1 MEETING
2 OF THE
3 SCIENTIFIC REVIEW PANEL ON TOXIC AIR CONTAMINANTS
4 CALIFORNIA AIR RESOURCES BOARD
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6
7
8
9
10 SOUTH SAN FRANCISCO CONFERENCE CENTER
11 255 SOUTH AIRPORT BOULEVARD
12 SOUTH SAN FRANCISCO, CALIFORNIA
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WEDNESDAY, OCTOBER 6, 1999
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9:00 A.M.
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24 Janet H. Nicol
Certified Shorthand Reporter
25 License Number 9764
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1 APPEARANCES
MEMBERS PRESENT:
2
Dr. John Froines, Chairman
3 Dr. Paul D. Blanc
Dr. Craig Byus
4 Dr. Gary Friedman
Dr. Anthony Fucaloro
5 Dr. Stanton Glantz
Dr. Peter S. Kennedy
6
7 REPRESENTING THE CALIFORNIA AIR RESOURCES BOARD:
8 Mr. Bill Lockett
Mr. Peter Mathews
9
10 REPRESENTING THE OFFICE OF ENVIRONMENTAL HEALTH HAZARD
ASSESSMENT:
11
Dr. George Alexeeff, Deputy Director for Scientific Affairs
12 Dr. James Collins, Staff Toxicologist
Dr. Melanie Marty, Supervising Toxicologist
13 Dr. Andy Salmon
Dr. Martha Sandy
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1 INDEX
2 PAGE
AGENDA ITEMS:
3
1 Continuation of consideration of draft report: 3
4 AIR TOXICS HOT SPOTS PROGRAM RISK ASSESSMENT
GUIDELINES, PART III TECHNICAL SUPPORT DOCUMENT
5 FOR DETERMINATION OF NONCANCER CHRONIC REFERENCE
EXPOSURE LEVELS
6
2 Review of health values for the air exposure 106
7 pathway for methyl tertiary butyl ether (MTBE)
8 3 Further Panel deliberations regarding the ---
Panel's September 1999 "Pesticides in the Air
9 Workshop"
10 Adjournment 150
11 Certificate of Reporter 151
12
13
14
15
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1 P R O C E E D I N G S
2 CHAIRMAN FROINES: Let's go on the record and
3 start the meeting.
4 Good morning, everybody. The meeting is now
5 official.
6 And the question I'm raising with the individual
7 panel members is they have all seen the modified findings,
8 SRP findings for methyl parathion. I'm just asking if there
9 were any other comments that we need to discuss, because
10 we'd like to finalize the document.
11 And unless I hear something else, I'll assume
12 we're okay.
13 DR. KENNEDY: I had some probably minor and fairly
14 insignificant concerns in terms of the overall piece. And
15 such issues as particularly in the area of biologic effects
16 there are discussions of depression of red cells, hemoglobin
17 and hematocrit. Those are obviously all the same thing.
18 CHAIRMAN FROINES: Peter, I think -- Bill, this is
19 not on the agenda, so it means we can't have a discussion?
20 It is not on the agenda, so we can't have a discussion. So
21 we'll have to resolve this separately.
22 MR. LOCKETT: Where it was last left at the last
23 meeting was that the panel was going to be given the
24 strikeout changes so they could review to determine that,
25 yes, the changes are within the ambit of the discussion of
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1 what the panel decided.
2 So my understanding from Craig's comments earlier
3 is that's the case in terms of the changes that were made as
4 lead person.
5 And we've gotten Peter Kennedy's comments, but
6 we've not reviewed them from that standpoint.
7 DR. BLANC: I think the easy way to resolve this,
8 as long as there's no substantive issue that is an important
9 omission or something which is internally contradictory, we
10 should just let it stand even if there are areas which, you
11 know, could be further honed, such as your comment about
12 redundancy.
13 So I'd probably just let it pass.
14 DR. KENNEDY: That's how I prefaced my remarks.
15 I have no concerns over the major revisions. I
16 have no concerns over the main points. These are minor
17 issues that I think we can deal with --
18 DR. BLANC: Prospectively, let's say, and the next
19 time we have one of these, we should just be cautious that
20 we are not overly redundant.
21 CHAIRMAN FROINES: If there are minor issues we
22 can just make them. If they are relatively minor issues
23 like redundancies, we can make the changes and not
24 necessarily go back to the panel again. Because
25 theoretically what we should be only talking about here is
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1 the cross-outs, because that's where the questions were from
2 the last meeting. We shouldn't be raising new issues.
3 DR. KENNEDY: That's fine.
4 CHAIRMAN FROINES: So we're okay.
5 DR. GLANTZ: So I think just to be clear, so we've
6 now finished with it?
7 CHAIRMAN FROINES: Yes.
8 DR. GLANTZ: Subject to any little minor editorial
9 adjustments that the chair makes.
10 CHAIRMAN FROINES: Yes. And we've already taken a
11 vote, so it's -- and we'll work out the final things with
12 Peter.
13 Peter Mathews, I don't have an agenda. Do you
14 have an agenda I can have?
15 I think basically the first, unless I'm mistaken,
16 the first item on the agenda -- that's September 16th -- is
17 the continuation of the discussion on the RELs.
18 And unless I'm really mistaken, I don't think Paul
19 Blanc is finished.
20 DR. BLANC: No. But you may have to remind me
21 which ones we discussed and which ones we didn't. I
22 remember doing formaldehyde.
23 DR. COLLINS: And hydrogen chloride and chlorine.
24 DR. BLANC: And chlorine.
25 DR. FUCALORO: Ammonia, dioxane, hydrogen cyanide.
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1 DR. MARTY: Dr. Froines, we had also put together
2 some information.
3 CHAIRMAN FROINES: Oh, that's right, Melanie. I'm
4 sorry, I'm preempting you.
5 Why don't we go ahead with what you were going to
6 provide the panel and then we'll go back to Paul and in the
7 meantime he can figure out which ones he didn't do.
8 DR. MARTY: Okay.
9 CHAIRMAN FROINES: The people who we have yet to
10 cover, though, today are Paul, Peter Kennedy, Stan Glantz
11 and myself.
12 DR. MARTY: I'm Melanie Marty from Office of
13 Environmental Health Hazard Assessment, and I have Jim
14 Collins on my left.
15 And Dr. Witschi and Dr. Glantz at the last meeting
16 suggested that we take a look at the reference exposure
17 levels that were based on human studies and see what the
18 reference exposure levels for those chemicals would be if we
19 based it on an animal study that we had some amount of
20 confidence in.
21 So we have done that. I have I think it's about
22 12 examples.
23 DR. GLANTZ: 13.
24 DR. MARTY: 13, thank you. 13 examples of that.
25 I think I need to preface it by saying that we are
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1 not suggesting that we would use that animal study. It's
2 more of this is what happens when you use the animal study
3 for those chemicals.
4 So this -- you should all have a handout so you
5 don't have to strain your eyeballs looking at the overheads.
6 So, Peter, did they get those handouts?
7 MR. MATHEWS: Yes.
8 DR. KENNEDY: Yes, twice.
9 DR. MARTY: We did fax a preliminary version of
10 these tables to the panel members and there have been
11 changes made, so it's best to follow the handout that we
12 have today.
13 CHAIRMAN FROINES: I just want to make one
14 comment. In my REL here for methylene chloride, you have
15 the REL as 300, and up there it's 400.
16 DR. MARTY: Interesting.
17 CHAIRMAN FROINES: What's in this document is 300.
18 But go ahead.
19 DR. MARTY: It was probably a rounding error.
20 Okay. As you can see by just perusing this table,
21 some of the numbers come in pretty close to each other.
22 Most of them are within a factor of three, but there are
23 some that are bigger than that.
24 Next slide, Andy.
25 CHAIRMAN FROINES: Before you go on, there are, I
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1 counted four where there are quite substantial differences.
2 DR. MARTY: Yes.
3 CHAIRMAN FROINES: And I don't know if I said this
4 last time, but I'm still concerned that what happens is we
5 tend to pick a value from a particular study and in some
6 ways I still think it would be useful to look at the values
7 you would get from a series of studies and then make a
8 judgment about what makes the most sense, rather than simply
9 picking the most conservative value.
10 In other words, I think that the scientific
11 justification for the number that -- I mean, I think that,
12 yes, we should proceed in a public health protective
13 fashion, but I think we should also look at all the studies
14 and decide what makes the most sense as we proceed as well.
15 Where is the consistent finding relative to the lowest
16 finding.
17 DR. GLANTZ: Go ahead.
18 DR. MARTY: I would say that at the staff level we
19 did try to do that, so we did look at the studies that we
20 thought were useful. In many cases there really aren't that
21 many chronic studies by the inhalation route. That's part
22 of the problem.
23 And we did look at the numbers that we would get
24 using several different studies or however many studies
25 there were that were available. And, you know, we had
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1 discussions among ourselves as to what the major
2 uncertainties were.
3 I think that part of the difficulty for the panel
4 in reviewing this document is all that thinking isn't
5 written into the document so it's very hard for you guys to
6 tell what we have looked at and what we haven't looked at.
7 So but I agree that if the numbers are really
8 wacky relative to the rest of the information you have on
9 that chemical, then there's a lot more uncertainty in using
10 that number.
11 So there may be cases where we probably should not
12 have developed a REL and we did. I think that's certainly
13 an issue for discussion.
14 DR. GLANTZ: Although, when I looked this stuff
15 over a couple days ago when you sent it, I was actually
16 impressed at how close the agreement was, given all these
17 problems. And I think 10 of the 13 they were within one
18 order of magnitude, which given the uncertainties that are
19 implicit in the process, especially if you're dealing with
20 animal data, is I thought quite remarkable.
21 So there are three or four where there were big
22 differences, but for the most part the thing that impressed
23 me was how close they were.
24 This actually increased -- actually I was
25 expecting either a completely random results or a situation
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1 where there were huge differences.
2 But I think, you know, when one recognizes that
3 this risk assessment process is not something you can do to
4 17 significant digits, this is quite reassuring to me about
5 the process that we've been using.
6 Not always, but 10 out of 13 were pretty good.
7 And they're actually, in this -- I walked off this morning
8 and left all my stuff at home, but I actually plotted this
9 stuff. If you do a log-log plot of these, they're pretty
10 well correlated.
11 DR. BLANC: Stan, you better be careful. Someone
12 might think you're an absent-minded professor.
13 DR. GLANTZ: No. I'm just a space-out.
14 CHAIRMAN FROINES: What makes me more worried
15 about it is if you walked out without, are you going to be
16 able to do your chemicals?
17 DR. GLANTZ: I'm going to try. But Blanc is here.
18 I talked to him on the phone about all this and anything I
19 don't know he knows.
20 But, I mean, I just think that that to me was -- I
21 thought this was a useful exercise actually.
22 DR. COLLINS: And we did pick the study we thought
23 was the best animal study we knew of, rather than what would
24 give us the closest.
25 DR. MARTY: I should also add, for this table that
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1 we just have where the human study was from an EPA RfC, that
2 is what is represented in this table. In a couple of cases,
3 we would have done a little bit differently with the same
4 study, and I'll show you that as we go through the
5 chemicals.
6 CHAIRMAN FROINES: I think it's important that I
7 believe that, because I do experiments, that there are
8 people do experiments very differently and there can be
9 wildly different outcomes.
10 And so I think in terms of protecting everyone's
11 interests, pursuing the most consistent pattern of findings
12 really makes the most sense, rather than picking studies
13 that are outliers, because they're conservative in public
14 health finding.
15 So that it's just something that I think we need
16 to be -- we need to try and do anything that increases our
17 confidence in the findings, and so that as well as having
18 public health protection as a key watchword. But anyway.
19 DR. COLLINS: At least one example we did that.
20 It's not in this cite. With creosols, we had a study from
21 the Russian literature which had very very low levels of
22 facts, and they just seemed to be such outliers that we
23 abandoned that and used another study. So that has entered
24 into the thinking, at least in some of them.
25 CHAIRMAN FROINES: I just wanted to make one other
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1 comment, because you had mentioned EPA RfCs.
2 Two or three or four years ago, you lose track
3 with all this, that when we were in the more controversial
4 phase of this panel's existence, when there was different
5 leadership at OEHHA, there was a significant press to have
6 our values be similar to those, if not identical, to the EPA
7 values. And this panel has always taken the position that,
8 yes, it would be good to -- what's the term that --
9 DR. COLLINS: Harmonize.
10 CHAIRMAN FROINES: Harmonize. That we harmonize
11 our risk assessment values with EPA.
12 This panel has always taken the position that
13 harmonization is a good idea, but only if it makes
14 scientific, good scientific sense, and it is a matter of
15 good judgment. It is not an ironclad rule. And I think I
16 just want to say that for the record.
17 And unless there's somebody in here that
18 disagrees, please disagree now, because I want to make sure
19 that this panel is on record saying that harmonization is
20 good, but it's the quality of the science that we're
21 interested in, not harmonization as the endpoint.
22 Go ahead.
23 DR. MARTY: Next slide, Andy.
24 The first example is ammonia, which I think is one
25 of Dr. Blanc's chemicals.
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1 We had a human-derived reference exposure level of
2 100 micrograms per cubic meter.
3 When we took the best study that we had on hand,
4 in guinea pigs the reference exposure level ends up being
5 ten.
6 The human study has a slightly different endpoint.
7 We're looking at pulmonary function as opposed to pathology,
8 pulmonary edema in the guinea pig.
9 And the duration of exposure was only six weeks in
10 the animal studies, so we have a subchronic uncertainty
11 factor there right away.
12 Also the human study, we identified a NOAEL from
13 that study.
14 Now, the US EPA when they evaluated this also
15 talked about a rat study, which they got a LOAEL from. It's
16 a different endpoint, but what they wanted to say was just
17 what Dr. Froines was just talking about is within the
18 confines of the data that you have available that 9.2 NOAEL
19 doesn't look too bad with respect to LOAEL from an animal
20 study. And that's the Broderson et al in the LOAEL row.
21 Of course the endpoint was an exacerbation of
22 effects of a microplasm infection, so it's not quite the
23 same as looking at pulmonary function or eye, skin or
24 respiratory irritation.
25 At any rate, I think use of the animal study is a
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1 little complicated, the Anderson study, because of the LOAEL
2 uncertainty factor. You also have to have an interspecies
3 uncertainty factor. And we have a subchronic uncertainty
4 factor, so you end up with a rather large cumulative
5 uncertainty factor of 3,000, versus 30 if you use the
6 Holness et al '88 human study. '89, I'm sorry.
7 So that's one example of the kind of stuff we're
8 faced with for ammonia.
9 And we were somewhat surprised that there's a lot
10 of acute studies on ammonia because it's an irritant, but
11 there really is not very much information on chronic
12 exposures, so that in and of itself is a problem.
13 We can do the next example if there's no
14 questions.
15 DR. BLANC: I think I'm not going to make my
16 comments now, I'll wait. I think we'll just confuse things.
17 DR. MARTY: Okay.
18 DR. BLANC: Only make comments as they relate to
19 the specific task at hand.
20 DR. MARTY: Okay. Benzene, here's another example
21 where OEHHA used a study of male refinery workers where they
22 had a diverse exposure duration, one to 21 years, with an
23 average of 7.4, and a third of those were more than ten-year
24 exposures.
25 In the study they did not observe any effects.
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1 They actually looked at a lot of different things, but in
2 particular we were interested in the hemotological effects,
3 which are noted for benzene exposure.
4 So they came up with basically a freestanding no
5 observed effect level of a half a ppm, which when we account
6 for exposure continuity and use an intraspecies uncertainty
7 factor of 10, we end up with 20 parts per billion basically
8 as our reference exposure level.
9 DR. BLANC: What's interesting here I think is you
10 have a fairly recent animal exposure study, whereas in the
11 previous ammonia example, it was a very old animal study.
12 And I think that one of the things that is worth
13 taking into account, perhaps in an introductory section to
14 the whole document, which would state why you weighted
15 things that were taken into account and study quality.
16 And one would be the time frame of the study, that
17 if there were two studies where they were both animal
18 studies, but one was more recent, and would therefore have,
19 you know, more currently accepted standards, that you would
20 tend to weight that more heavily.
21 But a question with something like this, since
22 basically you're looking at hematologic effects that are
23 probably not unrelated to benzene's oncologic effect, even
24 though this document is noncancer outcomes, it surprises me
25 that there wouldn't have been, for example, an animal study
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1 of longer duration which was primarily a carcinogenesis
2 study which nonetheless reported noncarcinogenic hematologic
3 outcomes. So it surprises me that all you have for an
4 animal study is an eight-week study. I mean, I know that
5 there are a lot of multi-month and even primate studies of
6 benzene.
7 DR. MARTY: Yeah, there are.
8 I think we used this, because they were looking
9 specifically at hematological effects, but that's a good
10 point. We could go back and look at some of the other
11 chronic studies that were oncogenicity studies and see what
12 else they looked at and what they measured. I think that's
13 a good point.
14 One of the problems is we had to use the
15 subchronic uncertainty factor of ten.
16 DR. BLANC: Right. Because it seems to me that
17 those data are probably in those studies. I would be very
18 surprised if somebody didn't -- somebody reported out on a
19 leukemia study and particularly in primates and didn't talk
20 about other hematologic effects.
21 Peter, this wasn't your chemical, was it?
22 DR. KENNEDY: No.
23 In man, of course, the exposure is acute in terms
24 of the induction of marrow aplasia malignancy. It's not a
25 chronic phenomenon.
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1 DR. BLANC: It depends on how you define chronic,
2 but I mean people have been exposed for months and years.
3 It's a relatively short latency in the big scheme of
4 carcinogenesis.
5 CHAIRMAN FROINES: But Paul's point is
6 particularly interesting, because in looking at your
7 references there are no references to chronic ano bioassays,
8 and we know benzene was the first chemical this committee
9 ever took up in 1984, and at that point we had a Maltoni
10 study, and I don't know if MTB has done one since, but if
11 MTB had done one, there clearly would have been -- I can't
12 say the word.
13 DR. BLANC: Hematologic.
14 CHAIRMAN FROINES: Whatever. So that there's no
15 reference to any chronic studies in this document.
16 DR. BLANC: Well, the other thing, the reason I
17 think it's particularly critical in something like benzene,
18 which is an air pollutant, people are likely to encounter,
19 there could be a lot of public health implications
20 between -- in the difference between 20 parts per billion
21 and six parts per billion, might really be important from a
22 public health action point of view. I mean, it might drive
23 different approaches. I don't know.
24 CHAIRMAN FROINES: What's the 10 to the minus
25 fifth dose?
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1 DR. COLLINS: For benzene? Seven micrograms per
2 day. That's the NSRL under Prop 65.
3 CHAIRMAN FROINES: How did that -- we need you to
4 translate that for us.
5 DR. MARTY: 3.35 cubic meters per day if you did
6 it gross --
7 DR. COLLINS: .35 micrograms per cubic meter.
8 DR. MARTY: So we're at 16 and 20.
9 I think that background levels and urban levels
10 have dropped from about four ppb to around one ppb now.
11 So but I think we do -- I do want to back up and
12 say that for this comparison we did this in a pretty quick
13 time frame, but I think that's a good point, though, is I
14 know there's chronic studies. Everybody has looked at the
15 carcinogenicity and so forth, so we should dig one up and
16 see what it looks like compared to the Tsai et al male
17 refinery worker study.
18 You know, it's the age-old problem with an epi
19 study in general that exposure is always an issue,
20 quantifying that exposure is not an easy thing.
21 Okay. Another example we have, which has all
22 sorts of different problems, is ethylene glycol. And you'll
23 recall that we used in the document a human study on
24 volunteers who were exposed, and respiratory tract
25 irritation was one of the endpoints that they looked at.
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1 We have a subchronic uncertainty factor because
2 the exposure was only for 30 days.
3 And the total cumulative uncertainty factor is 100
4 and it includes intraspecies uncertainty factor also.
5 We discussed at the last meeting whether or not
6 respiratory tract irritation was actually a good endpoint
7 for a chronic study, particularly if it's a sensory irritant
8 effect. So that's an issue right there.
9 When we look at Tyl et al 1995, it's a whole body
10 inhalation study in mice and they were looking at
11 reproductive and developmental effects. So they defined a
12 NOAEL in the study based primarily on fetotoxicity.
13 We have an interspecies uncertainty factor of
14 three, because there was an HEC estimate, a human equivalent
15 concentration estimate.
16 And then we have the intraspecies uncertainty
17 factor of ten, for a total uncertainty factor of 30. So
18 right there you can see a difference of the uncertainty
19 factors are different, human versus animal study. And the
20 results are two and a half fold different, 400 micrograms
21 per cubic meter versus a thousand.
22 If we didn't use the subchronic uncertainty factor
23 with the respiratory irritation endpoint, then our number
24 would be 800 micrograms or so -- did I get that right? Even
25 more than that. There's another issue there with whether or
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1 not we need that subchronic uncertainty facto that was used
2 with the human study.
3 We talked about formaldehyde last time. We had
4 based the reference exposure level on a couple of human
5 studies.
6 DR. BLANC: It's really one human study.
7 DR. MARTY: It's really one. The other one is in
8 there because it's I guess it's somewhat supportive of it.
