okay. I 4 understand that. I might worry a little bit about 5 this plasma cholinesterase level as having some 6 significance and not being benign." 7 DR. GLANTZ: I guess the part about 8 that -- and again -- the part about that that bothers 9 me, though, is if I was reading this report as just 10 sort of a guide or some guy on the street picked it 11 up and read the findings, that I would take that then 12 as the SRP saying we think these effects are not 13 adverse. And that's the part that bothers me. 14 DR. FROINES: Well, then maybe we need 15 to put a sentence or two in that -- he needs to put a 16 sentence or two in that says these -- there may be a 17 relationship between effects in the central nervous 18 system where cholinesterase is inhibited that may 19 mirror these effects and they cannot be considered 20 without -- 21 DR. KENNEDY: To leave it out entirely 22 you're abrogating your responsibility to recognizing 23 the limits of your understanding. I agree totally 24 with -- 25 DR. GLANTZ: Well, I would argue it the 124 BARNEY, UNGERMANN & ASSOCIATES 1-888-326-5900 1 other way. I mean, I think the NOEL is the way to 2 recognize the limits of your understanding. Because 3 I think -- I mean, to go with the NOAEL, I think we 4 would then want to have a whole big discussion of do 5 we agree what constitutes an adverse effect. 6 Whereas, if you say no effect, you 7 can't see anything happen, that's a pretty clearly 8 defined endpoint. And I think everybody could agree 9 that if you can't find any effect, it's unlikely -- 10 you know, then you didn't find any effects. You 11 don't have to argue about whether or not it's of any 12 biological importance. 13 Whereas, I think for these other things 14 we've got to argue about, well, you know, do we agree 15 with DPR about what constitutes an adverse effect. 16 And I'd rather -- and I think if we say, you know, 17 this is the definition of an adverse effect that's 18 being used, we're implicitly endorsing that 19 definition. And I would just as soon not do that. 20 But I think that the report -- again, I don't have 21 any problem with leaving it in the report. And if we 22 approve the report, we approve the report. 23 MR. FROINES: I don't agree with you. 24 DR. GLANTZ: Okay. 25 DR. FROINES: I think we do have an 125 BARNEY, UNGERMANN & ASSOCIATES 1-888-326-5900 1 obligation to say these are the -- these are the 2 endpoints that they consider adverse, and we either 3 should agree with them or not. And if we don't, we 4 should say why. 5 I think it's our obligation to accept 6 theirs or not accept them but give reasons why we do 7 or don't. It's all got to be transparent, out on the 8 table is all I'm saying. So taking away one-half of 9 this is, I think -- 10 But I think we need to make sure of the 11 definition of the two and then some discussion. 12 DR. FRIEDMAN: With making the point 13 that there may be some adverse effects at lower 14 levels in the NOAEL that haven't been detected yet. 15 DR. GLANTZ: How did you guys decide 16 what constituted an adverse effect? 17 MR. GOSSELIN: In -- 18 DR. SEIBER: In experimental animals, 19 you mean? 20 MR. GOSSELIN: Yeah. 21 DR. SEIBER: I thought you just 22 answered that. 23 MR. GOSSELIN: Yeah. 24 DR. SEIBER: Didn't you? 25 MR. GOSSELIN: I mean, it was from the 126 BARNEY, UNGERMANN & ASSOCIATES 1-888-326-5900 1 various studies on the acute and subchronic -- and 2 actually, Gary pointed out what I read to you earlier 3 was the subchronic signs that were listed in No. 25. 4 Generally what's looked at is all the 5 studies that are in, trying to look at not just each 6 one on its own merits but also a pattern that may 7 develop and looking at whether there's a consistent 8 pattern over the dosing, whether those -- on one hand 9 whether those signs continue with increased dosage 10 you'd expect and whether you start to get into 11 clinical measurable signs. 12 DR. GLANTZ: Right. But the question 13 is how big are they? You know, like how big an 14 impaired retinal function are you willing to call not 15 adverse? How much hematological change do you call 16 not adverse, you know? And what's the justification 17 for using those values? 18 DR. FROINES: Well, I think that the 19 real issues is also that DEF is an adverse effect, 20 presumably. But we try and -- if you can, what you 21 want to do is go away from that extreme to the place 22 where you think some change is occurring that isn't 23 just a physiologic homeostasis where you actually are 24 doing something that moves you out, that affects your 25 homeostatic patterns. 127 BARNEY, UNGERMANN & ASSOCIATES 1-888-326-5900 1 So what you're saying is what is that? 2 And we would like that to be relatively early because 3 presumably if you prevent that, then you prevent 4 anything else that's going to follow up to death. 5 So the ones he picked are pretty far 6 along the line. And the question is what could we 7 pick that would have a lower -- would be a lower 8 adverse effect level. Would lead measure ALAD 9 inhibition, for example, as an enzyme inhibition. So 10 that's a reversible biochemical process. 11 So it seems like the plasma 12 cholinesterase is in fact a good early adverse effect 13 that one could use. It seems to me. It doesn't mean 14 it has to be tied -- all the toxicokinetics has to be 15 tied down, but it's not a benign effect, I think 16 nobody would argue. I wouldn't think. 17 So anyway, I'm getting into a 18 subject -- so I think that the discussion we're 19 having here is what should be in the document so it's 20 clear to everybody who reads it. That's all I'm 21 saying. 22 DR. GLANTZ: Well, no, I don't 23 disagree. I mean, I think that's in the document. 24 DR. FROINES: No, in these. 25 DR. GLANTZ: I guess. But see, then 128 BARNEY, UNGERMANN & ASSOCIATES 1-888-326-5900 1 the thing I have if you take all these different 2 signs and things that they're measuring, I think we 3 would need to spell out what exactly is the threshold 4 for calling each one of these things adverse, which 5 I'm pretty sure is in the document. 6 MR. GOSSELIN: Yeah. In the document 7 it talks about the number of species -- the number of 8 the animals that were tested, the number that were 9 positive. And so each one of those things were 10 specifically described in -- 11 DR. GLANTZ: Right. But see, then -- 12 but the question -- and I mean, I seem to not be in 13 the majority to be worried about this. But the 14 problem is I think I'm just concerned about us 15 saying, "Okay. We accept those definitions of where 16 you get the number that you should consider of 17 concern" without, you know, a debate about, "Okay. 18 Well, how much of a change in retinal function would 19 we call 'adverse'?" 20 Do you understand what's concerning me? 21 And I think the way to punt on this, I mean, is to 22 leave it in the document just the first time out -- 23 it's fairly well explained in the document -- but to 24 not endorse the idea of the no observed effect level 25 quite yet. 129 BARNEY, UNGERMANN & ASSOCIATES 1-888-326-5900 1 If this is going to be something that's 2 going to come up in this workshop we're going to have 3 in a couple of months, maybe after that then I would 4 be more comfortable with doing it. 5 But I think that there's actually a big 6 policy decision about whether you should use NOELs or 7 NOAELs, and I'm uncomfortable with it, you know. And 8 I think to put them in the findings is for us to 9 basically be endorsing that approach and those -- and 10 those -- those definitions of what's adverse. 11 DR. SEIBER: See, I don't feel as a 12 panelist that I'm endorsing that by putting that in 13 there particularly if we define. I think if we set 14 out what's known about this chemical at this point in 15 time, I don't feel that I'm endorsing a position. 16 DR. GLANTZ: But the adverse -- well, 17 no. But what you're doing is you're endorsing your 18 position to what constitutes "adverse effect." And 19 we haven't really gone -- except for the 20 cholinesterase inhibition, we haven't had a big 21 discussion of constitutes and adverse effect on every 22 single one of these endpoints, and that's a big long 23 discussion. And I don't think -- I think -- I'm just 24 uncomfortable sort of de facto accepting that. 25 Again, I'm not saying they should take 130 BARNEY, UNGERMANN & ASSOCIATES 1-888-326-5900 1 it out of the document. I think the document 2 explains what they mean, and people can read that and 3 make their own judgment about whether or not they 4 consider that an acceptable procedure from a 5 regulatory point of view. 6 DR. FROINES: Well, I think that what 7 you just said is a very good point in a sense. 8 Because our history -- our history has been always 9 based on a dichotomous endpoint. Right? You either 10 have cancer or you don't. And that's the way we 11 viewed the world. 12 We did some stuff with lead. Now, 13 lead -- you know, all of a sudden you've got -- it's 14 pretty easy with lead because we got a national 15 academy of science and CDC and all these other people 16 come in and say, "Well, we want to keep everybody 17 below 10, and we want to keep everybody below 20." 18 And so we don't have to go into all the subtleties of 19 dealing with continuous variables around effects. 20 Now, here -- and this is where the 21 rubber is about to start to meet the road, because 22 now we have to take into account issues of severity 23 and issues of distribution, don't we? 24 How many animals -- and we have to take 25 into account individual susceptibility because you 131 BARNEY, UNGERMANN & ASSOCIATES 1-888-326-5900 1 may have some animals that show some effects and 2 others don't. 3 And if you take the mean of that, you 4 may have some results. But if you look at the 5 individual variability, you may want to say that 6 these animals do have an effect. 7 So you have interindividual 8 variability, you have the severity issue, and you 9 have distributional issues in general. We haven't 10 dealt with any of that, and it's obviously quite 11 complicated. 12 I mean, how much respiratory irritation 13 from formaldehyde do you have to have at one-tenth of 14 a part per million before you say that that's too 15 much. 16 Those are the kind of issues why people 17 haven't dealt effectively with non-carcinogens. 18 Carcinogens at some level are easy because they're 19 dichotomous. Not really when you get into mechanism, 20 but that's the way you do it. 21 So I think that we have to do exactly 22 what you said. I think we have to take up this issue 23 of non-cancer endpoints and how we're going to define 24 what do we take -- what do we mean by "severity," you 25 know. What's -- how many animals have to have these 132 BARNEY, UNGERMANN & ASSOCIATES 1-888-326-5900 1 effects and so on and so forth. 2 All of these are complicated questions. 3 And they're dealt with awfully simplistically by and 4 large by most people. And so my sense is that what 5 we have to do is come up with something that gets us 6 through this document -- 7 DR. GLANTZ: Right. 8 DR. FROINES: -- and then try and 9 address what are obviously difficult questions in 10 another forum. Otherwise we'll sit here and talk 11 about them. And most of the issues we'd like to talk 12 about we don't even know what we're talking about. 13 And there is something to be said for knowing about 14 what you're talking about. 15 DR. GLANTZ: And see, that's why what 16 I'm proposing to do. To get this document finished, 17 okay, is to simply leave this -- leave the NOAELs in 18 the document but leave them out of our findings and 19 then it may be that after we have this workshop and 20 figure more of this out, maybe we would want to go 21 back and re-add them. 22 But I just think there's a whole lot of 23 stuff implicit in these NOAELs that I'm uncomfortable 24 with, and I don't see where it would hurt anything to 25 take them out of the findings. 133 BARNEY, UNGERMANN & ASSOCIATES 1-888-326-5900 1 DR. FROINES: As the chair's 2 prerogative, I'm going to take a vote. And I'm -- 3 DR. GLANTZ: I'll probably lose. 4 DR. FROINES: -- going to make a 5 motion -- or somebody has to make a motion. I'm 6 going to say -- make a motion that says we leave the 7 NOELs in -- with the NOELs in our findings. 8 DR. GLANTZ: I'll move that. 9 DR. FROINES: So now we moved that so 10 we can move on. 11 DR. FUCALORO: I second for the purpose 12 of -- 13 DR. FROINES: The NOELS and NOAELs. 14 DR. GLANTZ: What he's moved is the 15 NOAELs be left in the findings. 16 DR. FROINES: My motion was essentially 17 the status quo with further explanation. 18 DR. FRIEDMAN: Right, with explanation. 19 DR. SEIBER: And you second it? 20 DR. GLANTZ: I seconded it, for the 21 purposes -- 22 DR. FUCALORO: Well, he made the 23 motion, and I seconded it. 24 DR. GLANTZ: I made the motion, and he 25 seconded it. 134 BARNEY, UNGERMANN & ASSOCIATES 1-888-326-5900 1 DR. FROINES: He's just showing that 2 he's friendly to the motion he's about to lose. So 3 all in favor of that motion raise your hand. 4 And Peter would have voted our way too. 5 DR. GLANTZ: Don't I at least get to 6 vote no for the record? 7 DR. FROINES: How many oppose it? 8 DR. GLANTZ: I oppose it. 9 DR. FUCALORO: How many extensions? 10 DR. GLANTZ: But if Byus had been here, 11 I would have won. 12 DR. FROINES: Can we move on then? 13 We're trying to finish this. 14 DR. FUCALORO: I don't think so. 15 DR. GLANTZ: Well, I could dream. 16 DR. FROINES: What time is it? 17 DR. FRIEDMAN: 20 to 1:00. 18 DR. SEIBER: John, where did we come 19 out with that last statement in the findings about 20 whether we recommend the DPR director take this under 21 to the next step or whether we in fact come out and 22 recommend -- 23 DR. FROINES: We hadn't finalized it. 24 We had basically -- I think let's leave that for 25 last. 135 BARNEY, UNGERMANN & ASSOCIATES 1-888-326-5900 1 But are there any other technical 2 issues within the findings that anybody wants to 3 comment on? Let's do the science before we do the 4 politics. 5 DR. SEIBER: I've got a few. 6 DR. FROINES: Your vote won. 7 DR. KENNEDY: I'm glad I wasn't here. 8 DR. GLANTZ: For the record, he should 9 vote just to -- right? No? He doesn't have to? 10 Okay. 11 DR. KENNEDY: I vote to leave it in. 12 DR. GLANTZ: Okay. We're all wrong. 13 DR. SEIBER: In the bulk of the 14 findings, again, I went through it and made some 15 cross-outs and changes like that which I'll be happy 16 to give to Peter or to you or to Paul. 17 What should I do? 18 DR. FROINES: Give it to Peter, and he 19 can be our person. 20 DR. GLANTZ: Do you mean additional 21 changes beyond the ones on this fax that we got? 22 DR. SEIBER: Right. Well, they're not 23 additional. They're things that either were 24 misspelled or -- 25 DR. GLANTZ: But it's nothing 136 BARNEY, UNGERMANN & ASSOCIATES 1-888-326-5900 1 substantive? 2 DR. SEIBER: No, no, not substantive. 3 DR. FRIEDMAN: But there's something 4 you said needs clarification. 5 DR. SEIBER: Well, I have subsequently 6 read it over, and I guess personally I'm happy. I 7 didn't make any changes on those things. 8 DR. FROINES: It does mean, by the way, 9 on this vote, that you need to put a value in for the 10 MOE based on the NOEL. 11 MR. GOSSELIN: I think that was in 12 there. 13 DR. FROINES: If it isn't -- 14 MR. GOSSELIN: We did add those in. 15 DR. FROINES: Okay. Good. So you're 16 okay. 17 DR. SEIBER: Yeah, I'm okay. 18 DR. FROINES: Tony's okay. You're 19 okay. So there are no more technical comments on the 20 findings. 21 DR. GLANTZ: I guess there's one thing 22 that I think before we vote on them, maybe at lunch 23 maybe Paul and the others can go write up the 24 definition of the NOEL versus NOAEL that we're going 25 to incorporate into the findings so we can consider 137 BARNEY, UNGERMANN & ASSOCIATES 1-888-326-5900 1 that. 2 MR. GOSSELIN: I did have one question 3 because I just wanted to clarify. Did you want it 4 just specifically stated that the report identified 5 a NOAEL for the purposes of DPR to consider in risk 6 mitigation or risk management? 