MEETING
BEFORE THE
SCIENTIFIC REVIEW PANEL
OF THE
CALIFORNIA AIR RESOURCES BOARD
MARIAN MINER COOK ATHENAEUM
385 EAST EIGHTH STREET
CLAREMONT, CALIFORNIA
WEDNESDAY, NOVEMBER 17, 1999
9:44 a.m.
Kathleen Knowlton, CSR
License No. 11595
BARNEY, UNGERMANN & ASSOCIATES 888 326-5900
MEMBERS PRESENT
Dr. John Froines, Chairman
Dr. Stanton Glantz
Dr. Craig Byus
Dr. Roger Atkinson
Dr. Anthony Fucaloro
Dr. Paul Blanc
Dr. Hanspeter Witschi
Others Present:
Jim Behrmann, ARB
Peter Mathews, ARB
Paul Helliker, DPR
Randall Segawa, DPR
Dr. Gary T. Patterson, DPR
Lynton Baker, ARB
Pamela C. Wales, DPR
Dr. Thomas Thongsinthusak, DPR
Dr. Andrew G. Salmon, CEPA
Dr.Martha Sandy, CEPA
Dr. Melanie Marty, CEPA
Dr. Andrew Rubin, DPR
Dr. James F. Collins, CEPA
BARNEY, UNGERMANN & ASSOCIATES 888 326-5900
I N D E X
* * *
Page
Proceedings 1
Call to Order 1
Opening remarks by Chairman Froines 1
AGENDA ITEMS:
Item 1 - Presentation on Monitoring 4
for Multiple Chemicals
Item 2 - Discussion of Revisions of Draft 23
Document 11-15-99
Item 3 - Presentation of MITC 43
Item 4 - Discussion of Methyl Tertiary 83
Butyl Ether
Item 5 - Assessment of MTBE's Human 130
Health Effects
Item 6 - Discussion of REL 157
BARNEY, UNGERMANN & ASSOCIATES 888 326-5900
1 PROCEEDINGS
2 * * *
3 CHAIRMAN FROINES: Shall we call the meeting
4 to order? We have a quorum. One person who will be
5 missing today, oh, is -- Peter Kennedy is unable to come
6 because of a health problem. But Gary Friedman, I assume,
7 is going to be here? Gary Friedman and Peter Kennedy will
8 not be here.
9 The first thing I'd like to do on the agenda
10 is introduce the panel to Paul Helliker who's the director
11 of -- the new director of the Department of Pesticide
12 Regulation. And so I ask Paul to say a few words. But we
13 welcome you, appreciate your coming to the meeting, and
14 look forward to be working with you.
15 MR. HELLIKER: Thank you. It's a pleasure
16 to be here. I assume this is the right spot to speak
17 from. I apologize for not having been able to participate
18 in the Scientific Review Panel meetings to date, but I'm
19 glad that I'm able to be here today, since I've been able
20 to review the draft findings that you've made, and look
21 forward to having a final document from you about the
22 workshops we've been having.
23 But let me just give you a little bit of
24 background. I have a -- an opportunity to meet with
25 Dr. Froines early on in my tenure and pointed out to him,
4
BARNEY, UNGERMANN & ASSOCIATES 888 326-5900
1 I think we've been marking some good progress over the
2 past year, and I want to see that progress continue in
3 getting a good collaborative, working relationship going
4 with the Scientific Review Panel.
5 And I think that's going to set a good
6 foundation for how we go forward with responding to the
7 recommendations you have with what sort of prioritization
8 plans that we implement at the department for bringing
9 additional compounds to your attention.
10 So I think part of the background that has
11 generated some of the controversy might be when we
12 evaluate pesticides, we have the ability to move fairly
13 quickly, and we have in the past. So I think that might
14 have been some of the source of the discussion or the
15 difference in approach that we have with ARB.
16 But my goal is to make sure that we go
17 through the similar process to what the Air Resources
18 Board does, and make sure that all of our decisions about
19 toxic air contaminants are decisions that merit by the
20 input from this panel.
21 Because I look to you as being one of our
22 primary guiding organizations when it comes to our
23 scientific decisions. So I won't take much more time than
24 that. But look forward to the discussions today. And I
25 did want to point out I did sign yesterday the
5
BARNEY, UNGERMANN & ASSOCIATES 888 326-5900
1 recommendation or the decision to list methyl parathion as
2 a toxic air contaminant. So thank you for your
3 recommendations on that. And I look forward to the
4 additional ones in the future.
5 CHAIRMAN FROINES: Thank you. Everyone has
6 a new record. That's great. Just great. And thank you,
7 Craig Byus, for the effort that went into methyl
8 parathion. I think that is, Paul, a good example of
9 interaction. Craig and Ruby Reed worked very closely and
10 worked very effectively. And I think that Craig is a real
11 advocate for Ruby. And so that -- that seems to me to be
12 a great model for how we can work effectively together.
13 So without further ado, we're going to --
14 we have -- the problem we have today is a problem we have
15 normally. It's with Stan. I'm not supposed to make
16 jokes, because he makes them back. But we'll cool it.
17 DR. GLANTZ: Let the record indicate that
18 Dr. Froines made me get up very early this morning to get
19 here. Actually, the problem is with Dr. Froines.
20 CHAIRMAN FROINES: Stan actually has to
21 leave early. And so we are going to try and move
22 relatively quickly, so we can at least get through item 3
23 before he leaves. He's finished item 4 from his
24 compound. So -- so we have some tension about working
25 through items 1 through 3.
6
BARNEY, UNGERMANN & ASSOCIATES 888 326-5900
1 Any case, so the first item on the agenda is
2 the case study of multiple pesticides sampling. And I
3 don't know who's presenting. This is, in essence, a
4 continuation of a workshop on prioritization and exposure
5 monitoring. So this will complete that small workshop.
6 MR. SEGAWA: Good morning. I am Randy
7 Segawa. Yeah. We're trying to get the lights fixed
8 there. I'm Randy Segawa with Department of Pesticide
9 Regulation. And this is a -- pretty much a continuation
10 of a workshop we had a couple months ago that got cut
11 short. And I will be presenting some case studies or
12 hypothetical examples on how we could possibly monitor for
13 multiple chemicals.
14 First off, I'd like to point out that this
15 is a hypothetical exercise. Department of Pesticide
16 Regulation and the Air Resources Board have had a series
17 of meetings to discuss the different alternatives and
18 options for monitoring multiple chemicals, but we haven't
19 settled on a concrete plan yet. So right now we're just
20 still in the discussion stage.
21 For this particular exercise, I put a couple
22 limitations on -- on how we might accomplish this. One,
23 I -- for this exercise, I wanted to come up with some sort
24 of objective criteria for grouping and prioritizing the
25 different chemicals that we might be monitoring.
7
BARNEY, UNGERMANN & ASSOCIATES 888 326-5900
1 The other restriction I had placed on it, is
2 that I set up the examples so they fit within the current
3 resources available to DPR and the Air Resources Board.
4 And the other factor I consider -- or did not consider,
5 actually, is the risk assessment and mitigation. Those
6 factors did not play any role in determining the groupings
7 and priorities that I'll be discussing.
8 I'm going to present three separate examples
9 on how we might group for multiple chemicals. And the
10 first example I'll look at a crop-type grouping using
11 cotton as an example. In this second example, I've done a
12 chemical-family-type grouping using organophosphates as an
13 example.
14 And then finally I'll present a county or
15 month-type group where we've looked at the highest county
16 and highest month for the various counts of pesticides and
17 group them together. For this exercise I've included 157
18 pesticides, both candidate toxic air contaminants as well
19 as those chemicals currently on the toxic air contaminant
20 list.
21 I've used our current priority system,
22 DPR's report 9601, which was published back in '96. And
23 so is somewhat outdated, but we are working to revise
24 that. But for this exercise, I've used that for all the
25 candidate scores. And then for those chemicals that are
8
BARNEY, UNGERMANN & ASSOCIATES 888 326-5900
1 currently toxic air contaminants, I assigned an arbitrary
2 score of 15.
3 A lot of this exercise, the priorities have
4 to do with the pesticide-use data. And I've used the 1996
5 through 1998 data for these examples. So for each of the
6 157 chemicals that we want to try and monitor for, I've
7 selected four different factors. I've looked at the crop
8 of highest use for each of a hundred fifty-seven. We
9 determined the chemical family each of the hundred
10 fifty-seven belonged to.
11 From the pesticide-use data, we determined
12 the county of highest use for each of the hundred and
13 fifty-seven. And we've also determined the month of
14 highest use for each of the hundred and fifty-seven.
15 So our first example, the crop grouping --
16 what we've done is taken, for each of the 157 chemicals,
17 the highest crop for each of those chemicals. And cotton
18 actually came out on top where 23 of the chemicals had the
19 highest use on cotton. Structural pest control was second
20 with 14 chemicals at highest use for that particular site.
21 And then almonds was number three.
22 DR. GLANTZ: Structural pest control is like
23 termites and things like that?
24 MR. SEGAWA: Correct. Yes. And so if you
25 look at the list of chemicals there, there are 23 that are
9
BARNEY, UNGERMANN & ASSOCIATES 888 326-5900
1 used on cotton, used throughout, mainly, the Central
2 Valley. You see that Fresno and Kern County are probably
3 the highest for virtually all those chemicals, which you
4 expect, since those are the largest cotton-growing areas
5 in the state.
6 DR. BYUS: Are they -- pardon me. Are --
7 you're not saying that 23 are used on -- all 23 are used
8 on one cotton field, are you?
9 MR. SEGAWA: No.
10 DR. BYUS: You're just saying between all
11 the cotton?
12 MR. SEGAWA: Correct. Correct. Yes.
13 CHAIRMAN FROINES: One other question --
14 DR. BLANC: But your house did have 14
15 chemicals applied prior to your purchase.
16 CHAIRMAN FROINES: And xylene you have
17 listed as a pesticide. Is that considered a pesticide on
18 cotton?
19 MR. SEGAWA: It's both considered an active
20 ingredient as well as an inert ingredient in many
21 products.
22 DR. FUCALORO: Solvent?
23 MR. SEGAWA: Correct.
24 DR. BLANC: Why would it be considered an
25 active ingredient if it's a solvent? Because it has
10
BARNEY, UNGERMANN & ASSOCIATES 888 326-5900
1 health effects, but not because it has pesticidal --
2 MR. SEGAWA: It does have some pesticidal
3 effects for cotton. I'm not sure exactly what pest they
4 are trying to get with xylene.
5 DR. BLANC: But actually, I guess I should
6 ask the question more clearly. Because, do you know from
7 a regulatory point of view, is a toxic additive to a
8 pesticide which is not pesticidal considered inert? Does
9 the term "inert" designate a non-pesticidal component or
10 does it imply nontoxic component?
11 MR. SEGAWA: It implies non-pesticidal
12 component.
13 DR. BLANC: So theoretically an insert
14 ingredient can still be toxic to humans?
15 MR. SEGAWA: Correct.
16 CHAIRMAN FROINES: I was on a National
17 Academy of Science Committee that actually discussed this
18 issue. And you find there are a lot of compounds listed
19 as inert that are by no means inert. And that's a problem
20 at some level that hasn't received attention, although
21 there has been some focus on it at some points.
22 DR. BLANC: And a follow-up to that
23 question. Do you know whether inert -- other inert --
24 well, do you know whether there are other solvents which
25 are considered inert? It seems that xylene is not
11
BARNEY, UNGERMANN & ASSOCIATES 888 326-5900
1 considered inert. That would reason I ask specifically
2 about solvents, because of their volatility, clearly they
3 would be of interest to this panel as potentially toxic
4 air pollutants.
5 MR. SEGAWA: If I understand your question
6 correctly, yes, there are solvents which we may consider
7 toxic. But our list is as inert ingredients in pesticidal
8 products.
9 CHAIRMAN FROINES: He's asking a different
10 question.
11 DR. BLANC: I'm asking, how -- would we end
12 up ever hearing about them at this panel? For example,
13 suppose there was a hypothetical pesticide that was very
14 widely used, which had a significant inert percentage of
15 the solvent dioxane, theoretically. Would that be
16 something that would ever enter into our inventories? Or
17 we ever hear about or that would appear in the --
18 otherwise on our radar screen?
19 MR. SEGAWA: I'm not real sure. I know that
20 under some of our regulatory authority -- for instance,
21 our groundwater program, we do have the authority to look
22 at inert ingredients as potential groundwater
23 contaminants. I'm not sure we have the same authority for
24 toxic air contaminants.
25 DR. BLANC: Can somebody from the ARB
12
BARNEY, UNGERMANN & ASSOCIATES 888 326-5900
1 comment on that?
2 MR. BAKER: I didn't hear the question. I'm
3 sorry.
4 CHAIRMAN FROINES: Paul is asking the
5 question, there are compounds that are listed as active
6 ingredients and inactive ingredients. There are times
7 when the inactive ingredients are toxic. And if they're
8 volatile, that has potential significance for the
9 designation of those compounds as toxic air contaminants.
10 And the question is, would that ever come
11 before this panel? And he's, I think, not entirely sure.
12 I think that -- and so the reason ARB comes into it is
13 because, if there was an inert volatile compound that
14 might be considered a toxic air contaminant, then that
15 might come -- well, ARB, I think, 1807 lists pesticides,
16 and that would be the role of DPR.
17 So I think their authority would be -- with
18 respect to DPR would be with respect to pesticides. But
19 inert ingredients might be with ARB. I don't know.
20 That's the question.
21 MR. BAKER: This is Lyn Baker from the Air
22 Resources Board. I would assume that solvents are
23 carriers that might -- might fall under this category that
24 would be toxic, but would not be pesticidal -- would not
25 have pesticidal activity.
13
BARNEY, UNGERMANN & ASSOCIATES 888 326-5900
1 That the Air Resources Board might look at
2 compounds like that under our toxic air contaminant
3 process, but not as carriers for pesticides. If they were
4 solvents, we would probably be viewing them from
5 industrial sources, and might have regulated in that way
6 rather than as a -- as an inert, pesticidal ingredient.
7 Jeannette, would that --
8 MS. BROOKS: That's correct.
9 DR. BLANC: But let's say a pesticide came
10 before this panel in the process that we were embarking
11 on. And we're going to come back to this subject later.
12 But let's take our grouped --
13 Suppose that our suggestion to group the
14 cholinesterase inhibiting -- suppose our proposal to group
15 the cholinesterase-inhibiting organophosphate pesticides
16 goes forward and we receive risk assessment on 35
17 organophosphates. Are we going to be assured that as they
18 are marketed, none of those organophosphate pesticides
19 perforce also include volatile, toxic-air-contaminant
20 solvent carriers?
21 Because if something is marketed in a
22 particular way, which means that when it's used there will
23 be release of a toxic air contaminant solvent then we
24 should -- I would assume it would be our obligation to
25 designate that pesticide a toxic air contaminant, even if
14
BARNEY, UNGERMANN & ASSOCIATES 888 326-5900
1 it's not on the basis of its active pesticidal component.
2 But rather on the basis of its inert solvent carrier,
3 unless it's reformulated to exclude that solvent carrier.
4 MR. BAKER: That would certainly make sense,
5 Dr. Blanc. But the Air Resources Board doesn't have
6 regulatory authority over pesticides. So to -- we would
7 not have the authority to regulate or to --
8 DR. FUCALORO: Is there any group, I mean,
9 within the state that is looking -- is this slipping
10 through the cracks, I guess is what Dr. Blanc is referring
11 to. That if you have a series of solvents that are used
12 to deliver pesticides, is there anyone paying attention to
13 those solvents?
14 I'm given to understand that xylene shows up
15 on this list, because the pesticidal action rather than
16 its use as a carrier or solvent. So between the two --
17 the two organizations, there anyone looking at these? I
18 mean, that's a fair question, and maybe you can get back
19 to us.
20 MS. BROOKS: Well, in the case of xylene,
21 xylene is already listed. It's a hazardous air
22 pollutant. So it's already a toxic air contaminant. And
23 Melanie was reminding me, there are some other solvents
24 that would be the same.
25 And the only -- at the Air Resources Board,
15
BARNEY, UNGERMANN & ASSOCIATES 888 326-5900
1 we do have a consumer products program where this would be
2 the public being able to go in and buy off the shelf Raid
3 or something like that. And we're limiting the volatile
4 organic content of those. And a lot of the carriers are
5 what we're regulating, trying to get as low as we can,
6 close to zero BOC.
7 And we know, too, those products are
8 labeled. If these carriers are toxic like xylene, and
9 maybe toluene, they have to be labeled for Proposition 65.
10 So there is at least a warning. But I know what you're
11 saying as far as control measurement development.
12 DR. FUCALORO: Yeah. Clearly if a carrier
13 were benzene, it would raise red flags all over the place.
14 I understand that. But suppose, for example -- I'm just
15 following up what Dr. Blanc is saying.
16 Suppose there is a solvent that is really
17 not being considered in any way as no one's done any
18 investigation of it, and a manufacturer uses a carrier
19 that uses a solvent that no one has investigated, is there
20 any mechanism within the state to say, this is something
21 we ought to be looking at? I assume it's the ARB.
22 MS. BROOKS: Under our toxics program, in a
23 consumer product that's sold, we can do a toxic control
24 measure for a toxic air contaminant. And in fact, we have
25 a branch at the board that's looking at break cleaners and
16
BARNEY, UNGERMANN & ASSOCIATES 888 326-5900
1 engine degreasers that contain perchloroethylene right
2 now. And they're planning to take a control measure to
3 the board next year.
4 So I think for a commercial product where
5 the Air Resources Board has authority, we could develop a
6 controller measure. And, in fact, we are. For a
7 pesticide that's used on application at a farm, I don't
8 think we could control the xylene content.
9 DR. GLANTZ: Could DPR?
10 MS. BROOKS: We have to double-check on
11 that.
12 MR. BAKER: I would think that would fall to
13 DPR.
14 CHAIRMAN FROINES: I'm going to cut this
15 off, because we are way off what this session is about.
16 DR. BLANC: Sorry. My fault.
17 CHAIRMAN FROINES: No, nobody should
18 apologize. It's a very important discussion, and we
19 should take it up at a later date. We've now certainly
20 raised it, and so let's leave it for the moment. I'll
21 just, as Chair's prerogative, will say this last word on
22 it.
23 DR. GLANTZ: This is part of Dr. Froines'
24 effort to always shorten discussions.
25 CHAIRMAN FROINES: Under AB 1807, compound
17
BARNEY, UNGERMANN & ASSOCIATES 888 326-5900
1 is listed as a toxic air contaminant. The law then says
2 that a risk-management process will follow. It doesn't
3 say, "only for these uses, compared to these uses."
4 So if there is a toxic air contaminant, say
5 xylene, then it seems to me that the issue is what is the
6 appropriate, regulatory-management strategy that you would
7 follow for that compound, for any and all of its uses.
8 And so it would be up to ARB to determine those uses and
9 to determine strategies for control.
10 MS. BROOKS: That's correct.
11 CHAIRMAN FROINES: That's, I think, what the
12 question is. And this is obviously something that hasn't
13 come up before, so we can talk about it later. Thanks.
14 Thank you.
15 MR. SEGAWA: Okay. This figure here shows
16 the use for all the 23 chemicals that we were just
17 discussing. As you can see, that the San Joaquin Valley
18 has the highest use for chemicals used on cotton. And of
19 course, that is where most of the cotton is grown.
20 But you can also see that there is use of
21 these chemicals throughout much of the state down, in the
22 Imperial County and southeast desert region, as well as
23 even far up north in the Modoc County area as well.
24 And don't forget, while these chemicals may
25 have highest use on cotton, cotton would not be their only
18
BARNEY, UNGERMANN & ASSOCIATES 888 326-5900
1 use. They would also be used on other crops. Okay.
2 Moving on to --
3 CHAIRMAN FROINES: Not much of those, do you
4 think, of the 20 -- we know xylene's organophosphate. But
5 how many of the others do you think are organophosphates?
6 MR. SEGAWA: Organophosphates? Phorate is
7 an organophosphate. Chlorpyrifos, of course,
8 methamidophos, naled, def, and ethephon.
9 CHAIRMAN FROINES: I only ask that question
10 because, clearly, where you have a common mechamism of
11 action, you would want to look at the compounds with
12 common mechanism of actions collectively, if one were able
13 to.
14 MR. SEGAWA: And that's a good segue into
15 the next slide. Because the second example does deal with
16 the chemical-family-type of grouping. Again, for the 157
17 candidate and TAC chemicals that we're looking at in this
18 exercise, 20 of them are organophosphates. And they came
19 out highest in the priority score in the grouping.
20 Organochlorines came in second. There are
21 eight chemicals in that group. And carbamates is third
22 with nine chemicals. And so if you look at the list here,
23 these are all organophosphates used on variety of crops.
24 And you can see, used at a variety of locations and
25 throughout most of the year.
19
BARNEY, UNGERMANN & ASSOCIATES 888 326-5900
1 DR. ATKINSON: So it looks as though at
2 least three of these are also organochlorines.
3 MR. SEGAWA: That's probably true, yes. And
4 then as a third example, we took the 157 chemicals and
5 determined the combination of county a month of highest
6 use. So that if we were to try and monitor for multiple
7 chemicals, it's, of course, ideal to be monitoring at the
8 same time in the same place for multiple chemicals.
9 And in this type of grouping, Fresno in July
10 came out as the highest -- scoring with seven chemicals in
11 that group. Fresno in June was second with five
12 chemicals. And Fresno in August was third with four
13 chemicals.
14 And the drawback to this type of grouping,
15 as you can see, is that the chemicals in the highest
16 group, the Fresno in July, are different groups of
17 chemicals. And so they would require several different
18 sampling and analytical methods to try to get them all at
19 the same time.
20 After looking through these various
21 exercises, we came to several conclusions regarding the
22 shortcomings and problems. Number one, it's difficult to
23 monitor the complete groups, whichever the three groupings
24 we chose. It requires monitoring in several different
25 seasons, as well as several different areas, and using
20
BARNEY, UNGERMANN & ASSOCIATES 888 326-5900
1 several different types of monitoring methods.
2 While this is, maybe, a good approach for
3 the ambient monitoring, it probably does not work for the
4 application monitoring, since in most application
5 monitoring, one to three chemicals would be applied at the
6 same time, not groups of 20 or more.
7 And of course, risk-assessment factors have
8 not been addressed in this exercise. And it's very likely
9 that, to do the risk assessment for multiple chemicals,
10 particularly outside the chemical-family grouping, would
11 be very difficult. Any questions?
12 DR. FUCALORO: Yeah. I guess you were
13 looking at some sort of intersection of these lists; is
14 that correct?
15 MR. SEGAWA: Correct.
16 DR. FUCALORO: And looking at the monitoring
17 multiple chemicals, county look, the month group, it seems
18 to me that quite possible that you don't need an
19 intersection. I missed the original pesticide workshop,
20 so I'm a little unclear as to what's going on. But what
21 you consider, the list under Fresno in July, probably
22 Fresno in June and August, too, as being a candidate for
23 multiple testing.
24 MR. SEGAWA: Yes, you're correct, that if we
25 were actually to follow this type of scheme, that we would
21
BARNEY, UNGERMANN & ASSOCIATES 888 326-5900
1 probably be monitoring in June, July, and August, yes.
2 And the list would expand as well, of course.
3 DR. FUCALORO: I'm not encouraging people to
4 go in Fresno in June, July, and August. In fact, I would
5 discourage them.
6 CHAIRMAN FROINES: I make just one comment.
7 That list of compounds, the seven chemicals -- 1, 2, 3, 4,
8 5, 6, 7 -- in terms of your '96 priorities, they -- we
9 have here the first compound the highest priority, the
10 fifth highest priority, the seventh highest priority, the
11 39th highest priority, and 42nd, 58th and 63rd.
12 So it represents, actually, a relatively
13 important cross section of compounds that your priority
14 document identified. And in fact, one would say, these
15 are all candidates that are worth taking a look at, given
16 their priority in the DPR '96 document. Has -- has Lyn --
17 have you and Lyn talked about the actual analytical and
18 sampling methodology required to look across --
19 MR. SEGAWA: We did ask Air Resources Board
20 to take a quick look at these various lists and come up
21 with a ballpark estimate as to how many methods are
22 required, and how they would go about doing it. In this
23 particular case for the seven chemicals in the
24 county-month grouping, they thought it would take two or
25 three methods.
22
BARNEY, UNGERMANN & ASSOCIATES 888 326-5900
1 CHAIRMAN FROINES: Two or three?
2 MR. SEGAWA: Yeah.
3 DR. BLANC: That sounds technologically
4 feasible.
5 MR. SEGAWA: Uh-huh.
6 DR. BLANC: I think from some of this,
7 probably be tempered by logistical considerations also.
8 But one advantage I think you may have, given the weather
9 and pesticide-use patterns, is that even for certain other
10 areas outside of Fresno County that you might be
11 interested in, the time frame when you would need to
12 sample would be a different time of the year, thus making
13 it, you know, physically possible for the staff to
14 contemplate sampling.
15 For example, you know, there's a -- there
16 certainly is a heavy concentration of use in -- probably
17 in Imperial County at certain times of the year, and
18 similarly in Salinas Valley which may differ from Central
19 Valley.
20 MR. SEGAWA: I would agree, yes.
21 DR. BLANC: So therefore, there would be
22 things that you -- sampling there, even if they -- they --
23 so I guess, another thing I would suggest, in addition to
24 the very excellent analysis, would be an analysis where it
25 was divided up by agricultural region, and you saw what
23
BARNEY, UNGERMANN & ASSOCIATES 888 326-5900
1 was the time at which the most number of chemicals were
2 used in Imperial County. So that you leave aside the
3 issue of, how does Imperial County rate compared to
4 Fresno.
5 It's going to be clear that areas in the
6 Central Valley are going to be the heaviest pesticide
7 use. But there may be very real issues in some of these
8 other geographic agricultural areas, because the types of
9 pesticides used are likely quite different.
10 MR. SEGAWA: Yes. My guess that
11 meteorological conditions would be different in those
12 areas as well.
13 DR. BLANC: I would suggest that you do that
14 analysis as well. I would like to see that analysis for
15 three or four of what you would imagine would be key
16 areas. And I guess, those key areas would be the North
17 Central Valley as opposed to Fresno and Kern, Salinas
18 Valley, Imperial, and then perhaps, based on your map
19 here, probably certain other hot spots.
