1 MEETING
2 OF THE
3 SCIENTIFIC REVIEW PANEL ON TOXIC AIR CONTAMINANTS
4 CALIFORNIA AIR RESOURCES BOARD
5
6
7
8
9
10 MILBERRY CONFERENCE CENTER
11 UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
12 500 PARNASSUS AVENUE
13 SAN FRANCISCO, CALIFORNIA
14
15
16
17
18
WEDNESDAY, DECEMBER 2, 1998
19
9:00 A.M.
20
21
22
23
24 Janet H. Nicol
Certified Shorthand Reporter
25 License Number 9764
PETERS SHORTHAND REPORTING CORPORATION (916) 362-2345
ii
1 APPEARANCES
2 MEMBERS PRESENT:
3 Dr. John Froines, Chairman
Dr. Paul D. Blanc
4 Dr. Gary Friedman
Dr. Anthony Fucaloro
5 Dr. Stanton Glantz
Dr. Peter S. Kennedy
6 Dr. Hanspeter Witschi
7
REPRESENTING THE CALIFORNIA AIR RESOURCES BOARD:
8
Mr. Bill Lockett, Deputy Ombudsman, Northern California
9 Mr. Peter Mathews, Office of the Ombudsman
10
REPRESENTING THE OFFICE OF ENVIRONMENTAL HEALTH HAZARD
11 ASSESSMENT:
12 Dr. George Alexeeff, Deputy Director for Scientific Affairs
Dr. Jim Collins
13 Dr. Melanie Marty, Senior Toxicologist
14
REPRESENTING THE DEPARTMENT OF PESTICIDE REGULATION:
15
Dr. Roger Cochran, Staff Toxicologist
16 Mr. Tareq Formoli, Associate Environmental Research
Scientist
17 Mr. Paul Gosselin, Assistant Director
Dr. Wynetta Kollman, Associate Environmental Research
18 Scientist
19
20
21
22
23
24
25
PETERS SHORTHAND REPORTING CORPORATION (916) 362-2345
iii
1 INDEX
2 PAGE
3 AGENDA ITEMS:
4 1 Continuation of discussion of the proposed 1
agenda for an SRP workshop entitled: "Pesticides
5 in the Air"
6 2 Review of draft report: The Determination of 6
Acute Reference Exposure Levels for Airborne
7 Toxicants
8 3 Review of draft report: Evaluation of Molinate 118
as a Toxic Air Contaminant
9
Adjournment 191
10
Certificate of Reporter 192
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
PETERS SHORTHAND REPORTING CORPORATION (916) 362-2345
1
1 P R O C E E D I N G S
2 CHAIRMAN FROINES: Unless there are reasons to the
3 contrary, we should officially call the meeting to order and
4 proceed.
5 And I believe we have a quorum, five people.
6 Yeah. And Peter will be back shortly.
7 On the agenda, the first item on the agenda is
8 continuation of the discussion of the proposed agenda for an
9 SRP workshop entitled "Pesticides in the Air," SRP and the
10 Pesticide Regulation.
11 I won't take much time. I'll just update you and
12 then we can move on.
13 We had a brief discussion with Craig Byus, Peter
14 Witschi and myself to talk about the workshop, and the next
15 workshop, the next conference call will include a
16 representative from DPR and from OEHHA. We wanted to have a
17 first meeting where we actually had a brief discussion just
18 amongst ourselves to see if there were issues that we wanted
19 to consider.
20 But it was a very useful meeting. Peter suggested
21 that the first workshop focus on the toxicology of
22 pesticides and that's of course very broad, and we'll have
23 to narrow that down to some degree.
24 And then, secondly, that we focus also on the
25 pesticide approval process, because there is some -- there
PETERS SHORTHAND REPORTING CORPORATION (916) 362-2345
2
1 are clearly some issues relating to the FIFRA process and
2 good laboratory practices on the one hand, versus more
3 traditional scientific peer review processes for evaluating
4 the literature.
5 So those issues need to be discussed and so we
6 thought that that was a second item for the workshop.
7 We then began to discuss potential people who
8 might be participants and a number of names came up,
9 including Barry Wilson from Davis, Don Jendon from UCLA and
10 some others who I won't go through. We know that Barry
11 Wilson has just chaired a committee, National Academy
12 Science Committee, on serum cholinesterase and so that might
13 be of particular interest.
14 There was stated interest in issues of delayed
15 neuropathy mechanism and neurobehavioral effects.
16 And we know that Peter Spencer is updating his
17 neurotoxicology book, so we're going to try to obtain from
18 him, from Peter, at Oregon, those chapters to, in a sense,
19 help us to define who are the most current, most advanced
20 scientists.
21 So the process is, I think, going forward and
22 we'll have a series of conference calls over the next month
23 and hopefully come up with a list of names by January, so
24 that we can move ahead with the February date.
25 So that's pretty much an update. If there are any
PETERS SHORTHAND REPORTING CORPORATION (916) 362-2345
3
1 questions, Peter or I can try to answer it.
2 I think it's still going to be tight, because we
3 have a lot of work to do to identify participants and narrow
4 the specific issues down, but I think we're moving ahead.
5 And I want to reiterate one thing that was said at
6 the last meeting, and that is Paul Blanc doesn't know that
7 we felt that there were so many issues that we may want to
8 have a series of workshops on pesticide health effects and
9 exposure related issues over the next year, and so I think
10 that that would help the general discussion about pesticide
11 health and exposure issues and bring to us the best level of
12 science that's available.
13 So that's that for the time being.
14 DR. BLANC: In terms of the mechanism of toxicity
15 theme, which you said has to be narrowed down for that
16 workshop, how will that narrowing process occur?
17 CHAIRMAN FROINES: I think we have a series of
18 discussions with ourselves, the subcommittee exists, which
19 is Jim Seiber and Peter and Craig and myself and OEHHA and
20 DPR representatives to define some of the specific --
21 obviously we can't -- we talk about having, quote,
22 toxicology of pesticides, which is like this, and we
23 obviously have to narrow it down to some specific issues,
24 and so we need input from the panel, we need input from
25 everybody on the panel of specific issues and specific
PETERS SHORTHAND REPORTING CORPORATION (916) 362-2345
4
1 participants, potential participants, and the committee will
2 have to put that together from there.
3 Is that an answer?
4 DR. BLANC: Yeah. Because it seems to me that
5 what would be useful in looking forward to the pesticides
6 that are likely to be coming forward for review are likely
7 to not be classic organophosphates or other ester
8 cholinesterases and inhibited pesticides by and large. And
9 therefore the kinds of mechanisms that would be important to
10 update us on I think would be novel mechanisms or mechanisms
11 of emerging groups of pesticides.
12 I mean, if we're thinking of it as sort of a
13 continuing education experience, then the areas where we're
14 most likely to have gaps in our knowledge, of course
15 speaking personally where I'm most likely to have gaps,
16 would be in those areas where there's emerging classes of
17 pesticides, particularly ones that have novel mechanisms.
18 I guess I would also urge to really not talk about
19 carcinogenesis almost at all, because I don't think there's
20 anything particular about if a pesticide happens to be a
21 carcinogen, I don't think there's anything specific to it
22 being a pesticide, that is the same general carcinogenesis
23 that would apply to any chemical. I think that there's been
24 a lot of experience on the panel in terms of the general
25 issues in terms of carcinogenesis.
PETERS SHORTHAND REPORTING CORPORATION (916) 362-2345
5
1 So I guess that's the way of saying that the
2 things I don't want to hear about are carcinogenesis and
3 classic cholinesterase inhibition.
4 CHAIRMAN FROINES: I think that you missed and I
5 missed one of the meetings where there was extensive
6 discussion about more traditional ester cholinesterase
7 processes and what is considered important and what's
8 considered not important. So there are some unresolved
9 issues that Craig Byus, at least, and I think others
10 raised, so there are some more traditional questions.
11 So but I hear you.
12 I think that the delayed neuropathy is one issue,
13 because it has obviously long-term effects, and with
14 molinate where you appear to have long-term neurotoxic
15 effects, those are the kinds of questions I think are
16 particularly important, that is issues associated with
17 chronic exposure and how we address that.
18 Anybody else?
19 I do think that this notion of having workshops to
20 bring our understanding of the science up to another level
21 the way Paul was just describing, it represents a departure
22 for this committee and represents a way of operating in the
23 future, which is different than the past, and I think is a
24 good idea.
25 Hopefully, since there was general agreement on
PETERS SHORTHAND REPORTING CORPORATION (916) 362-2345
6
1 having more than one workshop, if necessary, it seems to me
2 that's the road we're beginning to follow, although we also
3 have a very serious problem, which we don't need to talk
4 about now, but if we are at the current rate of pesticides
5 coming before the committee we're having monthly meetings
6 and whether or not that was the intent of the legislation
7 when it was originally passed is not entirely clear, and one
8 of the questions we're going to have to figure out is how
9 can we be effectively prepared when we are essentially
10 receiving a pesticide almost on a monthly basis.
11 And it makes it a very difficult task, and given
12 how busy everybody on this panel is, it's not clear to me
13 how we can address that over time. And I think that's
14 something we have to talk about, because I think the load is
15 pretty heavy.
16 And presumably it will become heavier.
17 I'm not used to saying things in this meeting and
18 not having any response, at least from Stan.
19 DR. GLANTZ: I'm sleepy.
20 CHAIRMAN FROINES: The silence is making me
21 nervous.
22 DR. GLANTZ: I'm sleepy.
23 CHAIRMAN FROINES: So we'll move on.
24 And then the second item on the agenda is
25 discussion of the acute reference exposure levels for
PETERS SHORTHAND REPORTING CORPORATION (916) 362-2345
7
1 airborne toxicants.
2 And George and Melanie, if you could --
3 I'm going to start off with I have one question
4 for you, which is at the last meeting you made it sound as
5 though this process of discussing the acute values was --
6 you gave the impression it was potentially an endless
7 process, that you could keep going over different substances
8 as long as we would give you time to do it. So you might
9 kind of clarify what your intent is about that.
10 DR. ALEXEEFF: My name is the George Alexeeff,
11 with the Office of Environmental Health Hazard Assessment,
12 and with me is Dr. Melanie Marty.
13 And what we have before us is this one of the what
14 we call the hot spots documents and we've made several
15 presentations over the last couple years explaining how
16 we're trying to develop hot spots guidelines that we're
17 required to do by statute.
18 And last year we brought forward that cancer
19 document, which was also related to this program.
20 This document is a little bit different, because
21 in this -- for the cancer document we had existing
22 methodologies and there are a lot of cancer numbers out
23 there developed by many different organizations that we can
24 adopt.
25 In this situation we had to actually put together
PETERS SHORTHAND REPORTING CORPORATION (916) 362-2345
8
1 a methodology based upon looking at existing methodologies
2 and what different groups were doing, but as far as we could
3 tell there were really no standards out there that were
4 exactly the kind of standards we needed to develop for the
5 program. In this case it's a bit of a new venture for us.
6 And so what we've done is we developed a
7 methodology and basically tested it or evaluated it for
8 approximately 51 chemicals.
9 And that way we could see how the methodology
10 plays out, what the weaknesses might be, what the research
11 needs are and also get some information about specific
12 chemicals.
13 One of the things that I wanted to make a point of
14 is that in terms of your endless discussion, there is
15 approximately 425 chemicals that we're supposed to evaluate
16 under this program, and we've only attacked 50 here.
17 So ultimately we could be coming back over time
18 with more chemicals.
19 We could also be spending a lot of time on
20 individual chemicals here.
21 One of the things you'll see also, the chemical
22 discussions are fairly short here, and there's a couple
23 reasons for that. One is, surprisingly there's for many
24 chemicals there's not a lot of data for acute toxicity. And
25 on the other case it was simply just of necessity to try to
PETERS SHORTHAND REPORTING CORPORATION (916) 362-2345
9
1 identify the key studies so it would fit in a volume and
2 that would not be an endless process for us. So hopefully
3 we've done that.
4 But our desire today was for definitely to begin
5 review of this document. The hot spots program, the
6 approval process by the science panel is a little bit
7 different from the TAC program in that it requires the
8 review, there's no time constraints about how long the
9 review takes or how you have to send it back to us and that
10 kind of thing.
11 So our thought was to try to begin to go through
12 the methodology, see how far we get discussing the technical
13 issues, and then if issues come up that you suggest that we
14 change our methodology, we may go back and change some of
15 the chemical assessments.
16 We thought we'd start with methodology, go through
17 that, discuss that, and then depending upon time we could be
18 discussing chemicals or we could discuss chemicals at a
19 subsequent meeting.
20 CHAIRMAN FROINES: Do you want us at the end of
21 some period of time to formally approve this document?
22 DR. ALEXEEFF: Yeah. Indicate that you feel that
23 it's, you know, representative of scientific information,
24 something like -- we can look at how we actually approved
25 the cancer document, but, yeah, some sort of approval would
PETERS SHORTHAND REPORTING CORPORATION (916) 362-2345
10
1 be helpful, although it's not required, but it does help us
2 bring to closure --
3 CHAIRMAN FROINES: George.
4 DR. ALEXEEFF: Endorse is basically the word you
5 used before.
6 CHAIRMAN FROINES: I think we should start and go
7 through it, but at some point the panel should discuss --
8 because if we in essence endorse the document, then the
9 implication is that we are endorsing each of the values for
10 the 50 chemicals as well.
11 And so the panel will have to decide whether or
12 not we should be reviewing every single chemical on the
13 assumption that there may be slight variations in the
14 consistency of the approach. And I don't really know that.
15 And so we need -- why don't you go ahead and we'll
16 come back and talk about it and see how we want to do it,
17 because it is going to be somewhat time consuming to have to
18 review every particular chemical, but somebody could come
19 back and say, well, the SRP didn't approve each chemical and
20 so therefore they hadn't met their responsibility.
21 DR. ALEXEEFF: Right. And there are some
22 chemicals in here where application of the methodology we
23 used is difficult, and they probably require some
24 discussion.
25 Some of those we've received some public comments
PETERS SHORTHAND REPORTING CORPORATION (916) 362-2345
11
1 on. We had a public comment period that ended day before
2 yesterday, Monday. So we have -- there's also a need for us
3 to come back and probably discuss those public comments as
4 well.
5 And those public comments kind of focused on two
6 areas. One is some specific chemicals to individuals or to
7 organizations, and the other is on some of the
8 methodological issues. So we thought we could focus on the
9 methodological issues, because like I said if there are some
10 key methodology that there's a problem with, it could impact
11 a number of the chemical calculations.
12 CHAIRMAN FROINES: One way we could do it would be
13 to do it in two stages. One would be -- this is only a
14 suggestion. One would be for you to pick out those
15 chemicals that you think are particularly troublesome or
16 have comments that need to be addressed, so that we're
17 picking the fruit at the high end of the tree. And then we
18 could take the chemicals that weren't addressed and divide
19 them among the panel members, so that four into 50 or nine
20 into 50, eight into 50, goes about six times, so each person
21 might have to review individually half a dozen chemicals and
22 make a report to the panel. In that way, if you want to go
23 into that level of detail. I just want to make sure --
24 DR. ALEXEEFF: That would be fine. Be happy to do
25 that.
PETERS SHORTHAND REPORTING CORPORATION (916) 362-2345
12
1 And there's also other ways of grouping it as
2 well. There's some tables that we'll get into where we
3 defined certain kinds of endpoints and some of them,
4 especially for some of the irritants, the respiratory
5 irritants, they have a similar kind of endpoint and the
6 process is the same as to how we dealt with them, so they
7 can all kind of be grouped and that's a large number of
8 them.
9 Then there are some that have unique mechanisms of
10 toxicity that therefore have to be talked about separately.
11 CHAIRMAN FROINES: Let's go ahead.
12 What I'm concerned about is that the panel does
13 not endorse something that they haven't reviewed. And we
14 just need to be cautious about that.
15 DR. ALEXEEFF: We're willing to work with you on
16 this. We realize it's a new process. We'll be coming back
17 with two other major documents, which are similar in the
18 sense that they're breaking new ground, methodological
19 issues, as well as chemical issues.
20 CHAIRMAN FROINES: Roy Albert at Cincinnati, you
21 know, wrote a paper on skin sensitizers, if you've seen
22 that, suggesting that there are thousands of skin
23 sensitizers that would probably be carcinogens. So you may
24 have to address that at some point.
25 DR. GLANTZ: Can I ask one question?
PETERS SHORTHAND REPORTING CORPORATION (916) 362-2345
13
1 Now I, and I think Seiber, worked with you on the
2 prioritization thing. Those are the same chemicals that you
3 ended up with here?
4 DR. ALEXEEFF: Right. Actually the way the
5 process was worked through, I believe in '92, 1992 we had
6 appointed -- Dr. Pitts appointed some liaison to work with
7 us, and it was Dr. Glantz and Dr. Seiber, and they reviewed
8 three or four versions of this just to figure out what's the
9 extent of the information, how much information should there
10 be in this kind of a document. And, yeah, and so we went
11 through a number of iterations.
12 DR. GLANTZ: But the other thing we went through
13 the chemical prioritization, so those are the same 50
14 chemicals that you ended up with here; is that right?
15 DR. ALEXEEFF: The chemical prioritization process
16 I believe is slightly different than this. There is no
17 prioritization information in here.
18 CHAIRMAN FROINES: Just one point for the panel.
19 The panel should be aware that there is a fundamental
20 difference in the way OEHHA has addressed these chemicals
21 relative to way DPR addresses pesticides. And that is the
22 calculation of REL is in contrast to the calculation of an
23 MOS, and that difference is quite important, I think, for
24 this panel to be aware of and to discuss about the validity
25 of the two approaches.
PETERS SHORTHAND REPORTING CORPORATION (916) 362-2345
14
1 And so please note that there is a very
2 substantial difference between an approach that calculates
3 an REL versus an approach that calculates an MOS and that
4 will come up as time progresses.
5 DR. ALEXEEFF: So Dr. Marty will kind of go
6 through and review the statutory requirements, and then go
7 through the technical. And please stop her along the way,
8 because the point is to discuss these technical issues and
9 we'll be glad to go into these things. There's a lot of
10 information behind all the technical points we'd be happy to
11 get into.
12 CHAIRMAN FROINES: You would agree with the
13 comment I just made, George?
14 DR. ALEXEEFF: I think that will definitely come
15 up. The panel will see that the margin of the safety and
16 the REL are two different approaches, and I think you need
17 to understand how they're similar and how they're different.
18 And I'm sure that will come up at some point.
19 DR. MARTY: Today we are discussing the Air Toxics
20 Hot Spots Program Risk Assessment Guidelines Part 1,
21 technical support document for "The Determination of the
22 Acute Reference Exposure Levels for Airborne Toxicants."
23 As George mentioned, we are developing this
24 guideline under the Air Toxics Hot Spots Information and
25 Assessment Act. The purpose of that act is to ascertain and
PETERS SHORTHAND REPORTING CORPORATION (916) 362-2345
15
1 measure the amounts of listed substances emitted from
2 stationary sources and to assess both the short- and
3 long-term health risks to those who are exposed.
4 OEHHA has a couple of roles in this program.
5 One of them is review risk assessments, which
6 we've been doing for the last, Jim, eight years.
7 And the other is to, per an amendment in 1992,
8 develop guidelines for facilities to conduct these health
9 risk assessments.
10 To date, the risks assessments have been conducted
11 per the California Air Pollution Control Officers'
12 Association's guidance.
13 The process of developing risk assessment
14 guidelines includes public input, public workshops, public
15 review and comment, and OEHHA's response to those comments.
16 The Scientific Review Panel also plays a role, as
17 you just heard, and the language in the statute actually
18 says that the SRP is to evaluate the guidelines and
19 recommend changes and additional criteria to reflect new
20 scientific data or empirical studies.
21 And then adoption, the final step, is adoption of
22 the guidelines by OEHHA.
23 There are four documents that we are producing as
24 the basis for the air toxics hot spots risk assessment
25 guidelines. These four technical support documents include
PETERS SHORTHAND REPORTING CORPORATION (916) 362-2345
16
1 the one that we're looking at today, "The Determination of
2 Acute Reference Exposure Levels."
3 We have a document determining chronic reference
4 exposure levels, which has gone through the public comment
5 period. We are responding to comments on that document and
6 the panel will see that in the spring.
7 There is a document that you've already looked at
8 describing the available cancer potency values, and that
9 document has completed the process now.
10 And then there's a technical support document
11 describing exposure assessment and stochastic analysis and
12 exposure. You guys have seen, at least Stan has, part of
13 that document or the whole document.
14 DR. GLANTZ: I hope it's just not part of it.
15 DR. MARTY: It's the whole document.
16 An earlier version, and we have responded to
17 public comment and revised that document and we're hopefully
18 going to send it to the panel by the end of January or early
19 February. So they can start looking at it again.
20 CHAIRMAN FROINES: Do we have a lead person?
21 DR. MARTY: Stan is the lead person on the
22 exposure document. And Dr. Seiber also.
23 DR. ALEXEEFF: I think Dr. Friedman is the lead on
24 the chronic document.
25 CHAIRMAN FROINES: Is the lead on what?
PETERS SHORTHAND REPORTING CORPORATION (916) 362-2345
17
1 DR. ALEXEEFF: Chronic --
2 DR. MARTY: Chronic reference exposure.
3 DR. GLANTZ: On the exposure assessments
4 stochastic analysis Seiber is sort of the exposure person
5 and I'm the stochastic person.
6 CHAIRMAN FROINES: No disrespect. I was just
7 hoping that we had an exposure, a real live --
8 DR. GLANTZ: A real exposure person, he's a real
9 exposure person. We're sort of the gruesome twosome.
10 DR. MARTY: We also are going to develop a risk
11 assessment manual, which basically distills out the
12 information in the four technical support documents, and
13 that's the document that will be used by individuals
14 preparing risk assessments.
15 There are about 725 chemicals listed under the air
16 toxics hot spots that are subject to the act. Of those,
17 about 425 are required to have their emissions quantified by
18 facilities that are subject to the act. Of those about 325
19 have been reported as emitted to ARB from facilities, and
20 230 of those are carcinogens.
21 When we looked at existing public health levels
22 and found, as mentioned earlier, that there really weren't
23 any acute reference exposures levels to utilize, there were
24 some existing chronic levels from US EPA and there were a
25 lot of cancer potency factors that both US EPA and OEHHA had
PETERS SHORTHAND REPORTING CORPORATION (916) 362-2345
18
1 developed.
2 We have proposed 51 acute exposure levels for
3 those chemicals, and you will see later in the year the
4 chronic, we have 120 chemicals that we have evaluated.
5 CHAIRMAN FROINES: Have you compared the TRI data
6 with the 325?
7 DR. MARTY: We have only for a certain subset.
8 What we did is we wanted to look at how accurate the TRI
9 data was with respect to the emissions data reported under
10 AB 2588, so we selected just a handful at this point.
11 But is ARB here?
12 The emissions inventory branch at ARB is a lot
13 more active in looking at the TRI versus the hot spots, so
14 I'm pretty certain they have looked at a lot more chemicals
15 than just the handful that we did.
16 We were looking specifically to see
17 perchlorethylene, benzene, chrom 6, because there's many
18 smaller facilities that are required to report under AB 2588
19 that don't report under TRI, so that's what we're doing.
20 DR. ALEXEEFF: What we generally found was that
21 for the large facilities there was fairly good agreement
22 between TRI and hot spots. There were some facilities that
23 seemed to be missed by both program.
24 DR. GLANTZ: What's TRI?
25 DR. ALEXEEFF: The Toxic Release Inventory that's
PETERS SHORTHAND REPORTING CORPORATION (916) 362-2345
19
1 been established by US EPA, but of course since it's a
2 national program they have a fairly large facility cutoff as
3 compared to our state program, which goes down to gas
4 stations, dry cleaners. The federal program does not go
5 down to that small of a facility. They just look at the
6 large facilities.
7 So what we found for those facilities where
8 there's a lot of small facility emissions like
9 perchlorethylene or emissions from gas stations, there's a
10 lot of emissions that weren't caught in the TRI program.
11 CHAIRMAN FROINES: The 2588 doesn't include gas
12 stations?
13 DR. ALEXEEFF: It does. 2588 includes gas
14 stations.
15 DR. MARTY: They're in a category that the
16 districts deal with as industry-wide, so the districts are
17 responsible really for estimating emissions from all their
18 gas stations.
19 The reference exposure level is essentially the
20 concentration at or below which no adverse health effects
21 are anticipated. It is generally based on the most
22 sensitive adverse health effects reported in the literature,
23 and is intended to protect most sensitive individuals in the
24 population.
25 It should be pointed out that exceedance of the
PETERS SHORTHAND REPORTING CORPORATION (916) 362-2345
20
1 REL by any facility's emissions does not automatically
2 indicate a health impact.
3 I mentioned earlier that there really is a lack of
4 standardized approaches to risk assessment, particularly for
5 acute exposures. There are no accepted guidelines for
6 assessing acute risks, per se. The US EPA has been
7 developing guidelines for acute exposure for some time now,
8 but they're still in draft format and they developed what
9 they call acute reference exposures, or AREs for just a few
10 chemicals, and those are out for public review.
11 And I should point out that the US EPA approach
12 and OEHHA's approach are very similar.
13 There's also a lack of standardized guidance for
14 site-specific exposure assessment of airborne emissions and
15 in particular for short-term exposures.
16 I mentioned earlier that we prioritized the
17 chemicals for development of an acute reference exposure
18 level. 32 of those chemicals were listed in the CAPCOA
19 guidelines, and they're listed there because they are a
20 concern to the air pollution control officers, and they had
21 sources in their purview and/or they have one-hour
22 California Ambient Air Quality Standards.
23 16 of the chemicals we evaluated were reported to
24 be emitted in relatively high quantities in the database.
25 Three others were of concern with known toxic effects and
PETERS SHORTHAND REPORTING CORPORATION (916) 362-2345
21
1 database useful to develop the RELs.
2 So we have a total in this document of 51
3 chemicals with proposed acute reference exposure levels.
4 This slide lists some of the chemicals that were
5 selected and these were selected due to high emissions
6 reported in the database.
7 CHAIRMAN FROINES: So that you do, you can include
8 pesticides in this process as well as nonpesticides?
9 DR. ALEXEEFF: Well, the program does not consider
10 pesticides that are used in their general pesticidal use.
11 The only clear exception would be methylbromide, which is
12 used in large fumigation chambers for fruit coming from
13 Chile, and in that case the fumigation chambers generally
14 also require not only agricultural permits, but also air
15 pollution control officer permits, so that falls under the
16 program, but general pesticidal use, such as the chemical we
17 talked about, methyl parathion and DEF don't fall under this
18 program.
19 It's a stationary source oriented program.
20 DR. MARTY: I believe the statute specifically
21 excludes pesticides and their pesticidal use. We have a --
22 DR. FRIEDMAN: Could you speak closer to the
23 microphone?
24 DR. MARTY: Sure.
25 CHAIRMAN FROINES: That's an important point to
PETERS SHORTHAND REPORTING CORPORATION (916) 362-2345
22
1 make sure that everybody hears.
2 DR. MARTY: I think that the statute, is there an
3 attorney here from the ARB?
4 The statute specifically excludes pesticides and
5 their pesticidal use. If you are a manufacturer of a
6 pesticide in California, that facility would be covered and
7 those conditions would be covered under the Hot Spots Act,
8 but using pesticides is not covered under hot spots.
9 DR. ALEXEEFF: You'll see there's a number of
10 substances that have some pesticidal use, as well as other
11 industrial uses, and just like in the toxic air contaminant
12 program, we're looking at those substances like carbon
13 tetrachloride, let's say.
14 DR. MARTY: The reference exposure --
15 CHAIRMAN FROINES: Can I ask a question? I'm
16 sorry for interrupting so many times, but you have selection
17 due to high emissions for these 16 compounds. And I'd have
18 to say in looking at some of those compounds, I'd be very
19 surprised if there were high emissions to some of them.
20 What's the evidentiary basis for high emissions to vanadium
21 pentoxide or to copper compounds or epichlorohydrin?
22 DR. MARTY: We basically look at the air toxics
23 emissions database that is the database put together by ARB,
24 which includes submissions from the districts for all of the
25 facilities under their purview, and that's what we used. It
PETERS SHORTHAND REPORTING CORPORATION (916) 362-2345
23
1 wasn't strictly high emissions because it was high emissions
2 in concert with available data to develop the REL. So it is
3 a little bit all over the map if you actually plotted pounds
4 per year emitted for each one of these chemicals.