7 DR. FROINES: Well, that's fine. But I 8 also want you to say what the NOAEL is. What are the 9 endpoints you're considering. 10 MR. GOSSELIN: That's in here. 11 DR. GLANTZ: In the findings? 12 MR. GOSSELIN: Yeah. 13 DR. FRIEDMAN: We should have our 14 caveat what we want to say in terms of the fact that 15 there may be adverse effects between the NOAEL and 16 NOEL that have not been detected. 17 MR. GOSSELIN: If you wanted the 18 specifics about the NOEL indicating the 19 cholinesterase suppression in the plasma, that's in 20 there. And in the clinical science, the specific 21 clinical science for the NOAEL, those are in there. 22 DR. FUCALORO: No. 18. 23 MR. GOSSELIN: No. 18 for acute and 24 No. 25 for the subchronic. 25 DR. FROINES: We have to stop for lunch 138 BARNEY, UNGERMANN & ASSOCIATES 1-888-326-5900 1 but -- well, let's look at these and see what we need 2 to do to meet that one. 3 DR. GLANTZ: I mean, I would actually 4 be happier if we took out the sentence about risk 5 management. I'm just uncomfortable saying basically 6 what we're doing is agreeing that this is the number 7 they should use for risk management. And I don't 8 agree with that, necessarily. So maybe we can -- 9 it's at the bottom of page 3. Take the last sentence 10 on page 3 out. 11 DR. FUCALORO: It's in item 18. 12 DR. GLANTZ: Yeah. 13 DR. FUCALORO: And when I pointed it 14 out earlier, which said -- 15 DR. GLANTZ: Maybe I can win. 16 DR. FUCALORO: -- assuming a 24-hour -- 17 well, it's the sentence prior to that. I'm wrong. 18 DR. GLANTZ: It says, 19 "Since the report will also 20 provide the basis for risk 21 management, NOAEL provides the 22 information required for risk 23 management." 24 DR. FRIEDMAN: We're not looking at the 25 same thing at the bottom of page 3. 139 BARNEY, UNGERMANN & ASSOCIATES 1-888-326-5900 1 DR. GLANTZ: Okay. It's No. 18. 2 MR. FROINES: Mine doesn't have that. 3 DR. FUCALORO: It disappeared in this 4 copy. 5 DR. KENNEDY: The one that Dr. Seiber 6 corrected doesn't have that statement in it. 7 MR. GOSSELIN: Because prior to making 8 the corrections of Dr. Seiber's, Bill had sent over 9 some comments and thoughts about wanting to define 10 what the NOEL versus the NOAEL. So -- 11 DR. GLANTZ: Well, if we're working off 12 of Seiber's edited version, then there's nothing to 13 discuss. 14 DR. KENNEDY: It's a non-issue. I tend 15 to agree with it. I think it's fine as it is here. 16 DR. GLANTZ: In Seiber's, you mean? 17 DR. KENNEDY: Yeah. 18 DR. GLANTZ: Okay. 19 DR. FROINES: In fact, in Seiber's it 20 doesn't exist. 21 DR. FUCALORO: It's eliminated, right. 22 DR. GLANTZ: That's fine. Nevermind. 23 DR. FROINES: Well, then let's take a 24 break and come back. And the only thing we have left 25 to do is the policy question which we've more or less 140 BARNEY, UNGERMANN & ASSOCIATES 1-888-326-5900 1 resolved right now. 2 Am I missing something? 3 DR. GLANTZ: We do need to know that 4 one extra sentence, and somebody needs to write that 5 about something could be happening between -- 6 DR. FRIEDMAN: Could you write that 7 sentence? 8 DR. GLANTZ: Well, you thought of it. 9 You write it. 10 DR. FRIEDMAN: Okay. I'll write it. 11 Where does it go? 12 DR. GLANTZ: In number -- 13 DR. FROINES: Why don't you sit with 14 George and his folks or Paul or whoever, somebody 15 from the staff to -- 16 DR. FRIEDMAN: I need to eat first. 17 DR. FROINES: We'll reconvene at 1:15, 18 a half hour lunch. 19 (Lunch recess.) 20 DR. FRIEDMAN: I would suggest we 21 insert this sentence to satisfy people's concerns: 22 "It should be recognized that NOAELs are based on 23 limited existing knowledge and that adverse effects 24 not yet measured may occur at lower levels of 25 exposures." 141 BARNEY, UNGERMANN & ASSOCIATES 1-888-326-5900 1 And Peter suggested that we could even 2 make that stronger by saying, "It is important to 3 note" rather than "It should be recognized." That 4 could go with either one. 5 So I propose that we insert that. I'm 6 not sure of the exact spot. People were saying in 7 item 18. 8 DR. GLANTZ: I move we insert that 9 sentence in item 18 with Peter's wording. 10 DR. SEIBER: Second. 11 DR. FROINES: All opposed? So it's 12 unanimous. 13 Are we ready to go? Bill? 14 MR. LOCKETT: Yeah. 15 DR. FROINES: We have to make one final 16 decision, I think, and that is are we comfortable 17 with section 34 in the way it's stated? 18 DR. GLANTZ: No. 19 DR. SEIBER: John, I'd like to ask a 20 question, and it's strictly out of ignorance. This 21 is the first pesticide, I think, that we're doing 22 this for, and I'd just like to know what we're 23 required to do and what this action triggers in terms 24 of follow-up. 25 Because it's quite different. With ARB 142 BARNEY, UNGERMANN & ASSOCIATES 1-888-326-5900 1 we make the recommendation, and then they have a 2 meeting and consider it further, and they may or may 3 not agree with us. 4 But in this case it's the director of 5 DPR. I think we go mainstream to the director, as I 6 understand it. Can somebody explain this a little 7 bit better? 8 MR. GOSSELIN: Actually, it says, and 9 this is from the statute, 10 "Within ten working days 11 following receipt of the findings of 12 the scientific review panel pursuant 13 to subdivision B, the director shall 14 prepare a hearing notice and proposed 15 regulation which shall include the 16 proposed determination as to whether 17 a pesticide is a toxic air 18 contaminant." 19 DR. FROINES: And he holds a hearing? 20 MR. GOSSELIN: That I will have to go 21 back and check. But I would read that once you 22 prepare findings and say "This document has all the 23 information" and with your findings and submit that, 24 we have ten working days to get a package together 25 and to propose -- to either agree to list or not list 143 BARNEY, UNGERMANN & ASSOCIATES 1-888-326-5900 1 but at least hold a hearing or propose a regulation 2 package. 3 DR. GLANTZ: Well, how about -- this is 4 not the way we've worded this conclusion in the past. 5 Does anybody have any of the other reports we've 6 done? 7 MR. GOSSELIN: I took this from either 8 lead or diesel. 9 DR. GLANTZ: Oh, really? 10 MR. GOSSELIN: Yeah. 11 DR. GLANTZ: And so it said the same -- 12 "We recommended that the ARB initiate regulatory 13 steps"? I just recall it just saying that "For these 14 reasons the SRP recommends identification as a toxic 15 air contaminant." 16 MR. GOSSELIN: That's different. I 17 wanted to cite this section, specifically, and that's 18 the section I read is 14023D. So what it's saying is 19 to initiate the steps under that section. 20 DR. FROINES: We could -- we could say 21 "For these reasons we agree with the science 22 presented in the report and recommend -- and based on 23 those scientific findings consider DEF a toxic air 24 contaminant. We recommend that the director of DPR 25 initiate regulatory steps to list it." 144 BARNEY, UNGERMANN & ASSOCIATES 1-888-326-5900 1 DR. GLANTZ: Okay. 2 DR. FROINES: So in other words, we 3 conclude that it's a toxic air contaminant and then 4 we recommend. 5 DR. GLANTZ: Okay. I'm happy with 6 that. 7 DR. FROINES: That's what we've done in 8 the past. 9 DR. FRIEDMAN: Yeah, that would be 10 better. 11 DR. GLANTZ: Okay. Is that okay with 12 you? Okay. I so move. 13 DR. FRIEDMAN: Second. 14 DR. GLANTZ: I want to win one. 15 DR. FUCALORO: You've won one already. 16 DR. GLANTZ: Oh, I did? 17 DR. FUCALORO: You're winning all of 18 them, for crying out loud. 19 DR. GLANTZ: I lost the last one. 20 DR. FROINES: No, you won the vote. 21 You simply lost the principle. 22 DR. GLANTZ: That's true. Actually, it 23 was my motion, wasn't it? 24 DR. FROINES: All in favor of that? 25 DR. FRIEDMAN: I am. 145 BARNEY, UNGERMANN & ASSOCIATES 1-888-326-5900 1 DR. BYUS: What was that? I missed it. 2 I'm sorry. 3 DR. FROINES: You know, we're all the 4 same. We're getting older, and you're not supposed 5 to ask people to repeat what they said. You say "For 6 these reasons we agree with the science presented in 7 the report and based on the science" -- 8 DR. FUCALORO: The scientific findings. 9 DR. FROINES: -- "the scientific 10 findings consider -- have included DEF as a toxic air 11 contaminant. We further recommend that the blah, 12 blah, blah." Now she knows it twice, and we're saved 13 from our Alzheimer's. 14 DR. GLANTZ: Just for Dr. Byus, we had 15 a big -- I had proposed removing the NOAEL from the 16 findings for reasons that were discussed endlessly. 17 Dr. Froines made a suggestion we make a 18 motion to keep them as a courtesy. I made the motion 19 and then lost. But as he pointed out, I actually won 20 because my motion passed with me voting no. I'm 21 ready for Congress. 22 DR. FROINES: This is a very collegial 23 group today. 24 Paul, it's -- it's just great working 25 with you on all of this. In the '80s it wasn't so 146 BARNEY, UNGERMANN & ASSOCIATES 1-888-326-5900 1 much fun. Stan and I remember. And this general 2 spirit, I think, is terrific. I think 3 we're really on the way on this. And I think this is 4 a good first step. It's good just after the election 5 to bring back a positive outcome. It's good. 6 MR. GOSSELIN: Thank you. And I think 7 the staff that worked on this put a lot of effort to 8 be responsive and put all the -- lay the science into 9 it. 10 DR. FROINES: Shall we move on to 11 parathion? 12 DR. GLANTZ: Can I move that we accept 13 the report as amended by the discussion and the 14 finding -- or we've already accepted the findings. 15 DR. FROINES: Yeah, I guess you're 16 right. 17 DR. GLANTZ: We didn't accept the 18 report. 19 Huh? 20 DR. FROINES: I always forget that -- 21 DR. GLANTZ: I'd like to move that we 22 accept the report with the appropriate changes that 23 were discussed today. 24 DR. SEIBER: Second. 25 DR. FROINES: All of in favor? 147 BARNEY, UNGERMANN & ASSOCIATES 1-888-326-5900 1 This is a landmark decision, isn't it? 2 This is our first in the history of this program. 3 Did we vote once before? Was there a formal vote 4 before? 5 UNIDENTIFIED SPEAKER: Ethyl parathion. 6 DR. ALEXEEFF: Ethyl parathion. 7 MR. GOSSELIN: Eleven years ago. 8 DR. FROINES: Eleven years ago. 9 DR. GLANTZ: But that was to turn it 10 down, wasn't it? 11 DR. FROINES: It's still a historic 12 event. 13 Let's move on. I'm sure we can find 14 something to disagree about. 15 MR. GOSSELIN: Thank you. 16 We're going to methyl parathion? 17 DR. FROINES: I think what we're going 18 to do, Paul, is what we'd like you to do is 19 essentially make a presentation that you were 20 thinking of making, and then we'll probably stop and 21 then take up the actual discussion at the next 22 meeting. Because you're going to have more material 23 and more comments -- I think Ruby said that there was 24 more coming. 25 DR. REED: Yes. Correct. 148 BARNEY, UNGERMANN & ASSOCIATES 1-888-326-5900 1 MR. GOSSELIN: And I should preface 2 that we did have the comment period that closed at 3 the end of October. We had a workshop. And I 4 apologize for not making arrangements for members to 5 be there, and we'll fix that in the future. 6 We didn't have a large number of 7 comments, but we did receive one significant set of 8 comments, and it was a stack of four new studies that 9 the representatives from the registrar submitted. 10 Those studies right now are in the 11 process of going through -- the first step is data 12 review which is to determine whether those studies 13 were complete and adequate, and it will go to the 14 group to characterize that. And we've kind of put 15 that on a fast track. 16 We're going -- taking those -- those 17 new data as comments, so we're largely holding that 18 the report itself is going to remain intact. Once we 19 complete the review of those studies, we're going to 20 report back in an addendum fashion to the report 21 because we figured there are going to be, as we go 22 through discussions, some changes to the report and 23 reflect how those new data either change or don't 24 change the assessment of methyl parathion. 25 The one other issue that was raised is 149 BARNEY, UNGERMANN & ASSOCIATES 1-888-326-5900 1 the changing -- and this is going to be the changing 2 use patent of methyl parathion, which is going to be 3 more typical of pesticide use versus what we saw with 4 DEF where methyl parathion has a variety of uses and 5 a variety of crops and we've seen some of the 6 counties and some of the cropping patents over the 7 past ten years change in the use patent. And that's 8 going to be sort of a dilemma we're going to have to 9 appreciate as we go through evaluating pesticides. 10 With that I'll have the first 11 presentation which will be Kevin Kelley on 12 environmental fate. 13 (Off the record.) 14 MR. KELLEY: Okay. I guess we're ready 15 to get started here. My name is Kevin Kelley. I'm 16 an associate environmental research scientist for the 17 Department of Pesticide Regulation. I'm the author 18 of the part A of "Evaluation of Methyl Parathion as a 19 Toxic Air Contaminant" document. 20 The overheads that I present today, you 21 all should have a copy of it. Peter passed them out. 22 So if you can't see something up on the overheads 23 there, you'll have a copy of it. 24 This afternoon I'm going to talk about 25 the physical and chemical aspects of methyl 150 BARNEY, UNGERMANN & ASSOCIATES 1-888-326-5900 1 parathion, the use of methyl parathion in California 2 including the crops on which it's used and the 3 counties in which it's used, then I'll move on to the 4 environmental fate of methyl parathion, and then 5 concentrations of methyl parathion in the air. 6 Next. 7 Okay. Since nobody can see this, I 8 guess you'll just have to look off your handouts. 9 DR. GLANTZ: Why don't you move the 10 projector further back. It's too faint. 11 MR. KELLEY: Methyl parathion is an 12 insecticide-acaricide registered for use in 13 California to control insect, mite, and other 14 arthropod pests in cropland situations. 15 Methyl parathion is a molecular formula 16 of C8 H10 NO5 PS and has a molecular weight of 17 263.21. At room temperature methyl parathion is in 18 the form of colorless crystals which emit a faint, 19 garlic-like odor. 20 Methyl parathion melts at approximately 21 35 degrees Celsius and has a boiling point of 22 approximately 119 degrees Celsius at 0.13 millibar. 23 Methyl parathion has a vapor pressure 24 of 2.3 millipascals at 25 degrees C and a Henry's Law 25 Constant of 10.3 times 10 to the minus 8th meters 151 BARNEY, UNGERMANN & ASSOCIATES 1-888-326-5900 1 cubed times atmospheres per mole. Specific gravity 2 is 1.3858. 3 Methyl parathion is sparingly soluble 4 in water at 12.9 milligrams per liter at 20 degrees 5 Celsius. It is slightly soluble in petroleum 6 distillates and readily soluble in most organic 7 solvents. In alkaline or acidic media methyl 8 parathion rapidly hydrolyzes. 9 Next. 10 Methyl parathion is used to control 11 insects and other invertebrate pests in more than 35 12 crops grown in California. It's also used to control 13 insect pests in and around nurseries and nursery 14 plantings, for public health control, for regulatory 15 pest control, and free landscape maintenance. 16 Methyl parathion controls lepidopterous 17 pests of alfalfa, almond, apricot, peach, and other 18 stone fruits. Methyl parathion is used extensively 19 in rice cultivation for the control of tadpole shrimp 20 and labeled for the use against the rice leafminer. 21 It is also used for the control of 22 aphids, grasshoppers, leafminers, scale, spider 23 mites, and other pests, and for the control of 24 mosquitoes in irrigated pastures. 25 Next. 152 BARNEY, UNGERMANN & ASSOCIATES 1-888-326-5900 1 This is a historical use of methyl 2 parathion which is shown from 1977, right here 3 (indicating), to 1995 at the left end or right end 4 over here. 5 DR. GLANTZ: How come the use fell off 6 so suddenly there? 