20 CHAIRMAN FROINES: Comments? Thank you very
21 much. This is a really nice piece of work. And I think
22 it just raises a lot of interesting questions. So
23 hopefully we can pursue it over time. I think it's really
24 well done and thought-provoking, as you can tell. Have
25 you ever done -- never mind. I'll ask another time.
24
BARNEY, UNGERMANN & ASSOCIATES 888 326-5900
1 MR. SEGAWA: Okay. Thank you.
2 DR. GLANTZ: Can I just ask one quick
3 question? So where are you planning to go next with this
4 in terms of -- I mean, I agree with the others who said --
5 I think it's real interesting. I mean, are you going to
6 further develop these ideas and come back again to us or
7 work with ARB? What's the sort of next -- what's the plan
8 over the next couple three months?
9 MR. SEGAWA: We can do that. We of course
10 need additional discussions with Air Resources Board to
11 see which approach we do want to take. If it's possible,
12 can go with our current resources, and we can come back to
13 the panel with a more updated recommendation.
14 CHAIRMAN FROINES: I should tell you, by the
15 way, that I have a Ph.D. student who's doing a study of
16 multiple-pesticide exposures in Mexico. She's looking at
17 about ten pesticides, and she's doing the analytical
18 chemistry herself.
19 And she's also looking at soil, water.
20 She's doing a multi-media, multi-environment and looking
21 at -- also at urinary metabolites, and looking at what
22 families and children of workers and applicators are
23 getting. So we will keep you informed of what that data
24 looks like, because it's very parallel, in some respects.
25 DR. GLANTZ: Getting back to the earlier
25
BARNEY, UNGERMANN & ASSOCIATES 888 326-5900
1 point, though. I hope that at some reasonable time they
2 can come back with a sort of next iteration on this.
3 CHAIRMAN FROINES: So we should define an
4 action item. What's a good action item of a report in
5 three months for this? What's a good reasonable time
6 frame for you?
7 MR. SEGAWA: We can do that in three months.
8 CHAIRMAN FROINES: That good? Thank you.
9 MR. SEGAWA: Thank you.
10 CHAIRMAN FROINES: The second item on the
11 agenda is the prioritization -- B and C we'll take
12 together, is a discussion of the prioritization and air
13 monitoring document that we wrote up.
14 If you'll remember -- if the panel will
15 remember at the September meeting, Stan and Paul, in
16 particular, recommended that the Chair write a document
17 that could be sent to DPR with our recommendations and
18 conclusions from the mini-workshop. And I said that I
19 would -- wanted to have input from the panel.
20 So we went ahead and wrote a document which
21 you all had for, I think, a reasonable period of time to
22 read and review. I know we've had comments from
23 Roger Atkinson up to this point. And what we would like
24 here is, on a discussion with the agencies -- this is
25 really an internal matter to the panel.
26
BARNEY, UNGERMANN & ASSOCIATES 888 326-5900
1 Basically what I need is for you to give us
2 final recommendations and suggestions so we can then take
3 this document or modified version, send it to
4 Paul Helliker at the agency for their consideration. So I
5 think the best way to handle this would be to go around
6 the room and get people's comments.
7 DR. GLANTZ: Well, I -- I think -- I think
8 it's basically quite good, actually. I think -- and I --
9 the revised draft, which I got a couple days ago, I agreed
10 with many, but not all of the changes. Because I think
11 that some of the changes, while perhaps toning it down a
12 little bit and making it a little bit more palatable
13 politically, have made it less clear.
14 And I just like to go through the specific
15 things that I would suggest we -- I'm working not off the
16 one that we were just handed, but the one that you
17 E-mailed around. Has a red-line, strike-out format.
18 So if you look under part A, number 1, I
19 actually think the original statement that prioritization
20 for the SB50 program has overshadowed -- or no. The
21 original thing which is shown as struck out, "DPR has not
22 used the AB 1807 prioritization method," was -- is just
23 clearer, I think. So I would suggest going back on that
24 one. And the same -- let's see. I want to make sure I
25 didn't --
27
BARNEY, UNGERMANN & ASSOCIATES 888 326-5900
1 DR. BLANC: How about "not appropriately
2 used"?
3 DR. GLANTZ: Well, I don't think they've
4 used it.
5 DR. BLANC: They may have used it in some
6 instances. I don't know. I mean, they may have in some
7 kind of ad hoc way. I don't know, but --
8 DR. GLANTZ: This was discussed endlessly
9 over many years. And we were told over and over and over
10 again that the SB950 program took -- was more important.
11 Maybe if you wanted an intermediary, you could say, "DPR
12 has used SB950 over AB 1807." But I think that's the
13 statement of fact which is correct. And I mean, the
14 other -- the statement --
15 CHAIRMAN FROINES: Stan -- Elinor, can you
16 try -- we'll get the transcript. Can you try and write
17 down what is being said?
18 DR. FANNING: Yeah. I'm, like, making
19 notes.
20 DR. GLANTZ: I don't feel violently about
21 any of these things. Let me just think here. And then
22 number two, I think that the original statement,
23 "Prioritization for SB950 does not necessarily reflect the
24 likelihood of being a toxic air contaminant," is also a
25 clearer statement than --
28
BARNEY, UNGERMANN & ASSOCIATES 888 326-5900
1 DR. BLANC: I'm sorry. Which one is that?
2 DR. GLANTZ: This is number two. I think
3 that was a clearer statement. For number three, I have a
4 third wording. I would say, "The process used to select
5 pesticides for active risk assessment at DPR has not
6 generally taken into account TAC candidate status."
7 CHAIRMAN FROINES: Is that --
8 DR. GLANTZ: That's number three. Huh?
9 CHAIRMAN FROINES: Did you write that?
10 DR. GLANTZ: Yeah.
11 CHAIRMAN FROINES: So you'll give that to
12 us?
13 DR. GLANTZ: Yeah. I mean, these are -- and
14 then let's see. With number five, I just had a question
15 about that. I think that original statement, "In the
16 past, pesticides selected for monitoring did not reflect
17 TAC priorities," is true.
18 The alternative wording, that it "better
19 reflects TAC priorities than in the past," is also true.
20 But in the past, they didn't seem to be paying much
21 attention to them at all, to me. So I would be a little
22 meaner, I guess.
23 The number six, I think the original
24 wording, "DPR does not routinely consider USEPA risk
25 assessments," is a clearer statement than the thing which
29
BARNEY, UNGERMANN & ASSOCIATES 888 326-5900
1 has been reworded. I think that was it. Let me just
2 look.
3 The other changes that were made were all
4 fine. Oh, and then, if you go to number -- page -- what
5 is my -- page 10, number 4, the -- where we -- it had
6 said -- the original wording was, "DPR should supplement
7 monitoring data," and it was changed to "could." And I
8 prefer "should." So --
9 DR. FUCALORO: Just want to subtract the
10 power of the subjective.
11 DR. GLANTZ: What? Whatever. I think we
12 want to make it affirmative recommendations here. You
13 know, because I think that one of the things that I think
14 came out of the workshop was, you know, trying to
15 couple -- you know, get a better job of getting a handle
16 of what's actually going on.
17 And -- and so, I think we should say
18 "should" there. But those are my -- the rest of it is
19 fine. The rest of the changes were fine. So I don't know
20 if you want to discuss that or just go around the table.
21 CHAIRMAN FROINES: I think if anybody has
22 comments as to what your recommendations are --
23 DR. GLANTZ: I'm keeping Dr. Blanc awake.
24 DR. BLANC: I don't feel strongly about the
25 things you said. I mean, it's fine. Only thing I would
30
BARNEY, UNGERMANN & ASSOCIATES 888 326-5900
1 say is, that I would defer to the Chair's discretion. If
2 after having heard your concerns, he still chooses in
3 certain of the instances to temper the tone of some of
4 these things, since you're closer on the ground to the
5 likely effectiveness of the document and how it might be
6 impactive, depending upon specific wording.
7 But I think that Stan's general direction of
8 trying to be as explicit as possible, assuming that it
9 wouldn't be counterproductive, is a good general
10 guideline. But you have final responsibility.
11 CHAIRMAN FROINES: And Paul Helliker has
12 heard both comments. He understands that the context --
13 DR. BLANC: Right. I have some specific
14 questions. On page 2, point 2 --
15 CHAIRMAN FROINES: Well, let's go around.
16 Craig?
17 DR. BYUS: Okay. I agree with what Stan
18 said. I'm not totally strong about it, but I think the
19 stronger language is probably the better choice. I just
20 would like to echo the point 2 here about considering a
21 vast approach relisting high priority organophosphates.
22 I really think this is an excellent idea,
23 considering how many organophosphates there are, and the
24 fact that they all do work by a common mechanism. So I
25 really think this is an excellent idea. The
31
BARNEY, UNGERMANN & ASSOCIATES 888 326-5900
1 possibility -- likely -- high likelihood of multiple
2 organophosphates being used on the same crop is, in fact,
3 likely.
4 So I pretty much like the document as it's
5 written. I would like to add, though, that I think that
6 some -- pardon me. Pardon me. That some examination or
7 incorporation of the food residue -- we have all this data
8 somewhere. There is somewhere a lot of data about what
9 pesticides actually are on foods.
10 Now -- and so this could really be a guide
11 for which pesticides are used together. I mean, clearly
12 they had to be used on the same crop. Now, clearly, it
13 wouldn't incorporate all pesticides, because some might be
14 less stable and maybe wouldn't show up in food residue.
15 But there's a lot of multiple-pesticide-use data in the
16 food-residue data somewhere.
17 It could -- could be used to guide
18 prioritizations for -- in terms of multiple risk for
19 multiple pesticides, when they were applied. I tried to
20 find out about some of that information, but I -- when I
21 was doing methyl parathion. But it became just too
22 cumbersome to try to do it. I do think there is a lot of
23 information there about it -- about multiple pesticide use
24 in the food-residue data.
25 CHAIRMAN FROINES: That sounds almost like
32
BARNEY, UNGERMANN & ASSOCIATES 888 326-5900
1 an academic research project.
2 DR. BYUS: It does. It does. But that's
3 all.
4 CHAIRMAN FROINES: Which would be good.
5 DR. BYUS: Yeah. Oh, sure.
6 DR. ATKINSON: Well, talking -- I'd like to
7 also echo the -- that I like the batched approach for
8 listing of chemicals. Certainly makes sense from an
9 environmental-type of approach, as well. Certainly
10 organophosphates, since there isn't a lot of data, they'd
11 be much more easily dealt with as a whole batch.
12 Another thing is, I'd like to -- I certainly
13 endorse the controlled applications, that DPR should do
14 controlled applications for site monitoring, rather than
15 preferably to spending time and energy doing ambient
16 monitoring.
17 CHAIRMAN FROINES: I think that's a very
18 important recommendation. And I think it was made
19 particularly clear by Bob Spear's presentation. And from
20 the standpoint -- again, from the standpoint of
21 identifying a compound as a toxic air contaminant, ambient
22 monitoring has different implications for risk-management
23 purposes. And that's also --
24 DR. ATKINSON: Yes.
25 DR. FUCALORO: As you know, I wasn't at the
33
BARNEY, UNGERMANN & ASSOCIATES 888 326-5900
1 September workshop. I couldn't make it. But I did read
2 this document and noted a few things that some of you
3 noted. The -- the monitoring -- the regulated monitoring,
4 that was a good one. Of course grouping the
5 organophosphates is another one.
6 The one thing I noted -- and I wasn't,
7 again, part of this discussion. This is on page 9,
8 number-one recommendation. Says, "DPR should consider
9 basing TAC listing on application site monitoring results,
10 and using ambient primarily in the risk-management
11 phase." I was just wondering, if that really meant TAC
12 priority listing or does it just mean --
13 DR. BLANC: I think that was the intent. I
14 circled the same thing. Because they don't actually list
15 something as a TAC.
16 DR. FUCALORO: That struck me.
17 DR. BLANC: We recommend that something be a
18 TAC; right?
19 CHAIRMAN FROINES: Yes.
20 DR. BLANC: So that wording needs to be
21 changed to be clearer. It implies that the DPR is
22 identifying -- is from a regulatory point of view listing
23 something as a TAC. Whereas what you're saying is how to
24 do their listing of priorities for consideration as a
25 TAC. Something -- I don't know that being too.
34
BARNEY, UNGERMANN & ASSOCIATES 888 326-5900
1 DR. FUCALORO: Well, their priority list --
2 I think that's become a common language with ARB and DPR,
3 the priority list in which chemicals are used and go to
4 next in order to see if we are going to designate them as
5 TACs.
6 CHAIRMAN FROINES: Well, the -- this goes
7 back in history to the -- to the debate that we've had
8 with DPR since the mid '80s where we have always strongly
9 disagreed with DPR on -- on the MOE as the basis for a TAC
10 listing.
11 We've always taken the position that a
12 compound should be designated as a toxic air contaminant
13 based on its toxicity. And that's different than the DPR
14 position. So that this recommendation for application
15 site monitoring is, in essence, to -- to -- is in essence
16 saying, if you're going to use the MOE, then we think
17 application site monitoring is the most appropriate
18 approach to that for purposes of identifying TACs.
19 DR. FUCALORO: And this highlights the
20 difference of what I think ARB does and DPR, on the other
21 hand. ARB will look at potency factors in some way and
22 designate something a TAC, and then use exposure as part
23 of mitigation; right?
24 Whereas DPR brings exposure in also --
25 exposure and potency factors, whatever they are, cancer or
35
BARNEY, UNGERMANN & ASSOCIATES 888 326-5900
1 noncancer effects, and then uses that as a basis for
2 designating something a TAC. But both, organizations as
3 far as I understand, use both of those in order to set up
4 a priority list. I think -- I think I have -- I think I
5 have that right.
6 CHAIRMAN FROINES: The problem, of course,
7 with the ambient monitoring, leaving aside the variability
8 issue is, you can go back to the data that is available
9 for us to review on methyl parathion and the actual
10 monitoring data that was available was very limited. So
11 we ended up, I think, used Jim Seiber's data, which was
12 one study from the '80s.
13 I mean, it's -- it's really, when you base
14 major policy and scientific decisions on one study done in
15 1988, 1987, and that forms the basis of whether
16 something's a TAC or not, you realize the limitations of
17 that approach.
18 So if we had lots of data that dealt with
19 variability, that's a different issue. But in any case,
20 to the degree that we continue this approach with the MOE,
21 then application site monitoring becomes obviously the
22 preferred approach, at least from the standpoint of this
23 panel. Paul?
24 DR. BLANC: I have a number of text changes
25 I'll just pass on to your colleague. But let me ask you
36
BARNEY, UNGERMANN & ASSOCIATES 888 326-5900
1 my substantive questions. In page 2, point 2, the last
2 line, "Further, the SB950 process does not use a
3 quantitative ranking scheme."
4 CHAIRMAN FROINES: Where are you at?
5 DR. BLANC: The last line of section 2, on
6 page 2, you know, "The criteria used to prioritize SB950
7 differ from those articulated by DPR." In that section,
8 the last line. "Further, the SB950 process does not use a
9 quantitative ranking scheme." I just wanted to be clear
10 on that. Do you mean you're not referring therefore to
11 their priority list, which did have some kind of rank?
12 CHAIRMAN FROINES: No. They have this
13 committee, remember?
14 DR. BLANC: Right.
15 CHAIRMAN FROINES: And the committee
16 basically defined the priority, and that they're not, in
17 essence, using this document for prioritization. This is
18 the quantitative document that effectively is not being
19 used.
20 DR. BLANC: Okay. And when they -- you --
21 you -- I think it was a little confusing, because they --
22 they rank things in three groups or something; right? So
23 it is -- it's very roughly a semi-quantitative. But it's
24 not the -- there's no process to it. It's two separate
25 issues to me.
37
BARNEY, UNGERMANN & ASSOCIATES 888 326-5900
1 And the stronger one is not that they -- not
2 so much that they group things in the three groups, you
3 know -- bad, very bad, and better -- but that there is no
4 rationally articulated process by which they do that. And
5 I thought that needed to be stated more clearly.
6 And I wondered, in fact, if on -- and this
7 is the related point, I think, in terms of recommendations
8 on page 5, where it says -- current language is -- the
9 third point is, "Develop a policy for coordination of
10 priorities under different programs that require DPR to
11 prepare risk assessments for pesticide." That's getting
12 at this process; right?
13 And what I would rather explicitly say, that
14 they need to delineate explicite criteria for ranking,
15 rather than the currently used ad hoc procedure. Because
16 of all of the things we heard, that was, for me, the most
17 disturbing, was that there could not -- maybe they have
18 something. But they could not explain it to me in a way
19 that sounded coherent.
20 That there was actually -- so I don't mean
21 that they have to prepare a 500-page document. But they
22 need to have a clearly delineated process. And I think we
23 need to say that.
24 CHAIRMAN FROINES: Does everybody agree with
25 that recommendation?
38
BARNEY, UNGERMANN & ASSOCIATES 888 326-5900
1 DR. BLANC: I mean, I wouldn't make it as a
2 new point, necessarily. But I think that's the point I'm
3 trying to get at. I also thought that -- going back
4 earlier, back to page 2 on point 3 where it says -- the
5 point that has to do with, "The process used to select
6 pesticides for an active risk assessment does not
7 necessarily take into account TAC candidate status." And
8 I would say that the decision --
9 CHAIRMAN FROINES: I'm sorry. Where are
10 you?
11 DR. BLANC: Point 3, on page 2. And I would
12 say that the problem is not that they don't seem to be
13 guided by a specific policy approach. I think they're not
14 guided by a coherent policy. It's not the lack of
15 specificity that bothers me so much, it's that it's
16 incoherent.
17 And similarly, on point 4 on the next page,
18 it's not that the process used to select pesticides for
19 air monitoring has been distinct from the risk assessment,
20 it's been disconnected from the risk assessment. I notice
21 you use the word "disconnected" later, but I really think
22 that that's --
23 On page 4, point 6. Well, after point 6.
24 These six points summarize the information which was
25 presented in that first part. And you get into this in
39
BARNEY, UNGERMANN & ASSOCIATES 888 326-5900
1 the second half. But the fact that the changing-use
2 patterns are not incorporated in a timely fashion to
3 priority setting, it's emphasized a lot in the sampling.
4 But I thought it was a critical issue that came up
5 relevant to the priority setting, as well.
6 Now, going on to the next section. In terms
7 of the -- the next set of -- next set of recommendations,
8 on the batching the organophosphate pesticides, this is a
9 technical question -- two technical questions. One is, do
10 we need to specify cholinesterase inhibiting
11 organophosphates?
12 The reason I ask, I know there are
13 carbamates which are not cholinesterase inhibiting and are
14 used for other purposes. Are there any -- technical
15 question for DPR. Are there any organophosphates which --
16 whose principal means of action is something other than
17 cholinesterase inhibiting?
18 CHAIRMAN FROINES: Well, there is the issue
19 of --
20 DR. BLANC: I'm going to get to the --
21 just --
22 DR. PATTERSON: I'm Gary Patterson from
23 DPR. And, no. It's -- organophosphates by nature are
24 cholinesterase inhibitors.
25 DR. BLANC: So unlike the carbamates, some
40
BARNEY, UNGERMANN & ASSOCIATES 888 326-5900
1 of which --
2 DR. PATTERSON: Diatomic carbamates usually
3 are not.
4 DR. BLANC: Right. Okay. Fine. But I do
5 think we may need this -- this section to say something
6 about organophosphates with delayed neurotoxicity.
7 Because in the batching process, we're certainly going to
8 have to take into account whether within those
9 organophosphates, any of them have delayed neurotoxicity.
10 Thanks.
11 And I thought that point 3 is really what
12 you really -- what we're really trying to say. They need
13 to delineate specific criteria for ranking rather than the
14 currently used ad hoc procedure. I think I said that
15 already. Okay. In Dr. Spear's comments --
16 CHAIRMAN FROINES: What page are you on?
17 DR. BLANC: Page 8. Under the heading,
18 "Ambient monitoring may not result in useful
19 characterization of population exposure." You have here
20 his critique of the ambient air monitoring, but not
21 necessarily alternatives that he also suggested.
22 And since you've come back to that in the
23 recommendations, invoking him. I guess, one question that
24 I have is, aside from the comment and discussion about
25 sampling in control applications, didn't Dr. Spear also
41
BARNEY, UNGERMANN & ASSOCIATES 888 326-5900
1 talk about the importance of modelling -- of theoretical
2 modelling exposure?
3 CHAIRMAN FROINES: Yes.
4 DR. BLANC: And there's no recommendation
5 here in -- A -- A, it's not described here. But B,
6 there's no follow-up recommendation that says that, in
7 addition to these other things, models of exposure should
8 also be used in estimating.
9 DR. ATKINSON: Point 5, the last sentence
10 has -- computer modelling is mentioned.
11 DR. BLANC: Where is that?
12 DR. ATKINSON: Same page.
13 CHAIRMAN FROINES: Last sentence of number
14 5. Page 8, last sentence.
15 DR. ATKINSON: That's just mentioned.
16 DR. BLANC: I'm sorry. Page 8, point 5?
17 CHAIRMAN FROINES: Last sentence.
18 DR. BLANC: Under "Currently proposed
19 changes to the ambient monitoring program may increase the
20 time required." Maybe -- page 8.
21 DR. ATKINSON: Page 8, point 5.
22 CHAIRMAN FROINES: Last sentence in the
23 paragraph under 5.
24 DR. FUCALORO: It says -- starts with "Other
25 ideas under consideration."
42
BARNEY, UNGERMANN & ASSOCIATES 888 326-5900
1 DR. BLANC: (Reading.) Well, I think you
2 should -- I think it got lost in the shuffle, because I
3 thought it warranted being a separate --
4 CHAIRMAN FROINES: Yeah, I think it could be
5 made more explicit. Take your results of application site
6 monitoring and use dispersion models for predicting
7 ambient concentrations.
8 DR. BLANC: Okay. Those were my --
9 CHAIRMAN FROINES: It's all good.
10 Everybody's fine with that? Peter?
11 DR. WITSCHI: Yeah. Not much to add, except
12 I picked up on Spear's point which says, "very limited
13 value." So first question must come to mind, why are we
14 doing it at all? The second one comes -- comes out like
15 Mark Twain in the weather, everybody complains about it,
16 but nobody's really doing something.
17 And I think what's really missing is some
18 overall master plan or great view of how the whole
19 exposure assessment could be improved so that it can serve
20 the purpose we would like things, and that's the
21 health-risk assessment.
22 Because the way I've seen -- this includes
23 this morning's presentation, that was very good. But we
24 are going to monitor more and more without really having a
25 clear view of what is going out to be, and for --
43
BARNEY, UNGERMANN & ASSOCIATES 888 326-5900
1 CHAIRMAN FROINES: Well, I think that DPR
2 has requested that we assign a panel member or more to
3 work with them on -- on these recommendations. And
4 certainly the issue of exposure-assessment monitoring
5 would be one of the question features.
6 Now, what I did was to propose that
7 Elinor -- Dr. Elinor Fanning, who's working with the
8 panel, and who has more time than the panel members to
9 work with them. But I -- but I think that we need to
10 assign at least one or two people to work with DPR to
11 address precisely the kinds of questions that you're
12 raising.
13 And so, if I can use your comments -- I wish
14 Stan were in the room. We -- it would be good to have a
15 volunteer or two to agree to work with DPR on the issues
16 that arise out of this document. And I think that the two
17 people who are missing are not the appropriate people for
18 this. I think it takes people who have some more
19 knowledge of exposure-related issues.
20 So I think this group here today is actually
21 the best. And if nobody wants to volunteer, I'll just
22 take that as -- take that silence as silence and then
23 we'll work it out outside, you know, the lights of the
24 meeting. Or we can assign Stan, because he's not in the
25 room.
44
BARNEY, UNGERMANN & ASSOCIATES 888 326-5900
1 DR. BLANC: And he's leaving early. So he
2 should be punished.
3 CHAIRMAN FROINES: So hearing no volunteers,
4 we'll take it up after the meeting. Anyway, go ahead,
5 Peter.
6 DR. WITSCHI: That's about all. I'm still
7 puzzled. I still do not see any good way how the human
8 data can be used for human health-risk assessment. And I
9 also see that we are doing more and more, which is going
10 to be less and less useful for this purpose.
11 CHAIRMAN FROINES: Well, this is a specific
12 example of a major problem, as you know, about how
13 monitoring data is used in air pollution exposure
14 assessment. It's one of the -- it is one of the -- it
15 is -- it is basically the first-stated priority by the
16 National Academy of Scientists, committee on Particulate
17 Matter. So it's a key issue.
18 So I think that we're finished with this.
19 We'll take all these suggestions -- we'll take all these
20 suggestions and develop a final document and send it off.
21 I don't know, Paul, if there's anything that you heard
22 this morning that makes you want to comment now or you
23 want to just wait till you receive the actual, formal
24 document. But it's your call.
25 MR. HELLIKER: My make of it is, I think
45
BARNEY, UNGERMANN & ASSOCIATES 888 326-5900
1 this is an excellent document, and it will help guide us
2 as we go forward. And as you just mentioned, there are
3 some fundamental problems that we face. And we will seek
4 your input and your assistance in helping to make a
5 reasonable choice as we go forward in all of our
6 regulatory programs.
7 But, I appreciate this. And certainly it
8 reflects some of my impressions, as I've come into the
9 department, that we do need to be clearer in defining for
10 you, as well as for other stakeholders out there, as what
11 our processes are, that we've gone through in making
12 decisions about the prioritization about different
13 monitoring and different risk assessments. So I'm looking
14 forward to responding to this.
15 CHAIRMAN FROINES: Thanks. Okay. Do we
16 want to take a break? Don't you? Just for everybody, got
17 a note from Peter that Stan was on the phone. We'll take
18 a ten-minute break.
19 (Brief recess taken.)
20 CHAIRMAN FROINES: The next item on the
21 agenda is MITC. This will be a staff report from DPR.
22 The panel will not take up the document today for
23 discussion purposes. That doesn't mean that we can't ask
24 questions as the presentation is made. And you're welcome
25 to do that.
46
BARNEY, UNGERMANN & ASSOCIATES 888 326-5900
1 But in terms of our formal -- a formal
2 discussion of the document, that will happen at our next
3 meeting, and we will have the benefit at that time, also,
4 of the OEHHA comments, which we currently don't have. And
5 we'll also have the benefit of Peter Witschi's final --
6 final review.