9 DR. BLANC: It's the same study, they just
10 analyzed a different endpoint. You need to be clear about
11 that.
12 DR. MARTY: Okay.
13 DR. BLANC: From what I can tell. I didn't pull
14 the papers, but it's the same study and it's just a
15 different --
16 DR. MARTY: Different order of authors.
17 This was the study where they had a group of
18 office workers as the control group, quote, control group,
19 and, of course everybody is exposed to some formaldehyde, so
20 they made measurements in the office and then they had a
21 groups of workers that were exposed to either formaldehyde
22 alone or formaldehyde-pressed wood desks.
23 And they did a series of measurements looking at
24 nasal and eye irritation, nasal obstruction, and also some
25 lower airway symptoms.
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1 So we ended up with an inhalation reference level
2 of three micrograms per cubic meter with a cumulative
3 uncertainty factor of ten for intraspecies variability in
4 humans, with the human study.
5 Then with the animal study that we used to make a
6 comparison it was a monkey study, and they actually looked
7 at squamous metaplasia in the nasal turbinates. They had a
8 no observed effect level of one ppm. It's a subchronic
9 study, so we have a subchronic uncertainty factor of ten.
10 We have interspecies uncertainty factor of ten and an
11 intraspecies uncertainty factor of a ten, for a total
12 uncertainty factor of a thousand. And that ends up giving
13 you a reference exposure level of ten micrograms per cubic
14 meter.
15 So the uncertainties are actually different. The
16 issues are different. We have good exposure measurements in
17 the monkey study, whereas you may not have such good
18 exposure measurements in the human study, but the
19 uncertainties are shorter duration of exposure interspecies,
20 any potential interspecies differences. Those are the key
21 issues there.
22 DR. BLANC: Can I ask a couple questions just to
23 again it would be related to global approaches.
24 The interspecies uncertainty factor, primate
25 studies don't get a break on that?
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1 DR. MARTY: Well --
2 DR. BLANC: It seems to me just from a biological
3 point of view that using an interspecies factor of ten for
4 primate studies and ten for rat studies is not the way, you
5 know, most -- well, I don't know. Just from a biological
6 point of view, it doesn't seem --
7 DR. MARTY: Yes, I would agree with that. It is
8 not really taken into account in the general methods by
9 either EPA or by us.
10 DR. BLANC: I know that we don't have the luxury
11 of very many primate studies, but it seems to me that if we
12 are going to use primate studies, maybe there should be a
13 decision, at least for this document, given the great
14 difficulties in these particular evaluations. This
15 particular set of evaluations seemed to be much more problem
16 ridden than either the acute or the cancer effects. And
17 maybe we should have some approaches that take into account
18 the limitations of data overall, and one of those, I think,
19 should be -- I'm curious to hear -- or more animal testing
20 oriented.
21 CHAIRMAN FROINES: Yeah. If it were -- I'm not a
22 wild enthusiast for primate studies, period, but leaving the
23 ethical issue aside, it would seem that I wouldn't use more
24 than a factor of three.
25 DR. BLANC: Which is what you use when you have
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1 human equivalencies, so it would be consistent.
2 DR. MARTY: You can do that.
3 DR. BLANC: You could assume that you have gotten
4 the --
5 DR. MARTY: Okay.
6 DR. BLANC: The other thing that I think this
7 side-by-side comparison underscores and comes back to your
8 allusion to the issue of respiratory nasal irritant symptoms
9 as compared to either a condition, such as chronic
10 bronchitis or asthma or a pathologic finding or a finding
11 such as airway nonspecific hyperresponsiveness or something
12 that one would assume was a more integrated measure of a
13 chronic effect rather than simply a repeated acute effect or
14 subacute effect, and that is that I think there needs to be
15 some weighting given to a pathologic finding such as
16 squamous metaplasia as opposed to an indeterminate issue
17 such as nasal and eye irritation.
18 As you remember from our discussion last time, I
19 did point out that there was another paper from the same
20 group where they did do, apparently, based on the title,
21 some kind of nasal biopsy or something. Did you pull that?
22 DR. MARTY: We didn't pull that paper yet, but,
23 yeah, that's an important paper to look at.
24 The other thing is I'm a little squeamish about
25 using metaplasia. It's a little worse than hyperplasia, so
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1 that's, to me, an issue also with at least using this
2 particular monkey study.
3 DR. BLANC: Although it's only 26 weeks, so.
4 DR. MARTY: Yeah. I know -- I don't know how
5 readily reversible metaplasia would be in these animals.
6 DR. FRIEDMAN: Isn't something like nasal and eye
7 irritation an acute effect, an effect of acute exposure,
8 rather than an effect of chronic exposure?
9 DR. MARTY: It is, but if you're exposed every
10 day, I mean, you know, have to -- you wouldn't want somebody
11 to be chronically exposed to a concentration that would
12 produce nasal and eye irritation, so that's why we consider
13 using those for chronic endpoints. But it is an issue.
14 CHAIRMAN FROINES: Does formaldehyde increase IGE?
15 Is it an adjuvant for asthma?
16 DR. BLANC: The whole literature on formaldehyde
17 and true allergic responses is very very murky. There are a
18 handful of case reports of formaldehyde-related asthma, and
19 it's really very murky. It's a low molecular weight
20 substance, so nobody is clear if it's acting as a half tone,
21 or something else is going on that it's a non IGE-effect or
22 as you were asking whether or not it's somehow increased the
23 risk of sensitization to ambient air or allergens or
24 something. It's a very murky literature.
25 But again as I said last time, so I'm not going to
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1 be making comments on the formaldehyde when you get back to
2 me, but I don't think that the formaldehyde thing can stand
3 as it was written.
4 DR. MARTY: Okay.
5 DR. BLANC: Otherwise we'd be telling the public
6 health policy makers that they'd have to evacuate this room
7 because of the REL has been exceeded for chronic health
8 effects. It just doesn't make sense.
9 DR. MARTY: Okay. Then we have another example
10 with one of Dr. Froines' chemicals, hexane.
11 CHAIRMAN FROINES: Why don't we just -- I thought
12 you agreed that this one, you agreed with my criticisms, and
13 so it was my assumption you were going to go back and redo
14 it. Remember, I mentioned that. You quickly said, yes, we
15 agree. And we -- so I didn't go through my criticisms
16 because you so quickly agreed.
17 DR. MARTY: Okay.
18 CHAIRMAN FROINES: It doesn't seem to make sense
19 to use something that last time you said you agreed with my
20 criticisms and then go through and show how a flawed study
21 compares to an animal study.
22 DR. MARTY: Well, the use of this is that there's
23 a flawed human study and a flawed animal study, and that's
24 basically what we have to work with, so that's why I thought
25 I would throw that up there, and also, you know, I think I
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1 was agreeing that I'm a little nervous just accepting US EPA
2 RfCs on face value or even after we've looked at it, and we
3 actually would have done something different with Sanagi et
4 al, so I had that up there.
5 Also there's a couple of issues that came up in
6 your comments last time, I believe you were concerned about
7 that in occupational settings there's also frequently dermal
8 exposure and these authors specifically said that these
9 folks were not exposed dermally so it was an inhalation
10 exposure.
11 And I think the bigger issue was the concurrent
12 exposures with acetone and potential potentiation. We need
13 to look at that a little further. I know that other C6
14 ketones that can also be metabolized to the hexanedione
15 would certainly potentiate the hexane exposure, because
16 there the ultimate toxicant is the same in their metabolism.
17 Acetone, I'm not familiar with in terms of the
18 interaction with hexane. It may be that it's another
19 mechanism by which it's potentiating.
20 So I did want to look at that a little more.
21 CHAIRMAN FROINES: We've got a paper that we are
22 publishing in Environmental Health Perspectives in which we
23 have done toxicokinetic modeling on 2,5-hexadiene's
24 potentiation of ketones, and it's in fact the acetone is
25 metabolized to the di-ketone and it's in the -- it's in the
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1 detoxification phase of the toxicokinetics where the
2 interaction occurs, so that I think that I'll send you the
3 paper and you can read it.
4 But I feel pretty strongly that where you have
5 exposure to these ketones where you can get toxicokinetic
6 interaction either in the formation of 2,5-hexadiene or in
7 the detoxification of it, that you just don't want to use
8 those studies because you really can't -- you have no
9 measure of the magnitude of the interactions, so you're not
10 really necessarily measuring the pure effect, you're
11 measuring -- it's a potentiation, so you're measuring -- so
12 it's your dose estimate is not accurate.
13 DR. MARTY: Right. Okay.
14 We did look at Miyagaki 1967. The study itself is
15 in Japanese with an English summary, so we need to find
16 somebody who speaks Japanese to make sure that the English
17 summary is really reflective of what's in the paper.
18 And also we need to search a little more to find
19 more animal studies for this.
20 The end result is that from the animal study you
21 have quite a bit higher REL than from that human study, and
22 that could actually reflect the potentiation that the
23 workers were experiencing by having concurrent exposures.
24 It did -- a couple issues came to my mind that the
25 Miyagaki study used commercial grade, which is only about 68
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1 percent n-hexane, from what I can gather, just looking at
2 other sources. The rest of it is branch chain hexanes,
3 which don't get metabolized to the hexanedione, so that may
4 not be an issue for this study.
5 It was a one-year study in mice, so we did not
6 apply a subchronic uncertainty factor, because we felt for
7 mice that that was sufficiently chronic.
8 We did a HEC calculation so we only have an
9 interspecies uncertainty factor of three, and a total
10 cumulative uncertainty factor of 30.
11 If we had used Sanagi ourselves and we wouldn't
12 have used EPA's modifying factor, which we can't ever really
13 figure out what they're using it for and they're not
14 consistent, so we would have actually had a slightly higher
15 number. It would have been 700 versus 7,000.
16 But we are going back and looking for more
17 information on hexane.
18 DR. BLANC: Here's another generic question for
19 you. You have a lot of rounding that you do in this
20 document and I'm not sure where the rounding -- what stage
21 the rounding happens, since it's really a cumulative
22 uncertainty of 90 and not a hundred.
23 DR. MARTY: You know what, that's because the
24 rounding actually, three represents really 3.16 rather than
25 three, so when we put that -- whenever it's three, it's
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1 really 3.16.
2 DR. BLANC: For which one?
3 DR. MARTY: For the intermediate, the quote,
4 intermediate uncertainty factors.
5 DR. BLANC: For both of them? For both the LOAEL
6 uncertainty factor and the subchronic uncertainty factor,
7 for both of them it's 3.16?
8 DR. MARTY: Right.
9 DR. FUCALORO: Remind me for a minute why it's
10 3.16.
11 DR. FRIEDMAN: Square root of ten.
12 DR. FUCALORO: Square root of ten.
13 DR. MARTY: Right.
14 DR. BLANC: Can you tell me why you would put a
15 subchronic uncertainty factor for a human exposure duration
16 of six years? I understand it's a part of -- it's because
17 it has to be more than 20 years for you not to put in the
18 factors.
19 DR. MARTY: It has to be more than 12 percent of
20 the lifetime, so 12 percent of 70, so if it's greater than
21 eight years, we don't use a subchronic uncertainty factor.
22 If it's between five and eight years, we use a subchronic
23 uncertainty factor of three and if it's less than five
24 years, we use a subchronic uncertainty factor of ten.
25 So that's why we would have applied a subchronic
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1 uncertainty factor in that case.
2 Actually, when you go back and read US EPA RfC,
3 they say we have applied an uncertainty factor of ten for
4 use of a LOAEL and for less than chronic. So they actually
5 don't spell it out, but they're doing three and three also
6 in that case.
7 I guess one of the reasons we do a lot of rounding
8 too is Stan's point earlier that there's so much uncertainty
9 it's kind of useless to have two or three or four or five
10 significant figures.
11 CHAIRMAN FROINES: We have done a review of all
12 the hexane literature, which we'll send you.
13 DR. MARTY: Okay. That's great.
14 DR. BLANC: I mean, hexane is a good example of a
15 chemical for which you really wouldn't want this kind of
16 analysis for, because really with hexane what you really
17 care about is a noncancer chronic exposure effect. So it
18 certainly is an example for which something this exercise
19 makes sense, wouldn't you say?
20 CHAIRMAN FROINES: Yeah.
21 I was going to ask you, I wonder if ARB knows
22 anything about the ambient hexane levels, since we have a
23 lot of -- down where I live we have a lot of petroleum
24 refining, and so there's a lot of hexane in the air from
25 gasoline, and we have a lot of automobiles too that are
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1 going to release it.
2 DR. BLANC: There's a lot of over-the-counter
3 rubber cement for which this is still the solvent.
4 DR. MARTY: Yeah. We can find that out, I'm
5 pretty sure.
6 DR. SALMON: The study that we are involved in
7 about in terms of the fuels projects, their predictive model
8 and atmosphere model, we're coming up with hexane levels
9 which were something between one and two orders of magnitude
10 below the proposed chronic REL for the South Coast air
11 basin.
12 DR. MARTY: Thanks, Andy. I had forgotten about
13 that. That's the ARB's project on --
14 DR. SALMON: So it varies quite a bit according to
15 the scenario, but basically it's what we learned.
16 DR. MARTY: It's interesting too that Miyagaki in
17 the hexane makes the statement in his summary that mice are
18 much less sensitive to the neurotoxic effects than humans
19 and I want to know if it's because he's looking at Sanagi,
20 which has the potentiation problem or not. So that makes me
21 want to look more.
22 CHAIRMAN FROINES: One of the most difficult
23 things about -- hexane is a very good example of one of the
24 problems we have insofar as you get people who do
25 essentially short-term animal studies at high dose and we
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1 really have very little information on chronic low dose for
2 neurotoxicity of this kind. And it's because toxicologists
3 do what's easiest, you know. They give a dose to the animal
4 over a period of couple weeks and they watch and see what
5 happens.
6 And even here you have a year, but for the most
7 part it's just not the way people do these studies. So that
8 the issue of the chronic low dose effects is still, from a
9 standpoint of neurotoxicity, it still seems to me to be a
10 problematic area.
11 It's pretty clear we have a lot of axonal
12 degeneration in people in Southern California, so you never
13 know where it comes from.
14 DR. MARTY: I can keep going if this is useful,
15 but I don't want to bog the whole meeting down with our
16 examples.
17 CHAIRMAN FROINES: How does the panel -- do you
18 want to go through all of them or is this --
19 DR. GLANTZ: I don't think that's necessary. I
20 mean, I think the points have been made. We're not really
21 reviewing this for setting levels. It's really for the
22 purposes of illustration.
23 I mean, again, despite all of the issues that are
24 being discussed, I was still impressed at how close the
25 numbers came out most of the time, which was the original
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1 issue.
2 But I think we should move on to the hot spots.
3 CHAIRMAN FROINES: We're coming to Craig.
4 DR. BYUS: I did mine.
5 CHAIRMAN FROINES: You're right.
6 The one I don't think we necessarily need to go
7 through it, but one of the ones that has the very large
8 difference is styrene, and styrene is an important chemical
9 and maybe it would be worth taking a minute just to relook
10 at that for a second, because styrene is such a widely used
11 chemicals and the numbers are so --
12 DR. BLANC: Discordant.
13 CHAIRMAN FROINES: Discordant.
14 DR. MARTY: For the styrene REL we used the
15 proposed US EPA RfC, which, incidentally if we had done it
16 would have been the same because we would have used an
17 interspecies uncertainty factor of ten rather than three,
18 and no modifying factors.
19 So but at any rate, the critical effects were
20 basically reflections of CNS toxicity in workers.
21 We have a NOAEL, so but the exposures, I guess the
22 8.6 years, but not too many more than that, so EPA had used
23 three and we just decided to go along with what they had
24 decided to use.
25 And the cumulative uncertainty factor is 30, so we
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1 get 1,000 micrograms per cubic meter as the REL.
2 There was a '98 study by George Cruzan, et al, in
3 Toxicological Sciences, which was essentially a chronic tox
4 oncogenicity study in CD rats and they did not observe a
5 NOAEL, but they have a LOAEL of 50 ppm. It's a chronic
6 study, so you don't need a subchronic uncertainty factor.
7 But we did look at two ways to look at it. If you
8 have the LOAEL factor of ten or because the pathology was
9 relatively low grade and low incidence, particularly in the
10 females, you could opt to use a LOAEL uncertainty factor of
11 three in that case.
12 So if you do that, you either end up with a
13 cumulative uncertainty factor of 300 or 100, and a REL of
14 either six parts per billion or 20 parts per billion,
15 depending on what you decide about the LOAEL uncertainty
16 factor.
17 So we have the difference between a cumulative
18 uncertainty factor of 30 and a cumulative uncertainty factor
19 of 300.
20 The Mutti study focused on central nervous system
21 effects. The Cruzan study was looking at degenerative
22 changes in the olfactory epithelium, so you actually have
23 different endpoints.
24 DR. BLANC: What is the central nervous system
25 effect we're looking at, just to refresh our memories.
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1 DR. MARTY: It was a battery of neuropsychological
2 tests, and they had a number of endpoints that were -- they
3 had higher incidence in the exposed versus control.
4 DR. COLLINS: Verbal learning skills were
5 significantly impaired in workers. Logical memory and
6 visual constructive ability were shown to be significantly
7 affected in workers.
8 DR. BLANC: These were using the computerized
9 battery of --
10 DR. MARTY: Yeah. There were a number. There was
11 vocabulary block design, the digit symbol, 30-minute recall
12 of ten words and 30-minute recall of --
13 DR. BLANC: The reference group was what?
14 DR. MARTY: I believe it was workers in the same
15 factory, but not exposed.
16 DR. BLANC: Well --
17 DR. MARTY: Am I remembering that correctly?
18 DR. BLANC: I would say that that's a difficult
19 endpoint, those batteries, and how they're interpreted, the
20 neuropsychiatric test batteries. So that would be an
21 example I think of what John was referring to of taking
22 studies in the context of other studies.
23 So it's a very very -- those are endpoints which
24 are first of all they're multiple tests that are done so you
25 have one issue with multiple test comparisons. Sometimes
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1 some of those batteries involve 30 or 40 different measures,
2 so you have to read the study very carefully and see whether
3 or not they have adjusted for multiple comparisons, which
4 frequently is not done.
5 Secondly, they are very very subject to
6 confounding effects, which may have been controlled for if
7 the reference truly was workers from the same facility or
8 the same socioeconomic background, but it's very prone to
9 confounding.
10 So this, quite a different weighting that one
11 would give to the degenerative changes of the olfactory
12 epithelium, which is again the kind of chronic effect which
13 makes a lot of sense to look at since some of the chemicals
14 that you're interested in do have -- probably do have
15 chronic olfactory effects.
16 DR. MARTY: I think when you look at the database
17 as a whole, you do -- there are other studies besides Mutti
18 that talk about central nervous system effects of styrene at
19 relatively low exposures. I think that was something that
20 was taken into consideration by EPA when they did their RfC.
21 And in this study also they looked at urinary
22 metabolites, so they had a fairly good exposure estimate and
23 they put the workers into two groups, based on their urinary
24 metabolites the following day.
25 DR. FRIEDMAN: If the central nervous system
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1 effects are based on retesting the same individuals, are
2 they before and after exposure?
3 DR. COLLINS: The 50 controls versus 50.
4 DR. FRIEDMAN: I was curious about what
5 confounding there would be in that case, but apparently that
6 wasn't the way the study was done. I would think that's the
7 way the study should have been done.
8 DR. COLLINS: Then you would have to get them
9 before they were employed or to get --
10 DR. MARTY: Workday --
11 DR. BLANC: Acute effect, not a chronic effect.
12 DR. MARTY: At any rate, there are a handful of
13 studies that have looked at reaction time and other things
14 that are also hard to measure and hard to interpret, but
15 that's the reason that EPA went with the human study.
16 DR. BYUS: So, Paul, in a occupational setting are
17 those sorts of -- I had some concerns about it last time
18 just because I didn't understand what the tests were. It
19 wasn't described very well. But is that a valid way to
20 measure neurological effects?
21 DR. BLANC: I mean, there is a discipline and it
22 is used and it's just something that you have to interpret
23 with caution. I think when a lot --
24 DR. BYUS: It's complex.
25 DR. BLANC: It became sort of vogue in, I would
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1 say around 1980 or so, the Baker battery and all that stuff.
2 It was popular, there was some batteries of computer
3 administrable neuropsychiatric tests, but they're really
4 challenged, I think, from a biostatistical point of view and
5 an epidemiologic point of view because you're talking about
6 batteries of 20 or 30 tests. So from that, from the
7 analytic point of view, people haven't really used, by and
8 large, don't use sophisticated analyses where they look to
9 see if the entire pattern is different, and then look at
10 individual subtests, and then from an epidemiologic point of
11 view it's very prone to a series of potential complicating
12 factors, including alcohol intake and educational intake.
13 When taken serially, which is not the issue here,
14 is a learning factor, it's just methodologically difficulty.
15 But in any event you come out with a much lower
16 level when you use the animal study in this particular
17 thing.
18 DR. COLLINS: It's also a very given endpoint with
19 the nasal problem, and then you have this huge RGDR
20 calculation, which keeps driving things down.