7 MR. KELLEY: Before 1977 we don't have 8 a lot of use reports, but for several years back it 9 was used in over a million pounds per acre, and then 10 in 1978 it just dropped down to about 260,000. And 11 basically there was less used in most of the crops it 12 was used on. 13 DR. GLANTZ: Do you know why? 14 MR. KELLEY: No. I haven't been able 15 to figure that out yet. 16 DR. SEIBER: Probably -- it could have 17 been new alternatives were brought in like 18 chlorpyrifos and some of the other newer 19 organophosphates. That's just a guess. 20 MR. KELLEY: Yeah, it didn't seem to be 21 a change in the commodities that it was used on, so 22 there wasn't some crop that just it stopped 23 completely on. 24 The high, as I said was 20 years ago, 25 was over one million pounds in 1977, and the lowest 153 BARNEY, UNGERMANN & ASSOCIATES 1-888-326-5900 1 used in the last 20 years was right here in 1991 of 2 72,000 pounds (indicating). And since 1991 uses 3 increased slightly to approximately 153,000 pounds in 4 1995. 5 The average use for -- the average 6 value -- excuse me. The average use of methyl 7 parathion in the last ten years is approximately 8 140,000 pounds per year. 9 Next. 10 Seven crops account for 73 percent of 11 methyl parathion applied from 1990 through 1995. 12 These crops are alfalfa, apple, grapes, nectarine, 13 peach, plum, and finally rice. 14 Next. 15 Methyl parathion is also applied to 28 16 minor use crops. Applications to these crops account 17 for approximately 27 percent of the remaining average 18 methyl parathion used from 1990 through '95. 19 Applications to -- of methyl parathion 20 to such crops as small grains and onions average over 21 3,000 pounds a year, whereas, applications to cotton, 22 lettuce, pears, sugar beets, and tomatoes average 23 between 1,400 and 2,000 pounds. And finally, 24 applications to remaining crops average from 40 25 pounds per year to 900 pounds. 154 BARNEY, UNGERMANN & ASSOCIATES 1-888-326-5900 1 DR. GLANTZ: What is "AI"? 2 MR. KELLEY: Active ingredient. Sorry. 3 Next. 4 Methyl parathion applications to most 5 of the major crops has shifted over the last ten 6 years. Applications to rice for approximately 55,000 7 pounds -- which is the black bar right here 8 (indicating) -- in 1990 and it's decreased to 31,000 9 pounds in 1995. 10 The reported amount of methyl parathion 11 applied to rice in 1993 was over 500,000 pounds 12 although according to the use report shows that 13 there's probably a 10,000-pound excessive just due to 14 calculation errors in the use report. As you can see 15 also, applications to grape, peaches, nectarines, and 16 plums have greatly increased since 1990. 17 Next. 18 DR. BYUS: Do you think that trend's 19 going to continue? Or I mean, is that -- 20 MR. KELLEY: Boy, I'd like to see the 21 1996 use report. I really would. Because you 22 know -- that's what this graph right here is 23 basically about. 24 As you can see in the straight line 25 here (indicating), this is use in rice. Use in rice 155 BARNEY, UNGERMANN & ASSOCIATES 1-888-326-5900 1 from 1996 to '89 averaged approximately 900,000 -- 2 90,000 pounds per year. 3 And in 19 -- 1988 there was a big 4 decrease that started in rice, and it went all the 5 way through until 1991 where use was at the lowest, 6 which is approximately 24, 25,000 pounds of rice. 7 And that's crept back up slightly to 31,000 pounds in 8 '95. 9 And since 1990 use on stone fruits, 10 which is the dotted line through here, this is where 11 it started to increase in stone fruits. And I 12 grouped all the stone fruits together because they're 13 generally grown in the similar areas and more or less 14 typed intercropped so that you -- it just made sense 15 to put them together. 16 DR. GLANTZ: What are stone fruits? 17 MR. KELLEY: Peaches, nectarines, 18 plums; fruits with pits -- apricots. 19 And since 1990 use in stone fruits has 20 increased to 64,000 pounds in '93, 67,000 pounds in 21 '94, and 62,000 pounds in 1995. 22 And I also have grapes listed on this, 23 which is the very faint line with the triangles. And 24 use on grapes has risen from approximately 2,500 25 pounds in 1992 to over 21,000 pounds in 1995. 156 BARNEY, UNGERMANN & ASSOCIATES 1-888-326-5900 1 Next. 2 And historically 42 counties in 3 California report a methyl parathion use from 1990 to 4 1995. Of these, eight counties accounted for 65 5 percent of the total use, and these counties are 6 Colusa, Fresno, Kern, Riverside, San Joaquin, Sutter, 7 Tulare, and Yuba Counties. 8 Next. 9 And in these counties application -- 10 excuse me, the amount of methyl parathion is applied 11 that's shifted and reflects basically the change in 12 pest control use patterns and the change in the 13 applications to the commodities grown within those 14 counties. 15 Applications to Colusa County have 16 decreased from 27,000 pounds to 4,600 pounds; 17 whereas, applications in Fresno County have risen 18 from 1,100 pounds in 1990 to 34,000 pounds in 1995. 19 Next. 20 And this next graph is just a graph of 21 counties -- the other counties of which methyl 22 parathion is applied. 23 Next. 24 What are the sources of methyl 25 parathion and methyl parathion and methyl paraoxon in 157 BARNEY, UNGERMANN & ASSOCIATES 1-888-326-5900 1 the environment? The sole source of methyl parathion 2 in the environment derives from its application and 3 use as a pesticide. 4 And since methyl paraoxon is a 5 breakdown product of methyl parathion, its sole 6 source in the environment comes from the use of 7 methyl parathion also. 8 As of September 1998 nine methyl 9 parathion containing products are currently 10 registered for use in California. Formulations of 11 methyl parathion include seven emulsifiable 12 concentrate products, one microencapsulated product, 13 and one emulsifiable concentrate mixture with 14 thiodan. 15 This graph shows a historical peak 16 using data from 1990 through to 1995, and it shows 17 that there's a seasonal peak for methyl parathion 18 used which occurs in May for these years. 19 This peak corresponds to its use in two 20 separate locales. The first locale is the 21 rice-growing regions in Sutter, Colusa, Tulare 22 Counties where applications begin in early May and 23 continue through early June, a four- to six-week 24 period. 25 The second locale is the alfalfa and 158 BARNEY, UNGERMANN & ASSOCIATES 1-888-326-5900 1 stone fruit growing regions in Fresno and San Joaquin 2 Counties where applications again begin in mid-May 3 and continued for eight to twelve weeks. 4 For most of the cropland situations 5 methyl parathion applications are made on an 6 as-needed basis for the control of damaging insect 7 populations. The fewest methyl parathion 8 applications occur in between November -- right there 9 (indicating) -- December, January, and February of 10 each year. 11 Next. 12 This is a yearly breakout of the 13 previous graph and again just shows that through the 14 time the applications tend to remain concentrated in 15 May and June with April and July as secondary high 16 use months. 17 Next. 18 What is the fate of methyl parathion in 19 the environment? In the environment methyl parathion 20 is graded by one of three major chemical or 21 microbial -- and microbial pathways. 22 The first involves the production of 23 methyl paraoxon. It's right here (indicating). 24 Reaction: hydrolytic in soil and water and 25 photolytic in air. 159 BARNEY, UNGERMANN & ASSOCIATES 1-888-326-5900 1 The second pathway -- this goes from 2 methyl parathion this way -- is also hydrolytic in 3 air and water and in soil and plants. Methyl 4 parathion is cleaved producing para-nitrophenol and 5 dimethyl phosphorothioic acid. 6 The third reaction is from methyl 7 parathion to methyl aminoparathion, and this reaction 8 involves reduction of the nitro group, and this 9 reaction occurs in flooded soils, soils high in 10 organic matter, and soils with strong reducing 11 conditions. Methyl aminoparathion is then further 12 degraded to para-aminophenol and dimethyl 13 phosphorothioic acid. 14 In air methyl paraoxon is considered 15 relatively resistant to further degradation. In soil 16 and water methyl paraoxon may be converted to 17 para-nitrophenol and dimethyl phosphoric acid. And 18 if conditions favor reduction, methyl paraoxon will 19 be converted to para-aminophenol and dimethyl 20 phosphoric acid. 21 The final fate of these degradative 22 products should be complete mineralization to CO2, 23 H20, oxygen, and phosphorus and sulfur compounds. 24 Recent information received by DPR 25 indicates that under laboratory conditions the half 160 BARNEY, UNGERMANN & ASSOCIATES 1-888-326-5900 1 life of methyl parathion in air may be as low as 2 30 minutes. 3 Other data indicates that in more real 4 conditions the half life would be approximately 13 5 hours with methyl parathion's completed lifetime may 6 be as short as 18 hours. 7 The information also indicates that 8 another compound, 2-methyl-4-nitrophenol, was 9 produced and intimates that many other breakdown 10 products should be produced and immediately washed 11 from air. 12 Next. If you could rotate that, 13 slightly. Thank you. 14 What are the concentrations of methyl 15 parathion reported in the literature? Airborne 16 concentrations of methyl parathion in the literature 17 range from .4 to 688.2 parts per trillion. 18 Formulation and sampler placement have major effects 19 on measured concentrations. 20 Jackson and Lewis in 1979 did a study 21 measuring one -- taking one- to two-hour samples at 22 the end of tobacco rows in North Carolina after 23 applications of methyl parathion. 24 Methyl parathion was applied in 25 approximately one pound per acre in both situations, 161 BARNEY, UNGERMANN & ASSOCIATES 1-888-326-5900 1 and there were two formulations that were used: one 2 was the emulsifiable concentrate; the second was a 3 microencapsulated formulation. 4 And this graph shows that immediately 5 following application for the emulsifiable 6 concentrate formulation, methyl parathion 7 concentrations were 688 parts per trillion; whereas, 8 for the microencapsulated formulation the 9 concentrations were 353 parts per trillion. 10 DR. SEIBER: Kevin, do you know offhand 11 in California is it microencapsulated or the 12 emulsifiable concentrate the more relevant formula? 13 MR. KELLEY: If you're talking about 14 the rice, it would be the emulsifiable concentrate. 15 I didn't get a chance to look at the data in the last 16 two weeks, but I'm trying to find out, especially in 17 stone fruits, if they're going to be using the 18 microencapsulated formulation or if they're using the 19 emulsifiable concentrate. 20 DR. SEIBER: Because there's quite a 21 difference here. 22 MR. KELLEY: Right. 23 DR. SEIBER: Yeah. 24 DR. FUCALORO: And they assume that to 25 be real. In other words, you mentioned that the 162 BARNEY, UNGERMANN & ASSOCIATES 1-888-326-5900 1 application was that roughly the same amount per 2 acre, but was the total amount -- I mean, were the 3 experimental conditions such that one could have some 4 confidence that the difference is real in these two 5 graphs? Not just the slope of the curve but the fact 6 that one seems to produce twice as much airborne than 7 the other? 8 MR. KELLEY: They were performed under 9 very similar environmental conditions. The size of 10 the fields were approximately similar, and sampler 11 placement was identical in all situations. So one 12 would assume from that -- 13 DR. BYUS: Do they spray the stone 14 fruits the same way, air application -- by airplane 15 or helicopter -- or is that sprayed from the ground? 16 MR. KELLEY: They do some applications 17 by airplane, but they also use air blast sprayers 18 where they're driving ground equipment through the 19 field with the spray blasted up through the bottom of 20 the trees as opposed to being up on top, you know, 21 spraying it down. 22 DR. BYUS: Excuse my ignorance. 23 MR. KELLEY: Sure. 24 DR. BYUS: Would you expect more or 25 less to be in the air or remain in the air under that 163 BARNEY, UNGERMANN & ASSOCIATES 1-888-326-5900 1 kind of application? I assume this was from 2 airplane. 3 MR. KELLEY: Yeah, this is aerial. 4 DR. BYUS: So what would you think? 5 MR. KELLEY: Well, there's -- it all 6 depends, again, on droplet size, concentration, the 7 amount they're spraying, whether they apply it via -- 8 as they say, rotary or fixed wing. 9 MR. GOSSELIN: The EPA has been -- and 10 we've been following what's called a spray drift task 11 force looking at off-site movement. And actually, 12 what they did find is certain air blast-type sprayers 13 produce such fine aerosols that you actually in many 14 instances get more off-site movement than in aerial. 15 And I think because a lot -- not just 16 in in-state but nationally a lot of agencies have 17 really been focused on aerial application off-site 18 movement because it presents such a higher risk that 19 they have actually been improving the nozzle design, 20 placement to really reduce the amount of aerosols 21 coming off the aerial application. 22 DR. BYUS: Okay. Thank you. 23 MR. KELLEY: Basically, the gist of 24 this graph shows that at application or immediately 25 following application you have high concentrations in 164 BARNEY, UNGERMANN & ASSOCIATES 1-888-326-5900 1 the air which the next day dropped significantly for 2 both groups and then finally after three, four, five, 3 six days, it's down to an amount undetected -- well, 4 actually, they were detected. But it was down to 5 approximately one part per trillion. 6 Next. 7 And this is a -- 8 DR. FROINES: What's the frequency of 9 spraying? Once spraying occurs, and then when do 10 they go back and spray a second time? 11 MR. KELLEY: Oh, for the fields? Most 12 fields are only sprayed once with methyl parathion. 13 So I mean, they could spray, you know, this 640 acres 14 today and then tomorrow spray the next one or spray 15 the both of them, you know, the same day. 16 But most methyl parathion applications 17 are singly, made once, to the commodity. And as you 18 start making more, then you start getting into some 19 very severe re-entry and preharvest restrictions. 20 Does that answer your question? Okay. 21 This Seiber -- or excuse me, this graph 22 is taken after a Seiber and McChesney study they did. 23 They were out in rice fields in 1977 sampling, and a 24 methyl parathion application occurred to a field 25 adjacent to where they were sampling. And so they 165 BARNEY, UNGERMANN & ASSOCIATES 1-888-326-5900 1 decided to see if methyl parathion would be found, 2 and indeed it was. 3 And their samplers were -- basically 4 this graph is hours after application, and then 5 samplers that were set up immediately following 6 application, methyl concentrations were approximately 7 95 parts per trillion. Ten hours after 8 application -- which is right here (indicating) -- it 9 was approximately 108 parts per trillion. 10 However, within two days 11 concentrations -- concentrations had dropped to 12 approximately 4.5 and 4.7 parts per trillion. 13 DR. FROINES: How far were these 14 samplers from -- 15 MR. KELLEY: The field? They were 20 16 meters away from the field? 17 DR. SEIBER: It says back in the 18 report -- it says the border of a tree to field, so 19 I'm assuming just a matter of a few meters. But I 20 would have to look back to -- 21 DR. FROINES: Border of a tree to the 22 field? 23 DR. SEIBER: Yeah. 24 Do you remember? 25 MR. KELLEY: That's why I said 20 166 BARNEY, UNGERMANN & ASSOCIATES 1-888-326-5900 1 but -- 2 UNIDENTIFIED SPEAKER: I believe it's 3 20 yards. 4 MR. KELLEY: Twenty yards, yeah. 5 DR. SEIBER: Twenty yards. Okay. 6 MR. KELLEY: About 17 meters, then. 7 DR. BYUS: Does that fit with the half 8 life that you said exists maybe for methyl parathion? 9 MR. KELLEY: The one that I had 10 mentioned earlier was information, I think, just come 11 into the department as part of the public comment 12 period. It has not been fully evaluated. 