5 DR. FUCALORO: Then you mean high emissions
6 relative to the REL, is that what you mean?
7 DR. MARTY: Not really. Relative to other
8 chemicals that are reported in the database.
9 DR. ALEXEEFF: Basically ARB has this database
10 called the ATEDS database, and all of the local districts
11 submit the emissions inventories for all the facilities that
12 are under this program to that database.
13 And then ARB summarizes it and comes up with what
14 chemicals are emitted in the higher quantities.
15 So it's from that database where we're looking
16 down, starting from the top chemicals emitted and going down
17 that list.
18 DR. FUCALORO: And mass per unit per year or is it
19 in concentration?
20 DR. MARTY: It's in pounds per year.
21 DR. FUCALORO: Pounds per year.
22 DR. MARTY: Year.
23 DR. BLANC: It doesn't surprise me, because it's
24 such a ubiquitous byproduct of fossil fuel burning, so that
25 should be there. That doesn't, I mean, it's a little
PETERS SHORTHAND REPORTING CORPORATION (916) 362-2345
24
1 surprising that vinyl chloride is there, for example.
2 CHAIRMAN FROINES: Is not there?
3 DR. BLANC: That is there. We don't have that
4 many polymerization facilities in California that I know of.
5 I guess there must be one spot.
6 CHAIRMAN FROINES: It may be off some landfill
7 where we're getting methanagenic generation of vinyl
8 chloride.
9 DR. BLANC: How do you handle the more common
10 acute intermittent releases that would not appear in sort of
11 an ongoing inventory, for example chlorine gas, which is
12 probably the most frequent? Is that already regulated or is
13 that you already have the values for that and it doesn't
14 need to be on this list?
15 DR. ALEXEEFF: Chlorine is in this package.
16 DR. BLANC: You called it --
17 DR. ALEXEEFF: It was part of the CAPCOA group,
18 the original 32, that's why. So it had already been
19 identified.
20 The first 32 were identified in the late '80s by
21 representatives of the local air districts of saying these
22 are chemicals that are of concern to us, before we had all
23 the inventory.
24 DR. BLANC: So this was just throwing a wider net
25 of the things that didn't appear there?
PETERS SHORTHAND REPORTING CORPORATION (916) 362-2345
25
1 DR. ALEXEEFF: Right.
2 DR. BLANC: And then we have an overhead handy
3 that has the entire list or just refers to which page in the
4 document?
5 DR. GLANTZ: Just look in the table of contents.
6 DR. MARTY: Probably the easiest is to look at
7 Appendix A, which lists the chemicals and their acute
8 reference exposure levels.
9 CHAIRMAN FROINES: But this is, you know, in terms
10 of large emissions, you have all sorts of chlorinated
11 hydrocarbons, like perchlorethylene. I'm assuming that
12 you're not including that because it's a carcinogen and not
13 having acute toxicity?
14 DR. MARTY: We have an acute REL for
15 perchlorethylene, so we did include it.
16 DR. BLANC: It was already captured, so these are
17 the other ones that they hadn't already had.
18 DR. ALEXEEFF: In other words we started with the
19 CAPCOA guidelines considered 32 substances, so that was kind
20 of our starting point looking at -- what we were involved in
21 the development of that document. So we started with that
22 document and then we said what additional chemicals do we
23 need to consider.
24 And the way we identified those additional
25 chemicals is by high emissions and that's what we're saying,
PETERS SHORTHAND REPORTING CORPORATION (916) 362-2345
26
1 and plus some unusual toxicity that we found.
2 Those are additional. Perc is in there, chlorine
3 is in there.
4 DR. BLANC: Page seven is the best place to see
5 how they capture --
6 CHAIRMAN FROINES: Page?
7 DR. BLANC: Seven.
8 CHAIRMAN FROINES: Why don't we go ahead.
9 DR. MARTY: Okay. We just mentioned that we
10 prioritized chemicals to be evaluated. We then conducted an
11 exhaustive literature search in that we captured existing
12 standards that were being used by other agencies for other
13 programs, and we evaluated those to see if any of them were
14 useful as reference exposure levels.
15 If they were not, then we chose the best study out
16 of the literature, emphasizing the human data.
17 We identified the critical endpoint for our acute
18 toxicity, and estimated a threshold for the effect, which is
19 essentially the no observed adverse effect level.
20 At times we had to do temporal adjustments because
21 the acute toxicity studies don't necessarily only expose for
22 one hour, and our reference exposure levels are designed for
23 one-hour exposures.
24 And we also had to account in some way for
25 uncertainties in the data, for example, applying animal data
PETERS SHORTHAND REPORTING CORPORATION (916) 362-2345
27
1 to humans or applying occupational studies to the general
2 population.
3 And after those adjustments for temporal and
4 uncertainty factors, we ended up with a reference exposure
5 level.
6 DR. GLANTZ: Can I ask, at the last meeting I gave
7 the DPR people a really hard time about the no adverse
8 effects level as opposed to the no effects level.
9 And I was equally concerned in going through the
10 document this time, because it's wasn't clear to me how -- I
11 mean, you seem to make an argument that there are effects
12 which are not adverse, you know, like something might smell.
13 But just as we gave them a hard -- or I gave them
14 a hard time about, you know, what do you call adverse seems
15 pretty arbitrary, do you have a more systematic definition
16 of what you're calling an adverse effect, which wouldn't
17 open you to the same criticism of, well, that seems pretty
18 arbitrary to me?
19 That was the one thing -- I mean, I've, as you
20 mentioned earlier, been working with you guys on this
21 document for a while, so this looked pretty good to me, but
22 that was the one place that I felt queasy.
23 Can you address that either now or later in your
24 presentation?
25 DR. MARTY: Might as well try now.
PETERS SHORTHAND REPORTING CORPORATION (916) 362-2345
28
1 I think one way to look at it is to first define
2 what the no observed adverse effect level is. That is
3 essentially the exposure level with no biologically or
4 statistically significant increase in the frequency or
5 severity of adverse effects among an exposed population
6 relative to controls.
7 And I guess the biggest difference is that with no
8 observed effect level there might be an effect, but it is
9 neither biologically nor statistically significant.
10 DR. GLANTZ: Okay. But if you say -- well, I
11 don't know quite what you mean by a statistically
12 significant effect, because, I mean, what do you mean by
13 statistically?
14 DR. MARTY: When we look at it, we look at the
15 study and they may say there was an increase in activity of
16 enzyme X, but it was not statistically significant over
17 controls. We would hone in on that as not statistically
18 significant, and it would be up to us to make sure that the
19 author of the study applied appropriate statistical tests to
20 make that statement.
21 DR. ALEXEEFF: We would also take into account
22 whether or not that enzyme or that test, clinical test, had
23 any relationship to what we knew were the adverse effects,
24 because it happens in a lot of studies that they run a bunch
25 of tests and they find some changes in various things, but
PETERS SHORTHAND REPORTING CORPORATION (916) 362-2345
29
1 we don't see how it fits in the continuum of severity or
2 toxicity. Those are most of the ones that we've excluded.
3 But I think probably the clearest, what we realize
4 this is a difficult situation, difficult concept to kind of
5 come into sort of agreement on, we felt the simplest way for
6 us to do it, other than to come up with a definition like
7 that, if you look on pages 20, 21 we've tried to categorize
8 them all.
9 In fact, we went further in terms of not only what
10 is adverse, but we actually made decisions on what's a mild
11 adverse effect and what's a severe adverse effect, which
12 could be also considered arbitrary, but we tried to -- the
13 reason we did that was there's a need on the part of the
14 districts to know is this an effect that is going to be
15 really severe, long-lasting, life threatening or is this
16 something that's minor and not that important, that will go
17 away. So we had to kind of characterize that.
18 So what we did is we put that information in these
19 tables, so as we find the health effect and classify it, we
20 list it in here. And there's five and six.
21 And since there are a lot of studies also on
22 pulmonary function, where you could have some statistically
23 significant changes in a pulmonary function test, we have
24 another table, I believe Table 7 on page 28, which also
25 tries to clarify, at least from our perspective, what is the
PETERS SHORTHAND REPORTING CORPORATION (916) 362-2345
30
1 adverse effect, what is not an adverse effect.
2 DR. GLANTZ: Right. But I thought these tables
3 were very clear, but the thing I couldn't figure out is when
4 you get back to Appendix C and start computing your
5 reference exposure levels based on your no adverse effect
6 levels, which of these numbers do you use?
7 You know, do you take something, would you require
8 it to be a mild effect or a severe effect? Or, I mean, how
9 do you -- you know, if you look, for example, in Table 5,
10 there is, you know, if you look at the EPA severity level, I
11 mean you have everything from one up to four as NOELs, and
12 which one of those do you use when you're computing your
13 reference exposure level?
14 DR. ALEXEEFF: I think we can, this slide actually
15 begins to discuss that. I think we'll get into that.
16 And there are some calls on individual chemicals
17 when we get into individual chemicals that I think will be
18 interesting to discuss.
19 DR. WITSCHI: With respect to those tables on 20
20 and 21 and 28, do they refer to animal studies or to human
21 studies or to me it looks like a mixture of both.
22 DR. ALEXEEFF: There are both animal and human
23 studies. In this particular document most of the levels
24 were developed based on human studies, because there's a lot
25 of --
PETERS SHORTHAND REPORTING CORPORATION (916) 362-2345
31
1 DR. WITSCHI: That's right. I looked at Table 5,
2 you know, I was struck because many of those things, unless
3 you do an exploratory autopsy, you're not going to see in
4 people.
5 DR. ALEXEEFF: Right. It's a mixture of
6 information and it's whatever is available. One of the
7 problems with acute toxicity in this nonpesticidal arena,
8 there is no standardized testing requirements, so it's
9 whatever the literature is reporting, based upon interest
10 mostly of academicians.
11 DR. GLANTZ: One thing, then I'll let you go on, I
12 mean, I actually found these tables very useful. The thing
13 again that I was confused about was how you operationalize
14 this when you got into doing the numbers.
15 And I think one thing that might help in the
16 discussions of the pesticides would be, and it may not be
17 fair to ask them now, but Paul or somebody from DPR to
18 comment on what they think about these two tables and how --
19 in the long run it might be helpful if we could agree on
20 some kind of categorization like this that everybody would
21 then use, so we have a common lexicon.
22 It's page 20, 21 and 28.
23 Because that might help to get around the
24 discussion, the problems that came up at the last meeting
25 regarding pesticides, because I think the classification and
PETERS SHORTHAND REPORTING CORPORATION (916) 362-2345
32
1 the sort of the various definitions you have here are pretty
2 reasonable, but again I can see why would you come in
3 category -- if you're US EPA security level one for one
4 chemical and four for another.
5 DR. MARTY: I think that's largely a function of
6 the data that are available on the individual chemicals.
7 DR. GLANTZ: Right. But you see then, again, if
8 you want me to stop and wait for later, I will, but see then
9 that gets into the thing that I was jumping all over DPR at
10 the last meeting, because if all that you have is data
11 available for a fairly severe effect, then that's going to
12 bias the number up, just because you don't have information
13 about the other things.
14 So do you do something like if all the data you
15 have is about the EPA level four, do you use a bigger safety
16 factor than if it's in effect level one? Is that one of the
17 things you're doing?
18 DR. ALEXEEFF: Sort of, but not really.
19 DR. GLANTZ: That's a precise answer.
20 DR. ALEXEEFF: When we get --
21 DR. GLANTZ: You want to defer this and come back?
22 DR. ALEXEEFF: I can just say what we are going to
23 get into is that what we would do if all we had was
24 information on that severe level, we would establish a
25 reference level, but say this is only protective of severe
PETERS SHORTHAND REPORTING CORPORATION (916) 362-2345
33
1 toxicity. So we let people know that this is a severe REL
2 and it's not -- we don't have information on lower effects.
3 It could be that the most sensitive effect is a severe
4 effect, and that is one of the quandaries that we come into
5 this and later on you'll see.
6 For example, there are some, let's say, for
7 example arsine, the effect is severe by our categorization
8 procedure. It's hemolysis. That's the most sensitive
9 endpoint. You can't come up with what's more sensitive.
10 There is odor involved, but that occurs at levels
11 that already would cause severe toxicity.
12 So in some indications it's not even the absence
13 of data, it's simply because the most sensitive effect is a
14 very severe one. And so we've categorized it that way. We
15 didn't add an additional uncertainty factor.
16 But you'll see when we discuss about the
17 uncertainty factors, you know, why we don't do that.
18 CHAIRMAN FROINES: We should go ahead, because I'm
19 about to ask you about why you didn't add another tenfold
20 uncertainty factor. Why don't we take that up when we get
21 further along, because if you have a very severe effect,
22 then that, quote, cries out for additional safety factors.
23 DR. ALEXEEFF: Psychologically it does, but we'll
24 see technically what happens. The short answer is, not to
25 be silly --
PETERS SHORTHAND REPORTING CORPORATION (916) 362-2345
34
1 CHAIRMAN FROINES: I would argue that that's an
2 intellectual process, not a psychological.
3 DR. ALEXEEFF: Intellectual then. I think what we
4 found is, we'll discuss this later, and becomes even more
5 important for life-threatening effects, like potential
6 lethality, is that as you get to the more severe effects,
7 the dose response curve becomes steeper, which suggests
8 there's less variability amongst populations, which suggests
9 a lower, a smaller uncertainty factor. So we'll be
10 discussing all those issues.
11 DR. FUCALORO: And you use benchmark
12 concentrations for those?
13 DR. ALEXEEFF: When there's data.
14 DR. FUCALORO: When there's data.
15 DR. MARTY: Why don't we go through it. I think a
16 lot of the questions will come up and be addressed.
17 CHAIRMAN FROINES: I think this issue of the slope
18 of the dose response curve becomes an important element in
19 the consideration.
20 DR. MARTY: We have, as you noticed in the
21 document, developed at least anywhere from one to three
22 acute severity levels for different chemicals, depending on
23 the availability of data.
24 The first is the level protected against mild
25 adverse effects, and in general this is the reference
PETERS SHORTHAND REPORTING CORPORATION (916) 362-2345
35
1 exposure level that is used in risk assessments.
2 The second level is a level protective against
3 severe adverse effects. It is sometimes the reference
4 exposure level if it happens to be the most sensitive
5 endpoint. George gave an example of arsine. There's a
6 number of reproductive toxicants where reproductive
7 developmental effects are the most sensitive endpoint. And
8 we consider those reproductive and developmental effects to
9 be severe effects.
10 And then for some chemicals we develop levels
11 protective against life-threatening effects and these are
12 never used as the reference exposure level in a risk
13 assessment.
14 The purpose of having those two higher categories
15 for chemicals where you have the mild adverse effect level
16 is so that when a facility emits a chemical and the
17 concentration exceeds the reference exposure level, the risk
18 manager can see how close they are to the next level up,
19 which would be the severe adverse effect. And so it's
20 informational really only, and not used per se in the risk
21 assessment process.
22 DR. ALEXEEFF: To touch on that, that itself
23 becomes an interesting point, because just to give two
24 examples, for formaldehyde, it's a very potent irritant and
25 its lethal level it requires -- well, the difference between
PETERS SHORTHAND REPORTING CORPORATION (916) 362-2345
36
1 irritancy and lethality is a fairly large range, like a
2 couple hundredfold, a hundredfold or so.
3 But if you look at arsine, the difference between
4 any effect and lethality is two to fivefold, so you need to
5 know where lethality is, because sometimes it can be very
6 close to the level you're involved in sort of evaluating.
7 DR. MARTY: In developing levels protective
8 against mild adverse effects, we did look at existing
9 guidelines, a number of them which are listed in the
10 document. But we determined that almost all of them, except
11 for the ambient air quality standards, were really not
12 suitable for our purpose, primarily because they were either
13 developed for occupational settings and were not appropriate
14 to apply to the general public, or they were developed for
15 emergency settings where you have to decide when you
16 evacuate or shelter employees and so forth.
17 So we were concerned that there was not a
18 consistent basis for a lot of them. Some of them seemed to
19 be not considering all available data.
20 So if the chemical was a criteria air pollutant,
21 we looked at the California Ambient Air Quality Standard.
22 If we thought that was appropriate to use as an acute
23 reference exposure level for one-hour exposure, we adopted
24 that value.
25 That is the case for carbon dioxide, nitrogen
PETERS SHORTHAND REPORTING CORPORATION (916) 362-2345
37
1 dioxide, ozone and sulfur dioxide. If it was not
2 appropriate, then we derived a value.
3 And in the case of hydrogen sulfide, we chose
4 effects on airways in asthmatics.
5 And in the case of sulfates we ended up adjusting
6 the 24-hour standard to a one-hour standard, so it actually
7 is based on the ambient air quality standard.
8 If the chemical was not a criteria air pollutant,
9 which is all the rest of them, then we derive a value based
10 on information in the literature.
11 CHAIRMAN FROINES: Let me interrupt you.
12 Are you going to take up hydrogen sulfide, because
13 we have a letter to me, that I haven't circulated to the
14 board yet.
15 DR. MARTY: We can talk about that.
16 CHAIRMAN FROINES: We'll circulate that.
17 Peter, why don't you go ahead and let everybody
18 have it, so that they at least have it in their possession.
19 DR. ALEXEEFF: Hydrogen sulfide is a very
20 interesting topic and I think something for us to discuss at
21 some point. We should discuss it, not necessarily today,
22 depending upon the time.
23 DR. MARTY: In developing levels protective
24 against severe adverse effects, we also evaluated existing
25 guidelines, including US EPA's air pollution warning levels,
PETERS SHORTHAND REPORTING CORPORATION (916) 362-2345
38
1 and those are for criteria air pollutants, to advise against
2 when the air quality is very poor, it acts as a health
3 advisory.
4 The SPEGLs, which are developed by National
5 Academy of Sciences for emergency exposures, and they're
6 really not appropriate for routine and predictable emissions
7 from facilities.
8 DR. GLANTZ: Would you say what these acronyms
9 are?
10 DR. MARTY: Sure. I have to open the book to --
11 Short-Term Public Emergency Guidelines Level is the SPEGL.
12 They're all on page -- early on.
13 The EEGLs are also developed by the National
14 Academy of Sciences in their ceiling concentrations of
15 substances for Department of Defense workers during rare
16 emergency conditions. So those are for people in the
17 military who are generally young and healthy, so we figured
18 they were not really appropriate either.
19 And EEGL is Emergency Exposure Guidance Level.
20 Then the American Industrial Hygiene Association
21 developed what they call ERPGs, which are Emergency Response
22 Planning Guideline levels, and they have three levels, one,
23 two and three.
24 ERPG 2 is the maximum airborne concentration to
25 protect people from irreversible or severe health effects,
PETERS SHORTHAND REPORTING CORPORATION (916) 362-2345
39
1 but in general when we looked into the documentation for
2 these chemicals there was inconsistent basis for developing,
3 and we felt that they were not appropriately health
4 protective for sensitive subpopulations.
5 We also looked at TLVs, occupational standards
6 from the ACGIH, and again you have the problem that it's an
7 occupational standard, primarily designed to protect healthy
8 workers and not the general public. And furthermore the
9 ACGIH recommends against using them for the protection of
10 the general public. So those are not appropriate either.
11 And then finally we did look at US EPA's level of
12 concern, which are concentrations in air above which there
13 may be severe adverse health effects, including death, and
14 in general these were not particularly health protective
15 either.
16 So we did end up adopting some of these levels
17 where we felt it really was appropriate, but in general we
18 felt there were no appropriate guidelines, and that is
19 usually the case, so we derived a value from studies in the
20 literature.
21 In developing the level of protective against
22 life-threatening effects, we looked at the ERPG 3, which is
23 the maximum airborne concentration that the AIHA deems is
24 without life-threatening effects, but again it was not -- we
25 felt they were not particularly health protective nor
PETERS SHORTHAND REPORTING CORPORATION (916) 362-2345
40
1 considered all of the available data.
2 We also looked at the immediately dangerous to
3 life and health values, which are developed by NIOSH. These
4 are 30-minute concentrations from which a worker could
5 escape without serious irreversible health effects in the
6 event of failure of the respiratory protection they were
7 using. So this does not seem appropriate for the general
8 public either.
9 So usually it was the case of the appropriate
10 guidelines did not exist. We may have actually adopted a
11 couple of ERPG 3's for the life-threatening effect level,
12 but in general we derived a value if there was information
13 in the literature.
14 But what I'd like to do now is go through a couple
15 of examples of how we developed the reference exposure
16 levels. I have three examples using the no adverse effect
17 level approach with uncertainty factors and then I have an
18 example of the benchmark concentration approach.
19 And as I talk about these, we'll see how the
20 uncertainty factors are used, and also what some of the
21 problems are with using uncertainty factors when the
22 database is poor.
23 So I think I mentioned earlier the no adverse
24 effect level as that exposure level with no biologically or
25 statistically significant increase in the frequency or
PETERS SHORTHAND REPORTING CORPORATION (916) 362-2345
41
1 severity of an adverse effect among an exposed population
2 relative to controls.
3 The first example I have is airway response to
4 sulfate and sulfuric acid aerosols in asthmatics, and this
5 is the basis also for the sulfate ambient air quality
6 standard.
7 The study was conducted by Utell and colleagues in
8 1983.
9 DR. FRIEDMAN: Can I interrupt just on that? Just
10 on that definition of no biologically or statistically
11 significant, from what George said before it sounded to me
12 like it was both requirements, no biologically and
13 statistically significant. Or in other words didn't you
14 say --
15 DR. MARTY: I did say and/or, didn't I?
16 DR. FRIEDMAN: -- that it's significant difference
17 you might not take it seriously if it wasn't biological?
18 Seems like you should change it to and rather than or.
19 DR. MARTY: I stand corrected.
20 DR. FRIEDMAN: In your document I think it says or
21 also.
22 DR. MARTY: I can't remember if it does or not.
23 It probably does. Okay.
24 DR. ALEXEEFF: In our document it says and/or, and
25 slash or, so it's a judgment call there in terms of --
PETERS SHORTHAND REPORTING CORPORATION (916) 362-2345
42
1 CHAIRMAN FROINES: Grammatically I think if you
2 say and/or that means or.
3 DR. MARTY: Yes.
4 CHAIRMAN FROINES: So it's or. So what is it?
5 DR. MARTY: We stole that definition from US EPA
6 and I'll have to look at --
7 DR. BLANC: Let me ask a different way. Are there
8 situations in which, let's say study groups were small, but
9 the effect was so biologically meaningful that even though
10 statistical significance in the classical sense was not
11 achieved, and there were no other data, useful data, so you
12 took into account or in conjunction with other data, because
13 I would --
14 DR. ALEXEEFF: Most of the cases are that way
15 where there's a group of five individuals and three out of
16 five responded. That probably would not be significant, but
17 we definitely used the data.
18 DR. BLANC: So then it is or.
19 DR. FRIEDMAN: No. Then it's only biologically.
20 DR. BLANC: No, because there are probably some
21 situations in which there was something that was
22 biologically meaningful, but there was a lot of other good
23 large data sets where it was clearly shown that in fact it
24 was a chance observation.
25 I mean, that's true with the human data, because
PETERS SHORTHAND REPORTING CORPORATION (916) 362-2345
43
1 so much of what you have to look at are isolated case
2 reports that could be meaningful, but then when you have a
3 larger group of data you don't -- you weight them less.
4 DR. FRIEDMAN: Even with a large set of data you
5 can't prove a negative, that there's no effect. I mean, you
6 always have some confidence limits around even if it's the
7 finding is null. You still have some confidence limits,
8 which could include an effect.
9 It sounds to me like you only use the biological
10 criteria.
11 DR. ALEXEEFF: It depends. On the example that
12 Dr. Blanc was giving was one where the biological criteria
13 overrides the statistical significance.
14 But there are many cases, particularly in some of
15 the animal studies, when they would do a large clinical
16 evaluation of various parameters that it wasn't clear to us
17 how they might be relevant to the toxic effect. It's not
18 similar to like we were discussing before, cholinesterase
19 and that could be relevant in certain circumstances.
20 But in this case they might look at just a general
21 blood screen of various things, but the effect is, you know,
22 irritation or something.
23 So sometimes some of the studies report extraneous
24 information that might be showing something that we didn't
25 see how it fit within the biological criteria.
PETERS SHORTHAND REPORTING CORPORATION (916) 362-2345
44
1 DR. FRIEDMAN: Did you use it then?
2 DR. ALEXEEFF: No. In those cases we would not
3 use it.
4 DR. FRIEDMAN: You're always relying on
5 biological.
6 DR. ALEXEEFF: I guess it probably would have to
7 have some biological, but then there would be other
8 situations where the effect is, let's say, like an organ
9 weight change where there clearly is an increase in organ
10 weight, or decrease, depending on what the effect is, and
11 that might be the significant effect, there's a significant
12 increase in organ weight.
13 DR. GLANTZ: Yeah. But, George, I think what Gary
14 is saying is right. Everything you've said has been
15 basically talking about a biological effect.
16 It seems to me that what you're saying is it's
17 statistical, you look at the statistical results to see how
18 much confidence you can have in the biological effect,
19 whether something is statistically significant or not isn't
20 really controlling, because of the point Paul made. I mean,
21 what if you've got a small study with low power.
22 And also what Gary said is you can never exclude a
23 null effect, I mean you can never prove a null effect.
24 It seems what you ought to do is change your
25 definition to take out the statistical part, and that's just
PETERS SHORTHAND REPORTING CORPORATION (916) 362-2345
45
1 something --
2 DR. BLANC: Maybe a more useful phrase, you can
3 work on the exact meaning, but the biologically meaningful
4 effects tempered by appropriate statistical interpretation.
5 And where there is appropriate statistical data, I'm sure
6 you can use it.
7 DR. GLANTZ: I guess, but I think that would be --
8 DR. FUCALORO: I think what Paul said is correct,
9 because in the way it was phrased it seemed to be some sort
10 of symmetry between those two, and in fact they really
11 aren't symmetrical.
12 DR. ALEXEEFF: I think that's a really good point.
13 We can go through and look at some --
14 DR. BLANC: The carcinogenicity data, for example,
15 let's take an example of you're comparing tumors in controls
16 versus exposed, and it's clearly tumor is a biologically
17 meaningful event. And yet if the controls have -- if it's a
18 large study and the controls have a lot of tumors or they're
19 both very similar and your statistical confidence is that
20 you have high statistical confidence in the statement that
21 there is unlikely to be a difference between the exposure
22 and controls, and basically it's the statistical data that's
23 driving your conclusion of that study, but it's not to say
24 that having the tumors is not biologically meaningful.
25 So maybe it's partly linguistic, but I think I
PETERS SHORTHAND REPORTING CORPORATION (916) 362-2345
46
1 would give them a lot of leverage, as long as you make it
2 clear that you're not -- that the statistical tail is not
3 wagging the dog.
4 I think that's true in your -- I think this will
5 come up later in the molinate discussion, because one of the
6 pitfalls I think in the document that's currently structured
7 is that they've done precisely that, they've put too much
8 weight on statistical tests in times where the data groups
9 are small and you can't exclude the null hypothesis
10 effectively.
11 DR. GLANTZ: Yeah. I mean the place that I would
12 take the statistical significance issue into account is more
13 when you're setting what your uncertainty factors are, or
14 whatever you call them, your safety factors, because if you
15 have a result which is statistically significant, then you
16 can have more confidence in it, than if you're just showing,
17 you know, some tumors or some positive effect, but not
18 enough to reach statistical significance.
19 So I would use that more in terms of how you
20 interpret the results, rather than amending the definition
21 itself.
22 DR. ALEXEEFF: I think the example Dr. Blanc gave,
23 although we're not dealing with tumors here, but that's the
24 kind of example maybe when we get into it, for example, I'm
25 not sure if -- is this a pulmonary function result?
PETERS SHORTHAND REPORTING CORPORATION (916) 362-2345
47
1 DR. MARTY: Yeah.
2 DR. ALEXEEFF: I think this particular example
3 right here is one that we can look at this definition here.
4 The chemical pulmonary function where there is some airway
5 conductance or biological control value, and you're really
6 determining whether or not those exposed are different from
7 the baseline control values.