7 So those two things are -- because they're
8 still outstanding, I want to not try to take it up. Also
9 the -- before we start on MITC, I have overlooked saying
10 something at the beginning that I want to catch up and say
11 thank you very much to Tony Fucaloro for hosting us here.
12 DR. FUCALORO: Actually, the thanks goes to
13 the staff of Athenaeum. They are very competent and very
14 helpful. I'll transmit that thanks to them.
15 CHAIRMAN FROINES: If you have any comments
16 you want to say about the history and anything else,
17 please feel free.
18 DR. FUCALORO: Yeah, but I'll probably get
19 it wrong. It's been told to me several times, and I'm not
20 sure I have it right. But this is a product of one of our
21 founding -- one of CMC's founders, Donald McKenna, who
22 recalls having students and faculty together for teas and
23 dinners at -- when he was a student at Pomona College.
24 So he tried to get that -- that to happen at
25 Claremont McKenna College, and he was successful. And
47
BARNEY, UNGERMANN & ASSOCIATES 888 326-5900
1 under Jack Stark raised money for this -- this building,
2 and to raise the funds to endow it.
3 So four nights a week, for example, we will
4 have a something -- we'll have -- similar to what you're
5 doing tonight, which we'll have a reception, we'll have a
6 dinner, and then a presentation in this main hall. And
7 students and faculty from all the colleges, whether they
8 have meal plans or not, eat for free.
9 And that's all endowed. And so it's quite a
10 program. Runs four times a week during the academic
11 year. So it's a great facility, and it brings faculty and
12 students together. And it's not a faculty high house --
13 high table as you would find at another institution.
14 Almost all events, with the exception of a few like this
15 one, require students' attendance and student
16 participation. So that's pretty much the philosophy and
17 the thinking behind this -- this program -- the Athenaeum
18 program.
19 CHAIRMAN FROINES: Well, thank you again. I
20 think it's lovely.
21 DR. GLANTZ: Where did the name come from?
22 DR. FUCALORO: Well, I was ambushed to give
23 a history of this place, and you're asking about -- I know
24 there's a city named Athens --
25 DR. GLANTZ: Okay.
48
BARNEY, UNGERMANN & ASSOCIATES 888 326-5900
1 DR. FUCALORO: -- that goes back to
2 antiquity and has quit a history. But beyond that, I'm a
3 chemist. What the heck?
4 DR. GLANTZ: Well, would you find out and
5 report back at the next meeting?
6 DR. FUCALORO: I know there's an Athenaeum
7 at Cal Tech -- at Cal Tech.
8 CHAIRMAN FROINES: This is not a graduate
9 student's oral, and you don't keep asking them questions
10 till you find the one he doesn't know the answer to.
11 DR. PATTERSON: We only do that to DPR.
12 CHAIRMAN FROINES: Okay. MITC.
13 DR. PATTERSON: Again, I'm Gary Patterson
14 from DPR. Paul Goslyn is unable to attend this meeting,
15 and he sends his apologies. And few statements that he
16 wanted me to start with was, he wanted me to emphasize the
17 importance of your input on MITC, and that it will be used
18 to help guide us through the risk-management phase for
19 this chemical.
20 In addition, he's very interested in hearing
21 your thoughts on the sensitivity of the end points that
22 will be presented today. And on one side note, we gave
23 you a list of four chemicals that we were going to do for
24 the year. We're going to replace naled with
25 chlorpyrifos.
49
BARNEY, UNGERMANN & ASSOCIATES 888 326-5900
1 And with that, then, I'll turn it over to
2 staff to make a presentation. The first person will be
3 Pam Wales to do the environmental fate.
4 MS. WALES: Good morning. My name is
5 Pam Wales. I'm with the Environmental Monitoring and Pest
6 Management Branch at DPR. And -- next slide. I'm going
7 to very briefly cover the valuation of MITC as a TAC on
8 the environmental fate of this chemical.
9 The three points that I'm going to cover
10 very briefly this morning are: The fate of MITC and the
11 environment, and focusing mostly on the air; the use in
12 California; and also cover some air monitoring to
13 determine levels of MITC following applications.
14 When we talk about MITC, we're really
15 talking about three pesticides. MITC, on the bottom of
16 the slide, is registered in California for use as a wood
17 preservative. Use in California is about 350 pounds per
18 year. MITC is very volatile. Its vapor pressure is about
19 16 millimeters of mercury, and the Henry constant is at
20 1.8 times 10 to the minus 4 atmospheres, cubic meters per
21 mole.
22 MITC is used to control wood decay
23 organisms in large structural timbers. It's typically not
24 used in crop-land setting. However, there are two other
25 pesticides. One is called Dazomet, and the other
50
BARNEY, UNGERMANN & ASSOCIATES 888 326-5900
1 Metam-Sodium, for which MITC is the principal active in
2 their formulations.
3 Dazomet is registered for use in California
4 as a slimicide and biocide. It's used in cooling water
5 treatments and also in -- just had a brain fade. Also,
6 one product is used as a pre-plant fumigant. The use of
7 Dazomet is about 20 thousand pounds per year, and it
8 breaks down to form MITC.
9 Metam-Sodium, on the other hand, is
10 registered for use as a pre-plant fumigant, wood
11 preservative, and also for root control. And in
12 California, in the agricultural setting, almost 16 million
13 pounds are used per year. While Metam-Sodium itself is
14 non-volatile, it does break down rapidly to MITC.
15 Next slide. As I've said, the primary
16 source of MITC in the environment is from the breakdown of
17 Metam-Sodium. Metam-Sodium is applied to a soil either
18 by soil injection or by chemigation. It's usually --
19 DR. GLANTZ: What is chemigation?
20 MS. WALES: Chemigation is irrigation --
21 treatment by irrigation.
22 DR. GLANTZ: Does that mean put it in the
23 irrigation water or they just spray it on?
24 MS. WALES: Yes, put into irrigation water
25 then spray it out over the field. When it's applied by
51
BARNEY, UNGERMANN & ASSOCIATES 888 326-5900
1 chemigation, after the treatment, a -- enough clear water
2 is ran afterwards through the sprinklers to produce a
3 one-inch seal of water, and also to drive the Metam-Sodium
4 into the soil.
5 When it's injected by soil-injection
6 methods, use special equipment that injects it about 10 to
7 12 inches into the soil. Afterward, the soil is bedded or
8 tarped or rolled and compressed. The purpose of this is
9 to keep the Metam-Sodium -- actually, the MITC vapors in
10 the soil so they actually do the fumigant activity.
11 The conversion in the soil of Metam-Sodium
12 to MITC occurs within about an hour. And conversion
13 occurs with 87 to 95 percent efficiency, depending on some
14 conditions of soil. Increased soil temperature, increased
15 concentrations of clay or organic materials, and increased
16 soil pH, coupled with decreased soil moisture content,
17 lead to rapid -- more rapid conversion.
18 Two other compounds may be formed in the
19 soil during that conversion. One is carbon disulfide and
20 the other is hydrogen sulfide. The generation of those
21 compounds really depends on the pH of the soil. If it's
22 more alkaline, hydrogen sulfide is expected to be
23 generated. And in basic soils, carbon disulfide.
24 About 60 percent of the MITC that's
25 generated in the soil volatilizes, leaves the soil and
52
BARNEY, UNGERMANN & ASSOCIATES 888 326-5900
1 enters the air. Once in the air, the main pathway for the
2 loss of MITC from the air is through photolysis. The
3 photo decomposition results in a variety of compounds, as
4 you can see on this overhead here.
5 MITC is there on the left. The activated
6 molecule is the one in the middle with the star. And
7 according to Geddes, the major, primary photochemicals
8 produced is methyl isocyanide. About 80 percent of the
9 MITC is converted to methyl isocyanide.
10 That follows some secondary photochemical
11 processes and results in methyl isocyanate, and
12 methylformamide, and some other compounds which you see
13 here. Geddes proposed that the -- the methyl isocyanate
14 may be the -- may be photochemically stable, because he
15 observed that it increased over time.
16 Next page. Briefly to cover the use of
17 Metam-Sodium --
18 DR. BLANC: Can you go back to the last
19 slide?
20 MS. WALES: Sure.
21 DR. BLANC: Point out to us which
22 formulas -- which moiety --
23 MS. WALES: I'm sorry. I can't hear you.
24 DR. BLANC: Which chemical structure is
25 which?
53
BARNEY, UNGERMANN & ASSOCIATES 888 326-5900
1 MS. WALES: If you follow the main pathway,
2 that's MITC.
3 DR. BLANC: Yeah.
4 MS. WALES: That's MITC, the activated
5 state. To the right of that is methyl isocyanide. To the
6 right of that is methyl isocyanate. A-ha. This structure
7 right here is N-methylformamide. This right here is
8 methylamine. Methylamine is also generated in this
9 pathway. This is carbonyl sulfide, sulfur dioxide, and
10 in this pathway, you also generate the MIC plus hydrogen
11 sulfide.
12 DR. BLANC: Thank you.
13 MS. WALES: This is -- this slide shows
14 overall Metam-Sodium use in California. This is, once
15 again, in the agricultural setting, from 1990 through
16 1998. As you can see, Metam-Sodium use began to increase
17 in 1994. It is pretty-well stabilized at about 15 to 16
18 million pounds a year since then.
19 The reason for this increase in 1994 was
20 largely due to two things. One was the reduced use of
21 telone, 1-3 dichloropropene, which is another fumigant,
22 and methyl bromide. Also, researchers discovered that
23 Metam-Sodium was very effective in controlling root
24 nematodes in carrots, and also nightshades in the
25 nightshade crops. So they applied -- so use went up to
54
BARNEY, UNGERMANN & ASSOCIATES 888 326-5900
1 account for that.
2 Next slide. This is the use of Metam-Sodium
3 from 1990 to 1998 on a month-by-month basis. You can see
4 that it's used pretty much year round. However, there are
5 couple large peaks. The first one, right here in February
6 through April. And another peak that occurs in the late
7 summer, early fall, from about July through October. And
8 this is throughout the whole state.
9 As I said, Metam-Sodium is primarily used on
10 carrots. Almost 30 percent of what's applied in
11 California is used on carrot crops. Another 25 percent --
12 23 percent is used on tomatoes, cotton, and potatoes
13 account for the major crops. All the rest of the uses are
14 from a variety of crops -- root crops, bulb crops, lots of
15 different crops.
16 When we say that the use is associated with
17 a crop, it's actually a pre-plant application. It's
18 applied before the crop is put in the ground. This map
19 shows how Metam-Sodium is used throughout the state. This
20 is from 1998 --
21 CHAIRMAN FROINES: Question.
22 MS. WALES: Uh-huh.
23 CHAIRMAN FROINES: This document that we had
24 earlier this morning, Monitoring Multiple Chemicals by
25 Crop Root, and he's got the 23 chemicals for cotton.
55
BARNEY, UNGERMANN & ASSOCIATES 888 326-5900
1 MS. WALES: Uh-huh.
2 CHAIRMAN FROINES: And Metam-Sodium is not
3 listed on this list. So there's a disconnect between your
4 11 percent here, and this document. Which seems -- would
5 seem to imply that -- well, they're different. Anybody
6 know the answer to that?
7 MR. SEGAWA: I do.
8 CHAIRMAN FROINES: Oh, there you are. I
9 keep looking for you.
10 MR. SEGAWA: That's because, in the chemical
11 listed for cotton, I only listed those chemicals which had
12 their highest use on cotton. And in this particular case,
13 you can see that highest use is on carrots. And so in the
14 crop grouping, it would have been grouped with carrots,
15 rather than cotton.
16 CHAIRMAN FROINES: Okay. For us, it's
17 probably better to know which is the highest pesticides on
18 cotton.
19 MR. SEGAWA: Yes. For instance, we could
20 have one -- I just put the highest crop use. I could have
21 put highest two or highest three crops, which would have
22 been another way to do it.
23 CHAIRMAN FROINES: Well --
24 DR. GLANTZ: Well, no. I think the
25 difference -- I think what you're saying, John, is the
56
BARNEY, UNGERMANN & ASSOCIATES 888 326-5900
1 list should have been a list of the -- of the pesticides
2 used on cotton, perhaps. And what he did was, he said,
3 let's look -- it was the other way around.
4 It said, let's look at the pesticides and
5 pick the crop that each pesticide is used the most on.
6 And those are the -- the ones on the list we had earlier
7 were the pesticides where cotton was the most heavily --
8 was the greatest use of that pesticide.
9 CHAIRMAN FROINES: But you see the potential
10 contradiction?
11 DR. GLANTZ: Yeah, yeah. I just think you
12 need to be clear, though.
13 CHAIRMAN FROINES: So we -- so the panel,
14 you see, doesn't know right now what are the most
15 important pesticides on cotton.
16 DR. BLANC: Because -- to follow up on that,
17 you could have a pesticide which actually isn't used that
18 much anywhere, but the one crop that it is used on is
19 cotton; right?
20 MR. SEGAWA: Correct.
21 DR. BLANC: And another pesticide which is
22 used, like Metam-Sodium is -- only ten percent of it's
23 used on cotton, but it happens to be one of the most
24 widely used pesticides in California. Therefore ten
25 percent of 13 million pounds is still a million pounds
57
BARNEY, UNGERMANN & ASSOCIATES 888 326-5900
1 used on cotton.
2 MR. SEGAWA: That's correct.
3 DR. BLANC: And so, therefore, what would
4 probably interest us more would be, of the heaviest-use
5 pesticides overall in California, which are -- which of
6 them are used in rank order in cotton? So that if you
7 talked about one crop --
8 MR. SEGAWA: Yes, but then we would have to
9 come up with some sort of cut off. As you say, one
10 million pounds -- everything above one million pounds, we
11 have concerns about. Everything below, we do not monitor
12 for.
13 DR. GLANTZ: Or some reasonable cut off.
14 Just show us -- or show us if you use a cut off of one
15 million pounds, then you use it to cut off 500 thousand
16 pounds. How does it change?
17 CHAIRMAN FROINES: I mean, we're interested
18 in the scope of the problem. And so, if you arbitrarily
19 limit that, we're left without a real sense of what --
20 what's the pattern of use, basically. Let's go on.
21 MS. WALES: Next slide. Map of the 1998
22 use in California. This is of Metam-Sodium. So you can
23 see the bulk of the Metam-Sodium is applied, once again,
24 through the Central Valley. Heaviest -- these darkest
25 spots are the highest use.
58
BARNEY, UNGERMANN & ASSOCIATES 888 326-5900
1 The highest use is in Kern County. This is
2 1998 now. We have Kern County, and then up through
3 Fresno, that's quite a bit in Madera area. And then on
4 down here in Imperial County. But you can see, it's
5 also -- it's used pretty much through all the agricultural
6 areas. Including, if you look up at the north part of the
7 map there, you'll see some use on the potatoes up in Modoc
8 and bulbs, I believe, in Del Norte.
9 Now, these things that I've mentioned about
10 the locations of where it's used and also the soil
11 conditions actually played a big part in determining where
12 we wanted to do our studies. The ambient studies were
13 designed to measure pesticide concentrations in ambient
14 air during the time and region of peak use.
15 The samplers were placed on roof tops of
16 schools, fire houses, and other public buildings. And for
17 ambient studying -- studies, we did not associate the
18 monitoring with any specific application. This was to
19 provide an estimate of exposures that people living in
20 proximity to pesticide applications might experience.
21 Three studies were conducted in California,
22 and they're summarized in the report. This is a table
23 with the information from the three studies. I'm not
24 going to read this to you in the interest of time. And
25 especially since Tom, who's after me, is going to cover a
59
BARNEY, UNGERMANN & ASSOCIATES 888 326-5900
1 lot more of this in exposure assessment.
2 What I did want to point out to you, was
3 that the ambient studies were conducted in Kern County,
4 and in Lompoc, and then again, very new study that was
5 just published this year in Kern County. And these were
6 conducted in the summertime.
7 Dr. Seiber's study went from May until
8 August, and then the Air Board study was in July. And in
9 Kern County, we have soils in the summertime that are very
10 warm. They're dry. The pH is a little bit on the
11 alkaline side. And the soil-moisture content is low. And
12 so that would indicate that that's probably the best time
13 to find MITC in the air.
14 These are the positive-sample results. And
15 the number of samples that were taken and then the number
16 of samples -- of the positive samples. This recent study
17 by Dr. Seiber did something a little different than the
18 others did. And that was, he put monitors inside
19 residential homes, outside residences, very close to the
20 external walls of the homes.
21 And then he also placed monitors on tops of
22 roof tops, other public buildings in the Kern County area
23 where Metam-Sodium was being applied. Interesting thing
24 to notice is that the positive detections indoors was not
25 that much different from the outdoors, and the ambient
60
BARNEY, UNGERMANN & ASSOCIATES 888 326-5900
1 studies or ambient samples.
2 In the wintertime, he took samples in
3 January and in March. And now, those cool air/cool soil
4 conditions, and the results are much lower than what they
5 were in the summer studies. This is a map from the study
6 that was conducted by the Air Board of 1993. Hard to see,
7 because it's not on the scale here.
8 But the samplers were placed in Shafter and
9 Bakersfield, in Lamont, and Weed Patch. The red hashed
10 marks and checker-board marks that you see here on the map
11 are where the applications of Metam-Sodium occurred during
12 this study.
13 As you can see, we had applications
14 surrounding all of the areas. An interesting thing that I
15 noted was that at Bakersfield, which was the background
16 site, there were positive detections in all eight of the
17 samples that were collected. And the nearest applications
18 of Metam-Sodium were approximately six miles to the
19 northeast -- or to the northwest, and about seven or eight
20 miles to the southeast.
21 CHAIRMAN FROINES: On your previous
22 overhead --
23 MS. WALES: Uh-huh.
24 CHAIRMAN FROINES: -- you say "ambient air
25 monitoring, MITC." My guess is that you mean
61
BARNEY, UNGERMANN & ASSOCIATES 888 326-5900
1 Metam-Sodium.
2 MS. WALES: We're monitoring for MITC after
3 applications of Metam-Sodium. Because Metam-Sodium is not
4 volatile, we don't expect to find it in the air. Also,
5 because conversion is so rapid, yes.
6 CHAIRMAN FROINES: But it's a Metam-Sodium
7 application.
8 MS. WALES: It's a Metam-Sodium
9 application. One other thing to note, I checked. There
10 was no Dazomet or MITC applied anywhere in Kern County
11 during the course of the study. So all of the results
12 would presumably be from the Metam-Sodium applications.
13 This is from the Lompoc study. Now, while
14 this study wasn't conducted solely for Metam-Sodium, one
15 of the chemicals was Metam-Sodium. There were -- samplers
16 were placed at these locations around the city of Lompoc.
17 And two applications were made during the study, one right
18 here, and the other one is right here.
19 DR. FUCALORO: Just one question. Came up
20 when I was reading the report. A -- AI, what does that
21 stand --
22 MS. WALES: Active ingredient.
23 DR. FUCALORO: Thanks.
24 MS. WALES: Okay. On the application site
25 air monitoring studies --
62
BARNEY, UNGERMANN & ASSOCIATES 888 326-5900
1 DR. GLANTZ: Before you go on, on this
2 figure 11-A, I'm a little confused.
3 MS. WALES: The Lompoc map; okay.
4 DR. GLANTZ: Yeah. Where -- were the -- is
5 this whole gray area where it was applied? That's the
6 city of Lompoc; right?
7 MS. WALES: Yeah. Let's go back to that
8 map.
9 DR. GLANTZ: So where is the actual -- is
10 the actual application a little box sort of on the --
11 MS. WALES: Yeah, on the map here, it's
12 purple. This is the city of Lompoc. This is where one
13 application occurred.
14 DR. GLANTZ: I see.
15 MS. WALES: That was the 1,058 pounds were
16 applied. And then this field right here to the -- almost
17 due west --
18 DR. GLANTZ: I see. Okay.
19 MS. WALES: -- is the 952. For the
20 application site monitoring studies, we have five studies
21 that were conducted, and they're summarized in the
22 report. Once again, I'm not going to -- on the next slide
23 I have a table. I'm not going to read all this again.
24 However, two of the studies were from --
25 were based on sprinkler irrigations. One of them we
63
BARNEY, UNGERMANN & ASSOCIATES 888 326-5900
1 monitored for MITC, hydrogen sulfide, and carbon disulfide
2 following a sprinkler irrigation application. And then
3 these are the results.
4 Tom is going to discuss this a lot more
5 following me, so I'm not going to say much, other than we
6 did detect hydrogen sulfide. And that could be expected
7 because of the alkaline of the soil. And we did not
8 detect carbon disulfide.
9 Three studies were done following soil
10 injection. One in 1993, one in 19 -- all three -- well,
11 two in 1993, and one in 1995. And once again, following
12 the application, MITC was detected in all of the
13 samples -- nearly all of the samples in all of those
14 studies. There are no questions? Tom.
15 CHAIRMAN FROINES: Thank you.
16 MS. WALES: Thank you.
17 DR. BLANC: Actually, I have one question.
18 Sorry.
19 MS. WALES: Oh, okay.
20 DR. BLANC: Because this may not be covered
21 later.
22 MS. WALES: Okay.
23 DR. BLANC: Your third overhead --
24 MS. WALES: The third one?
25 DR. BLANC: -- where you talked about the
64
BARNEY, UNGERMANN & ASSOCIATES 888 326-5900
1 structure of Metam-Sodium and Dazomet.
2 MS. WALES: Okay.
3 DR. BLANC: So is the -- should I assume
4 that each molecule of Dazomet yields two molecules of MITC
5 as opposed to Metam-Sodium on the one-for-one basis?
6 MS. WALES: According to the manufacturer
7 of the one -- of one of the Dazomet products, when Dazomet
8 breaks down, there's a ring --
9 DR. BLANC: Rearrangement?
10 MS. WALES: Well, a ring break that occurs.
11 And you yield one molecule of MITC, one molecule of
12 formaldehyde, one molecule of hydrogen sulfide, and one
13 molecule of methylamine, I believe. And together, that
14 whole collection of compounds constitutes the active.
15 DR. FUCALORO: In the presence of water;
16 right?
17 MS. WALES: In the presence of water, yes.
18 DR. BLANC: Say it again. One molecule of
19 MITC, one molecule of formaldehyde --
20 MS. WALES: Of formaldehyde, one molecule
21 of hydrogen sulfide, and one molecule of methylamine, I
22 believe. Let me check to make sure. Yes. Formaldehyde,
23 MITC, hydrogen sulfide, and mono-methylamine.
24 CHAIRMAN FROINES: What is it again?
25 MS. WALES: I'm sorry?
65
BARNEY, UNGERMANN & ASSOCIATES 888 326-5900
1 CHAIRMAN FROINES: Say it again.
2 Methylamine --
3 MS. WALES: MITC, formaldehyde, hydrogen
4 sulfide and mono methylamine.
5 DR. BLANC: What's the form of formaldehyde?
6 CHAIRMAN FROINES: CH2O. There are two
7 formaldehydes.
8 MS. WALES: You would get two?
9 CHAIRMAN FROINES: You said methylamine,
10 MITC, H2S and formaldehyde.
11 MS. WALES: Yes.
12 CHAIRMAN FROINES: Seems to me you get two
13 formaldehydes. What am I missing here?
14 DR. BLANC: You got to get something
15 different, because there's five carbons in this molecule.
16 CHAIRMAN FROINES: You get MITC, H2S,
17 methylamine --
18 MS. WALES: And formaldehyde.
19 CHAIRMAN FROINES: So you have to have two
20 formaldehydes.
21 MS. WALES: That could be.
22 CHAIRMAN FROINES: Break the bond between
23 the -- you look at the sulfur. You break the bond between
24 the two sulfur breaks, break the bond between the
25 hydrogen, the methylamine, you can see you take that right
66
BARNEY, UNGERMANN & ASSOCIATES 888 326-5900
1 out. See, the MITC is the right-hand side, so you've got
2 two carbons unaccounted for. So that must mean two
3 formaldehyde.
4 MS. WALES: That could be.
5 CHAIRMAN FROINES: I'm sorry. Thank you.
6 MS. WALES: Is that good? Thank you.
7 DR. THONGSINTHUSAK: My name is
8 Thomas Thongsinthusak. I'm with DPR. My presentation
9 will come -- will cover part B, the exposure assessment of
10 the MITC. Next one, please. My presentation will cover
11 six different topics, starting from estimate production of
12 MITC in California and the calculated exposures for adults
13 and children. And so I touch on the production of MIT,
14 hydrogen sulfide, and then exposure appraisal.
15 Next please. Estimated production of MITC
16 in California. I use the -- use report format and sodium
17 from 1992 to 1997 and the amount of Metam-Sodium, MITC are
18 shown as million pounds. The first column, Metam-Sodium
19 use in California in 1992, is about 8.6 million pounds.
20 And the amount was doubled in about 1995.
21 This is the column show the MITC generated
22 from Metam-Sodium use. This column here. I use the
23 equation shown in foldout B. The conversion of
24 Metam-Sodium to MITC is about 60 percent by weight, which
25 is about one mole of Metam-Sodium per one mole of MITC.
67
BARNEY, UNGERMANN & ASSOCIATES 888 326-5900
1 The amount of MITC products used in California is very
2 low. For 1992, it's about 8,500 pounds. In 1997, it's
3 about 400 pounds, only.
4 In the last column show the total estimate
5 amount of MITC produced from '92 to '97. The last part of
6 this slide show the amount of use of the estimate in
7 California. Which is -- California, which is very small
8 compared to amount use of Metam-Sodium.
9 Next slide, please. This slide show the
10 calculation of the exposure estimates calculated for
11 adults and children. The -- first of all, I use the data
12 from what Pam mentioned, and then those of amount of
13 concentration of MITC were adjusted for molecular weight,
14 and application weights, and a percent recovery.
15 First of all, I use the MITC concentration
16 times the maximum application rate, divided by the
17 application rate, if known or used in the study, and then
18 divided by percent of self-recovery. I can convert from
19 the amount expressed as microgram per cubic meter to parts
20 per billion using this equation.
21 The estimate calculated as an observed daily
22 dosage or ADD. For ADD I use the short-term concentration
23 of MITC times adult female ventilation rate and divided by
24 body weight. Short-term ADD concentration, that means 24
25 hour times average or closest to 24 hour TWA. Further
68
BARNEY, UNGERMANN & ASSOCIATES 888 326-5900
1 exposure estimates for male -- adult males, I can use the
2 factor of 1.5, which is obtained from the ratio of
3 ventilation rate and body weight between males and
4 females.