13 DR. BYUS: What was it? You said the 14 half life was -- 15 MR. GOSSELIN: 13, 18 hours. 16 MR. KELLEY: Yeah, that's -- in an 17 environment that's what they were proposing. But in 18 the laboratory the half life they were getting was 19 down to 30 minutes. 20 DR. SEIBER: Yeah, it's probably -- the 21 methyl parathion's put in the water -- in the rice 22 field water, so it probably reflects the hydrolysis 23 in the water, not the breakdown in the air. That 24 would be my guess. 25 MR. KELLEY: These half lives that I 167 BARNEY, UNGERMANN & ASSOCIATES 1-888-326-5900 1 was quoting, they were setting up chambers in which 2 they dropped the air pressure until methyl parathion 3 would volatilize, and then they would expose that to 4 wave -- you know, lights of all sorts of different 5 wavelengths. And they were measuring the actual half 6 life of the breakdown of methyl parathion in that. 7 DR. SEIBER: In the air. 8 MR. KELLEY: In the air. 9 DR. SEIBER: Yes. 10 MR. KELLEY: So it's -- 11 Next. 12 And this is just more general 13 information from the literature on methyl parathion 14 concentrations. 15 A variety of studies that were 16 conducted from 1971 through 1983; a variety of 17 authors or several authors either conducted their 18 studies in rural areas in the east and also the west. 19 Riverside was also one of their sample sites. And 20 the -- these are some of the concentrations that they 21 came up -- that they detected. 22 In Mississippi the highest 23 concentration they detected is right here 24 (indicating): 191 parts per trillion. And in 25 various other places it was anywhere from 73 parts 168 BARNEY, UNGERMANN & ASSOCIATES 1-888-326-5900 1 per trillion to approximately .5 parts per trillion. 2 Next. 3 DR. FUCALORO: Can you go back to that. 4 You have Mississippi, and then you have 5 below it three years, '72 through '74 inclusive; 6 right? 7 MR. KELLEY: Correct. 8 DR. FUCALORO: Now, what -- that's also 9 Mississippi '72 through '74 inclusive? 10 MR. KELLEY: Right. 11 DR. FUCALORO: And this is just a 12 Mississippi no year indicated; right? 1976 was -- 13 oh, I see. Weekly samples taken from -- why is that 14 number so large? I mean, there's a -- it's so much 15 larger than all the others. I mean, is there 16 anything special about that? Is that something to 17 be -- 18 MR. KELLEY: There's nothing mentioned 19 in the actual paper. It could have been the fact 20 that they sat out there and either there was a lot of 21 use or possibly, you know, they happened to set it 22 out at the time when the plane flew over the sampler. 23 You know, it did not state in the paper. 24 DR. FUCALORO: It had no statement. 25 Because just looking at -- looking at the Jackson and 169 BARNEY, UNGERMANN & ASSOCIATES 1-888-326-5900 1 Lewis paper the highest was 700 parts per trillion. 2 MR. KELLEY: And this one right here is 3 only 191 parts per trillion. 4 DR. FUCALORO: I guess. All right. 5 DR. FRIEDMAN: Is the numbers under 6 Mississippi supposed to be the breakdown of that 7 total? 8 MR. KELLEY: Yes. 9 DR. FRIEDMAN: Why wasn't the maximum 10 achieved in any one of those years? 11 DR. FUCALORO: That's right. And you 12 know, if you add up the total number, 52 times 3, you 13 do get 156, which implies that what you're saying is 14 correct. It is the total. I mean, it does imply 15 that. But yet it's strange. 16 MR. KELLEY: I have no answer for that. 17 DR. FUCALORO: Look at that again. 18 MR. KELLEY: I'll have to get back 19 and -- 20 DR. FUCALORO: Yeah. You have to look 21 it up. 22 DR. FRIEDMAN: The other numbers make 23 sense but not the two columns under "Maximum Value." 24 The two columns under "Maximum Value" don't make 25 sense because the maximum should have occurred at 170 BARNEY, UNGERMANN & ASSOCIATES 1-888-326-5900 1 least one of those years. 2 MR. KELLEY: Correct. I agree with 3 that. Like I said, I'll have to go back and check 4 that out in my report and also the paper there. 5 DR. FROINES: But the data is 6 considerably skewed so the geometric mean would be 7 probably pretty low, huh? 8 MR. KELLEY: Yeah, because they do have 9 a lot of non-etects. They -- 10 DR. FUCALORO: Is it a geometric mean? 11 DR. FROINES: No, this is an arithmetic 12 mean. 13 DR. FUCALORO: An arithmetic mean? 14 MR. KELLEY: Correct. 15 DR. FROINES: But my guess is that it's 16 going to be skewed. 17 MR. KELLEY: Could you explain? I'm 18 sorry. I don't understand. 19 DR. SEIBER: I think it's always a 20 problem when you use the maximum value out of -- 21 let's say make 50 measurements and you take the max, 22 that number's not going to hold up. It's not going 23 to show much consistency, I wouldn't think. And it 24 probably is way out on the extreme of distribution 25 here. 171 BARNEY, UNGERMANN & ASSOCIATES 1-888-326-5900 1 DR. GLANTZ: That's true. But the 2 point -- I mean, I agree with you, but the point 3 they're making is that the maximum should have been, 4 if you look at the table here, 791. 5 DR. SEIBER: I agree with that. I 6 don't know what -- I don't remember that. 7 MR. KELLEY: Right. It's in '73. So 8 like I said, I have to go back and look at this. 9 It's -- 10 Next. 11 In 1986 DPR requested the state Air 12 Resources Board to document the presence of methyl 13 parathion in ambient air and in air associated with 14 specific pesticide application. And the ARB 15 subsequently requested the Environmental Tox 16 Department at the University of California Davis to 17 perform monitoring studies. 18 Most samples were collected in the 19 communities of Maxwell and Williams in Colusa County 20 and Trowbridge and Robbins in Sutter County. And the 21 background samples were collected in Yellow County on 22 campus of University of California Davis. 23 Methyl parathion was detected in both 24 Colusa and Sutter Counties. And methyl parathion 25 concentrations ranged from 0.05 to 2.8 parts per 172 BARNEY, UNGERMANN & ASSOCIATES 1-888-326-5900 1 trillion in Colusa with the highest 24-hour average 2 of three samples' concentrations methyl parathion was 3 2.4 parts per trillion measured at Maxwell. 4 DR. FRIEDMAN: It looks like 26. 5 MR. KELLEY: Actually, it's 2.4 -- no. 6 It's 2.4 on the graph here. The decimals are wrong. 7 That should be 2.5 instead of 25 there. 8 DR. FUCALORO: Where's that? The Y 9 axis is up by a factor of 10? 10 MR. KELLEY: Yeah, the Y axis is up by 11 a factor of 10 on here. 12 DR. FUCALORO: Is it fair to say that 13 the -- there were two studies on the oxon, Maxwell 14 and Williams; right? 15 MR. KELLEY: Correct. 16 DR. FUCALORO: Are we talking about a 17 three-to-one ratio in parathion versus paraoxon? 18 MR. KELLEY: I think it's close to five 19 to one. 20 DR. FUCALORO: Five to one. 21 MR. KELLEY: And then I guess Tareq 22 will discuss that more when he talks. 23 DR. FUCALORO: All right. 24 DR. FROINES: But here's my problem 25 with this: I don't know where the samplers are 173 BARNEY, UNGERMANN & ASSOCIATES 1-888-326-5900 1 placed, and I don't know the temporal, the 2 characteristics so that I don't know what the 3 take-home lesson is. 4 Did somebody put a sampler out -- some 5 samplers out in some place at some time and -- what I 6 am -- when I'm all finished, I don't -- tell me what 7 the take-home lesson is. 8 MR. KELLEY: Okay. Samplers were 9 located within the communities, generally within a 10 quarter to a half a mile from where methyl parathion 11 was being applied. 12 And I think the farthest case the 13 sampler was placed would be a mile from where the 14 actual samples were collected, and that, I think, was 15 Maxwell -- was Williams. 16 Samplers were collected for 24 hours in 17 all cases. They were collected four days a week 18 determining on just how Davis was able to get out and 19 sample. 20 And basically the take-home message for 21 this is that they detected it in the air. 22 DR. FRIEDMAN: What is the oxon -- what 23 do the oxons mean? 24 MR. KELLEY: That's methyl parathion 25 oxon. When methyl parathion is -- the sulfur's 174 BARNEY, UNGERMANN & ASSOCIATES 1-888-326-5900 1 replaced by an oxygen molecule. 2 DR. FROINES: My point is simply this: 3 Numbers like this end up getting used for a variety 4 of uses, and my point is I like to know things like 5 wind directions and location of samplers and time of 6 sampling and all the various parameters that help you 7 define the nature of the sampling protocol. And then 8 I can interpret it. Without that it's a 9 two-dimensional picture. 10 MR. KELLEY: Correct. Excuse me for a 11 second. 12 DR. FROINES: It's just a point, just a 13 general issue. 14 MR. KELLEY: That information is in the 15 document. And I see your point about how it makes it 16 better for a discussion to -- for me to have it. I 17 just don't have that here right now. 18 DR. SEIBER: Yeah. For example, there 19 was a -- there's, I believe, an acres treated table, 20 table 9 in your document -- 21 MR. KELLEY: Correct. 22 DR. SEIBER: -- that says how many 23 acres were treated in the vicinity of these. 24 Now, it's still not a good answer to 25 your question. Specific fields, you know, wind going 175 BARNEY, UNGERMANN & ASSOCIATES 1-888-326-5900 1 from here to there. I don't think that level of 2 detail was in this study. 3 DR. FUCALORO: In fact, we never -- we 4 hardly ever see that level of detail. 5 DR. FROINES: I think that it might be 6 useful if we start having some GIS maps developed so 7 that we can look at this kind of data in its 8 entirety. 9 MR. KELLEY: I agree with that. I do 10 have a juxtaposition of -- in fact, if you go to the 11 next two -- the next one and the one after that one, 12 the overhead there, I have a juxtaposition here of 13 used versus detections. 14 DR. FROINES: Which one am I looking 15 at? I'm sorry. 16 MR. KELLEY: That would be this one 17 here (indicating). 18 DR. FUCALORO: It's on the back. 19 MR. KELLEY: And in this graph 20 basically what I have plotted here is the figures for 21 detection are the black symbols. In Maxwell it would 22 be the diamond, and Williams it's the circle. 23 And then the actual value of the -- 24 of -- the amount of methyl parathion applied, which 25 is on the right side on the Y axis, then you can see 176 BARNEY, UNGERMANN & ASSOCIATES 1-888-326-5900 1 that on this at least it shows some sort of a 2 correlation of the fact that it's being applied and 3 that you detected it in the air. 4 DR. FROINES: You see, my sense is that 5 what happens is you go out and you -- people debate 6 the NOEL level for methyl parathion and the NOAEL 7 level, and we talk about health effects. And so we 8 have -- what we're concerned about is 9 population-based health effects. 10 So what I think we need then is a 11 population-based exposure assessment so that in fact 12 the -- we know who's being exposed over what periods 13 of time over what regions with what proximity the 14 samplers and so on and so forth. 15 In other words, so much of the exposure 16 assessment is two-dimensional often, and this is not 17 a criticism. Don't -- this is just for -- I think 18 over time what we want is the exposure -- rather the 19 airborne concentrations should be collected in such a 20 way to give us information on population-based 21 exposure which is what the endpoint -- which is the 22 endpoint of need if you want to ask about health 23 effects. 24 MR. KELLEY: Okay. I can see that. 25 But unfortunately what we find with a lot of 177 BARNEY, UNGERMANN & ASSOCIATES 1-888-326-5900 1 pesticide use is that the area that we would prefer 2 to sample would be the area of high use. 3 It's -- and so therefore, in most cases 4 that tends to be in areas that are -- you know, 5 generally removed from high concentrations of human 6 population. 7 DR. SEIBER: Yeah, these little towns 8 are surrounded by rice fields so, you know, they 9 would presumably be the worse case -- the population 10 with the highest exposure, and I think that's 11 probably why you selected them. 12 DR. KENNEDY: The reality is that that 13 information is simply not available. You're looking 14 at community-based exposure levels. 15 MR. GOSSELIN: I think on one hand what 16 Dr. Froines is talking about is having the geographic 17 basis of where -- how the monitoring was conducted, 18 and I think it's fair that we should continue to 19 monitor in the high use areas as the most 20 conservative approach. 21 You can then take that information and 22 bridge that to presumably any theoretical area where 23 you would have populations. But I think what we'll 24 find is -- 25 DR. FROINES: But then you also have to 178 BARNEY, UNGERMANN & ASSOCIATES 1-888-326-5900 1 define the criteria for that sampling, which is, for 2 example, what is the prevailing wind direction? 3 Which way does it flow when you sample in the morning 4 and in the evening? Is there an off flow and an -- 5 you know, so on and so forth. You know, there's lots 6 of different variables. 7 So that what I'm saying is if we're 8 going to rely -- have to rely on exposure 9 measurements in pesticides as opposed to ambient 10 concentrations, then the characterization of that 11 exposure becomes really crucial. And without 12 knowledge of the character -- of the nature of it, 13 you can't judge it. 14 DR. BYUS: I have a related question. 15 Excuse my ignorance. But if you actually -- if you 16 assume you're spraying one to three pounds per acre 17 and the planes fly in at -- I don't know, how high is 18 it? 19 If you took the volume of air and, you 20 know, immediately after spraying is complete, the 21 concentration in the air is what? In like parts per 22 trillion, it must be. 23 MR. KELLEY: Parts per million. 24 DR. BYUS: Or million. Or whatever it 25 is. It must be quite high. And then it would be 179 BARNEY, UNGERMANN & ASSOCIATES 1-888-326-5900 1 interesting -- as a scientist. I mean, we're all 2 scientists, but I mean it would be nice to have some 3 monitoring, something that monitored with time in the 4 middle of the field right after -- maybe they do 5 this, Jim. I don't know. 6 DR. SEIBER: Yeah, they do some. 7 DR. BYUS: Right after you spray it, it 8 should be extremely high, and how fast does that fall 9 off with time even in the field. I have in the 10 middle of it. I have some -- you know, I can't -- 11 it's hard for me to realize what that would be. 12 And then if you had the data from 13 surrounding the field say in certain places with time 14 and compared all that data, you'd have a really good 15 picture of the exposure. I mean, do people do this? 16 DR. SEIBER: Yeah, they do two kinds of 17 things: one is put them out in the towns; and put 18 them right down -- right next to a treated field to 19 get the absolute worse situation. I'm not sure. Did 20 we do that for methyl parathion? 21 MR. KELLEY: I don't know. 22 DR. SEIBER: Maybe we'll get to it. 23 MR. GOSSELIN: But I think also in the 24 future is as monitoring went on over more recently, 25 more data has been collected including the weather 180 BARNEY, UNGERMANN & ASSOCIATES 1-888-326-5900 1 data that will allow more modeling out to 2 characterize what levels are going to be out there. 3 MR. KELLEY: And actually, my last 4 slide here -- or penultimate, I should say -- no, no. 5 The one just before this. Yes. 6 This is concentrations of methyl 7 parathion in the air following an application. And 8 samplers in this situation were placed approximately 9 17 meters from a field, 20 yards. 10 Treatment field size was 80 acres, and 11 80 pounds of methyl parathion or one pound of active 12 ingredient per acre was applied. This was done in 13 May -- June, I believe, and I don't have air 14 temperatures and/or wind directions for this. 15 But from the background there was no 16 methyl parathion detected. The first sample 17 collected was collected during application and for 18 one hour following application. 19 And you can see that in the samplers 20 that were located north of the field the 21 concentration of methyl parathion was approximately 22 50 parts per trillion, whereas, samplers to the south 23 side of the field were only 20 parts per trillion. 