21 DR. BLANC: By a factor of four, though, right?
22 DR. COLLINS: Five for the RGDR thing.
23 DR. BLANC: That's because it's something in the
24 nose? That's what we went through before. Whereas if it
25 was truly an extrapulmonary factor --
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1 DR. COLLINS: Extrathoracic.
2 DR. BLANC: This is extrathoracic, but if it was
3 some kind of systemic absorption, then you don't use this
4 factor.
5 DR. COLLINS: That's right.
6 DR. BLANC: So this only has to do with nose
7 things. Did I understand that from the last time?
8 DR. FRIEDMAN: I'm sorry I wasn't here at the
9 beginning.
10 I'm just curious what is the bottom line of this
11 exercise? Are you just trying to show us how different the
12 RELs are when you use animal versus human or you suggesting
13 that we always use the lowest or always use the human or
14 what?
15 DR. MARTY: No. What we're doing is responding to
16 Dr. Witschi's and Dr. Glantz at the last meeting suggested
17 that for the human, the RELs that were based on a human
18 study, that we look at a REL based on a animal study and
19 make the comparison.
20 DR. FRIEDMAN: With what purpose?
21 DR. MARTY: Just sort of an educational purpose to
22 see what we go through and the types of uncertainties and
23 how they're different and where they're different and
24 whether or not the numbers come even close.
25 DR. FRIEDMAN: If they don't, do you have an idea
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1 of which one you would pick?
2 DR. MARTY: We have tended to bias towards the
3 human studies, just because of the uncertainty with
4 extrapolating from an animal to a person. So that's -- and,
5 you know, we've tried to go with human studies that we
6 thought were fairly well conducted. And they all have some
7 flaws. There's just no way around that.
8 But the general thinking is it's better to use
9 humans if you're trying to figure out what happens in a
10 human, than to use the rat.
11 And, you know, I was actually somewhat surprised
12 at the result that the styrene, that it came out so much
13 lower from the rat study.
14 CHAIRMAN FROINES: What do you get if you use
15 Guillemin?
16 DR. MARTY: I don't know. That's, how did you say
17 his name?
18 CHAIRMAN FROINES: It's Swiss, and so I can't ever
19 get it right.
20 DR. MARTY: I don't know. We could whip that out
21 and see what happens. I know --
22 DR. FRIEDMAN: Do you plan to modify the report to
23 include these comparisons or not? Just for our education.
24 DR. MARTY: Right. We hadn't planned on doing
25 that.
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1 And also we did it with a fairly fast turnaround,
2 so it's not like we went and hunted through all the
3 literature that we may have missed or --
4 CHAIRMAN FROINES: Whose study is this, the
5 Cruzan?
6 DR. MARTY: Cruzan.
7 DR. COLLINS: It's from several industries. One
8 woman is at Chevron and he's at Tox Works in New Jersey.
9 Somebody else from Arco. Someone else from Hunting Life
10 Sciences.
11 CHAIRMAN FROINES: It's an industry chronic animal
12 bioassay?
13 DR. COLLINS: That's correct. Mainly looking
14 at -- they were mainly interested in not finding
15 carcinogenicity and that's what they did.
16 CHAIRMAN FROINES: They're interested because of
17 the IARC changes in the classification for styrene.
18 DR. COLLINS: It was funded by the SIRC, the
19 Styrene Industry Research --
20 DR. MARTY: But it was primarily focused on
21 oncogenicity, rather than other endpoints.
22 CHAIRMAN FROINES: Any other comments?
23 I think Paul's points are very well taken. These
24 studies that were so popular in the late '70s and early '80s
25 are really troubled by confounding historically. And it's
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1 worth trying to look at that in detail. I mean, there were
2 lots of styrene, but the old studies where people were
3 looking at JP 4 jet fuels and they weren't taking into
4 account alcohol intake. I mean it was ridiculous. And in a
5 heavily drinking population too. So it was these things
6 come up over and over again.
7 DR. MARTY: Yeah. If I'm not mistaken, Mutti they
8 did in that study look at alcohol intake as a huge problem.
9 DR. BLANC: It's a bit less an issue for you with
10 the styrene, because we'd be concerned about all those
11 confounders to the extent that they would have somehow given
12 you an oddball, you know, positive finding.
13 But since your real policy issue is going to be
14 whether or not you used this more recent study, which US EPA
15 did not have available to it when they did their analysis,
16 and whether or not your cumulative uncertainty factors
17 should be 300 or 100, depending on the LOAEL uncertainty
18 factor.
19 I think those are your methodologic issues, not so
20 much because the animal study would give you a more
21 conservative value in this particular case.
22 DR. MARTY: Yes.
23 DR. BLANC: So since we've been going for almost
24 an hour and a half, we should take a break for your
25 reporter.
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1 CHAIRMAN FROINES: I should say just before
2 leaving this that the Swiss investigator is an extremely
3 fine investigator, and that's one of the factors that we
4 haven't really talked about was the quality of the
5 scientists, as well as the science, so it's always worth
6 noticing when you see somebody you know that does good work.
7 Let's take a break for ten minutes and then we'll
8 go on.
9 (Thereupon a short recess was taken.)
10 CHAIRMAN FROINES: Melanie, I had one question.
11 Are you going to make a presentation?
12 DR. MARTY: No.
13 CHAIRMAN FROINES: On methyl bromide.
14 DR. MARTY: No, not on methyl bromide. We have
15 for the second agenda item.
16 DR. COLLINS: We deferred methyl bromide.
17 CHAIRMAN FROINES: You deferred methyl bromide.
18 DR. MARTY: In the meantime I've spoken to
19 Dr. Glantz, who the lead on methyl bromide, and also the
20 panel got a response to comments sent to them a couple weeks
21 ago from -- it was our response to the methyl bromide
22 industry panel comments, but we don't have a presentation,
23 but when Stan comes to -- when he's at bat, we're going to
24 talk about what the issue was with the methyl bromide.
25 CHAIRMAN FROINES: I think that's important to be
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1 as thorough as possible on that particular substance.
2 We're back on the record.
3 Because there is obviously sufficient interest,
4 significant interest.
5 So do you have more before we turn it back to the
6 panel?
7 DR. MARTY: No.
8 CHAIRMAN FROINES: Then let's turn it back to Paul
9 Blanc.
10 We're turning the heat up, literally. The
11 temperature in the room is going to increase, we hope.
12 DR. BLANC: So, Melanie, I'm going to start with
13 ammonia.
14 DR. MARTY: Okay.
15 DR. BLANC: Because I think we didn't do ammonia.
16 DR. MARTY: Let's go with ammonia.
17 DR. BLANC: Then I'll go through in alphabetical
18 order maybe.
19 Here's a generic comment on the document.
20 When you do physical properties, I think it would
21 be more consistent, and I think this came up in a previous,
22 and maybe in the acute, if you would give us physical
23 properties at some kind of standard temperature and
24 pressure. You know, anhydrous ammonia may be a liquid on
25 the planet Jupiter, but not on the surface of Earth.
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1 DR. MARTY: Dr. Fucaloro has already pointed that
2 out to me.
3 DR. GLANTZ: But, Paul, we should take a broad
4 view.
5 DR. BLANC: Secondly, I would like to see for each
6 inhalation reference exposure level where it's done at the
7 beginning, to also include the parts per million, that
8 conversion, so that somebody doesn't have to do that.
9 DR. MARTY: Okay. Right up in the front.
10 DR. BLANC: I know you have it other places. You
11 have the conversion factor, but when you say inhalation its
12 reference level, for example, for ammonia, is hundred
13 micrograms per meter. I think in parentheses it would be
14 helpful to have the parts per million.
15 Another generic comment is that there's a lot of
16 heterogeneity in the document in major uses and sources in
17 that section.
18 Now, I don't think each of these things needs to
19 be a NIOSH criteria document, but it does seem to be overly
20 telegraphic in places and this is one where it does. For
21 example, a major use of ammonia is as a refrigerant. That's
22 not listed.
23 Secondly, the whole section on ammonia disregards
24 that the major public exposure to ammonia is in ammonia in
25 solution. So unless you know something about ammonia, it's
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1 really hard from this document to understand the difference
2 between anhydrous ammonia and aqueous ammonia solutions,
3 which are going to off gas them, ammonia or aerosolized
4 ammonia. So I think it would be useful -- and the place to
5 do that I think would be in the major uses or sources and
6 maybe to say something about commercial over-the-counter
7 ammonia containing products as compared to industrial
8 ammonia products which tend to be 25 percent ammonia or
9 whatever.
10 I actually don't know what the max you can go to
11 in an industrial solution, but you can get pretty
12 concentrated aqueous ammonia.
13 So that would be a comment there.
14 This is a fairly brief section on what is a fairly
15 major industrial chemical, and that may simply be driven by
16 the extremely limited nature of any kind of chronic exposure
17 data, so I recognize that.
18 And there may need to be some generic approach to
19 the document which explicitly acknowledges that inconsistent
20 way.
21 And it may be that what you need in addition as
22 one -- an additional fixed section, you know how you have
23 one, two, three, four, five, six, et cetera. Maybe, you
24 know, a section for each one needs to be data limitations,
25 which has animal data, you know, limited modern excellent
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1 human data, limited modern excellent, you know, overall
2 quality of data including recent publication methods, study
3 size, some kind of comment like that for each section.
4 CHAIRMAN FROINES: Can I ask a question.
5 Melanie, when you have document like this and say
6 let's just use ammonia that has, following up on what Paul
7 said, has basically four pages, but that most of which is in
8 references, when if there were a person who submitted
9 comments, they are kept in some kind of record that's
10 accessible to the public. If somebody wanted to read the
11 comments as well as this short text, because one of the
12 things that does bother me about we're so used to the big
13 fat documents that are this thick for diesel, and we end up
14 with files like this and these turn out to be the other
15 extreme. So in a way you don't have as much as you might
16 like. On the other hand you may not need it. But if people
17 do have comments you do need to have that in a place that
18 becomes accessible, it seems to me.
19 DR. MARTY: They're on the Web. What we do is we
20 pretty much take the comments that are sent in to us, we
21 scan them in and we respond. We respond -- we try to keep
22 the comments as verbatim as possible to avoid us
23 paraphrasing and misinterpreting the comment, but that is
24 the material that the panel gets and that is available on
25 the Web. And if people are interested in actually looking
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1 at the letter they came in, they can always do that also.
2 So we've got that in our files.
3 DR. GLANTZ: Yeah. That's another document we got
4 was the comments documents.
5 CHAIRMAN FROINES: I know we get it. I was just
6 thinking about the public.
7 DR. BLANC: Just another example where you have a
8 mixture of critical effects. The one where you're on more
9 solid ground I think is pulmonary function and then the eye,
10 skin and respiratory symptoms, irritation are more problem
11 ridden for all the reasons that we said, and I think that
12 there does need to be some kind of generic approach in the
13 document when you're dealing with that.
14 The corollary to pulmonary function would be, you
15 know, studies of olfactory deficits.
16 And I forget whether some of this human exposure
17 data had that. That's something that for ammonia, because
18 of the high water solubility is particularly the area in
19 which I would give a clear look, like your case, even more
20 so, since there's good evidence that acute overexposure of
21 formaldehyde can cause an acute olfactory deficit.
22 But you have some pulmonary functions.
23 Okay. So should I move on?
24 One other thing.
25 The number that you come out with at the end is .1
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1 part per million which you then translate as 100 micrograms
2 per cubic meter, but your conversion factor would say that
3 it's 70 micrograms per meter, 71 micrograms per meter, and
4 there's an area where I think there's too much rounding, if
5 that's what you're doing.
6 DR. MARTY: Okay.
7 DR. BLANC: I mean, just as a reader it was
8 confusing to me.
9 Chlorine we did, so now we can go to dioxane.
10 CHAIRMAN FROINES: Can I make a generic comment.
11 Melanie, you know what I'd like to see you do with
12 these, since we have a hundred million of these chemicals --
13 no, I know.
14 DR. COLLINS: It seems like that way.
15 CHAIRMAN FROINES: I'd like to have a little
16 notation with each chemical where ARB has done airborne
17 monitoring and there's actual exposure or airborne
18 monitoring data. So that I don't know whether you've done
19 it for styrene, I don't know whether you've done it for
20 methyl bromide, I don't know whether they've done it for
21 ammonia, but in the document, right in the beginning, if you
22 just had a little thing, air monitoring, yes, air
23 monitoring, no, then the reader would know that they could
24 go to, presumably go to the Web and look for any air
25 monitoring data that may exist, so the reader at least knows
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1 that somebody has -- that there may be some comparable air
2 monitoring information that they can then compare the REL to
3 something that somebody is actually taking a look at it. I
4 think it would be helpful to everybody who might be
5 interested in these issues.
6 DR. MARTY: Okay. Also I'll see if they have any
7 modeling information based on some of their modeling
8 efforts.
9 DR. BLANC: Dioxane if I -- there seems to be an
10 arithmetic error, again this can't even be a rounding error,
11 the inhalation reference exposure levels is listed as 3,000
12 micrograms per meter, but it is at the end of the document
13 3.8 milligrams per meter, which should be 3800 micrograms.
14 DR. COLLINS: That should be 2.8, and actually it
15 came out to be 2.88 milligrams per cubic meter. The three
16 was an error and it rounded to 3,000. Sorry.
17 DR. BLANC: At least I knew something wasn't
18 right.
19 DR. COLLINS: I like to say, we did look up that
20 review you gave us and they basically said the animal study
21 available was this study.
22 DR. BLANC: Okay. Good.
23 And I think that in the major uses section here
24 there is one thing I would add, and that is, unless it's
25 changed, dioxane had a major use as a stabilizing additive
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1 to chlorinated hydrocarbon solvents, such as
2 1,1,1-trichloroethane, and I think probably that's the major
3 source of exposure would be my guess.
4 DR. MARTY: Yeah. It's my understanding that that
5 use has declined, but I can --
6 DR. BLANC: Can you double check that?
7 DR. MARTY: I can check with ARB folks and ask
8 about that.
9 DR. BLANC: Because historically that was
10 certainly --.
11 DR. MARTY: Yes, correct.
12 DR. BLANC: Since you're basing in part your
13 reference exposure level on a study by Thiess et al, if I
14 understand the section correctly, which is described as in
15 German described in NIOSH 1977 and not otherwise listed in
16 the reference, meaning that you got everything you got about
17 it from the NIOSH summary and you never pulled it yourself,
18 that study.
19 DR. MARTY: I'm not sure why it's not listed.
20 DR. BLANC: Well, that's what I would suspect when
21 I read it that way. That's nicht gut.
22 DR. COLLINS: Which one?
23 DR. MARTY: It's not in here. That's what he's
24 saying.
25 DR. BLANC: So please pull that original.
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1 I think what I think would be more precise when
2 you talk about the enzyme abnormalities, transaminase
3 elevations, particularly, I think the language that I would
4 suggest you use in this section and elsewhere, if there are
5 other cases where that's your endpoint is that you talk
6 about abnormal values, rather than increased activities,
7 because it's not really increased activities. What it is is
8 liver cells leaking out the enzymes into the circulation, so
9 it's not really an increased activity in that sense.
10 DR. MARTY: Right. Okay.
11 DR. BLANC: It would be more precise, I think, to
12 say that. And you may want to use along with the older
13 terminology, which is SGOT and SGPT, the preferred current
14 is AST and ALT.
15 DR. MARTY: Okay.
16 DR. BLANC: Even though I'm sure when they
17 published it -- and these are really measures of liver
18 dysfunction. I know they're called liver function tests,
19 but just to clarify.
20 And there's also in the next paragraph where you
21 say dioxane levels ranging from less to 25 to greater than
22 75 parts per million. Do you mean ranging from 25 to 75
23 parts per million? It's page A-50.
24 DR. MARTY: Let's check. I see what you mean. It
25 doesn't make sense. I think --
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1 DR. BLANC: You mean between 25 and 75. Maybe the
2 arrows got reversed.
3 DR. MARTY: Exactly.
4 DR. COLLINS: These are the others.
5 DR. MARTY: We will check that, because Dave Lewis
6 just informed me that it could be that there was groups
7 exposed to less than 25 ppm and groups exposed to greater
8 than 75.
9 DR. BLANC: However it is, you should just
10 clarify. It's not very clear.
11 And then I guess in the next page there was a
12 whole discussion about a rat study by Torkelson from 1974
13 where they had increased red blood cells and decreased white
14 blood cells. I think you should say concentrations, if
15 that's what you mean, by the way.
16 DR. MARTY: Counts or concentrations.
17 DR. BLANC: Or something.
18 And then there's this sort of this comment a
19 little bit later, although Pilipyuk et al, 1978 considered
20 the changes to be a reflection of adverse effects due to
21 exposure to dioxane, Torkelson et al in 1974 do not consider
22 the hematological and clinic changes of toxicologic
23 importance.
24 And could you tell me what --
25 DR. MARTY: Purpose of that statement is?
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1 DR. BLANC: Yeah. Because you go on, you use in
2 part the Torkelson study --
3 DR. MARTY: I think we're just pointing out --
4 DR. BLANC: As a no effect level. But I assume
5 that these effects were seen, right?
6 DR. MARTY: Yes.
7 DR. BLANC: You used it as a NOAEL and not a
8 LOAEL, because you're discounting the fact that there were
9 increased concentrations of red blood cells and white blood
10 cells and decreased alpha and phosphatase, which doesn't --
11 I think it doesn't have a lot of meaning whether it's
12 decreased.
13 DR. MARTY: We're going to look at the paper.
14 It's not clear.
15 DR. BLANC: And then such dysfunctions, however,
16 were observed in rats exposed to dioxane by ingestion, and
17 in humans. So I really found this whole thing rather
18 confusing. That's sort of the bottom line.
19 DR. MARTY: Looks like we were trying to figure
20 out why Pilipyuk et al '78 and Torkelson et al '74 seem to
21 be not arriving at the same conclusion.
22 DR. BLANC: Because basically isn't what's going
23 to happen if you accept that those do matter, then you're
24 going to have to use 111 as a lowest effect level and not as
25 a no effect level and then that's going to drive everything
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1 down by a factor of --
2 DR. COLLINS: Three or ten.
3 DR. BLANC: Three or ten, depending.
4 DR. MARTY: Torkelson is saying that the minor
5 differences between a control and exposed rats with respect
6 to the hematological values were within normal physiological
7 limits and were not considered of any toxic importance.
8 DR. BLANC: But they were statistically unlikely
9 to be due to chance.
10 DR. MARTY: Correct.
11 DR. BLANC: And then but on the other hand the
12 study in German, which you haven't pulled, in humans, which
13 is described by NIOSH, did observe such changes, maybe, if I
14 understand what you mean. But I don't know what levels.
15 So, you know, it's really badly put together. It's put
16 together in a way which I can't figure out whether it's --
17 CHAIRMAN FROINES: I think what I'm going to do is
18 take the prerogative of the chair and say this one should be
19 redone.
20 And I think that you really should avoid
21 statements like that. Torkelson et al do not consider the
22 hematologic and clinical changes of toxicologic importance.
23 Quite frankly, that is a highly self-serving statement. And
24 if you go back and look at that paper, it's not entirely
25 surprising.
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1 So I think that one should look at that with some
2 care.
3 I think Paul is right about the --
4 DR. BLANC: I'm not going to revisit the
5 formaldehyde, hydrogen chloride and cyanide, because --
6 actually I never did cyanide. That's the one I need to do
7 also, is that right?
8 DR. MARTY: We talked about formaldehyde.
9 DR. BLANC: Formaldehyde I did.
10 DR. MARTY: I'm not sure you finished.
11 DR. BLANC: Chlorine we did.
12 DR. GLANTZ: All the ones that were discussed you
13 finished.
14 DR. BLANC: Let me do hydrogen cyanide as the last
15 one. That's under H.
16 Here's an example where we really have lousy
17 chronic human data. And I know that the EPA used, and I
18 know because I've contributed some of the lousy chronic
19 hydrogen cyanide data. Although, I don't think my study was
20 any worse than El Ghawabi.
21 And it would seem to me that here's an effect for
22 which animal data of some sort must be more informative, and
23 particularly I don't see why you couldn't use animal dietary
24 values, because for inhalation we have good data to tell you
25 how much the delivered systemic dose would be from
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1 inhalation, and there's nothing particular about the
2 inhalation other than it being one route of exposure.
3 So since there's a lot probably of dietary chronic
4 cyanide feeding data in animals, I would assume -- it seems
5 to me it would make much more sense to extrapolate from
6 feeding studies in animals than to use the El Ghawabi study
7 of metalplaters in Egypt.
8 DR. COLLINS: We do have this chronic animal
9 study, which is in the summary in which we used two studies
10 from Scandinavia about 1980, which ended with inhalation
11 reference level of two micrograms per cubic meter, so in
12 that case the animal data went along well with the lousy
13 human data.
14 DR. BLANC: They were given fairly short shrift in
15 summary, though.
16 DR. COLLINS: There's EPA -- deference to the EPA
17 at that time.
18 DR. BLANC: Yeah.
19 DR. MARTY: Yeah. We could -- that was one of the
20 other examples I had where we compared the human versus the
21 animal.