8 Now, in that circumstance there is a statistical
9 requirement or some other requirements that we look at.
10 So go ahead.
11 CHAIRMAN FROINES: Let's go ahead. I mean, some
12 of this is inherent and Kenny Crump's written about it way
13 back in 1984, when he talked about the limitations of this
14 traditional REL approach, and some of the problems with
15 statistical significance in terms of rewarding small
16 studies, and so we have to be careful about it.
17 Let's go ahead.
18 DR. MARTY: The Utell study found that exposure of
19 asthmatics to 450 micrograms --
20 CHAIRMAN FROINES: Excuse me, Melanie. Let me
21 just stop.
22 I think, George, it would be useful to give the
23 panel copies of Crump's paper. I think it's useful to read,
24 for people who haven't sort of been in the world. You know
25 who I mean. That deals with the benchmark dose concept.
PETERS SHORTHAND REPORTING CORPORATION (916) 362-2345
48
1 DR. ALEXEEFF: Okay.
2 CHAIRMAN FROINES: Go ahead, Melanie.
3 DR. MARTY: Utell found that exposure of
4 asthmatics to 450 micrograms sulfate per cubic meter as
5 sulfuric acid, but not as the ammonium sulfate for 16
6 minutes resulted in decrease airway conductance and this
7 study compared to a thousand microgram sulfate per cubic
8 meter of either type of sulfate resulted in decreased airway
9 conductance and decreased forced expiratory volume in one
10 second.
11 In the document we have our reference exposure
12 levels approach outlined in that format that you see on the
13 slide. That identifies the study and the study population,
14 which in this case was 17 human asthmatics.
15 The exposure method, which is by inhalation, the
16 critical effect decreased in airway conductance, a low
17 observed adverse effect level of a thousand micrograms
18 sulfate per cubic meter and a no observed adverse effect
19 level of 50 micrograms sulfate per cubic meter --
20 DR. WITSCHI: I don't understand that one, because
21 in the previous one it said the 450 also resulted in
22 decrease in airway conductance.
23 DR. COLLINS: For sulfuric acid. We are just
24 looking at the sulfate.
25 DR. WITSCHI: Thank you.
PETERS SHORTHAND REPORTING CORPORATION (916) 362-2345
49
1 DR. FRIEDMAN: I don't understand. It says the
2 450 resulted in decreased airway conductance, but then you
3 say that the no effect level is 450.
4 DR. MARTY: Something is wrong.
5 CHAIRMAN FROINES: It says the ammonium sulfate
6 did not result in decreased airway conductance, so that's
7 the ammonium sulfate, that's the NOEL, but not for sulfuric
8 acid.
9 DR. FRIEDMAN: The next one only refers to
10 sulfuric acid. It doesn't say a word about ammonium
11 sulfate.
12 DR. ALEXEEFF: The sulfuric acid numbers, this is
13 just for sulfate, non-sulfuric acid sulfates. I think
14 that's the key point.
15 DR. MARTY: Right.
16 DR. GLANTZ: In that study they gave 450
17 micrograms per cubic meter of non-sulfuric acid sulfates and
18 nothing happened, is that what you're saying?
19 DR. WITSCHI: Yeah, but then you say hundred
20 micrograms per cubic meter sulfate as sulfuric acid.
21 CHAIRMAN FROINES: Where are you reading?
22 DR. WITSCHI: Sulfuric acid is --
23 DR. ALEXEEFF: That's the quantitation procedure
24 in terms of --
25 DR. WITSCHI: But if you go by the logic, it would
PETERS SHORTHAND REPORTING CORPORATION (916) 362-2345
50
1 mean that 450 sulfate of sulfuric acid would also have an
2 effect. Something got mixed up in putting together those
3 simplified slides.
4 CHAIRMAN FROINES: We're hoping this is just a
5 slide preparation problem.
6 DR. MARTY: Me too.
7 Yeah. We're going to have to go back and
8 definitely check that one, because, you're right, something
9 seems very funny if we're saying a NOAEL is LOAEL.
10 CHAIRMAN FROINES: Why don't we go forward and
11 assume that 450 is the NOEL for ammonium sulfate, and even
12 if it's not true, at least we're going to learn the process
13 you went through.
14 DR. FUCALORO: And just for clarification, when
15 they say micrograms per meter cubed sulfate, is it
16 micrograms of the entire compound or just the sulfate
17 portion of it?
18 DR. ALEXEEFF: That's where the confusion here,
19 it's micrograms when expressed as sulfuric acid.
20 DR. FUCALORO: As sulfuric acid.
21 DR. ALEXEEFF: Even though there is no sulfuric
22 acid at this point, it quantifies it's like per microgram
23 for arsenic, for -- that's the confusion on that slide.
24 DR. FUCALORO: Got you.
25 DR. MARTY: Assuming we're correct about the NOAEL
PETERS SHORTHAND REPORTING CORPORATION (916) 362-2345
51
1 then, what we have to do is decide if time extrapolation is
2 necessary, because we're trying to set up a reference
3 exposure level for one-hour exposures.
4 The study exposure duration, of course, vary
5 depending on the protocol and this necessitates
6 extrapolating to the equivalent concentration for a one-hour
7 exposure.
8 What we did in this document is use a modified
9 Haber's Law. The equation is concentration to the nth
10 power, times time is equivalent to a constant, and the
11 constant in this case would be a constant rate of response.
12 The value of N is frequently empirically derived
13 and we have a table in the document, which has a number of
14 compounds, which have had this exponent derived for them.
15 If it is -- it's page 50, Table 12. If there are
16 not enough data to empirically derive that value of N, we
17 have set a default value to one for extrapolating from less
18 than one hour to one hour, and a default value of two for
19 extrapolating from exposures that were greater than one-hour
20 duration back to a 60-minute concentration.
21 DR. FRIEDMAN: Could you explain why you used
22 those two different numbers for those two different
23 situations?
24 DR. ALEXEEFF: We can on the next slide.
25 DR. FRIEDMAN: Can I make another suggestion
PETERS SHORTHAND REPORTING CORPORATION (916) 362-2345
52
1 related to this? You introduced this equation on page 40,
2 but don't explain it, and then on page 48 you talk about
3 Haber's Law and explain it. I wonder if you couldn't give
4 some explanation or introduction to Haber's Law on page 40
5 when this first appears.
6 DR. ALEXEEFF: Okay.
7 DR. FRIEDMAN: Because I didn't know what it was
8 until I got to 48.
9 DR. ALEXEEFF: Okay.
10 DR. FUCALORO: Just the form of it looks like an
11 empirical law.
12 DR. ALEXEEFF: That's what it is.
13 DR. FUCALORO: There's no theoretical foundation
14 for that.
15 DR. FRIEDMAN: On page 40 you have C to the N
16 times T equals K, but there's no explanation what K is.
17 DR. ALEXEEFF: Right.
18 DR. FRIEDMAN: Until you got to 48.
19 DR. ALEXEEFF: We can clarify that example.
20 DR. WITSCHI: Well, Fritz Haber was a German
21 chemist who invented succession of nitrogen from the air,
22 and he was very instrumental in World War I with war gases.
23 He was directing the first gas attack on the Western Front
24 with chloride gas.
25 And Haber's Law really is originally stated is he
PETERS SHORTHAND REPORTING CORPORATION (916) 362-2345
53
1 said that he found it very useful in judging the acute
2 toxicity of the war gas by multiplying the concentration in
3 air times the time it took for half the animals to die, and
4 the smallest number, the more toxic was the gas.
5 And then only later on it became to be used that
6 you could say that the concentration and times product
7 always gives you the same response, but that's a gross
8 misuse of Haber's Law, and there have been volumes written
9 about that one.
10 But it was just originally something that was
11 describing the acute toxicity of war gases.
12 DR. FUCALORO: On the applications of the
13 military.
14 DR. WITSCHI: He then took it one step further
15 after the World War I and because it went from war gases to
16 pesticides, like cyanide and all these kinds of things, you
17 could fumigate around the mills and these kind of things.
18 But he is most famous for two things. The one is
19 really he invented the succession process, and the other one
20 very few people know he's also the Haber of the Haber-Weiss
21 equation for neurotoxicology. That was the last paper he
22 wrote before his death.
23 Haber-Weiss, it's somehow free radical formation
24 in certain chemical reactions and is important, the
25 Haber-Weiss reaction, and nobody knows that that's the same
PETERS SHORTHAND REPORTING CORPORATION (916) 362-2345
54
1 person.
2 CHAIRMAN FROINES: We're currently doing work on
3 quinones in diesel exhaust associated with the Haber-Weiss
4 reaction, so it's actually current.
5 DR. WITSCHI: He wrote this paper in exile. He
6 was director of the Kaiser Wilhelm Institute in Germany and
7 he was Jewish, and he had to go in 1933, and he wrote this
8 paper, but he was in exile and it appeared three or four
9 months after his death.
10 DR. ALEXEEFF: This slide is just an example of
11 how one would derive this empirical equation when you would
12 have several studies evaluating the same endpoint whether
13 they expose -- well, the individuals were exposed to
14 different concentrations at different times, and you just
15 fit the curve and derive N from the value.
16 Now, if N were one, in this case N is somewhere
17 around two or three, if N were one, you could see the two
18 points on the end of that curve they would be a straight
19 line. It would be sort of a linear relationship if N was
20 one, between those, the first and the last point.
21 DR. MARTY: That would mean that concentration and
22 time were both important, about equally important.
23 DR. ALEXEEFF: If this point exists, and we didn't
24 know what the curve was, but if we took this point and used
25 N as one, we'd have some straight line, assuming some linear
PETERS SHORTHAND REPORTING CORPORATION (916) 362-2345
55
1 relationship this way.
2 So the reason we choose, made this decision of N
3 versus one, versus two, it's a health protective choice,
4 because if you extrapolate one way, you can either
5 overpredict or underpredict versus extrapolating the other
6 way.
7 See, if you started here and drew a straight line
8 to there, that would have a certain meaning of the
9 concentration, versus if you started here and drew a
10 straight line like if you didn't have this point but just
11 drew a straight line like that.
12 So I can show you in the calculation and come back
13 with an example of showing exactly how the different
14 calculations result in different concentrations.
15 DR. FRIEDMAN: That would be interesting to see.
16 DR. ALEXEEFF: Okay.
17 DR. MARTY: Also on that table on page 50, you can
18 see where the values of N fall for a whole bunch of
19 different chemicals. And the mean ends up around two. So
20 that is one reason why we've chosen a default of two for
21 extrapolating from greater than one hour back to one hour.
22 After adjusting for differences for protocol in
23 terms of exposure duration to one hour, we also have to deal
24 with other types of uncertainties, and so we apply
25 uncertainty factors to the no observed adverse effect level
PETERS SHORTHAND REPORTING CORPORATION (916) 362-2345
56
1 in deriving the reference exposure level.
2 For example, if you have an animal study which
3 identifies a no observed adverse effect level, you need to
4 account somehow for the differences between animals and
5 people, so you apply an interspecies uncertainty factor,
6 generally of ten. Sometimes you can get away with using
7 three, if you have accounted for toxicokinetic differences
8 between humans and animals for that particular substance.
9 I don't believe we've done that in any of these
10 numbers. That's why I have the or three in parentheses.
11 You have to have a lot of good data to do that.
12 We also need to account for inter-individual
13 variability in human population, so we have an additional
14 intraspecies uncertainty factor, which is generally ten, if
15 you start with an animal NOAEL.
16 CHAIRMAN FROINES: I should tell you that Dale
17 Haddis has just completed a major study for OSHA on
18 individual variability relative to the safety factor of ten,
19 and concludes that the safety factor of ten is inadequate,
20 and so you'll be seeing that work in print shortly.
21 DR. MARTY: If you start with a human study that
22 starts with a no observed adverse effect level, you
23 obviously don't have to extrapolate for interspecies
24 differences, so the uncertainty factor is set to one.
25 But you still need to account for intraspecies
PETERS SHORTHAND REPORTING CORPORATION (916) 362-2345
57
1 uncertainty, so what we've done if the study has included
2 sensitive subjects that are sensitive to the endpoint under
3 consideration for that study, then we have an uncertainty
4 factor of one.
5 Sometimes you would choose to use three, if you
6 know there are other subpopulations that are sensitive to
7 that chemical for a different reason, but you don't know
8 really where they lie in their sensitivity with respect to
9 the population study.
10 If the study did not include sensitive subjects,
11 then the uncertainty factor is set to ten.
12 Sometimes the key studies do not identify a no
13 observed adverse effect level and the extrapolation then
14 starts with the lowest observed adverse effect level. And
15 in that case that's just the lowest dose in the study that a
16 biologically or statistically significant response was
17 noted.
18 So we need to figure out where the NOAEL is for
19 that chemical and that endpoint with respect to the LOAEL.
20 Generally you don't have data if you're using a LOAEL, so
21 you use uncertainty factors to account for this difference.
22 In the past we've always used ten for the LOAEL to
23 NOAEL extrapolation and we got lots of public comments
24 saying that there may be some cases where you can use a
25 factor less than ten.
PETERS SHORTHAND REPORTING CORPORATION (916) 362-2345
58
1 So in the case of lethality, George mentioned
2 earlier, and also at some other frank effect endpoints, that
3 the dose response slopes are rather steep. And I think we
4 have a table in here which indicates for mild effects versus
5 lethality what the typical slope response curve is. So we
6 have determined that you can get a uncertainty factor of
7 three for extrapolating from a LOAEL to a NOAEL if the
8 endpoint is lethality.
9 Generally we don't derive RELs based on endpoint
10 lethality that would apply only to the level protected
11 against life-threatening effects, which is an informational
12 level and it again is not used in the risk assessment, per
13 se.
14 DR. GLANTZ: That seems counterintuitive to me.
15 It seems to me that if the endpoint is more severe you want
16 to use a bigger uncertainty factor.
17 DR. MARTY: That's a good point, because a lot of
18 people look at the uncertainty factors as trying to account
19 for severity. In this case, the uncertainty factor is
20 specifically trying to account for the slope of the dose
21 response curve, where the no adverse effect would be where
22 low adverse effect level. And for lethality the slopes look
23 like this, rather than this, and so there really is a lesser
24 difference between LOAEL and NOAEL for lethality than there
25 are for many other endpoints.
PETERS SHORTHAND REPORTING CORPORATION (916) 362-2345
59
1 CHAIRMAN FROINES: Then one could argue that you
2 should have double effect. One is to get you to the NOEL by
3 the using three with a sharp dose response curve, but then
4 because of lethality as an important endpoint, you add to it
5 the safety factor to get you further away from the
6 lethality.
7 DR. FUCALORO: Prudence factor.
8 DR. ALEXEEFF: We've looked at this issue
9 extensively and what you end up finding, and this is why it
10 becomes interesting when you look at the three levels of
11 effect, what concentration causes mild, what concentration
12 causes severe, and what concentration causes lethality.
13 When you look at that whole spectrum of toxicity
14 for a specific chemical, you'll find in most cases it does
15 not span a huge range. The example of formaldehyde is
16 probably the widest. It's somewhere around hundred or so
17 fold.
18 So if you started adding an uncertainty factor for
19 lethality, what we found is that the, quote, level that
20 protects against lethality is levels that aren't -- that we
21 have human data showing that it just causes irritation.
22 So that's what happening on these steep dose
23 response curves.
24 And that is actually one of the difficulties we
25 have. It's an area we think it's important for research in
PETERS SHORTHAND REPORTING CORPORATION (916) 362-2345
60
1 terms of evaluating this, because in the document one of the
2 reasons we don't have a lot of lethal levels is because the
3 uncertainty factor approach starts coming up with levels
4 that we have other data showing that there's not likely to
5 be lethality. There's human data that counteracts the other
6 information.
7 CHAIRMAN FROINES: But you should -- it seems to
8 me that you can develop different numbers and discuss those
9 numbers, because then the question then becomes what is it
10 that one needs to do to mitigate against those effects,
11 what's the next step in this whole process, and having those
12 different numbers would be helpful in that regard.
13 DR. ALEXEEFF: Yeah. Well, that's why we provide
14 them in here. So the different numbers are in here when the
15 data is available. And it's something that if like for
16 certain chemicals, and I think it's because again the dose
17 response curves are really tight for like arsine, the
18 difference between lethality and any effect is like two- or
19 fivefold with the experiments we used for hemolysis in their
20 higher dose group shows high lethality. And so you add an
21 uncertainty factor of ten, you end up getting below the
22 level that causes just hemolysis, so you start getting these
23 contradictions if you follow the uncertainty factors a
24 little bit too closely.
25 CHAIRMAN FROINES: If you were going to develop an
PETERS SHORTHAND REPORTING CORPORATION (916) 362-2345
61
1 alarm system at an arsine plant, and you were going to
2 trigger that alarm system at some level of airborne
3 concentration, you want to have a reasonable margin of
4 safety when that alarm goes off so people don't end up being
5 killed.
6 DR. ALEXEEFF: Right. So all we're saying --
7 CHAIRMAN FROINES: The control mechanism must
8 reflect the sharp dose response curve.
9 DR. ALEXEEFF: Right. We're not developing the
10 alarm system, but we are telling them is that this is the
11 concentration that protects against hemolysis, and you just
12 go a little bit more and we've got lethality.
13 Now, we let the risk managers think about, okay,
14 if I'm designing an alarm system and this is what I'm faced
15 with, lethality and hemolysis, then I should err on the
16 side --
17 CHAIRMAN FROINES: And these are things, these
18 need to be very clearly stated, because it's -- because
19 somebody ultimately takes the values that you've come up
20 with, and does have to design something to prevent people
21 dying, falling over.
22 DR. ALEXEEFF: Right.
23 DR. FRIEDMAN: Can I ask if the slope of the dose
24 response slope is not steep for mild effects, why did you
25 use the three for mild irritation?
PETERS SHORTHAND REPORTING CORPORATION (916) 362-2345
62
1 DR. MARTY: I was just getting to that.
2 We've got, and this again reflects the concern
3 that we just heard, that you should have -- you've got a lot
4 of public comments that you should have less of an
5 uncertainty factor for the mild effects.
6 So what we did, there are not a lot of data to
7 look at to determine what the real appropriate uncertainty
8 factor is to go from a LOAEL to NOAEL, but some folks had
9 done analyses, including ourselves, where you have sets of
10 chemicals where you actually have both a NOAEL and a LOAEL
11 and you look at what the ratios are. When we do that, most
12 of them clump around two and three.
13 It's actually sort of a weird-looking
14 distribution. I don't think -- I think it may be either bi-
15 or tri-modal, but anyhow, most of them -- I think I have an
16 overhead of this.
17 Since most of them clump at the lower end, we
18 decided to try using an uncertainty factor of three only for
19 mild irritation. Data behind these represent data for mild
20 adverse effects, including mild irritations, but there's
21 other adverse effects mixed in with that. So it's not the
22 best possible comparison.
23 DR. GLANTZ: Yeah, but it's there. Looking at
24 that it looks like you should be using six, five or six.
25 This puts you down in the middle of your pretty -- that's
PETERS SHORTHAND REPORTING CORPORATION (916) 362-2345
63
1 kind of near -- that's the mean, I guess.
2 DR. ALEXEEFF: Yeah. The mean -- yeah. What it
3 tells us is, well, our default factor is ten. Okay. Just
4 for sort of the default factor is ten. But it's telling us
5 that there are some health effects here for which if we knew
6 which health effects these were or if these fit into a
7 certain kind of category, then we could provide a lower
8 uncertainty factor.
9 DR. GLANTZ: I think this is a good argument for
10 using five or six.
11 DR. FUCALORO: Are these real data?
12 DR. ALEXEEFF: This is real data.
13 DR. FUCALORO: From what?
14 DR. ALEXEEFF: This is from all of the studies
15 that we had. This is 112 studies where we were able to
16 compare for these mild effect levels the LOAEL and the
17 NOELs, to see how much difference there was between those.
18 So it's for probably about 50 chemicals in this case.
19 There's additional chemicals, chemicals in addition to the
20 ones in this document, some additional analysis we were
21 doing.
22 DR. FUCALORO: Forgive me for asking this
23 question, because I think I should know the answer to it,
24 but there is a bit of confusion in my mind with LOAEL. The
25 lowest observed effect; right?
PETERS SHORTHAND REPORTING CORPORATION (916) 362-2345
64
1 DR. ALEXEEFF: Adverse effect.
2 DR. FUCALORO: Adverse effect.
3 And that doesn't really have any theoretical
4 significance, does it, like a NOEL or REL? In other words,
5 it's just what happens to be out there in the literature, so
6 someone observes an effect here and then all of a sudden you
7 choose that as a LOAEL and then apply UFs to them in order
8 to get to a NOEL, which presumably has a real meaning. You
9 may not have the right NOEL.
10 And I think some of the concern I think that's
11 expressed among the members of this panel is the -- I say
12 the ambiguity of that LOAEL. There's really -- whether or
13 not you can go ten times lower than that and still observe
14 effects.
15 DR. ALEXEEFF: That is true.
16 DR. FUCALORO: And I think that's --
17 DR. ALEXEEFF: Here's examples right here where
18 you can go more than ten times lower and still observe
19 effects. So I think we're --
20 DR. FUCALORO: That's --
21 DR. ALEXEEFF: We're in agreement.
22 DR. FUCALORO: That's the basis I think --
23 DR. GLANTZ: Why are you using three? I mean, I
24 can see where the industry people will come in and say
25 using, based on this, using ten is like being way too
PETERS SHORTHAND REPORTING CORPORATION (916) 362-2345
65
1 conservative. I mean, if you read the public comments I
2 think that's sort of macho.
3 I think if you look at this, this sort of
4 tradition is to use the 95 percent upper confidence limit,
5 and that is six, and so why don't you use six? I think you
6 made a good case here for six.
7 DR. ALEXEEFF: That's a good point.
8 What we were doing -- well, I can explain. I
9 think you make a good point.
10 But what we -- there's -- first of all, our
11 default value is ten, and the reason we chose three, there's
12 a reason for that, and that is primarily since the
13 uncertainty factors are multiplied, that basically two
14 factors of three is actually, you know, 3.16 or something,
15 results in a factor of ten. So it's a geometric mean.
16 Three is chosen essentially as a geometric mean of ten on
17 this multiplicative scale. That's why three is chosen for
18 both throughout OEHHA documents and throughout US EPA
19 documents as sort of for that basis.
20 I think you have a good point here, that you're
21 saying that the data is suggesting --
22 DR. GLANTZ: Six.
23 DR. ALEXEEFF: Six.
24 DR. GLANTZ: The problem I have with what you just
25 said is the whole idea of these uncertainty factors is that
PETERS SHORTHAND REPORTING CORPORATION (916) 362-2345
66
1 they adjust for different things. You knew, one of them is
2 the LOAEL versus NOEL, one of them is the interspecies. And
3 so I think to take, you know, to say, well, if we take a
4 couple of them and compound them we get ten, and here it's
5 ten. It's sort of an apples and oranges thing, because
6 these different uncertainty factors are accounting for
7 different forms of uncertainty, so I think here, you know --
8 I mean, the geometric mean being three, that's true. That's
9 what this thing shows, but I don't think you want to be
10 picking the mean value. But I think on the other hand I
11 think using ten you could argue that that's being way way
12 too conservative.
13 DR. ALEXEEFF: Right. So that's the dilemma we
14 came up with and our sort of default approach is to go from
15 ten to three or to one. I mean, that's just generally the
16 realm that we've used, but we haven't gotten to the point of
17 being able to say, yes, six does look good and we're going
18 to use six.
19 DR. GLANTZ: I think you should put this graph in
20 the report.
21 DR. FUCALORO: Before you do, make sure you have
22 the coordinate right. The interval between one and four is
23 three. I learned that in school. And the interval between
24 four and six is two, and then it's three again and then it's
25 two again and then it's three again. I'm wondering if I am
PETERS SHORTHAND REPORTING CORPORATION (916) 362-2345
67
1 missing something there. Your hatch marks --
2 DR. ALEXEEFF: Yeah.
3 DR. GLANTZ: You've heard of the log scale, this
4 is the Alexeeff scale.
5 DR. FUCALORO: A logarithmic alternate.
6 DR. GLANTZ: That's the new and improved.
7 DR. ALEXEEFF: Let me ask a question then. Would
8 you suggest then our standard approach has been to use ten,
9 except for certain effects we would use three. So you're
10 suggesting that let's presume that -- I happen to have the
11 numerical calculations that we actually rely on more than
12 the graphical, bu you're suggesting that something like in
13 this case the 95th percentile would suggest that six overall
14 would be a better choice than either ten or three?
15 DR. GLANTZ: Yeah. For a LOAEL to NOEL.
16 DR. ALEXEEFF: Right. For this subset of
17 calculations.
18 DR. GLANTZ: I think you made a good case for that
19 here.
20 DR. MARTY: For all mild effects, not just --
21 DR. ALEXEEFF: For all.
22 DR. FRIEDMAN: But the severity you're going to
23 keep it three? You're going to keep the severe at three
24 because of the steep slope? I mean --
25 CHAIRMAN FROINES: We have to be careful about
PETERS SHORTHAND REPORTING CORPORATION (916) 362-2345
68
1 time, folks. This is a very interesting, but somewhat
2 glacial process we're in.
3 And the problem is for people who haven't lived in
4 this world of noncarcinogen risk assessment, we're in a
5 sense discussing all the inherent issues why this is a
6 terrible way to do risk assessment. Nonmechanistic
7 noncarcinogen risk assessment is still an absolute mess and
8 we're identifying all the inherent problems with this sort
9 of very subjective, as you can tell, uncertainty factor
10 approach.
11 DR. GLANTZ: Just I don't want to like --
12 CHAIRMAN FROINES: Everybody hates this process.
13 DR. GLANTZ: I don't want to slow the glacier
14 down.
15 DR. FUCALORO: But you'll do it.
16 DR. GLANTZ: But I'll do it anyway.
17 At the beginning Froines said I wasn't talking
18 enough.
19 CHAIRMAN FROINES: I want to go on record, I will
20 never say that again.
21 DR. GLANTZ: I had a post doc once who said he
22 didn't have enough work to do too. That's become a legend
23 around here.
24 But, anyway, my understanding that the lethality
25 of certainty factor of three gets you from the lethality to
PETERS SHORTHAND REPORTING CORPORATION (916) 362-2345
69
1 mild irritation.
2 DR. MARTY: No. It gets you from lethality to no
3 lethality.
4 CHAIRMAN FROINES: Right.
5 DR. MARTY: It gets you from the lowest observed
6 lethal effect level to a no observed lethal effect level.
7 DR. GLANTZ: What do you do after that?
8 CHAIRMAN FROINES: It's two processes. You are
9 going to calculate a NOEL for mild irritation and lethality
10 for lethality. Those are different. That's what I'm saying
11 to George, I think that the document should always clearly
12 state --
13 DR. GLANTZ: I see.
14 CHAIRMAN FROINES: -- the two, because those are
15 the things that people then use subsequent to that to make
16 decisions about.
17 DR. ALEXEEFF: See, what we find in sometimes
18 increased from local air districts is that they may come
19 back to us and say, well, we've done these calculations, we
20 find out that we're above the reference level by a factor of
21 two.
22 And other cases they'll come back and say we're
23 over the reference level by a factor of 40. Okay. And the
24 factor of 40, they want to know now am I in some sort of
25 danger zone if I'm over by a factor of 40?
PETERS SHORTHAND REPORTING CORPORATION (916) 362-2345
70
1 So we provided the severity information to know
2 where we are on this.
3 DR. GLANTZ: So you're not -- so in other words,
4 and then I'll drop this for a few seconds, but the -- so
5 what you're saying is the lethality is the endpoint, you're
6 treating that as a distinct endpoint. You're not trying to
7 say if we only have one study and the endpoint is lethality
8 that we're trying to get down to a reference exposure level
9 where you wouldn't see anything.
10 DR. ALEXEEFF: Correct. We're not doing that.
11 We're not doing the latter.
12 So the 95th percentile for lethality was 3.5.
13 DR. GLANTZ: Okay.
14 CHAIRMAN FROINES: Let's go. We really have got a
15 time problem. Can we finish this, because I think we want
16 to give the transcriber a break.