24 In samples collected one to three hours 25 following application these concentrations dropped to 181 BARNEY, UNGERMANN & ASSOCIATES 1-888-326-5900 1 20 parts per trillion for those south of the field 2 and to approximately 17 parts per trillion for the 3 sampler located north of the field. 4 At three to seven hours the sample 5 south of the field concentrations increased to 6 approximately 27 parts per trillion, whereas, to the 7 north the concentration dropped to approximately 10 8 parts per trillion. 9 Samples collected 7 to 18 hours, the 10 concentration rose again to approximately 30. 11 Samples north of the field, they dropped to 12 approximately 10 for samplers located south of the 13 field. 14 And then from 18 to 25 hours, 25 to 48 15 hours -- 49 hours, and the last which is 49 to 73 16 hours, concentrations were all below 10 parts per 17 trillion. 18 And I don't have the data right in 19 front of me, but I can say anecdotally that wind 20 direction at this point in time where the 21 concentrations to the north dropped so much, the wind 22 was blowing more towards the east and away from the 23 samplers and then back at the 7 to 18 hours as the 24 winds had taken again a northerly direction so that 25 depending on which way the wind was blowing. 182 BARNEY, UNGERMANN & ASSOCIATES 1-888-326-5900 1 Which -- and from this data is where 2 we've modified our request to the Air Resources Board 3 and now instead of having north and south samplers we 4 have them on the east and west also and request them 5 to collect a lot more -- wind direction once every 6 six minutes, is it, I think? They're averaging on a 7 six-minute basis so that we can get a lot closer to 8 what's actually happening on the field. 9 DR. BYUS: And again, I -- the aerial 10 spraying is accurate, so I imagine it's very accurate 11 so they don't -- you didn't actually spray the 12 samplers? 13 MR. KELLEY: No, I didn't. 14 DR. BYUS: So this is a true -- 15 DR. SEIBER: Commercial field. 16 DR. BYUS: But those other really high 17 values on the other table might have occurred, but 18 you don't know. One might think they occurred 19 through direct application. 20 You said it was 17 meters. I 21 don't know whether -- they spray that well, do they? 22 I mean -- but in this study they must have is what 23 you're saying. 24 MR. KELLEY: And in conclusion -- 25 DR. FUCALORO: Every once in a while 183 BARNEY, UNGERMANN & ASSOCIATES 1-888-326-5900 1 they get the farmhouse. 2 MR. KELLEY: Actually, they do. 3 In conclusion methyl parathion is an 4 organophosphate insecticide that's used to control a 5 variety of insects and other arthropod pests in a 6 variety of crops in California. 7 Applications of methyl parathion have 8 decreased from a high of over one million pounds 9 previously in 1977 to 72,000 pounds in 1991. Average 10 use for '86 through '95 was approximately 140,000 11 pounds active ingredient. 12 Methyl parathion is applied to a 13 variety of crops. Before 1990 rice accounted for 14 most methyl parathion applications. However, since 15 1990 the major use of methyl parathion has shifted 16 from rice to stone fruit and grapes. 17 Methyl parathion is applied in all 18 counties throughout all months in the year in 19 California. Most applications are made during the 20 months of May -- excuse me, of March, April, May, 21 June, and July. Peak applications occur from 22 mid-June through mid-July. 23 Methyl parathion air concentrations 24 reported in the literature range from 0 to 688 parts 25 per trillion, and formulation plays an important role 184 BARNEY, UNGERMANN & ASSOCIATES 1-888-326-5900 1 in the atmospheric loading of methyl parathion. 2 In ambient air studies conducted in 3 California air concentrations of methyl parathion 4 ranged from 0 to 2.8 parts per trillion. 5 DR. FROINES: I don't understand 6 something about that sentence because this last 7 overhead you showed showed levels up to 50 parts per 8 trillion. 9 MR. KELLEY: Correct. I said in 10 ambient air studies. I will get to that one in just 11 a second. 12 Methyl parathion concentrations, which 13 is my last conclusion, measured at rice fields 14 following application were 47 per trillion, 15 decreasing to less than 3 parts per trillion after 48 16 hours. 17 The ambient air studies -- perhaps I'm 18 using "ambient" incorrectly, but those are the 19 studies that we have conducted which are not 20 associated with specific applications but the 21 monitoring is conducted in areas where applications 22 are occurring during the time of high use. 23 And finally, methyl paraoxon is a 24 breakdown product of methyl parathion, and ambient 25 concentrations ranging from 0 to 0.73 parts per 185 BARNEY, UNGERMANN & ASSOCIATES 1-888-326-5900 1 trillion. 2 That's basically it. Any questions? 3 DR. FUCALORO: Yeah. You know, just on 4 the first page, on that first slide, just a small 5 thing. 6 I don't quite understand that 7 solubility. It says 55 to 60 milligrams per liter in 8 water at 250 degrees centigrade. Now, I don't think 9 you mean 25 degrees centigrade either considering the 10 fact that at 25 degrees centigrade it's somewhere 11 between 13 and 15 milligrams per liter. 12 So I'm not sure what that means, that 13 number. Super heated water? I'm putting it in here. 14 I don't know. Just that. I mean, it's nothing -- 15 nothing that affects any conclusion. 16 And again, I just point out the Henry's 17 Law Constant really I'm pretty sure is temperature 18 dependent. I don't see how it can not be temperature 19 dependent. 20 Because it goes is the log -- I mean, 21 if it goes like normal vapor pressures, it goes is 22 the log, you know -- is the log of the heat of 23 vaporization times one over the temperature. 24 MR. KELLEY: Yeah, you're correct. 25 Since you mentioned it. I didn't have the time to 186 BARNEY, UNGERMANN & ASSOCIATES 1-888-326-5900 1 change it. It's 25 degrees Celsius. 2 DR. FUCALORO: That's 25 -- the 3 solubility? 4 MR. KELLEY: Yeah, the 250 should be 5 25. 6 DR. FUCALORO: Yeah, but then it's at a 7 variance with what you say in your report, I believe. 8 MR. KELLEY: No, in the report I say 9 it's 55 to 60 milligrams per liter in water and 25 10 degrees -- 11 DR. FUCALORO: Maybe I just read it 12 wrong. It's quite possible. I have made mistakes 13 before. It's hard to remember when, but I've made 14 mistakes. 15 MR. KELLEY: Any other questions? 16 MR. GOSSELIN: The next report will be 17 the hazard identification. 18 DR. FROINES: I think -- just to make 19 one comment. I think there's lots of room for 20 expanded exposure characterization based on these 21 limited data, and I think we ought to talk about how 22 to incorporate GIS approaches to some of this 23 exposure modeling. Because we all do it in air 24 pollution work, but it's not GIS -- 25 DR. KENNEDY: What is GIS? 187 BARNEY, UNGERMANN & ASSOCIATES 1-888-326-5900 1 DR. FROINES: Geographic Information 2 Systems. 3 DR. FUCALORO: It's a database that 4 gives altitudes and -- 5 DR. FROINES: Makes maps. 6 DR. FUCALORO: -- makes maps. 7 DR. KENNEDY: Are those formulations 8 routinely available for this sort of data? 9 DR. FROINES: Yeah. 10 DR. KENNEDY: So it's just a matter of 11 providing -- 12 DR. FROINES: Do you have any -- you 13 don't have any with you, do you? 14 UNIDENTIFIED SPEAKER: No, I don't. 15 With all the databases that EPR has with pesticides, 16 I think they can easily be combined with 17 geographic -- 18 DR. FROINES: You can develop a map of 19 the geographical area. You can put in towns, you can 20 put in farms, you can put in the pesticides, and you 21 can overlay it all. And it's all done in a computer. 22 So you can end up with a complete 23 picture of all pesticide use in terms of amount, 24 timing, every variable you would want to. It is in 25 the computer, and you can develop overlaying maps. 188 BARNEY, UNGERMANN & ASSOCIATES 1-888-326-5900 1 DR. KENNEDY: If that's available. We 2 ought to have it. Sure. 3 MR. GOSSELIN: We do sort of extensive 4 work with that. I mean, the new support information 5 we have now is digitized, and we routinely use that 6 in GIS. We have done it for endangered species 7 protection and a lot of other programs. 8 Part of the dilemma we're facing is a 9 lot of -- the work that was done for this predates 10 having the level of detail in the use reports where 11 we don't have it down to the actual geo codes to know 12 where the use was. 13 But you're absolutely right. I think 14 you'll see in the subsequent reports, in the more 15 contemporary assessments we have, you'll see that it 16 will be in GIS format. That will be another tool to 17 help evaluate what all this data means. 18 DR. FROINES: You know, Peter, one of 19 the things that comes up, you know, that EPA went and 20 developed these new particle standards and standards 21 for ozone, and then they -- in their new latest RFA 22 on grant for particle centers they asked a question 23 what's the relationship between ambient monitoring 24 and exposures to human beings, to people. 25 And so you have this disconnect of 189 BARNEY, UNGERMANN & ASSOCIATES 1-888-326-5900 1 the -- of the -- you have emission sources on the one 2 hand, you have ambient monitoring, and then you have 3 personal exposure questions. 4 And so but within that continuum there 5 are -- it's very unclear what the relationship is 6 between ambient monitoring and personal exposure. 7 And it seems to me that one of the problems that 8 regulatory agencies get into is they get into doing 9 ambient monitoring. 10 That's what they do. They set the 11 stations out. But then you go later and you say, 12 "Well, are there any health effects from breathing 13 this stuff in the air?" 14 Well, then the ambient monitoring 15 stations can't help you answer that question because 16 it's really not directed towards people's exposure. 17 And I think that over time we need to develop our 18 sampling systems such that they can actually have 19 implications or relevance to questions about human 20 health that we might want to ask at some point in 21 time. 22 And it's that kind of notion that is 23 where the regulators and the -- in the sense the 24 health science community differ because the 25 regulators want to see if people are over certain 190 BARNEY, UNGERMANN & ASSOCIATES 1-888-326-5900 1 values. 2 But what we're really interested in is 3 whether or not these exposures have actually affected 4 anybody's health. And it's within that context that 5 I think we have to look at how these sampling 6 programs are designed, and GIS modeling for 7 pesticides is the state the art. 8 And Lupita back there has spent almost 9 a year in Mexico doing precisely that and trying to 10 figure out how you then relate some of that to actual 11 person exposure. 12 MR. GOSSELIN: We're going to have a 13 slight change in the format in the presentation. I 14 think it's going to be more helpful. And instead of 15 the getting into the exposure assessment immediately 16 like we did last time, we're going to have Ruby Reed 17 give a presentation on the hazard ID portion that 18 will then bridge into the exposure assessment, and 19 then she'll follow up with the risk characterization 20 and risk assessment, which I think flows more 21 logically through the process. 22 DR. FROINES: Are we talking -- I think 23 we're talking about closing about 3:30. 24 DR. FRIEDMAN: Some of us are leaving 25 at 3:00. At least I'm leaving at 3:00. 191 BARNEY, UNGERMANN & ASSOCIATES 1-888-326-5900 1 DR. FROINES: Who's leaving at 3:00? 2 Gary is. Stan's out making important phone calls. 3 Well, right now we don't have a quorum at all. Maybe 4 we could get some of the quorum into the room. So 5 are we talking about -- if Gary leaves, we still have 6 a quorum. If we can get Stan off the telephone. 7 DR. FRIEDMAN: Do you need a quorum to 8 listen to a presentation? 9 DR. FROINES: I don't know to answer 10 that. That's the lawyers' -- 11 DR. FROINES: George. 12 DR. ALEXEEFF: I just have a question. 13 We have -- OEHHA has some findings on the document. 14 It's probably not necessary for us to verbally 15 present them. They're fairly self-explanatory. 16 Last -- for DEF, when we began to present it, it was 17 clear it would be redundant to some of the 18 presentation of the DPR staff. 19 So I think in that sense maybe we can 20 just -- I think we can just submit them to the panel 21 for consideration. They can -- we can look at them. 22 And there's no reason for an OEHHA presentation 23 because we generally concur with their report. 24 DR. FROINES: Well, that's good to 25 know. 192 BARNEY, UNGERMANN & ASSOCIATES 1-888-326-5900 1 DR. ALEXEEFF: Not to steal your 2 thunder, but I just thought -- 3 DR. FROINES: No blood on the floor. 4 We are going to take this up next 5 month, and I'll -- and I know that -- see, I have to 6 be back at UCLA by 6:00. Gary's leaving at 3:00. So 7 we have -- I'd like to leave about 3:30. So if we 8 can go until 3:30 and just start next -- why don't we 9 say 3:30 is our cutoff, and then we'll start next 10 time where we didn't get to. 11 Is that okay? 12 DR. GLANTZ: I'm back. Sorry. 13 DR. FROINES: You're our quorum because 14 Seiber may have left. No, he's still here. 15 Go ahead. 16 DR. REED: Thank you. I am Nu-May 17 Reed. People call me Ruby. I answer to both names. 18 But if you call our department and ask for Nu-May, 19 you'll get a no for an answer. That's what happened 20 to Craig. 21 DR. BYUS: You are really there, 22 though; right? 23 DR. REED: Yes, I have been. 24 Can we have the lights off, please. 25 The next slide is just going to be sort 193 BARNEY, UNGERMANN & ASSOCIATES 1-888-326-5900 1 of a graphic location in terms of what I will be 2 presenting with respect to the four components of 3 risk assessment. 4 DR. FROINES: We have had handouts. 5 DR. REED: Yes. 6 Tareq, could I have the next slide, 7 please. 8 This particular slide is not in your 9 handout. As I said, this is just sort of a graphic 10 presentation in terms of what I will be presenting 11 now. It will be on the hazard identification and 12 dose response assessment. And then Tareq will come 13 back to present the exposure assessment, and then I 14 will come back and present the risk characterization. 15 Next slide, please. 16 A well-characterized mechanism of 17 toxicity of methyl parathion is the inhibition of 18 cholinesterase and cause an accumulation of 19 neurotransmitter acetylcholine at the nerve 20 junctions, and the consequences are manifested in 21 neurological signs and symptoms of both the 22 peripheral and central nervous systems. 23 The estimated rates of methyl parathion 24 absorption through oral and inhalation routes are 100 25 percent. Methyl parathion crosses the brain barrier 194 BARNEY, UNGERMANN & ASSOCIATES 1-888-326-5900 1 and the placenta. 2 Methyl parathion is metabolically 3 activated to methyl paraoxon which inhibits 4 cholinesterase by binding to its active site. Methyl 5 parathion is eliminated as para-nitrophenol in the 6 urine. 7 Age specific sensitivity to methyl 8 parathion is evident in rats. Neonates can be 9 approximately tenfold more sensitive than the adults 10 to the acute toxicity of methyl parathion. 11 The activities of paraoxonase, the 12 enzyme that breaks down methyl paraoxon, can vary in 13 human population by more than sixtyfold, and this is 14 illustrated as a -- sort of a profile of 15 polymorphism. 16 Next slide, please. 17 The endpoints of toxicity have been 18 identified in the following areas: 19 In humans symptoms of acute poisoning 20 of methyl parathion are typical of cholinergic 21 abundance such as salivation, lacrimation, myosis, 22 defecation, urination, headaches, dizziness, labored 23 breathing, twitching, convulsion, and death. It 24 depends on the dose. 25 Methyl paraoxon acute -- parathion 195 BARNEY, UNGERMANN & ASSOCIATES 1-888-326-5900 1 acute poisoning can result in intermediate syndrome 2 which typically appears one to four days after 3 successful treatments of cholinergic crisis. 