22 DR. BLANC: Right.
23 DR. MARTY: And in human we have a cumulative
24 uncertainty factor of a thousand and the animal we have a
25 cumulative uncertainty factor of 300, so that tells you
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1 right there that there's issues with both studies. But we
2 do end up with in one case three micrograms per cubic meter
3 and the other case two micrograms per cubic meter.
4 Also I do want to comment on the route-to-route
5 exposure extrapolations. We do them as a last resort. The
6 issues are primarily pharmacokinetic differences which may
7 or may not be well characterized.
8 DR. BLANC: I'm just saying for cyanide it's one
9 of the ones where you have less trepidation of all the
10 things I could think about. We know it's absorbed very well
11 systemically from diet or from inhalation, rapidly lethal in
12 the acute model. So, you know, reason to think it's pretty
13 well distributed to where it matters.
14 DR. MARTY: We can certainly look at it. We can
15 look at the Hugod studies of '79 and '81 and also some
16 dietary studies and see what --
17 DR. BLANC: Or put in your final table, you know,
18 make the animal study appear more prominently in your -- I
19 just, that's just my take on it. Since you have animal
20 data, which is very supportive, I would probably put a
21 little more prominently, it just makes your argument a lot
22 more strong, a lot stronger, because the El Ghawabi study is
23 both in terms of what, you know, how they measured the
24 thyroid stuff and --
25 DR. MARTY: Okay. We'll actually in the document
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1 then discuss the REL derivation from the animal studies and
2 the fact that it's close and then we'll also go ahead and
3 take a look at the oral studies.
4 DR. BLANC: And actually cyanide, despite there
5 aren't good chronic human inhalation data because, thank
6 goodness, there aren't occupational settings where people
7 are chronically exposed to levels of cyanide that are that
8 high, by and large.
9 DR. COLLINS: The only comment we had was from the
10 mining industry, which is because of the large amount of
11 cyanide used there.
12 DR. BLANC: But we do have really large
13 epidemiologic studies of dietary cyanide, so it is an
14 epidemiologic, chronic epidemiologic issue and there
15 probably are really important and chronic health effects
16 from chronic cyanide exposure. Where at risk people are --
17 CHAIRMAN FROINES: I spent quite a while looking
18 at chronic neurologic effects of cyanide.
19 DR. BLANC: Okay. That's it. I'm done.
20 CHAIRMAN FROINES: You're done with everything.
21 So we can shift over to -- Craig's finished.
22 So let's shift over to Stan.
23 DR. GLANTZ: Okay. Well, I have to say that I
24 read all the stuff getting ready for the last meeting and
25 thought that -- and there were a lot of public comments on
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1 several of the chemicals that you assigned me, and I thought
2 OEHHA actually did a pretty reasonable job.
3 And then I listened to all of Paul's detailed
4 comments, and I felt inadequate, so I went back and read it
5 all again and I still thought --
6 DR. BLANC: I told him it was criticism envy.
7 DR. GLANTZ: Yes, it was. It was criticism envy.
8 I still thought OEHHA did a pretty reasonable good
9 job. I don't have a whole lot to say, actually.
10 I just want to clarify a couple of points and that
11 is on the isopropanol, that was one place where the
12 commenters made a lot of very specific suggestions for
13 changes, and OEHHA, seemed to me, accepted almost all of the
14 changes. And I just wanted to make sure that AL is reading
15 that right. I thought it was appropriate to accept it, by
16 the way, and that the document that we have before us
17 reflects all those changes.
18 DR. MARTY: Yes.
19 DR. GLANTZ: I don't know, I don't think it's
20 worth going through them, but that was one place.
21 And then the other one that I thought was worth
22 some discussion is the issue of methyl bromide, because
23 that's one where there were a bunch of comments received
24 fairly late before the last meeting, and issues relating to
25 the pathology that underlied the study that they used, and
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1 whether the number, the exposure in the study should be
2 considered NOAEL or a LOAEL. And I just think it would be
3 worthwhile for the panel letting OEHHA kind of review that
4 correspondence and the comments and how it all worked out.
5 Again, I think the resolution was fine, but I just
6 think, given the back and forth, it would be worth a brief
7 discussion of what happened.
8 Is that okay?
9 DR. MARTY: That's fine.
10 DR. GLANTZ: Do you want copies of the letters?
11 CHAIRMAN FROINES: Could I ask a question?
12 DR. GLANTZ: Yeah.
13 CHAIRMAN FROINES: Why did you use EPA RfC?
14 DR. GLANTZ: For which one?
15 CHAIRMAN FROINES: Methyl bromide.
16 DR. MARTY: We did.
17 Why did we?
18 DR. GLANTZ: Can we just go through this other
19 thing first and then if --
20 DR. MARTY: I think I can sum it up pretty
21 quickly, and that is that the methyl bromide industry panel,
22 CMA, sent in a letter saying that they had requested another
23 pathologist to review the slides of the histologic lesions
24 in the olfactory epithelium.
25 DR. GLANTZ: It was a study they used to get the
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1 REL.
2 DR. MARTY: Right. And Dr. Hardesty, who was the
3 pathologist, reviewed the slides and was in general
4 agreement with the higher dose that with the initial study
5 pathologist with regards to the impacts on the olfactory
6 epithelium at the higher doses, but at the lower doses there
7 was disagreement as to whether or not there was in fact any
8 histopathology.
9 The methyl bromide industry panel concluded that
10 therefore that that dose, rather than treating it as a
11 LOAEL, as was done, should be a NOAEL.
12 So I contacted the methyl bromide industry panel
13 and asked them to have the original study pathologist send a
14 letter stating that she agreed with the reevaluation.
15 And I got a letter and she agrees with it to an
16 extent, but if you look at where she disagrees, that low
17 observed effect level is still a low observed effect level.
18 She thinks that there were effects in one sex that are
19 statistically significant.
20 However, yesterday or the day before, they sent me
21 another letter from the original study pathologist, in which
22 she implies that it's such a minor difference that in her
23 opinion we shouldn't use more than an uncertainty factor of
24 two, and we have used an uncertainty factor of three.
25 So I am suggesting that we stay with the
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1 uncertainty factor of three for the extrapolation from the
2 LOAEL to the NOAEL.
3 So that basically sums up the issue.
4 DR. GLANTZ: So the bottom line of all this
5 correspondence is nothing changed.
6 And I think that the decision by OEHHA to leave
7 things as they were is justified.
8 So that was basically all that I had to say on
9 these compounds. I mean, if you guys, I'm sure Paul will
10 have incredibly insightful comments or something, but I read
11 through all of the stuff several times and I'm satisfied
12 with OEHHA's responses to the public comments. And in
13 reading the report itself it all seemed reasonable to me,
14 subject to the changes that they made in response to the
15 comments.
16 DR. BYUS: I read with great care all of the
17 correspondence with the pathologists and all that you sent
18 forward, and I find it a little disturbing when they
19 reanalyze the pathology and don't do it in a blind way
20 fielding a panel.
21 And then where they assess the quality of the
22 panel by giving them known slides in a blind way, and then
23 they -- then you look at the slides in a blind way by a
24 panel, recording votes and then do it.
25 The way this methyl bromide was not done that way.
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1 The pathologist, from my reading of it, knew what he was
2 looking at when he looked at it. And I find that not
3 necessarily a good way to do it.
4 And I think my reading of your interpretations of
5 all this is very good. So I mean I think you did exactly
6 the right thing.
7 And then the original letter it appeared that I
8 had the impression that the original pathologist agreed
9 completely with the re-evaluation, and then when you
10 actually read her letter, which was nice for you to get, it
11 was some letter, that was not the case.
12 And so I think there is a lot of times when
13 reanalysis of the pathology is a good idea, but it has to be
14 done under, say, good laboratory practices guidelines or
15 definitely blind, and preferably a panel of pathologists,
16 rather than one. So.
17 DR. GLANTZ: I guess just for the record I had
18 very similar feelings and I'm really glad that you went back
19 and contacted the pathologist, rather than taking a
20 secondhand assessment of what -- I think it was a woman,
21 wasn't it, what she said?
22 DR. MARTY: Yes.
23 DR. GLANTZ: But as I say, I thought these were
24 relatively well done and the responses to the public
25 comments were good and that when the commenters had made
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1 good points there were appropriate changes made to the
2 report.
3 So I think we can, unless somebody else has
4 something, we can just go on.
5 CHAIRMAN FROINES: Why did you not, going back to
6 my question, why did you not do -- why is this listed as an
7 US EPA RfC? Because what you're -- because the way you're
8 talking about the study, it's as though you did an
9 evaluation such that the number that you're using is in fact
10 a number that you would have come up with had you described
11 it yourself, and if that's the case, I'd rather you said
12 it's your finding, not an EPA finding.
13 DR. MARTY: Okay. I can say that when we looked
14 at the EPA RfCs, we did go back and look at all of their
15 documentation and pulled the original studies and so on.
16 If we really had heartburn over what we did, then
17 we decided we weren't going to forward it on as a proposal.
18 If we agreed that the study chosen was appropriate
19 and the endpoints were appropriate, there may have been some
20 slight disagreement over the modifying factor, which I
21 pointed out earlier, but we in general we did look at the
22 information that was used as the basis of the EPA RfC and in
23 this case we do agree with that choice of study and
24 et cetera.
25 CHAIRMAN FROINES: The reason I say that is more a
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1 policy than a science statement in the sense that methyl
2 bromide is a very important compound in the State of
3 California, and it seems to me that it's worth saying that
4 OEHHA, these are OEHHA's findings and this is your
5 conclusions, rather than saying this is EPA's finding and we
6 sort of agree with them.
7 I would think it would be stronger if you said
8 this is the OEHHA position on the chronic noncancer effects
9 of methyl bromide.
10 And methyl bromide obviously is a, you know, we
11 spend a fair amount of time on dioxane, which does have
12 virtually no exposure by relative basis, by comparison, so
13 that this is important.
14 Do we know -- I was hoping Lyn Baker would be
15 here, but there's no reason why he should have been here, so
16 do we have some sense of how this value compares to what we
17 found in air monitoring from methyl bromide?
18 DR. MARTY: We don't. We will follow up with Lyn
19 and find out what he knows.
20 CHAIRMAN FROINES: If you take the NTP study --
21 I'm glad I asked. It's nice to see George get out of his
22 chair in this meeting.
23 DR. ALEXEEFF: George Alexeeff with OEHHA.
24 Just to let you know about methyl bromide, it's
25 currently DPR has prepared a risk characterization document
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1 on methyl bromide. For this particular chronic effect they
2 have the same value. They have developed the same value as
3 this number. It's a slight different way they calculate it,
4 but it ends up being the same number.
5 And their -- since the document is a risk
6 characterization document and not yet a TAC document, okay,
7 they are having it right now peer reviewed by the National
8 Academy of Sciences Committee, which is supposed to be done
9 fairly shortly. I believe at some point it will come also
10 to the panel when it's further completed, but it's a
11 slightly different format, for some reason, that they chose
12 that.
13 CHAIRMAN FROINES: Does the National Academy
14 Committee do methyl bromide, per se?
15 DR. ALEXEEFF: No. They're just paying the
16 National Academy of Sciences to peer review it on some sort
17 of expedited basis.
18 So but there is some -- so that is undergoing peer
19 review. I think it will be done sometime in the next few
20 months.
21 So they probably do have levels that they
22 measured. They have had levels. I've seen a draft of the
23 document that's available. But it's not a TAC document that
24 they have. It's what they call -- it's prior to the TAC,
25 but they felt because of the findings they had in that risk
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1 characterization document, they felt to be peer reviewed
2 before they even developed a TAC document.
3 So that's the status of that.
4 CHAIRMAN FROINES: Well, we'll put on the record
5 that this was a matter that Dr. Froines and Bill Lockett and
6 Jim Behrmann will follow up on, because we'd like this to
7 be -- we'd like something -- the panel to be informed as to
8 what's happening on methyl bromide because it is such an
9 important compound.
10 DR. ALEXEEFF: They could possibly give a status
11 next meeting.
12 CHAIRMAN FROINES: If you, back to science, if you
13 look at the NTP bioassay and you had a dose level for mice
14 that was down to as low as ten, do you remember what the
15 findings were with the mice in terms of the various
16 parameters?
17 In other words, did they find effects in at ten
18 parts per million, because your LOAEL is three parts per
19 million in rats. Do you remember what the NTP findings were
20 in mice at ten?
21 DR. MARTY: I don't. I need to go back and look
22 at that.
23 CHAIRMAN FROINES: Again, it goes to what I was
24 raising at the very beginning, which is looking for
25 consistency across findings, and that's obviously is a
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1 well-done study and it's obviously a dose range that has
2 relevance to your Reuzel study.
3 DR. MARTY: I'm looking at our document on page
4 153, it does say a low incidence of sternal dysplasia and a
5 significant decrease in locomotor activity were noted in the
6 ten ppm group. This is --
7 CHAIRMAN FROINES: I don't think I have that.
8 DR. MARTY: Fourth paragraph down.
9 CHAIRMAN FROINES: I don't have that document. My
10 methyl bromide is A-470.
11 It doesn't matter. Let's just --
12 DR. COLLINS: Are you looking at the original
13 October 1997 draft?
14 CHAIRMAN FROINES: Yeah.
15 DR. COLLINS: I'm sorry. May 1999.
16 DR. BLANC: That's all right. He's always a
17 couple years behind.
18 DR. COLLINS: I don't think this changed much.
19 CHAIRMAN FROINES: I know.
20 DR. COLLINS: An exposure of mice --
21 CHAIRMAN FROINES: I left the other one.
22 DR. COLLINS: An exposure of mice, 86 animals per
23 group, to 0, 10, 33, a hundred ppm methyl bromide for six
24 hours a day, five days a week for 103 weeks, a low incidence
25 of sternal dysplasia and a significant decrease in locomotor
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1 activity where noted in the ten ppm group.
2 Would you like to know what -- we can look up what
3 the incidence is.
4 CHAIRMAN FROINES: No, that's okay.
5 DR. BLANC: Stan.
6 DR. GLANTZ: If you'd like.
7 DR. BLANC: Can we go to inorganic mercury.
8 For consistency, first of all, I think it should
9 be mercury, comma, inorganic, since you're going in
10 alphabetical order and you have it under M.
11 DR. FUCALORO: I was looking it up under I.
12 DR. BLANC: Okay. Let's go to the chemical
13 property summary.
14 First of all, clearly the critical thing about
15 inorganic elemental mercury is that although it's a heavy
16 liquid, at room temperature it's easily vaporized.
17 And is the vapor pressure correct? The vapor
18 pressure that's listed there.
19 DR. MARTY: I can check it against another source.
20 We used HSDB, a secondary source, and we found it's full of
21 mistakes.
22 DR. BLANC: Doesn't it have a high vapor pressure?
23 DR. FUCALORO: I don't know.
24 DR. BLANC: I mean, it's weird because it is
25 mercury and it's vapor pressure and mercury --
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1 DR. FUCALORO: You know, the modern symbology for
2 millimeters mercury is torr, t-o-r-r. And I only mention
3 that because it was named after that famous Italian
4 scientist Torracelli.
5 DR. COLLINS: You mean the guy from New Jersey?
6 DR. BLANC: There's a tendency to shorten last
7 names, so it's a good thing there's nothing in your name.
8 DR. FUCALORO: There's plenty of them.
9 DR. MARTY: We will double check the vapor
10 pressure.
11 DR. BLANC: You seem to be dealing in this section
12 with both inorganic elemental mercury and then with mercuric
13 chloride? Are those the two things, or have I got --
14 DR. MARTY: Mercuric.
15 DR. BLANC: That the same thing as sublimate, you
16 know, what they used to call --
17 DR. COLLINS: It may be. Corrosive sublimate.
18 DR. BLANC: Corrosive sublimate, I'm sorry. Is
19 that the same thing?
20 DR. MARTY: I think so.
21 DR. BLANC: Those are the only two substances
22 you're dealing with here, because those are the only two
23 things that would become airborne with any likelihood; is
24 that right?
25 DR. COLLINS: Maybe.
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1 DR. BLANC: As opposed to a whole bunch -- I mean
2 there are a whole bunch of mercuric salts, which wouldn't
3 make sense for you to deal with here.
4 DR. COLLINS: I think those are the ones that tend
5 to be the ones with the most information.
6 DR. MARTY: ARB may have to comment on that,
7 because the emissions are not speciated that we get hold of.
8 We just get total mercury emissions.
9 I would assume that the majority are elemental,
10 particularly from a combustion source, but there may be
11 salts of mercury that end up being emitted into the air
12 under high temperatures or high pressure.
13 DR. BLANC: I wouldn't think -- I would think it
14 would be very minor and only situation where you would get
15 airborne. And actually I'm not sure with corrosive
16 sublimate, what the ultimate exposure is, whether it is in
17 fact -- but since you have a boiling point for it, which is
18 actually lower than the boiling point for mercury, that was
19 the other thing that I was surprised at. I thought mercury
20 boiled a little bit lower than that temperature, elemental
21 mercury.
22 DR. FUCALORO: Can't help you.
23 DR. BLANC: Just double check that.
24 Then if you could in the text of this kind of
25 break out or deal with separately what would be the exposure
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1 routes and uses for corrosive sublimate if there are still
2 any, if that's what you're really dealing with, because it
3 would be, I think fairly obscure to any reader otherwise.
4 DR. MARTY: Okay.
5 DR. BLANC: And it would also perhaps affect when
6 you say inorganic mercury, if you're talking about both
7 elemental and this one other compound and there's some other
8 common names for them, it's going to make the whole thing
9 more complicated, since you're not talking about simply
10 elemental mercury.
11 But I can see why you need to treat it as one
12 thing, but I think it needs to be clarified.
13 And I think that if your RfC, which is derived
14 from the EPA, and you cite that the study is the Piikivi
15 study.
16 DR. MARTY: Andy, can you turn on that slide.
17 Yeah, I am going to apologize for what is in the
18 text in that it did not really explain well enough all of
19 the studies that ended up being the basis.
20 DR. BLANC: Right. They were all at 25
21 micrograms, so it is actually a much -- this is one of the
22 ones where you really have very strong human data that's
23 consistent.
24 DR. MARTY: Exactly. Interestingly enough, the
25 rat study came up with same REL.
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1 DR. BLANC: I think you're really on firm ground.
2 DR. MARTY: I have notes to myself to flesh that
3 out and make it clearer.
4 DR. BLANC: And then can you tell me why there's
5 this whole lengthy appendage at the end about the --
6 DR. MARTY: Oral reference dose?
7 DR. BLANC: Yeah. What is -- why does that have
8 to be in there?
9 DR. MARTY: In the air toxics hot spots site
10 specific risk assessments certain compounds are looked at by
11 multiple routes of exposure. So things that may end up in
12 particulate for metals, semivolatile organics like PAHs and
13 dioxanes and furans, we evaluate not just from inhalation
14 route of exposure, but we also have an exposure paradigm
15 looking at deposition onto food that you might be growing in
16 your backyard onto soil where you may have dermal contact
17 and some ingestion from hand to mouth.
18 DR. BLANC: Is there anything else in this
19 document --
20 DR. MARTY: I'd have to look through, but
21 certainly dioxanes, which I believe is in this set, and any
22 of the metals.
23 DR. BLANC: So nickle has this too?
24 DR. MARTY: Nickle should have this too.
25 DR. FUCALORO: If I can get back to the mercury
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1 just for a second, the numbers you point out, it's not
2 hard -- it's hard to get a good sense of this thing just
3 from looking at the numbers without doing the calculation.
4 At a boiling point of 360 degrees centigrade, that
5 means that the atmospheric pressure, vapor pressure, is one
6 atmosphere or 760 torr. Vapor pressure at 25 degrees is two
7 times ten to the minus three torr, .002.
8 You can put that in something called a Celsius
9 clapper on the equation to calculate, estimate the heat of
10 vaporization, and, by so doing, you come up with about 60
11 kilojoules per mole, which is not unreasonable. I mean, I
12 don't have the numbers with me.
13 Water, for example, is about 44 kilojoules per
14 mole.
15 So maybe it's those numbers are correct, even
16 though it does look -- I mean I have to say, it's a .002
17 millimeters mercury looks a little low, but the calculation
18 seems to indicate that it's ballpark. That's about -- I can
19 check it. It's easy enough.
20 DR. BLANC: Yeah. Well, for those few places
21 could you have a brief one sentence that says because this
22 is, the following section is included.
23 DR. MARTY: Okay.
24 DR. BLANC: And I forgot to say something on
25 cyanide. Can I go back to that for a just a second?
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1 And it's not unrelated to the mercury, which made
2 me come back to it.
3 In cyanide, which you describe as a colorless
4 liquid/gas, again I think it would be useful to simply have
5 a sentence or two that says that hydrogen cyanide is a gas,
6 but that there are multiple cyanide salts, which, if they
7 come in contact with an acid environment, will release
8 cyanide gas. It's the parallel to the whole discussion
9 about hypochlorite containing products, because that's
10 really the route that most people are exposed or the
11 releases occur, not because somebody has got compressed
12 hydrogen cyanide gas in tanks that's released, but because
13 they've got metal cyanide salts that --
14 DR. MARTY: Okay.
15 DR. BLANC: And so the colorless liquid also,
16 cyanide gas is not a liquid in any kind of normal condition,
17 but a lot of these cyanide salt solutions are liquids. So
18 plating operations or cyanide salts.