17 DR. MARTY: I'll go as fast as I can.
18 Assuming that the NOAEL is actually 450 micrograms
19 per cubic meter for sulfate, we did the extrapolation which
20 we talked about using modified Haber's Law from 16 minutes
21 to a one-hour concentration, and that gets us to 120
22 micrograms per cubic meter.
23 We had identified a NOAEL, so there is no LOAEL
24 uncertainty factor. It's set to one.
25 There is no interspecies extrapolation in this
PETERS SHORTHAND REPORTING CORPORATION (916) 362-2345
71
1 case, because it's people, so that's set to one.
2 We use sensitive subjects, asthmatics, for
3 sulfate, so that intraspecies uncertainty factor is also set
4 to one.
5 For cumulative uncertainty factor of one the
6 reference exposure level is then 120 micrograms per cubic
7 meter in this example.
8 CHAIRMAN FROINES: So if you had used children and
9 not asthmatics what would you do then?
10 DR. MARTY: I think we would -- knowing that
11 sulfate impacts asthmatics more than non-asthmatics, I think
12 you'd be wise to use, if you used kids who were not
13 asthmatics, you would still need to add an additional
14 uncertainty factor to that.
15 The second example --
16 CHAIRMAN FROINES: I'm confused.
17 DR. BLANC: Because she's saying that if you use
18 general kids, who would include by chance maybe asthmatics,
19 but mostly normal kids, you'd have to put a factor in to
20 take into account that wouldn't be protecting asthmatic
21 children. Because they had asthmatics in the group, they
22 already had the highest risk groups.
23 DR. MARTY: In this example we end up with a total
24 uncertainty factor of 100. This study was the examples for
25 arsine, the study was done in mice. The exposure method was
PETERS SHORTHAND REPORTING CORPORATION (916) 362-2345
72
1 inhalation. The critical effect is lysis of red blood
2 cells. The study identifies a LOAEL and a NOAEL.
3 The exposure duration is one hour, so there's no
4 need for time extrapolation in this case.
5 Since the study identified a NOAEL, there's no
6 need to extrapolate from the LOAEL, so there's no
7 uncertainty factor for that.
8 However, it was done in mice, so we have the
9 interspecies uncertainty factor of ten.
10 And then in order to account for human variability
11 in response, we have an additional uncertainty factor for
12 intraspecies variability of ten for a total cumulative
13 uncertainty factor of ten for a total cumulative uncertainty
14 factor of 100. Thus your reference exposure level ends up
15 at 0.05 ppm, 100-fold lower than the identified NOAEL in the
16 animal study.
17 And then I'm using this example because here we
18 have a cumulative uncertainty factor of 1,000, and it's just
19 going to point out some other problems, which Dr. Froines
20 mentioned, with the general evaluation of noncancer
21 endpoints.
22 In this case it's ethylene glycol monoethyl ether
23 acetate, or EGMEA.
24 The study was done in pregnant rabbits. The
25 exposure was via inhalation, six hours per day, days 6 to 29
PETERS SHORTHAND REPORTING CORPORATION (916) 362-2345
73
1 of gestation.
2 So here we have a relatively long exposure period
3 in terms of trying to extrapolate backwards to one hour.
4 This is one issue that's brought up regularly in our
5 comments.
6 The critical effect in this case is developmental
7 defects.
8 There was a low observed adverse effect level
9 identified of 25 parts per million in the study, but a no
10 observed adverse effect level was not identified.
11 Because this a developmental toxicant, we chose to
12 extrapolate from the six hour per day time point to one
13 hour. Because it is not -- it is conceivable that exposure
14 during any day of pregnancy would result in the
15 developmental defect.
16 So we extrapolated from six hours to one hour,
17 using the Haber's Law, modified Haber's Law, with an
18 exponent of two. That gives us an extrapolated one-hour
19 concentration of 61 parts per million.
20 Since there was not an identified NOAEL, we used a
21 LOAEL uncertainty factor of ten.
22 Because the study was not done on people, we use
23 an interspecies uncertainty factor of ten.
24 And to account for individual variability response
25 in the human population, we use an intraspecies uncertainty
PETERS SHORTHAND REPORTING CORPORATION (916) 362-2345
74
1 factor of ten for a total cumulative uncertainty factor of a
2 thousand. And reference exposure level is 0.06 ppm.
3 DR. WITSCHI: I think this shows at least two
4 potential problems with this approach.
5 One of them is that if you're talking about
6 long-term effects in C times T product, it's usually true
7 conditions, which it certainly wouldn't get with six hours a
8 day exposure.
9 The other one, this kind of extrapolation ignores
10 something completely, and that's the influence of dose rate
11 on toxicity, which can be a very determining factor.
12 DR. MARTY: Yes.
13 DR. ALEXEEFF: Do you have a suggestion or -- this
14 is one of our most difficult issues, is dealing with a
15 reproductive endpoint where the standard test methodology is
16 this type.
17 DR. WITSCHI: You are right that it's not only
18 dose rate either. In reproduction you hit the moving
19 target.
20 DR. ALEXEEFF: Right.
21 DR. WITSCHI: A very moving target.
22 DR. MARTY: It's difficult with developmental
23 toxicants, because the standard test is to expose the animal
24 all through gestation. It would be incredibly costly to
25 figure out which hour in gestation is the --
PETERS SHORTHAND REPORTING CORPORATION (916) 362-2345
75
1 DR. WITSCHI: That's right. You leave out certain
2 days. You are not going to see any effect with it.
3 DR. MARTY: Right. So that's what we're stuck
4 with when we try to look at developmental toxicants. We're
5 stuck with the protocol that logistically makes sense.
6 DR. ALEXEEFF: We gave this example to show the
7 most difficult situation that we've come up with.
8 DR. WITSCHI: It's a great one.
9 DR. ALEXEEFF: We've spent a lot of time trying to
10 decide how to go with it. That's the best approach we come
11 to other than somehow just avoiding the calculation.
12 DR. WITSCHI: I think you brought up a very
13 interesting problem. We're not going to solve that one
14 today.
15 CHAIRMAN FROINES: It's really something to take
16 back as a subject for further investigation, because Peter
17 is right, the dose rate issue is really crucial in the
18 developmental effect.
19 DR. ALEXEEFF: Yeah, it is.
20 DR. MARTY: I'm going to go through an example of
21 benchmark concentration approach and just as a quick
22 overview, the NOAEL uncertainty factor approach --
23 CHAIRMAN FROINES: Just so Paul Gosselin and
24 others realize, this is going to come up later, your
25 reference exposure level is .061 part per million. If this
PETERS SHORTHAND REPORTING CORPORATION (916) 362-2345
76
1 was a pesticide, the NOEL would be 61. Right?
2 DR. MARTY: I think that was a LOAEL.
3 CHAIRMAN FROINES: Yes. It would be .61 as
4 opposed to .061, so it would be a factor of ten difference,
5 so using the DPR system that their MOS would be -- since the
6 MOS is based on the --
7 DR. MARTY: Factor of a hundred. It would be 6.1.
8 CHAIRMAN FROINES: I'm not educated like Tony. I
9 don't multiply by tens too often.
10 But so that we have a clear -- seems to me to be a
11 fundamentally different approach, because the value of the
12 denominator that you used to calculate the MOS would be the
13 same. It's a value in the numerator that changes.
14 So let's be aware that we have to talk about this
15 one.
16 DR. MARTY: The NOAEL and uncertainty factor
17 approach, as you can plainly see, has a lot of issues
18 associated with it that are problematic. You're somewhat
19 dependent on the investigator's choice of dose level. You
20 don't account for the number of subjects in your study. You
21 frequently haven't gotten an idea of what the slope of the
22 dose response curve looks like, between the LOAEL and NOAEL,
23 so you have to make a lot of assumptions.
24 The benchmark concentration approach tries to get
25 around some of those uncertainties. It can't fix all of it,
PETERS SHORTHAND REPORTING CORPORATION (916) 362-2345
77
1 but essentially allows an estimation of a concentration that
2 produces a predetermined specified level of response, and
3 it's an alternative extrapolation point to the no observed
4 adverse effect level.
5 In the case of ammonia we had four human studies
6 of irritation.
7 The first thing we did was ingest each of those
8 studies from the exposure duration, which varied, to a
9 one-hour concentration.
10 And we used a log-normal probit analysis to
11 identify the dose response curve and in particular chose the
12 95 percent lower confidence limit on the five percent
13 response rate. That is the definition of the benchmark
14 concentration, BCO 5.
15 This just depicts essentially the graph that you
16 produce when you do the log probit analysis.
17 And you can see that the benchmark concentration
18 for a five percent response rate is 13.6 ppm in this
19 example. The X axis is the log part per million ammonia
20 concentration. The Y axis is the probit scale of the
21 response.
22 We, in analyzing the benchmark concentration,
23 we've looked at one percent, five percent, we also looked at
24 ten percent response rates. And these are the likelihood
25 estimates of part per million in the 95 percent lower
PETERS SHORTHAND REPORTING CORPORATION (916) 362-2345
78
1 confidence limit on the concentrations that produce both the
2 one percent rate in the first line and the five percent in
3 the second.
4 Since there is a lot of uncertainty when you start
5 getting below five percent response rates, we decided to
6 stick to the five percent, rather than try to evaluate
7 benchmark concentrations for the one percent response rate.
8 Now, you still need to use uncertainty factors to
9 account for specific uncertainties in the benchmark
10 concentration in order to get to a reference exposure level.
11 There are slightly different than those used with the NOAEL
12 and LOAEL approach.
13 We have chosen to use an interspecies uncertainty
14 factor of three to extrapolate from animal studies benchmark
15 concentration to a human situation. The reason this was
16 done was because there are investigators who believe that
17 some of the variability is taken into account by using the
18 95 percent lower confidence limit on that five percent
19 response rate concentration.
20 And so it was felt that it was okay to not use an
21 interspecies factor of ten when you have a benchmark
22 concentration, because the precision of your estimate of the
23 five percent response rate is much greater than any
24 precision in your estimate of either the LOAEL or NOAEL.
25 We still use an intraspecies uncertainty factor of
PETERS SHORTHAND REPORTING CORPORATION (916) 362-2345
79
1 ten when we're starting with an animal study, and that's to
2 account for human individual variability study.
3 If we started with a human study and calculated a
4 benchmark concentration, which is the case for ammonia, then
5 we obviously have no interspecies extrapolations. That
6 uncertainty factor is set to one.
7 Then we ask the question does the study include
8 sensitive subjects. If the answer is yes, then the
9 uncertainty factor again is one. If the answer is no, we
10 use an uncertainty factor of three for intraspecies
11 variability, and that is again because we have chosen the 95
12 percent lower confidence limit on that five percent response
13 rate concentration.
14 We had four studies and the endpoint was eye and
15 respiratory irritation in humans. The low observed adverse
16 effect levels and no observed adverse effect levels varied
17 with each study.
18 And we do not need a low observed adverse effect
19 level uncertainty factor in the benchmark concentration
20 approach, because we've specified a response rate, which is
21 usually below the observed range anyhow in the experimental
22 studies.
23 Extrapolating to the one-hour concentration we get
24 a benchmark concentration of 13.6 ppm. We applied an
25 intraspecies uncertainty factor of three, so the total
PETERS SHORTHAND REPORTING CORPORATION (916) 362-2345
80
1 cumulative uncertainty factor was three. And we developed
2 then a reference exposure level of 4.5 ppm for irritation of
3 the respiratory and eye irritation in humans.
4 Then I can quickly summarize the document. We
5 developed 51 acute reference exposure levels. Our --
6 CHAIRMAN FROINES: Did you -- what's the
7 comparable value if you used -- didn't use the benchmark
8 approach?
9 DR. MARTY: For ammonia, do you remember, George?
10 We have looked at a lot of those, and depending on
11 the endpoint and the response rate you choose, generally if
12 you're choosing a five percent response rate, the comparison
13 to a NOAEL is very close. It's, you know, plus or minus 20
14 percent.
15 If you use a ten percent response rate, generally
16 your BC 10 is a little above the NOAEL for most studies, but
17 it does vary. It jumps around a little bit because of the
18 quality of the database. You don't necessarily with the BCO
19 find not necessarily lower than a NOAEL that you would
20 develop say from a LOAEL divided by ten. So it jumps around
21 a little but, but it's actually fairly close.
22 DR. ALEXEEFF: If we chose the highest no effect
23 level in these four studies, and then divided by a factor
24 of -- we divide by a factor of ten in that case, because
25 it's not a benchmark dose, okay, we come up with a value of
PETERS SHORTHAND REPORTING CORPORATION (916) 362-2345
81
1 three, instead of 4.5.
2 DR. MARTY: There are 51 proposed acute reference
3 levels in the document.
4 CHAIRMAN FROINES: Melanie, how long do you think
5 you're going to go now?
6 DR. MARTY: I can wrap this up in a few minutes,
7 five minutes.
8 CHAIRMAN FROINES: How many is a few minutes?
9 DR. ALEXEEFF: We wanted to mention just this
10 slide and then some of the research issues. And that's it.
11 So there's probably two more slides.
12 CHAIRMAN FROINES: Five minutes.
13 DR. MARTY: We'll skip the hazard index slides.
14 Although, I want people to be aware of how the numbers are
15 used.
16 Skip the hazard index target organ, over to
17 research needs.
18 DR. GLANTZ: I would actually, at the risk of
19 being glacial, why don't we take a break? I'd kind of like
20 to hear the rest.
21 CHAIRMAN FROINES: Let's take a break. I think
22 what will happen is that it will be hard to ask questions
23 once -- if you're rushing.
24 DR. GLANTZ: Let's take a break and let them
25 finish the whole presentation.
PETERS SHORTHAND REPORTING CORPORATION (916) 362-2345
82
1 (Thereupon a short recess was taken.)
2 CHAIRMAN FROINES: Okay. George, Melanie.
3 DR. MARTY: I think it's important for people to
4 understand how the reference exposure levels are used in a
5 risk assessment, put it in a little bit of perspective.
6 Essentially, we use a hazard index approach for
7 estimating the potential for public health impact for
8 noncancer endpoints, and it involves the facility estimating
9 the ground-level concentration of the chemical, and that's
10 done with air dispersion modeling.
11 And then you generate a hazard quotient, which is
12 essentially the ratio of the ground-level concentration to
13 the reference exposure level.
14 If that quotient is greater than one, then you
15 have exceeded the reference exposure level. If it's less
16 than one, you're under the reference exposure level.
17 In some cases you're emitting or there is present
18 more than one chemical that impacts the same target area.
19 In that case the hazard quotients are added together to get
20 a total hazard index.
21 This is an example that we drummed up where a
22 facility would be emitting acrolein and ammonia. Both of
23 these are eye and respiratory irritants. We have
24 ground-level concentrations in one column. That's the GLC.
25 And the reference exposure level in another. When you ratio
PETERS SHORTHAND REPORTING CORPORATION (916) 362-2345
83
1 those, you can see that the hazard quotient for acrolein is
2 about 0.9, and the hazard quotient for ammonia is about 0.4.
3 DR. FUCALORO: Acrolein is actually one, isn't it?
4 I mean, significant figures.
5 DR. MARTY: Yes.
6 When you add those two together you have a total
7 hazard index of 1.3 for both eye irritation and respiratory
8 irritation. So for each toxicological target organ or
9 system we add those chemicals, those hazard quotients for
10 those chemicals that impact that system.
11 CHAIRMAN FROINES: I don't understand. Can you --
12 that means that you are exceeding the value of one?
13 DR. MARTY: Right. What we're doing there, what
14 we're saying is that you have to take into account multiple
15 chemical exposure in the risk assessment. If you only were
16 emitting acrolein, and acrolein were the only chemical
17 concern, your hazard index would be .9, but we're saying if
18 you emit both acrolein and ammonia, you're going to have an
19 additive, potential additive effect of both of those
20 emissions in the risk assessment.
21 So that's why we do a hazard index approach,
22 summing the effects of the different chemicals.
23 CHAIRMAN FROINES: So but you're making an
24 assumption that as a mechanistic issue, the mechanism of the
25 irritation is the same in both cases. If you're adding
PETERS SHORTHAND REPORTING CORPORATION (916) 362-2345
84
1 apples with apples, not apples with oranges, because it
2 doesn't -- if you added apples and oranges you shouldn't do
3 that to come up with a value greater than one; right?
4 DR. MARTY: Yes. We make assumptions not only
5 that the mechanisms might be the same, but that if they are
6 different, there still is at least an additive effect on the
7 whole organism.
8 And this is an area of controversy.
9 We do have respiratory irritants lumped together
10 that impact different parts of the respiratory tract, and we
11 have gotten that comment before that they should not be
12 added together, but we don't have any data that shows why
13 they should not be added together.
14 We also are not accounting for synergistic effects
15 in methodology either. So if you do have two pulmonary
16 irritants that happen to act synergistically, you may be
17 underestimating the impact just by adding them.
18 DR. FUCALORO: This is for purposes of
19 demonstration, obviously, and the RELs of 300 for ammonia,
20 that's a number you just made up, right? It's not the
21 number you have for the ammonia.
22 CHAIRMAN FROINES: It is.
23 DR. MARTY: These are probably in micrograms per
24 cubic meter, Jim?
25 DR. COLLINS: Concentrations would have to be.
PETERS SHORTHAND REPORTING CORPORATION (916) 362-2345
85
1 DR. ALEXEEFF: Yeah.
2 DR. MARTY: Yeah. Microgram per cubic meter,
3 rather than ppm. Sorry.
4 DR. ALEXEEFF: There is that issue, and then
5 there's also we're looking at a threshold response here and
6 we're not considering the background of all whatever
7 respiratory irritants might be out there.
8 So there's some, you know, we've chosen sort of an
9 overall approach that we hope is not too complicated for
10 anybody to evaluate, but at the same time it has its
11 assumptions.
12 So if things start getting to be very -- if an
13 important decision starts resulting as a result of like a
14 value of 1.3, usually in our guidelines we ask the districts
15 to call us and talk to us about what the issues are, and we
16 would try to look at it more thoroughly if there is other
17 information.
18 DR. MARTY: This slide shows the groupings of
19 organs or systems that we used for the chemicals, the 51
20 chemicals that are in here. We can add other organs and
21 systems as we go along, if we get chemicals that impact
22 different parts of the body.
23 But currently we have the respiratory system as
24 one target organ, the nervous system as another.
25 Reproductive developmental toxicants if there's more than
PETERS SHORTHAND REPORTING CORPORATION (916) 362-2345
86
1 one emitted you add the hazard quotients for those.
2 Hematologic system, the alimentary tract, the
3 skin, eye, cardiovascular and immune.
4 DR. GLANTZ: What's left?
5 DR. MARTY: We don't add across those systems, so
6 we don't add a cardiovascular toxicant to a nervous system
7 toxicant. So although that has been done in the past, we
8 have not ever recommended doing that.
9 In summary then, we have developed or adapted
10 values for the reference exposure levels for one-hour
11 exposure for 51 chemicals. And 32 of these are based on
12 data in humans.
13 We have applied a consistent methodology, which is
14 good in some respects, and has problems in other respects,
15 as we saw with the examples.
16 The methods we use are basically the same as the
17 US EPA proposal.
18 These values, again, are designed for ambient
19 exposure to routine emissions and not emergency planning.
20 And our methodology attempted to account for
21 sensitive individuals.
22 There's always more research that could be used.
23 In general, we need more acute toxicology data to develop
24 reference exposure levels, and also to develop all three of
25 the levels that we spoke about, the severity levels for
PETERS SHORTHAND REPORTING CORPORATION (916) 362-2345
87
1 severe and life-threatening, for more chemicals.
2 And speaking with George earlier, we really were
3 surprised at the relatively poor quality of the database for
4 a lot of chemicals that had been used for many many years.
5 So it's more basic research is needed for a lot of
6 chemicals.
7 CHAIRMAN FROINES: Peter.
8 DR. WITSCHI: This call for more acute toxicology
9 data brings up a problem, because I'm convinced for many of
10 those compounds that exist, they're just in public demand.
11 And now we really have to think about it, you know, is it
12 worthwhile just to get something in the public demand to
13 kill more animals, when the data exists, because we are not
14 talking about mechanistic research or sophisticated
15 research, just talking about animals keeling over.
16 And if there's one way or the other we could get
17 hold of those data, that would be very very much in favor,
18 because many of the studies have been done in industry to
19 acceptable levels, and there's no point in wasting animals.
20 DR. MARTY: We do get submissions from industry
21 during the public comment period of data that has not been
22 published in the open literature, and we actually have used
23 some of that data before.
24 So your point is well taken that there are data
25 that are just not available. I don't know how to shake the
PETERS SHORTHAND REPORTING CORPORATION (916) 362-2345
88
1 trees to get it, other than have these public comment
2 periods.
3 CHAIRMAN FROINES: I assume that EPA has that
4 data.
5 DR. ALEXEEFF: No.
6 DR. MARTY: Not necessarily. Lot of it was done
7 in-house or not for a regulatory purpose.
8 DR. ALEXEEFF: There's a separate committee that
9 I'm on with US EPA and they're looking at acute information
10 for in this case emergency planning, so slightly different
11 purpose, but they have the authority to request or demand
12 additional data either to come from the vaults, if it's
13 already done, or to be generated.
14 So but we did on a number of comment periods, both
15 comment periods we had on this, we did get submissions from
16 industry of unpublished data they had, which we tried to
17 use. Sometimes it was human data, sometimes it was animal
18 data.
19 DR. WITSCHI: I really feel that doing some work
20 with those studies, acute toxicology data would be a step
21 backwards.
22 DR. ALEXEEFF: Okay. That's a good point.
23 DR. MARTY: There are other research needs that we
24 would like to point out, which don't necessarily require
25 more basic research, but require OEHHA -- we would like to
PETERS SHORTHAND REPORTING CORPORATION (916) 362-2345
89
1 evaluate existing data to improve the uncertainty factors
2 for all the categories for which we use uncertainty factors.
3 For example, George showed one slide comparing
4 LOAEL to NOAEL ratios, and that was for a specific subset of
5 chemicals. We would like to do more of that and even look
6 specifically at not just subsets of chemicals, but
7 endpoints, specific endpoints to look at dose response
8 slopes for specific endpoints. I think that would help
9 refine the uncertainty factors some more.
10 We would also like to look at comparison of data
11 on different species to further evaluate the interspecies
12 differences and hopefully try to refine that interspecies
13 uncertainty factor.
14 There may be instances where you really don't need
15 a tenfold interspecies uncertainty factor, for example
16 lethality from irritant-induced lung edema. Such a basic
17 cellular attack, that it may not be much difference between
18 a mouse and a person.
19 Also the studies done to date comparing the
20 interspecies differences have focused primarily on oral
21 exposures, rather than inhalation exposure. So there's
22 really very little comparison work that has been done on
23 inhalation exposures.
24 We'd also like to evaluate data to better
25 characterize intraspecies variability. So that's been a
PETERS SHORTHAND REPORTING CORPORATION (916) 362-2345
90
1 popular topic at the SOT and SRA meetings the last couple
2 years and there have been some analyses which indicate that
3 a factor of ten is about the 85th percentile, 80th to 85th
4 percentile. And Dr. Froines mentioned Dale Haddis' work and
5 he had some papers indicating that the intraspecies
6 variability can be anywhere from two to several orders of
7 magnitude, depending on the chemical and the endpoint.
8 So more work needs to be done there.
9 CHAIRMAN FROINES: I have Dale's paper, and I'll
10 check with him to see if we can release them to people.
11 They're not easy reading, you know.
12 DR. MARTY: We also would like to look a little
13 more at the time extrapolation issues. There have been --
14 there are some people who think that the value of that
15 exponent for irritants should be different than for other
16 types of chemicals. So we would like to look at that a
17 little more, since irritants tend to be more concentration
18 dependent than time dependent.
19 Our modified Haber's Law does allow us to take
20 that into account. If you have empirical data, you can
21 derive a pretty big exponent. Ammonia irritation, for
22 example, that exponent is 4.6, because normally the
23 lethality exponent is two, so it varies by endpoint and by
24 chemical.
25 We'd also like to look more at children as
PETERS SHORTHAND REPORTING CORPORATION (916) 362-2345
91
1 sensitive subpopulations. Are they adequately protected
2 with the tenfold uncertainty factor for interspecies
3 variability. That of course is going to be dependent on the
4 chemical involved.
5 And in addition we want to look at whether our
6 additive approach is warranted for the cumulative or
7 multiple chemical exposures the way we do it, as I just
8 mentioned in the hazard index approach.
9 So the next steps then are to address SRP's
10 comments, incorporate SRP's suggested changes, complete the
11 evaluation of our public comments, and incorporate any more
12 of those changes, finalize the document and give it to the
13 panel again.
14 DR. ALEXEEFF: You asked if there were some
15 specific chemicals that the panel should specifically focus
16 on, and I've identified 15 that are both interesting in
17 terms of we've had public issues raised about it, and also
18 they kind of cover the major kinds of endpoints. So there's
19 15 chemicals and there's five different toxicologic
20 endpoints. I think it's better to group them by endpoints
21 because some of the issues are the same. The endpoints are
22 like eye and respiratory irritation. Another one is
23 reproductive developmental. Another one is arsine. A third
24 one is the immune responses. And the last one is CNS
25 effects.
PETERS SHORTHAND REPORTING CORPORATION (916) 362-2345
92
1 And so the 15 chemicals can be grouped into those
2 five groupings. If that makes sense, grouping the five and
3 make sure that someone, the panel can discuss those
4 specifically, that might be helpful at the next meeting.
5 CHAIRMAN FROINES: What are the five?
6 DR. ALEXEEFF: The 15, if you want to flip open to
7 page seven or someplace where you can mark them off, the
8 ones are acrolein, ammonia, arsenic and arsenic compounds,
9 arsine, benzene, chloropicrin, ethylene glycol monobutyl
10 ether.
11 DR. WITSCHI: The last one --
12 DR. ALEXEEFF: Eye irritation -- I'm sorry.
13 Formaldehyde.
14 CHAIRMAN FROINES: EGBE?
15 DR. ALEXEEFF: EGBE, yeah.
16 Formaldehyde, hydrogen sulfide. Actually,
17 hydrogen sulfide is probably its separate group. So you
18 need somebody to specifically look at hydrogen sulfide. And
19 the issue there is the toxicologic response that occurs in
20 response to odors, in contrast to a respiratory irritation,
21 which is another kind of toxicological response and how
22 those two interact. It's a very complex issue and it's the
23 subject of the letter that was submitted to you.
24 Isopropyl alcohol, methyl bromide, nickle
25 compounds, phenol, toluene, and xylenes.
PETERS SHORTHAND REPORTING CORPORATION (916) 362-2345
93
1 DR. FRIEDMAN: What's the nature of these 15
2 again?
3 DR. ALEXEEFF: Okay. Actually for the eye
4 irritation, you have acrolein, ammonia. There's another
5 table, maybe I should have you flip to Table A 2, which
6 actually lists the endpoints. That is what I was looking
7 at.
8 Look at Table A 2, which is just right before we
9 start looking at all the chemicals. There's a listing of
10 the chemicals and the toxicologic endpoints upon which
11 they're based, the type of endpoint.
12 So I picked -- the reason I picked these is
13 because these are chemicals that primarily we've had a lot
14 of comments or comments raised from members of the public of
15 concern and raising ultimate issues and that sort of thing.
16 DR. BLANC: What is the comment or the problem,
17 it's not necessarily related to the end organ, it's maybe
18 related to the available data. I mean, the only end organ
19 controversy you seemed to have raised is that potential link
20 between odor triggered physiologic phenomenon with hydrogen
21 sulfide. The other issues are not related to methodologic
22 problem with measuring eye irritation, for example.
23 DR. ALEXEEFF: Correct. I was trying to think of
24 a way of grouping them other than having 15. Either way, we
25 want to -- I just chose it --
PETERS SHORTHAND REPORTING CORPORATION (916) 362-2345
94
1 DR. BLANC: What's the genre of issues?
2 DR. MARTY: It's mixed.
3 DR. BLANC: Is it insufficient data, overly
4 conservative interpretation of safety factors?
5 DR. MARTY: Yes. It's that too. For specific
6 chemicals some comments -- some commentators think we can be
7 getting away with less conservative uncertainty factors.
8 DR. ALEXEEFF: Or choice of a different study.
9 Some are suggesting alternate studies to be looked at.
10 DR. BLANC: Which in general would have a less
11 sensitive measurement?