4 Intermediate syndrome includes myopathy, respiratory 5 paralysis, nerve palsies, and muscle weaknesses. 6 In animal studies acute and subchronic 7 exposure to methyl parathion in terms of 8 neurotoxicity results in plasma, RBC, and brain 9 cholinesterase inhibition. And cholinergic effects 10 include similar things as I have sort of enumerated 11 for the humans: lacrimation, salivation, shivering, 12 muscle fasciculation, labored breathing, and other 13 neurological effects. Neurobehavioral changes have 14 also been identified. 15 Chronic exposure to methyl parathion in 16 the animals resulted in cholinesterase inhibition 17 again and tremors, alopecia, body weight changes, 18 paralysis, as well as myelin degeneration of nerves. 19 Long-term feeding studies in rats and 20 mice showed no clear evidence of oncogenicity 21 although data indicated that methyl parathion has 22 genotoxic potential. 23 In terms of reproductive developmental 24 effects methyl parathion decreases the survival in 25 body weight of rat pups in two- and three-generation 196 BARNEY, UNGERMANN & ASSOCIATES 1-888-326-5900 1 reproductive studies and can cause male and female 2 reproductive toxicities also. 3 Methyl parathion causes lower fetal 4 body weight, increased resorption, reduced pup 5 survival, and abnormalities and variations of the 6 fetal ossification in rats and rabbits. 7 Neurobehavioral changes can result from in utero 8 exposures. 9 Methyl parathion is not known to show 10 organophosphorous-induced delayed neuropathy in hens. 11 Methyl parathion suppresses the immune 12 system, and methyl parathion causes hematological 13 changes which includes decreased RBC, hemoglobin, and 14 hematocrit. 15 Next slide, please. 16 There's no inhalation studies available 17 for directly establishing the NOELs for the 18 inhalation exposures, so oral NOELs are used to 19 assess the risk of inhalation exposures. 20 There's two acute NOELs identified for 21 risk assessment: one is a human NOEL at 0.31 22 milligram per kilogram a day; and based on the LOEL, 23 just slightly above that level, which is 0.34 24 milligram per kilogram a day. 25 And the endpoints identified at the 197 BARNEY, UNGERMANN & ASSOCIATES 1-888-326-5900 1 LOEL are at the plasma and RBC cholinesterase 2 inhibition. And the figure that I presented here in 3 the overhead represents the individual that has the 4 highest inhibition. 5 DR. SEIBER: Is the -- is the L -- 6 let's see, NOEL calculated from the LOEL, or are they 7 both -- 8 DR. REED: No. 9 DR. SEIBER: What's the relationship 10 between those? They seem awfully close together. 11 DR. REED: Right. Right. There were 12 just a group of five volunteer human subjects being 13 dosed with different amounts, and they have a very 14 close range. 15 DR. BYUS: It's one of the most poorly 16 designed studies I've ever read. 17 DR. REED: You're correct. 18 DR. BYUS: I encourage you all to read 19 about it in the document to see how poor. And the 20 fact that EPA, according to your document, actually 21 used this experiment in humans to make regulatory 22 decisions and do calculations is actually very 23 appalling to me. So I encourage you to read it just 24 so you can -- to Ruby's credit she doesn't think much 25 of the study either. 198 BARNEY, UNGERMANN & ASSOCIATES 1-888-326-5900 1 DR. REED: And I will -- in the next 2 round I will talk about the uncertainty factors 3 associated with all the NOELs that we have determined 4 here. 5 DR. FRIEDMAN: Excuse me. Can I just 6 ask where they got the volunteers and did the 7 study -- 8 DR. REED: Prisoners in the late '60s 9 and early '70s. 10 DR. FRIEDMAN: I see. I don't know 11 that this would pass an institutional review board 12 anymore. 13 DR. REED: So I didn't think that that 14 human NOEL is adequate. So I've also identified a 15 NOEL in rats is at 0.1 milligram per kilogram a day. 16 And this one is estimated from the LOEL because 17 there's no NOEL from a group of studies that have all 18 identified the LOEL at one milligram per kilogram a 19 day. And the effects that the LOEL included brain 20 cholinesterase inhibition, cholinergic signs, pup 21 survival in the developmental toxicity studies, and 22 also reproductive studies, and neurobehavioral 23 effects. 24 DR. GLANTZ: So for No. 2 did you just 25 take one-tenth of the LOEL? 199 BARNEY, UNGERMANN & ASSOCIATES 1-888-326-5900 1 DR. REED: Correct. Yes, I did. 2 DR. GLANTZ: But in No. 1 that's a real 3 NOEL to the extent that crummy study didn't find 4 anything. 5 DR. REED: Right. Sort of real NOELs 6 because I have the dose divided by 70 kilograms 7 because the study did not give me the body weight of 8 the humans. 9 Okay. A list of all the relevant acute 10 toxicity NOELs and LOELs is presented in table 19. 11 And I have two columns. One is based on 12 cholinesterase inhibition including plasma and RBC 13 cholinesterase inhibition, and the other column is 14 the other effects other than cholinesterase 15 inhibition. 16 There's also in the document data on 17 cholinesterase inhibition from acute subchronic, 18 chronic exposures so that you could read them back 19 and forth and decide for yourself what will be the 20 NOELs and LOELs based on plasma and RBC 21 cholinesterase inhibition. 22 DR. FROINES: Are you assuming that 23 neurobehavioral effects are related to the 24 cholinesterase inhibition? 25 DR. REED: I am not sure. The only 200 BARNEY, UNGERMANN & ASSOCIATES 1-888-326-5900 1 sort of known mechanism is the cholinesterase 2 inhibition. However, there's many effects, as I 3 identified in here, and I'm not sure what are the 4 mechanisms. 5 Next slide, please. 6 In terms of subchronic toxicity, 7 because the human NOEL was determined for an exposure 8 duration of 30 days, so theoretically that could also 9 be used as a subchronic NOEL. But as I said, the 10 human NOEL was not very satisfying. 11 I've also identified NOEL from a group 12 of studies in rats, and, again, in these studies 13 there's not NOEL. The lowest dose was having an 14 effect, so that was the LOEL at 0.2 milligram per 15 kilogram a day. 16 And so the NOEL extrapolated down by 17 tenfold would be 0.02 milligram per kilogram a day, 18 and the effects of the LOEL are brain cholinesterase 19 inhibition and neurobehavioral effects. 20 DR. GLANTZ: Now, why did you use a 21 factor of 10? 22 DR. REED: This is the default for not 23 having enough data to do any benchmark dose or 24 extrapolations or interpolations. 25 DR. GLANTZ: Where does that -- who 201 BARNEY, UNGERMANN & ASSOCIATES 1-888-326-5900 1 decided that and why? 2 DR. REED: This has been sort of a 3 default for risk assessment, and one of sort of the 4 maybe not so fancy sort of layman explanation is 5 because in choosing dose groups for toxicity studies, 6 usually you're not seeing a distance or the 7 differences between two doses greater than tenfold. 8 Usually it's three- to tenfold. 9 So it's sort of saying that okay. 10 Well, if you had included a lower dose and assuming 11 that point would give you the NOEL, then it's within 12 three- to tenfold down. And so that was sort of the 13 default. 14 DR. FUCALORO: So experience shows you 15 it's somewhere in the range of 3 to 10. Is that -- 16 DR. REED: Only by considering dose 17 selection in a study. So it's a very soft default. 18 DR. GLANTZ: Right. But like what if 19 the person had happened to have done the study say at 20 a dose 10 times the dose they used, then you would 21 say the NOEL for rats was .2 which in fact when they 22 did the study they found an effect. 23 So I mean, doesn't that bother you? 24 DR. REED: It does, because this is 25 a -- as I said, it's a default, a soft default. And 202 BARNEY, UNGERMANN & ASSOCIATES 1-888-326-5900 1 so that will go into the uncertainty factor -- 2 uncertainty analysis that I was going to show you at 3 the end. 4 DR. FROINES: I think that one thing 5 you should be aware of -- and I don't know if George 6 has seen Dale's latest paper, but Dale Patters has 7 just written a very large paper on interindividual 8 variability for non-cancer effects. 9 And one of the things that's clear from 10 his paper is that the tenfold safety factor for 11 individual intervariability is a wonderful historical 12 premise but it's wrong in that regulatory agencies 13 are going to have to look at the issues using more 14 quantitative techniques now because there is clearly 15 so much more heterogeneity in humans that the simple 16 tenfold factor simply isn't adequate. And if 17 anybody's interested, I can send you the paper. 18 DR. REED: That was -- 19 DR. FROINES: It's a brilliant piece of 20 work. 21 DR. REED: That was sort of indicated 22 in the database in methyl parathion also. As I said, 23 within the human population, for example, just by 24 looking at methyl paraoxonase which detoxifies methyl 25 paraoxon, you would have more than sixtyfold of 203 BARNEY, UNGERMANN & ASSOCIATES 1-888-326-5900 1 differences within human population, not tenfold. 2 However, we don't know how to translate 3 that particular enzyme to the wholistic -- the whole 4 body responses. It doesn't look like it's one to one 5 in animal -- in rabbits and rats. So we don't know 6 how to translate that. But it could be greater than 7 10. You're right. 8 But what I think we're talking about is 9 going from LOEL down to NOEL, not even getting into 10 the interspecies extrapolation yet. So that's 11 another soft number. 12 DR. GLANTZ: Right. But the thing that 13 concerns me -- 14 DR. FROINES: I'm not talking about 15 interspecies. I'm talking about interindividual. 16 DR. REED: Right, right. 17 Inter-individual. Correct. 18 DR. GLANTZ: The thing that concerns 19 me, though, is that you're just assuming that the 20 NOEL would be an order of magnitude smaller than the 21 lowest dose that somebody happened to study. 22 DR. REED: Right, right. 23 DR. GLANTZ: So but what if they 24 happened to study a higher dose? 25 DR. REED: Correct. Correct. 204 BARNEY, UNGERMANN & ASSOCIATES 1-888-326-5900 1 And I -- maybe this is a good time to 2 bring this up. In terms of receiving comments, Paul 3 had mentioned that we received studies, four studies 4 that we have not seen before. Amongst the four 5 studies was one acute neurotoxicity study, and that 6 was exactly what happened, what you're talking about. 7 The LOEL was at 7.5 milligram per 8 kilogram a day. However, they have the large space 9 between that and the next lower dose which is 0.025. 10 And so if you were to call a NOEL and a LOEL based on 11 the study itself, the LOEL would be 7.5. The NOEL 12 would be 0.025. A large distance. 13 DR. GLANTZ: See, that's what I would 14 do. Because what that's -- what I interpreted NOEL 15 as is the small -- is the largest dose that had been 16 given that produced no detectable effect. 17 DR. REED: Yes, yes. 18 DR. GLANTZ: So rather than just 19 saying -- taking the smallest dose that produced an 20 effect -- 21 DR. REED: Right. 22 DR. GLANTZ: -- and cutting it by a 23 factor of 10, I think -- to me what it means is it's 24 the largest dose where you didn't see any effect. So 25 in that case I would take the .02 or whatever the 205 BARNEY, UNGERMANN & ASSOCIATES 1-888-326-5900 1 number was. 2 DR. REED: Correct. Right. For that 3 study, yes. But this group of studies that have the 4 lowest to LOEL, there is the NOEL attached -- 5 associated with these studies, so that's sort of all 6 that we can do. And it comes with a lot of 7 uncertainties, yes. 8 DR. GLANTZ: But what I would do is say 9 that you don't know what the NOEL is rather than put 10 a number down which is really very arbitrary. 11 DR. REED: Sure, sure. 12 DR. GLANTZ: I'd say a NOEL is unknown. 13 DR. REED: Sure. We have a different 14 term for it, which I did not use in this document. 15 Sometimes we use the term as "estimated NOEL" and 16 then explain how it was estimated. 17 DR. GLANTZ: But I wouldn't even do 18 that. I would just say it's unknown. 19 DR. REED: Okay. 20 DR. GLANTZ: I mean, that's why you 21 have -- I mean -- anyway, I've said enough. 22 DR. FUCALORO: Well, you know, it's 23 hard to know. I think it's a good point. Obviously 24 it's a clear flaw if you give a dosage to 25 something -- a dosage to some animal or to a human 206 BARNEY, UNGERMANN & ASSOCIATES 1-888-326-5900 1 being and you find that there's an adverse effect and 2 you just say at 10 times the reduced amount there 3 will be none. That clearly is -- I don't know what 4 basis that has. 5 But it seems to me, though, there's 6 another built-in factor when you look at your MOEs; 7 right? 8 DR. REED: Uh-huh. 9 DR. FUCALORO: You're looking at 10 factors of 10 or 100 where the 10 is human studies 11 and 100 animal studies to put in yet another 12 buffering, another effect. 13 So if one does what Stan suggests, one 14 has to look at the reason for putting in the factor 15 of 10 and 100 in the MOEs. I mean, there must be a 16 reason for doing that, and maybe it's just the reason 17 he's talking about. I don't know. 18 DR. GLANTZ: I mean, I think it would 19 be -- 20 DR. REED: That's a different factor. 21 DR. SEIBER: That's the safety factor 22 that John was talking about. 23 DR. REED: Yes, that John was talking 24 about. 25 DR. SEIBER: That and the interspecies 207 BARNEY, UNGERMANN & ASSOCIATES 1-888-326-5900 1 extrapolation. 2 DR. REED: Yes, yes. 3 DR. GLANTZ: I think it would be 4 clearer to say we don't know what the NOEL is so 5 we'll take the LOEL, apply a safety factor of some 6 multiplier, you know, plus the other safety factors 7 or multiply by the other safety factors rather than 8 calling it a NOEL. Because when I see that number I 9 think it's a piece of data, and it's not. It's an 10 assumption. 11 DR. SEIBER: I would argue slightly 12 differently and say don't throw it out but go study 13 by study. If in fact there was a big jump between 14 where the effect was observed and the next one, then 15 you've got a problem, just as you pointed out. 16 But if there was a small jump, this is 17 standard fare in risk assessment, and I don't think 18 I'd want to throw out all the data that has only 19 LOELs and not use them at all. 20 DR. FROINES: I think that you 21 ultimately are going to have to look at the issue 22 distributionally and not simply taking these 23 averages. 24 DR. FUCALORO: John, did you say look 25 at the issue what? I missed it. 208 BARNEY, UNGERMANN & ASSOCIATES 1-888-326-5900 1 DR. FROINES: Distributionally. 2 DR. REED: Right. 3 DR. FROINES: You want to look and see 4 how the animals are affected and to what degree 5 across the range -- 6 DR. REED: Right. But the response 7 at the LOEL is very important and so that the ideal 8 case would be to do a benchmark dose approach where 9 you identify the percentage of response, like 10 10 percent of response, and instead of extrapolating, 11 you're sort interpolating it -- 12 DR. FUCALORO: But benchmark assumes 13 dose response -- doesn't it -- data? Availability 14 of -- 15 DR. REED: Right. In this case it was 16 not available. 17 DR. FUCALORO: Right. That's what I 18 mean. That's the problem. You don't have -- 19 DR. REED: That's the problem, yes. 20 Thank you. 21 DR. FROINES: But you're still right 22 that in -- that I still would argue that the 23 benchmark approach is the better approach in the long 24 run and that these historical safety factor 25 approaches are really in a sense unsatisfactory from 209 BARNEY, UNGERMANN & ASSOCIATES 1-888-326-5900 1 a statistical standpoint. 2 DR. REED: Right. For many 3 considerations it's unsatisfactory, yes, you're 4 right. 5 DR. BYUS: Isn't there one study that 6 was used for serum cholinesterase to calculate the 7 NOEL? The real NOEL -- calculated NOEL based on 8 knowing a dose response and knowing an inhibition 9 serum cholinesterase? 