19 And I also think it would be useful to emphasize
20 that there are chemicals which can be airborne, which are
21 metabolized to cyanide in the body such as a acrylonitrile
22 and acetonitrile. And I think that needs to be alluded to
23 in that section.
24 DR. FUCALORO: Can I say something about --
25 something that was said earlier regarding the conversion
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1 factor. We saw parts per million into so many milligrams
2 per meter cube. I'm assuming that's done the same way each
3 time, in other words you take the molecular weight and
4 divide it by 24.4, which is so many liters per mole. It's
5 the standard --
6 DR. COLLINS: 25.
7 DR. FUCALORO: 298 kelvin.
8 So why don't you just put that down in the
9 beginning and people can do the conversion themselves. Just
10 a suggestion. I mean, you just take the molecular weight
11 divided by 24.4, and you come out with equivalency of one
12 part million to so many milligrams per meter cubed.
13 DR. BLANC: I just think they have that in the
14 general introduction, but most people who deal with, you
15 know, OSHA literature and NIOSH literature will be looking
16 for conversion factor, because it's in most standard
17 industrial hygiene related so I think it's useful to have it
18 for each one too.
19 DR. MARTY: We can also put it in the introduction
20 what the formula is.
21 DR. FUCALORO: Is it in the introduction?
22 DR. MARTY: You know, I don't think it is.
23 DR. FUCALORO: I didn't notice it, but then I
24 didn't look.
25 CHAIRMAN FROINES: Can we finish, Paul?
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1 DR. BLANC: Yeah. That was the one I wanted to
2 comment on.
3 CHAIRMAN FROINES: I have a quick question. It's
4 just of interest.
5 I don't know if there are things like mercury
6 thermometer plants in the State of California, but are there
7 hot spot -- this is a relatively low REL, four hundredths of
8 a part per billion, so it seems like there's a potential for
9 hot spots.
10 Are there, as far as you know, under -- does the
11 2588 have any indication that there are?
12 DR. MARTY: What we have available to us is the
13 total statewide emissions from the facilities that report in
14 the hot spots.
15 CHAIRMAN FROINES: Oh, so you wouldn't find most
16 of them.
17 DR. MARTY: Right. If it's evenly divided over
18 thousands of facilities, then you may not have a hot spot.
19 DR. COLLINS: I think a lot of it's fuel
20 combustion too.
21 DR. FUCALORO: I bet you there's a hot spot in
22 your laboratory, just as in my laboratory and his
23 laboratory, that there's a lot of mercury vapor there.
24 CHAIRMAN FROINES: We never spilled any mercury.
25 DR. MARTY: I can go back and look at our
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1 inventory risk assessments and see if mercury ever came up
2 as an issue in any of the risk assessments, but I don't
3 remember that it has.
4 CHAIRMAN FROINES: Well, it's the other way around
5 in a sense, that the trouble with that kind of risk
6 assessment is there's only certain companies that have to
7 comply with 2588, but if you did it logically and said who
8 releases mercury, then you would say thermometer plants,
9 electroplating plants, et cetera, et cetera, and you could
10 then --
11 DR. GLANTZ: Toxicology professors.
12 CHAIRMAN FROINES: College professors who don't
13 put sulfur all over their floors to prevent it.
14 But one could ask the question if you wanted to
15 identify problems, you got a number like this, then there
16 may be some places that you'd want to take a look at, see if
17 there is.
18 Mercury is obviously not inconsequential problem.
19 Okay.
20 I think we're at Peter Kennedy.
21 DR. KENNEDY: My list begins with ethyl chloride.
22 I have the same generic comment regarding the
23 consistency of enumeration of the description of the
24 conversion factor.
25 I don't deal with this stuff at all, and would
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1 like to see it all the same way, so I can be more
2 comfortable with it.
3 It appears that the total sum of human exposure is
4 some nutty lady who spilled two to three hundred cc's on her
5 sleeve daily for four months. Hard to know how to make any
6 sense of that.
7 This is, I have a question really informationally
8 for me as much as anything. In terms of developmental
9 toxicity, delayed ossification, particularly in the skull,
10 is apparently a fairly common parameter that's used as an
11 endpoint in these evaluations.
12 It is also seen with developmental abnormalities
13 in ribs and particularly cervical ribs. At least at an
14 intuitive level that suggests to me not one, but maybe two,
15 mechanisms of action is -- do you all have any information
16 on that or are these just observations that are made?
17 DR. MARTY: Primarily observations. In speaking
18 with our developmental and repro tox group at OEHHA, the
19 delayed ossification is rather indicative of general
20 fetotoxicity and general chemical stress.
21 DR. KENNEDY: Okay.
22 DR. MARTY: I'm not sure that anybody has really
23 outlined a actual mechanism, but I can certainly talk to
24 them about that.
25 DR. KENNEDY: I can accept that.
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1 But if you assume that, I have trouble linking
2 that and cervical ribs, which is really probably a
3 mutational or developmental malady of the other direction.
4 You've got bone being hypertrophic, rather than delayed in
5 its development. It's a small point, but it keeps coming
6 up.
7 DR. MARTY: The supernumerary ribs?
8 DR. KENNEDY: Yeah.
9 Hey, that's better.
10 DR. MARTY: Yeah. We can look into that further
11 and add some information if there's information with regard
12 to that.
13 DR. KENNEDY: Since that's all you have to work
14 with in this, I mean that's basically what you have. It
15 might be interesting.
16 The remaining animal studies with inhalation for a
17 hundred odd weeks with extensive histopathologic review
18 shows nothing.
19 I think some interest is this issue of cardiac
20 sensitization when used in anesthetic concentrations. But
21 there's, I guess, no more data. It's very very old and
22 there's nothing else that's presented.
23 So you really have only the development effect,
24 developmental effect as your observed endpoint.
25 I'm not sure that the strengths of the inhalation
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1 REL include multiple species, multiple concentrations and
2 multiple histopathologic analysis, since all those are
3 negative. I mean, it's true enough, but it doesn't really
4 contribute to anything.
5 DR. MARTY: We can strike that.
6 DR. BLANC: Can I ask a question about this
7 compound?
8 Did you double check the Med Line or Tox Line
9 since you did this, just to double check, since -- I'm not
10 saying that you have to systematically reiterate and never
11 be finished with the document, but for something which has
12 so little information, I would just do a double check of
13 your own.
14 DR. MARTY: We have been doing that, but Jim says
15 he hasn't done it in a while. We can do it again.
16 DR. BLANC: I'm not saying --
17 DR. KENNEDY: I thought I had missed some lead
18 article in the New England Journal or something when you
19 brought it up, but it's a good point.
20 DR. MARTY: Pretty surprised there's not more on
21 ethyl chloride myself.
22 CHAIRMAN FROINES: Could I ask a question that's
23 related to Paul and Peter's question?
24 Under three major uses and/or sources you have
25 ethyl chloride is used as a starting point in the production
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1 of tetraethyl lead. Is there a lot of tetraethyl lead made
2 in the United States these days?
3 DR. BLANC: Yes, there is.
4 DR. MARTY: No.
5 DR. BLANC: It's exported.
6 DR. FUCALORO: It would be for an export industry.
7 DR. BLANC: Ethyl Corporation it's still their
8 major source of income. Unless they make it off shore.
9 CHAIRMAN FROINES: There is?
10 DR. BLANC: I don't -- I don't know that for a
11 fact that they make it in the United States. I do know that
12 Ethyl Corporation it's still their major cash cow, as far as
13 I understand.
14 CHAIRMAN FROINES: I bet it's in CNA news.
15 DR. BLANC: The reason why Ethyl Corporation has
16 pushed organic manganese is because they have a patent on
17 that. For their future they think that's going to be --
18 CHAIRMAN FROINES: We're coming to that.
19 DR. BLANC: I think that the phrase it is also
20 used as a topical anesthetic. Based on Patty's Industrial
21 Hygiene from 1994, perhaps it would be more conservative to
22 say it has been used. I doubt that it's being used very
23 much.
24 DR. KENNEDY: It's still a major component of
25 walk-in clinics.
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1 DR. BLANC: Is it?
2 DR. KENNEDY: Yeah.
3 DR. BLANC: So it's on the pharmacopeia, because
4 it evaporates so quickly?
5 DR. KENNEDY: Yeah.
6 DR. BLANC: I stand corrected.
7 DR. GLANTZ: You have to pop a stitch in a little
8 kid, it's right there. Less traumatic than infiltrating.
9 DR. BLANC: There's got to be data out there, I'm
10 sorry, on exposure, it seems to me. There's got to be.
11 Somebody has got to.
12 And when you say it's an alkylating agent.
13 DR. KENNEDY: I had an question about that too.
14 At least not in the sense of how I think of an alkylating
15 agent.
16 DR. MARTY: In chemical production it's used as
17 the source --
18 DR. KENNEDY: It might be worth stating that
19 specifically.
20 DR. MARTY: Not as like nitrogen mustard, which is
21 what you guys are thinking about.
22 DR. FUCALORO: Craig, you must have a lot of
23 organic chemistry. Is it in fact a alkylating agent?
24 DR. BYUS: I think it is. I think you're right.
25 That's exactly my interpretation of it, in inorganic
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1 chemistry it's alkylating, but it's not a DNA alkylating
2 agent.
3 DR. KENNEDY: You might --
4 CHAIRMAN FROINES: Wait a second. Wait a second.
5 I am an organic chemist. I have a Ph.D in that field.
6 And so it is an alkylating agent. In fact when
7 you take undergraduate inorganic chemistry you know that
8 ethyl chloride will react with sulfate to form ethyl
9 sulfate. And you study it, it undergoes SN 2 reaction, not
10 SN 1 reaction, so you don't get pure carbonium, but still it
11 will obviously interact with nuclear files.
12 DR. KENNEDY: I'm sure it would.
13 CHAIRMAN FROINES: The related question is has
14 anybody ever looked at it as a carcinogen, since it is an
15 alkylating agent?
16 DR. MARTY: There is an NTP study, apparently.
17 DR. BLANC: Well, then I would like --
18 DR. MARTY: It's an older one.
19 DR. BLANC: Appropre of the discussion on whatever
20 that other chemical is on benzene where I said look for the
21 noncarcinogenic hematologic effects, then I would pull --
22 seemed like this is one where you just relied too much on
23 the EPA and maybe they were not as aggressive.
24 CHAIRMAN FROINES: Must have been tested for
25 carcinogenicity at some point by somebody.
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1 DR. COLLINS: The NTP --
2 CHAIRMAN FROINES: They have. Well, then,
3 that's -- I would have had that referenced in here.
4 DR. KENNEDY: The low little compound gets more
5 attention.
6 DR. MARTY: It doesn't have a lot of play. We
7 talked about the study. It does say --
8 CHAIRMAN FROINES: I got it.
9 DR. MARTY: Yeah. It's at necropsy a complete
10 histopath examination failed to identify evidence of
11 toxicity up to 15,000 ppm.
12 CHAIRMAN FROINES: All that proves is that it's
13 not a very good alkylator.
14 DR. BLANC: Sorry, Peter.
15 DR. KENNEDY: No problem.
16 I guess my one last comment with regard to that is
17 that ethyl chloride you comment that it produced
18 vacuolization in hepatocytes. There are a whole lot of
19 things that do that. I'm not sure of what significance that
20 is.
21 The next compound is ethylene glycol monoethyl
22 ether.
23 Limited human study. And sounds as if it was
24 contaminated significantly, since sperm counts were lower
25 both in exposed and control subjects. May be important to
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1 find out where these people worked. We may not want to go
2 there.
3 Animal studies, I guess my thoughts on this relate
4 to the comments that Dr. Froines had made previously.
5 Obviously, the major point of reference that you
6 use in developing the REL is the study by Barbee in rabbits
7 and rats.
8 Again, as suggested by the human study, the main
9 issue that you were concerned with or that was identified
10 was degenerative changes in seminiferous tubules, and
11 reduced testes weight.
12 The hematologic effects that this keeps coming
13 around again and again and bothers me that we -- the
14 hemoglobin, hematocrit and red count are all the same thing,
15 just different measures of expression, and we never really
16 find out whether this is a suppressive effect or a
17 destructive phenomenon.
18 And this is the study that you used to develop the
19 LOAEL. Some of your other studies, however, suggest that
20 you, even in the absence of a poor dose response curve,
21 which you don't really see even in the Barbee study, that we
22 see there are CNS effects seen in the offspring at 100 ppm
23 per meter squared, bone alterations at 175.
24 I guess the hundred is close to the 103 that you
25 recorded.
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1 But it may be valuable to -- again it brings up
2 the issue of do you take a single study to develop our
3 NOAEL, or can you collect the information from multiple
4 studies, which are certainly suggested by the teratologic
5 effects.
6 I'm not sure how you respond to that, but it seems
7 that this is a compound where that's of substantial
8 importance.
9 Again, your final statement, your final paragraph
10 is repetition of the last compound. Availability of
11 subchronic inhalation, well-conducted histopathologic study
12 and observation of a NOAEL. I would suggest to you that the
13 strongest study at least in the information that we have
14 here is really the neurodevelopmental studies from the
15 pregnant animals.
16 DR. MARTY: Nelson et al, '81. I think that's a
17 good point. We should revisit that. Your point is that
18 Nelson et al, if I'm reading this correctly, has effects at
19 100 ppm.
20 DR. KENNEDY: Right.
21 DR. MARTY: And that we adopted the EPA RfC, which
22 used 100 ppm basically as a no observed adverse effect level
23 for testicular toxicity.
24 CHAIRMAN FROINES: I'm sorry. I'm missing
25 something. Where are you at?
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1 DR. KENNEDY: Where am I at?
2 CHAIRMAN FROINES: What paragraph, what page?
3 DR. KENNEDY: In the, I think this is the May '99
4 version. Yeah.
5 DR. COLLINS: The effects of animal exposure
6 paragraph, behavioral teratogenic effects were examined in
7 pregnant --
8 DR. KENNEDY: Two basic --
9 CHAIRMAN FROINES: Why are we in the May '99
10 version?
11 DR. KENNEDY: The first study done relates to
12 degenerative changes in the testes with a NOAEL at 103.
13 The second study suggests that there are
14 neurodevelopmental changes in offspring of pregnant animals
15 at that dose level.
16 That starts on the bottom of page 70, Nelson's
17 work.
18 DR. MARTY: Okay. I think we should go back and
19 revisit that.
20 DR. KENNEDY: Okay.
21 CHAIRMAN FROINES: I was on the monomethyl of
22 rats, so that's why I was off.
23 But you're going back to this monoethyl, Nelson's
24 work is very good. He's with NIOSH and his work is quite
25 solid. So I would look at it pretty carefully if I were
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1 you.
2 DR. KENNEDY: That's all I've got for that.
3 DR. MARTY: George just pointed out to me that
4 when using repro studies we don't have a subchronic
5 uncertainty factor because the effect is reproductive, so if
6 we --
7 DR. KENNEDY: We're back to that again. We went
8 through that in February.
9 DR. MARTY: If we used Nelson et al we'd get about
10 the same number, because we wouldn't have this subchronic
11 uncertainty factor of 10 but we would have a low observed
12 adverse effect level uncertainty factor of 10, so the
13 uncertainty -- you exchange the type of uncertainty, but you
14 end up with the same number, but I think we need to put that
15 in there.
16 DR. KENNEDY: At least express that --
17 CHAIRMAN FROINES: It's also the issue of trying
18 to put a round peg in a square hole, which is, you know, we
19 have these categories, subchronic, chronic, carcinogenesis.
20 We always seem to have problems of trying to figure out
21 whether reproductive problem is a chronic or acute. Why
22 don't we have a category called reproductive and make a
23 document that has that and has all the chemicals which you
24 can put numbers in based on those endpoints, and not sort of
25 always trying to justify whether it's chronic and acute.
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1 And I know Paul is rolling his eyes because he
2 knows it's a lot of work but --
3 DR. BLANC: Drop it. Don't even go there.
4 CHAIRMAN FROINES: It's worth considering. Let's
5 leave it at that.
6 DR. BLANC: At some future date.
7 CHAIRMAN FROINES: At some future date.
8 DR. KENNEDY: Monoethyl ether acetate, same issue
9 of reproductive effects. I guess I don't know how you'll
10 deal with that.
11 But you do in this case obviously develop your
12 references using that as the endpoint, although this is
13 direct fetotoxicity. All those poor little animals die.
14 Does anybody ever do any real analysis on any of
15 these hematologic effects except to make basic observations?
16 You've got decreased red counts and now you've got little
17 red cells as well suggesting a possibility of a hemolytic
18 response, which would be destructive, rather than just
19 marrow suppressive effect. If these small cells are
20 spherocytes --
21 DR. BLANC: You know in that regard, which is the
22 one of this family of glycol ether or glycol ether acetates
23 that was associated with bone marrow effects in humans and
24 this series that Cullen did of printers where they actually
25 did bone marrow aspirates. I looked quickly through this
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1 group to see where he was cited, because I don't remember
2 which --
3 DR. COLLINS: Spell his name.
4 DR. BLANC: C-u-l-l-e-n.
5 DR. COLLINS: C-u-l-e-n?
6 DR. BLANC: C-u-l-l-e-n. Mark. I think he was
7 first author.
8 CHAIRMAN FROINES: I think it's EGME --
9 DR. COLLINS: It will show up in Med Line.
10 CHAIRMAN FROINES: I think it's one of those two.
11 DR. BLANC: I think, Peter, the thing is that
12 there is in this group it's one of these is the only one, is
13 the only chemical really, industrial chemical, outside of
14 benzene, for which there is really quite convincing human
15 data in the workplace of bone marrow suppression with bone
16 marrow aspirates, quite a good clinical case series.
17 DR. MARTY: We should look at those studies and
18 see what --
19 DR. KENNEDY: Run that down.
20 DR. MARTY: How that relates to the dose levels
21 we're calling NOAELs.
22 CHAIRMAN FROINES: Paul is right, because we were
23 doing a study on glycol ethers in cleaning solvents in
24 janitors at one point, and we found, for example, the most
25 widely used was the butyl compound, and it was contrary to
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1 the rat data. There is a species difference. And I think
2 it's relatively specific that there's -- that there may be
3 only one or two for which there was actually hematologic
4 data, although there's a much more rich database with the
5 animals.
6 DR. MARTY: The butyl is, if I recall, is the one
7 that causes hemolysis in laboratory rodents, EDBE. But that
8 effect doesn't appear to happen in people, although the data
9 isn't that strong to say that it absolutely doesn't happen.
10 It just may be not a very strong effect.
11 EGME has the bone marrow effect, so I guess we
12 cited an EG monoethyl ether in that tox summary.
13 DR. BLANC: I'm sorry. It's the monomethyl ether?
14 DR. COLLINS: Page A-81, Larese, et al, appearing
15 in the British Journal of Industrial Medicine.
16 CHAIRMAN FROINES: Let's go ahead.
17 Let's Peter finish and then we'll go on.
18 DR. KENNEDY: I think I would only say in
19 finishing up EGEEA that I think your comment at the end
20 indicating the difference, that the difficulties in using
21 reproductive effects as an endpoint is clear and reasonable.
22 And monoethyl ether, don't have a whole lot to
23 say. Interesting human observation of transient, presumed
24 granulopenia during exposure, which is reversable. They
25 were also exposed to acetone, for whatever reason. It
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1 popped up in ancient literature as well.
2 No major comments otherwise.
3 CHAIRMAN FROINES: You know, this compound, these,
4 the EGME, EGEE and their respective acetates, they were very
5 important, because when people shifted, for example, from
6 acetone in 1973 when they had the gasoline shortage and
7 people started to use a lot of these compounds in place of
8 acetone, there was a heck of a lot of case studies on
9 neurobehavioral and neurologic effects, and I'm surprised
10 that either you didn't quote it or there isn't any, but I'm
11 surprised there is so little data on neurotoxicity on these
12 compounds.
13 I know people have been looking at the
14 reproductive effects for years, because that's the endpoint
15 of most concern, because the effects are closest to the
16 existing occupational standard.
17 But that it does seem to me that, you know, these
18 older data that Peter just cited on neurologic effects, I
19 think there must be some animal data that -- don't go back
20 and change it, but I mean it's just worth being aware of.
21 The other comment I was going to make is that for
22 these ethyl glycol, monomethyl and monoethyl ether is,
23 remember, that where this whole controversy about these two
24 compounds got started was when they were used as a solvent
25 in photoresistance and semiconductor manufacturing. That's
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1 where the interest all emerged about glycol ethers. It was
2 in the spontaneous abortions associated and at teratogenesis
3 associated with photoresistance in the semiconductor
4 industry.
5 Now I think it's pretty much all gone from that
6 industry. I think they've gotten rid of it essentially
7 entirely, but you might want to have at least a reference to
8 it in your uses, since it is at least a historical use.