5 The next is the long-term or moderate-term
6 exposure estimates for MITC or seasonal average daily
7 dosage or SADD. The ADD that used to calculate the SADD
8 is used from the moderate term, ADD concentration of MITC
9 times exposure days per season 120-days season. For the
10 exposure days, I used 23 days per season. Currently DPS
11 is working on exposure days for current exposure
12 assessment.
13 This slide show the ADD for adult females.
14 And for B.2, B.7, and B.8, they were from ambient
15 monitoring studies. And the first one, wherever I can, I
16 will use the Atkinson concentration as TWA. And if they
17 were not available, I will use the highest exposure --
18 highest MITC air concentrations.
19 In this case, only one applicant from each
20 site. I use the highest concentration. This study was
21 conducted in --
22 DR. GLANTZ: What was TWA again?
23 DR. THONGSINTHUSAK: Times weight of
24 average. This study was conducted in 1993. B.7 conducts
25 in 1997 and '98. As it's shown earlier, the amount of use
69
BARNEY, UNGERMANN & ASSOCIATES 888 326-5900
1 of Metam-Sodium for B.7 in California was about doubled to
2 the amount of Metam-Sodium use in 1993. The range of the
3 ADD from .62 to about 5 for B.2, B.7. They were very
4 similar to B.2. For the study in Lompoc, the ADD was
5 about .14 micrograms per kilogram per day.
6 Next slide, please. This table show the ADD
7 obtained from five studies. This is application site
8 studies. Contra Costa, B.3, and Kern County. And B.4
9 also in the Kern County. B.5, Madera. And B.6,
10 Bakersfield. There will be one more study that will be
11 added in the future. The industry conducted one latest
12 study. I will add that study, once the final report is
13 available.
14 There's a wide range of ADD from application
15 site study. When I say it doesn't say how far away from
16 the treated field, it's normally range from 12 to 40 yards
17 from the treated field, kilometers. You can see that the
18 farther away from the treated field, pyramid of the ADD is
19 lower than the station that is located closer, like five
20 meters. Next, please.
21 CHAIRMAN FROINES: Will you then use these
22 now for the MOE calculations?
23 DR. THONGSINTHUSAK: Next person, Andy
24 Rubin, will use these ADD for MOE calculations.
25 DR. BLANC: Why do the ranges on these ones
70
BARNEY, UNGERMANN & ASSOCIATES 888 326-5900
1 that you have here differ from the ranges on the last
2 slide that Pam showed us?
3 DR. THONGSINTHUSAK: That Pam show?
4 DR. BLANC: Yeah, for the same studies. For
5 example, for the Madera County, she had a maximum -- a
6 range of 1.29 to maximum of 435 parts per billion. And
7 you have a series of ranges, but none of them are as high
8 as 435 parts per billion. Whereas, your Kern County one
9 there, range -- upper range is higher than the upper
10 range.
11 DR. THONGSINTHUSAK: Pam's data have not
12 been corrected for the maximum application weights and the
13 percentage of recoveries. In my case, before I calculate
14 the ADD, I will make adjustment for maximum application
15 weight, and the percentage of recoveries.
16 DR. BLANC: So your value will always have a
17 slightly higher --
18 DR. THONGSINTHUSAK: Pardon me?
19 DR. BLANC: So your values will have a
20 slightly higher upper range?
21 DR. THONGSINTHUSAK: Yes, in most case, they
22 will be higher. Next is to calculate the seasonal average
23 daily dosage. I will use the ADD concentration from a
24 moderate-term air monitoring studies. In this case, I
25 will have more samples like for B.2.
71
BARNEY, UNGERMANN & ASSOCIATES 888 326-5900
1 For B.2, B.7, and B.8, represent ambient air
2 monitoring data. And I calculate use ADD, multiplies
3 exposure days per 120-day season. And the range is like
4 for the B.2 from .02 to about .45. I will not go over all
5 these numbers. They are in your handouts.
6 Next, please. The SADD from the application
7 site monitoring studies, five studies all together. And
8 for the first one, B.1, 27.2 micrograms per kilogram and
9 per day. And the numbers vary according to the sampling
10 site, based on the distance from the treated field
11 kilometer.
12 Next, please. Now, there's a question about
13 a potential retention of MITC on silica gel drying tubes
14 which is placed in front of a charcoal sampling tubes,
15 not only in a sampling tray. There will be section of the
16 tubes, the front will be the silica gel drying tube, and
17 the other two absorb the excess moisture, and the other
18 two will be the charcoal sampling tube.
19 Normally, there will be two sections. The
20 first section will contain 400 milligrams of charcoal, and
21 subdivided by -- and the last part will contain about 200
22 milligrams charcoal.
23 Most studies use just charcoal tubes to
24 collect their samples. But there are two studies that use
25 the silica gel drying tubes. The first one by Wofford in
72
BARNEY, UNGERMANN & ASSOCIATES 888 326-5900
1 1994, and the second one by Zeneca -- okay. They found
2 right by -- Wofford found at four out of ten tubes of the
3 silica gel, they can retain from zero to four percent of
4 the total MITC. And for the internal two, the retention
5 ranged from 58 to a hundred percent. So there's a
6 question there.
7 Silica gel may retain some MITC, but it
8 is -- doesn't seem to be so from the study by the
9 industry. The recovery of MITC range from 71 to 95
10 percent. So in this case, after desorption deficiency
11 correction, retention would be -- should be around ten
12 percent or less. Next, please.
13 DR. BLANC: Can you say what the
14 implications of this is?
15 DR. THONGSINTHUSAK: Pardon me?
16 DR. BLANC: And what do you believe the
17 implications of these data are?
18 DR. THONGSINTHUSAK: The implications? The
19 implications of those data is, it's likely that silica gel
20 drying tubes can retain some MITC. But I have got to have
21 some more proof for that. And most studies accept the
22 tube. Most study does not use silica gel drying tubes.
23 So, in general, I do not see any problem for that.
24 DR. BLANC: But you said that Wofford used
25 silica drying tubes.
73
BARNEY, UNGERMANN & ASSOCIATES 888 326-5900
1 DR. THONGSINTHUSAK: Yes.
2 DR. BLANC: And the highest values that you
3 had were from the Wofford study.
4 DR. THONGSINTHUSAK: Yes.
5 DR. BLANC: And if the retention was high,
6 means that you couldn't remove some of the material, and
7 therefore underestimated those very high values; is that
8 right? Did I have the direction of the effect?
9 DR. THONGSINTHUSAK: Yes. If the Wofford
10 study did not include MITC in the silica gel tubes, but
11 they did. So they combine MITC from both -- both types of
12 tubes. So there's no problem for that. But that's
13 another study conducted by Zenneca. They did not analyze
14 MITC in the silica gel drying tube. But from the lab from
15 the study, they did not see that that is an important
16 issue.
17 DR. BLANC: And did you use their data in
18 any of your calculations?
19 DR. THONGSINTHUSAK: Yes, uh-huh.
20 DR. BLANC: Which calculations involved the
21 Zenneca study?
22 DR. THONGSINTHUSAK: I think B.6.
23 DR. BLANC: B.6? The Bakersfield study?
24 DR. THONGSINTHUSAK: Madera, I think.
25 Madera. Would you show the table 7.2?
74
BARNEY, UNGERMANN & ASSOCIATES 888 326-5900
1 DR. BLANC: 7.2 or 8.2?
2 DR. THONGSINTHUSAK: B.5. Madera.
3 Actually, it's ICI. They used silica gel drying tubes,
4 but they did not analyze MITC in the tube.
5 CHAIRMAN FROINES: They didn't analyze the
6 MITC in the --
7 DR. THONGSINTHUSAK: Silica gel.
8 CHAIRMAN FROINES: So that underestimates
9 the overall approach.
10 DR. THONGSINTHUSAK: It is possible that
11 MITC concentrations were underestimate. But as I
12 mentioned before, from their study, the recovery with or
13 without silica -- with a silica gel drying tube was very
14 high. So I assume that it is not their concern, because
15 of the their findings.
16 CHAIRMAN FROINES: Well, it seems to me,
17 this is actually an issue that needs to be resolved. It's
18 not enough to say, "I think it was not important."
19 That's -- that's -- I think falls in the category of a
20 subjective comment. I think the issue is, is it important
21 on a quantitative basis?
22 DR. THONGSINTHUSAK: I agree. Thank you.
23 CHAIRMAN FROINES: So the point is, if we're
24 going to be using silica tubes to remove water, then we
25 need to know, one, is there a material being absorbed, and
75
BARNEY, UNGERMANN & ASSOCIATES 888 326-5900
1 two, can you -- what's the efficiency of desorption to
2 determine the residual?
3 DR. ATKINSON: It should only effect the
4 ICI, whether it's analyzed the silica gel.
5 DR. THONGSINTHUSAK: The reason I cannot
6 make an adjustment for this set of data, because I don't
7 have any solid information to make an adjustment. Because
8 from the study by Wofford and her colleagues, it show a
9 high and low. And normally, the temperature or the
10 relative humidity will affect that.
11 But from the two intervals, the relative
12 humidity and the temperature are very similar. So I don't
13 know what cause that -- what cause the absorption or
14 absorption by silica gel. Okay.
15 CHAIRMAN FROINES: I state -- I only press
16 it insofar as goes back to the same old, same old, same
17 old, which is, if we're using MOEs to determine toxic air
18 contaminants, then these kind of matters become part of
19 the uncertainty and the exposure characterization. They
20 therefore become elements in the actual designation of the
21 compounds of TAC. So it actually becomes potentially
22 significant, in a broad policy context.
23 DR. FUCALORO: It's kind of worse than
24 that. When you talk about uncertainty, you're talking
25 about quantitative thinking. And this is just uncertainty
76
BARNEY, UNGERMANN & ASSOCIATES 888 326-5900
1 in knowing what the meaning of the number is. Can you put
2 it -- from what you know, can you put an uncertainty in
3 some of these numbers?
4 DR. ATKINSON: Must be able to.
5 DR. FUCALORO: And then just get --
6 DR. ATKINSON: If the recovery is between 75
7 and 95 percent you can bracket --
8 DR. FUCALORO: You can bracket, it seems.
9 DR. THONGSINTHUSAK: Can you put table 7.2
10 back again? I would like to point out one more thing.
11 Lynn Baker pointed out to me, actually. Under Wofford's
12 study, I can say that this is the worst case here, because
13 the -- they use the silica gel drying tube. And you
14 compare -- this stands from the five meter to air
15 concentration up to 1100. But the same distance under
16 ICI, a hundred and eighty-six.
17 This seem to represent the worst case. They
18 were -- when we compare the same distance from the field
19 parameters. 450, and from Wofford's study, 468. Similar
20 distance from ICI, a hundred and eighteen. So I assume
21 that for the first -- before represents the worst-case air
22 concentration of MITC. This one compared to this one.
23 May I move on?
24 CHAIRMAN FROINES: I'm confused, but maybe
25 we'll deal with it later. Did you understand?
77
BARNEY, UNGERMANN & ASSOCIATES 888 326-5900
1 DR. BYUS: Which number are you going to use
2 to calculate the MOE?
3 DR. THONGSINTHUSAK: Both. Both.
4 DR. BYUS: You're going to use the low one
5 and the high one?
6 DR. THONGSINTHUSAK: Yes.
7 DR. BYUS: Why? Just out of curiosity.
8 DR. THONGSINTHUSAK: We will show the
9 worst-case MOE, as well as the MOE for the lower air
10 concentrations.
11 DR. BYUS: But the lower one could very well
12 be due to an analytical error and not getting total
13 recovery. So I mean, in a sense, what Dr. Froines' been
14 saying, yes, you could put a value of uncertainty on that
15 number based upon your clear understanding of the
16 analytical difficulties.
17 So I would -- I mean, we'll get to this.
18 But off the top of my head, I would tend to go with the
19 higher values for the MOE, and not even bother calculating
20 the lower ones, since you know that there's an analytical
21 error, perhaps, in the generation of that number.
22 DR. THONGSINTHUSAK: Yes, we can disregard
23 this study, because of the deficiencies.
24 DR. ATKINSON: Well, the ICI ones could be
25 increased by about 50 percent, since they are the recovery
78
BARNEY, UNGERMANN & ASSOCIATES 888 326-5900
1 70 percent, apparently.
2 DR. THONGSINTHUSAK: But if it's increased
3 by a hundred percent, it's still less than half of the
4 first one. That's the worst case.
5 DR. BYUS: My understanding, that's kind of
6 Wofford's estimation of analytical problem, not
7 actually --
8 DR. ATKINSON: That was ICI.
9 DR. BYUS: Was it ICI's numbers? I just
10 don't --
11 DR. ATKINSON: That's what I got out of it.
12 DR. BYUS: Okay.
13 CHAIRMAN FROINES: Let's go ahead. Let's go
14 ahead. Are you throwing your hands up or do you have a
15 comment?
16 DR. BLANC: I was wrestling paper.
17 DR. THONGSINTHUSAK: I also estimate the
18 exposure of children to MITC. I used the data calculated
19 for adult females times a correction factor. And this
20 correction factor is 4. And correction factor was
21 calculated from ventilation rate of children and body
22 weight of children versus ventilation rate and body weight
23 of adult females.
24 CHAIRMAN FROINES: Can I go back and ask you
25 a question?
79
BARNEY, UNGERMANN & ASSOCIATES 888 326-5900
1 DR. THONGSINTHUSAK: Yes.
2 CHAIRMAN FROINES: When -- when these
3 determinations are made, whether it be ICI or Wofford or
4 Caar, do you have written down somewhere what the
5 meteorology is? Do we know where you're upwind and
6 downwind of the application? I mean, the numbers can vary
7 widely depending upon --
8 DR. THONGSINTHUSAK: Yes, in my document, I
9 mentioned that most short-term and long-term,
10 moderate-term air concentrations were from downwind MITC
11 concentrations.
12 CHAIRMAN FROINES: They were downwind?
13 DR. THONGSINTHUSAK: Yes.
14 CHAIRMAN FROINES: Do you have the
15 characteristics of the meteorology?
16 DR. THONGSINTHUSAK: There's some data in
17 the report. And then I picked the MITC according to the
18 downwind direction. So that would be a wind direction
19 of different directions. I picked downwind and picked the
20 air concentration according to the downwind direction.
21 Except two. I forgot which one. That they were not in
22 the downwind direction. I mentioned that in the document,
23 which one.
24 DR. FUCALORO: So you have some description,
25 although it's not necessarily very detailed?
80
BARNEY, UNGERMANN & ASSOCIATES 888 326-5900
1 DR. THONGSINTHUSAK: Yes, that's right. So
2 whenever I can, I will use a downwind air concentrations
3 of MITC.
4 CHAIRMAN FROINES: And presumably you've
5 calculated the distribution of your data, as well as these
6 means. Because it seems to me that one doesn't want to
7 use the mean for an MOE calculation.
8 DR. THONGSINTHUSAK: I presented both mean
9 and the range. The range -- the ranges are in the
10 parentheses. So there were too many, so I did not go over
11 those ranges. May I proceed?
12 CHAIRMAN FROINES: Yeah, please. I'm
13 sorry. I think this issue of distribution is one that we
14 want to talk about.
15 DR. THONGSINTHUSAK: Okay. There was some
16 concern about a production of MIC, CS2 and H2S, hydrogen
17 sulfide. There were two studies that found MIC and CS2
18 and H2S, the first one by Air Resources Board, for MIC
19 from the downwind direction, the range of .4 to 2.5 parts
20 per billion. For the overall MIC production of recover
21 from range from .3 to 2.5 parts per billion.
22 This the only study that analyze MIC, as far
23 as I know. For carbon disulfide, 8 out of 16 samples
24 detected under the detection limit of 4 parts per
25 billion. For hydrogen sulfide, there are three ranges.
81
BARNEY, UNGERMANN & ASSOCIATES 888 326-5900
1 The first one is from 3 parts per billion to 76 parts per
2 billion. This is the sampling from one to four hours.
3 From five to seven hours, non-detectable, and from 21 to
4 24 hours, non-detectable up to 8 parts per billion.
5 Next, please. My final slide shows my
6 exposure appraisal. For the number of exposure days that
7 were used to calculate the SADD were obtained from limited
8 surveys and other information. We use currently 23 days.
9 But the industry suggested 8 days per season.
10 I mention number two about silica gel drying
11 tube can retain MITC in two of the studies. The study by
12 Wofford combine MITC recovered in silica gel tubes, plus
13 MITC recovered in charcoal sampling tube.
14 Currently there's a technical information
15 relating, which is the guidelines for all application
16 methods for Metam-Sodium in California. This is the
17 guideline issue by the industry. And that's the way to
18 reduce the emission of MITC from sodium.
19 Many studies conducted in the past were not
20 in compliance with these technical information relating.
21 But the exposure, especially those that sampled inside are
22 shorter than the buffer zone, maybe overestimate the
23 exposure for residences by standards.
24 DR. GLANTZ: Well now, is that -- is that
25 because of something unusual about this exposure or about
82
BARNEY, UNGERMANN & ASSOCIATES 888 326-5900
1 these applications? Because it would seem to me, just as
2 a person who occasionally has used pesticides, that I
3 don't always exactly follow the exposures, you know,
4 because I'm a clod or something.
5 And so, I mean, is there any evidence that
6 the -- that the exposures that you were monitoring are in
7 any way unusual? Because, if they're not, and given that
8 people sometimes don't follow the guidelines -- probably a
9 lot of times don't follow them, would seem to me, this
10 last conclusion is unwarranted.
11 DR. THONGSINTHUSAK: Yeah, that's possible.
12 And we still don't know the compliance rate, even though
13 this technical information bulletin is attached to product
14 labels.
15 DR. GLANTZ: Right. Right. Well, given
16 that, I mean, if you have actual data in the field, I
17 would believe that over -- rather than saying, well, we're
18 just going to assume that we had a few odd people who
19 didn't follow the technical specifications the
20 manufacturer produced.
21 DR. THONGSINTHUSAK: That is very likely to
22 happen.
23 DR. GLANTZ: Yeah. Well then, that's why I
24 would say the last statement you have here about
25 overestimating actual exposure, you don't have any
83
BARNEY, UNGERMANN & ASSOCIATES 888 326-5900
1 evidence to support that statement.
2 DR. THONGSINTHUSAK: Sorry. Go ahead.
3 DR. BLANC: Go ahead.
4 DR. THONGSINTHUSAK: If you think that's not
5 appropriate, I would remove that. I agree to do that.
6 CHAIRMAN FROINES: We're going to take up
7 the whole document. So probably don't need to -- should
8 avoid -- we should take up major issues and avoid --
9 DR. BLANC: Well, isn't a major issue the
10 fact that if the application amount has doubled in the
11 time since the sampling was done to the present, there
12 needs to be some comment in the document on whether or not
13 the use patterns in terms of doubling is because of added
14 acreage that's used versus added pounds per acre when it's
15 applied.
16 And also whether or not the sampling that
17 was done representing certain isolated fields being
18 sampled -- being -- having use is really applicable to the
19 real-world use where there might be much bigger areas used
20 simultaneously.
21 I don't know the acreage of these little
22 plots where the application was. But if the application
23 has doubled -- if it's doubled in a geographic area -- if
24 that's consistent across geographic areas, and not simply
25 that there are new geographic areas that have been
84
BARNEY, UNGERMANN & ASSOCIATES 888 326-5900
1 recruited, then the actual exposure areas would likely be
2 twice as high.
3 DR. THONGSINTHUSAK: I can double check on
4 the area, if it correspond to the amount of use.
5 DR. BLANC: But you know what I mean?
6 DR. THONGSINTHUSAK: Yes.
7 DR. BLANC: If within a three-square-mile
8 area of Lompoc five years ago over a two-week period there
9 would be, you know, 50 acres where it was applied over
10 that time period, and now it's a hundred acres, then the
11 exposure would probably be higher or the -- you know, I
12 mean, the sampling is very dependent on how many acres --
13 over how many acres applications occurring at the time
14 that you're sampling.
15 CHAIRMAN FROINES: Stan, what time is your
16 plane?
17 DR. GLANTZ: Quarter -- I have to leave
18 about a quarter to 2:00.
19 CHAIRMAN FROINES: If we go to 12:30, break
20 for lunch, that's 1:30. Have 45-minute lunch, that's
21 1:15. We get about a half hour on MTBE with you. Let's
22 go ahead and we're going to try to bring this discussion
23 to closure. May be tight, but we're going to try to bring
24 this to closure by 12:30. I really want Stan to have
25 input on MTBE.
85
BARNEY, UNGERMANN & ASSOCIATES 888 326-5900
1 DR. GLANTZ: Actually, I was going to
2 suggest, because I am a little worried about that. Maybe
3 we could table -- finish this one part of the
4 presentation, and maybe do MTBE, and then come back to
5 this. Because I'm a little worried about having to leave
6 in the middle of that discussion.
7 CHAIRMAN FROINES: Okay. You want to break
8 to lunch and then come straight back to MTBE and then take
9 this up?
10 DR. GLANTZ: Yeah. Or work through lunch,
11 if people want to do that.
12 CHAIRMAN FROINES: Is that okay, Paul? Or
13 who's ever handling this presentation? I'm very worried
14 about not getting to MTBE with Stan gone. Can -- can we
15 defer till after lunch, after the MTBE discussion?
16 MR. HELLICKER: Sure. We're here at your
17 disposal today. We do have another segment to this
18 presentation.
19 CHAIRMAN FROINES: Yeah. I think -- I hate
20 to hurry that, because we're all the health types, and so
21 we're interested in hearing that part. So -- but I know
22 we're -- what's going to happen. Things -- time drifts a
23 little bit more than -- even if I thought we could be done
24 by 12:30, you know. It's -- so let's take a 45-minute
25 break for lunch. Then let's do MTBE. Then we'll go
86
BARNEY, UNGERMANN & ASSOCIATES 888 326-5900
1 straight back to MITC.
2 (Lunch recess taken.)
3 CHAIRMAN FROINES: We'll take up MTBE. And
4 I want to quote two sections from the transmittal letter
5 from Michael Kenny to me. He said,
6 "This letter is to formally request the
7 Scientific Review Panel review the Office of
8 Environmental Health Hazard Assessments' enclosed
9 documentation on the carcinogenic potency of methyl
10 tertiary butyl ether in accordance with the usual
11 procedures for peer review of the health values for
12 toxic air contaminants."
13 So that's the defining question. Now, say
14 more about that in a second. Secondly in his letter, he
15 says the following:
16 "On April 26th, 1999, the Air Resources
17 Board requested OEHHA to develop health values for
18 the air exposure pathway for MTBE. OEHHA's
19 assessments incorporated carcinogenicity
20 information already contained in the technical
21 support document compiled for the public health
22 goal for MTBE in drinking water and the recent
23 report on MTBE completed by the University of
24 California."
25 Because of that request, it means that this
87
BARNEY, UNGERMANN & ASSOCIATES 888 326-5900
1 panel is now going to, in part, be reviewing the public
2 health goal. But this letter also includes the recent
3 report completed by the University of California, which I
4 was responsible for the health-effect section.
5 So what I have decided to do, to avoid any
6 appearance of conflict, I don't want to be in the position
7 of defending my document. And so what I decided to do was
8 to transfer the chair for this discussion to Tony
9 Fucaloro, who will chair the discussion.
10 But I also felt that I had no reason to not
11 be able to participate in the discussion as a scientist
12 who's familiar with MTBE. So Tony is going to take it
13 over.
14 Last thing I'll say is, came up last time,
15 we are basically voting on the following: We are voting
16 to determine that the health effects report is based on
17 sound scientific knowledge, methods, and practices.
18 "Scientific Review Panel determines that the health
19 effects are based upon sound scientific knowledge -- sound
20 scientific knowledge, methods or practices," that
21 criteria.
22 DR. BLANC: Tony, I'd like the record to
23 show that there is consensus on the panel that John's
24 approach to handling this matter meets with our agreement.
25 DR. FUCALORO: Sure. I think if I -- if I
88
BARNEY, UNGERMANN & ASSOCIATES 888 326-5900
1 look around -- ask around the table, I see no problem. I
2 personally would have had no problem with John chairing
3 this section. But I also have no problem -- I have a
4 little problem with my chairing. Means I have to work
5 harder. But other than that, I have no problem with it.
6 And does anyone disagree with what I just said? Speak
7 now. So --
8 DR. GLANTZ: Is this why -- never mind.
9 DR. FUCALORO: I think that certainly
10 approved by the panel to follow John's suggestion on
11 this. To refresh your memory -- and I've had my memory
12 refreshed on this -- MTBE, methyl tertiary butyl ether, is
13 a TAC by virtue of being an HAP. It's a toxic air
14 contaminant by virtue of being hazardous air pollutant
15 designate by the U.S. Government.
16 So -- so it is a TAC. So what is our
17 purpose here? Our purpose is to validate a document
18 prepared by OEHHA, actually applying some risk factors --
19 stating some -- some risk factors that they've estimated
20 so that MTBE especially -- I mean, important especially
21 because of the clean up one anticipates for MTBE in the
22 groundwater and vapors that would come from that
23 groundwater. With that in mind, is there a presentation
24 from OEHHA at this point?
25 DR. MARTY: No, we actually gave the
89
BARNEY, UNGERMANN & ASSOCIATES 888 326-5900
1 presentation at the last meeting, so we don't have --
2 DR. FUCALORO: I do recall. And the
3 document that you are handing out to everyone is a
4 document that was handed out at the last meeting. And
5 this is the document which we are to find as being based
6 upon sound, scientific principles; is that correct as you
7 understand is it?
8 DR. MARTY: We sent that document out, along
9 with the public-health-goal description to the panel
10 members, and I'm recalling the middle of September.
11 CHAIRMAN FROINES: This document?
12 DR. SALMON: Yes.
13 DR. MARTY: Yes.
14 DR. FUCALORO: And -- and Attachment 1 is
15 essentially a condensation of that document in terms of
16 the -- at least the part that you're interested in, the
17 potency factors.
18 DR. MARTY: It's a condensation, and also
19 the presentation of how we derived unit risk factors for
20 inhalation exposure.