12 DR. ALEXEEFF: Correct.
13 DR. BLANC: Or more sensitive.
14 DR. ALEXEEFF: More sensitive. Except for the
15 hydrogen sulfides.
16 CHAIRMAN FROINES: George, are you saying that the
17 15 chemicals you mentioned here are specific chemicals for
18 which you have public comments?
19 DR. MARTY: Correct.
20 DR. ALEXEEFF: Correct.
21 DR. BLANC: Can you give us a sense of which were
22 the most difficult chemicals internally for your group to
23 come to terms with? What were the most challenging, if you
24 had to name the five most challenging?
25 DR. MARTY: My opinion is that the reproductive
PETERS SHORTHAND REPORTING CORPORATION (916) 362-2345
95
1 developmental toxicants offer a lot of challenge in terms of
2 extrapolating to a one-hour concentration.
3 DR. ALEXEEFF: So the reproductive ones, like
4 ethylene glycol monoethyl, that would be an example right
5 there, and the other one would be nickel. We spent quite a
6 bit of time looking at the nickel because it's an immune
7 response, and there's some animal data and it's kind of
8 different.
9 CHAIRMAN FROINES: I don't think there are
10 developmental effects with EGBE.
11 DR. ALEXEEFF: Well --
12 DR. MARTY: That's not been considered
13 developmental toxicant under Prop 65.
14 And Jim is shaking his head.
15 CHAIRMAN FROINES: Monoethyl ether acetate that
16 you're talking about. MGBE is hemolysis.
17 DR. ALEXEEFF: I think that question for EGBE is
18 is there a repro concern, and we based it on repro concern,
19 the comment is that there's not a repro concern, so that's
20 something to look at.
21 DR. BLANC: For example, can you give me a sense
22 of what the issue was with the acrolein in your commentary,
23 because that was probably a separate --
24 DR. ALEXEEFF: Probably the choice of study --
25 DR. BLANC: That was not mechanistically an issue?
PETERS SHORTHAND REPORTING CORPORATION (916) 362-2345
96
1 DR. MARTY: No. There was not.
2 What we can do is, and we intend to do, is respond
3 to the public comments that we received. The deadline was
4 Monday. And we have generated a draft response, but we need
5 more time to polish those off and give them to you, so you
6 can get an idea of what the issue was that was being raised
7 in the public comment.
8 Some of these chemicals were also commented on in
9 the first round of public comments and you folks have that,
10 the responses to those comments.
11 And in general they raised the same issues with a
12 couple of new twists.
13 DR. BLANC: I think that we can be most useful not
14 in getting into adjudicating an argument between the public
15 commenter which says why did you use the Smith study, you
16 should have used the Jones study which showed less risk, but
17 really we have issues such as a yes-no question, is
18 compound -- should compound X, should your endpoint be
19 reproductive or should it be not, and if that's an issue.
20 And, you know, in the issue of you're finding a
21 particular hazard assessment challenges, as you mention with
22 just generically with reproductive, or if in looking at
23 these we have a particular compound that, you know, our own
24 sense is that the data are a bit more nebulous than it even
25 seems, even if it's a nebulous topic.
PETERS SHORTHAND REPORTING CORPORATION (916) 362-2345
97
1 I think one of the most challenging ones from that
2 point of view of the endpoint is so serious is formaldehyde.
3 And I'm not sure that is a pitfall in terms of how low you
4 need to go for your safety level or what the rationale may
5 need to be extricated a little better.
6 DR. ALEXEEFF: Yeah. What we can do then is we
7 can provide copies of the comments and our responses and to
8 all the panel members, and then one could -- we can just
9 leave it open, these are the 15 that we identified and --
10 CHAIRMAN FROINES: We have to meet our obligation
11 to have reviewed this document, and I don't know -- I'm a
12 little bit confused about what our legal requirements are,
13 Bill, in terms of what does the panel have much -- Melanie
14 talked about the word endorsement, but that's certainly not
15 in the legislation. The question is what do we need to do
16 as a panel --
17 DR. ALEXEEFF: You're required to review it.
18 CHAIRMAN FROINES: We have to review it.
19 DR. MARTY: And make -- that slide that I --
20 CHAIRMAN FROINES: We then say we find this
21 document to be acceptable, then are we then saying in our
22 findings that all the values which you've done in the
23 document is acceptable to the panel?
24 DR. ALEXEEFF: Well --
25 CHAIRMAN FROINES: If so, we have to go over
PETERS SHORTHAND REPORTING CORPORATION (916) 362-2345
98
1 everything, if that's going to be the case.
2 DR. FUCALORO: Do we have a statutory requirement
3 here, Bill? I don't believe we do.
4 DR. ALEXEEFF: You do have a statutory
5 requirement. The requirement was one of the slides, to
6 evaluate guidelines and recommend changes and additional
7 criteria to reflect new scientific data or empirical
8 studies. That's your statutory requirement.
9 DR. GLANTZ: See, reading it that way, my
10 interpretation would be that we are basically endorsing the
11 body of the report, not necessarily the specific numbers in
12 the appendices because --
13 CHAIRMAN FROINES: If you're a lawyer for an
14 opposing, some interest, you may come back and say SRP
15 didn't do their job, they didn't look at this issue, which
16 is clearly OEHHA did it poorly. That's what I'm trying to
17 project.
18 DR. GLANTZ: Yeah, I agree.
19 What I think is a practical matter, having worked
20 on this with OEHHA for a while, I think the next step that
21 George and Melanie are suggesting is a good one.
22 I think that we should bring the document back at
23 the next meeting, look at the public comments that come in,
24 because I always find those very enlightening to look at the
25 issues which are raised, and then discuss in some rational
PETERS SHORTHAND REPORTING CORPORATION (916) 362-2345
99
1 way, which I will leave it to the chair to figure out how we
2 should do that, those 15 compounds.
3 And, you know, in groups, because as I said, I
4 think you're going to find that the issue that's going to be
5 some common issues in each one.
6 And then after we've come to closure on that, I
7 think the rest of it will proceed fairly quickly, because
8 what we've come up with is a basic strategy. And I think
9 that the discussion of the more controversial compounds will
10 allow us to come to some closure on the strategies.
11 OEHHA can then go back and make any amendments to
12 the overall procedures that come out of the discussion of
13 the 15, and then we can have one more meeting to deal with
14 the rest of the report.
15 So it would take a couple more months, but I think
16 that will break it into more bite-size pieces.
17 So I think the discussion today has raised some
18 good issues in terms of the overall approach, which will
19 lead to some amendments of the document, and I think if they
20 come back and we focus on these and have everybody, have you
21 maybe assign a couple people to each subgroup of compounds
22 or something.
23 CHAIRMAN FROINES: I think first we should say
24 that I think this is a very good document and the process is
25 clearly systematic and you paid obvious attention to detail
PETERS SHORTHAND REPORTING CORPORATION (916) 362-2345
100
1 and have been very thorough, and I think all that speaks
2 very well for the document overall.
3 So my question, I think we've made a major and
4 very positive start.
5 Paul, how do you feel about Stan's suggestion,
6 because I think it's in conflict with what you said, but not
7 necessarily so.
8 DR. BLANC: No. I assume, you didn't say
9 explicitly, but I assume that while this next phase is going
10 on you're also going to incorporate the factor of six rather
11 the factor of three and recalculate those values that are
12 affected by that and also --
13 DR. ALEXEEFF: We could. I think that's a fairly
14 minor change that we can do, but I don't think it's
15 worthwhile to revise the whole document and bring that back
16 with just that change.
17 DR. BLANC: No, no. That's one thing that is
18 going to be going on and then I'm just trying to go through
19 the concrete suggestions that were made.
20 There was another suggestion in that as part of
21 documentation for that, there be an appendix which included
22 the figure or the rationale for how you arrived at that.
23 And it sounded like there were a few other areas
24 where the rationale just needed to be a little bit more
25 explicit.
PETERS SHORTHAND REPORTING CORPORATION (916) 362-2345
101
1 DR. ALEXEEFF: Dr. Friedman, the clarification of
2 the default calculation for that end value for Haber's
3 constant.
4 CHAIRMAN FROINES: He's also talking about the
5 discussion of the Haber stuff.
6 DR. FRIEDMAN: I don't know. Do we have some time
7 to go through other things?
8 CHAIRMAN FROINES: Sure. Absolutely.
9 DR. FRIEDMAN: I don't want to interrupt this
10 discussion but --
11 CHAIRMAN FROINES: Can you live with Stan's
12 suggestion?
13 DR. BLANC: Oh, that's fine.
14 DR. GLANTZ: The other thing that I would, sort of
15 following up with what Paul said, it might be helpful not to
16 produce a whole new draft, but maybe you can prepare some
17 sort of the amended pages or something, and even just, you
18 know, draw lines through the thing and give us some inserts
19 so we can see how you would be changing the document in
20 response to these comments, without a whole new draft. And
21 so that would kind of move that process forward.
22 The other thing I would like to say for the
23 record, I looked through the public comments and the
24 responses, and I thought the responses were quite good,
25 actually. I think there were many places where the
PETERS SHORTHAND REPORTING CORPORATION (916) 362-2345
102
1 commenters raised issues that you guys said, yes, these are
2 valid issues, and made appropriate changes to the document,
3 and there were other places where I think you made a good
4 defense for not changing it. So I thought that was very
5 well done too.
6 DR. ALEXEEFF: In many cases the comments we got
7 were new studies, which were perfectly -- we were perfectly
8 happy to incorporate. Again, these were data that existed,
9 but we were unaware of, because sometimes they're hard to
10 find or they're unpublished.
11 DR. GLANTZ: I think the comments really did add
12 to the report, and I think that OEHHA responded very
13 positively to them in either accepting them or having a good
14 reason not to.
15 CHAIRMAN FROINES: Peter wanted to make a comment.
16 DR. WITSCHI: Yeah. I have certain concern on a
17 few, actually involved in setting some of those numbers, and
18 so my concern is what John said to some extent, we're
19 dealing with a document which provides 52 numbers which we
20 as a committee, we don't have the time to scrutinize all
21 those numbers.
22 On the other hand, all those numbers have been
23 developed in-house, and have not been subjected to external
24 review.
25 Now, we probably can't do it, but I was wondering
PETERS SHORTHAND REPORTING CORPORATION (916) 362-2345
103
1 whether we shouldn't look for a mechanism where you farm out
2 those documents individually, maybe to outside reviewers, so
3 we can get an opinion on how sound they are.
4 And I certainly would not agree to endorse this
5 document without having -- when the implication could be
6 that we are endorsing the numbers.
7 DR. GLANTZ: I don't agree with that. I think
8 that's what the public comment period provides, and
9 particularly the industry groups are -- they seem to be
10 quite careful in the reviews that they come back with.
11 So I mean if they're not -- I think if they're
12 going to be giving you the very -- that's why I always read
13 the public comments first. I think they're coming back --
14 DR. WITSCHI: I see your point, but that's the
15 system if you throw stones among the souls, the ones that
16 are getting hit scream, but what we need is to have everyone
17 review it, not just the sensitive ones.
18 DR. ALEXEEFF: There's two things.
19 One is when you said external review, there is the
20 public comment period, but statutorily in terms of the
21 scientific peer review, that really is your responsibility.
22 It's the panel's responsibility.
23 Now, if the panel needs to identify some
24 additional expertise to assist, I don't know what the
25 process would be. I assume, you know, Bill Lockett could
PETERS SHORTHAND REPORTING CORPORATION (916) 362-2345
104
1 assist on that, if that was something that was needed, if
2 that's what you're suggesting.
3 DR. WITSCHI: That's what I'm suggesting.
4 DR. ALEXEEFF: I think statutorily it's the panel
5 that provides the scientific peer review for this document.
6 DR. MARTY: I think it's also important to point
7 out that there is extensive internal review, not just within
8 OEHHA, but within other Cal EPA boards and departments have
9 also reviewed this. And scientists in the other
10 departments.
11 DR. WITSCHI: I'm sorry. That's still an internal
12 review. I mean academy reports, they are being sent out,
13 and this is this kind of thing that we're dealing with.
14 CHAIRMAN FROINES: This is really part of the
15 dilemma that we find ourselves in right now, because it was
16 in the old days -- I hate those expressions, in the old
17 days.
18 DR. WITSCHI: In your days.
19 CHAIRMAN FROINES: In earlier periods.
20 DR. FUCALORO: Eons ago.
21 CHAIRMAN FROINES: We were all out milking cows at
22 3:00 a.m.
23 No, seriously, when we had a chemical we would
24 look at that chemical in depth.
25 Now we have 12 to whatever it is pesticides, and
PETERS SHORTHAND REPORTING CORPORATION (916) 362-2345
105
1 we have 50 of these compounds, and the numbers keep growing.
2 And it's clear that I don't think the Legislature ever
3 really understood the dimension that this was going to grow
4 to.
5 So we clearly are not prepared to have to spend
6 that kind of time, not at $100 a meeting, that's for sure.
7 And so the question is how do we get out of this
8 dilemma, because we clearly, I think Peter is right, I think
9 we have an obligation to endorse this document, which means
10 endorsing everything in it.
11 Now, if we can get somebody to help us do that, I
12 think that's fine. And I think suggestions to that
13 effect -- or we can take the 50 chemicals and divide them up
14 into groups of nine.
15 DR. BLANC: I think the other approach would be to
16 have our resolution, our final resolution, regarding this
17 document, when we pass our findings, be slightly different
18 and approach them and the finding would be for a toxic air
19 contaminant decision, and that we are very explicit in
20 endorsing the details of the methodologic approach, say we
21 have reviewed thoroughly and find that the standard approach
22 used is correct and should continue to be applied.
23 And that the -- we recognize that for each
24 specific chemical the findings may change as new data
25 emerge, and that we view the specific RELs in this document
PETERS SHORTHAND REPORTING CORPORATION (916) 362-2345
106
1 as being current guidelines subject to change.
2 So that we essentially divide up the intensity of
3 our endorsement into two parts, one part being the method,
4 so that nobody questions the methods, and the argument would
5 be on, no, we don't think it should be the study by Jones,
6 it should have been the study by Smith, or we think that it
7 should really be reproductive endpoint, and that may change
8 as new data emerge.
9 DR. GLANTZ: May I make a suggestion, in order to
10 speed the glacier --
11 CHAIRMAN FROINES: I don't think we can.
12 DR. GLANTZ: I think -- wait, I think what we
13 ought to do, we're not taking any action now, and having
14 been involved in this for a long time, I think that the
15 solution to this problem will emerge as we, if we proceed
16 along the pathway that we're suggesting, that I suggested
17 earlier, if we discuss the thing in general, let's look at
18 the more controversial compounds, and I think by the time
19 we're done, exactly what we want to say will become fairly
20 obvious, more so than when it's being discussed in the more
21 abstract.
22 CHAIRMAN FROINES: I think your suggestion is good
23 and certainly acceptable. I think that suggestion is good
24 and acceptable.
25 However, we need to have a ruling from the agency
PETERS SHORTHAND REPORTING CORPORATION (916) 362-2345
107
1 as to whether or not this kind of suggestion is acceptable
2 within the context of our legislation, because if we are to
3 endorse the document, thereby endorsing the RELs, then as
4 far as I'm concerned we have to have done a full evaluation
5 of them.
6 If we are -- if that's not the case -- so I don't
7 think we can resolve this question, Bill, under the current
8 circumstances. Any of the suggestions that come up are fine
9 with me. It's not -- I don't have a perspective that says
10 we have to do it one way or the other. All I care about is
11 we meet our statutory obligation.
12 So for the time being what we can do is we can
13 agree that the approach has been taken is appropriate and
14 acceptable, and I think we can make a motion to that effect
15 at this or the next meeting.
16 At the next meeting we'll take up the 15 chemicals
17 for which there was public comments, and we can agree on
18 that.
19 But the ultimate answer, I think we need more
20 clarification on it.
21 DR. FUCALORO: Can you put up the slide which had
22 the charge, our charge with regard to this? That isn't
23 in --
24 DR. ALEXEEFF: When we get to the chronic
25 document.
PETERS SHORTHAND REPORTING CORPORATION (916) 362-2345
108
1 DR. FUCALORO: I have it. I just realized it.
2 Thank you.
3 DR. ALEXEEFF: When we get to the chronic
4 document, there will be 120 substances, okay. And then when
5 we get to the exposure document, there will be a multiple
6 number of all kinds of parameters and various partition
7 factors and all kinds of additional things that people, that
8 scientists in this field like to discuss intensely.
9 CHAIRMAN FROINES: We just have our toe in the
10 water right now on this, and the issue is going to get
11 larger and larger.
12 And so we need clarification to ultimately decide
13 how to go.
14 Go ahead, Bill.
15 MR. LOCKETT: Bill Lockett. We'll come back to
16 you with a clarifying response at the next meeting.
17 CHAIRMAN FROINES: Now, let me ask a question.
18 Without Gary's questions notwithstanding, we can get to
19 those shortly, but is the idea that we've made a good start
20 here today and we will take up the 15 chemicals at the next
21 meeting, is that a reasonable approach to move this forward?
22 Any opposition to that?
23 DR. FUCALORO: We'll get the word from Lockett on
24 what our responsibilities are under the law.
25 CHAIRMAN FROINES: Yeah. I personally always hate
PETERS SHORTHAND REPORTING CORPORATION (916) 362-2345
109
1 to get the word from lawyers about these things, but I think
2 we should define, scientists should try to define these
3 things, but I think in this case we actually do need some
4 clarification.
5 DR. FUCALORO: California needs at least one
6 lawyer.
7 MR. LOCKETT: My anticipation is that we will lay
8 out what we understand to be the applicable legal
9 requirements, but I suspect that since there's no court
10 ruling, that there will be some room for the panel to decide
11 exactly what they want to do.
12 CHAIRMAN FROINES: I have extensive legal
13 experience, it's just that I've not taken the bar.
14 Gary.
15 DR. FRIEDMAN: I had some specific comments on
16 couple of pages, but before I start, the material you
17 presented on the ground level concentration and the hazard
18 index, was that in this document?
19 DR. MARTY: No. There is a description of the
20 hazard index approach in there, but the example is not in
21 the document.
22 DR. ALEXEEFF: There will be a separate document
23 that kind of explains, shows how these are used, but we
24 wanted to give you some sense as to what the application of
25 these are.
PETERS SHORTHAND REPORTING CORPORATION (916) 362-2345
110
1 DR. FRIEDMAN: I see.
2 On page 11 you have a Table 3 that lists the
3 target organs used in acute hazard index calculation, and
4 you have the health effects included. And to me it seemed
5 that they were very limited. For example, cardiovascular
6 system, all you have is aggravation of angina. You have
7 things like arrhythmia, tachycardia, myocardial infarction.
8 Under alimentary tract, you have -- you don't include
9 diarrhea. Under eyes you don't include blurred vision. I
10 was wondering, is this meant to be an exhaustive list and
11 why don't you include the others?
12 DR. ALEXEEFF: Yeah. This is simply of those 50
13 chemicals we have looked at, what effects have been found
14 for those 50, and where would they fit. It's simply a
15 tabulation of thus far. So maybe we should clarify that.
16 DR. FRIEDMAN: I think so, because it looks like
17 this is what you used in any case.
18 And then on the same page, I didn't understand the
19 last, the line three from the bottom, it says OEHHA has
20 defined the lowest available acute severity level as the
21 REL. I thought RELs have no effect.
22 But this, I wonder if you mean to have the words
23 protect, something protective against the lowest available
24 severity level. There's something missing there.
25 DR. ALEXEEFF: Okay.
PETERS SHORTHAND REPORTING CORPORATION (916) 362-2345
111
1 DR. FRIEDMAN: Then on page 25 you talked about,
2 in the second paragraph, negative epidemiologic studies,
3 failure to show an effect and that the way to approach that
4 is to do power calculations. I think another thing you
5 should put in there is the confidence limit, even if you
6 don't have power calculation, if you have statistical
7 confidence limits around a negative finding, such as a risk
8 ratio of one, this could also serve that purpose to show how
9 high an effect this study excluded.
10 DR. ALEXEEFF: Okay.
11 DR. FRIEDMAN: Also on that page, I don't know
12 much about this area and about these controlled human
13 exposure studies. Are these still being done? Are these
14 done with volunteers? If so, are they being looked at by
15 institutional review boards?
16 DR. ALEXEEFF: Yes. There's a very extensive
17 review process, and they are being done, in fact this is one
18 of the leading institutions here.
19 DR. FRIEDMAN: What kinds of people volunteer to
20 be subjected to a poison? Is this prisoners who are
21 expecting some kind of reward?
22 DR. ALEXEEFF: For the most part these are
23 substances that are already present in the air, to certain
24 extent, like ozone and sulfur dioxin. Those are, for this
25 type of studies it's mostly that type of thing. So they're
PETERS SHORTHAND REPORTING CORPORATION (916) 362-2345
112
1 not like exposing them to cyanide gas or something, but
2 it's -- these are -- probably you can answer it since I
3 think you're probably --
4 DR. BLANC: I'm little confused as to why you're
5 asking the questions.
6 DR. FRIEDMAN: I'm wondering if these studies are
7 ethical, that they are exposing humans, volunteers, to a
8 toxin. I'm on an IRB for Kaiser and I don't think we'd ever
9 permit such a study to go forward.
10 DR. BLANC: I think you would if you saw the
11 documentation that's provided, depending on what the
12 chemical is and how the study is done and what the level of
13 exposure is.
14 So these are studies -- you know, I was toying
15 with the thought -- the reason I ask you why are you asking
16 the question, because if you think this is a question, then
17 other people reading the document are going to be struck by
18 it, then I think it would be important for you to take that
19 into account and have a one liner in there about reviewing,
20 using studies that are consistent with standard practice in
21 terms of institutional review, both for human subjects and
22 for animal studies, bearing in mind that some of your older
23 data probably don't meet those criteria, but I think it
24 would probably be useful for you to say in terms of how you
25 chose studies that you used, that for modern studies that
PETERS SHORTHAND REPORTING CORPORATION (916) 362-2345
113
1 was part of, you know, what you have taken -- one of the
2 factors you've take into account, because it's if Gary has
3 this response, then other people will have the response too.
4 But I can tell you, for example, that one of the
5 studies, one of the studies that is used in this document as
6 the basis for one of the levels is a study that I did, a
7 human exposure study to chlorine at one part per million.
8 And I think that if I had put that study into the
9 Kaiser human subjects, they would have approved it, just the
10 way UC did.
11 Frankly, the problem with review boards is not
12 that typically that kind of protocol. Really it's the
13 problem is that review boards are much more sensitive about
14 questionnaire-based studies than they are human exposure
15 studies in general.
16 DR. FRIEDMAN: Not in our case.
17 Maybe I should be reading some of these papers to
18 get a better feel before I take more time with this, but I
19 was just uncomfortable seeing people, telling about the
20 effects of exposures on people, volunteers, and I just don't
21 know that much about it.
22 DR. BLANC: I'm saying if you had that response,
23 then somebody else will have that response too and it would
24 be wise for you to have something in there, general comments
25 at the beginning, about how you chose the studies that you
PETERS SHORTHAND REPORTING CORPORATION (916) 362-2345
114
1 chose.
2 Because an animal rights advocate might have the
3 same question about how possibly have these studies that
4 expose these rodents to this stuff.
5 DR. FRIEDMAN: That's right.
6 CHAIRMAN FROINES: That's an interesting question.
7 In your papers you put in the paper that this had IRB
8 approval.
9 DR. BLANC: Oh, yeah.
10 CHAIRMAN FROINES: That probably is one of the
11 criteria that should be used in evaluating the studies,
12 because if you have a study and part of the problem is
13 studies that are done outside the United States, I suspect,
14 often don't have IRB approval.
15 DR. BLANC: There's international, there is
16 Helsinki thing. Whenever you use a modern study it's going
17 to have IRB approval or the equivalent, believe me.
18 And so one of your criteria is to use modern
19 studies if you have a choice, right, or you don't base
20 things on a 1935 study if you have anything more recent.
21 With something like chloropicrin you're forced
22 into citing a lot of literature from 1920, because there is
23 not a good modern literature on chloropicrin with humans.
24 So you have a series of priorities, you prefer
25 human data over animal data and you prefer modern data over
PETERS SHORTHAND REPORTING CORPORATION (916) 362-2345
115
1 less modern data, ethical data over unethical data,
2 et cetera.
3 And just a question of the wording, but I don't
4 think we need to do a lengthy exposition on that.
5 DR. FRIEDMAN: If the --
6 DR. BLANC: All our air pollution data in this
7 country is driven by human exposure.
8 DR. FRIEDMAN: We can't get rid of that. Well,
9 that's something that people are going to be exposed to
10 whether they volunteer or not, because they're breathing it.
11 DR. BLANC: Not at those levels. Not at the ozone
12 levels that expose people to for study that we are using.
13 DR. FRIEDMAN: I would never volunteer for such an
14 exposure. I'd like to know more about it, because I'm
15 curious about it.
16 CHAIRMAN FROINES: Well, for example, we are doing
17 studies on humans in terms of cardiopulmonary effects using
18 concentrated particles from air, so we're actually exposing
19 people to particles that have been concentrated by a
20 particle concentrator and we've been able to get human
21 subjects approval for that.
22 But it doesn't mean that they are -- one shouldn't
23 say that there are real questions about it either. It
24 always does bother me, frankly.
25 DR. FRIEDMAN: Nowadays you can't get a paper
PETERS SHORTHAND REPORTING CORPORATION (916) 362-2345
116
1 published unless it says IRB approval and I think the same
2 kind of criterion should be applied to the studies that you
3 use for these evaluations, unless of course it's before the
4 era of IRBs.
5 DR. ALEXEEFF: Most of them are before the IRB.
6 DR. FRIEDMAN: If you had some data about a
7 chemical from Auschwitz, would you use it?
8 DR. ALEXEEFF: No. No. There are some limits on
9 that. This is the ethical-unethical issue.
10 DR. BLANC: I would be explicit about it because
11 of the questions.
12 DR. FRIEDMAN: I'm sorry. I couldn't hear you.
13 DR. BLANC: I said I would address it in a general
14 way and I would probably save that as a template to use in
15 your other documents, so it's a recurring issue.
16 CHAIRMAN FROINES: I would actually, George, in
17 this document put in a sentence or two that says in
18 reviewing studies this issue will be addressed.
19 DR. BLANC: But you don't want to explicitly
20 comment on each and every chemical. I think that is
21 redundancy.
22 CHAIRMAN FROINES: In the overall, talking about
23 controlled human exposure studies, it takes one sentence.
24 DR. BLANC: Yeah.
25 DR. FRIEDMAN: That's it.
PETERS SHORTHAND REPORTING CORPORATION (916) 362-2345
117
1 CHAIRMAN FROINES: Well, I think we're finished
2 with this topic for this day, and it's 12:20.
3 I think we should break for lunch and come back at
4 1:00 o'clock. I don't think we can push ourselves to get
5 through molinate before people start to have hypoglycemia.
6 DR. BLANC: Can we start promptly at 1:00?
7 CHAIRMAN FROINES: We can start promptly at 1:00.
8 The meeting is officially closed until 1:00
9 o'clock.
10 (Thereupon the lunch recess was taken.)
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
PETERS SHORTHAND REPORTING CORPORATION (916) 362-2345
118
1 A F T E R N O O N S E S S I O N
2 CHAIRMAN FROINES: We think we basically made 1:00
3 o'clock.
4 I was about to comment that you weren't here, and
5 then you sneak in the door.
6 So the next item on the agenda is molinate report,
7 and so welcome, Paul.
8 MR. GOSSELIN: Thank you.
9 CHAIRMAN FROINES: I'm afraid I'm going to start
10 out in the negative.
11 I don't know what other people's experience was,
12 but my document on molinate arrived Monday, November 30th,
13 and I talked to some other people and clearly their
14 documents arrived very late as well.
15 Peter hasn't received his document yet.
16 So that we have a problem.
17 And what's going to have to happen is we're going
18 to have to set out guidelines for submission of the
19 documents to the panel, and we won't try to do that in this
20 meeting today. We can work on it separate.
21 But in the past we've always had with ARB, OEHHA,
22 we've always had well-structured deadlines. So when the
23 comment period is -- when the comments need to be in, when
24 the report needs to be finished, what the comments made, and
25 then the time that that document goes to the SRP.