9 DR. KENNEDY: You certainly do for NMEA, sort of
10 scary defects in a woman not only exposed acutely who had a
11 child with terrible deformities, but then three years later
12 she had another one. Presumably she didn't keep -- she
13 broke off her exposure.
14 I think NMEA basically looking at the same issues
15 again. Would be interested personally in some details about
16 the changes in blood counts, what the mechanism is here,
17 whether it's a suppressive or not. It seems to be specific
18 to at least one cell line.
19 DR. MARTY: We can look at the studies on
20 hemotologic and bone marrow effects and flesh that
21 information out in this section.
22 DR. KENNEDY: It looks to be important as in the
23 group as a whole. It might be worth doing that.
24 There's one of these that where you go and it goes
25 stir crazy over the so-called immunosuppressive effects and
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1 the methodology is pretty crude. Depression in splenocytes,
2 give me a break. Is there anything that's more contemporary
3 than that?
4 This is in a monomethyl ether.
5 I've lost it.
6 The immune compromising effect of these compounds
7 is referred to a couple of times, but the methodology is
8 pretty archaic. I'm not sure what significance it has.
9 DR. MARTY: The decreased --
10 DR. KENNEDY: How relevant.
11 DR. MARTY: Decreased spleen cell numbers. That's
12 the Exxon et al, '91.
13 DR. KENNEDY: It would be of value, I think, to
14 see whether that's -- unless there's a -- unless it exists
15 as a model that's well accepted in the field, it borders on
16 being not real relevant.
17 And then finally for propylene glycol, which looks
18 to save the day in terms of being the gentler, kinder
19 compound, I think you've done what you can.
20 There's not really chronic exposure information,
21 but apparently you've gotten some comments from the Chemical
22 Manufacturers' Association where they're doing a study and
23 will keep you appraised of that. So I think that would be
24 important when it comes down the pike.
25 DR. MARTY: Yes. We did get a new chronic study
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1 to look at for PGME, and as far as we can tell it's a
2 well-conducted study, and so we are going to recalculate the
3 REL. It indicates a chronic REL of 7,000 micrograms per
4 cubic meter, rather than 2,000. So the EPA did not have the
5 benefit of that study when they developed their EPA RfC,
6 which is based on a subchronic study.
7 So that change is coming down the pike. We got
8 that comment in the latest public comment period, and
9 received the report in July.
10 CHAIRMAN FROINES: All right.
11 DR. KENNEDY: That's it.
12 CHAIRMAN FROINES: I think we can finish before we
13 break for lunch.
14 I'm sorry, Gene, if we're going to hold you over
15 after lunch.
16 So I can be very quick, I think.
17 Melanie, if you're okay.
18 DR. MARTY: Okay.
19 CHAIRMAN FROINES: Hexane, I won't say anything
20 more about. I've made my comments about that.
21 I'll come back to manganese.
22 We're going to deal with MTBE this afternoon.
23 I only wanted to make one comment about MTBE,
24 wherever the devil I put it, but that I only had one comment
25 about the document on MTBE, and that is that if I remember
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1 correctly the problem I noticed that the NOAEL is 403 ppm,
2 and your LOAEL is 3,023 ppm. Seems to me that one could use
3 this as a textbook case for students as to why the safety
4 factor approach isn't worth the paper it's printed on
5 sometimes.
6 Sometimes, I don't want the record to reflect some
7 rejection of the safety factor approach, but I am -- I do
8 want to say that when you have a study where somebody looked
9 at 403 parts per million and they jump up to the next dose
10 level of 3,000 and then we call the 403 as the no effect
11 level, that's strange credibility, I think. And it is
12 reflective of the kind of problems that we get into when we
13 have to force ourselves to have NOAELs that are based on
14 experimental dose levels that we've all read about over and
15 over again and the criticism of this kind of approach, that
16 we end up with these values that are ultimately defined by
17 the dose levels that people picked in their studies.
18 So that's the only comment I make.
19 Whether or not that's a correct, 403 is in fact a
20 NOEL, is a reasonable question, I think. Any rate.
21 Naphthalene we were going to -- let me say one
22 thing about methylene chloride.
23 Stan, what's the blood hemoglobin levels of people
24 who are exposed to environmental tobacco smoke?
25 DR. GLANTZ: Blood?
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1 CHAIRMAN FROINES: Carboxy hemoglobin.
2 DR. GLANTZ: Oh, boy, I don't remember those
3 numbers.
4 DR. BLANC: Low.
5 DR. GLANTZ: They're low.
6 DR. BLANC: An active smoker gets up to, unless
7 they're really really heavy, only gets up to about four or
8 five percent.
9 DR. GLANTZ: Yeah.
10 DR. BLANC: So, I would bet it would be --
11 DR. GLANTZ: Well under a percent, I think.
12 Seven-tenths of a percent is what I remember, but I'd have
13 to look those up.
14 CHAIRMAN FROINES: Just a second. So where people
15 who are exposed to 50 parts per million of methylene
16 chloride, and they had peak blood carboxy hemoglobin levels
17 of 1.9 percent, do we assume that that is --
18 DR. GLANTZ: That could be enough to be
19 significant in some people, because what happens is you run
20 very close to a hundred percent or to high levels of oxygen
21 saturation and if you get -- in some people if you
22 compromise that a little bit the curve is not linear.
23 CHAIRMAN FROINES: So we're running here about,
24 what? What's my blood carboxy hemoglobin right now?
25 DR. BLANC: Less than one percent.
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1 CHAIRMAN FROINES: Less than one percent.
2 DR. MARTY: We also note in the document that the
3 ambient air quality standard for carbon monoxide is based on
4 a carboxy hemoglobin -- or avoiding a carboxy hemoglobin
5 level of two percent.
6 So there was lots of discussion at some point
7 about what a adverse carboxy hemoglobin level would be.
8 CHAIRMAN FROINES: I had one question and it's
9 just a very minor matter.
10 You wrote down a LOEL is 33 parts per million, but
11 when I look at your document it says that the 19 workers
12 were exposed to 40 parts per million, so I don't understand
13 where the 40 gets to 33.
14 It's not a big deal. Let's go on.
15 DR. MARTY: It's actually underneath, the
16 paragraph underneath that. Workers were exposed to average
17 measured concentrations of 40 ppm during the workday and the
18 personal monitors on three of the subjects indicated an
19 eight-hour time-weighted average of 33 ppm over a two-week
20 period.
21 CHAIRMAN FROINES: And you have their specific
22 carboxy hemoglobin levels?
23 DR. MARTY: It's not clear from looking at this
24 whether that average carboxy hemoglobin level of 3.9 percent
25 at the end of the work shift refers -- I think that refers
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1 to all of the 19 workers, not just the three that were used
2 to calculate the time-weighted average.
3 CHAIRMAN FROINES: That's the point. If it's 40,
4 then use 40. If you are saying 3.9 relates to 40, and then
5 you use 40. If it means three people related to 33, then
6 use 33. But you shouldn't -- you should be internally
7 consistent. And it's not a big enough issue to spend any
8 time on. It's almost the kind of thing you could talk about
9 outside of the --
10 Melanie, I made a number of notes on manganese and
11 now that we're doing manganese, I've lost track of what my
12 notes mean. I may talk with you about it separately.
13 I think manganese is an important compound if it's
14 going to be used as a gasoline additive at some point, and
15 that's an organic manganese compound, I would assume.
16 So do we know that that's happening? Is manganese
17 currently now being used --
18 DR. COLLINS: Not in California.
19 CHAIRMAN FROINES: -- as a gasoline additive or is
20 it just proposed to be used?
21 DR. MARTY: I asked the Air Resources Board, who
22 called back home, and they said that it's illegal to use
23 manganese in California as a gasoline additive.
24 And that the US EPA has rejected the use of
25 manganese as a gasoline additive.
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1 I think there are some legal issues remaining with
2 the US EPA's decision.
3 It is used in Canada.
4 CHAIRMAN FROINES: It is used?
5 DR. BLANC: I think it's used by the military, and
6 I'm not sure whether or not they're prohibited under
7 California law. It's used in certain, I think, military
8 uses.
9 CHAIRMAN FROINES: I had a question about the LOEL
10 based on the Roels study. And if I understand it, correct
11 me if I'm wrong, that we're looking at what is essentially a
12 systemic effect. That is neurobehavioral changes.
13 It looks to me as though in your LOEL it's .15
14 milligrams of respirable manganese dust per meter cubed.
15 That's, to me, means that that's an
16 underestimation of the actual dose, because the workers were
17 breathing manganese that included both respirable and
18 nonrespirable, and so they were getting some manganese being
19 absorbed into their systemic circulation through their GI
20 tract, as well as through the lung.
21 Therefore, the amount reaching the brain is a
22 combination of what goes in through the lung and what goes
23 into the GI tract, and so this is not an accurate
24 representation of their dose, of their internal dose.
25 So I don't think you can use -- either you have to
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1 adjust for that or you need to do something, but looking at
2 a respirable fraction -- now, if these people were only -- I
3 didn't look at the paper, so if it is a situation where they
4 were only exposed to fume, then one might --
5 DR. MARTY: It's dust. It's manganese oxide dust.
6 CHAIRMAN FROINES: If it's manganese oxide dust,
7 then most of what they breathe was not respirable, so that
8 the estimate of using respirable dust is an absolute and
9 it's especially since the mass changes by the cube root,
10 that the amount that they got into their GI tract was
11 obviously the vast majority of the material.
12 I don't know what the actual efficiency is
13 absorption to the GI tract is, but it's not zero.
14 So that you can't use this study or at least you
15 can't use this dose level for this determination. It's
16 incorrect.
17 DR. BLANC: It's actually more complicated and
18 interesting than that.
19 And there's, Melanie, there's a recent issue of
20 one of the toxicology journals devoted to this, which was --
21 or the proceedings of a symposium that just came out, but
22 the symposium was two years ago, and you really need to take
23 a look at that. I have the reference back at the office, if
24 you can't find it.
25 But there's a lot of stuff happening with
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1 manganese and you may have better animal and human data.
2 It turns out that there's animal data suggesting
3 that part of the toxic mechanism in terms of route of
4 delivery for manganese may be uptake of manganese by
5 olfactory nerves and direct translocation to the CNS and
6 that that's why manganese has some of the targeted effects
7 it has in the, you know --
8 CHAIRMAN FROINES: Brain.
9 DR. BLANC: In that area of the brain. I think
10 it's in the putamen, but I'm not absolutely sure.
11 So it may not only matter what the nonrespirable
12 part is, but that may be more important.
13 But it actually is very poorly absorbed and very
14 tightly regulated by the GI tract. So GI absorption is
15 probably not particularly an issue with manganese.
16 CHAIRMAN FROINES: I don't agree. Because you
17 should read the papers by Froines on this subject.
18 You find, for example, that lead is deposited, is
19 absorbed with an efficiency of about 40 percent in the lung
20 and it's absorbed with about the efficiency of five percent
21 in the GI tract. But when you calculate the dose to the GI
22 tract based on the amount, the percentage of the size
23 distribution of the particulate, then the amount that is
24 going to the GI tract is way over --
25 DR. BLANC: I believe that's true for lead. I
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1 just don't think it happens to be true for manganese.
2 CHAIRMAN FROINES: I don't think it's going to be
3 zero.
4 DR. BLANC: It's really really low, because there
5 are a lot of dietary additives with manganese, in fact.
6 It's a really important issue, but I think all the data
7 suggests that it just so happens that for manganese that's
8 not particularly an issue.
9 CHAIRMAN FROINES: Okay. Well, I think that the
10 key question is, Melanie, is the size distribution of the
11 particulate, the potential for olfactory nerve uptake and GI
12 tract absorption efficiency.
13 And we need GI tract absorption efficiency in
14 fasting and non-fasting. We need -- it's obviously
15 complicated.
16 Lead goes up to about 50 percent in fasting. So
17 it varies depending on what's going on.
18 DR. MARTY: Okay. We can look at into that.
19 We can also look at the Roels paper. They have
20 some discussion of manganese measured in blood, in urine and
21 we may be able to relate that --
22 CHAIRMAN FROINES: But the point is --
23 DR. MARTY: -- back to using that, rather than the
24 concentrations somehow relate that back to a total dose.
25 CHAIRMAN FROINES: Depending on the issue of the
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1 efficiency of uptake, I would bet that the vast majority of
2 the exposure is to nonrespirable manganese. What then
3 happens, we can argue about it.
4 DR. BLANC: I would say that for consistency you
5 should title this section manganese, comma, inorganic,
6 because you really are not dealing with organic manganese
7 compounds here. Not just the gasoline additive, but, you
8 know, man ebb as well, which is going to be coming up to us
9 separately from our friends at Food and Ag.
10 CHAIRMAN FROINES: And can Paul send us that
11 reference. I think that would be interesting to look at.
12 DR. MARTY: Yeah.
13 CHAIRMAN FROINES: Do you have it? Do you know
14 that?
15 DR. BLANC: I don't know it by heart, but I was at
16 the conference and it took them a year and a half, but they
17 did finally send it.
18 DR. COLLINS: It's a whole series of articles.
19 DR. BLANC: Yeah.
20 CHAIRMAN FROINES: Good.
21 DR. BLANC: It's driven in part by the concern
22 over gasoline additive, obviously.
23 CHAIRMAN FROINES: This issue of nonrespirable and
24 respirable is very important. There are lots of people who
25 go out and use cyclones to sample for various metals,
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1 thinking that you want to look at the respirable fraction
2 when in fact there's -- it's as though people believe this
3 stuff is silica or something and it's pulmonary effects
4 they're looking at and in fact most of the time it's not,
5 especially where it's systemic effects.
6 Anyway, let's take a break for lunch and come
7 back.
8 DR. BLANC: What's left afterwards?
9 CHAIRMAN FROINES: We're going to do MTBE.
10 DR. BLANC: And that's it?
11 CHAIRMAN FROINES: That's it.
12 DR. FUCALORO: When do you anticipate us breaking?
13 CHAIRMAN FROINES: So if we get back here in say
14 45 minutes, and then we'll break about, I would guess 2:00.
15 Let me say this, MTBE is an extremely important
16 compound, so that we shouldn't short-circuit it. We
17 shouldn't try and not have a lunch and short-circuit that
18 discussion.
19 (Thereupon the lunch recess was taken.)
20
21
22
23
24
25
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1 A F T E R N O O N S E S S I O N
2 CHAIRMAN FROINES: Melanie, why don't you go
3 ahead.
4 DR. MARTY: George.
5 DR. ALEXEEFF: George Alexeeff with OEHHA.
6 I thought I'd just give a little bit of a
7 introduction to this document, because it's a little bit
8 different from some of the other documents.
9 First of all, MTBE is already a toxic air
10 contaminant, so we're not necessarily identifying it as a
11 toxic air contaminant.
12 In this case the question was if we considered it
13 carcinogenic or do we consider it carcinogenic and should we
14 have a potency for it, something more along that manner.
15 And another thing that's unusual about this
16 document is most of the information has been based upon a
17 previous OEHHA document that we developed for our water
18 program, it's called a Public Health Goal Program. And that
19 particular document was developed last year.
20 It went out for public comment. We had two peer
21 reviewers, quote, review it, two members of the faculty in
22 the UC system, and then we also had a public workshop. We
23 had public comments. We revised it in response to public
24 comments. So there's a lot of information with regards to
25 development of the document.
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1 And that process all went through last year and
2 then the document was finalized earlier this year.
3 So what we thought what we would do is since that
4 document was fairly recent, up-to-date in the literature, it
5 made sense to not write a whole new MTBE document, but just
6 to base as much of that as possible on the PHG document.
7 And finally we're also, as part of the Governor's
8 Executive Order to phase out MTBE, we're required to write
9 our report, which we're doing right now, and Melanie and
10 Andy are writing that report on replacement fuels for MTBE
11 and what are the risks of replacement fuels of MTBE, or
12 alternative fuels from the current fuel that's in use.
13 And in that process of comparing alternative fuel
14 risks, we would be using the MTBE potency number to help
15 evaluate what are the risks of using one fuel versus another
16 fuel.
17 I wanted to give you that background as to why --
18 I know that you've probably heard it's being phased out so
19 why are we concerned about it or why are we using it.
20 And there's two reasons. One is we have a recent
21 literature review and the other is we still need it to
22 evaluate some relative risk alternatives.
23 And Dr. Andy Salmon will be sort of presenting the
24 document and then we have Dr. Martha Sandy, who prepared the
25 document or the characterization portion of the cancer
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1 portion for our water program, and she'll be providing some
2 information too.
3 CHAIRMAN FROINES: Wait a second.
4 George, we have three people who have to leave at
5 2:30. And I think actually it's four. I think
6 Dr. Friedman, Dr. Fucaloro, Dr. Kennedy and Dr. Byus, so
7 that will leave Paul and me, which doesn't constitute a
8 quorum. So we can only go to 2:30. Point one.
9 Point two is, just to reiterate, this compound has
10 already been designated a toxic air contaminant. There is
11 no Part A document on exposure. There is no Part C
12 document, although the formal Part C document, although
13 you've had comments.
14 So in essence the question is what are you asking
15 the panel to do besides take notice of it.
16 And so I'm assuming for the sake of argument that
17 the risk assessment that you are going to present this
18 afternoon is in the context of in a sense the risk
19 assessments we've been doing today where the panel isn't
20 identifying the TAC and then sending findings or rather a
21 submittal of findings, but that we are rather simply
22 reviewing what you say and then basically approving what you
23 say.
24 DR. ALEXEEFF: That will be fine, since we're not
25 identifying a toxic contaminant. That's fine to review it
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1 in that context.
2 DR. GLANTZ: But does that mean, George, that then
3 we will at some point vote to recommend or to make a
4 conclusion that we agree with the document?
5 DR. ALEXEEFF: Right.
6 DR. GLANTZ: In particular with the unit risk
7 number that you come up with, that comes up at the end of
8 this process.
9 DR. ALEXEEFF: Yes. As we did with the previous,
10 with the acute documents, let's say, or the cancer potency
11 documents in the past.
12 DR. GLANTZ: Okay.
13 CHAIRMAN FROINES: So we're not doing a full --
14 this is not a formal TAC procedure then in that context, as
15 I understand it.
16 DR. ALEXEEFF: It's not following all the formal
17 aspects of the TAC program where findings are then presented
18 to the board and there's a presentation to the Air Board.
19 That is not -- that portion is not happening.
20 CHAIRMAN FROINES: Okay. Is everybody happy with
21 that? Okay.
22 Andy, go ahead.
23 DR. SALMON: I've got the structure and a few
24 details of the compound on the first slide for your
25 information.
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1 What I'm going to do in fact is I'm just going to
2 very briefly describe the studies which are the basis of the
3 number which we calculated, and describe to you how we
4 reached that number.
5 If I can have the next slide, please.
6 The effects on which we based the number,
7 obviously, is the suspected carcinogenicity of MTBE. There
8 are no data on human cancer risk. However, there are
9 several studies that are available in animals.
10 One study in rats by gavage and a study in rats
11 and study in mice by inhalation.
12 If I could have the next slide, please, Jim.
13 The first study I want to describe is the gavage
14 study conducted by Belpoggi and colleagues. This is from
15 Dr. Maltoni's laboratory.
16 The original report appeared in 1995. In response
17 to some comments about the original report, in fact they
18 undertook a pathology review which was published in 1998.
19 The results of that review are also presented in the slide.
20 We have used the revised data from the pathology
21 review in our numerical analysis.
22 The principal findings are, firstly, in female
23 rats an increase in the incidence of lymphomas and leukemias
24 and in male rats an increase in the incidence of
25 interstitial cell tumors in the testes.
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1 If I can have the next slide, please.
2 DR. BYUS: Excuse me. Do you want us to ask
3 questions sort of now or what do you want us to do?
4 DR. SALMON: I'm happy to answer them now.
5 DR. BYUS: Since you have that up there, put the
6 previous one back.
7 DR. SALMON: Sure.
8 DR. BYUS: As I read the report, I have no
9 problems with grouping the lymphomas and leukemias together.
10 I realize that was a concern.
11 DR. SALMON: There's been considerable amounts of
12 debate about that and one of the purposes of the pathology
13 review was to in fact clarify that and get a second opinion
14 on that.
15 DR. BYUS: I think one of the documents, I think
16 from peer reviews, did a very nice job of reviewing that and
17 putting it in the right context.
18 My concern with this study has to do with this --
19 well, there's two concerns.
20 Number one, in regards to lymphomas and leukemias,
21 why did only the female mice show up with increased
22 incidence? I see no explanation for it. It's never
23 commented on. Some of these, a number of these studies are
24 sex specific, other than the Leydig cells, which is sex
25 specific.
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1 DR. SALMON: Easy to understand that, certainly.
2 DR. BYUS: I just find it somewhat unusual.
3 And also the fact that it wasn't commented on.
4 DR. SALMON: I think it's one of the -- as far as
5 I am prepared to say on this occasion, it's an observation.
6 It's an observation which is not, by any means,
7 unprecedented.
8 DR. BYUS: Okay. That was one question.
9 My next question was about doing the tumor
10 incidences on the surviving rats.