10 And that actually turned out to be 11 higher. As I recall, it was a higher value, a real 12 NOEL, than what she used based on a LOEL to NOEL 13 factor of 10 conversion. It was actually higher. 14 DR. REED: And that was what I was 15 going to present. 16 DR. BYUS: I'm sorry. I just tried 17 to -- 18 DR. REED: It's okay. 19 DR. FROINES: Did George want to say 20 something? 21 DR. ALEXEEFF: Yeah. I just had one 22 thing to add to Ruby's comments here, and it's 23 actually in our acute document so when we get to 24 that. 25 But there is -- the relationship 210 BARNEY, UNGERMANN & ASSOCIATES 1-888-326-5900 1 between the NOEL and the LOEL actually is a 2 reflection of the steepness of the dose response 3 curve, so if one has the benchmark dose, you're 4 taking it into account right off the bat. 5 And we did an analysis which we 6 referred to in that report that we presented at the 7 cytotoxicology meetings where we looked at LOELs and 8 NOELs from over 100 studies, different types of 9 endpoints, and then did a distributional approach 10 where -- to look at what -- what percent of the 11 studies would a factor of 10 be predicting accurately 12 or better -- or more health protectively. And it 13 kind of came out to around 85 percent. 14 And that was sort of what was used to 15 create this originally in -- or to justify the NOEL 16 originally in the early '80s or the late '70s. They 17 looked at the low -- they looked at what doses caused 18 the effect and didn't cause it and sort of figured, 19 well, tenfold protected most of the situations. And 20 that's the default that we generally use, and it 21 seems to be about 85 percent of the results. But 22 again, if you use the dose response curve and that's 23 doing the same thing in the benchmark dose 24 analysis -- 25 DR. FUCALORO: But the dose response 211 BARNEY, UNGERMANN & ASSOCIATES 1-888-326-5900 1 essentially gives you those values. 2 DR. ALEXEEFF: Yes, it's exactly doing 3 that. So if you have a shallow dose response, the 4 other issue to point out is in a situation like this 5 where you have brain cholinesterase, the dose 6 response curve will be shallower than if it's 7 lethality. Lethality is generally a steeper dose 8 response curve. 9 So 10 is probably more appropriate or 10 maybe more appropriate in this case. We don't have 11 the data. But maybe more appropriate in this case 12 than it would be in the situation like lethalities. 13 DR. FROINES: But we haven't said a 14 word about metabolism. We don't know about 15 nonlinearese yet either. And there must be some 16 nonlinearese depending upon the dose. 17 DR. REED: On the system that maxes out 18 at the higher dose. 19 In terms of using plasma and RBC 20 cholinesterase as an endpoint, using the same set of 21 subchronic toxicity data, the NOEL would be at .3 22 instead of 0.02 that have been extrapolated from the 23 NOEL. 24 DR. BYUS: So you're actually choosing 25 a lower value? 212 BARNEY, UNGERMANN & ASSOCIATES 1-888-326-5900 1 DR. REED: Yeah. Almost tenfold lower 2 than -- 3 DR. FROINES: I was saying goodbye to 4 Jim. What did you say? I'm sorry. This is 5 important. 6 DR. REED: Using the same set of 7 database, the subchronic toxicity database, if I were 8 to pick a NOEL based on plasma and RBC cholinesterase 9 inhibition, the NOEL would be 0.3 instead of the NOEL 10 that I estimated from the LOEL. 11 DR. FROINES: You said the LOEL would 12 be 0.3? 13 DR. REED: NOEL. No effect level would 14 be 0.3. 15 DR. FROINES: With what endpoint? 16 DR. REED: Plasma and RBC 17 cholinesterase inhibition. 18 DR. FROINES: Plasma -- 19 DR. REED: And RBC cholinesterase 20 inhibition. 21 DR. BYUS: There basically was one 22 fairly decent study where they actually measured over 23 quite a large number of doses in animals. They 24 actually measured the serum cholinesterase. 25 And if you take that value -- I 213 BARNEY, UNGERMANN & ASSOCIATES 1-888-326-5900 1 couldn't figure out why she wasn't taking that value. 2 Well, that value turns -- which is a real NOEL, and 3 essentially you can measure that in the dose below 4 which you don't get any reduction in serum 5 cholinesterase, which the EPR doesn't like by policy 6 to pick for a NOEL because they don't feel it -- I 7 mean, I'm not -- you know what I mean. Because I 8 don't feel it has any function. 9 But it's really not a very good way to 10 do it. That dose actually turns out to be 11 significantly higher than the dose that they chose 12 based on the tenfold lower than the LOEL. 13 DR. FROINES: I think the tenure of the 14 conversation today is I don't see anybody in the room 15 saying that the blood cholinesterase is not a measure 16 of some adverse effect. 17 DR. BYUS: I don't either anymore. 18 DR. FROINES: I think that one has 19 problems with validation of the relationship, but I 20 think that nobody would argue that it's good for you. 21 Nobody -- not even Paul. That was a joke. 22 DR. BYUS: But the point is -- 23 DR. GLANTZ: Paul's boss might. 24 DR. BYUS: She was health conservative 25 in choosing these values, by my estimation. 214 BARNEY, UNGERMANN & ASSOCIATES 1-888-326-5900 1 DR. FROINES: What do you get if you 2 take the neurobehavioral effect and calculated NOEL? 3 DR. REED: The neurobehavioral effect 4 LOEL is .2 milligram per kilogram a day. And so it's 5 estimated as 0.02 as the NOEL. 6 DR. BYUS: Which is the lowest value. 7 The one she picked is actually based on the neuro -- 8 excuse me. 9 DR. REED: Yes. 10 DR. BYUS: As I understand -- I'm just 11 trying to clarify it in my own mind. 12 DR. REED: Yes. 13 DR. BYUS: It's based on the 14 neurobehavioral effects, but the NOEL is based on the 15 calculated from the LOEL. Do you see what I'm 16 saying? 17 She takes the NOEL tenfold from the 18 LOEL based on the neurobehavioral effects. That is 19 the lowest value of all the data that's out there, 20 and that's the one she uses to do the 21 characterization. 22 DR. FROINES: I just want to make sure, 23 because I'm -- I'm waiting to deal with the -- in 24 part with neurobehavioral effects as also a chronic 25 phenomenon and how one does that. 215 BARNEY, UNGERMANN & ASSOCIATES 1-888-326-5900 1 DR. REED: Well, in terms of chronic 2 toxicity there is not a neurobehavioral study for 3 that, and so the lowest NOEL -- Tareq, I'm sorry, 4 next slide, please. 5 DR. FROINES: Is that because nobody's 6 looked for any, or is it because -- 7 DR. REED: Nobody did chronic 8 neurobehavior. It's a long time. 9 DR. FROINES: So it's not a negative 10 study. It's a non -- no study. 11 DR. REED: Correct. It's no study. 12 In terms of chronic toxicity the NOEL 13 is 0.02, which you notice is the same as the 14 subchronic NOEL that I estimated from the subchronic 15 LOEL. And the chronic NOEL is based on myelin 16 degeneration in proximal sciatic and tibial and 17 peroneal nerves. 18 DR. FROINES: And there's no evidence 19 of axonal involvement? There's no -- you know -- 20 DR. REED: No. 21 DR. FROINES: -- the kind of things you 22 would see with central neuropathy? 23 DR. REED: Right. No. Not the delayed 24 neuropathy kind of -- 25 DR. FROINES: You don't see any axonal 216 BARNEY, UNGERMANN & ASSOCIATES 1-888-326-5900 1 bulging at the nodes? 2 DR. REED: Yeah. Not the nodes. But 3 in the nerve fibers there's bubbling in the myelin 4 degeneration, yes. 5 DR. FROINES: So the bubblings is in 6 the myelin? 7 DR. REED: Right. 8 DR. FROINES: And you're not seeing any 9 axonal effects there? 10 DR. REED: No, no. 11 DR. FROINES: Like a hexane neuropathy? 12 DR. REED: Right. No. 13 Methyl parathion is -- was presented 14 coexists in the air with methyl parathion. And since 15 methyl paraoxon is the active moiety or analogue of 16 methyl parathion, we thought it's important to look 17 at the toxicity of methyl paraoxon. 18 In terms of toxicity data all we have 19 are the acute toxicity data, LD 50 data, and 20 inhibition dose of 50 percent inhibition of 21 cholinesterase. 22 In rats it varies from 4.5 to 8.2 in 23 terms of the ratios between methyl paraoxon and 24 methyl parathion. So we have established a toxicity 25 equivalency factor for methyl paraxon as 10. 217 BARNEY, UNGERMANN & ASSOCIATES 1-888-326-5900 1 That would mean methyl paraoxon could 2 be 10 times more toxic than methyl parathion. And 3 that toxicity equivalency factor is used in 4 calculating the total exposure which includes methyl 5 parathion and methyl paraoxon. 6 And this is where I will stop, and we 7 will talk about the exposure assessment and then come 8 back to do risk characterization. 9 DR. FROINES: What time is it? 10 DR. REED: Five minutes after 3:00. 11 MR. GOSSELIN: Next Tareq Formoli will 12 present the exposure assessment, and then we'll have 13 Ruby come back and wrap up, if we have time, putting 14 the pieces together on the risk assessment. 15 DR. GLANTZ: Just while they're getting 16 it together. So we're not acting on this report 17 today, then? 18 DR. FROINES: Not even close. We're 19 not even really discussing it. 20 DR. GLANTZ: So now, are we going to be 21 getting another draft of this before we actually 22 start working on it in earnest? 23 MR. GOSSELIN: Yeah, we have been 24 working with the leads on this. Like I said, we have 25 received public comments during the public comment 218 BARNEY, UNGERMANN & ASSOCIATES 1-888-326-5900 1 period including four studies that came in that may 2 or may not change some of the endpoints and 3 conclusions, and we need to review that and come 4 back. So inevitably this report is going to be 5 amended. 6 DR. FROINES: If it was said earlier -- 7 and I have forgotten -- Tony and -- 8 DR. FUCALORO: Craig. 9 DR. FROINES: -- Craig are the leads. 10 DR. FUCALORO: And a good job we're 11 doing. 12 DR. BYUS: We deserve a raise. 13 DR. FROINES: I just want to comment 14 from the chair and say I wanted to make sure 15 everybody realizes what a good job you're doing. 16 DR. GLANTZ: And Bill Lockett will get 17 them a raise. You know how the issue of raises comes 18 up. 19 MR. GOSSELIN: Even if they did it on 20 performance, you got it made. 21 DR. FUCALORO: How kind you are. 22 DR. BYUS: They could pay us by the 23 document, piecework. 24 DR. FROINES: Let's go. Please 25 continue. 219 BARNEY, UNGERMANN & ASSOCIATES 1-888-326-5900 1 MR. FORMOLI: My name is Tareq Formoli, 2 and I prepared the exposure assessment part of this 3 methyl parathion document. 4 Kevin Kelley already talked about the 5 products and usage of methyl parathion. I just would 6 like to reiterate a few points about the usage that 7 are relevant to the exposure assessment and the 8 ambient air monitoring studies that we are going to 9 discuss later on. 10 Despite the trend that we talked about 11 that more methyl parathion is used on fruit trees and 12 vines, 20 to 30 percent of the total use still is 13 used on rice, and that's based on the use report for 14 the last five, six years that are available. 15 The window of application for rice is 16 very narrow, and it's applied during the month of 17 May. Other uses the season is pretty much it's 18 applied during the entire year but mostly during the 19 month of April, May, and June. Very little is used 20 during the November and December and January. 21 For the last 10 years of illness 22 reports that is available, there are 18 illnesses 23 reported for methyl parathion. Sixteen of those 24 illnesses were associated with occupational exposure; 25 two illnesses were associated with non-occupational: 220 BARNEY, UNGERMANN & ASSOCIATES 1-888-326-5900 1 one was an attempted suicide, and one was a drift, 2 associated with drift. 3 There are several studies of methyl 4 parathion ambient air monitoring. The first study 5 that -- that is the Stanley, et al., study. They 6 looked at 10 states including California at Fresno 7 and Riverside. They did not detect any methyl 8 parathion in Fresno and Riverside, but in other 9 locations the maximum they detected was 148 nanogram 10 per cubic meter with an average of 29 nanogram per 11 cubic meter. 12 Arthur, et al., we -- in Stoneville, 13 Mississippi, they observed the maximum level of 2,060 14 nanogram per cubic meter which was the highest 15 reported in the literature. 16 DR. FUCALORO: And you'll check that 17 number; right? 18 MR. FORMOLI: Yes. 19 DR. FUCALORO: That's the number? 20 MR. GOSSELIN: Actually, we looked -- 21 if you look at -- Lynn Baker, actually, pointed out 22 the -- the footnote E actually explains where they 23 took -- where those numbers actually came from. 24 It had to do with they took weekly 25 averages versus the monthly averages. So the numbers 221 BARNEY, UNGERMANN & ASSOCIATES 1-888-326-5900 1 are correct, and they're not from the same source of 2 data. 3 DR. FUCALORO: Okay. 4 MR. FORMOLI: Kutz, et al., study, they 5 looked at 15 states. They did not look in 6 California. The levels ranged from non-detectable to 7 a maximum of 278 nanogram per cubic meter which was 8 in Oklahoma. 9 Kutz in 1983, they looked at ten 10 locations in eight states including Pasadena and 11 Fresno cities. They actually looked for 12 p-nitrophenol which is a breakdown of methyl 13 parathion. The average was 2.9 nanogram per cubic 14 meter with a maximum of 160 nanogram per cubic. 15 Sava looked at Salinas residential 16 areas, and only one sample was positive, and that was 17 17 nanogram per cubic meter. 18 The Seiber, et al., study, which was 19 the most -- the study with the considerable amount of 20 information, this study conducted -- was conducted in 21 two counties of Colusa and Sutter which are the rice 22 growing areas of California. 23 This is 24-hour sampling for four days 24 throughout the use season of methyl parathion to 25 rice, and it was from May 12 to June 12. They looked 222 BARNEY, UNGERMANN & ASSOCIATES 1-888-326-5900 1 for methyl parathion and also for methyl paraoxon. 2 The highest level of methyl parathion 3 was observed in Maxwell, and it was 34.7 nanogram per 4 cubic meter with an average of 8.4. The highest 5 level of methyl paraoxon was 9 nanogram per cubic 6 meter with an average of 1.8 nanogram per cubic 7 meter. 8 Would you go to the next slide, please. 9 Figure 1 shows the use of methyl 10 parathion around the areas of Maxwell and Williams 11 during this -- when the study was conducted. 12 As we see, the use starts somewhere 13 around May 3, and it peaks about May 11 to May 23, 14 then it drops, and by end of early June it's -- there 15 is no application. 16 And the areas of Sutter County and 17 around Trowbridge and Robbins the application 18 started -- you know, there were just some 19 applications May 2, but there were no applications 20 until May 18, and then it just lasted for 10 days or 21 so. 22 Next one. 23 Figure 3 shows when we put the 24 application along with the levels of methyl parathion 25 in the air in Colusa County. As we see, the highest 223 BARNEY, UNGERMANN & ASSOCIATES 1-888-326-5900 1 levels were observed during the peak application 2 season with highest levels in the town of Maxwell. 3 Figure 4 also shows the use versus 4 levels of methyl parathion in the air, as we see, and 5 Sutter County, it's mostly -- the levels of methyl 6 parathion were mostly non-detectable except for the 7 high peak application periods. 8 There were also -- we also looked at 9 several application site air monitoring for methyl 10 parathion. The first study, ARB study, they 11 monitored 80 acres of rice field in Sutter County. 12 They had monitoring stations at 13 20 yards downwind and 20 yards upwind and at 250 14 yards -- I believe it was downwind also. Right after 15 one hour after the application, they did not detect 16 any methyl parathion at 250 yards. 17 But at 20 yards the levels are shown in 18 table 3, and as we see, as time passes, the level of 19 methyl parathion declines considerably to -- from 512 20 nanogram per cubic meter at 1 hour after the 21 application to 28 nanogram per cubic meter at 49 to 22 73 hours after the application. 23 The other study of application site was 24 by Seiber and McChesney. They -- the monitoring site 25 for this study was at 17 yards downwind rice field in 224 BARNEY, UNGERMANN & ASSOCIATES 1-888-326-5900 1 Glenn County. 