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
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 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


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 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


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 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


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 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


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 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


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 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.


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 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


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 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


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 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


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 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


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 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


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 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


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 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.


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 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?


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 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.


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 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


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 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


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 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?


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 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


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 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


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 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


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 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


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 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


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 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


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 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


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 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?


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 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,


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 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


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 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.


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 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


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 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


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 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 --


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 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


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 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


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 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 --


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 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


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 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


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 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


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 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,


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 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,


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 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


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 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


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 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 --


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 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


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 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.


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 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


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 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


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 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?


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 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.


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 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.


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 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


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 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


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 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


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 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


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 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


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 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


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 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


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 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


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 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.


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 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.


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 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


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 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


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 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?


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 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


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 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?


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 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


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 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


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 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


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 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


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 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


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 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?


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 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


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 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


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 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


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 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


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 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 --


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 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


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 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,


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 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


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 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


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 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


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 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


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 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.


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 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


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 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


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 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.


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 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


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 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


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 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


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 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


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 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


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 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


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 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.


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 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.


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 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 --


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 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


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 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?


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 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.


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 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


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 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


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 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


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 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.


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 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


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 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


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 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


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 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


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 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


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 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


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 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.


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 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


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 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.


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 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.


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 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


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 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


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 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


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 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


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 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


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 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.


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 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.)

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 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.


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 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


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 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


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 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


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 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.


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 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


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 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


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 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


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 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.


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 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,


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 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


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 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


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 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


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 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,


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 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


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 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,


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 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


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 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


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 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


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 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


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 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 --


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 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.


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 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.


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 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.


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 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


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 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


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 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


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 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


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 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.


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 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?


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 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


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 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


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 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


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 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


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 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.


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 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


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 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


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 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.


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 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


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 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


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 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


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 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


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 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.


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 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


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 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


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 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.


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 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,


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 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


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 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


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 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.


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 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


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 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


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 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,


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 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


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 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,


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 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


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 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.


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 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


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 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


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 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.


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 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.


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 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.


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 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


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 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


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 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


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 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


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 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 --


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 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


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 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.


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 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


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 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.


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 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


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 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


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 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.)

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 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.

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                                     Janet H. Nicol
17                                   Certified Shorthand Reporter
                                     License Number 9764
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