11 DR. SALMON: Yeah. In fact, because of the
12 duration of the starting, there's a complexity which is
13 explained in the PHG document, which gives the full
14 analysis. We actually didn't do the survivor analysis for
15 the potency calculation. We present it here, because it's
16 important for the significance calculation to show there was
17 real effects.
18 But the actual potency calculation was not using
19 this survival adjustment.
20 One of the things which we tried to do on the
21 inhalation study was to use a difference survival
22 adjustment.
23 DR. BYUS: It's very confusing.
24 DR. SALMON: Yes.
25 DR. BYUS: It's extremely confusing.
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1 DR. SALMON: I apologize for the complexity of the
2 issues.
3 DR. BYUS: And I'm not -- let me ask another
4 question. My other question would be why are the rats in
5 this study, there's a significant number of rats dying
6 before the end of the experiment even in the control groups,
7 I believe.
8 DR. SALMON: This experiment was in fact run for a
9 rather longer period than the standard 104 weeks. The study
10 design they used actually continued, although dosing
11 terminated 104 weeks, their actual observations --
12 DR. BYUS: Was a lifetime study.
13 DR. SALMON: Was literally, yes. I think it went
14 out to about 132 weeks for some groups. So some of that
15 reflects the difference in study design.
16 DR. BYUS: I got the impression that wasn't the
17 main reason. I got the impression from reading that there
18 was just a lot of animals dying. And why they died, that
19 was my next question, is why they were dying. Were they
20 dying due to the tumors or were they dying from the
21 leukemias or were they dying due to something else? You
22 know what I'm saying?
23 DR. SALMON: I think I must admit I don't have the
24 full mortality analysis at hand, but certainly the --
25 DR. SANDY: If I can answer that.
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1 For the females in the study, there was a dose
2 related decrease in survival.
3 DR. BYUS: There's a dose decrease in survival?
4 DR. SANDY: Right. For the females. They did not
5 see that effect for the males.
6 DR. BYUS: Another one that is very unusual in a
7 sense.
8 But were they -- was the death due to the tumors
9 or was it due to infection or renal toxicity, which is the
10 inhalation study which is what kills everything off.
11 DR. SANDY: It's not reported by the investigators
12 that there was any infection.
13 DR. SALMON: I think if you look at the lymphomas
14 and leukemias are in fact a regular cause of death in aged
15 rats. So if we assume that the tumors here are lethal
16 tumors, then the incidence reported in the high dose group
17 would have a significant impact on the survival.
18 DR. BYUS: Right. If that is in fact the case.
19 And then you can do the aged -- you can somewhat adjust your
20 incidence values if that's the cause of death, but if it's
21 not the cause of death, then it becomes much more
22 complicated to do that.
23 DR. SALMON: One of the problems with this
24 particular study, as far as doing this type of analysis is
25 concerned, is that whereas with the inhalation studies we do
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1 have the full individual animal data, actually Dr. Maltoni's
2 group have never published the individual animal typed tumor
3 and mortality data. We don't have that. So we're basically
4 left with the analysis of the --
5 DR. BYUS: And you did do the incidence aged --
6 the death rate adjusted without that data?
7 DR. SALMON: We used the data as reported, which
8 for the statistical analysis, which you see on the slide
9 here, includes the information on the number of animals
10 alive at the point in time of appearance of the first
11 characteristic tumor, but that information is reported.
12 But for the potency analysis, we felt that that
13 would actually distort the number, because of the
14 considerably longer observation period, which is included.
15 So for the potency analysis we actually used the number at
16 risk as the number started on the start date.
17 DR. FRIEDMAN: I'd like to follow up with another
18 question that relates to other studies of this type. I mean
19 I am impressed with the trend as you increase the dose going
20 from a 3.4 percent up to 25.5 percent, but I'm wondering
21 could there be a multiple comparisons problem here? In
22 other words, was it any special reason to pick those cancer
23 sites where they hypothesized in advance? In other words,
24 there's many potential cancer sites. Could others have gone
25 the opposite way and this just be a chance finding?
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1 DR. SALMON: In fact, if there are any significant
2 changes in, as you say, in the opposite direction, those
3 would have been identified by the pathology analysis, and
4 should have been reported had they occurred. So and
5 certainly if you have the full report of the study like
6 this, you are in a position to examine the possibility of
7 trends like that.
8 This particular analysis is not in any way
9 different from the analyses which are done on studies of
10 this type generally, and in fact there has been quite a
11 debate of some years ago on whether or not it was
12 appropriate to apply a continuity correction to significance
13 tests and things of that sort.
14 And so the statistical tests which we used and the
15 ones which Dr. Maltoni's group used here to some extent
16 reflects the fact that those types of issues have been
17 hashed over in the analysis of study designs of this type
18 over a number of years.
19 Is that -- am I missing anything?
20 DR. FRIEDMAN: Is there an overall -- was the
21 incidence of all cancers combined higher in the treated
22 rats? I mean, because you might think of that as a first
23 screen --
24 DR. SALMON: To be honest, I don't have those
25 numbers in front of me, but I'm pretty confident that that's
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1 the case.
2 DR. FRIEDMAN: Is that something that's routinely
3 looked at and sort of as a first screen before you look at
4 the individual sites?
5 DR. SALMON: The way one of these studies would be
6 conducted, the animals would be subject to gross
7 pathological examination which would identify all tumors,
8 including of course the control groups. And then a
9 histopathological analysis of all observed tumors and of
10 tissues from either all exposed animals or a selection of
11 tissues.
12 But normally there's a comprehensive analysis
13 which looks specifically not just at things which jump out
14 at you, but what are the backgrounds in various tissues.
15 And a well-designed study typically will include a fairly
16 thorough histopathologic analysis of any tissues in which
17 effects are either seen or anticipated.
18 DR. FRIEDMAN: Thank you. That's reassuring.
19 DR. SANDY: If I can add a few things.
20 Dr. Sandy, OEHHA.
21 Back to the number of animals in the study. The
22 females, there were 60 animals per group and males 60
23 animals. So in the females you see there was not much high
24 mortality down to 58 in the controls, the 56 weeks.
25 And just another point that the statistical
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1 analysis that was reported in the Belpoggi study was
2 performed by Dr. David Hoel and his group, and that is
3 indicated in the paper.
4 DR. BYUS: My last question. Sorry.
5 This was a two-tailed analysis or one-tailed, for
6 the significance.
7 DR. SANDY: I believe it's a one tail.
8 DR. BYUS: One tail? Is that right?
9 DR. SANDY: I believe that --
10 DR. BYUS: That's bad.
11 DR. SANDY: -- is often common, commonly used when
12 we --
13 DR. BYUS: It was only done one tail. That
14 increases the significance significantly. I just went
15 through this with a journal.
16 DR. SANDY: I'll have to check.
17 DR. BYUS: Check, please.
18 DR. SANDY: The report --
19 DR. BYUS: It doesn't say anywhere in any of these
20 documents.
21 DR. SANDY: What we were able to do in OEHHA was
22 we did a one-tail T test or Fisher --
23 DR. SALMON: Fisher Exact.
24 DR. SANDY: It was analyzed in the paper and we've
25 indicated that here as significant by a log-ranked test and
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1 I'm --
2 DR. BYUS: But the P values you report are one
3 tailed or two tailed here in this document? That's all I
4 need to know, because if they're one tailed it's usually
5 much higher degree of significance than a two tailed.
6 DR. BLANC: All I was going say is it's only an
7 issue for your values there that are presented as P less
8 than .05 and presumably are between .05 and .01. If that's
9 your concern, you can just divide the ones by .01 by one and
10 a half and --
11 DR. BYUS: The one is .05 and the other one is --
12 nothing is above --
13 DR. SALMON: It's just the way it's always done
14 for this kind of analysis is the -- I mean, certainly if
15 what you're saying is that is the gold standard of
16 significance the .O1 and the .05 not quite so good, then,
17 yes, I would agree with you.
18 The methodology here is exactly what you've seen
19 for the last, however many other hundred --
20 DR. BYUS: Sure. Is it one tail?
21 DR. SALMON: It's one tail, because it's whether
22 or not it's significantly different from the control group.
23 DR. FRIEDMAN: It sounds like you're making the
24 assumption that it can only be harmful. You aren't looking
25 at the possibility that it could be beneficial, if you don't
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1 do a two-tail test.
2 DR. COLLINS: The controls are two at 58. If you
3 went down to zero, 58 you couldn't see any significance.
4 DR. SALMON: I think the expectation -- there are
5 very very few cases in which the effects which you're seeing
6 is anything other than harmful. There are a small number of
7 instances where you see reduction of incidents relative to
8 the control group, due to the variety of interests, many of
9 which actually are reflective of defects in the execution of
10 the study or something like that, differential mortality,
11 things of that sort, but usually that isn't an issue.
12 DR. FRIEDMAN: Craig, if you agree with that
13 assumption that these --
14 DR. BYUS: I don't agree.
15 DR. FRIEDMAN: -- can only be harmful, then the
16 one tail --
17 DR. BYUS: I just went through this long
18 discussion of this with a journal editor and we did the
19 analysis both ways.
20 Statistically, if you design your experiment to
21 look for only an increase in incidents, and for example if
22 you set up so that your control groups have a very very low
23 tumor incidence and you're only looking for an increase,
24 there's only any room to see an increase, a one-tailed
25 analysis, at least by my estimation, is appropriate,
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1 although the journal -- and this is the way we did the
2 experiment to look for an increase only, because it was not
3 set up to look for a decrease. If you want to look for a
4 decrease you want to pick an incidence, we can control tumor
5 incidence, we would pick an incidence that was higher, so
6 you can see it go both ways.
7 So we argued that a one tail was appropriate, and
8 the journal refused this and said that the standard is a
9 two-tailed test.
10 And in this case since you weren't -- you were in
11 a sense looking for whatever in the beginning, either an
12 increase or a decrease, you're not -- the experiment wasn't
13 biased one way or the other by design ahead of time.
14 DR. SALMON: Yes. It's biased in the sense that
15 the control incidence of any these tumors is relatively
16 extremely small. So your chances of seeing --
17 DR. BYUS: In this experiment it is.
18 DR. SALMON: That's --
19 DR. BYUS: The other Leydig cell it's very very
20 high.
21 DR. SALMON: I think where the control incidence
22 is high, that certainly seems a defect of the experimental
23 data.
24 DR. BYUS: Most the literature will report the
25 two-tailed test, which is usually lower significance.
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1 DR. SALMON: I can't --
2 CHAIRMAN FROINES: Can we hold on. Stan's been
3 trying to enter in.
4 DR. GLANTZ: I actually was just talking about
5 this in my statistics class yesterday, and I think --
6 DR. BLANC: Glad you're taking a class.
7 DR. GLANTZ: I am. Thank you for sharing that.
8 Actually, I think you were right and the journal
9 was wrong.
10 DR. BYUS: Thank you, Stan.
11 DR. GLANTZ: Okay. And it really does come down
12 to -- and Gary made this point earlier. It comes down to
13 what the question is. If the null hypothesis is that
14 there's no increase in tumor incidence, then a one-tail test
15 is completely appropriate, but then you are also basically
16 saying you don't care if this is good for you to be drinking
17 MTBE. And I mean if that's the case, then it's appropriate
18 to use a one-tail test.
19 I mean the thing that I'm a little confused by in
20 looking at the slide here and that I was confused by when I
21 read the report was when you're talking about a log-rank,
22 it's not quite clear what you did here, because when you
23 talk about a log-rank test, that's usually done as a
24 two-tailed test and then you're saying you're doing a
25 one-tail Fisher Exact test and it seems that those are
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1 inconsistent. I mean, you need to be consistent in the
2 approach that you're taking.
3 DR. SANDY: Maybe I didn't explain it correctly.
4 We're reporting what was reported by the
5 investigators. They have the original data, the
6 time-to-tumor data. We could not obtain that. So we're
7 reporting their statistical result.
8 DR. SALMON: Fisher Exact.
9 DR. SANDY: Their result, the investigator's
10 result, was the logged-ranked test.
11 Then we have done, based on just the data that's
12 here presented in front of you in the table, without
13 time-to-tumor data, the Fisher Exact test, which was a
14 one-tailed test.
15 DR. SALMON: If I can append to that, certainly
16 Dr. Glantz has hit the nail on the head when he points out
17 that the expectation in the design of a standard
18 carcinogenesis bioassay, the default assumption is that
19 there is no tumor increasing effects and the study design is
20 predicated on that as a null hypothesis.
21 Now, that's the standard approach which is used in
22 conducting bioassays and that is the model which we used in
23 choosing the analysis which we reported that we were able to
24 do, but it clearly -- Dr. Hoel's analysis is different and
25 somewhat more complicated, but unfortunately we're actually
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1 not privy to many of the details of that.
2 DR. GLANTZ: At the very least, I think you need
3 to clarify this in the report.
4 The other thing is it's called the log-rank test,
5 not the log-ranked test. No e-d.
6 DR. SALMON: We can amend that.
7 CHAIRMAN FROINES: Let's go ahead.
8 DR. GLANTZ: That's a major criticism.
9 DR. SALMON: Actually, I don't know if we actually
10 cite that in the report, which we have for the -- but
11 anyway. We will note that for future reference.
12 The next study is an inhalation study which was
13 conducted in rats. One of the things to note is that in
14 fact this was a different strain of rat. This was the
15 Fisher 344 as opposed to the Sprague-Dawley, which was used
16 by the Belpoggi study.
17 The observations in this case were in male rats
18 only, the renal tubular adenoma and carcinoma and again and
19 interstitial cell tumor of the testes.
20 And many of the same comments about the
21 statistical analysis apply here, except that in this case we
22 are reporting the usual analysis by Fishers Exact test.
23 And one of the problems with this study is
24 relatively poor survival. Mid and high dose animals did
25 suffer quite significant mortality during the study. In
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1 fact the exposed groups were terminated somewhat earlier
2 than the projected 104-week duration of the study.
3 DR. BYUS: I've got a comment, question.
4 Now, the incident of the Leydig cell tumors here
5 is much higher in this strain of rats than the other strain.
6 I mean, clearly there's this huge strain dependence on this.
7 And people commented that even in incidence in the controls
8 of 64 percent is on the low side of the historical range for
9 Leydig cell tumors in Fisher rats. They're even up to 70, I
10 forget what the number is, the range is quite high.
11 DR. SALMON: Yes.
12 DR. BYUS: So my question to you is what this
13 looks likes to me for this Leydig cell tumor data, which is
14 used as the best evidence for a dose response, somewhere in
15 the document, it's one of the documents --
16 DR. SALMON: It's not that result actually.
17 DR. BYUS: It is not that result?
18 DR. SALMON: No.
19 DR. BYUS: But in any --
20 DR. SALMON: I'll describe that in a little while.
21 DR. BYUS: I'll show you where it's in here. Not
22 your document.
23 Anyway, what this looks like to me for the Leydig
24 cell tumors is really an effect on lag time, not on
25 incidence. In other words, all these animals basically
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1 ultimately are going to get Leydig cell tumors, and what
2 you're seeing here is an increase or decrease in the time
3 that it takes for them to show up.
4 DR. SALMON: I think you could describe any
5 carcinogenic effects which involves a naturally occurring
6 tumor as an effect on the time to incidence of the tumor.
7 DR. BYUS: You can, but it becomes much more a
8 relevant argument when the incidence approaches 100 percent
9 in the controls. Especially historical, but even here is 60
10 something percent.
11 In my opinion it's much more likely.
12 And the reason I'm making this point is if it is
13 an effect on lag time it's more of a promotional stimulus,
14 and that means it's likely to have some kind of threshold,
15 rather than being a nonthreshold type of response. That's
16 why I think it's important at least to consider it.
17 So in other words if you wait long enough, they're
18 all going to have the same incidence, which is not the case
19 in the leukemia study that you showed before or in the
20 Leydig cell study you showed before.
21 CHAIRMAN FROINES: Remember, that you notice again
22 your mid and high dose animals are terminated at 97 and 82
23 weeks, so that in fact your high dose animals are being
24 terminated earlier in the study, rather than later in the
25 study.
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1 DR. BYUS: That's true. But the problem is
2 because over on top of this problem with this study is this
3 horrible renal toxicity that is killing off the animals in
4 the high doses.
5 So I just think it's just not very good from these
6 points of view. You have a very high toxicity, renal
7 toxicity. You have certainly in the Leydig cell, you have a
8 very high incidence, which is increased statistically here.
9 But to me it looks like an effect on the lag time only and
10 not necessarily any real effect on an incidence mechanism.
11 DR. SALMON: A theoretical analysis of tumor
12 incidence actually does treat the time to tumor appearance
13 being reduced by the exposures to the carcinogen as a
14 carcinogenic effect. So that isn't conceptually -- there's
15 not conceptually saying anything different than what the
16 underlying assumption of the model is in the first place.
17 However, I would entirely agree with you that
18 there are significant problems with this study, one of which
19 is the high incidence of tumors in the testes and another of
20 which is the relatively severe toxicity and early mortality
21 in the study.
22 I would say that although clearly this study, in
23 our opinion, has some very significant defects, and contrary
24 to some of the comments of which we've heard from elsewhere,
25 we inclined to the view that the Bellpoggi study is actually
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1 a much better one in terms of both its conduct and it
2 interpretability.
3 Nonetheless, yes, there are certainly some
4 significant defects to this study.
5 However, I think it's a moot point as to whether
6 those are any worse than the defects of studies which are,
7 you know, often used in other contexts.
8 But I would also say that, you know, one of the
9 ways that we can address whether or not these defects are
10 fatal is to actually look at the dose response calculations,
11 which I will describe in a minute, in a few minutes, to see
12 to what extent those results are consistent with other
13 studies, because I think that where you have a study which
14 has defects of this sort that does become an important
15 question.
16 CHAIRMAN FROINES: I think at this point we should
17 go through and let you finish, because we're going to have
18 to stop and I'd like to have a complete presentation on the
19 material before the panel.
20 I know Craig wants to jump in, but --
21 DR. BYUS: It's all right.
22 CHAIRMAN FROINES: I think it be better if we got
23 through the entire discussion.
24 DR. SALMON: Okay. Well, the mouse study
25 inhalation study in fact reports incidence of hepatocellular
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1 adenoma and carcinoma, again with significant mortality
2 issues with this study.
3 Obviously, there are other things which can be
4 said about all these studies.
5 I'd like to proceed now to just describing what we
6 did with these data, which basically we were trying to make
7 the best of what we had available in coming up with a
8 number.
9 And one of the things we did, because we had
10 studies both by inhalation and by gavage, we developed a
11 pharmacokinetic model, which was designed to allow us to
12 compare the results of the studies by the two routes.
13 We did not have sufficient pharmacokinetic data in
14 mice to be able to apply the model to the mice, so we were
15 only able to consider the rat data for the pharmacokinetic
16 models.
17 If I can have the next slide, please.
18 This is one of the sort of one of those
19 isn't-that-neat type pictures. This is a diagram of the
20 model. Obviously, if you require more details, then we can
21 point you to those.
22 But the idea here was, as I said, was to allow us
23 to compare the results of the inhalation studies and -- or
24 the rat inhalation study and the mouse.
25 DR. GLANTZ: Can I ask a quick question here.
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1 When you look at this model and you describe it in
2 the report, there's a zillion parameters.
3 DR. SALMON: Yes.
4 DR. GLANTZ: That go into all these
5 pharmacokinetic models. How good are those parameters?
6 DR. SALMON: As many of them as are possible are
7 externally determined. Things like blood flow rates and
8 breathing rates and things of that sort are obtained
9 independently from other sources.
10 The partition coefficients are things which in
11 general can be at least estimated on the base of independent
12 experimental observations.
13 However, I think that that's a legitimate question
14 as to how good the individual detail predictions of the
15 model are.
16 As far as the use that we are putting the model to
17 is concerned, I think the primary thing is does it make a
18 reasonable job of fitting the observed data and is it
19 therefore appropriate for making a fairly crude level of
20 estimate.
21 And what we were looking for basically was the
22 overall amounts of material metabolized at the various doses
23 and by the two routes.
24 So I think what I'm saying is that some of this
25 detail, obviously the individual parameters, particularly
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1 those which are not externally measured and valued against
2 data obtained from other sources, are somewhat uncertain,
3 but that the overall conclusion of the model, if you like,
4 is probably not too far from the truth, especially provided
5 you don't extrapolate too far away from the starting point.
6 DR. BLANC: Stan, we better move on or we're not
7 going to be able to hear from our other speaker.
8 DR. GLANTZ: If I can say one quick thing.
9 I think that -- and this is something I've talked
10 about and we've done before -- I think it would be useful to
11 do a little sensitivity analysis on the parameters and make
12 sure that the results are not highly dependent on the
13 specific values.
14 Let's just go on.
15 DR. SALMON: Yes, I agree with you. And in
16 general we do do things like that.
17 DR. GLANTZ: Go on. I'm sorry.
18 DR. SALMON: I also wanted to just include a slide
19 explaining what we were doing here was using the LED 10
20 methodology as described in the proposed risk assessment
21 guidelines from US EPA, rather than the traditional
22 linearized multistage model.