PETERS SHORTHAND REPORTING CORPORATION (916) 362-2345
119
1 So obviously nobody has had an opportunity to do a
2 thorough reading of this document at this time.
3 The second thing I want to say at the outset about
4 this document is that it's dated, this is basically a 1996
5 document, and it's not up to date. So I'm not clear, to be
6 perfectly frank, that this document should have ever come to
7 this panel.
8 The document does not contain scientific
9 literature from 1996 to 1998. It does not contain -- it's
10 missing a lot of new material that has actually appeared in
11 the peer review material. And we found out about some of
12 that because in the OEHHA's comments they specifically refer
13 to papers and submissions that have occurred in the last
14 couple of years.
15 The thing I want to say is that the OEHHA
16 comments, and we have comments from OEHHA and we also have
17 an exchange with Paul Blanc. Paul Blanc's letter to DPR is
18 to Pam Whales and it's dated 8-12-98, and the response to
19 Paul from Paul Gosselin is dated November 20th, 1998.
20 That's essentially two or three days before this meeting.
21 And that can't happen.
22 Just to make everything clear, Paul is the lead on
23 the health effects for molinate. That's not an ongoing --
24 that's an ongoing process. The lead person is to ensure
25 that problems with the documents get dealt with prior to the
PETERS SHORTHAND REPORTING CORPORATION (916) 362-2345
120
1 document being submitted to the panel. That's the whole
2 concept of the lead person.
3 And when the relationship is based on a letter on
4 8-12-98 with a response November 20th, '98, for a December
5 2nd meeting, that's, one, not timely, but, secondly, it is
6 not within the spirit of the lead person's role.
7 And the last thing I'll say at the outset is that
8 the comments that we've got from OEHHA are also dated
9 November 25th, 1998. So that we got them -- I don't know if
10 everybody has gotten them in fact.
11 So what's happening is, to be perfectly frank, I'm
12 of the opinion that this document should not be before this
13 panel today, that, in fact, we can go through some elements
14 of it, but in fact it's a waste of our time to be spending
15 time on documents that are not up to date and not timely.
16 And we can't have that and function effectively in
17 the panel, especially when we're dealing with a large number
18 of documents.
19 Then there's the issue of the substance.
20 We would assume, I think as a panel, and correct
21 me if you disagree, that like the lead person, the role of
22 OEHHA is to have OEHHA's comments incorporated into the
23 draft document to make the best document possible.
24 We're not interested in a war between agencies.
25 The idea is to work through the differences and to come out
PETERS SHORTHAND REPORTING CORPORATION (916) 362-2345
121
1 with the best possible document. If that's not possible,
2 then I guess we will be the arbiter of that.
3 But it seems to me that we have a breakdown in
4 terms of the role of OEHHA and the role of the lead person,
5 vis-a-vis molinate.
6 I should say quite frankly molinate is a very
7 toxic chemical and I think that when we look at it in
8 detail, we're going to find it to be one of the more
9 hazardous compounds that we've had to deal with.
10 So with all of that, Paul --
11 DR. GLANTZ: Welcome.
12 CHAIRMAN FROINES: Why don't you go ahead.
13 MR. GOSSELIN: This isn't Riverside? The last
14 meeting.
15 CHAIRMAN FROINES: This is friendly comments, and
16 they're intended to be friendly, but they're intended to be
17 very critical, because this is a terrible process.
18 MR. GOSSELIN: And I agree with a large measure of
19 what you said about the timing of getting the responses to
20 Dr. Blanc and I apologize for that.
21 DR. BLANC: I was out of the country, so it was
22 part of --
23 MR. GOSSELIN: Yeah.
24 Obviously, that's not something that I or the
25 department like to do. It's also out of the norm of having
PETERS SHORTHAND REPORTING CORPORATION (916) 362-2345
122
1 comments or responses to come out so late, and I can come up
2 with a litany of excuses, my own excuses, but I won't do
3 that.
4 The other issue is the timeliness on getting the
5 documents to you all, and frankly, no excuses for that.
6 This is a process that we shouldn't do.
7 Some of it gets back to maybe our overloaded
8 schedule on trying to get a lot of these documents to you
9 and through the process swiftly.
10 And I think you mentioned it earlier in the
11 meeting that I think we need to take a look at the timing
12 and what we have on the plate and make sure that we go
13 through this process more deliberately, because I will say
14 that it's been over ten years since we actually had
15 documents come through the panel, and most notably DEF last
16 time that came through, that this process is not, for us, is
17 not, I think historically we could argue and bicker about
18 the process, but we've got a lot of value out of the last
19 go-around with DEF and halfway through methyl parathion,
20 particularly working with the leads, and the good
21 interaction at these meetings.
22 So I will say that the process that we're engaged
23 in now, bringing documents, that we do hold value to that,
24 and these are documents I don't want us to have to rush
25 through.
PETERS SHORTHAND REPORTING CORPORATION (916) 362-2345
123
1 So with that, you know, I was considering whether
2 in fairness to even withdraw the agenda item today on
3 molinate, but given the time frame I thought it might be
4 worthwhile to at least have the presentation and at least an
5 outline of the issues, the key issues that are going to be
6 raised up.
7 And I also should say on OEHHA's behalf, this
8 whole process also has, sort of the commitments we have made
9 have been very burdensome for them on some of the pressures
10 that we put on them to come back with comments. So the
11 lateness on their comments has a lot been driven by the
12 schedule we put together.
13 But I think in fairness, the whole schedule we
14 have now, I'd like to make sure that we do take enough time
15 to go through these issues.
16 One other point is that the document dated '96
17 does reflect the risk assessment that we completed two years
18 ago, two and a half years ago.
19 We have been continuing, staying up to date with
20 the uses, the changes in formulation and literature. And
21 what we've attempted to do, again, to try to keep documents
22 flowing, is to take the foundation of our risk assessment
23 that you have and then build upon that with the new
24 information through addendums to the document.
25 And molinate is going to be different. It's going
PETERS SHORTHAND REPORTING CORPORATION (916) 362-2345
124
1 to be sort of in time the format of our risk assessments
2 with the focus being on the toxic air contaminant evaluation
3 end of it, so it's not going to be the three-volume set.
4 But the document itself does have and will have, because we
5 just got some new data in, evaluation of all the current
6 literature.
7 CHAIRMAN FROINES: Let me ask you one question
8 about that.
9 Unless I'm mistaken, ARB may want to comment on
10 this, is that the current formulation of molinate, and I
11 don't have that specific statement in front of me, but it's
12 the --
13 MR. GOSSELIN: 15 G.
14 CHAIRMAN FROINES: 15 G.
15 Is the current, is what's currently being used
16 relative to what's been used in the past, so that means we
17 have no monitoring data, unless I'm mistaken, air monitoring
18 data or other micro environment monitoring for the new
19 formulation; is that correct?
20 MR. GOSSELIN: Yes. Except for the fact that the
21 rate of application per unit area acreage remains the same.
22 What it is it's, correct me if I'm wrong, a more
23 concentrated formulated product, mostly dealing with the
24 bulk handling and the worker exposure issues that were
25 placed upon the registrant to do that, so they went to a
PETERS SHORTHAND REPORTING CORPORATION (916) 362-2345
125
1 higher concentrated formulation.
2 DR. COCHRAN: My name is Roger Cochran. I'm the
3 author of the document.
4 The 15 G formulation is 50 percent more molinate.
5 However, the application rate in terms of active ingredient
6 per unit acre is the same. It has not changed.
7 What it allows the people to do is, first off,
8 what's in it for the registrant, is to put more into the
9 plane, so the plane can cover more territory in putting it
10 out.
11 The level of molinate that's in the atmosphere
12 comes from what in essence is out of the rice paddies and
13 out of the system, not from what is spread from the air.
14 Once it's in the water, that's when it starts to
15 come out of the formulation and becomes an air toxic.
16 So if the application rate is the same in terms of
17 active ingredient per unit area, then we would not expect
18 that the air concentrations would be different. However,
19 the UR factor has not been in the air monitoring associated
20 with the new formulation.
21 MR. GOSSELIN: So with that, if everyone is
22 comfortable with that, with the understanding that we know
23 that the comments we got from OEHHA are going to be part of
24 the document and the document is going to go under
25 revisions, and we have significant discussions to continue
PETERS SHORTHAND REPORTING CORPORATION (916) 362-2345
126
1 with the leads, what we wanted to do is give sort of the
2 foundation presentation, and then at some future date come
3 back with some resolution to some of the key scientific
4 issues.
5 And they are particularly complicated issues, and
6 I think even the comments from OEHHA and Dr. Blanc are
7 not -- they're really true legitimate scientific issues that
8 we can spend probably a lot of time with this material in
9 particular discussing.
10 From my standpoint, I think it gets down to
11 somewhat of the art and the science on looking at these
12 compounds that I think is going to be real interesting on
13 how the discussion goes.
14 So that's something I'm actually looking forward
15 to. I don't think it's a negative that there is some
16 disagreement among department scientists. There's even
17 internal disagreements from time to time within our own
18 department and other agencies. And I think that has to be
19 expected with some of these compounds that are going to be
20 more complicated to assess than maybe what we've seen in the
21 last couple times.
22 With that, what I'd like to do --
23 CHAIRMAN FROINES: I should say one thing. I can
24 say a lot, but I won't.
25 DR. GLANTZ: Yes, you will.
PETERS SHORTHAND REPORTING CORPORATION (916) 362-2345
127
1 CHAIRMAN FROINES: No, no.
2 OEHHA refers in a number of places to the US EPA
3 occupational document on molinate. It contains some what
4 appears to be some relatively important information.
5 We've never seen any US EPA documents on molinate,
6 so that I think that somehow since the US EPA occupational
7 health document on molinate seems to have relevance in terms
8 of their conclusions, that's probably something the panel
9 should be able to see. So you should try and make that
10 available to us, or else we'll get it from George. That's
11 not the way to do it.
12 MR. GOSSELIN: We have that and we'll make that
13 available.
14 CHAIRMAN FROINES: I just have a question. How
15 many people on the panel have read the OEHHA comments?
16 Three.
17 How many have read the molinate document?
18 Two, three.
19 So, no, you see -- I won't ask how many have
20 read -- how many have read Blanc's comments and the
21 response?
22 DR. FUCALORO: I just read the response. I didn't
23 have Blanc's comment.
24 CHAIRMAN FROINES: So, you see, we're playing, we
25 are literally playing with a half a deck here. So that,
PETERS SHORTHAND REPORTING CORPORATION (916) 362-2345
128
1 what, only half the panel have read the comments, and some
2 not at all.
3 DR. FRIEDMAN: I'm one of the people who hasn't
4 read anything because of time limitations on this, but I
5 would be happy to hear the introduction that Paul is
6 proposing to the scientific issues as preparation for
7 reading it.
8 CHAIRMAN FROINES: Oh, yeah. I'm not suggesting
9 we don't -- Paul doesn't make a presentation. I just wanted
10 a sense of what our state of preparation was. It was not by
11 any means -- no, I'm assuming we're going to hear from Paul,
12 because I think there are enough people who have read some
13 of this that I think will want to raise questions about some
14 of the comments.
15 DR. KENNEDY: John, can I ask a fairly stupid
16 question?
17 Is there, or what is the pathway for information
18 coming from DPR? Does it come directly to us, does it go to
19 OEHHA first, does it go to Peter first and then to us? I
20 mean how --
21 CHAIRMAN FROINES: Historically what's happened,
22 and I think this is still the best way to do it, but I'm
23 open, is that say on this document, the document would go
24 from Paul's office to Bill Lockett's office and then Bill
25 Lockett would distribute it to us and that way we have kind
PETERS SHORTHAND REPORTING CORPORATION (916) 362-2345
129
1 of an internal count that Lockett then becomes responsible
2 for ensuring and keeping a record that everybody has the
3 document.
4 DR. KENNEDY: Bill, may I suggest that just for
5 consistency's sake, when we get perhaps a copy of Paul's
6 comments, and if we get the response, can we -- the response
7 comes out, can we have them both, so it all sort of sticks
8 together.
9 CHAIRMAN FROINES: Is that -- my sense is that
10 this panel is used to the process going through Lockett's
11 office and of course now we're dealing with a different
12 agency, is everybody comfortable with that historical way?
13 We could also have Paul to send, have somebody in
14 his office send it to us, so it's -- I don't want to open it
15 up to a whole nother level of discussion on how to transmit
16 material.
17 DR. BLANC: You just decide whatever works.
18 DR. KENNEDY: Whatever works.
19 DR. FUCALORO: Be consistent to make sure it all
20 gets out.
21 CHAIRMAN FROINES: Okay.
22 DR. BLANC: I think we should start the
23 presentation.
24 CHAIRMAN FROINES: Yes, I think so.
25 MR. GOSSELIN: Okay. What we're going to do is
PETERS SHORTHAND REPORTING CORPORATION (916) 362-2345
130
1 first hear from Environmental Monitoring and Pest
2 Management, and then we'll hear from on the exposure
3 assessment side with the monitoring, and then we'll have
4 sort of the meat of the discussion on the hazard
5 identification risk assessment, which will have probably the
6 most compelling issues and topics for discussion.
7 So the first off is Wynetta Kollman from
8 Environmental Monitoring and Pest Management.
9 DR. KOLLMAN: I'm going to briefly describe the
10 physical and chemical properties of molinate, its
11 application and use patterns in California, its fate in the
12 environment.
13 I will also list airborne concentrations of
14 molinate that have been reported in the literature and
15 summarize the results of the monitoring study conducted by
16 the Air Resources Board to document concentrations of
17 molinate in ambient air.
18 Molinate is a selective systemic herbicide
19 belonging to the thiocarbamate class of pesticides. It
20 inhibits the growth of emerging reed shoots.
21 Listed are the chemical names and trade names for
22 the compound.
23 Molinate is a non-corrosive nonreactive clear
24 liquid with an aromatic odor. It is stable under normal
25 conditions and stable to acidic and alkaline hydrolysis. It
PETERS SHORTHAND REPORTING CORPORATION (916) 362-2345
131
1 is soluble in water and emulsible with common organic
2 solvents such as benzene or acetone.
3 This overhead lists additional physical and
4 chemical properties for molinate.
5 Molinate is used in commercial rice fields to
6 control barnyard grass and water grasses.
7 There are currently three active registrations for
8 products containing molinate, emulsifiable concentration,
9 with the signal word "warning" on the product label, and two
10 granular formulations with the signal words "warning" and
11 "caution."
12 Molinate is applied either preplant-preflood or
13 postflood-postemergent.
14 For preplant-preflood applications, molinate is
15 applied by air- or ground-based equipment directly to the
16 soil, and incorporated by mechanical equipment to a depth of
17 two to three inches. The application rate is three to four
18 pounds of active ingredient per acre for the granular
19 formulation.
20 The emulsifiable concentrate is metered into the
21 field with ground-based equipment with incoming irrigation
22 water at the rate of three to six pounds per acre.
23 Postflood-post emergent applications are made by
24 air only at the rate of three to five pounds per acre.
25 DR. FRIEDMAN: Can I interrupt with a question,
PETERS SHORTHAND REPORTING CORPORATION (916) 362-2345
132
1 please?
2 I don't know anything about how you grow cotton,
3 so I don't know what postflood, preflood --
4 DR. BLANC: Rice.
5 DR. FRIEDMAN: Rice. Pardon me. I don't know
6 anything about how to grow rice either.
7 DR. KOLLMAN: What was the question?
8 DR. FRIEDMAN: I just don't understand some of
9 these terms, preplant, preflood, postemergent. I don't know
10 what that means.
11 DR. KOLLMAN: Preplant, preemergent means before
12 the weed comes up.
13 DR. FRIEDMAN: The weed or the rice?
14 DR. KOLLMAN: Weed.
15 MR. GOSSELIN: What they'll do is it gets into
16 there are different herbicides they may use to control
17 different grasses at different times of the year, and in
18 some of it they'll do before, almost before, almost a plant
19 preparation type treatment. And because rice is very water
20 dependent, they'll flood it, they'll dry it and have the
21 different types of rice.
22 There's some materials that will work during the
23 flood stage when they have the rice underwater. Others will
24 work when it's dried out.
25 And so that's where the water run-on term comes in
PETERS SHORTHAND REPORTING CORPORATION (916) 362-2345
133
1 or the postemergent term will come in.
2 DR. FRIEDMAN: So actually someone turns on a
3 spigot and floods the rice fields?
4 MR. GOSSELIN: Yes. They're all connected through
5 irrigation systems running off the Sacramento River, in
6 particular.
7 DR. FUCALORO: Just to make it simple for us urban
8 types, preplant is before they plant and then they plant it,
9 and then they flood the field, then they get rid of the
10 flood, and then the rice comes up?
11 MR. GOSSELIN: The rice is up, comes up when it's
12 still flooded, I believe. I'm an urban guy too.
13 DR. FUCALORO: I don't even like rice all that
14 much.
15 CHAIRMAN FROINES: He's Italian.
16 DR. FUCALORO: Have it with broccoli.
17 CHAIRMAN FROINES: Please go ahead.
18 DR. GLANTZ: This is what happens when you're
19 second on the agenda.
20 CHAIRMAN FROINES: Come on, folks. It's time to
21 move this process forward.
22 DR. KOLLMAN: This table summarizes molinate use
23 patterns on rice for reporting years 1991 through 1995 by
24 county and county populations. These data show that
25 historically more than 83 percent of use occurred in Butte,
PETERS SHORTHAND REPORTING CORPORATION (916) 362-2345
134
1 Colusa, Glenn and Sutter counties.
2 Based on the 1990 census, the total population of
3 these four counties constitutes less than one percent of the
4 total population of California.
5 This is a graphical representation of the data,
6 molinate reported use by county from 1991 through 1995. And
7 as you can see, use was highest in Butte, Colusa, Glenn and
8 Sutter counties.
9 This overhead is 1991 through 1995 average
10 reported use of molinate by county.
11 And as you can see, this indicates that Colusa
12 County had the greatest use.
13 This is a graphical representation of the monthly
14 molinate use for 1991 to 1995. Molinate is only applied
15 during the months of April, May, June and July. This
16 overhead indicates that the period of peak use occurs during
17 the month of May.
18 Degradation pathways of molinate in plants and
19 soil under both flooded and nonflooded conditions are shown
20 in the overhead.
21 CHAIRMAN FROINES: If I can comment here. This
22 picture is a nice picture for a chemist. There is no
23 similar picture in the document describing the various
24 metabolism pathways, and there's no discussion in the
25 document about any toxicity evaluation for metabolites or
PETERS SHORTHAND REPORTING CORPORATION (916) 362-2345
135
1 biotransformation products.
2 So this is only when -- one is talking here about
3 the molinate sulfoxide and the molinate sulfone, those are
4 interesting pieces, but there should be a discussion and
5 section on biotransformation metabolism. Otherwise it's
6 just one or two sentences, no discussion whatsoever.
7 DR. KOLLMAN: The sulfur atom is oxidized to yield
8 molinate sulfoxide and molinate sulfone, with further
9 hydrolyzation to hexamethyleneimine.
10 Carbon atoms at the two and four position of the
11 azepine ring are oxidized to form hydroxy and oxo
12 derivatives. Oxidation of the carbon atom of the sulfur
13 ethyl yields molinate acid and alcohol.
14 Oxidation of the azepine ring, which is the center
15 pathway, is the major degradation route in soils under
16 nonflooded conditions.
17 The major degradation route in soils under flooded
18 conditions, which are the conditions for the production of
19 rice, is oxidation of the sulfur ethyl carbon to molinate
20 alcohol and molinate acid.
21 It has been reported that molinate dissipates
22 rapidly from flooded rice fields and that volatilization is
23 the primary mode of dissipation.
24 Photodegradation is not a significant route.
25 Airborne concentrations of molinate have been
PETERS SHORTHAND REPORTING CORPORATION (916) 362-2345
136
1 reported in the literature.
2 In one study, the study at the top, ambient air
3 monitoring was conducted at four sites in Sutter and Colusa
4 counties to coincide with application of molinate to rice
5 fields. The Maxwell site in Colusa County had generally
6 higher air concentration. The maximum high was 1.72
7 micrograms per cubic meter.
8 Molinate was also found in air following two
9 applications to a commercial rice field in Glenn County.
10 And the numbers are pictured at the bottom of the overhead.
11 Concentrations range from 48 micrograms per cubic meter on
12 the day of the second application to 8.3 micrograms per
13 cubic meter on the third day.
14 CHAIRMAN FROINES: May I ask a question?
15 In the Seiber data the maximum concentration that
16 you identified was 1.17 micrograms per cubic meter. Yet, in
17 the Ross and Sava data, you have values as high as 48
18 micrograms per cubic meter. In other words, the
19 concentration is two times 24, 24 times as great in the Ross
20 and Sava study.
21 What's different? How do you -- how do these
22 studies, why are there significantly higher concentrations
23 in one study as compared to the other?
24 DR. COCHRAN: The principal reason there is a
25 difference is that in the Ross and Sava study, that was
PETERS SHORTHAND REPORTING CORPORATION (916) 362-2345
137
1 taken with air measures approximately 18 inches over the
2 surface of the rice paddy immediately after application.
3 Whereas in the Maxwell and Williams places, and
4 Trowbridge and Robbins, these are measurements that were
5 actually taken in the towns themselves. They're not
6 situated right over rice paddies, so you have air
7 dissipation before it gets to it.
8 CHAIRMAN FROINES: How far are the towns?
9 DR. COCHRAN: We have some later data that she's
10 going to be showing you, applications within one square mile
11 of the towns.
12 CHAIRMAN FROINES: Thank you.
13 DR. KOLLMAN: This summarizes the molinate ambient
14 air monitoring studies conducted by the Air Resources Board
15 at the request of DPR.
16 Air monitoring was conducted in Colusa County, the
17 county of highest molinate use during May of 1992, the time
18 of year where peak use occurs.
19 This study was scheduled to coincide with
20 applications to rice.
21 The top portion of the overhead shows the results
22 of molinate concentrations found, ordered in descending
23 order. You will notice that the maximum concentration found
24 of 1.17 micrograms per cubic meter is comparable to what was
25 found in the Seiber study, which was 1.72 micrograms per
PETERS SHORTHAND REPORTING CORPORATION (916) 362-2345
138
1 cubic meter.
2 The 75th percentile, 25th percentile mean
3 concentration and median concentration found is also
4 presented in this table.
5 CHAIRMAN FROINES: I don't think you can make a
6 comparison like that, not without telling us what the --
7 where the samplers were. It has no meaning to say that.
8 DR. KOLLMAN: The bottom portion of this overhead
9 summarizes the monitoring study at both sites, in Maxwell
10 and Williams. Maximum positive concentration, second
11 highest positive concentration, number of samples, number of
12 samples above the minimum detection limit, which was 0.011
13 micrograms per cubic meter for a 24-hour sample.
14 The table shows the molinate ambient air results
15 and molinate use in Colusa County five days before and
16 throughout the monitoring period.
17 The highest amount of molinate applied in Colusa
18 County occurred on May 22nd, 1992, where 19,203 pounds of
19 molinate was applied. On that day, 0.15 ppb of molinate was
20 detected at the Maxwell site. There was no sampling at the
21 Williams site on that day.
22 This is a --
23 DR. FUCALORO: So we have to multiply those
24 numbers -- let's see --
25 DR. KOLLMAN: The 0.15 ppb is --
PETERS SHORTHAND REPORTING CORPORATION (916) 362-2345
139
1 DR. FUCALORO: Multiply by eight to get the
2 microgram per meter cubed.
3 DR. KOLLMAN: The 0.15 ppb of molinate is equal to
4 1.17 micrograms per cubic meter.
5 DR. FUCALORO: 1.17?
6 DR. KOLLMAN: 1.17.
7 Roger, if you could go back one more.
8 The top portion shows the residues found in both
9 micrograms per cubic meter and parts per billion.
10 DR. FUCALORO: So you're saying -- right. Got
11 you.
12 DR. KOLLMAN: This is a graphical representation
13 of the data shown in the previous overhead. It shows the
14 molinate ambient air monitoring results in pounds of
15 molinate applied in Colusa County five days before and
16 throughout the monitoring period. Pounds applied is
17 represented by the vertical bars.
18 The molinate ambient air results for Maxwell is
19 the top line and for Williams the bottom.
20 As you can see, the greatest amount of molinate
21 total applied in Colusa County at 19,203 pounds occurred on
22 May 22nd, 1992.
23 The greatest amount of molinate detected on May
24 22nd, 1992, was the -- was at the Maxwell site of 1.17
25 micrograms per cubic meter.
PETERS SHORTHAND REPORTING CORPORATION (916) 362-2345
140
1 To summarize, the primary application method is
2 postflood-postemergent aerial applications of the granular
3 formulations. This means that molinate granular formulation
4 is applied by air to a flooded rice field.
5 Based on historical pesticide use data, Colusa
6 County is the county of highest molinate use and the peak
7 use of molinate occurs during the month of May.
8 The major degradation route of molinate in soils
9 under flooded condition, which is the conditions for the
10 production of rice, is oxidation of the sulfur ethyl carbon
11 to molinate alcohol and acid.
12 Molinate dissipates rapidly from flooded rice
13 fields with volatilization the primary mode of dissipation.
14 DR. FRIEDMAN: Could I ask a question? Are there
15 rice plants, have they sprouted above ground at the time
16 this is applied?
17 DR. KOLLMAN: I believe they're like a couple of
18 inches high.
19 DR. FRIEDMAN: So this selectively kills off the
20 weeds, but not the rice?
21 DR. KOLLMAN: Right. It kills the barnyard
22 grasses and water grasses.
23 MR. GOSSELIN: If there aren't any other
24 questions, we'll move to the exposure assessment part, and
25 Tareq Formoli will give that presentation.
PETERS SHORTHAND REPORTING CORPORATION (916) 362-2345
141
1 DR. BLANC: I think there are some questions. I
2 don't know when you want them. When do you want the
3 questions that sort of were coming up previously, aired
4 again? Do you want to go through everything or would it
5 make more sense to raise a few of them now?
6 DR. GLANTZ: Why don't we do it now.
7 DR. BLANC: One of the questions that I had
8 reading the document, it seemed to be the same question that
9 OEHHA had, and it probably is easily clarified, but will
10 need to be clarified in your revision, was this apparent
11 contradiction that appears between the issue of the half --
12 what the half-life of the substance actually is and its
13 photo breakdown. The document was contradictory.
14 And as I recall, this came up in conversation with
15 an explanation as to why that is, but clearly OEHHA had the
16 same confusion I did on reading the document. So there
17 needs to be -- that needs to be clarified. I remember there
18 was some explanation, but I can't remember what it was.
19 DR. COCHRAN: There basically is no breakdown of
20 molinate. It simply dissipates out of the water and goes
21 off into the atmosphere. The metabolism that you see is
22 what would take place in the rice plant or by bacteria that
23 are in the soil, but by and large, virtually none of the
24 molinate breaks down in that fashion. It simply dissipates
25 through air dilution.
PETERS SHORTHAND REPORTING CORPORATION (916) 362-2345
142
1 DR. BLANC: Is it or is it not broken down by
2 sunlight?
3 DR. COCHRAN: No. It's not broken by --
4 DR. BLANC: Is that an error in that one place in
5 the document where it seems to suggest that there is --
6 DR. COCHRAN: There's no photolysis, there's no
7 hydrolysis of the compound.
8 DR. BLANC: When you go back through the document
9 just make clear, because there is someplace, maybe it's an
10 error, maybe a word was left out, because it seems to
11 contradict.
12 Now, the OEHHA comments, also in terms of this new
13 formulation was not just a question of the concentration,
14 but also whether its time of application in terms of
15 preflood, postflood was the same. Is that an issue in fact?
16 MR. GOSSELIN: That was --
17 MR. FORMOLI: My name is Tareq Formoli.
18 The time of application stays the same. The rate
19 of application, as we mentioned, also stays the same. The
20 rate of application is, I believe, three to five pounds per
21 acre. That's active ingredient. That doesn't change.
22 Basically it is the matter of efficiency for the
23 plant.