2 Samples were collected at 1, 7, 48, and 3 55 hours after the application, and the 4 concentrations were 1,030, 1,160, 51, and 48 nanogram 5 per cubic meter, respectively. 6 The last study was by Jackson and Lewis 7 in North Carolina. This is not -- this was not in 8 California. They looked at the concentration 1 meter 9 from the tobacco field. And there were two fields: 10 one was applied with EC formulation, and the other 11 was applied with microencapsulated formulation. 12 As it was pointed out before, the 13 levels of methyl parathion were much lower with 14 the -- when the microencapsulated formulation was 15 used. 16 Next, please. 17 To estimate public exposure to methyl 18 parathion we divided the humans in three subgroups: 19 children of six years old for -- to present children; 20 adult female; and adult male. 21 Type of exposure was also divided in 22 three groups: absorbed daily dosage to represent 23 acute exposure; seasonal average daily dosage to 24 represent subacute or seasonal exposure; and annual 25 average daily dosage to show the annual exposure. 225 BARNEY, UNGERMANN & ASSOCIATES 1-888-326-5900 1 Acute exposure or absorbed daily dosage 2 was based on 95th percentile of the concentration of 3 methyl parathion in the air; seasonal average daily 4 dosage was based on average of the season; and annual 5 average daily dosage was based on average of the 6 season for nine months of the season -- in a year 7 which is 12 months. 8 Based on the Seiber, et al., 1987 9 study, the estimates of exposure ranged from -- we're 10 going to look at the location with the highest 11 concentration of methyl parathion, which was in the 12 Maxwell, and it ranged from 5.4 nanogram per kilogram 13 per day for adult female to 21.9 nanogram per 14 kilogram per day for a child. 15 Seasonal average daily dosage ranged 16 from 1.5 nanogram per kilogram per day for an adult 17 female to 6.2 nanogram per kilogram per day for a 18 child. And annual average daily dosage ranged from 19 1.2 nanogram per kilogram per day to 4.7 nanogram per 20 kilogram per day for a child. 21 The estimate of exposure from 22 application site airborne methyl parathion based on 23 ARB study and also Seiber and McChesney study are 24 shown on table 6. 25 At 20 yards the estimate of exposure 226 BARNEY, UNGERMANN & ASSOCIATES 1-888-326-5900 1 ranged from 39 nanogram per kilogram per day for 2 adult female to 159 nanogram per kilogram per day for 3 a child. At 17 yards the range was approximately 99 4 nanogram per kilogram per day for an adult female to 5 360 nanogram per kilogram per day for a child. 6 For the ambient air monitoring that 7 they did look at both methyl parathion and the methyl 8 paraoxon, and for the application site monitorings 9 they did not look at the methyl paraoxon. 10 So what we assumed was we looked at the 11 ratio of methyl parathion to methyl paraoxon that was 12 observed in the ambient air monitoring study, and we 13 assumed that that ratio would stand for application 14 site also. 15 We made some assumptions to come up 16 with the exposure, and some of these assumptions, we 17 believe, are conservative assumptions. We assume 18 inhalation uptake and absorption of 100 percent. 19 We also assumed DEF indoor 20 concentration would be as much as outdoor. And since 21 the source of ambient air in this case is outdoor and 22 children and adults spend most of their time indoors, 23 then we would assume that would probably be a 24 conservative assumption. 25 As far as dermal exposure from the 227 BARNEY, UNGERMANN & ASSOCIATES 1-888-326-5900 1 ambient air, we believe that there is potential for 2 dermal exposure. However, there are no studies to 3 monitor that, and we believe that dermal protection 4 and clothing protection would give adequate 5 protection that makes this exposure insignificant. 6 I think I would end my presentation at 7 this point. 8 MR. GOSSELIN: We have about ten 9 minutes, and Ruby said she can get through the final 10 piece in ten minutes if you wanted to race. 11 DR. FROINES: No, I'd rather not. 12 DR. GLANTZ: No? 13 I think it would -- I'd like to at 14 least maybe get a summary of it. I think it's 15 helpful to -- we were going through these reports to 16 have sort of this overview. 17 DR. FROINES: What time is it now? 18 DR. GLANTZ: It's 20 after 3:00. 19 DR. FROINES: We can finish it, but I'm 20 not -- 21 DR. BYUS: I'm prepared to stay all 22 night if necessary. No, just kidding. 23 DR. FUCALORO: As far as I'm concerned, 24 you can stay all night. 25 DR. GLANTZ: We're not going to take 228 BARNEY, UNGERMANN & ASSOCIATES 1-888-326-5900 1 any action, but it would be helpful to me, having 2 come this far, to just hear the last bit of it. 3 DR. FROINES: Okay. I have a reception 4 I have to be at in UCLA. 5 DR. REED: I will speed talk. 6 DR. FROINES: No questions, Stan. 7 DR. REED: I want to start with the 8 first slide which is a continuation of what Tareq was 9 presenting. Just one highlight: The fact that I'm 10 only showing data for the highest exposure group 11 amongst the three exposure age groups that Tareq had 12 shown, and in this case it's six years old because it 13 has higher breathing rate per body weight basis. And 14 the total exposure would be the exposure of methyl 15 parathion plus methyl paraoxon's exposure times 10 as 16 the toxicity equivalency factor. 17 DR. FUCALORO: Just quickly, the 18 exposure for the paraoxon is roughly 13.5 of the 19 parathion; is that right? 20 DR. REED: It's 2.5. 21 DR. FUCALORO: 2.5? 22 DR. REED: Yes. And then you add one 23 from methyl parathion, and it becomes 3.5 in total. 24 DR. FUCALORO: Got you. 25 DR. FROINES: And we haven't had any 229 BARNEY, UNGERMANN & ASSOCIATES 1-888-326-5900 1 discussion and we won't today but about dermal or 2 oral uptake. 3 DR. REED: Correct. I think Tareq 4 covered a little bit on the insignificance of dermal 5 exposure. But we need to talk about this. 6 DR. GLANTZ: Just for the record the 7 chair is asking questions. I'm sitting quietly. 8 DR. FROINES: But you would not 9 actually accede to the rules so -- 10 I think that this other issue of 11 microenvironmental monitoring is one that we haven't 12 addressed, and I think we need to talk about it in 13 the future. 14 DR. REED: All right. 15 So with the table I have in the 16 transparency for you is the exposures of the six 17 years old since they're the highest amongst the 18 three, and I have one column on ambient air exposure, 19 and the other column is for off-site exposure at 17 20 yards away from the edge of the field. And I'm not 21 reading the numbers now. 22 Next slide, please. 23 The risk is characterized by the 24 calculation of margin of exposure which is NOEL 25 divided by the exposure. And again, I've shown you a 230 BARNEY, UNGERMANN & ASSOCIATES 1-888-326-5900 1 table in the transparency calculated both based on 2 human NOELs for the acute seasonal exposures and also 3 animal estimated NOELs for acute seasonal, and then 4 chronic NOEL as at 0.02 milligram per kilogram a day. 5 I failed to mention that if I were to 6 select a chronic NOEL based on cholinesterase 7 inhibition, then NOEL would be 0.1 milligram per 8 kilogram a day, about fivefold higher than the NOEL 9 that I'm using here. 10 The off-site exposure is based on 11 24 hours of exposure, and the margin of exposure is 12 250 based on human NOELs and 80 based on estimated 13 NOELs in rats. 14 Next slide, please. 15 I have just summarized five areas of 16 uncertainties. The first one is the uncertainty 17 surrounding the human NOEL of 0.31. The strength of 18 that is that if I were to use human NOEL, then I 19 don't need the interspecies extrapolation and the 20 uncertainties associated with it. 21 However, the study -- or this series of 22 three studies are fairly limited in terms of 23 observation and reporting. The endpoint that they 24 were looking for was just cholinesterase inhibition. 25 And there's only five adults in each 231 BARNEY, UNGERMANN & ASSOCIATES 1-888-326-5900 1 group with unspecified body weight, so I have to 2 assume a body weight of 70 kilograms. And I was not 3 quite sure about the NOEL because the LOEL was just 4 10 percent above the NOEL, and it has a substantial 5 RBC cholinesterase inhibition. 6 The other concern that I have is that 7 this is a 30 day NOEL, and when I used it for the 8 seasonal exposures, which is assumed to be nine 9 months, I was not sure how adequate it is to address 10 the nine months of exposure. 11 The uncertainties surrounding the acute 12 subchronic NOELs -- estimated NOELs in rats, of 13 course, the strength is that the endpoint seemed to 14 be more sensitive and that LOELs was determined in 15 multiple studies. I think there was a total of four 16 studies. So that sort of supported each other. 17 And I was happy because the 18 subchronic -- estimated subchronic NOEL comes out at 19 the same level as the chronic NOEL, and I felt more 20 comfortable using such a level to address the nine 21 months of the season of exposure. 22 The weaknesses of course is because 23 these studies are published in open literature so 24 there was not a lot of details about this study and 25 its reporting. And the measure of uncertainty was 232 BARNEY, UNGERMANN & ASSOCIATES 1-888-326-5900 1 because it was estimated from a LOEL. 2 Next slide, please. 3 The third area of uncertainty is about 4 the toxicity of methyl parathion. The data is really 5 limited only regarding the acute toxicity database. 6 And TEF was estimated based on a range of 4.5 to 8.2 7 and scaled up to 10. 8 There was also an uncertainty 9 associated with the calculation of total exposure 10 fractioned into the exposure of methyl paraoxon, 11 which is assuming that the concentration of methyl 12 paraoxon in the air is 25 percent of the 13 concentration of methyl parathion. And we all know 14 that a fixed ratio of that just doesn't exist in 15 time, and so that was another area of uncertainty. 16 The fourth area about is exposure 17 assessment, and I think that Tareq fairly adequately 18 covered that. I just highlighted three points. 19 Using default parameters does not 20 account for the variation in humans, even within the 21 six years old. The monitoring data are limited. And 22 the off-site exposure, we assume, is at 24 hours at 23 16 yards away from the edge of the field. In most 24 cases it would be probably less than 24 hours unless 25 you have a farmhouse there, which is a possibility. 233 BARNEY, UNGERMANN & ASSOCIATES 1-888-326-5900 1 The fifth area of uncertainty is about 2 the Food Quality Protection Act mandated 3 consideration of uncertainty factor or the safety 4 factor of up to 10 to address the possibility of 5 increased sensitivity or heightened sensitivity in 6 infants and children or in pre- and postnatal period. 7 And from the database it looks like one 8 may need to consider an additional uncertainty factor 9 for the pre and postnatal sensitivity. And this is 10 really based at looking at the developmental and 11 reproductivity toxicity database. It's covered in 12 more detail in the document. 13 Next slide, please. 14 We then calculated the reference 15 concentration using the NOELs, and the calculated 16 reference concentration is for 24 hours of exposure, 17 and the accounted for methyl parathion's 18 concentration of 25 percent of methyl paraoxon and 19 TEF of 10 from methyl paraoxon, and uncertainty 20 factor of 10 is used if I were calculating reference 21 concentrations from the animal NOELs. And again, 22 this is based on exposure parameters of the six year 23 old. And so it comes out to be in that table the 24 acute reference concentration could be as low as 40 25 PPT and seasonal chronic would be 8 PPT. 234 BARNEY, UNGERMANN & ASSOCIATES 1-888-326-5900 1 Attention to the -- next slide, 2 please -- to the transparency is three -- are three 3 equations, just of a derivation of how the reference 4 concentration is calculated. 5 Essentially it's a back calculation 6 from the exposure equation with the exposure being at 7 reference concentration which is NOEL divided by 8 desirable margin of exposure. And then you can back 9 calculate the concentration. And this takes into 10 account again the concentration or the concomitant 11 presence of methyl paraoxon with methyl parathion. 12 That's it. 13 DR. GLANTZ: Could I just ask one 14 procedural question? 15 DR. REED: Yes. 16 DR. GLANTZ: How is this going to 17 proceed now? When's this going to come back to us 18 for consideration, formally? Do you know? 19 DR. FROINES: Next month. 20 DR. GLANTZ: Next month? And it will 21 be the same report with the -- 22 DR. REED: With the added studies, the 23 studies that they -- 24 DR. GLANTZ: That you handed out? 25 DR. REED: Yeah. 235 BARNEY, UNGERMANN & ASSOCIATES 1-888-326-5900 1 DR. GLANTZ: Are you going to send us 2 like another full draft of it or what? 3 MR. GOSSELIN: Yeah. What I'll do is 4 when we complete the review of the studies, we'll 5 send those sections out so you'll have that separate. 6 And then you'll have sort of the full clean report 7 like you had today. But you'll have separate sheets 8 on the description of what those four studies had. 9 DR. GLANTZ: Now -- so are you going to 10 give us a new -- the question is do I need to take 11 this home? Or are you going to give us the new one 12 that has the changes in it? 13 MR. GOSSELIN: We are going to give you 14 the new ones with the changes in it. 15 DR. GLANTZ: Then what I suggest you 16 do -- and we had OEHHA do this -- is when you put 17 changes in, do a red-line strike-out version of it so 18 that the deletions and the additions are obvious. 19 MR. GOSSELIN: Okay. 20 DR. FROINES: Let's ask a different 21 question. When do you think you'll get that to us? 22 MR. GOSSELIN: I can't say. 23 DR. FROINES: Ballpark. 24 MR. GOSSELIN: We might need to push 25 this off until the next meeting, then. 236 BARNEY, UNGERMANN & ASSOCIATES 1-888-326-5900 1 DR. FROINES: I don't understand. 2 MR. GOSSELIN: They were saying it 3 might take three to four weeks to complete the final 4 review of those studies. 5 DR. FROINES: So -- 6 DR. BYUS: And actually, I'm not going 7 to be here, and I'm the lead person on this. And I'm 8 not going to be here. I will not be here for the 9 next meeting. 10 DR. FROINES: You won't be? 11 DR. BYUS: I won't be. 12 DR. FROINES: So we don't have -- 13 January 15, since we're not having the workshop, 14 let's just have the meeting because we already know 15 people are available. So let's take up methyl 16 parathion on the January 15th meeting. 17 MR. GOSSELIN: And we can do a -- we 18 can make a presentation on molinate. 19 DR. FROINES: It sounded to me like we 20 have the workshop, we have George who will go on as 21 long as you let him, and we have molinate. So I 22 don't think we're short of material. 23 So Stan, you don't have to carry it 24 home then. I was thinking that you should carry -- 25 no -- yeah, that's right. You should carry it home. 237 BARNEY, UNGERMANN & ASSOCIATES 1-888-326-5900 1 You should carry it home. Because you should read it 2 over the next month. 3 DR. GLANTZ: If you could get it to us 4 a couple of weeks before the meeting, I'd rather read 5 that. 6 MR. GOSSELIN: If the -- we're going to 7 bring this back formally again January 15, you'll 8 have it more than a couple weeks in advance. But I 9 would say that if you read that, you will have the 10 foundation for the changes. 11 DR. FROINES: I have a different view 12 of this. My view is that George -- I mean, rather 13 Stan can take it home if -- doesn't have to take it 14 home if we can find a recycling box here. If it's 15 thrown in the garbage -- this panel has got to have 16 its recycling act together. 17 DR. GLANTZ: Peter is very efficient. 18 Peter, Peter, you'll find a recycling bin; right? 19 MR. MATHEWS: Right. I will. I 20 promise.