1 MEETING OF THE SCIENTIFIC REVIEW PANEL
2 ON TOXIC AIR CONTAMINANTS
3 CALIFORNIA AIR RESOURCES BOARD
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13 TRANSCRIPT OF PROCEEDINGS
1200 University Avenue
14 Riverside, California
Wednesday, November 11, 1998
15 9:00 A.M.
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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
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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
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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
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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
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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
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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.
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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
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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
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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.
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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
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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
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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.
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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
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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
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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
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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
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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
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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
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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
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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.
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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
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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
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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
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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
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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
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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
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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
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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,
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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 --
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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.
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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
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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.
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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.
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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
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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.
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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
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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
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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.
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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
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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,
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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
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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
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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
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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
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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
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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
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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
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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
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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.
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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.
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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."
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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
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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
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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?
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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.
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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
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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
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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.
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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
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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.
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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
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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
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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.
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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
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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
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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.
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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
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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.
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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
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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
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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
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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
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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
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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
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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
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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
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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."
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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
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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
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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
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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.
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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
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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.
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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
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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
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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
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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.
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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.
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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.
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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
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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
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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
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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.
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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
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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."
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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
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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
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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."
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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.
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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
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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?
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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.
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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
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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
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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
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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.
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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
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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.
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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
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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.
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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
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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
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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.
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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
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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,
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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
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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
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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
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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
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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
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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
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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
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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
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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
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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.
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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
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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
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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
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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
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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
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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
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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
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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
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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
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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
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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.
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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
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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
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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
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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
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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?
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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.
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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
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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
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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.
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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.
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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
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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
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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
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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
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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
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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.
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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?
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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
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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
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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
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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
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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.
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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
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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
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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
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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.
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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
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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
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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
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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?
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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
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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.
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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.
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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
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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.
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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
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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.
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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:
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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
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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
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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.
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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
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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
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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
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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
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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.
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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.
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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.
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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.
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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.
21 DR. FUCALORO: He won't put that in it.
22 DR. FROINES: And it's in the
23 transcript, ladies and gentlemen.
24 DR. FUCALORO: The SRP recycles.
25 DR. FROINES: Let me say Paul, Ruby,
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BARNEY, UNGERMANN & ASSOCIATES 1-888-326-5900
1 everybody else, thank you very much. I think this
2 was a long, sometimes slow session, but I think we
3 actually accomplished a lot.
4 And as you can tell, we are going
5 through something of a learning curve ourselves, and
6 so I think the slowness and the tedious quality, I
7 think, will change with time, but I think we're
8 clearly moving in a very good direction at this
9 point. And it's very nice to have -- to have a new
10 document that we say that we've approved.
11 DR. REED: Yes. I just wanted to thank
12 Dr. Byus and Dr. Fucaloro. Both of you have been
13 very, very helpful in reviewing the document and
14 getting back to me and very good interaction. And I
15 really enjoyed it.
16 DR. BYUS: Me too.
17 DR. FUCALORO: Yeah, me too. I thought
18 we had good discussion.
19 DR. FROINES: Good. Let's hope this is
20 the harbinger of the future.
21 Thanks again, everybody.
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239
BARNEY, UNGERMANN & ASSOCIATES 1-888-326-5900
1 STATE OF CALIFORNIA )
) ss.
2 COUNTY OF LOS ANGELES )
3
4 I, Katherine Gale, CSR 9793, a Certified
5 Shorthand Reporter in and for the State of
6 California, do hereby certify:
7 That said proceedings was taken before me at
8 the time and place named therein and was thereafter
9 reduced to typewriting under my supervision; that
10 this transcript is a true record of the proceedings
11 and contains a full, true and correct report of the
12 proceedings which took place at the time and place
13 set forth in the caption hereto as shown by my
14 original stenographic notes.
15 I further certify that I have no
16 interest in the event of the action.
17 EXECUTED this 20th day of November,
18 1998.
19
20
____________________________
21 Katherine Gale, CSR #9793
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