24 DR. BLANC: Well, what I would suggest then as
25 sort of a minimum revision to the document is since the data
PETERS SHORTHAND REPORTING CORPORATION (916) 362-2345
143
1 should be available through your resources would be to carry
2 through on the pounds of active ingredient used per year
3 through the 1998 season, which has already passed. Is that
4 correct? It's already --
5 MR. GOSSELIN: Yeah. We have a lag time in having
6 the new reports cleaned up and published, and right now the
7 '96 report is getting ready to be published and we'd have to
8 have that part of this document.
9 DR. BLANC: But I think clearly since the new
10 formulation went into effect in '97 --
11 DR. COCHRAN: '96.
12 DR. BLANC: It went into effect in the '96 season.
13 What you need to do is have that and if you can get the
14 unpublished data for '97 it will look better, with an arrow
15 saying introduction of new formulation.
16 I would also suggest the table that has the
17 population also have the square miles of the county, so that
18 we know how many pounds are being used per square mile,
19 because it also depends on the population density if that's
20 what we're trying to get at in terms of population over what
21 size of area. People aren't going to necessarily know how
22 big Colusa County is.
23 In terms of the clarification that all data
24 actually are fairly irrelevant to the health concerns that
25 we're dealing with because it's the unmetabolized product
PETERS SHORTHAND REPORTING CORPORATION (916) 362-2345
144
1 which is volatilized, I think it would be useful to state
2 that a bit more explicitly in the document than it is,
3 because when one sees all this information about the
4 metabolic pathways, you tend to think that that has some
5 implication.
6 If there is any data, since that's all metabolic
7 data on how the plants break it down, if there's any
8 metabolic data, it would be useful to present, because that
9 will actually give more interest than the plant metabolic
10 data.
11 So those are, I think, a few of the things in
12 terms of that.
13 Then, finally and more fundamentally, the exposure
14 data, given that there were ten samples taken, is extremely
15 limited, and therefore that the safety factor that's going
16 to have to be put into that in later calculations is going
17 to have to be considerable in terms of the very small number
18 of samples that you have.
19 CHAIRMAN FROINES: Which samples are you talking
20 about?
21 DR. BLANC: The last group of samples that were
22 essentially five samples from one site and five from
23 another.
24 You have some of the published data from Seiber as
25 well, but you're going to need to combine all the data and
PETERS SHORTHAND REPORTING CORPORATION (916) 362-2345
145
1 then not only put in a factor for the small sampling size
2 and the sample variability, but I think it will, assuming
3 that you're not going to have new sampling data based on
4 this new formulation, you're going to have to put in a
5 safety factor based on an assumption that the new
6 formulation may evaporate, may give some X percent higher,
7 as a safety margin, because you don't know whether it gives
8 off more or less, because you've never sampled.
9 So you're going to have to build into your
10 exposure assumption model some factor that you wouldn't have
11 to put in if you had measured using the current formulation.
12 Unless you can absolutely be convincing that this
13 new formulation would have no effect at all on the amount
14 that's released, from a public health point of view.
15 MR. GOSSELIN: We'll go back and take a look at
16 that.
17 We also have the actual formulation too, we can
18 look at and other chemical properties we can take a look at
19 that.
20 MR. FORMOLI: I'm going to talk about the exposure
21 assessment part of the molinate in the ambient air.
22 I want to start with the products. This item has
23 been discussed, I just want to mention briefly that there
24 are two formulations. One is the EC, or emulsifiable
25 concentrate, formulation, and the other is granular
PETERS SHORTHAND REPORTING CORPORATION (916) 362-2345
146
1 formulation.
2 The use of EC formulation is very little in
3 California. The usage is on rice only and that is kind of
4 partly will answer the question of the amount would
5 increase, because if we have the rate of application per
6 acre the same as it used to be and also the amount of
7 acreage that is applied, we would expect that the amount of
8 applied per year would still stay the same.
9 In California we have some restrictions for
10 molinate.
11 First of all it is a restricted material, which
12 means that it can be used only by licensed applicators.
13 We also have some worker safety permit conditions
14 in place for molinate. That's basically for the safety of
15 occupational exposure. However, that safety permit
16 conditions require that the liquid formulation, which is the
17 EC formulation, be applied only by ground. No air
18 application for the EC formulation.
19 We also have water holding periods for molinate
20 before the water is released.
21 The other item is the illness reports for the last
22 ten years, that is from 1986 to 1995, there were 12 reported
23 illnesses for molinate. And most of them were occupational
24 on exposure and occupational illnesses. It's basically most
25 of them were skin and eye irritation.
PETERS SHORTHAND REPORTING CORPORATION (916) 362-2345
147
1 CHAIRMAN FROINES: I asked how many were
2 occupational.
3 MR. FORMOLI: From these 12, nine of them were
4 occupational, three were nonoccupational. And those three
5 were the one case that some pellets of molinate,
6 contaminated pellets, were taken to a store, a big
7 department store, and people complained of odor because this
8 product has a strong odor. And three people went to the
9 doctor with some illnesses.
10 Next, this is a map, just to give you an idea of
11 where these small towns that we are talking about in the
12 rice-growing areas that we are talking about. At the bottom
13 right you can see Sacramento, and Maxwell and Williams is
14 more to the north along the Highway 5, and the shaded areas
15 are the rice-growing areas of Sacramento.
16 Next slide, please.
17 DR. KENNEDY: Can I ask a quick question?
18 In your document there were, you mention five
19 total injuries, one systemic, two eye and two skin injuries.
20 That's different from what you described in the
21 presentation.
22 MR. FORMOLI: The presentation I gave this is the
23 report from 1986 to 1995. I can give you update. The
24 numbers are still 12.
25 DR. KENNEDY: That will be modified?
PETERS SHORTHAND REPORTING CORPORATION (916) 362-2345
148
1 MR. FORMOLI: Well --
2 DR. KENNEDY: I mean, it's bigger. This one
3 starts before and ends before your current --
4 MR. FORMOLI: Yes, when we produced the document
5 we have the information up to the year, I think it was 1992.
6 And now we have the information up to 1995.
7 Basically from 1992 on, when I looked at it, there
8 are no illnesses reported.
9 So the 12 illness reports are basically from '86
10 to '92, but we have the information up to '95, which '93,
11 '94, '95 didn't have any illness for molinate.
12 The studies that we looked at, the first one is
13 Seiber et al study, the 1989 study, which was conducted in
14 1986.
15 This study was conducted along with the methyl
16 parathion study that we presented to you a while back, so it
17 is pretty similar to that study. It was conducted in Colusa
18 and Sutter counties. It was 24-hour sampling, five weeks,
19 four days a week.
20 The highest levels were observed in Maxwell, with
21 the highest of 1.7 microgram per cubic meter with a mean of
22 .65.
23 CHAIRMAN FROINES: Go back to your previous
24 overhead.
25 Within the limits of the map, where were the
PETERS SHORTHAND REPORTING CORPORATION (916) 362-2345
149
1 sampling stations relative to this map, and relative to the
2 rice fields?
3 MR. FORMOLI: The samplings were in the little
4 towns that are marked kind of dark areas. Maxwell is right
5 on top. And the area, I believe that is approximate. It's
6 not to the -- it is a map that I borrowed it from one of the
7 studies that we discussed.
8 MR. GOSSELIN: Do you want to know distance was
9 like 120 feet or half mile? Do you know offhand?
10 MR. FORMOLI: No. It's within these rural towns.
11 MR. GOSSELIN: We can get -- I'm sure in the
12 studies we'll go back and take a look at the approximate
13 distance to the next rice fields, but up in this area it's
14 virtually right outside of the towns, the rice fields.
15 CHAIRMAN FROINES: Yeah. But what I think we
16 should be -- first, there should be an analysis done of the
17 pathways to the human, which could include more than
18 inhalation.
19 Secondly, there needs to be a description of where
20 people live relative to the fields that are being sprayed,
21 because the most -- the person at greatest risk may not be
22 in Williams, it may be people who have houses that are much
23 closer proximity to the field.
24 We need to see the maps that describe how the
25 sampling was done and show prevailing wind directions. We
PETERS SHORTHAND REPORTING CORPORATION (916) 362-2345
150
1 need -- there is so much invested in the issue of exposure
2 that people -- you come up and you show them these kind of
3 data, but this kind of data has no meaning whatsoever,
4 unless you have it within some kind of context.
5 And the context is where is the most exposed
6 person likely to be and what are the most -- what are the
7 most likely exposure routes to be.
8 And so it is the difference between people who are
9 used to doing air monitoring, for air monitoring persons,
10 and people who are used to doing personal sampling to
11 identify significant exposures.
12 But for us to understand anything you do, you
13 basically need a GIS process where you can document, one,
14 when did the spraying occur, where did the spraying occur,
15 what are the houses that are closest to the spraying and so
16 on and so forth, so people can make a judgment as to whether
17 this is a average exposure that one might anticipate or it
18 may be weighted low, it may be weighted high, and so on and
19 so forth. It is some -- we have to have some basis where we
20 can make an assessment of the adequacy of the sampling
21 frame.
22 DR. FUCALORO: I think the temporal data is there.
23 We saw that in the previous presentation. I think where
24 they had the pounds sprayed and the measured --
25 CHAIRMAN FROINES: But what if they're not
PETERS SHORTHAND REPORTING CORPORATION (916) 362-2345
151
1 spraying the day the samples are being taken?
2 DR. FUCALORO: No, no. But they did have it day
3 by day. That's temporal. Spatial, I'm a little less
4 certain about. I think that has to be -- wasn't it, if I
5 can find it.
6 I was satisfied with the temporal, maybe wrongly
7 satisfied, but I just --
8 MR. FORMOLI: I think if you go a little further
9 we could see some of the information that you're asking, but
10 not to that detail and sophistication that you are saying.
11 This is, I think, one of the examples.
12 CHAIRMAN FROINES: But the point is, since you
13 people -- we don't agree with this. We don't agree and we
14 disagree strongly. You people have to define whether or not
15 you have a potential problem based on this MOS calculation,
16 and your MOS calculation is very much determined by the
17 projected exposures, then that data better be pretty damn
18 good, otherwise the MOS calculation has no validity. That's
19 the issue.
20 We have to know that the data that you're using to
21 make ultimately major decisions on are the sampling -- the
22 air sampling is appropriate. And that's the key question.
23 Because everybody knows that you can mess around
24 with NOELs and you can get factors of one, two or ten, but
25 you can get enormous differences in exposure that really
PETERS SHORTHAND REPORTING CORPORATION (916) 362-2345
152
1 drive the conclusions, and that's what I'm trying to be
2 careful about.
3 We all know what it is, and we have seen people
4 cheat like hell on exposure estimation, not you folks
5 necessarily, but I've seen it in so many situations, and we
6 all know it goes on, whether it be in a coal mine or a 2588
7 process, both of which occur.
8 So we have to make sure that when we're doing
9 something as vague as this, we really do know what our
10 exposure protocols are.
11 DR. COCHRAN: Did you want me to continue where we
12 were before?
13 MR. FORMOLI: Next one.
14 I think I'm going just to show this figure for
15 Seiber et al study.
16 It shows it started on May 12th, the monitoring
17 started on May 12 and it ended June 12th. And it shows the
18 levels of molinate in the air in Maxwell.
19 After, I think it's close to May 30th, then the
20 level dropped to pretty much to nondetectable level.
21 DR. FUCALORO: Doesn't these data suggest they
22 should have started on May 12, 11th or 10th?
23 MR. FORMOLI: I do agree with you. It shows the
24 application started before, and obviously that early May the
25 application started.
PETERS SHORTHAND REPORTING CORPORATION (916) 362-2345
153
1 CHAIRMAN FROINES: Must have been a big day on the
2 11th.
3 DR. KENNEDY: Then there was light.
4 MR. GOSSELIN: Chase the monitors out of the
5 field.
6 DR. BLANC: Can I make a procedural suggestion? I
7 know that we were -- we wanted to get the presentation, but
8 I think that I'm convinced now, having heard as much as
9 we've heard, in fact it's not going to be that useful to
10 proceed in this manner.
11 What I would simply suggest is that you give Tony
12 and me and John and any others that have read the materials
13 a chance to raise some of the questions that we have.
14 And it would -- because I feel like you're a
15 little bit at a disadvantage in the situation in that it
16 will come out, you know, there will be so many questions
17 that we'll have, and I know some of them you're already
18 working on. What you're presenting is not really your
19 current state of the art. What you're presenting is what
20 the document was, but there's a lot of stuff in process that
21 you're in the process of responding to, rather than put you
22 in the position of having to present a status quo, which is
23 no longer really valid.
24 I would just rather go through some of the
25 questions that I have and give you a chance at your next
PETERS SHORTHAND REPORTING CORPORATION (916) 362-2345
154
1 presentation, because I think that for technical reasons,
2 because, John, you've formally received a submission of this
3 document, if I understand the November 19th memo to you, in
4 other words the molinate document was formally presented to
5 you to have the panel comment on it, and I think that we are
6 sort of limited in our choices from a technical point of
7 view what we're going to say today, because it's been
8 formally submitted, even though in a sense we're saying it's
9 not formally submitted.
10 DR. GLANTZ: I have a suggestion for dealing with
11 that, which we have used in the past on a couple of
12 occasions with OEHHA.
13 What I'd suggest -- I agree with your idea of just
14 giving them the feedback on the record and we'll have the
15 transcript.
16 I'd suggest that we continue the item to the next
17 meeting, and in between now and the next meeting, say by
18 around the first of the year, that you guys get us a revised
19 draft that integrates the results of the comments in this
20 meeting and whatever else, and then we'll take it up as an
21 action item at the next meeting, rather than ruling it
22 seriously deficient.
23 Because I think that it would just be fairer to
24 you guys, and you would just bring this back, a revised
25 version, and it would be a couple weeks before the meeting
PETERS SHORTHAND REPORTING CORPORATION (916) 362-2345
155
1 that we get it.
2 CHAIRMAN FROINES: Paul, are you -- if I
3 understand you correctly, you're asking to stop the
4 presentation?
5 DR. BLANC: To just open it up so that we can give
6 you some feedback on the data that we have received.
7 CHAIRMAN FROINES: Well --
8 DR. BLANC: I think this is a very inefficient way
9 of getting briefed. This is nothing new for me and it's
10 really not a good use of time, I think.
11 And for you who haven't read the document it's
12 also not a good way, so it's the worst of all possible
13 worlds.
14 So it would be better to be briefed on a revised
15 document in full and have everybody be on the same page.
16 Because I can't tell -- you see, one of the
17 problems is that the response to my comments, the memo and
18 response to my comments, leaving aside when it was received,
19 doesn't make it clear to me that anything that I said is
20 actually going to change your final document, because what I
21 received was a response delineating why you weren't taking
22 any of my comments into account in your document.
23 Now, that may just be the way it was structured
24 and in fact your process does allow for revision of the
25 document.
PETERS SHORTHAND REPORTING CORPORATION (916) 362-2345
156
1 So I don't know, I have no sense of what the
2 document is going to look like at this point, because I
3 would say that if that was, for example, if you had
4 submitted to me a scientific paper and I was a reviewer,
5 peer reviewer, and I had made the comments that I made and
6 your letter back to me with the resubmission was the same
7 paper with those comments, I would reject it.
8 I mean, because I would say you have not
9 responded, you haven't given me any credit for anything that
10 I've said. All it is is a series of, you know, of saying,
11 no, this is why we're going to do what we're going to do,
12 no, you're wrong, no, there's no validity in that, or
13 there's only marginal validity in that suggestion.
14 What I'd like to do is take a step back and make a
15 sort of global suggestion again, which was the bottom line
16 of my initial memo, and that is that I think rather than
17 locking yourself into the approach which you have to use in
18 the pesticide regulatory framework, if you would take an
19 approach that would allow you to present in your document
20 several risk assessments that will take into account
21 differing assumptions, so that we can get a sense of the
22 range of the risk, that it would allow us to more
23 appropriately comment on whether this material is a toxic
24 air contaminant or not.
25 The material on the face of it is strongly
PETERS SHORTHAND REPORTING CORPORATION (916) 362-2345
157
1 suggestive that this is a toxic air contaminant no matter
2 how you cut the mustard, but I think it would be useful,
3 since there seems to be a series of arguments and
4 discussions that you have had internally in your own agency
5 about how to interpret data which may or may not be
6 conflicting with the methodology, which are difficult, if
7 you could present to us one NOEL that's based on -- or maybe
8 even two or three based on reproductive endpoints, depending
9 upon how you define them, and also on neurologic endpoints,
10 we would get a sense of what the range of risk possibilities
11 are, rather than forcing yourself into a situation where you
12 have to take a yes-no stand, which I think is not as
13 productive as it would be to get a sense of the
14 uncertainties involved in a lot of the data that you've been
15 forced to deal with.
16 The uncertainties in the exposure data because the
17 data are so limited and the formulation now has changed.
18 But in health endpoints, as the OEHHA comments
19 point out, for example, the way the neurologic data are
20 interpreted has differed between your agency and the EPA,
21 for example.
22 To return to the analogy of a review of a paper, a
23 lot of times I get a review back I'm not happy with, but if
24 I have two reviewers telling me the same thing, both of whom
25 have reviewed something independently of each other, then I
PETERS SHORTHAND REPORTING CORPORATION (916) 362-2345
158
1 say, well, I don't agree with them, but clearly this is
2 something that I'm going to have to engage.
3 And I was struck by the fact that a lot of the
4 things that were confusing to me or that I had fundamental
5 questions about, OEHHA in their review honed in on some of
6 the same things, and I don't think that they had seen the
7 questions that I had submitted for our conference call.
8 So that's kind of the big picture, as I see it.
9 MR. GOSSELIN: Yeah. I think the points
10 particularly that you raised are going to be the key
11 discussion points.
12 And I don't want the response to be taken that the
13 issues we raised were just arbitrarily dismissed or weren't
14 considered.
15 As we will go through, and Roger will go through,
16 these are issues that, you know, we've wrung our hands over
17 internally, the scientists have done and had a lot of
18 dialogue amongst themselves about why we reached the
19 conclusions we did reach.
20 And I think maybe the best thing is to get into
21 that, to that discussion.
22 We know that the document we have and any risk
23 assessment we do can be changed upon new data or new
24 perspectives, and we did have a lot, I think, a pretty
25 healthy discussion on DEF and methyl parathion about kind
PETERS SHORTHAND REPORTING CORPORATION (916) 362-2345
159
1 of, I think, one of the areas where we ended up the panel
2 and department were really talking past each other was our
3 perspective and our staff writing these assessments as a
4 regulatory document for risk assessment and for the audience
5 being a risk manager, versus the assessment that the panel
6 has, which is slightly different.
7 And they're both valuable processes and I think
8 that's where we started to learn that we're really not
9 talking about different things, but they are different
10 things that both of us are trying to accomplish, that in
11 these documents provides the answers for that I think
12 accommodate both of us, but I think it's a matter of trying
13 to make sure they're raised up.
14 But I agree, it might be worthwhile to get into
15 these issues, because I think this is going to be probably a
16 lengthy discussion in some of the details of the two or
17 three points that we have on the toxicity.
18 DR. BLANC: Is there a fundamental regulatory
19 reason in terms of the document that you prepare for us why
20 you couldn't present more than one endpoint calculation?
21 MR. GOSSELIN: We could. I mean, in this -- this
22 was kind of fleshed out in DEF where the tables were changed
23 to have NOELs and NOAELs, which we typically, there was a
24 lot of discussion as to the appropriateness of it, we used
25 the NOAELs as sort of a regulatory endpoint from a pure
PETERS SHORTHAND REPORTING CORPORATION (916) 362-2345
160
1 endpoint standpoint, the plasma cholinesterase was the
2 visible effect, whether that's adverse or not, our staff
3 didn't think so, and we don't regulate from that, but from a
4 document evaluation standpoint that was done.
5 So some of that, and I think when we get through
6 with this, there's some flexibility in the executive summary
7 and even particularly the findings that the panel presents
8 to us and what you find in the document as significant
9 issues and endpoints also is another vehicle to bring those
10 issues.
11 DR. GLANTZ: Yeah. But the problem with what
12 you're saying, Paul, is in the end you have to make us happy
13 with this document.
14 And what you've heard Paul saying and what OEHHA
15 said is there's some very fundamental problems with the way
16 you guys chose to do this, and it isn't -- I mean it isn't
17 just the matter of you -- you're sort of saying now the same
18 thing you said in the letter to Paul, which is, well, we
19 talked it over and we decided this is the way we wanted to
20 do it.
21 But the fact is that you've got to get us -- you
22 either got to convince us that what you decided is right or
23 you need to change it.
24 And what you guys do later in terms of regulatory
25 activity is not our purview.
PETERS SHORTHAND REPORTING CORPORATION (916) 362-2345
161
1 But I really think what you need to do is to
2 fairly substantially revise the document in light of these
3 criticisms and, you know, or come back with a very very
4 strong reason why not, you know.
5 CHAIRMAN FROINES: Let me make -- I want to
6 inject, because I want to deal with the issue procedurally.
7 Is the presentation -- I want to go back to Paul's
8 original suggestion and put that aside, if that's what we're
9 going to do. I don't want to have a series of comments now
10 as to follow-up.
11 Is what you were going to present in terms of the
12 overheads over the next hour or two, was it going to be what
13 is essentially in this document?
14 Because if it is, I agree with Paul and if it's a
15 modified version then that's maybe a different story.
16 But and if it's this, this document is seriously
17 flawed in my view. And I read it before reading these
18 OEHHA's comments, and so independently speaking there's a
19 problem.
20 If what was going to be presented is essentially
21 this document, then I agree, I think we should give you our
22 comments and for the sake of time and then go back and have
23 it come forward again.
24 MR. GOSSELIN: The presentation was largely going
25 to be the document itself, but I fully was going to
PETERS SHORTHAND REPORTING CORPORATION (916) 362-2345
162
1 introduce it and Roger was going to be prepared to talk
2 about the issues, because it's not -- I mean, there's no
3 expectations that that was going to be the end of the
4 discussion. I mean, I expected a long lengthy discussion
5 today and in between the next meeting we bring this back on
6 the issues to kind of hash out the perspectives and the
7 rationale why the document is presented the way it is.
8 DR. BLANC: I think we should hash out, again to
9 return to the same issue I brought up before, we should
10 probably hash out fundamentally whether your group can
11 visualize the document which presents a range of risk
12 estimates with the accompanying assumption for each of them,
13 rather than be locked into coming down yes-no on one series
14 of assumptions. Because that's from a public health point
15 of view what makes me very uncomfortable, because what if
16 those assumptions, those series of assumptions are wrong?
17 DR. COCHRAN: Can I respond to that, Paul?
18 Before I came to the Department of Pesticide
19 Regulation I was with the Maryland Department of the
20 Environment for about a year and a half. I went to ATS --
21 DR. FRIEDMAN: Could you use the microphone,
22 please.
23 DR. COCHRAN: I was with the Department of the
24 Environment for about a year and a half, and then I went to
25 the Agency for Toxic Substances and Disease Registry
PETERS SHORTHAND REPORTING CORPORATION (916) 362-2345
163
1 Training. And essentially what they do is simply identify
2 all the chemicals that are there and say these are the toxic
3 effects of those various chemicals, but there's no attempt
4 to make a risk assessment.
5 And so you don't know what you're supposed to do
6 about the fact that you have all these various chemicals and
7 have all these toxic effects.
8 What it does is it tends to scare the public,
9 because, golly, you've got all these toxic chemicals and
10 you've got all these toxic effects.
11 But putting into various assumption of what they
12 are and so forth, it doesn't change the fact that you
13 presented a panoply of various effects and whatever, some of
14 which are meaningful, some of which are not.
15 From a regulatory standpoint, we have to identify
16 those effects that are meaningful and whether the exposures
17 that are associated with those effects are likely to cause
18 problems.
19 If for the sake of the panel here you simply want
20 us to identify what all the various endpoints are, that's
21 easily doable. I mean, that's already in the document
22 itself as to what all the various endpoints are.
23 If you want to calculate what the risks are from
24 those various endpoints, even though they may not be
25 applicable, I don't think that's necessarily of any value.
PETERS SHORTHAND REPORTING CORPORATION (916) 362-2345
164
1 DR. BLANC: Well, I mean, some of them are
2 applicable depending on what the assumptions are. I mean,
3 that's what it boils down to, what assumptions are you
4 making, and I didn't necessarily find the arguments
5 overwhelmingly convincing.
6 DR. COCHRAN: That's part of the process, that is
7 part of the reason that I was going to be here, so that
8 instead of having a document to look at where you have
9 questions that arise, you have a chance to question one of
10 the persons who was the principal in coming up with the --
11 CHAIRMAN FROINES: No, I'm sorry. This is not Joe
12 Blow comes in and says, well, let me tell you my thoughts on
13 the issue.
14 We are evaluating a document. We're not
15 evaluating your personal point of view. We're evaluating a
16 document to determine whether it's scientifically valid, and
17 our answer at this point is that this document -- I hate to
18 say, this is one of the worst documents we have ever
19 received since I've been on this panel since 1983. That's
20 pretty harsh language, but this is really quite poorly put
21 together.
22 And I'm not interested in your coming here and
23 saying, well, let me tell you what my current thoughts are.
24 I want to see a well-organized, well-structured,
25 well-thought-through document in which things are justified,
PETERS SHORTHAND REPORTING CORPORATION (916) 362-2345
165
1 not opinions given.
2 MR. GOSSELIN: No.
3 CHAIRMAN FROINES: I think, I don't like what was
4 just said. I'm sorry. And I've been very friendly.
5 You mishandled this very badly. And this document
6 is not very good.
7 And I think we should go over, if we're going to
8 discuss it, we should discuss it perhaps the way Paul says,
9 with our comments, because this is not the way to do
10 business.
11 MR. GOSSELIN: As I said, I agree, and I apologize
12 for the timing on it. I would have liked more time to go
13 through and spend more time with the leads on this. And in
14 hindsight I think we're going to do that in the future,
15 because I don't think any of these documents should be
16 rushed.
17 And, again, I mean, this is, what, the third
18 document we've prepared for the panel in recent times, and
19 so I think from our standpoint this is something fairly new
20 for us to get into bringing actual specific pesticides to
21 you. So I think this is something that we're looking to
22 make improvements to the risk assessments --
23 CHAIRMAN FROINES: Wait a second. You don't live
24 in a closet. OEHHA has been bringing documents to us since
25 1983. You could go read them and you could figure out how
PETERS SHORTHAND REPORTING CORPORATION (916) 362-2345
166
1 we approach them.
2 And the document that George prepared this morning
3 was a terrific document in terms of the level of detail and
4 the thoughtfulness of the approach.
5 This document you can barely read it through
6 because it's so disorganized.
7 DR. BLANC: Wait. Let's not descend into polemic.
8 I think that there are, as you pointed out, there
9 are things that have driven the document that are related to
10 the regulatory requirements in the pesticide framework, and
11 some of that was clear to me in the response to my comments
12 that had to do with why FIFRA drove certain things and not
13 other things, and also that's partly why the document is
14 organized in the way which is not useful, as useful, for our
15 purposes. For example, why neurotoxicity may appear in one
16 place and then neurotoxicity again appears in another part
17 of it, so it's not organized in a way that from a health
18 effects point of view is as useful.
19 Let me be more structured in my suggestion.
20 What I would like to see is a revised document
21 which has at least one risk assessment based on a
22 neurotoxicity endpoint, at least one risk assessment which
23 is based on reproductive endpoint, and at least one risk
24 assessment based on a carcinogenicity endpoint.
25 And, furthermore, if for any of those risk
PETERS SHORTHAND REPORTING CORPORATION (916) 362-2345
167
1 assessments you use a value for a no effect level, which is
2 higher than the values that would be generated by the data
3 from one of the other species in your own document, then the
4 rationale for doing that has to be absolutely transparent
5 and convincing.
6 And anything short of that, I think, will not
7 serve a useful purpose from our point of view in terms of
8 determining whether or not this is a toxic air contaminant.
9 After all, whatever decisions are taken after that
10 in terms of regulation of it as a toxic air contaminant can
11 be tempered by many of the questions that are still
12 outstanding, some of which may be settled by then.
13 But we're basically, our job is much more
14 qualitative in a way than what you're forced to do in a lot
15 of the pesticides situation, because we're one step away
16 from certain actions. Like, this would be the level at
17 which, you know, these certain things have to be done to
18 achieve X level or Z level.