21 DR. FUCALORO: Now, we discussed this. And
22 I'm going to call upon the panel members to make comments
23 about it. So I want to give you -- want to give you a
24 head's up on that. But I will -- I will indicate that I
25 recall some of this -- I recall a lot of this
90
BARNEY, UNGERMANN & ASSOCIATES 888 326-5900
1 conversation, now that I've seen the document. And one of
2 the concerns was that these numbers were based upon
3 studies that use very high concentrations of MTBE.
4 And there was some concern by some members
5 on this panel that -- that we were looking at problems
6 associated with clearing of the chemical in the mice or
7 rats -- that is, mice studies. And I think that was at
8 issue. Is that your recollection?
9 DR. MARTY: I'm recalling that people were
10 concerned about the carcinogenistic bioacids using high
11 doses. However, that is not unique to MTBE.
12 DR. FUCALORO: I'm not asking to you defend
13 it. That was the issue.
14 DR. MARTY: That was one issue that was
15 raised.
16 DR. FUCALORO: So with that, I would ask if
17 there's anyone wants to add to it, because we're going to
18 have to vote on this, it seems to me.
19 DR. GLANTZ: Well, I -- since I have sort of
20 limited time here -- why are you smiling? The --
21 DR. FUCALORO: She's grimacing.
22 DR. GLANTZ: Okay. Good. Good. Well, my
23 understanding of -- and this is a preface to a question.
24 But I just want to make sure I understand what you did
25 here. Is that you -- you took the oral data or the data
91
BARNEY, UNGERMANN & ASSOCIATES 888 326-5900
1 from drinking water, and you combined that with a
2 pharmacokinetic model to get applied dose. And then you
3 used the pharmacokinetic model on a couple of assumptions
4 to figure out the equivalent inhaled dose to get the same
5 target organs. And that's where the number -- the error
6 number came from; is that correct?
7 DR. SALMON: The -- yes, the original
8 studies on which the calculation is based -- in fact,
9 the -- one of them is an inhalation study. But there's
10 also an oral study. So what we were doing was using the
11 pharmacokinetic models to enable us to compare all the
12 data sets we had on a single basis.
13 And the pharmacokinetic model was actually
14 used on the basis of the -- predicting the area under the
15 curve for MTBE. That was the index parameter for the
16 model. And the inhalation calculation for human exposure
17 at low dose is related back to that metabolized-dose
18 estimate.
19 So the pharmacokinetic model is basically
20 used to tie together, on the one hand, the animal studies
21 by either root. And on the other hand, the human
22 exposure. Which for the PHG, actually, we used both an
23 oral number and an inhalation number, because there's
24 some, you know, secondary exposure by the inhalation root
25 when you have drinking-water contamination. But in this
92
BARNEY, UNGERMANN & ASSOCIATES 888 326-5900
1 particular case for the TAC, we were interested
2 specifically and only in the inhalation number.
3 DR. GLANTZ: Okay. Well -- so to me,
4 everybody brings their own perspective to these things.
5 The model and getting comfortable with the model is really
6 the key part of this. And I had a couple of questions
7 about the model. One of them -- and let me just tell you
8 what they are. Just rattle through them, and then you can
9 address them in whatever order makes the most sense.
10 So if you go to the drinking-water
11 document -- I mean, I think from my perspective, and the
12 things I know about, if I'm satisfied with the model,
13 the -- to go from that to your unit risk for air exposure
14 is just arithmetic. So -- and that all seemed reasonable.
15 But the questions I have is, if you look at
16 table 10 of the drinking-water report, which is on page
17 72, you've got -- and this is sort of my standard question
18 about these things. You've got a ton of parameters
19 there. And, you know, how sensitive is the model to those
20 assumed parameters?
21 How confident are you in the values of those
22 parameters, if there are -- because it's -- a lot of this
23 is just from one study or one or two studies, and then --
24 and then -- you know, if -- if these are off, how much
25 difference does it make and what are the critical ones?
93
BARNEY, UNGERMANN & ASSOCIATES 888 326-5900
1 So that's one question I had.
2 The second question is, in here, you talk
3 about using a polynomial model, but it wasn't ever quite
4 clear to me exactly what that was or what the
5 justification for using the specific model that you had
6 was, you know.
7 Let me just ask all the questions, because
8 I'm feeling kind of pressed for time. And I want to --
9 and you can -- and then the third question is -- and this
10 may just be my own not understanding what you wrote
11 here -- but if you look at tables 11 and 13, which is on
12 page 73 and 75, which is presented as the -- as the
13 validation of the model, and you guys say this stuff shows
14 that the model works pretty well, as I read it.
15 And maybe I'm misunderstanding the table.
16 It looked -- it didn't look like they worked all that well
17 to me. So the -- especially at the high -- with the
18 larger rats. And so what I'd like to you do is -- and
19 then you can deal -- these are three interrelated
20 questions -- is, I think it may just be my -- me not
21 understanding these two tables.
22 But I need to be convinced, A, that the
23 model parameters are reasonable, and that the model isn't
24 overly sensitive to the values that you picked. B, why
25 you used the polynomial model that you used, and what
94
BARNEY, UNGERMANN & ASSOCIATES 888 326-5900
1 effect -- how sensitive the results are to those
2 assumptions.
3 And then C, to be convinced or explain how
4 to read tables 11 and 13 to draw the conclusion that the
5 model actually works pretty well. So that's what I'm
6 looking for. You can put -- come back to them however is
7 most efficient in terms of time.
8 DR. SALMON: Okay. Well, I'll start by
9 talking about the parameters in the PBPK model
10 simulation. By the way, the Borgoff Paper and the Row and
11 Ginsberg Paper are actually describing previous modelling
12 exercises which drew on quite a wide range of different
13 data sources.
14 So in a sense, it's not just two papers that
15 are the source of that. Those are in themselves
16 compendiums and evaluations of the data which we choose to
17 cite as prior authorities, basically. The parameters, all
18 of which are essentially typical inputs for a PBPK model,
19 are things like the compartment volumes and flows fairly
20 generic sort of parameters which describe rats,
21 basically.
22 And so those, to some extent, would
23 represent sort of consensus values from the modelling
24 literature. Neither we nor Borgoff would have -- you
25 know, would have departed very far from the standard
95
BARNEY, UNGERMANN & ASSOCIATES 888 326-5900
1 assumed values for those.
2 The parameters which are a little bit more
3 specific to the MTBE case are the partition coefficients
4 and the metabolic constants. And certainly among the
5 important issues are the actual values of the partition
6 coefficients, which are usually estimated on the basis of
7 experimental data. And we're using for this the
8 precedents of the Borgoff paper.
9 And the metabolism, again, that is usually
10 partly, at least, estimated from other experimental data.
11 And that, in particular, can be an important one in
12 determining how well the predictions of the model fit the
13 observed excretion profile of the MTBE. This is where we
14 transfer to tables 11, 12 and 13. Is that an adequate
15 explanation?
16 DR. GLANTZ: Well, I understand that's where
17 you got them from. But the concern that I have -- what I
18 am interested in, is how sensitive are the results to the
19 specific parameter values that you've got here? And of
20 these large number of parameters, what are the important
21 ones?
22 I mean, some of them aren't going -- I mean,
23 we've been through this before with other modelling
24 exercises. And some of the parameters aren't going to
25 make much difference at all. And you can have big errors,
96
BARNEY, UNGERMANN & ASSOCIATES 888 326-5900
1 and it wouldn't matter. And other ones might be highly --
2 where the results might be highly sensitive.
3 And so, which ones are those, and how can
4 you be sure that -- that, you know, that the risk numbers
5 you're coming up with aren't highly dependent on parameter
6 estimates, which may or may not be reliable?
7 DR. SALMON: Well, in terms of the model's
8 sensitivity, I think probably the most critical parameters
9 would be the V-max and KM values for MTBE. And the blood
10 air and fat-blood partition coefficients. Those would
11 probably be the most critical ones.
12 The -- as far as the extent to which we can
13 validate our choice of the values which we're using there,
14 for the purposes of this risk assessment, we are not using
15 what I would call the details of the model. We're not
16 trying to say, this is the concentration in the liver or
17 the kidney or whatever.
18 So in a sense, our risk-assessment
19 conclusion is not actually very sensitive to the finer
20 details of the model. The only thing which we're actually
21 using is the prediction of the -- the metabolized dose of
22 MTBE.
23 One of the things which we did attempt to
24 do -- and this I will explain from -- as part of what's
25 happening in table 11. One of the things we looked at was
97
BARNEY, UNGERMANN & ASSOCIATES 888 326-5900
1 the question of whether we could use the concentration of
2 the metabolite TBA as an index of some perhaps more
3 critical exposure than just how much MTBE is around.
4 The conclusion that we came to was, firstly,
5 subjects of various other discussions in the document, we
6 really don't have any evidence to suggest directly that
7 TBA is the critical metabolite. So it wasn't safe to base
8 a risk-assessment conclusion on that assumption.
9 And secondly, we do have problems with the
10 model in terms of predicting the TBA concentrations. What
11 this shows in table 11 is that the MTBE C-max and
12 area-under-the-curve predictions between the -- where
13 you've got the observed figures, which are in bold
14 italics, those are actual observations which match to the
15 theoretical values.
16 And by the standards of these things, the
17 match is considered reasonably good. I think it may be
18 worth commenting that the C-max -- this is the peak
19 concentration achieved immediately after dosing -- is
20 actually a very difficult parameter to model.
21 It's highly sensitive to all the inputs.
22 And in particular, it's sensitive to details of the exact
23 compartmentalization, and things like differential
24 absorption, and different regions of the gut, and local
25 blood flows, and things like that, which our simple model
98
BARNEY, UNGERMANN & ASSOCIATES 888 326-5900
1 simply doesn't accommodate.
2 So allowing for that known imperfection of
3 the complexity of the model that we're using, I think you
4 would look at the observed versus predicted concentrations
5 as not being too awful for C-max for MTBE.
6 DR. GLANTZ: So the observed are in light
7 type and the predicted value -- no.
8 DR. SALMON: The predicted are in bold.
9 DR. GLANTZ: And the observed values are in
10 heavy type?
11 DR. SALMON: We have predictions at 40
12 milligrams per kilograms, which match one set of observed
13 values, and predictions at 400 milligrams per kilogram,
14 which match the second set of observed values. And what
15 I'm saying is, basically, the C-max is, if we're anywhere
16 in the right ballpark, we're actually doing fairly well.
17 And what we would actually be looking for,
18 which isn't easy to show in a table, but if you -- you
19 know, I mean, the model produces a fat stack of paper as
20 its output. And if you look through that, what we're
21 looking for, in fact, is a reasonable approximation
22 between observed and predicted over a time-course type of
23 experiment.
24 And what we're saying is, over that
25 time-course experiment, we have a reasonable match. And
99
BARNEY, UNGERMANN & ASSOCIATES 888 326-5900
1 in fact, C-max is probably the hardest point on that curve
2 to model. The other one --
3 DR. GLANTZ: Well, but if you look,
4 though -- I mean, if you look at the 40 milligram per
5 kilogram dose, you're saying that -- you're predicting
6 .068, whatever the units are here.
7 DR. FUCALORO: What are the units?
8 DR. SALMON: Minimolar.
9 DR. GLANTZ: But what you're observing is
10 two or three times that.
11 DR. SALMON: Well, if --
12 DR. GLANTZ: And if you go down to the 400
13 milligram per kilogram dose, you're off by -- maybe a
14 factor of two, isn't so bad.
15 DR. SALMON: I'm saying for C-max, that is
16 actually fairly good. And the -- the match against the
17 observed profile will actually probably be quite a lot
18 better further out in the curve. But -- so, yeah. That's
19 exactly what I'm saying. That C-max within a factor of
20 two for that is, in fact, quite reasonable by the
21 standards of these things.
22 The one which is closer to what we're
23 actually using for the -- for the basis of the risk
24 assessment, is the area under the curve, the units of this
25 being millimolar times hours. And the area under the
100
BARNEY, UNGERMANN & ASSOCIATES 888 326-5900
1 curve figures -- as you may notice, the match is still not
2 perfect for MTBE. But it is, in fact, quite a bit closer.
3 And I think given the -- essentially, you
4 could say the parameter we're using for the basis of the
5 risk assessment is -- is closely related to that
6 area-under-the-curve figure. And if we're within, you
7 know, 20 or 30 percent of the right value, bearing in mind
8 that, you know, there's a significant variation between
9 the different experimental observations.
10 So there's quite a bit of uncertainty in the
11 data here. But in a worst case, we're probably all right
12 within a factor of 20 or 30 percent. Which means that the
13 uncertainties in this parameter are substantially less
14 than the other uncertainties with which we have to deal.
15 And -- but on the other hand, I would point
16 out, as noted in the document, we're not satisfied with
17 predictions for the tertiary butyl alcohol metabolite.
18 And the reason for this is, there are some
19 compartmentalization and further metabolism issues with
20 TBA, which we have currently insufficient information to
21 make a proper prediction.
22 And that is one of the reasons why we chose
23 to use the relatively unsophisticated model parameter of
24 simply looking at thing area under the curve to validate
25 the model and predicting the basis -- the dose basis on
101
BARNEY, UNGERMANN & ASSOCIATES 888 326-5900
1 total absorbed and metabolized MTBE, which is shown in
2 table 12.
3 The -- these -- so what we're doing is,
4 we're looking at the model structure, and we're choosing a
5 parameter which we feel we can predict with a reasonable
6 degree of confidence across a fairly wide range of doses.
7 And we can use that as the basis for our
8 dosimetry and the risk assessment, without making any
9 unsupported assumptions, either about the pharmacokinetics
10 or about the mechanism. That's what we hoped we were
11 doing, anyway.
12 DR. GLANTZ: Well, so basically what you're
13 saying is, you're within a factor of two. You think
14 that's pretty good.
15 DR. SALMON: For the -- for the C-max, I
16 think so, yes. I mean, one of the things is, that's an
17 extremely difficult parameter to measure accurately.
18 DR. GLANTZ: So -- so how much did you --
19 did you wiggle these parameters around to get that? Or
20 did you -- or did these -- Borgoff and Row and Ginsberg
21 wiggle their parameters to get that fit?
22 DR. SALMON: We've used a number of
23 different combinations of parameters and chosen,
24 basically, the parameters here. The fact that we were
25 using it -- the V-max values from Row and Ginsberg, and
102
BARNEY, UNGERMANN & ASSOCIATES 888 326-5900
1 also one of the partition coefficients from Row and
2 Ginsberg basically reflects the fact that we feel that was
3 the combination of available and peer reviewed and
4 respectable parameters that --
5 DR. GLANTZ: Now, were those values -- were
6 the data on the observed levels of these parameters, the
7 variables and tables 11, 12, and 13 -- were those involved
8 in deriving the parameter values in table 10 or did the
9 values in table 10 come from independent sources? You
10 plug them into the model, cranked out a set of predictions
11 independent of the data --
12 DR. SALMON: The essence of this is one
13 should be using externally derived parameters. There are
14 a couple of things like the -- for instance, the
15 gastrointestinal absorption rate, which we simply had no
16 data. So that had to be an assumed parameter, as noted in
17 the table. But --
18 DR. GLANTZ: Right. But that's a different
19 question, though.
20 DR. SALMON: But Borgoff and Row and
21 Ginsberg are using externally validated values for their
22 parameters.
23 DR. GLANTZ: How does that -- how does the
24 data in tables 11, 12 and 13 relate to the Borgoff and Row
25 and Ginsberg models? Did they use the data in 11, 12 and
103
BARNEY, UNGERMANN & ASSOCIATES 888 326-5900
1 13 to get their parameter values?
2 DR. SALMON: They would have used some -- I
3 think that they were actually, possibly using a slightly
4 different subset of the data than -- I don't have that
5 exact information at hand. Certainly they would have been
6 looking at a slightly different combination of inputs. So
7 what we're saying --
8 DR. GLANTZ: But you took -- I mean, I don't
9 mean to be rude. I'm just feeling kind of pressed for
10 time here. So would I be correct in saying that the
11 parameter values in table 10 basically came from the
12 literature?
13 DR. SALMON: Yes.
14 DR. GLANTZ: You took them out of the
15 literature, you didn't do anything to them?
16 DR. SALMON: We didn't do anything very
17 high-handed. We attempted to make a synthesis.
18 DR. GLANTZ: Right. But in particular, you
19 didn't wiggle these parameter values to get the
20 predictions?
21 DR. SALMON: No.
22 DR. GLANTZ: Okay. Is the data in 11, 12
23 and 13, the light numbers --
24 DR. SALMON: Yes.
25 DR. GLANTZ: Were those values in any way
104
BARNEY, UNGERMANN & ASSOCIATES 888 326-5900
1 involved in developing the parameter values in table 10?
2 Or is that subsets of completely independent data?
3 DR. SALMON: Apart from the cases like the
4 GI absorption, where it's -- has to be used as a model
5 assumption, the parameters of the input and the prediction
6 numbers of the output, it isn't an iterative process.
7 DR. GLANTZ: Okay. I don't mean to hammer
8 on this. When you're talking about the GI values, you say
9 you assumed those. Okay. You didn't adjust those in
10 order to --
11 DR. SALMON: We had to figure out what was a
12 reasonable assumption.
13 DR. GLANTZ: Right. But that's -- there's
14 two different ways you can do that.
15 DR. SALMON: Yes.
16 DR. GLANTZ: One way, you can sit down and
17 consult your Ouija board or whatever and come up with what
18 you think a reasonable value would be. And then you take
19 all the reasonable values, plug them into the model and --
20 DR. SALMON: See what comes out, yes.
21 DR. GLANTZ: And then -- and you do that.
22 And you take your blindfold off, and you look at what the
23 data is.
24 DR. SALMON: Yes.
25 DR. GLANTZ: The other way, you can use the
105
BARNEY, UNGERMANN & ASSOCIATES 888 326-5900
1 data to help you estimate what values to use. So would it
2 be a correct statement to say that you didn't do that?
3 DR. SALMON: We didn't do that. We -- if we
4 found a mismatch between our model output and the
5 experimental data, what we would do is realize that we had
6 a problem and go back and look for better externally
7 estimated model parameters. Not to mess with the values
8 of the physiological parameters in -- inside the model.
9 DR. GLANTZ: Well, but that -- that seems
10 inconsistent. See, what I'm trying to get at is how, you
11 know -- if you came up with a set of values with a model
12 that was defined independently of the data that you've
13 shown in 11, 12 and 13, and you plug those numbers into
14 this a priori model, and a bunch of parameters that you
15 got a priori from the literature, and then you came within
16 a factor of two to independently observed data, that's
17 pretty good.
18 DR. SALMON: That's essentially what we're
19 doing.
20 DR. GLANTZ: Then you went on and said, if
21 the fit wasn't that good, then we went back and
22 reconsidered --
23 DR. SALMON: We basically, if we saw we had
24 a problem, we would have had to have done something about
25 it. I'm not saying that this is quite -- I mean, this --
106
BARNEY, UNGERMANN & ASSOCIATES 888 326-5900
1 as you know, this business of PBPK modeling is somewhat of
2 an arcane science.
3 But we have -- we have consistently tried to
4 avoid the process which some modelers have used of
5 tweaking the parameters until they get a decent-looking
6 fit. We've tried to use, at all times and whenever
7 possible, to use externally derived and validated
8 parameters.
9 DR. GLANTZ: But the part I'm still -- I'm
10 hanging up on, I don't mean to just hammer on this. But I
11 mean, you either did adjust the parameters one way --
12 DR. SALMON: We didn't adjust them. We
13 selected them.
14 DR. GLANTZ: Well, but that's -- that's the
15 same thing. I mean, the thing that I'm concerned about
16 is, you've got a huge number of degrees of freedom here in
17 this model. And -- and, you know, you don't have --
18 you're basically trying to predict one number, which is
19 the C-max number. And so I'm a little bit concerned
20 that -- that you can, by turning the knobs on the model --
21 DR. SALMON: Yeah.
22 DR. GLANTZ: -- you're going to be able to
23 get the fit, and then you're turning around and using --
24 so the model parameters are essentially determined by
25 the data you --
107
BARNEY, UNGERMANN & ASSOCIATES 888 326-5900
1 DR. SALMON: No, that is not the case.
2 DR. GLANTZ: But you told me before,
3 though -- this is where you're giving me two different
4 answers. One is you're saying, no, the model is taken a
5 priori. The parameters are taken a priori, and we came
6 within a factor of two. But then you're saying, if we
7 looked at it --
8 DR. SALMON: If it had been out with a
9 factor of 10, we would have had to gone back to the
10 drawing board and figured out why --
11 DR. GLANTZ: Did that happen?
12 DR. SALMON: No, it didn't. Borgoff and Row
13 and Ginsberg both have previous reasonably successful
14 models. We -- we basically used their prior work and
15 selected a combination of what they -- of their
16 conclusions, their model structure, and their parameters
17 to build what we felt was a good consensus model.
18 DR. GLANTZ: And you did that before you
19 looked at the data in tables 11, 12 and 13?
20 DR. SALMON: Yes. Then we would have
21 used -- then the process is to validate the model after
22 it's being created.
23 DR. GLANTZ: Okay. So the data in 11, 12
24 and 13, there were no adjustments made. Is this a true
25 statement? That after you went through the process of
108
BARNEY, UNGERMANN & ASSOCIATES 888 326-5900
1 looking at these published models and coming up with what
2 you thought, in your best professional judgment, was the
3 right model to use with the right parameters. So you did
4 that, and then you plugged it in, and you cranked out a
5 group of predictions.
6 DR. SALMON: Yeah.
7 DR. GLANTZ: And then after that was done
8 and those predictions were then chiseled in stone, and
9 those are the numbers in tables 11, 12 and 13; is that
10 true?
11 DR. SALMON: I believe it's --
12 DR. GLANTZ: And then after you did that,
13 then you went out and looked at the data that's bold
14 face --
15 DR. SALMON: Yes.
16 DR. GLANTZ: -- in 11, 12 and 13? So the
17 numbers in 11, 12 and 13, the bold-faced numbers, played
18 no role whatsoever --
19 DR. SALMON: No, that's axiomatic. They're
20 not input to the model. That's axiomatic.
21 DR. GLANTZ: If that's the case, and now I
22 do understand. I mean, I do understand how to read the
23 tables.
24 DR. SALMON: I have to say that, running
25 these models is a rather messy and approximate kind of a
109
BARNEY, UNGERMANN & ASSOCIATES 888 326-5900
1 business. But one does one's best to make an
2 independent --
3 DR. GLANTZ: Now you're back to kind of
4 waffling. I mean, I -- let me ask --
5 DR. BLANC: I think, if I could intervene, I
6 think your question has been asked and answered.
7 DR. GLANTZ: But I don't under the answer.
8 Well, tell me the answer, then.
9 DR. BLANC: The answer is, they satisfied
10 your requirements, and they did not go through an
11 intergroup process where they kept choosing a better model
12 based on the results that was given.
13 DR. FUCALORO: Better -- or tweaking of
14 parameters.
15 DR. GLANTZ: Is that a true statement?
16 DR. SALMON: Yeah.
17 DR. GLANTZ: Okay. I'm happy.
18 DR. BLANC: Verging on asking the questions,
19 are you still beating your numbers?
20 DR. GLANTZ: Sort of. Every time I thought
21 he said that --
22 DR. FUCALORO: One science.
23 DR. GLANTZ: If that's the case --
24 DR. BLANC: If he said it with a New York
25 accent, you would have accepted it the first time.
110
BARNEY, UNGERMANN & ASSOCIATES 888 326-5900
1 DR. GLANTZ: I'm not from New York. Okay.
2 If that's the case; okay -- he is. If that's the case,
3 then I'm satisfied with this. I mean, because I think --
4 I think to get -- to get from -- you know, if the model --
5 to get an a priori model to get within a factor of two is,
6 in fact, pretty good. And I think --
7 DR. FUCALORO: Almost unbelievable.
8 DR. GLANTZ: Well, not necessarily. I
9 think -- and then I think that -- that the -- that going
10 from there to the oral -- the oral unit-risk number is
11 just pretty straight forward arithmetic at that point. So
12 that to me was the nub of the issue. So I am satisfied
13 with the numbers in the report, then.
14 DR. FUCALORO: Thanks, Stan. I didn't want
15 to seem like a weak chair, but I realized that you had to
16 go, so I'm going to give you every minute you wanted.
17 DR. GLANTZ: I'm going to have to leave in
18 about two minutes. I think if the discussion, which looks
19 like it will go on after I'm -- after I have to leave, in
20 terms of the -- my level of expertise and input into this
21 process, I am now satisfied. There may be some other
22 things that other people want to raise.
23 DR. FUCALORO: Well, Craig is ready.
24 DR. GLANTZ: Craig is ready.
25 CHAIRMAN FROINES: The important question
111
BARNEY, UNGERMANN & ASSOCIATES 888 326-5900
1 for you, though, because I think that within the context
2 of this room -- and not to take anything away from anybody
3 else -- you're the most familiar with the quantitative
4 issues. And, so remember what I said at the beginning, if
5 you consider this, quote, "sound science," then that's --
6 DR. GLANTZ: Yeah.
7 CHAIRMAN FROINES: You need to leave us with
8 your views.
9 DR. GLANTZ: Yeah, I think it's fine.
10 DR. FUCALORO: Thank you, Stan. I
11 understand. Craig, did you want to --
12 DR. BYUS: Yeah, let me go over a few
13 things. I guess I had the most concerns the last time,
14 and I still have them. Just -- and I have another one,
15 which I thought of in their intervening time.
16 My main concern was over the animal
17 experiments, themselves. Although one thing I have
18 concern over is the performing of the genetic modelling,
19 as well. I was concerned, there's relatively small
20 numbers of animals in most of these studies.
21 I did have some concern that they were done
22 at very high levels, some of them exceeding the maximum
23 tolerated dose, some of the studies. Which overlays a lot
24 of toxicities on the interpretations of some of the
25 results, particularly the renal toxicity, which I'll get
112
BARNEY, UNGERMANN & ASSOCIATES 888 326-5900
1 to in a minute.
2 Because the compound is a, apparently, quite
3 lethal toxic, no matter how it's administered, probably.
4 So small numbers of animals, the high doses, again, I know
5 that studies are done in high doses. And I'm going to ask
6 you in a minute what was the actual dose extrapolation?
7 How many logs did you actually extrapolate down to
8 ambient? Because it's kind of buried in all the
9 calculations.