23 We actually did both calculations, and they don't
24 produce a very substantially different result. But we tend
25 to prefer this methodology, especially in cases where the
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1 underlying mechanism is uncertain and we aren't therefore
2 necessarily entitled to assume that the linearized
3 multistage model is a good description of the dose response
4 across all levels of dose right away from the experimental
5 doses down to low levels of exposure in the environment.
6 However, one of the things which received quite a
7 bit of discussion in the PHG reports was the fact that the
8 mechanism of the effect here by MTBE is uncertain.
9 We therefore chose the default methodology, which
10 does assume a linear dependence of risk on dose, low doses.
11 So we are using a linear extrapolation here, but it's based
12 on the LED 10 benchmark, rather than basing it on the
13 traditional linearized multistage model.
14 DR. FRIEDMAN: What do P and D stand for in that
15 equation?
16 DR. SALMON: Probability of tumor at dose D.
17 Okay.
18 Now, this slide reports the route-to-route
19 extrapolation for the rat oral inhalation studies.
20 And what I want to point out to you, I'll try and
21 do this briefly here, is that with the exception of the
22 testicular tumors in the inhalation rat study, the Chun et
23 al study, the other numbers are in fact consistent within a
24 fairly narrow range, and we do believe that the divergence
25 of the number for the testicular tumors in the Chun et al
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1 rat does in fact reflect the problems with the high
2 background incidence and such things, which is exactly what
3 Dr. Byus was just talking about just now.
4 So in a sense I think what I'm saying is that I
5 agree that this defect does cause a problem for the
6 analysis, but it isn't perhaps disastrous, but we can see
7 how it is influencing the number.
8 Apart from that, the Leydig cell tumors in the
9 leukemia lymphomas in the Belpoggi study and the renal
10 tubular cells in the male rats of Chun et al are fairly
11 concordant, at least very much so within the sort of bounds
12 of confidence that we have with these kinds of estimates.
13 The other thing which I haven't actually got on
14 this slide, which is described in the PHG report, is the
15 fact that although we can't compare the mouse results on the
16 slide, because we don't have a mouse pharmacokinetic model,
17 in fact the mouse liver tumor results are also consistent
18 with the Chun et al rat renal tubular cell adenoma and
19 carcinoma data.
20 So by and large we're seeing that although there's
21 a diversity of sites, a diversity of species, a diversity of
22 strains, and a number of questions which have been raised
23 about the individual studies, by and large we are able to
24 obtain a reasonably consistent estimate of carcinogenic
25 potency.
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1 This slide also incidentally illustrates the point
2 I made just now, that in this particular data set, the LED
3 10 methodology does not produce a highly different result
4 from what you see with the traditional linearized multistage
5 model, which is what is reported here as Q 1 star in the
6 table.
7 If I can have the next slide, please.
8 DR. GLANTZ: Can I ask one other quick question?
9 DR. SALMON: Sure.
10 DR. GLANTZ: One other thing that I had a hard
11 time figuring out, which this slide I also maybe I wasn't
12 understanding, is how the model predictions from the PBPK
13 model compared to the actual observed data. I mean, that's
14 not in this slide, is it?
15 DR. SALMON: No. The numbers from the -- well,
16 from the -- with the actual pharmacokinetic data --
17 DR. GLANTZ: Well, no. You had --
18 DR. SALMON: You talking about the potencies
19 calculated on the basis of the exposed concentrations?
20 DR. GLANTZ: Again, I don't want to derail the
21 conversation, but if need be we can come back to this.
22 DR. SALMON: Those data are presented in the PHG
23 report, so we can discuss those later if you would like to
24 do that.
25 DR. GLANTZ: I don't want to derail. We can put
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1 this on the agenda for later.
2 But when I was looking through the report, like I
3 think it was table 11, 13, yeah, 11 and 13, where it looked
4 like you were coming up with predictions the PBPK model and
5 then presenting actual data, and I was having a very hard
6 time making the comparison and deciding if the predictions
7 were good or bad.
8 I think I don't want to derail the discussion.
9 DR. SALMON: The data are in the report.
10 DR. GLANTZ: Maybe next time we discuss this you
11 can address that specifically.
12 Go on. I'm sorry.
13 DR. SALMON: So in order to obtain a best estimate
14 for the cancer potency, we actually took a geometric mean,
15 and the data we used were those data sets which were
16 reasonably consistent, which was the kidney tumors in the
17 rat inhalation study, and both the leukemia lymphoma in
18 females and the Leydig cell tumors in the males from the
19 Bellpoggi study.
20 The individual tumor endpoints varied over what by
21 the standards of these sorts of estimates is considered to
22 be a relatively small range.
23 The other thing which we considered was we did
24 look at a time-to-tumor analysis, which we could do from the
25 inhalation study, because we have those data, but we didn't
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1 particularly have much confidence in that, because we felt
2 that one of the problems with the time-to-tumor analysis is
3 that you're actually extrapolating to a theoretical end of
4 lifetime tumor incidence, which in this case unfortunately
5 is well outside the range of any observations in the study.
6 So we felt this estimate, which was rather higher
7 than the one we quoted, it had a rather low degree of
8 confidence. We didn't use that estimate.
9 If I can have the next slide.
10 We used the potency estimate calculated using the
11 pharmacokinetic model to derive an inhalation potency for
12 humans at low dose, and we relied on the recently published
13 data by Nihlen and colleagues suggesting that approximately
14 50 percent of the inhaled MTBE at low doses would be
15 metabolized.
16 And making the usual assumptions we come up with
17 an inhalation potency estimate as a unit risk factor of 9.3
18 times 10 to the minus 7 part per billion, or 2.6 times 10 to
19 the minus 7 per microgram per cubic meter.
20 I'm just going to briefly summarize.
21 We're relying on the identification of this
22 substance as a toxic air contaminant with other hazardous
23 air pollutants as Dr. Alexeeff described at the beginning.
24 We are depending for the further analysis of the
25 carcinogenesis data, firstly on the University of California
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1 report, which Dr. Froines has, I think, already drawn to
2 your attention, and also on the hazard identification and
3 quantitative analysis by OEHHA, which is in the PHG report.
4 Cancer slope factors based on oral and inhalation
5 experiments in two different strains of rats at three sites.
6 Pharmacokinetic model is used for interroute
7 extrapolation in animals.
8 That's the end of what I have to say.
9 DR. MARTY: We had a public comment period on the
10 derivation of the inhalation unit risk factor at the
11 beginning of the summer, and we got comments from the
12 Oxygenated Fuels Association, the Western States Petroleum
13 Association, and from Dr. Richard Wilson for Lyondell
14 Chemical Company.
15 Basically, most of the comments concerned what I
16 call hazard identification issues, is it or is it not a
17 carcinogen.
18 And also the choice of the model used to develop
19 our public health goal number, and also our cancer potency
20 factor.
21 I think it's easiest just to briefly go over the
22 hazard ID issues. The concerns raised were that it's
23 probably not genotoxic, therefore you should not use a
24 linear, type of a linear model to estimate the cancer
25 potency factor.
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1 That carcinogenicity may be a result of toxicity
2 resulting from high doses that were used.
3 And that the types of tumors present have
4 questionable relevancy to people, namely the male kidney
5 tumors, the mouse liver tumors and the Leydig cell tumors,
6 for a variety of reasons.
7 I thought it would be most appropriate to let
8 Martha Sandy address those issues. The same issues came up
9 when they sent the public health goal out for a public
10 comment and peer review.
11 And then finally there was one comment from
12 Dr. Richard Wilson. What he did was went back and he
13 calculated his own estimate of what the cancer potency
14 factor would look like and it's about he estimated a PHG
15 based on carcinogenicity that's about six fold higher than
16 the PHG that was eventually adopted by OEHHA. He based it
17 on his own estimates of potency and exposure assumptions.
18 So given that there's a lot of uncertainty and
19 there's all these issues that come to bear, my personal
20 opinion is that that's pretty good agreement and doesn't
21 really represent a major disagreement.
22 CHAIRMAN FROINES: Six fold meaning six fold less
23 health conservative?
24 DR. MARTY: Right. Correct.
25 CHAIRMAN FROINES: We have a cab for the people
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1 who are leaving and so they should leave here about 25 to
2 3:00.
3 Is that right, Peter?
4 He says ten minutes, the cab will be here in ten
5 minutes.
6 DR. MARTY: Martha has six slides.
7 DR. SANDY: You have copies of them. I don't know
8 if you'd like me to go through them or not.
9 CHAIRMAN FROINES: Just go through what you want.
10 DR. SANDY: Very quickly. You've seen this
11 before, this is just a summary of the data we have, where
12 this data is coming from.
13 And again the tumor sites, lymphomas and
14 leukemias, which are, as far as I know there is no question
15 as to whether they're relevant to humans.
16 Leydig cell tumors are still considered for risk
17 assessment purposes relevant to human risk.
18 Renal tubular adenomas and carcinomas, the
19 question here was whether alpha 2 U globulin nephropathy was
20 involved.
21 And very quickly it appears that MTBE may be
22 binding weakly to that male rat specific protein. So there
23 may be some interaction there, but it's very very weak and
24 it doesn't seem to explain the entire picture or explain
25 entirely the concerns of those tumors in the bioassay.
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1 And then in mouse we have the hepatocellular
2 adenomas and carcinomas.
3 MTBE is not nonpositive in a number of
4 genotoxicity assays. There are a couple where we have seen
5 positive results. It's positive in the activated mouse
6 lymphoma forward mutation assay and the rat lymphocyte comet
7 assay for DNA strand breaks.
8 The metabolites, I guess I should back up. We
9 don't know if it's MTBE that's the active carcinogen, or if
10 there are metabolites of MTBE that are contributing to the
11 tumors we see on the animal studies.
12 The tumors -- the metabolites that have been
13 tested in genotoxicity assays, there's only two. One is
14 tertiary butyl alcohol, it's nonpositive. Formaldehyde has
15 been tested and is positive.
16 And further studies of the possible involvement of
17 formaldehyde in inducing the mouse liver cell tumors, the
18 studies that have been performed to date do not suggest a
19 role for formaldehyde at that tumor site, but we haven't
20 looked at other tissues.
21 Next slide.
22 MTBE has induced renal tubular cell adenomas and
23 carcinomas --
24 CHAIRMAN FROINES: I should say that, remember,
25 that isobutane is also a combustion product and it is
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1 mutagenic.
2 DR. SANDY: That's right.
3 For tertiary butyl alcohol, we have observed the
4 same type of kidney tumors in Fisher rats exposed via
5 drinking water.
6 The inhalation studies were in Fisher rats as
7 well.
8 Formaldehyde is induced, leukemias in
9 Sprague-Dawley rats exposed via drinking water, so there's a
10 commonality of tumor sites between these metabolites and
11 MTBE.
12 And the next slide.
13 There are a number of concerns, as Andy has
14 alluded to, with the data. All of the studies have their
15 problems. High doses, et cetera, for study design problems.
16 Early mortality.
17 Study reporting, we would like to have more
18 complete reporting of all the studies, not just the
19 Bellpoggi study.
20 Relevance of tumor site and type. I've just
21 described.
22 Next slide, please.
23 Then I have slides on the alpha 2 U globulin,
24 nephropathy, which I don't know if I need to go into detail
25 here.
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1 Dr. Froines, or the committee, would you like me
2 to elaborate a little bit on this?
3 CHAIRMAN FROINES: We're not going to really have
4 any time to discuss any of this so you might as well go fill
5 out the time and then we'll take it up next time.
6 DR. SANDY: Let me back up a bit then.
7 There are no mechanistic hypotheses that are out
8 there to explain the lymphomas or leukemias that have been
9 seen in the female rats in the gavage study.
10 It has been hypothesized that the liver tumors
11 seen in the mouse, and specifically the female mouse, which
12 had an increase of adenomas and carcinomas. The male mice
13 only had a an increase in the carcinoma.
14 DR. BYUS: This thing is very unusual, that
15 effect. Go ahead.
16 DR. SANDY: People have looked at whether looking,
17 focusing just on the liver tumors in the female mice, if
18 there could be some sort of hormonal interaction going on or
19 promotional effect of MTBE. And the data available to date
20 does not show that out. There is no hypothesis that has
21 been supported by the data, so we do not know what the
22 mechanism of action in the mouse liver is.
23 To go to the rat kidney tumors, the alpha 2 U
24 globulin nephropathy hypothesis has been pursued to a large
25 extent, and there's a lot of data.
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1 There are criteria that have been developed by
2 both US EPA and more recent by IARC, which are there to help
3 evaluate a study to decide if in fact an agent is working
4 through this mechanism. We have looked at that using both
5 the US EPA criteria and the IARC criteria and we felt that
6 the data available for MTBE just do not indicate that this
7 is an agent working solely through this mechanism.
8 The data supporting this mechanism include
9 observed of mild to moderate number of {SKPAOEUZ} drop
10 {HREUTS} in {PHAOEPBL} approximate mall tubular cells which
11 stains weakly for alpha 2 U globulin.
12 There's a slight dose dependent increase in alpha
13 2 U globulin in renal reactivity in the rat kidney cytosol
14 by the Elisa assay and here we're reporting results that
15 came out in '97 by inhalation where they found an increase
16 of up to 150 micrograms of the alpha 2 U globulin per mig
17 total protein was the control level and the level in the
18 MTBE treated at the high dose by inhalation was 200. So
19 there wasn't much of an increase.
20 There's a recent paper out in Toxicological
21 Sciences where by an oral dose of MTBE they now have they're
22 observing the bindings up to 250 micrograms. So it's still
23 very weak binding. They have statistical significance, but
24 it's not great level binding.
25 And MTBE binds weakly to alpha 2 U globulin in
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1 vitro.
2 There's a dose dependent increase in cell
3 proliferation in the renal cortex.
4 And MTBE has little or no genotoxicity activity.
5 Next slide, please.
6 Now, there's on the other side data indicating
7 that there's lack of a significant role of this nephropathy
8 in the development of tumors. It does not appear to be
9 specific to the male rat for the nephropathy or the renal
10 tumorigenicity. There was an observation of one renal cell
11 adenoma in the female and the females had chronic
12 progressive nephropathy dose dependent with MTBE.
13 No clear exposure related increase in staining for
14 alpha 2 U globulin was observed in the MTBE treated male
15 rats.
16 And there's no alpha 2 U globulin positive
17 proteinaceous casts at the junction of the proximal tubules
18 in the thin loop of Henle, and these casts are something
19 that's a hallmark of alpha 2 U globulin nephropathy.
20 No linear mineralization of papillary tubules was
21 observed. Again, that's another hallmark of this condition.
22 No binding of MTBE to alpha 2 U globulin or male
23 rat renal proteins was observed in vivo.
24 And a very weak interaction between MTBE and the
25 male rat renal proteins hasn't been observed in vitro using
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1 a kidney homogenate system and the interaction did not
2 survive dialysis or anion exchange chromatography. Again,
3 this has been looked at in this more recent paper and again
4 confirming it's a very weak interaction. It doesn't survive
5 chromatography.
6 In summary, we do see tumors, Leydig cell tumors
7 in the testes, leukemias and lymphomas in both sexes of the
8 rat in a lifetime gavage study.
9 We have Leydig cell tumors in the testes and renal
10 cell tumors in male rats of a different strain in a 24-month
11 inhalation study.
12 We have hepatocellular tumors of both sexes of the
13 mouse in an 18-month inhalation study.
14 There's little or no genotoxicity observed.
15 The mechanism is unknown for induction of tumors
16 at all these sites.
17 There's supporting evidence provided by the
18 carcinogenic activity of formaldehyde and TBA, which are
19 primary metabolites of MTBE.
20 Thank you.
21 CHAIRMAN FROINES: Well, Peter, what do we have
22 time wise?
23 Five minutes. Five minutes of comments.
24 Who would like to start?
25 DR. BLANC: Well, I'm very, again, I'm, despite
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1 what you said at the beginning, I'm a little unclear as to
2 how this panel can be most useful in regard to this single
3 point estimate that I assume you are required to promulgate
4 as a supplement to previous analyses. So how can we be of
5 service?
6 DR. ALEXEEFF: I think here's the issue.
7 Like a previous compound that the panel dealt
8 with, DEF, MTBE has not been identified as a carcinogen,
9 either in the state or by IARC or nationally, so it's not a
10 identified carcinogen. But there is data, as you've seen,
11 and now you've seen the good, the bad and the ugly of that
12 data.
13 But under the statute that we're working under
14 where in the face of uncertainty we're supposed to estimate
15 a range of risk, and we're supposed to -- that is the sort
16 of the area that we're working in, so the question we're
17 asking you whether or not our use or our development of a
18 potency cancer potency estimate for this compound is
19 appropriate and whether the actual number we develop is
20 reasonable, scientifically speaking. That's really what
21 we're asking you for.
22 How you actually agree with it or review it or
23 adopt it --
24 DR. BLANC: And then you would be transmitting it
25 or having us transmit to the Air Resources Board?
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1 DR. ALEXEEFF: No. There's no transmittal to the
2 Air Resources Board. We will simply be -- we would record
3 the conclusions similar as we did with the other chemicals
4 we're working on, these multiple chemicals, and we would use
5 that number and probably the Air Resources Board use that
6 number of any calculations they need to make.
7 DR. FUCALORO: So the number you're thinking of
8 recording is the one that's 2.3 times 10 to the minus 7
9 meters cubed per microgram, is that right?
10 DR. ALEXEEFF: Right.
11 DR. BLANC: Is there some reason why you wouldn't
12 want to take, given the level of uncertainty, wouldn't want
13 to take the approach that you took with diesel exhaust of
14 having a range of estimates or reporting a range of
15 estimates, rather than coming down with a single number?
16 DR. ALEXEEFF: We have a range of estimates in the
17 document already presented.
18 Previously in our PHG, in our water standard, we
19 pretty much had to come up with one level. We had to sort
20 of make a decision for our water standard. So part of it is
21 simply we just made -- decided to make the same decision for
22 the air.
23 But definitely we do have a range, and you can see
24 the uncertainty.
25 But once you throw out that study that Craig was
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1 referring to, that Leydig tumors where the high incidence,
2 once you throw that out, the other numbers are fairly
3 consistent, so the range would be fairly narrow. I mean,
4 it's not like diesel where you have a range of some, you
5 know, at least an order of magnitude, let's say.
6 DR. BLANC: I mean, then I would say it would make
7 your document even stronger if you would say, and
8 furthermore if we take a range excluding the most
9 problem-ridden study, the range is from 1.7 to 2.3, or
10 whatever the hell it is.
11 CHAIRMAN FROINES: Let me interject, because we
12 have to stop.
13 I have a letter here from Mike Kenny from the Air
14 Resources Board and he says, and I quote, this letter is to
15 formally request that the Scientific Review Panel review the
16 Office of, well, OEHHA, enclosed documentation on the
17 carcinogenic potency of methyl tertiary butyl ether in
18 accordance with the usual procedures for peer review of the
19 health values for toxic air contaminants.
20 So we have a request basically to follow, quote,
21 usual procedures. And within the context of the 1807 law,
22 that means that we have to determine whether or not your
23 document is, what's the words?
24 DR. GLANTZ: Scientifically horrible.
25 CHAIRMAN FROINES: No, no. What is the word,
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1 Bill? What's the expression?
2 DR. ALEXEEFF: It's scientifically sound.
3 CHAIRMAN FROINES: Not seriously deficient.
4 DR. ALEXEEFF: That language has been struck from
5 ours. It's now scientifically sound.
6 CHAIRMAN FROINES: This is from the Air Resources
7 Board. Therefore we have to meet the criteria within the
8 context of the law that establishes this panel, I think.
9 I don't know about what law you operate under, but
10 I know the law we operate under, and so we have to determine
11 whether or not this document is seriously deficient.
12 Is that correct or not correct, Bill?
13 This is from Mike Kenny, not from Joan Denton, and
14 he says the usual procedures for peer review. And so by
15 that definition, as far as I know, we have to determine
16 whether it's seriously flawed.
17 MR. LOCKETT: I think there is the statute allows
18 you to find the document acceptable in terms of current
19 science.
20 There is also under 1807 if you were going to do a
21 finding that it's not seriously deficient.
22 But I think in this case, review and approval of
23 the document will satisfy the statute.
24 CHAIRMAN FROINES: Okay.
25 DR. ALEXEEFF: The statute says you have to find
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1 that it's based upon sound scientific knowledge, methods or
2 practices. So it's a slight revision.
3 DR. BYUS: It's in the statute, which is not
4 mentioned, I mentioned to you, it's whether or not a
5 threshold exists for this compound. We usually answer that
6 question for each compound that we think is a carcinogen,
7 does a threshold exist or not.
8 That's another -- I mean, as I told you, it's
9 another concern I have, especially on this compound.
10 CHAIRMAN FROINES: Unfortunately, there's no
11 evidence whatsoever about a threshold. It's almost moot.
12 DR. ALEXEEFF: The question is can we identify a
13 threshold, is really what's asked, not does it exist or not,
14 but can we identify.
15 DR. BYUS: Can we identify it. Okay.
16 DR. BLANC: I'd like to move that we adjourn the
17 meeting.
18 DR. KENNEDY: Second.
19 (Thereupon the meeting was adjourned
20 at 2:43 p.m.)
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Janet H. Nicol
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