19 So for us to say that something is not a toxic air
20 contaminant has major implications.
21 And this chemical, given its testicular effects
22 and given its neurotoxicity, makes me extremely
23 uncomfortable. It will take an exceeding burden of evidence
24 to convince me that this is not a toxic air contaminant.
25 And that evidence is not in the current document.
PETERS SHORTHAND REPORTING CORPORATION (916) 362-2345
168
1 And there's so many places in the document where
2 assumptions have been made leading to choosing what
3 ultimately leads to a lower risk calculation, rather than a
4 higher risk calculation, that is one of the sources of
5 trouble.
6 And clearly that was a source of trouble to OEHHA
7 too, because the theme of their commentary was very parallel
8 to the areas in which I was troubled, and my trouble was not
9 settled by the memo back to me.
10 So what I'm suggesting I think is a good
11 compromise because it will present several different
12 scenarios, some of which might be very close to your
13 existing calculations, but some of which I dare say will be
14 in order of magnitude of greater risk.
15 MR. GOSSELIN: If I can say, I agree, I'd like to
16 get into some discussion here today on the key issues that
17 you raised.
18 The second point is I don't want to sort of have
19 the expectations that this is all going to be wrapped up
20 today by any stretch of the imagination.
21 And if it would help, and I don't know about your
22 procedures about having us hold back or hold over the
23 document or withdrawing the official submission, that would
24 help.
25 But thirdly, and this leads into, because I think
PETERS SHORTHAND REPORTING CORPORATION (916) 362-2345
169
1 those scientific issues are legit, and we're going to have
2 to spend a lot of time discussing them.
3 But thirdly, what I did introduce, and I said it
4 when DEF came out also, is that the documents coming
5 forward, some of which are older risk assessments, this one
6 going back a couple years, that were prepared for different
7 purposes that we're trying to add different sections on to
8 fulfill the requirements, it's going to be to get some
9 things into the system. And it's a patchwork and it wasn't
10 documents you were used to seeing.
11 DR. GLANTZ: You've said that. And, I mean, I
12 think people are trying to be nice because --
13 MR. GOSSELIN: I'm not disagreeing with --
14 DR. GLANTZ: It may not look like it.
15 But I've been on the panel long time too and I can
16 remember it took a while for OEHHA to get to the point where
17 they were producing things this polished on the first try.
18 So, I mean, I think I understand why you've done what you've
19 done. And I think what we're trying to do is rather than
20 taking a formal action on this today, at least what I'm
21 suggesting, is to put it over, but have you prepare a
22 revised document in the meantime and hopefully will come
23 back and people will be a lot happier with, and then we can
24 act on it and either approve it or if need be do as we did
25 with the last one where we might have to vote it seriously
PETERS SHORTHAND REPORTING CORPORATION (916) 362-2345
170
1 deficient, but not a big problem, you know. And you can
2 come back and finalize it after that.
3 But because I just think that's the way we're
4 going to get this thing done.
5 I mean, I understand why you did what you did and
6 how it got there, but I think you've really hit -- it's a
7 little like what Paul said, when all the reviewers come back
8 and say this is wrong, even when you don't agree with them
9 you've got to realize that, well, maybe it is wrong.
10 And I think that the issues that are being raised
11 are -- you just need to rework the thing.
12 CHAIRMAN FROINES: Well, I think that there are
13 two issues.
14 I agree with what you're saying.
15 I think that the other thing is that we need to
16 move closer to a risk assessment process that is more
17 transparent.
18 I pretty much know how OEHHA is going to come down
19 on issues, not because of experience but because they have a
20 well-described sort of process they go through.
21 And I saw it with captan. I've seen it now with
22 molinate. I've seen it with others, where it's not entirely
23 clear what the underlying agency basis for decision making
24 is as part of the risk assessment process.
25 It's more ad hoc. Decisions get made as you go,
PETERS SHORTHAND REPORTING CORPORATION (916) 362-2345
171
1 rather than based on a kind of a process that is well
2 articulated.
3 So one of the things that has to happen within the
4 agency, irrespective of the TAC, is to think through how are
5 we doing risk assessments and to describe that process and
6 then put specific documents within that context.
7 So that there's actually a larger issue before
8 you, I think, because there's a little bit of our risk
9 assessments reflect the situation that we find ourselves in
10 at a particular time. I think that's a problem.
11 I think the second thing I want to say is we don't
12 want this document back in January. I don't think this
13 document can be anywhere near complete by January. I think
14 that we can have it back perhaps in February, but I don't
15 think they can do it by January.
16 MR. GOSSELIN: I was actually going to suggest we
17 bring the document back when everyone is comfortable that
18 it's ready to come back.
19 CHAIRMAN FROINES: Well, yes and no.
20 MR. GOSSELIN: I think we've been pre -- you
21 know --
22 CHAIRMAN FROINES: We went through -- DEF was the
23 first document in about 15 years beside the contentious
24 period.
25 I wasn't polemic with Paul. I used to be really
PETERS SHORTHAND REPORTING CORPORATION (916) 362-2345
172
1 polemic.
2 But we don't want you to pull back a document and
3 never appear again.
4 MR. GOSSELIN: No. I'm saying after this --
5 DR. GLANTZ: Actually, I don't think you can pull
6 it back.
7 MR. GOSSELIN: Continue the discussions with the
8 leads, talk to these issues and sort out --
9 DR. GLANTZ: I don't think you can pull it back,
10 because I mean the way the law is written, kind of once you
11 put it forward, I mean we're supposed to act on it and then
12 if we -- and then you have like a month to get it, deal with
13 the thing.
14 CHAIRMAN FROINES: No. Last month we heard --
15 DR. GLANTZ: We stretched a bit.
16 CHAIRMAN FROINES: We have a methyl parathion
17 document that we basically did not take up this month, but
18 we had a presentation last month, and we can take methyl
19 parathion up in January, and we can do the same with
20 February and molinate.
21 DR. GLANTZ: So you can put on -- okay. I mean,
22 if we'll put it on the agenda for February that's okay.
23 MR. GOSSELIN: February is the workshop.
24 CHAIRMAN FROINES: If it doesn't make February,
25 you can give us a progress report and we can -- we can have,
PETERS SHORTHAND REPORTING CORPORATION (916) 362-2345
173
1 as long as we can be assured that progress is being made, I
2 think we can defer.
3 DR. BLANC: Do we have -- I think the first thing
4 I need to hear back from your group is after you've had a
5 chance to regroup and consider this is to hear back whether
6 or not you think this is a viable option to present a small
7 group of risk assessments.
8 I don't think -- I'm not asking for no editorial
9 assessment at all. What I'm asking for is a range of risk
10 estimates with some very clearly stated assumptions behind
11 those.
12 And you can say this is a model which we think is
13 a less likely scenario, and here's one which is our
14 preferred one, but here is a range of risk, depending on
15 what the assumption is.
16 That's really what we went through with diesel
17 exhaust based on a series of models of what the exposure
18 data showed, and I think it would be a reasonable approach
19 if you have that much internal -- if you -- clearly you've
20 had internal discussions about which endpoints to use and
21 OEHHA differs from what you've taken as the final view, and
22 certainly my initial take on it is also to differ in terms
23 of what I would choose and to be pressed more conservative
24 in certain of those endpoints.
25 MR. GOSSELIN: Yeah. I think that is open
PETERS SHORTHAND REPORTING CORPORATION (916) 362-2345
174
1 actually after what we went through in the discussion with
2 DEF, particularly on plasma versus brain cholinesterase.
3 You know, that gets to the issue about what the panel is
4 looking for for documents and how we use documents and there
5 is some area for accommodating both interests we have.
6 So, yeah, I think that's something that we can
7 talk about, how to craft that.
8 DR. BLANC: Clearly, I think that we can't -- it
9 would be very hard, for example, for us to have a document
10 before us which had risk assessments which differed quite
11 markedly from what the EPA was saying. It doesn't have to
12 be the same risk assessment, but somewhere within the range
13 of your risk assessment should fall the EPA version of it.
14 CHAIRMAN FROINES: Well, but they should have the
15 EPA data in their document.
16 DR. BLANC: Also. Yeah. Absolutely. Should be
17 referred to as if you were including another study.
18 MR. GOSSELIN: And we did that with DEF and I
19 think methyl parathion also referred to what EPA came up
20 with.
21 But I think those are all the issues that I was
22 looking at that in hindsight how we actually made progress
23 in the other two documents, not only with molinate, but in
24 the future we're going to start to resolve some of these
25 issues, the newer documents that are in progress.
PETERS SHORTHAND REPORTING CORPORATION (916) 362-2345
175
1 CHAIRMAN FROINES: I think in fact that the -- I
2 think we need to get away from this format, because all this
3 stuff at the end, which is FIFRA driven, presumably, I don't
4 know what value it has.
5 I think you ought to prepare documents that are
6 documents that go to this panel.
7 And I know we've talked about trying to do that,
8 but it's hasn't really worked, because we get these things
9 and you look at this summary in the back and you realize as
10 soon as you look at them that there's not enough data to
11 understand what the hell they're all about.
12 So all they do is actually add problems. They
13 don't clarify problems. And that's where the more in-depth
14 discussion of the issues would be useful.
15 MR. GOSSELIN: That was one of the things that
16 came out about the beefing up the rationale for some of the
17 choices and endpoints and responding to the comments that we
18 need to look at in some of the existing risk assessments.
19 This molinate and a couple of the other risk
20 assessments are going to represent sort of a middle step in
21 where this -- where DPR is going with documents you're going
22 to see.
23 Historically, one of the problems that caused us
24 not to have documents brought forward is that we were
25 actually having two separate documents prepared for the same
PETERS SHORTHAND REPORTING CORPORATION (916) 362-2345
176
1 chemical, and it was very inefficient, because they had to
2 break it up and you had the same people preparing two
3 different documents.
4 So one of the things we wanted to do was to revise
5 the existing risk assessments that would be in a format that
6 you would be used to seeing, but also serve our format.
7 Molinate and couple of the old risk assessments
8 predate that sort of call on where we wanted to go.
9 The risk assessments we have going now are going
10 to be more understandable, more readable, because they are
11 all intended that they're going to come before the panel and
12 have an open review process.
13 So what we're dealing with now is risk assessments
14 that were done historically for other purposes, served those
15 purposes, that we're trying to jump start the process.
16 DR. GLANTZ: Well, no. And I think that hopefully
17 as things move forward, things will move better, but I think
18 that the issues that I'm hearing discussed are not just
19 issues of sort of formatting and presentation.
20 MR. GOSSELIN: Right.
21 DR. GLANTZ: They're very substantive and
22 technical issues.
23 MR. GOSSELIN: Right.
24 DR. GLANTZ: Which I think what you need to do in
25 addition to fixing this is the same questions are going to
PETERS SHORTHAND REPORTING CORPORATION (916) 362-2345
177
1 come up in every one of the documents, so as you're writing
2 the newer ones you should try to anticipate these issues.
3 CHAIRMAN FROINES: I think, let me give you an
4 example of a big problem area.
5 At one point in the oncogenicity study you review
6 the cancer bioassays and a conclusion is made that there
7 must be a threshold for the carcinogenicity and no risk
8 assessment calculation using a multistage model can be done.
9 And it's not exactly an MTD bioassay where you
10 have an MTD and MTD over two, and MTD over four, you're
11 saying dose point was ten percent of your high dose point.
12 And so it's you're drawing a policy conclusion
13 about mechanism based on a misreading of your own data.
14 The fact that there's no cancer in the second dose
15 group is exactly what you would predict, given the fact that
16 it's ten percent of the higher dose group.
17 And if you had an MTD over two, you might expect
18 to see cancer.
19 Well, you've made a major policy and scientific
20 conclusion incorrectly.
21 I think these are serious matters, and I think
22 that it's something that you really have to go back and look
23 at, because I notice that, and I read the OEHHA's documents
24 and they say the same thing.
25 Paul didn't address that.
PETERS SHORTHAND REPORTING CORPORATION (916) 362-2345
178
1 But these are fairly major issues to have a
2 document go forward to this panel in which the chronic and
3 bioassays are not adequately reviewed.
4 And so when people are here raising questions,
5 they're raising questions because they're quite serious
6 matters.
7 MR. GOSSELIN: One of the things we wanted to do
8 was to come and explain the background of why -- why we had
9 reached the conclusions we did, and I don't know if this is
10 a good time, if you want to hear on that specific issue.
11 CHAIRMAN FROINES: Paul left.
12 MR. GOSSELIN: But, I mean, the specific technical
13 issues are something that are real important and critical
14 that I think that we are going to have to spend a lot of
15 time and talk about and hear sort of our side of the story
16 and have a dialogue on it.
17 CHAIRMAN FROINES: No. But it's not -- what
18 Paul's complaining about is that what appears to happen is
19 that there are positions established, then there are
20 criticisms made and then there is a back argument saying
21 we're going to keep our position. It's not as though it's a
22 dialogue.
23 That's what -- that's what the exchange of letters
24 between Paul and you reflected, was not a dialogue, but it
25 was a rejection. You rejected Blanc's letter.
PETERS SHORTHAND REPORTING CORPORATION (916) 362-2345
179
1 And as far as I'm concerned, you were
2 scientifically not correct.
3 So you've essentially rejected the Scientific
4 Review Panel and said we're going to hold on to our
5 scientific interpretation of this data.
6 Well, that's going to be hard to get the document
7 through this panel if you're rejecting the comments of the
8 lead person.
9 And so I think that that's -- one has to go back
10 and think about that a little bit.
11 There's not enough -- there seems to be a lot
12 of -- I mean, here is a mouse study that goes 18 months. No
13 comment about a short-term study and its relevance to not
14 finding cancers.
15 There's no discussion of the mesotheliomas. I
16 mean, there's lots of things in here that are missing and
17 that's -- I think you need to look at that rather carefully,
18 because it's not complete.
19 DR. KENNEDY: I would like to hear their position.
20 I have heard, been here for three of these sessions now, and
21 I have heard the panel describe from three members, and
22 maybe more, that the purpose of DPR presenting this
23 information is to make us happy.
24 That pretty clearly is not their perception of why
25 they're here.
PETERS SHORTHAND REPORTING CORPORATION (916) 362-2345
180
1 I'd like them to articulate it, so we get all the
2 cards on the table and we figure out exactly how we get to
3 where we need to go.
4 So say it.
5 MR. GOSSELIN: Well, we don't want to make you
6 unhappy.
7 I mean, part of this goes back to, one, is we want
8 to make sure that obviously that you're comfortable and
9 supportive of the science that's contained within these
10 documents.
11 As I said, we did gain a lot out of DEF and methyl
12 parathion, finally getting pesticides through the process.
13 I think we're going to be bringing some more
14 compounds to you that we are going to need peer review prior
15 to us actually regulating, so the peer review we've gotten
16 here has been probably the most valuable peer review that
17 we've gotten.
18 I think what we're talking about now, at least
19 from my standpoint, is bridging what we've been looking at
20 as a regulatory process, and versus taking a look at the
21 broader scientific view point that you're looking at on a
22 risk assessment.
23 And, you know, in the end, and I think a couple of
24 you have said it, that the risk management part on which
25 endpoint we actually select to regulate from is sort of our
PETERS SHORTHAND REPORTING CORPORATION (916) 362-2345
181
1 call to make and having to follow through.
2 It's different than actually taking a look in how
3 we've actually characterized and described all the endpoints
4 contained in all the data.
5 So I think part of it is that we're trying to work
6 through older documents that were produced for different
7 purposes, and this one knowing full well that besides having
8 that document not be sort of a flesh, clean document for the
9 panel, coupled with the fact is that there were some serious
10 scientific issues going along, made this document
11 particularly difficult.
12 DR. KENNEDY: Where does this document go
13 ultimately?
14 MR. GOSSELIN: After the panel's deliberations,
15 let's say it gets appropriate modifications and cleaned up,
16 and you do your findings.
17 DR. KENNEDY: So its approval by this body is sine
18 qua non of further proceeding for the document.
19 MR. GOSSELIN: Then it comes back to us with your
20 findings.
21 DR. KENNEDY: No. It's not what I said. The sine
22 qua non of the ultimate destination of this document is
23 acquiescence of the panel?
24 MR. GOSSELIN: Yeah.
25 DR. KENNEDY: So you're right, you got to make us
PETERS SHORTHAND REPORTING CORPORATION (916) 362-2345
182
1 happy.
2 DR. FUCALORO: You don't have to verify that.
3 MR. GOSSELIN: The point is that do you want -- I
4 think the dilemma we're in is how the document is crafted
5 and characterized versus does that necessitate us changing
6 what the scientific staff have told us what the critical
7 regulatory endpoints are. I don't think you want us to --
8 and I'm not sure how the process --
9 DR. KENNEDY: Maybe the scientific staff has got
10 to -- the dichotomy here, the bridge that nobody is talking
11 to, is that the regulatory endpoints are a relatively
12 distant issue for us at this moment. They're obviously not
13 for you, and so you're fighting with one arm tied behind
14 your back, and you really come out with fair amount of
15 doublespeak, because you're having to talk to two masters.
16 It isn't working. It's hard on you and it's hard
17 on us.
18 DR. WITSCHI: I was just wondering, you know, if
19 your regulatory endpoints give you the perspective under
20 which you develop these documents are probably not concerned
21 with public health at large, they're concerned with
22 pesticide applicators and maybe people surrounding in
23 immediate surrounding. And this is a totally different
24 ballgame from OEHHA and this panel is concerned.
25 So I think you almost have to go back in the
PETERS SHORTHAND REPORTING CORPORATION (916) 362-2345
183
1 history, that's always been a hobby of mine, but also
2 rethink some of your premises when you look at the data you
3 have at hand.
4 CHAIRMAN FROINES: I think that the important
5 thing, going back to the issue of whether we endorse
6 George's document or not, we have a legislative mandate.
7 Our legislative mandate says nothing whatsoever about
8 regulation. That happens -- that occurs after a compound is
9 declared a toxic air contaminant. Up to the time it's
10 declared toxic air contaminant, there's no, zero, regulatory
11 significance of what the process has.
12 The law also says very clearly that it is up to us
13 to determine if the best science has been used in preparing
14 the reports. That's the law. The law says is the best
15 science used.
16 And then they put this group of people together,
17 because this group of people, theoretically, and some may
18 disagree, but I think do a reasonable job, that this group
19 of people has some ability to judge what the best science
20 is. That's why we exist.
21 So we are, first, to have no regulatory
22 responsibilities.
23 Second, we must evaluate the science in terms of
24 the quality of the science.
25 So what comes before us must meet those two
PETERS SHORTHAND REPORTING CORPORATION (916) 362-2345
184
1 criteria and no others. There are no other criteria.
2 And therefore bringing it as a document that meets
3 FIFRA guidelines, but has not well-defined science in it,
4 doesn't meet our requirements.
5 DR. WITSCHI: Actually, it does. I think it's two
6 aspects, you know, and one of them is we have to judge the
7 validity of scientific endpoint, but we also have to judge
8 the validity of how the scientific data have been
9 interpreted.
10 And this goes back to John's comments. You
11 can't -- it's not good science any more these days just to
12 say because you found cancer at one dose level that's a
13 threshold. That's no longer good science. That's gone out
14 of the window some 20 years ago.
15 CHAIRMAN FROINES: So, Paul, the means of when you
16 develop a document for this panel, what you're trying to do
17 is do the best science possible on that pesticide, and then
18 the subsequent regulatory activities will occur following
19 the decision as to whether or not it's a toxic air
20 contaminant.
21 But before that you don't need to worry about
22 whether or not it meets good laboratory practices, except
23 insofar as you shouldn't be judging to taking studies that
24 are very poorly done, obviously.
25 But it seems to me that --
PETERS SHORTHAND REPORTING CORPORATION (916) 362-2345
185
1 MR. GOSSELIN: One thing I was just thinking of is
2 that I was starting to get deja vu all over again talking
3 about process and what might happen and where we are going.
4 We spent a lot of years doing that. And I was encouraged
5 about actually getting into an in-depth discussion on some
6 scientific issues, the last couple meetings.
7 Maybe as a point of departure on molinate, one is
8 I think I have a good idea on sort of the discussions we
9 need to have after this meeting to accommodate the
10 formatting and scientific issues for the panel.
11 But I think also coupled with that, how the
12 discussion goes on the technical issues that were raised by
13 Dr. Blanc and OEHHA is probably worth discussing, if not
14 this time here today, right after this meeting and
15 continuing it.
16 But I don't think with what you're saying, I don't
17 think given what I think we've learned over the last couple
18 meetings that any of this is a lost cause.
19 So and going into this full well, knowing that we
20 were patching something different that didn't really fit
21 with the panel, this was really an intermediate type of
22 something that we could get off and get rolling.
23 CHAIRMAN FROINES: I think the panel is very very
24 enthusiastic about working with you. I think that there's
25 no question that people are working their butts off to get
PETERS SHORTHAND REPORTING CORPORATION (916) 362-2345
186
1 to all these meetings and try to deal with this in the
2 spirit of really making it work. So it's I think a
3 positive.
4 The fact that we're critical doesn't damage --
5 it's not a chronic injury, it's an acute injury.
6 DR. WITSCHI: Paul, the scientific issues, dealing
7 with the scientific issues, one of the reasons why you all
8 survive this process to some extent is because you're
9 absolutely right, the scientific issues need to be
10 discussed, but most of the time they are discussed with the
11 lead person before the meeting and this apparently has
12 broken down this time.
13 CHAIRMAN FROINES: In part due to Paul Blanc was
14 away on sabbatical for two months. It's not entirely your
15 fault.
16 MR. GOSSELIN: I think we've talked about the
17 schedule we put together was, in hindsight, you know, kind
18 of overzealous on trying to feasibly for all of us to sit
19 down and spend the time to go through all these issues.
20 I think we're starting to trip over documents.
21 DR. GLANTZ: Can I just say, I think we're
22 repeating ourselves and it's almost 3:00 o'clock.
23 And I think what I'd suggest, first of all, you
24 made me think of this thing a surgeon friend of mine has, it
25 always gets worse before it gets better.
PETERS SHORTHAND REPORTING CORPORATION (916) 362-2345
187
1 And I would second what John said, I think
2 everybody wants to work with you guys and have you produce
3 good documents, and I think you're trying.
4 But what I'd suggest is if there's any more
5 technical suggestions to put into the record, we do that,
6 and then maybe we can finish.
7 CHAIRMAN FROINES: I think there's -- I have tried
8 to set this up all day by raising issues. I think there is
9 a fundamental question about the OEHHA approach using an REL
10 and your approach using an MOS, and I think that needs
11 discussion and I think this is probably the wrong time to
12 start that discussion, because I think it's probably going
13 to take a while.
14 But I think that why you don't establish an REL
15 and then divide it by your air concentrations or whatever.
16 I was also serious about one other technical issue
17 is that this issue of thinking about what is the pathway to
18 the human is really quite important, because we're not just
19 talking about inhalation, we're talking about resuspended
20 dust. We're talking about that you can be blown away.
21 You need to -- we can talk about all sorts of
22 different ways people can get exposed to these substances,
23 and so we need to make sure that if we're going to rely
24 on -- if exposure is going to be important, we need to make
25 sure we do the best possible job. And I'm now repeating
PETERS SHORTHAND REPORTING CORPORATION (916) 362-2345
188
1 myself.
2 DR. FUCALORO: I want to understand it myself, and
3 this has to do with the new formulation. Your question is
4 based upon that new formulation?
5 CHAIRMAN FROINES: Mine is more general.
6 DR. FUCALORO: Because the monitoring has been
7 done for the old formulation. And that presumably does not
8 distinguish whether or not it comes from evaporating from
9 the water or from dust particles. Maybe particulate matter,
10 maybe not.
11 Regardless of that, so I guess what we're saying
12 is are we convinced that the new formulation doesn't
13 present -- Paul's not convinced, but are we convinced that
14 the new formulation does not present different exposure
15 pattern?
16 CHAIRMAN FROINES: I think the answer is there is
17 no answer to that question. Roger or somebody said no
18 problem, because the actual concentration is higher, but the
19 amount used --
20 DR. FUCALORO: The amount applied is the same.
21 CHAIRMAN FROINES: So it's the same, so we expect
22 that everything will be the same.
23 But that's the Pollyanna point of view.
24 Let's take another point of view and say maybe you
25 get hot spots that are actually worse.
PETERS SHORTHAND REPORTING CORPORATION (916) 362-2345
189
1 So we don't really know. We've got to be sure
2 that we don't draw assumptions that we don't have evidence
3 for.
4 DR. FUCALORO: Absent any new studies, of course
5 that would have to show up.
6 The other issues, we're talking about issues,
7 because I looked at some of these things and most of this is
8 toxicology, but we talked about the monitoring, when it was
9 done. I'm pretty happy with the temporal. We saw the
10 temporal, except the one bit of data you showed me at the
11 end with Seiber when he started the studies a day late,
12 maybe two days late.
13 In any event, that aside, the point that
14 Dr. Froines brought up is a good one, and I don't remember,
15 I don't think it was addressed, and that is the spatial.
16 Although we did talk about somehow, and forget all
17 the arguments, there was a farmhouse nearby --
18 MR. GOSSELIN: Yeah. I don't know if it was this
19 one or DEF, there was a farmhouse --
20 DR. FUCALORO: Maybe I'm making a mistake there,
21 but it would be useful to put in spatial analysis of the
22 concentration in air, and that's that I think has to be
23 completeness.
24 We've actually pushed for that in several things.
25 In fact, I've been most vociferous about it, because someone
PETERS SHORTHAND REPORTING CORPORATION (916) 362-2345
190
1 said I measured it, well, where was the spraying done, one
2 has to know temporal and spatial characteristics of the
3 studies.
4 I think there's some real questions. I think
5 things I don't understand in what Dr. Blanc was pointing out
6 and mentioning on the toxicology question, which of course
7 is not my area, but of course I think you can answer those
8 questions. I think you can sit down and be responsive to
9 his concerns and the same with OEHHA's concerns. I think
10 you could be.
11 CHAIRMAN FROINES: I think my one thing I wanted
12 to make sure you got is I think there needs to be an
13 improved metabolism section and there needs to be some
14 discussion about any of the metabolites are toxic and what
15 the toxicokinetics are all about, what kinds of
16 distributions to people are seen, and so on, so forth.
17 Toxicokinetics is not just a series of articles,
18 they're conclusions that derive from the toxicokinetic
19 investigations and that's kind of what is missing in those.
20 In all the sections in all the documents that I
21 felt so far that toxicokinetics is still in a sense could be
22 improved upon.
23 And I'll just leave it at that.
24 But putting the pathway to the oxidation product,
25 we're saying goes to the reaction of glutathione, if it
PETERS SHORTHAND REPORTING CORPORATION (916) 362-2345
191
1 reacts with glutathione it probably is electrophilic, and if
2 it's electrophilic, then it can combine with macro
3 molecules, and what macro molecules is it binding to, and so
4 on and so forth.
5 There are implications of glutathione binding and
6 then you have to ask are glutathione polymorphisms that may
7 have people at risk, and you've got -- in other words there
8 is complicated scientific issues that we need to consider in
9 these documents.
10 I think we've worn everybody out.
11 DR. GLANTZ: I move we adjourn.
12 DR. FUCALORO: Second.
13 CHAIRMAN FROINES: All in favor.
14 (Ayes.)
15 (Thereupon the meeting was adjourned
16 at 2:58 p.m.)
17
18
19
20
21
22
23
24
25
PETERS SHORTHAND REPORTING CORPORATION (916) 362-2345
192
1 CERTIFICATE OF SHORTHAND REPORTER
2
3 I, JANET H. NICOL, a Certified Shorthand Reporter
4 of the State of California, do hereby certify that I am a
5 disinterested person herein; that I reported the foregoing
6 meeting in shorthand writing; that I thereafter caused my
7 shorthand writing to be transcribed into typewriting.
8 I further certify that I am not of counsel or
9 attorney for any of the parties to said meeting, or in any
10 way interested in the outcome of said meeting.
11 IN WITNESS WHEREOF, I have hereunto set my hand
12 this 8th day of December 1998.
13
14
15
16
Janet H. Nicol
17 Certified Shorthand Reporter
License Number 9764
18
19
20
21
22
23
24
25
PETERS SHORTHAND REPORTING CORPORATION (916) 362-2345