10 That also gives you some idea of how
11 confident you can be in the numbers. There's the one
12 study that has the very sex-specific outcome. I think it
13 was one the leukemias where only female mice got the
14 tumors. And again, that's not totally uncommon. But
15 there was some lack of consistency among the kinds of
16 tumors across the experiment. Some consistency, but there
17 was also some inconsistency.
18 The other thing from last time was my
19 concern about the dose-response data. We discussed this
20 briefly. Within an individual experiment I'm talking
21 about. Within an individual tumor experiment, did you see
22 a dose response? So as you increase the dose, did you see
23 more tumors? And there is some dose-response data in
24 here. But it is relatively minimal.
25 And this is also overlaid on the fact that
113
BARNEY, UNGERMANN & ASSOCIATES 888 326-5900
1 the significances -- the degrees of significance were
2 calculated, as we went over last time, one-tailed, as
3 opposed to two-tailed. We can discuss this. But this is
4 a one-tailed analysis, not a two-tailed analysis --
5 okay -- which affects how you want to interpret it. It's
6 not said anywhere in here. That -- you told me that. Or
7 somebody told me that the last time.
8 So I just -- just as an indication of
9 what -- I mean, about the lack of dose response, you say
10 on page 55 -- you disagreed with me about the statement,
11 so I'm going to read it to you. And I think it's the next
12 to the last paragraph.
13 "Despite the reduced sensitivity of bioacid,
14 a statistically significant increase in
15 interstitial cell testicular tumors was observed in
16 mid and high-dose mammals with a clear dose
17 response evident."
18 Table 8. If you turn to table 8 and look at
19 the bottom, in the testes to the lytic cell, this is not
20 what I would call a clear indication of a dose response.
21 I mean, I just don't think the data states that. Okay.
22 So that is the kind of concern I had.
23 Now, the last concern I had, in addition to
24 the fact there's no human data and there's no clear
25 mechanism. And again, it's -- you did a very nice job
114
BARNEY, UNGERMANN & ASSOCIATES 888 326-5900
1 trying to come through, figure out a mechanism, but there
2 really is no clear mechanism.
3 But my last concern, which I didn't discuss
4 last time, has to do with the clearance. If this is a
5 fairly renal-toxic compound -- and according to your
6 paper -- I mean, to this document, it's very renal
7 toxic -- all treated mammals, both female and male rats,
8 had a progressive, chronic nephropathy, all kinds of
9 changes in kidney function. Mid, high dose, is where it
10 occurred.
11 "Mineralization and interstitial fibrosis of
12 the kidney, which increases in mild to moderate" -- oh,
13 I'm sorry. Sorry.
14 "Mineralization and interstitial fibrosis of
15 the kidney while increases in mild to moderate
16 glomerulosclerosis, interstitial fibrosis, and
17 tubular proteinosis were observed in females."
18 So my last point is, if this is a really
19 renal-toxic compound, which it is, what is happening to
20 the pharmacokinetics in these long-term tumor experiments
21 at the high doses? Since this compound is cleared
22 both the parent compound and the metabolites by the
23 kidney, what's probably happening, as you increase the
24 dose and as you give it over time is, the kidney's
25 becoming damaged.
115
BARNEY, UNGERMANN & ASSOCIATES 888 326-5900
1 And so the metabolites might be building up
2 to very high levels. The parent compound might be
3 building up to really high levels. And so you probably
4 have a much higher real dose than your externally applied
5 dose.
6 And your pharmacokinetic modelling doesn't
7 really take that into consideration. It takes it into
8 consideration, I believe -- and correct me if I'm wrong --
9 just for an acutely administered dose, not the chronic,
10 two year or year and a half, whatever, where kidney damage
11 would be occurring.
12 So again, I mean, I think the data is
13 there. I do believe that it is a carcinogen that is
14 causing cancer in animals, clearly. But all these
15 concerns, you know, I start thinking about a
16 threshold-type mechanism, et cetera. So I mean, there --
17 that's -- I'm done.
18 DR. SALMON: Okay. I will comment on a
19 couple of these issues. And I think I will then hand over
20 to my colleague, Dr. Sandy, to address some of the
21 others. If I can take your last point first about
22 pharmacokinetic model, it's certainly true that the
23 pharmacokinetic experiments are single-dose based.
24 So if there is accumulating damage, then the
25 pharmacokinetic model will fail to reflect that. I'm not
116
BARNEY, UNGERMANN & ASSOCIATES 888 326-5900
1 sure that we can -- I mean, one of the problems, of
2 course, is that we're entering the realms of speculation
3 as to how substantial that effect might be.
4 If the -- for the sake of argument, the
5 clearance of MTBE were to be reduced by a factor of 2 or
6 something like that, then obviously that would be seen as
7 fairly significant in terms of an impact on renal
8 function. But I don't think that it would make an
9 enormous difference to the -- either the qualitative or
10 quantitative conclusions that we would be able to draw
11 from the data.
12 If the impact on kidney function were much
13 more severe than that, then it's -- I would imagine that
14 you would be getting into the zone where the kidney damage
15 would be fatal, which may well have occurred with some of
16 the animals. But of course, at that point, they cease to
17 play a part in the study anyway. So they would not be
18 impacting the result.
19 But I would -- basically what I am saying
20 is, I agree with you that this is an uncertainty in our
21 conclusion, and we have been at some pains to point out
22 that there are a number of considerable uncertainties in
23 the conclusion.
24 But we've done our best to work through what
25 information we did have, and could interpret. And
117
BARNEY, UNGERMANN & ASSOCIATES 888 326-5900
1 basically to follow -- follow our guidelines in
2 determining an appropriate and public-health-protective
3 level, in spite of the uncertainties. I think that's all
4 I'm -- I'll say.
5 DR. SANDY: And I'll address a few points.
6 Animal bioacids, in general, that are conducted now, for
7 example, by the National Toxicology Program, which is
8 considered the gold standard for design, it's 50 animals
9 per group, per sex. And that's what was used in the
10 inhalation studies for the rat and the mouse, and for the
11 Gavage studies, they used 60 animals per group, per sex.
12 So I would not characterize those as small
13 numbers. Those are -- those are the numbers that we work
14 with when we look at animal bioacid data, if we're lucky.
15 Small numbers is 20, and that's from historical studies.
16 We do acknowledge that, in the
17 rat-inhalation studies, MTBE was renal toxic. And, in
18 fact, the study pathologist, as well as -- I guess had a
19 second pathologist look at the slides, confirmed that MTBE
20 seemed to exacerbate the chronic, progressive nephropathy
21 seen in rats of both sexes. So that is something that is
22 going on. You're correct.
23 There are a number of carcinogens -- kidney
24 carcinogens which are also nephrotoxic. And that's just
25 something that we'll have to deal with. As Andy said,
118
BARNEY, UNGERMANN & ASSOCIATES 888 326-5900
1 it's part of the uncertainty. Let's see. For the dose
2 response, we do see a dose response in the combined
3 incidence of lymphomas and leukemias of lymphoid origins
4 in the female Dawley rats used in the Gavage study.
5 The incidence that was reported in the 1998
6 pathology review by Belpoggi was 3.4 percent in the
7 controls, 13.7 percent in the low dose, and 25.5 percent
8 in the high dose. Now, only the high dose was
9 statistically significant. And we did not do a trend
10 test, because this data -- the authors of the paper, they
11 did not analyze it using a Fisher exact test. They
12 analyzed it using a log rank test.
13 DR. FUCALORO: Using what?
14 DR. SANDY: A log rank test. And that
15 entails having time-to-tumor information, which we could
16 not obtain, so we could not replicate that analysis. We
17 just took the data and did a Fisher exact test, which is
18 one-tailed. And that is, again, a -- the accepted, common
19 way of analyzing animal bioacidic data.
20 DR. BYUS: We just repeated this the last
21 time.
22 DR. SANDY: Well, so --
23 DR. BYUS: That's okay. But in any case,
24 you should indicate one-tailed versus two-tailed. It
25 should be stated what statistical test you're using,
119
BARNEY, UNGERMANN & ASSOCIATES 888 326-5900
1 clearly.
2 DR. SANDY: Again, just like to emphasize,
3 the data was analyzed by the study authors by another
4 method. And it was also significant, the incidence of the
5 high dose.
6 DR. BYUS: The incidence of high dose or the
7 dose-response relationship?
8 DR. SANDY: The incidence of high dose. In
9 the -- the male Fischer rat -- that's the inhalation
10 study -- the -- that's table 8. The tumor incidence for
11 testicular tumors, 64 percent of control, 70 at the
12 400-parts-per-million dose, 82 at the 300 -- sorry --
13 3,000-parts-per-million dose, and 94 percent of the
14 8,000-parts-per-million dose. I believe that's a dose
15 response.
16 Again, this study had early mortality in the
17 mid and high-dose groups. So you're seeing -- you're
18 still seeing a dose response, even those these animals are
19 dying sooner.
20 DR. BYUS: I know I would never call that a
21 clear evidence of a dose-response effect. I mean, I would
22 say that is very weak evidence if -- at the best. I
23 wouldn't call this a clear-dose response.
24 DR. MARTY: Craig, is your concern that high
25 incidence in the controls -- is that part of the issue?
120
BARNEY, UNGERMANN & ASSOCIATES 888 326-5900
1 DR. BYUS: That is part of it, sure. Of
2 course. Plus, if you factor all of this in, the
3 variability of the control incidence and the cross
4 studies, the very incidence of it, which as I said last
5 time is -- what you're probably doing is simply affecting
6 time-to-tumor, rather than actually affecting the overall
7 incidence.
8 And I don't want to argue -- you know what I
9 mean -- about that. What that means -- what the
10 significance is. But I would not call this a clear
11 evidence of a dose response -- tumor-incidence dose
12 response.
13 The reason it's important, of course, is
14 whether or not there's a threshold. I mean, that's the
15 point. That's why seeing a clear evidence of a dose
16 response is important, in a sense. You see what I'm
17 saying? Clear evidence.
18 DR. MARTY: I think it's -- we should point
19 out that at the mid and high dose, those were both
20 significantly different than control. So it may -- maybe
21 is a semantic issue versus a clear --
22 DR. BYUS: I teach pharmacology to the
23 medical students. I also do tumor studies where we try
24 and establish a clear dose response. And that is
25 different. Yes, they may be different than control. But
121
BARNEY, UNGERMANN & ASSOCIATES 888 326-5900
1 it is not indication of a clear dose response, I mean, in
2 my opinion.
3 DR. BLANC: Well, perhaps what you're trying
4 to say, there's a difference in a qualitative statement
5 saying that the data can be interpreted as showing a dose
6 response, versus the implication that there is statistical
7 relationship between the group suggesting a step up, in
8 effect, or consistent with it.
9 And so it sounds, if I see -- hearing the
10 difference in the two points of view, you, from a
11 qualitative point of view, felt the data consistent with
12 the dose response. But there isn't a statistical test
13 that you can state you performed that's consistent. In
14 the one case, said you couldn't do a test of a trend
15 because of the way the data was presented. And in the
16 latter case, was there indeed a test for trend?
17 DR. SANDY: I think we can and probably
18 should have done a trend test. I would --
19 DR. BLANC: Because I think --
20 DR. SANDY: -- hazard to guess it would be
21 significant.
22 DR. BLANC: Well then, I would suggest you
23 do that. And I think that that -- and then rather than
24 get hung up on, you know, one man's meat is another man's
25 poison, you simply say that it was a statistical
122
BARNEY, UNGERMANN & ASSOCIATES 888 326-5900
1 relationship that was consistent with the trend.
2 DR. SALMON: One of the other things is that
3 I think, for the purposes of our risk assessment, which
4 is, you know, essentially what we're looking at here, we
5 were concerned to follow the letter, both of our
6 assessment guidelines, and also the Health and Safety Code
7 applicable to the TAC program.
8 And I quote, "Where it can be established
9 that a threshold of adverse health effects exist, the
10 estimate shall include a appropriate factor." Our risk
11 assessment assumptions would only consider a threshold
12 analysis if there was solid evidence for a threshold.
13 DR. BLANC: Which there isn't?
14 DR. SALMON: Which, I think, regardless of
15 which side of the fence you come down on -- I'm sensitive
16 to the fact there's a debate here, obviously. The point
17 is, either way you think about that debate, I don't think
18 you could argue that there is any substantial evidence for
19 a threshold. Or at least, that was the interpretation
20 which we made when we undertook the risk assessment.
21 DR. BYUS: It's mainly -- it's mainly the
22 language. It seems -- in my opinion, it seems to be
23 overstated in the document. That's all I'm getting at.
24 DR. SANDY: Okay.
25 DR. BYUS: I don't disagree with the
123
BARNEY, UNGERMANN & ASSOCIATES 888 326-5900
1 conclusion that this is a carcinogen or causes cancer in
2 animals, clearly. I'm just disagreeing with some of the
3 language, in my opinion, tends to be overstating the
4 animal data.
5 DR. FUCALORO: I do want to point out, the
6 issue is not whether -- the only issue is not whether it
7 is carcinogen -- whether it's carcinogen or not. What I
8 think we are charged to do is to come up with a potency
9 factor. And I think that -- and your comments really
10 address that issue. And I think that's something --
11 something we need to discuss. I don't believe they
12 answered your first question regarding how high these
13 doses were.
14 DR. BYUS: The extrapolation. How many
15 orders of magnitude did you extrapolate?
16 DR. FUCALORO: I think you used the words
17 "logs." Orders of magnitude; right?
18 DR. BYUS: What is the extrapolation here?
19 DR. SALMON: We don't actually make an --
20 such an extrapolation in the document. Because, of
21 course, we're not saying that, you know, there is a
22 specific exposure level to MTBE out there, which we're
23 trying -- which we're evaluating at this point.
24 However, I think it would be fair to say
25 that, taking the typical ambient levels of MTBE which are
124
BARNEY, UNGERMANN & ASSOCIATES 888 326-5900
1 out there at the moment, it's something around 4 or 5
2 orders of magnitude, which is not untypical for the sort
3 of extrapolation --
4 DR. FUCALORO: So 4 or 5 orders of magnitude
5 greater than what is --
6 DR. SALMON: Than what is ambient, yes.
7 DR. FUCALORO: 10 to a 100,000 times more?
8 DR. SALMON: I believe that's correct.
9 DR. BYUS: We have put that in documents
10 before. First document I ever did, which I can't even
11 remember what the chemical is now. We did, in fact, say
12 that we extrapolated 5 orders of magnitude. It's just
13 something that, you know, especially -- again --
14 DR. MARTY: I think we can add that. We can
15 add that to our attachment, based on the information we
16 get from ARB regarding concentration of air.
17 DR. BYUS: I know. And I understand what
18 you've done. And I understand the quantitative risk
19 assessment, and what you're trying to do. But, I mean, in
20 a sense, we're talking about mechanism. In a way
21 there's -- you're trying to interpret -- trying to put
22 some substance on some kind of mechanism and validity.
23 And really the further -- I mean, it troubles me that
24 we're extrapolating 5 orders of magnitude for this number.
25 DR. MARTY: I would agree.
125
BARNEY, UNGERMANN & ASSOCIATES 888 326-5900
1 DR. BYUS: It always troubles me when we
2 extrapolate 5 orders of magnitude or 4. Much better if it
3 was one order.
4 DR. MARTY: Yes, I don't think we would
5 disagree with that at all.
6 DR. BYUS: No one would disagree with that,
7 I hope.
8 DR. SALMON: It's just we don't have the
9 means to do anything else.
10 DR. BYUS: I know. I'm not saying you
11 should have the means. It's part of the, in a sense, the
12 language here.
13 DR. SALMON: Characterizes the uncertainty.
14 DR. BYUS: Characterizing the uncertain,
15 exactly.
16 DR. BLANC: You know, I have a solution to
17 this. Because, if I understand what we're being asked to
18 do, we're being asked to make our finding, in light of
19 their document -- which once again, I think would be some
20 kind of written memorandum, not of great -- or are we just
21 being asked to make sentence --
22 CHAIRMAN FROINES: We're being asked to vote
23 on whether what they've done is sound science, period.
24 There will be no finding on this.
25 DR. BLANC: There's no finding? Are we
126
BARNEY, UNGERMANN & ASSOCIATES 888 326-5900
1 asking -- and the attachment of health effects of exposure
2 to methyl tertiary butyl ether, is that the only thing
3 we're commenting on or commenting on the entire document?
4 How does this relate to the entire document? As an
5 addendum to it?
6 DR. MARTY: Can I --
7 CHAIRMAN FROINES: We're voting on that
8 document.
9 DR. BLANC: Not on this. What is this?
10 DR. MARTY: Can I drop in here maybe a
11 little bit? When we were asked to come up with the unit
12 risk factor by inhalation exposures by the Air Resources
13 Board, we had just completed a document to our public --
14 our Public Health Goal Drinking Water Program.
15 So we took that document and used the
16 information in there, and had to do some more calculations
17 to get to the dose via inhalation -- target dose via
18 inhalation, and then back to a unit risk factor for use
19 with concentrations in air. That little end piece of it
20 is what is attached to the attachment. In terms of
21 commenting on the PHG document, you know, you guys needed
22 to see that because --
23 DR. FUCALORO: This document?
24 DR. MARTY: Right.
25 DR. FUCALORO: This is the document where we
127
BARNEY, UNGERMANN & ASSOCIATES 888 326-5900
1 have to render judgment on whether or not --
2 DR. MARTY: And you need the bigger document
3 in order to understand what we've done in the little
4 document.
5 DR. BLANC: So this is actually what we're
6 commenting on?
7 DR. MARTY: Right.
8 DR. SALMON: We don't have a mandate to
9 modify the PHG document at this point.
10 DR. MARTY: Right. We can't modify this
11 document. But we can address your concerns by putting
12 information into that appendix.
13 DR. BLANC: But wouldn't that delay the
14 whole process? You have to come back to us again.
15 DR. FUCALORO: That was -- I was going to --
16 do you need to come back to us again or is it possible for
17 to us vote now? I'm not clear -- I'm not clear on that.
18 Craig brought up a lot of -- many points, and there was
19 some disagreement and some agreement, I think, on the
20 points he brought up. What do you -- what do you suggest
21 at this point?
22 DR. MARTY: Well, I would suggest that we
23 modify the little document to address the uncertainty
24 issue, which is what Craig was getting at. And then --
25 DR. BYUS: That's clearly all I'm getting at
128
BARNEY, UNGERMANN & ASSOCIATES 888 326-5900
1 is clearer explanation on the uncertainties, not on the
2 overall process. Because you did a very good job. It's
3 just at the level of the uncertainties.
4 DR. BLANC: I would say its fine if you do
5 that. I would also say, if I understand the charge to us,
6 if the charge to us is to comment on whether what you did
7 is consistent with standard and acceptable scientific
8 process, then I think, it's about as easy as saying that
9 diesel exhaust is toxic air contaminant.
10 Which is -- that's kind of a no-brainer. Of
11 course it's a toxic air contaminant. And, you know, yeah,
12 you dealt with the uncertainties that we deal with every
13 single time you have to do on these exercises. But what
14 you did is what is standardly done.
15 I really think that the discussion is --
16 because it's so applicable to every single one of these
17 cancer-potency things we have to deal with. But on the
18 other hand, I don't think it would, in any way, make me
19 say that this wasn't consistent with standard practice.
20 All the more so. So I would certainly feel comfortable
21 just calling the question.
22 DR. FUCALORO: Well, I think -- jumping
23 ahead. I think, though, I'd like -- I think give everyone
24 an opportunity to comment, because we certainly asked Stan
25 to comment, and Craig. And there may be no other
129
BARNEY, UNGERMANN & ASSOCIATES 888 326-5900
1 comments. I mean, I frankly -- I think Craig and Stan --
2 I made my comments, I feel. Roger?
3 DR. ATKINSON: I have no comments.
4 DR. FUCALORO: John, did you want to say
5 something on this? Yes, he did. But he won't.
6 CHAIRMAN FROINES: Maybe I'll let it go. I
7 think that the -- I think Craig's comments are very useful
8 and valuable. I think that we have to keep fighting the
9 tendency on, where does the burden lie on these things.
10 And that is, it is not -- the burden is not
11 up to the state to demonstrate mechanistically the
12 relevance of animal-cancer data to humans. I take that as
13 not being the burden of the state. I take it as the
14 burden of the critics to demonstrate the irrelevance of
15 the animal data.
16 DR. BYUS: That's right. Very good.
17 CHAIRMAN FROINES: And there are enormous
18 difficulties with MTBE. There's no question, whatsoever,
19 that there are scientific difficulties. But the
20 conclusion that we came to was that we found no evidence
21 to demonstrate the irrelevance of lytic cell tumors or
22 liver tumors, what have you, even though we didn't like
23 lots of stuff about that science.
24 But it's this notion of who has the burden,
25 that I think is really quite important. The other problem
130
BARNEY, UNGERMANN & ASSOCIATES 888 326-5900
1 is, the two inhalation studies were done by industry. And
2 they have the most problems, in many ways, in my view.
3 They're the ones with real toxicity problems, so on and so
4 forth.
5 And we find ourself in this very strange
6 position of having industry studies, which we criticize.
7 And if we don't then accept the positive findings, we, in
8 a sense, are rewarding the people who did the bad
9 studies. So that's really contradictory in terms of the
10 way we have to look at it, it seems to me.
11 And the other thing is, that if this was an
12 abstract question, we really could debate it. But it's
13 not, because we have 15 percent of the stuff in all our
14 gasoline. So actually we're breathing it as we speak.
15 So I frankly -- frankly, as far as I'm
16 concerned, this is not a quantitative issue. It's a
17 qualitative issue. I would rather not have this in my
18 gasoline, as a qualitative matter. So I agree that you
19 want to do reasons that I don't even understand the
20 quantitative risk assessment. That -- seems to me, that's
21 not even the issue here.
22 The issue is, the government should never
23 have pushed this. We shouldn't be in this position in
24 1999 arguing over an EPA decision from 1992. And this is
25 a bad -- was a flawed policy decision to begin with. It's
131
BARNEY, UNGERMANN & ASSOCIATES 888 326-5900
1 still a flawed policy decision. And I think there's light
2 at the end of the tunnel, so we should proceed with it.
3 So it becomes, for me, at some level, sort of a
4 no-brainer --
5 DR. FUCALORO: All right. Paul, did you
6 want to comment further? How about you, Hanspeter? Then
7 I would ask the panel. This is the pleasure of the panel
8 to make a motion that I will suggest in a moment, to
9 essentially have closure on this issue.
10 Is there anyone who objects to that? If
11 not, let me make a suggestion at a motion. I won't
12 move it. I'll allow someone else to, because I have the
13 language here.
14 "That the -- this panel finds that this
15 document titled, 'Attachment 1, Health Effects of
16 Exposures to Methyl Tertiary Butyl Ether, MTBE' be
17 found to have sound -- be based upon sound,
18 scientific knowledge, methods, and practices."
19 And the record shows that John Froines is
20 still with us. I need to say that parenthetically for
21 matters of quorum. And that we -- that's finding one.
22 And finding two, that we recognize that OEHHA may wish to
23 expand upon the document at a future time for purposes of
24 clarity; okay, and to introduce more pertinent information
25 for the purpose of clarity.
132
BARNEY, UNGERMANN & ASSOCIATES 888 326-5900
1 Let me stop it there. That's a motion I
2 suggest. If anyone thinks that's a good motion, I will
3 entertain that motion from the floor.
4 DR. BYUS: I so move.
5 DR. FUCALORO: Is there a second to that?
6 DR. BLANC: Second.
7 DR. FUCALORO: Is there any further
8 discussion on that? Hearing none, I will take the vote.
9 All in favor please indicate by saying aye.
10 MEMBERS OF THE PANEL: Aye.
11 DR. FUCALORO: Opposed? Anyone wishing to
12 be recorded as abstaining? The motion carries
13 unanimously. With that, I leave, and turn back orders to
14 Dr. John Froines.
15 CHAIRMAN FROINES: You know, the tragedy of
16 this thing is, the --
17 DR. BLANC: John, I suggest we let our
18 stenographer take a break.
19 CHAIRMAN FROINES: Let's take a ten-minute
20 break.
21 (Brief recess taken.)
22 CHAIRMAN FROINES: Okay. MITC. We are back
23 in business. And then, Melanie, we're going to get to the
24 REL. We're going to finish. It will go fast, I think.
25 No, no. They may not. I don't want to -- I realized
133
BARNEY, UNGERMANN & ASSOCIATES 888 326-5900
1 who's doing them.
2 DR. FUCALORO: Don't forget it.
3 CHAIRMAN FROINES: Forget I said anything
4 about it.
5 DR. BYUS: He knows too much. He knows too
6 many things.
7 DR. FUCALORO: You know too much.
8 CHAIRMAN FROINES: Andrew, please go ahead.
9 DR. RUBIN: Are we looking at a finishing at
10 3:00 o'clock?
11 CHAIRMAN FROINES: No, go ahead. We don't
12 have any --
13 DR. RUBIN: Okay.
14 CHAIRMAN FROINES: We'll all try and push
15 this panel along. You work at your pace.
16 DR. RUBIN: All right. First -- first
17 slide. Let me just start, before the first slide, which
18 is -- has my name on it, basically. My name is
19 Andy Rubin. I'm the staff toxicologist at DPR responsible
20 for the risk assessment on MITC.
21 In opening up the subject of the assessment
22 of MIT's health effects, I really wanted to be clear from
23 the outset that there are some very interesting problems
24 in determining the critical end-point values. These
25 relate to the significance of the actual end points.
134
BARNEY, UNGERMANN & ASSOCIATES 888 326-5900
1 That is, the toxicological effects that were
2 observed, the quality of the studies used, the
3 availability of the sufficient number of studies, and the
4 issue of assigning a subchronic NOEL value that is higher
5 than a -- an acute NOEL value. Which goes against sort of
6 standard toxicologic dictum.
7 And I'd like to ask for and recommend that
8 the panel, as you read the document, consider these issues
9 that I bring up as we get to them, and as you read the
10 document and critique the document. We're not to the
11 slides yet.
12 MS. WALES: Technical problems.
13 DR. RUBIN: The slides are so amazing that
14 they've broken the overhead projector.
15 DR. FUCALORO: Is it on?
16 DR. BYUS: It just started.
17 DR. FUCALORO: Let the record show it was my
18 finger that -- dumb luck.
19 MS. WALES: It's on.
20 DR. FUCALORO: We'll be impressed with this
21 high technology.
22 DR. RUBIN: I could hold it up, but I don't
23 think you can see it. You actually have copies of it.
24 DR. FUCALORO: We actually all have the
25 copies of it.
135
BARNEY, UNGERMANN & ASSOCIATES 888 326-5900
1 DR. RUBIN: There we go. There's
2 something -- yeah. Okay. This is an overview of the
3 subjects I'd like to cover. First, the Cantara Loop
4 spill, which I'll explain in a minute. Little bit about
5 the pharmacokinetics of MITC in mammalian systems.
6 Then on to the acute toxicity, subchronic
7 toxicity, chronic toxicity, oncogenicity, and the famous
8 DPR margin of exposure calculations, reference exposure
9 level concentrations, and the possibility of toxicity due
10 to other Metam-Sodium breakdown products. In particular,
11 methyl isocyanate and hydrogen sulfide.
12 Next. Any consideration of the potential
13 human health impacts of MITC must or should begin with the
14 realization that we actually have some real-world human
15 toxicity data out there, courtesy of the Southern Pacific
16 Railroad.
17 Back on July 14th, 1991, a train -- a
18 mile-long train heading north near -- about six miles
19 north of the town of Dunsmuir couldn't quite make it up a
20 grade. Some of the cars skipped the track, and a tanker
21 car containing 19,500 gallons of 32.5 percent Metam-Sodium
22 went into the river.
23 In the hour or two after -- within the hour
24 or two -- within the next few hours after that accident
25 occurred, it was felt that there was only a breach above
136
BARNEY, UNGERMANN & ASSOCIATES 888 326-5900
1 the water line that was soon dispelled -- to dispell
2 within 12 hours when it was learned that all 19,500
3 gallons had gone into the river.
4 And this map just -- this, by the way, much
5 of the data -- very creditable data comes from OEHHA and
6 DHS's assessment of the health effects of this spill. And
7 this map simply shows -- you probably can't seen see it
8 too well. But basically the Sacramento River with the
9 railroad running next to it.
10 And right up at the top there -- do I point
11 this or -- okay. There it is -- is the Cantara Loop,
12 which is a -- which is a loop that goes up a grade.
13 There's a bridge over the river here. And that's where
14 the spill occurred. This occurred at 9:39 at night. By
15 9:15 the next morning, the plume of Metam-Sodium -- the
16 big green plume had run by the town of Dunsmuir where the
17 major exposures occurred.
18 That's probably the major population center
19 near the spill. Population of about 3,000 people. Had
20 run down and had reached Castle Crags. Basically by
21 the -- by the morning of the 17th, three days later -- two
22 and a half days later, say, the plume was emptying into
23 Shasta Lake.
24 The primary human exposures, as I've -- as I
25 said, probably occurred in the town of Dunsmuir. Now,
137
BARNEY, UNGERMANN & ASSOCIATES 888 326-5900
1 the -- from a toxicological standpoint, we're very
2 interested in what the levels of -- of exposure to MITC
3 were in the town of Dunsmuir near the river so that we can
4 gauge what kind of levels caused what kinds of effects.
5 Unfortunately, it wasn't until three days
6 after the spill that good, reliable monitoring was in
7 place. Consequently, in the modelling that --
8 consequently, the levels of Metam-Sodium had to be
9 estimated based on environmental-fate and transport
10 modelling.
11 Actually, there were a couple of models that
12 were used to estimate the air concentrations of MITC
13 around Dunsmuir after the spill -- after the spill. One
14 was an environmental-fate and transport model that took
15 into account the evaporation rate, the amount of sunlight,
16 the wind, the meteorologic conditions and so forth, as
17 well as the known physical, chemical properties of Metam
18 in water and how it breaks down to MITC, and how fast MITC
19 will go from a water phase into a gas phase, and so forth.
20 Another model relied on measured
21 concentrations, concentrations that were measured three
22 days later in the river, and compared them to measured
23 concentrations in the air. Basically, a ratio was set
24 up. So there were two -- there were at least these two
25 different models, and some variations in between.
138
BARNEY, UNGERMANN & ASSOCIATES 888 326-5900
1 The only reason I mention this, is that
2 there are some estimates of the levels of MITC in the
3 Dunsmuir area soon after the spill. Within -- but please
4 recognize that these are only estimates. These are not
5 measured values. Actually, there are one or two people in
6 the room who actually did these studies, and I want to
7 recognize that they are here.
8 In the 4 to 12 hours after the spill, the
9 maximum estimates, based on the model and the assumptions
10 used, ranged from a hundred and forty to 1600 ppb.
11 Between hours 12 -- and these are -- these are levels that
12 were at the river. At hours 12 to 24, we're dealing with
13 88 to 200 ppb. And at 24 to 48 hours, we were dealing
14 with 15 to 88 ppb.
15 These are very important considerations
16 in -- in this risk assessment, because we have to consider
17 not only -- we have to consider the whole spectrum of
18 toxic effects that occurred there. When we're looking at
19 a laboratory assay that may only be measuring one toxic
20 effect.
21 In other words, as you'll see on the next
22 slide -- I don't know if I made clear, but the next slide
23 shows that there are -- there was a whole plethora of
24 toxic effects that were detected, mostly in the town of
25 Dunsmuir following the spill. And this is all from
139
BARNEY, UNGERMANN & ASSOCIATES 888 326-5900
1 OEHHA's publications on the issue on the spill.
2 There were 848 spill-related hospital visits
3 from 705 separate individuals in the month following the
4 spill. These are the effects that people were reporting.
5 Headache in 64 percent of those visits. Eye irritation in
6 49 percent. Throat irritation in 42 percent. Nausea, 46.
7 Dizziness, shortness of breath, diarrhea, nasal
8 irritation, and chest tightness. These were the -- I only
9 listed on this table the most commonly expressed toxic
10 effects.
11 There were seven hospitalizations, four
12 people with respiratory problems. Two with fainting
13 problems. One person with disorientation and irregular
14 heartbeat. And according to the paper -- one of the
15 papers, that person may have received an excessively high
16 dose. None of these are known for sure, though.
17 There were eight -- we know about eight
18 exposed pregnant women. Two of them were exposed during
19 the first trimester, and they opted for abortion.
20 Particularly sad outcome to this accident. Four exposed
21 during the second trimester were advised that their
22 pregnancies were progressing normally. I assume that that
23 probably came from their doctors.
24 DR. FUCALORO: Follow up -- was there follow
25 up on that?
140
BARNEY, UNGERMANN & ASSOCIATES 888 326-5900
1 DR. RUBIN: I believe that's the extent of
2 the follow up, at least in the published literature.
3 There was some evidence for the initiation of or
4 exacerbation of asthma over the longer term. And this is
5 a syndrome that was recognized in 1985 associated with
6 exposures to other isocyanates. Syndrome known as RADS or
7 Reactive Airways Disfunction Syndrome.
8 There were, I believe, oh -- there were
9 30 -- 30 of 197 adults referred to health practitioners
10 for spill-related reasons, were considered positive for
11 RADS.
12 DR. BLANC: Can you tell me where, for
13 example, in the document -- in the draft document those
14 data --
15 DR. RUBIN: Yeah.
16 DR. BLANC: Because it's not in the acute
17 toxicity piece.
18 DR. RUBIN: Right. It's before it. The
19 acute toxicity deals with the laboratory studies.
20 DR. BLANC: It also talks about the Plutara
21 incident. That's why I was confused.
22 DR. RUBIN: Maybe I've got things mixed up.
23 Page 16, 17 and 18 is the discussion of the Cantara spill.
24 DR. BLANC: Okay. Great.
25 DR. RUBIN: So RADS is a syndrome that is a
141
BARNEY, UNGERMANN & ASSOCIATES 888 326-5900
1 little more disturbing, because it implies that there may
2 be longer term effects from acute exposures. RADS -- the
3 criteria for RADS include onsets of symptoms within 24
4 hours of a single exposure, persistence of such
5 symptoms -- and by "symptoms," I'm talking about
6 asthmatic-types of symptoms, dyspnea, wheezing, air-flow
7 obstruction that may be measured in standard spirometry
8 assays in a lung-function lab.
9 And the possibility that there's
10 sensitization later on. In other words, that a person
11 who's experiencing this -- this syndrome, may have an
12 exacerbation of the syndrome on subsequent exposures to
13 much smaller amounts. I think this is really important.
14 But it's not well-characterized in this particular
15 incident. But it is, at least, a possibility.
16 We know of at least 30 people, however, that
17 were positive for this syndrome after the Cantara spill.
18 One more issue, and this took a little bit of digging on
19 my part. There were three railroad workers that were
20 dispatched into the spill area within a few hours of the
21 spill by their employers -- by Southern Pacific.
22 They came in to pull the -- the salvagable
23 part of the train out of there. And they went in there,
24 and they were -- well, let me start this by saying, this
25 does not appear in the scientific literature or in the
142
BARNEY, UNGERMANN & ASSOCIATES 888 326-5900
1 medical literature. It appears in a 1997 article in the
2 Sacramento Bee. I did some calling around to some people
3 at OEHHA. And one psychologist that had worked on some of
4 the --
5 DR. BLANC: I hope it wasn't
6 Rosemary Bowler.
7 DR. RUBIN: It was. I called her. She had
8 no information about this. It was simply a Bee article on
9 the three guys running a locomotive in there to try and
10 pull out this mile-long train, salvage what they could of
11 it.
12 And while this is not something that I would
13 perhaps base an entire risk assessment on, a newspaper
14 article, I wanted to recognize that there were three --
15 three workers that claim, six years after the spill, to
16 have experienced quite a number of symptoms. Permanent
17 neuropsychological damage, RADS, irregular heartbeat, low
18 blood oxygen, coughing, depression, coughing fits,
19 back-to-back colds, loss of drive, peeling away of mucous
20 membranes in the mouth.
21 I'm not sure how to -- how to assess that
22 kind of thing. But I think it should be brought to the
23 attention of the panel, and it's in this document
24 referenced, the Sacramento Bee, 1997. So --
25 DR. BLANC: Well, I think -- I think what
143
BARNEY, UNGERMANN & ASSOCIATES 888 326-5900
1 you'll hear from the panel, is that section should be
2 excluded. And the -- in fact, the most salient and
3 documentable issues of the respiratory complaints, at
4 least one, and perhaps all three of those people were
5 included in the paper by Cohn, et al. And so you've
6 already included the respiratory findings.
7 DR. RUBIN: Yeah.
8 DR. BLANC: And I would probably also say
9 that, I don't disagree with you that the issue of Reactive
10 Airways Disfunction Syndrome and irritant-induced asthma
11 is an important end point in acute --
12 DR. RUBIN: Assessment.
13 DR. BLANC: -- acute exposure. And
14 acute-exposure outcome, that's important, and very
15 well-documented from the Plutara spill. But I don't think
16 you need to include, you know, newspaper account where it
17 gets into some of these other very nebulous and probably
18 unsupportable issues of subjective, neurological --
19 DR. RUBIN: Agree.
20 CHAIRMAN FROINES: We need to remember that
21 this is the day in which we're having a staff
22 presentation, and then we're going to have a full panel
23 discussion later. So I -- I'd like to give him -- the
24 time is moving on -- to try and move ahead with the
25 presentation and not --
144
BARNEY, UNGERMANN & ASSOCIATES 888 326-5900
1 DR. BLANC: Get into the details.
2 CHAIRMAN FROINES: Doesn't preclude
3 discussion, but it --
4 DR. RUBIN: Okay. Well, let's move on from
5 the -- from the Cantara incident to what we know from
6 laboratory investigation of MITC's toxic end points.
7 First of all, as far as pharmacokinetics are concerned,
8 all we have is oral-exposure pharmacokinetics. That is,
9 exposure of rats to label MITC via the oral route.
10 We do not have exposures via the inhalation
11 route. We can say that using doses of 4.433 milligram per
12 kilogram radio label MITC, that 88 to 96 percent was
13 absorbed within the hour. 80 to 82 percent was excreted
14 in urine, and small amounts were excreted in the feces. 6
15 to 15 percent in the expired air CO2, and less than 1
16 percent is carboneal sulfide or carbon disulfide within 24
17 hours.
18 There was at the end of a week, 168 hours, 1
19 to 3 percent remained bound in tissues. There -- MITC is
20 conjugated and is excreted as cysteine conjugates, about
21 which, nothing is known toxicologically.
22 The acute toxicity and the bulk of the
23 toxicity that was observed at Cantara had to do with the
24 irritative capacity of MITC. Oral presentation of MITC to
25 animals always or generally results in irritation of the
145
BARNEY, UNGERMANN & ASSOCIATES 888 326-5900
1 stomach lining, the esophagus, and so forth. I'm not
2 going to cover those.
3 What I'm going to concentrate on now is the
4 acute toxicity via the air, because that is where we think
5 virtually all the exposure to MITC is coming from. When
6 OEHHA did their original risk assessment on the spill --
7 and indeed, when DPR did a conditional risk assessment in
8 1994, the only study we had available to assess the
9 toxicity of MITC came from the Ukraine, what we call the
10 Ukrainian Cat Study by Nesterova.
11 We feel, and I have felt, that this study
12 was so bereft of experimental and analytical detail, that
13 it is virtually unusable. So we got -- we have another
14 study. Another study came along in 1996, an
15 eye-irritation study which was a rather careful study that
16 characterized the chamber -- exposure concentrations and
17 the end points rather carefully.
18 And I think we can -- well, I will make an
19 argument that this is an appropriate, acute end-point
20 study. This was a human study done in Sacramento --
21 actually, at UC Davis Medical Center -- in which there
22 were 70 subjects, 38 males, 32 females, mean age of 32
23 years were the range, from 18 to 67 years old.
24 And they were exposed to gaseous MITC
25 through specially fitted goggles. Pam, if you put the
146
BARNEY, UNGERMANN & ASSOCIATES 888 326-5900
1 next one up there, you get a sense of what it looked like.
2 DR. SALMON: That slide's not --
3 DR. RUBIN: It's not in there? Oh. Okay.
4 Well --
5 DR. BLANC: It's okay. We'll take your
6 word.
7 DR. RUBIN: They were goggles. They were
8 airtight around the seam. They were fed by a feeding tube
9 and a distribution manifold across the top. When the
10 study was originally commissioned, DPR was approached as
11 to what end points they should measure.
12 They originally wanted to put a mask on the
13 subjects. And what I am told by the person who initiated
14 this risk assessment was, "No mask here. The pulmonary
15 end points are serious enough that we don't want human
16 subjects breathing this stuff." So all we have from the
17 acute -- from this experiment is an eye-irritation end
18 point.
19 DR. BLANC: Isn't there -- just as an aside.
20 I hope this doesn't violate your guidelines. But I always
21 understood that one of the issues with the Cantara spill
22 and the immediate health-risk assessment was, that it was
23 a licensed pesticide, and there was pesticide-toxicity
24 data other than just the Ukrainian Cat Study that was
25 deposited with the Department of Pesticide Regulation, but
147
BARNEY, UNGERMANN & ASSOCIATES 888 326-5900
1 unfortunately, none of that data was available for
2 anybody's health review. Or is that not true? How did it
3 ever get licensed without any submission of any data?
4 DR. RUBIN: Well, the spill, I'm -- first of
5 all, I'm not sure I can answer that question, as to what
6 data were available.
7 DR. BLANC: I mean, are there data relevant
8 to its pesticide registration which is not otherwise in
9 the public domain that you have also evaluated for the
10 purposes of this risk assessment?
11 DR. RUBIN: Definitely.
12 DR. BLANC: Does that predate --
13 DR. RUBIN: Some of it, yes. It does
14 predate the spill.
15 DR. BLANC: Okay.
16 DR. RUBIN: In fact, you will notice when
17 you read -- I know this has been at issue before the panel
18 in the past. There are very few open literature studies
19 on the toxicity of MITC. There are a few, and many of
20 them come from the spill and human -- human exposures.
21 But we're dealing mostly with contracted studies.
22 The human eye irritation study, 70 people
23 exposed for -- just to the eyes through goggles for 14
24 minutes, 4 hours or 8 hours. They were sitting at tables,
25 and they had a little graph next to them, so that they
148
BARNEY, UNGERMANN & ASSOCIATES 888 326-5900
1 could put on the graph a little mark as they felt some
2 level of irritation, say between zero and a hundred. And
3 they would put a little mark on.
4 That is a subjective sort of
5 semi-quantitative, at best, level of assessment of eye
6 irritation. That -- that technique is called -- is known
7 as the Likert technique or the Likert scale. It's a
8 subjective technique for assessing eye irritation.
9 There were a number of other end points that
10 were used, including blink rate, tearing, visual acuity,
11 and photographs of the eye. By "visual acuity," I mean
12 put your hand over your right eye and tell me if you can
13 see the chart. And photographs of the eye meaning, before
14 and after, how red were these -- how red were the eyes of
15 these people.
16 Results were, the Likert scale measurements
17 indicated there was an irritation response at 800 ppb
18 after one hour of exposure. Blink rate indicated an
19 irritation response at 800 ppb after two hours of
20 exposure. There were no -- none of the other three
21 parameters exhibited positivity.
22 The other factor that is of interest is
23 that, when the subjects were withdrawn from the stimulus,
24 the -- their perception of irritation and their blink rate
25 went back down very quickly. We have -- we have decided
149
BARNEY, UNGERMANN & ASSOCIATES 888 326-5900
1 that this was an adequate study to assign a LOEL value of
2 800 ppb and a NOEL value at the lowest concentration
3 tested of 220 ppb.
4 CHAIRMAN FROINES: Why don't you skip to the
5 studies that form the basis of the NOEL and LOEL.
6 DR. RUBIN: Okay. This was the first one.
7 This is the acute critical NOEL.
8 DR. BLANC: This is the acute one. The next
9 one is going to be subchronic.
10 DR. RUBIN: I'm actually only going to talk
11 about those studies. Moving on to subchronic. We're
12 dealing here with a 12 to 13 week, 4 hour a day -- 5 days
13 a week, nose only, inhalation-exposure experiment. This
14 one came from Germany by Ross Kamp, et al. First I'll
15 tell you a little bit about what they observed. Then I
16 will attempt to go into some of the weaknesses of this
17 study.
18 There were ten rats per sex, per dose
19 exposed to 0, 1, 10, or 45 ppm MITC. Clinical signs at
20 the high dose -- and the signs I've listed here in the
21 symptoms I've listed here are ones that were observed in
22 many of the animals at this dose, not just one animal.
23 Included apathy, increased salivation and nasal discharge,
24 vocalization -- vocalization we usually take to mean that
25 those animals are uncomfortable. They want out.
150
BARNEY, UNGERMANN & ASSOCIATES 888 326-5900
1 Also body-weight gain was 37 and 53 percent
2 male and females of the sham dose controls. Turns out to
3 be important, because sham dosing itself in this
4 experiment is really hard on these animals. At 10 ppm,
5 which is where we assign the LOEL, we're dealing with
6 much-less overt toxicity. We have decreased body-weight
7 gain, compared to sham dose controls, 89 and 85 percent of
8 sham dose controls in males and females, not statistically
9 significant.
10 However, I felt that, given the much greater
11 decrement in weight gain at the next higher dose -- at the
12 high dose, that this was a real effect. It can be argued,
13 though, that the lack of statistical significance is
14 problematic. There was also, interestingly, increased
15 water consumption at the LOEL dose of 10 ppm, about 15
16 percent above sham controls. This was statistically
17 significant.
18 However, at the high dose, there was also
19 about a 15-percent increase, but it wasn't statistically
20 significant. And there was no dose response. So, that's
21 possibly a problematic end point. I have considered it as
22 a positive toxicological end point.
23 There was a slight statistically significant
24 reduction in serum total protein. Those are the three end
25 points that we are basing the subchronic risk assessment
151
BARNEY, UNGERMANN & ASSOCIATES 888 326-5900
1 on. So one needs to examine the toxicologic significance
2 of these end points, the fact that there's no dose
3 response in this for the increase in water consumption,
4 the possibility that the effect on serum protein may be
5 related to the increased water consumption.
6 I would say here, parenthetically, that you
7 can find when you feed MITC to rats, and their water
8 consumption actually decreases, because the water that the
9 MITC is in tastes so bad, that they don't want anything to
10 do with it.
11 But under those conditions, you get drops in
12 serum protein as well. Which made me think that it is at
13 least possible that the drop in serum protein was not
14 related to the increase in water consumption. There was
15 also no histological examination of the nasal cavity. And
16 for an irritant as powerful as MITC, you should be looking
17 at the nasal cavity, the trachea, for irritation effects.
18 Finally, there is insufficient analytic data
19 in this experiment. First of all, there's no report of
20 daily levels of MITC. This is a difficult thing to do for
21 13 straight weeks, to put into a -- an inhalation chamber
22 exactly the same amount of MITC every day, and to measure
23 it, and to express those results in -- in interpretable
24 fashion.
25 What these investigators did was simply add
152
BARNEY, UNGERMANN & ASSOCIATES 888 326-5900
1 up all the data that they had, which they did not supply,
2 and give us a mean value. So the implication of that is,
3 that we don't really know what the excursions of the MITC
4 levels were in those experiments. And those, say, at the
5 high dose where the mean value was 45, maybe it went down
6 to 10, and maybe it was occasionally -- and maybe it was
7 up at 165, but we just don't know.
8 And those are some of the weaknesses in this
9 study. When you don't know the daily doses, what those
10 animals are daily exposed to, and you don't have daily
11 toxicologic data, you can't really tell what the animals
12 are responding to.
13 But -- and here's -- here is one of the
14 problems that we're dealing with with MITC. This is the
15 extent -- this is really the extent of the studies that we
16 have. And so I feel that, given the overtness of the --
17 of the response at 45 ppm, and the admitted marginality of
18 the responses at 10 ppm, that that is good enough to call
19 10 ppm a LOEL dose. Moving on. Okay.
20 DR. FUCALORO: The LOEL -- the NOEL was
21 calculated from the LOEL?
22 DR. RUBIN: Yeah.
23 DR. FUCALORO: By just doing --
24 DR. RUBIN: No, the NOEL is a determined
25 NOEL. In other words, those animals were actually exposed
153
BARNEY, UNGERMANN & ASSOCIATES 888 326-5900
1 at that dose.
2 DR. FUCALORO: And experienced nothing?
3 DR. RUBIN: And experienced no observable
4 effects. So that's our NOEL. And that's the NOEL that
5 we're going to calculate our RELs and our MOEs based on.
6 Chronic toxicity. This is an issue, because it's become
7 apparent to us that there is chronic exposure to MITC.
8 It's not included in this document. The data are
9 currently being crunched through at DPR to give us
10 chronic-exposure data.
11 But with chronic toxicity, we don't have any
12 inhalation experiments. And I understand that probably
13 with -- probably not a very common thing to see
14 chronic-inhalation experimental data. Anyway, but I
15 thought I would flash this slide by just to show you that
16 we do pick up some chronic effects.
17 We determine NOELs of 10 -- 10 ppm in the
18 water, which is equal to 463 mics per kick per day in a
19 rat study. And 0.4 milligram per kilogram per day in a
20 dog study. Dog study was very problematic, because the
21 animals at the beginning of the study were exposed to huge
22 doses of corn oil, and they were getting sick on the corn
23 oil. So it's not a real clear study to begin with.
24 But I want to move on from chronic, because
25 we don't really have a study to base anything on there.
154
BARNEY, UNGERMANN & ASSOCIATES 888 326-5900
1 Is there a question? Okay. The issue of oncogenicity --
2 DR. FUCALORO: Wait. I have a question.
3 DR. RUBIN: Okay.
4 DR. FUCALORO: Previous slide. Study 1 and
5 Study 2 have essentially the same NOELs and LOELs, don't
6 they?
7 DR. RUBIN: Yes.
8 DR. FUCALORO: Did you note that? I'm
9 sorry.
10 DR. RUBIN: Not only do I note that, but
11 it's interesting to note that those NOELs and LOELs are
12 similar to the subchronic inhalation study.
13 DR. FUCALORO: And I would point out there
14 was missing, of course, some signs, vomiting, excessive
15 salivation, liquid feces, at -- and the number's missing.
16 DR. RUBIN: Oh, it -- that's at the LOEL
17 dose.
18 DR. FUCALORO: Is that the LOEL?
19 DR. RUBIN: Yeah. At 2.
20 DR. WITSCHI: Wasn't this on the dog study,
21 the .4 milligram per kilo per day produced some signs of
22 toxicity? That's what it says.
23 DR. RUBIN: Excuse me?
24 DR. WITSCHI: At the .4 milligram kilo dog
25 study. You had --
155
BARNEY, UNGERMANN & ASSOCIATES 888 326-5900
1 DR. RUBIN: Oh, I'm sorry. I have that
2 wrong. That's a mistake. That should be 2.
3 DR. WITSCHI: Oh.
4 DR. RUBIN: That should be 2. It's in the
5 report, sloppily. Okay. Should I move on? Okay.
6 Oncogenicity, MITC does not appear to be oncogenic in any
7 of the three chronic studies where it was looked at. And
8 again, these are oral-exposure studies.
9 However, I want to bring to your attention
10 that in the two-year rat study, the drinking-water study,
11 there was an apparent increase in multiple benign mammary
12 tumors in terminal survivors. Consideration -- and I have
13 a whole slide of this, if we want to go through this, the
14 numbers.
15 Consideration of incidence rates for single
16 benign tumors separately and in combination with the
17 multiple benign tumors, as well as the incidence rates for
18 malignant mammary tumors favors the conclusion that the
19 increase in multiple benign tumors was not
20 treatment-related. It did not achieve statistical
21 significance. And basically, there was nothing else going
22 on in the mammary gland with related tumors, single tumor,
23 in decedents, in terminal survivors.
24 We made a judgment that this was not a
25 treatment-related effect. I want to say in passing,
156
BARNEY, UNGERMANN & ASSOCIATES 888 326-5900
1 however, that I have included in this document a draft of
2 the Metam-Sodium risk assessment, which I wrote. And with
3 Metam-Sodium, you do get clear, frank, oncogenicity, but
4 not in the mammary gland. You get blood-vessel
5 carcinomas -- not carcinomas, sarcomas.
6 And this is something that we should
7 recognize, that the parent compound, but apparently not
8 the daughter compound, is carcinogenic.
9 DR. BLANC: That was in the same species
10 that the -- these studies were negative with?
11 DR. RUBIN: In two species, actually. Rats
12 and mice. This one here, this is a rat study with MITC
13 where you get a small blip in mammary.
14 DR. BLANC: Right. And it was a rat study
15 with the angiosarcoma?
16 DR. RUBIN: Angiosarcoma, rats and mice.
17 DR. BLANC: Well, I think it's going to be a
18 problem, and I think it's going to have to be addressed.
19 Because it doesn't -- on the face of it, if it's a
20 compound which is quickly transformed -- that is to say,
21 Metam-Sodium quickly transformed, in an aqueous
22 environment quickly broken down, it's hard to believe that
23 even in the animal studies where Metam-Sodium was
24 associated with angiosarcoma of the liver, it was actually
25 the parent compound that was causing angiosarcoma of the
157
BARNEY, UNGERMANN & ASSOCIATES 888 326-5900
1 liver.
2 So the two sets of findings are inconsistent
3 with each other, unless it's related to one of the
4 other -- well, no. Even so, it would -- you know, it
5 would have to be carcinogenesis-related to hydrogen
6 sulfide or something. It's hard to understand how the two
7 findings --
8 DR. RUBIN: It is hard. It is very
9 difficult to tease this out.
10 DR. BLANC: And I think it raises a larger
11 point, which I don't think we can get into today. But
12 which is, that structuring the document as a health
13 assessment of methyl isothiocyanate carries with it a
14 certain problem.
15 Which is, that the real issue that we're
16 dealing with is Metam-Sodium, and all of its breakdown
17 products, of which methyl isothiocyanate is a prominent,
18 but not the only one. And whether organizing the entire
19 document -- I don't mean organizing, necessarily. But
20 titling it as a evaluation of methyl isothiocyanate, I'm
21 not sure if that's a help or hindrance.
22 DR. RUBIN: Right.
23 DR. ATKINSON: The Metam-sodium will not get
24 into the atmosphere.
25 DR. BLANC: I understand that. But MIC
158
BARNEY, UNGERMANN & ASSOCIATES 888 326-5900
1 does.
2 DR. ATKINSON: Yeah.
3 DR. BLANC: And the carbon disulfide and the
4 hydrogen sulfide does. And all those are breakdown
5 products. And then if we're dealing with this other
6 product, you also have to think about formaldehyde and --
7 and other breakdown products as well. So I think it's a
8 real challenge. I'm not quite sure I have a solution to
9 it.
10 But I see that there's a real problem in
11 the -- I don't know how you're struggling with it with the
12 health effects. But it seems it must be a nightmare.
13 DR. RUBIN: This is a very sticky one. And
14 it's part of the reason why I decided to include the draft
15 of the Metam-Sodium document, so that it's very clear that
16 we recognize that it's positive for carcinogenicity, the
17 parent compound.
18 It is not at all clear to me why the
19 daughter compound doesn't register as such. There could
20 be -- there could be any number of explanations. It
21 wasn't stable, it broke down in certain ways. And how we
22 are to assess this in the real world where people are
23 exposed to air levels of MITC, but not to Metam perhaps in
24 the air, that's something I'm willing to take the
25 direction of the panel on how to handle that. That's a
159
BARNEY, UNGERMANN & ASSOCIATES 888 326-5900
1 very sticky problem.
2 DR. WITSCHI: I have a question about those
3 tables. You know, I think you really should treat lumps
4 as lumps. And look again at the tumor data. If you just
5 take total number of lumps, regardless of whether they are
6 benign and malignant, the total numbers of animals that
7 were at risk.
8 DR. RUBIN: I think I did that.
9 DR. WITSCHI: Not to -- not this slide.
10 Then when you do this, you find that the guys on the MITC,
11 in all treatment groups, the incidence of tumors higher.
12 Now, whether it would be significant, I don't know.
13 DR. BLANC: No-treatment group -- the
14 no-treatment group is higher.
15 DR. WITSCHI: No, the treatment ones. All
16 three treated groups are higher than the controls.
17 CHAIRMAN FROINES: Where are you reading?
18 DR. WITSCHI: Can you --
19 CHAIRMAN FROINES: We have to stop,
20 actually. Let's do this, and then we have to stop. We
21 have to be out of here at 3:45, and we have to finish the
22 RELs.
23 DR. RUBIN: Okay.
24 CHAIRMAN FROINES: Go ahead, Peter.
25 DR. WITSCHI: I should see the bottom.
160
BARNEY, UNGERMANN & ASSOCIATES 888 326-5900
1 DR. RUBIN: The bottom is the malignant.
2 DR. WITSCHI: Okay. See, if you -- if you
3 add up those and those --
4 DR. RUBIN: Total benign plus total
5 malignant?
6 DR. WITSCHI: Total benign and total
7 malignant in the ones that died before, and the ones that
8 were cured. Then you have 60 at the bottom. You had 60
9 animals at risk. And in every single group, the sum of
10 total tumors is higher than was in the control group.
11 CHAIRMAN FROINES: Thank you very much.
12 DR. RUBIN: That's it?
13 CHAIRMAN FROINES: That's it.
14 DR. RUBIN: Okay.
15 CHAIRMAN FROINES: Sorry we can't
16 accommodate you further, but we had these other items on
17 the agenda before we found out this was going to be on.
18 Let's go, Melanie. Let's go, folks. We've got to be out
19 of here. At 3:45, we're out.
20 DR. MARTY: I think all that we're missing
21 for the comments from the panel on the chronic REL
22 document is comments from Dr. Witschi.
23 DR. FUCALORO: Is he the only -- comments
24 only from --
25 CHAIRMAN FROINES: Okay. Peter.
161
BARNEY, UNGERMANN & ASSOCIATES 888 326-5900
1 DR. WITSCHI: Okay. I -- the first one,
2 chlorinated dibenzo dioxins, and I worked with the panel
3 which reviewed the dioxins assessment of the EPA. And
4 after the EPA had given its presentation, the Chairman
5 asked, "Why does the EPA spend so much effort on dioxin?"
6 And the EPA administrator said, "Well, because we have a
7 large basis of scientific data on dioxin." And in view of
8 those facts, I'm not going to comment on the dioxins. The
9 chloroform, I have a question.
10 CHAIRMAN FROINES: You've finished dioxins?
11 DR. WITSCHI: Oh, yeah. I am not going to
12 touch this with a pole.
13 CHAIRMAN FROINES: Good.
14 DR. WITSCHI: No way. Okay. In page A-41,
15 chloroform; right?
16 DR. COLLINS: Uh-huh.
17 DR. WITSCHI: You have in the second
18 paragraph a human study which showed some effects between
19 10 and 995 milligrams per cubic meter. Now, if you go to
20 the -- the previous page, then you certainly would have an
21 inserted factor for LOAEL of 10, and an interspecies
22 factor of 10. So you would have an uncertainty factor of
23 100. The animal in the species falls out; right? Okay.
24 Then you take the 100 and divide it by 100,
25 and you come up either 10 milligrams per cubic meter, and
162
BARNEY, UNGERMANN & ASSOCIATES 888 326-5900
1 divided by 100. And you wind up with the value which is 3
2 times lower than the one you derived from the animal
3 experiments.
4 DR. MARTY: Correct.
5 DR. WITSCHI: Okay. So --
6 DR. MARTY: Why did we not do that?
7 DR. WITSCHI: Yes.
8 DR. MARTY: As I'm recalling -- and I will
9 go back and look. But the Bomski paper and the Phoon
10 paper, part of the issue is, you can't tell who had the
11 liver toxicity -- that the people that had the liver
12 toxicity, what exactly were their exposures. So it's an
13 exposure-uncertainty issue.
14 But I do agree that that is one thing we
15 should do, is take the bottom end of the range of
16 exposures, make the assumption that that exposure was
17 associated with hepatotoxicity and create a REL.
18 The fact that it's a little -- it's
19 three-fold lower, but that's actually fairly close
20 agreement, given all the uncertainty. But the reason we
21 didn't focus on that was this exposure issue.
22 DR. WITSCHI: Well, it's really the question
23 of, if you have human data that are usable, wouldn't we
24 rather use them? I agree it's trivial difference. It's
25 rather question of -- I don't know.
163
BARNEY, UNGERMANN & ASSOCIATES 888 326-5900
1 CHAIRMAN FROINES: Your call.
2 DR. WITSCHI: I'd go with the human data.
3 DR. COLLINS: I think the other problem we
4 have is that it's jaundice rather than some of the mild
5 effects we deal with. In fact, how do you deal with a
6 seriously adverse effect? We put a hundred false-safety
7 factor instead of a 10?
8 DR. WITSCHI: Oh, I see. No, no. No, we
9 are talking about interspecies difference. There you have
10 to go by the rules. We have -- in people, we don't assume
11 more than 10. Although, might be, in the case jaundice, a
12 larger factor might be appropriate, because of people
13 could have preexisting liver disease or there is
14 interaction with other things. I don't know.
15 DR. BLANC: Well, did they -- how did they
16 define jaundice?
17 DR. COLLINS: I don't know. I really -- I
18 didn't develop -- that's one I have to go back and find.
19 DR. BLANC: You need to find out. Because
20 if they were -- you could make the -- for people to be
21 clinically jaundiced, they have to have bilirubin that is
22 probably more than twice the upper limit of normal. So
23 you could, you know, put in an added factor for that, and
24 assume that -- in other words, if what they were doing was
25 observe jaundice in humans and not measure bilirubin
164
BARNEY, UNGERMANN & ASSOCIATES 888 326-5900
1 abnormalities, you could assume that a level half that
2 amount might cause an elevated bilirubin absent clinical
3 jaundice.
4 DR. MARTY: There was actually a more
5 significant issue. And that is in both studies, the
6 workers had viral hepatitis. So --
7 DR. BLANC: Oh, never mind.
8 DR. WITSCHI: Well --
9 CHAIRMAN FROINES: That kind of takes out
10 the jaundice.
11 DR. MARTY: It wasn't sure if it was the
12 cart before the horse. In one of the studies, the authors
13 thought that chloroform exposure was a predisposing
14 factor.
15 DR. BLANC: To viral hepatitis?
16 DR. MARTY: To viral hepatitis.
17 DR. WITSCHI: See, now considering the fact
18 of how much hepatitis is around these days, you might
19 start thinking we are not even a sensitive population, by
20 the guys who have subclinical hepatitis.
21 DR. BLANC: Well, that's your factor of 10.
22 I think if the studies are that flawed, then you shouldn't
23 use the human studies. But you should have a
24 rationale --
25 DR. COLLINS: See, the other thing with
165
BARNEY, UNGERMANN & ASSOCIATES 888 326-5900
1 Bomski, we have to throw in a factor of 10 for subchronic,
2 was one to four years.
3 DR. MARTY: We could take another look at
4 the Phoon study. I have read that paper. It's been a
5 long time. But I may be mistaken that they initially
6 thought it was viral hepatitis, and then attributed it to
7 chloroform. I'll go back and look at that Phoon study in
8 '83 and see if it's usable.
9 CHAIRMAN FROINES: Why don't you go back,
10 look at it, communicate with Peter, and we'll -- we'll
11 basically -- if the panel agrees, we'll agree with the
12 conclusions that you two come up with. I don't think we
13 need to hold this for some sort of meeting at some point.
14 It's not --
15 DR. FUCALORO: I agree.
16 DR. MARTY: Okay.
17 CHAIRMAN FROINES: When it gets to 3:30,
18 everybody will agree to almost anything. I'm getting a
19 little --
20 DR. FUCALORO: I mean, that was an honest
21 agreement on my part, for the record.
22 DR. WITSCHI: Okay. Next one?
23 Ethylbenzene. I think on page A-61 I would take issue
24 with the term "subacute developmental toxicity study,"
25 because this would imply -- if you say "subacute
166
BARNEY, UNGERMANN & ASSOCIATES 888 326-5900
1 developmental toxicity," this would imply there are acute
2 developmental toxicity or chronic developmental toxicity.
3 This doesn't exist; okay? But that's a trivial point.
4 DR. COLLINS: I thought just cross the word
5 out.
6 DR. WITSCHI: That's a trivial point. My
7 question is -- and I don't know if that's come up before.
8 On page 60, third paragraph from the bottom, you have what
9 looks like a perfectly well-designed study for -- for a
10 subchronic study; right?
11 DR. COLLINS: Weeks, yeah.
12 DR. WITSCHI: Yeah.
13 DR. FUCALORO: Is this Clark?
14 DR. WITSCHI: That's Clark.
15 DR. COLLINS: At least through the
16 comparison, we could do that --
17 DR. WITSCHI: So then, I was wondering
18 when -- then going with the developmental study is the
19 right thing to do.
20 DR. COLLINS: One thing I'd like to say, we
21 are going back and looking at everything. This is an EPA
22 RFC. We're going back and redoing them by our own
23 methodology based on what the panel said. And I think
24 this would be to see whether the developmental study agree
25 well, for instance, doing our analysis on the Clark study,
167
BARNEY, UNGERMANN & ASSOCIATES 888 326-5900
1 do they agree or not. And as one method, to see whether
2 the thing is an outlie or whether it agrees with the other
3 data.
4 DR. MARTY: We also looked at the NTP
5 bioassay. And it -- it has some information, but it's a
6 little hard to interpret. But if you look at that
7 bioassay, and also the subchronic study -- but that was
8 done by NTP prior to the bioassay. The numbers actually
9 are in fairly reasonable agreement with the REL we
10 developed from the developmental text. We can actually
11 insert that information into the text, so it's clear.
12 DR. WITSCHI: Well, yes. Again, I was
13 wondering, because a developmental toxicity studied in
14 rats, kind of a special case. It's a question of
15 principle, again. Whether you go for something which
16 would be your run-of-the-mill toxicity study or whether
17 you are going for this, a rather special case. Because
18 many things which show up in developmental toxicity
19 studies in rats are not really too relevant for a human
20 situation, if I am correct.
21 DR. BLANC: Why would you be correct? Why
22 would that be correct?
23 DR. WITSCHI: Well --
24 DR. BLANC: I think it's more of an example
25 that, by chance, they happen to have a more sophisticated
168
BARNEY, UNGERMANN & ASSOCIATES 888 326-5900
1 study with subtler end points for analysis. Take lead,
2 for instance. Would you -- you know a lot about lead. If
3 I have a developmental study in rats that show the effects
4 of lead, I'd say it's very relevant.
5 DR. WITSCHI: I'd say it depends on what you
6 looked at in rats.
7 DR. BLANC: Their SAT scores.
8 DR. COLLINS: What's the rat population here
9 at the colleges?
10 DR. FUCALORO: You're looking at them.
11 DR. BLANC: I mean, I'm not sure there's a
12 general principle there.
13 CHAIRMAN FROINES: Where are we on this
14 issue?
15 DR. COLLINS: Where on this? That we've
16 based on a developmental study, we'll go back and make
17 some comparison, using some of the other studies and see
18 how well they agree. And then decide whether we have --
19 we can find out -- we have an outlier with the
20 developmental study. Then maybe we are going to have
21 to --
22 DR. WITSCHI: Well, first of all, I would
23 take issue with this developmental studies. Because in
24 the rat study, as described, you have control toxicity.
25 And we now know these days, if you have a maternal
169
BARNEY, UNGERMANN & ASSOCIATES 888 326-5900
1 toxicity, forget about it. That's not relevant. So that
2 was one of the reasons why I questioned why taking the --
3 not looking at the rat study. Because I think that's
4 pretty well-established, maternal toxicity is a no-no with
5 teratology study.
6 DR. MARTY: I think that there's maternal
7 toxicity in the rats, but not the rabbits in that study.
8 We had the same NOAEL. So I think, you know, we always
9 get heart burn about using numbers where you have maternal
10 toxicity, because of that whole issue.
11 But one of the reasons we thought it was
12 okay to use this, is because there was also the decreased
13 live kits in the rabbits that were exposed to the same
14 concentrations. In fact, it was the same study. And it
15 was also the NOAELs is supported by Clark when you do that
16 calculation.
17 So I do agree that there are uncertainties
18 using, first of all, the developmental studies for chronic
19 end points. Although, we have concerns that if you do
20 that in your REL is much lower than any other study that
21 you use, are you protecting against developmental
22 effects. So we have that concern. And that's why we have
23 opted in some cases to use developmental studies.
24 CHAIRMAN FROINES: Yeah. Except I would
25 almost argue -- we've had this discussion before. I would
170
BARNEY, UNGERMANN & ASSOCIATES 888 326-5900
1 almost argue that you should have a category for
2 developmental studies and that -- keep that separate from
3 a classic chronic toxicity. Because it is a case in and
4 of itself, so to speak.
5 We've had that discussion. Because the time
6 frame of the developmental studies is different than what
7 we normally think about. So we're also into the issue of
8 averaging. I should say, by the way, he said something
9 that made me nervous. I don't -- yeah, I don't want to be
10 taking up compounds and taking this panel's time if you
11 are in the process of reviewing those compounds. Because
12 you want to have a state RIR versus a EPA.
13 We should get to it when you get to where
14 you need to go. We shouldn't be -- I really don't want a
15 hundred and twenty compounds coming back to me that you've
16 now got new RELs for and have to redo this whole process.
17 I mean, everybody will quit.
18 DR. MARTY: What we've done is we've -- we
19 are responding to --
20 DR. BLANC: Your request.
21 DR. MARTY: -- to the previous instruction
22 from the panel to go back.
23 CHAIRMAN FROINES: I understand that. But
24 that means that, if we have compounds that we're doing,
25 and you've got at least 80 more compounds to give us;
171
BARNEY, UNGERMANN & ASSOCIATES 888 326-5900
1 right? We've only gotten 40. We've got 80 to go.
2 DR. BLANC: John, John, for these first 40,
3 one of our comments was, we wanted them to go back on
4 certain ones. And that's what they're doing.
5 CHAIRMAN FROINES: I'm not talking
6 about that. I'm simply saying, he said, "We're looking at
7 all the compounds that are EPA documented to develop our
8 own RELs." And I'm simply saying, for the next 80
9 compounds, subtract out the ones that are EPA that you're
10 re-looking at, and don't bring them forward until you're
11 ready.
12 DR. MARTY: Yes, we don't intend to bring
13 them forward until we've done that.
14 DR. WITSCHI: Go on? Okay. Hydrogen
15 sulfide. The only thing I have, Andy Rubin's
16 assay at the end of his presentation of some values, just
17 make sure that they are about the same, you know, between
18 the two agencies. Okay.
19 CHAIRMAN FROINES: Realize, everybody, that
20 the levels of -- never mind.
21 DR. WITSCHI: No, I know.
22 CHAIRMAN FROINES: Of H2 is that of being
23 reported with MITC exceed their realm.
24 DR. MARTY: Exceeds our proposed realm.
25 DR. WITSCHI: Okay. The last one I have is
172
BARNEY, UNGERMANN & ASSOCIATES 888 326-5900
1 methyl chloroform. And if you look through these data,
2 the way I -- they are described, the gerbil is more
3 sensitive as man; right? And then you take the gerbil
4 data and still build in the interspecies factor of 10 in
5 an example where man is definitely less sensitive than the
6 test animal was.
7 You have -- on page A-158, you have some of
8 NOELs for men, 250 ppm, hundred and -- 345 ppm, 350 ppm,
9 almost. And the gerbil is much lower. And yet you
10 introduce the factor of 10. It doesn't make sense, to
11 some extent.
12 DR. MARTY: Well, I think we were concerned
13 about the quality of the data that came out of the human
14 studies, whether they could actually have found a
15 neurological effect. There were also case studies which
16 are not usable in quantitative risk assessment, but that
17 indicated that methyl chloroform is capable of producing
18 neurotoxicity in humans.
19 DR. WITSCHI: I have problems, in view of
20 data, where man seems to be five times more sensitive than
21 the gerbil, to take the gerbil and make man ten times more
22 sensitive.
23 DR. MARTY: Well, I guess the only thing I
24 would argue, I'm not convinced that humans are much less
25 sensitive than gerbils, by looking at the information that
173
BARNEY, UNGERMANN & ASSOCIATES 888 326-5900
1 we have, which isn't very strong. It would take more than
2 that to convince me.
3 DR. WITSCHI: Okay. We have this study on
4 page 158. One, two, third paragraph from top. 250 ppm,
5 no changes, exposed for more than one year, 150 workers.
6 Then --
7 DR. MARTY: That was cardiovascular, Kramer.
8 Am I looking at the right one?
9 DR. COLLINS: Yeah, yeah.
10 DR. WITSCHI: Then one down, we have 22
11 female workers, hundred ten received -- had a ppm 6.7
12 years. Failed to identify neurotoxicity. I mean; okay.
13 What's wrong with those data? At least the way they are
14 presented here, nothing.
15 DR. MARTY: Well, I can go back and look at
16 those studies, but I'm -- I'm certain that the person who
17 wrote this, the reason they didn't want to use Maroni at
18 all, they didn't have a lot of confidence in the study.
19 The fix would be to go back and look at it and also to
20 explain why we're concerned about using that study.
21 DR. WITSCHI: Well, and see -- then the
22 gerbil, you take a neurological end point, astrogliosis,
23 a-s-t-r-o-g-l-i-o-s-i-s, so -- okay. I mean --
24 CHAIRMAN FROINES: It seems to me that
25 the -- Peter's right, that the automatic adoption of
174
BARNEY, UNGERMANN & ASSOCIATES 888 326-5900
1 ten-fold safety factor, irrespective of the data, is
2 something we need to avoid.
3 DR. COLLINS: We had an additional problem
4 here. We couldn't use the EPA's RGDR factor, because
5 there was not enough data on gerbils to do it. Otherwise,
6 this could have been a 3.
7 DR. MARTY: The interspecies --
8 DR. COLLINS: Interspecies factor.
9 DR. MARTY: Would have been a 3 if we'd
10 done --
11 DR. COLLINS: But there's no basis on which
12 to do an OGC calculation on gerbil.
13 DR. MARTY: Another thing we could do is
14 look again at the body of Maroni and other studies. And
15 if it really appears that way, we can use the Rosengren
16 study in gerbils, but don't include the interspecies
17 factor, if that makes sense.
18 DR. WITSCHI: Now, the thing with man being
19 ten times more sensitive than the most sensitive species,
20 that's a notion that goes back to about 1910. But I do
21 not think that it's really true. Actually, I find man is
22 remarkably resistant to quite a few things. So --
23 CHAIRMAN FROINES: I have a question. With
24 this information -- by the way, the senior author on this
25 paper is a fellow named Foa, F-o-a, who's quite a good
175
BARNEY, UNGERMANN & ASSOCIATES 888 326-5900
1 investigator. So it seems to me that this burden to
2 demonstrate why this study isn't appropriate. The second
3 question I had, was --
4 DR. MARTY: Dr. Froines, I don't know where
5 you are.
6 CHAIRMAN FROINES: I'm talking about the
7 Maroni study.
8 DR. MARTY: Okay.
9 CHAIRMAN FROINES: Senior author -- last
10 author is F-o-a, and I know him. Now, the next paper down
11 I'm confused about, because that's the paper that the
12 first author is Mattson. And I may be missing it, but I
13 don't see it in here. Can you help me find it? I'm sure
14 it's me. I don't see it.
15 DR. COLLINS: It's on page A-159, the third
16 paragraph.
17 "No evidence of peripheral neuropathy or
18 other neurotoxicity was detected in rats exposed to
19 200, 620 or 2,000 ppm methyl chloroform six hours
20 per day, five days a week for 13 weeks."
21 CHAIRMAN FROINES: Yeah, I got it. I'm
22 sorry. Now, that's a very good group of investigators.
23 DR. COLLINS: That would have a 2,000 ppm
24 NOEL.
25 DR. WITSCHI: That's actually referenced is
176
BARNEY, UNGERMANN & ASSOCIATES 888 326-5900
1 Spencer -- it's a C, not an S -- in the Mattson reference,
2 I guess.
3 CHAIRMAN FROINES: Peterson.
4 DR. MARTY: Oh, Spencer's name is
5 misspelled. Oh, yeah. Sorry. Well, what we try to do,
6 if you have animal studies that are conflicting, and you
7 have evidence of an effect in one species but not another,
8 we would take the more sensitive species to use in the
9 case of people. Because, you don't know where humans are
10 on the sensitivity scale. So that's, you know, something
11 that we've always done.
12 DR. WITSCHI: Well, that was my point with
13 this particular -- I thought we knew where humans are on
14 the sensitivity scale.
15 DR. MARTY: I guess knowing is a comfort,
16 you know. There's a comfort level there issue. But I'm
17 happy to go back and look at Maroni, and anything else we
18 can find to see if that's the case. And then if it is,
19 what interspecies uncertainty factor, if any, needs to be
20 applied.
21 DR. WITSCHI: Well, that's what I had to
22 say.
23 DR. COLLINS: Thank you.
24 CHAIRMAN FROINES: And you did it with two
25 minutes to spare. You're the first person today to come
177
BARNEY, UNGERMANN & ASSOCIATES 888 326-5900
1 in under the time line.
2 DR. WITSCHI: I'm Swiss.
3 DR. FUCALORO: Well, he sure clocked you.
4 DR. WITSCHI: I believe in running trains on
5 time.
6 CHAIRMAN FROINES: And my watch is two
7 minutes fast, so I think you're five minutes ahead. Can
8 I -- can somebody -- I'd entertain a motion. Shall we
9 adjourn?
10 DR. BLANC: I make the motion that we
11 adjourn.
12 DR. FUCALORO: Second.
13 CHAIRMAN FROINES: All in favor?
14 THE PANEL: Aye.
15 (Thereupon the Scientific Review Panel
16 meeting was adjourned at 3:39 p.m.)
17 * * *
18
19
20
21
22
23
24
25
178
BARNEY, UNGERMANN & ASSOCIATES 888 326-5900
1
2 STATE OF CALIFORNIA
3
4
5 I, Kathleen Knowlton, CSR No. 11595, a
6 Certified Shorthand Reporter in and for the state of
7 California, do hereby certify:
8 That the foregoing proceedings were taken
9 down by me in shorthand at the time and place named
10 therein and were thereafter transcribed under my
11 supervision; that this transcript contains a full, true
12 and correct record of the proceedings which took place at
13 the time and place set forth in the caption hereto.
14
15
16 I further certify that I have no interest
17 in the event of the action.
18
19 EXECUTED this ____ day of __________________, 1999.
20
21
22 ____________________________________
Kathleen Knowlton
23
24
25
179
BARNEY, UNGERMANN & ASSOCIATES 888 326-5900