1                             MEETING

 2                              OF THE









11              1400 J STREET, THIRD FLOOR, ROOM 306

12                      SACRAMENTO, CALIFORNIA





                     WEDNESDAY, OCTOBER 14, 1998
                              9:00 A.M.




     Janet H. Nicol
24   Certified Shorthand Reporter
     License Number 9764



 1                           APPEARANCES


 3   Dr. Craig Byus
     Dr. Gary Friedman
 4   Dr. Anthony Fucaloro
     Dr. Stanton Glantz
 5   Dr. Peter S. Kennedy
     Dr. James N. Seiber
 6   Dr. Hanspeter Witschi

     Mr. Lynton Baker, Staff Air Pollution Specialist
 9   Mr. Bill Lockett, Deputy Ombudsman, Northern California
     Mr. Peter Mathews, Office of the Ombudsman

     Dr. George Alexeeff, Deputy Director for Scientific Affairs
13   Dr. Melanie Marty, Senior Toxicologist

     Dr. Nita Davidson, Associate Environmental Research
16                      Scientist
     Mr. Tareq Formoli, Associate Environmental Research
17                      Scientist
     Mr. Paul Gosselin, Assistant Director
18   Ms. Carolyn Lewis, Associate Toxicologist
     Mr. Douglas Okumura, Branch Chief
19   Ms. Jean-Mari Peltier, Chief Deputy Director
     Dr. John Ross, Senior Toxicologist
20   Dr. Lisa Ross, Senior Environmental Research Scientist








 1                              INDEX

 2                                                         PAGE


 4   1  Discussion of Department of Pesticide Regulation     3
        timetable for presenting pesticide reports and
 5      fact sheets to panel

 6   2  DPR presentation of the proposed agenda for an       6
        SRP workshop entitled: 'Pesticides in the Air'
     3  Review of report:  Evaluation of S,S,S-Tributyl     24
 8      phosphorotrithioate (DEF) as a Toxic Air
     4  DPR presentation on a draft Fact Sheet for the     147
10      pesticide coumaphos

11   Adjournment                                           150

12   Certificate of Reporter                               151
















 1                      P R O C E E D I N G S

 2             DR. SEIBER:  I think we should go ahead and call

 3   the meeting into session.

 4             We want to welcome everyone this morning to this

 5   meeting of the Scientific Review Panel, which, as you know,

 6   is a panel that was constituted under the AB 1807, the Toxic

 7   Air Contaminant Act of California.

 8             I would like to break a little bit from tradition

 9   and start out now by asking our panelists to identify

10   themselves so everybody in the room will know who we are and

11   where we're from.

12             Pete, would you mind starting?

13             DR. WITSCHI:  Yes.  I'm Peter Witschi from the

14   University of California at Davis.

15             DR. BYUS:  I'm Craig Byus from the University of

16   California at Riverside.

17             DR. KENNEDY:  Peter Kennedy, medical oncologist,

18   Los Angeles.

19             DR. FUCALORO:  Anthony Fucaloro, Claremont McKenna

20   College.

21             DR. SEIBER:  And I'm Jim Seiber from the

22   University of Nevada, Reno.

23             Dr. Stanton Glantz will join us a little bit

24   later, probably in about a half an hour or so.

25             Today's agenda deals with pesticides as toxic air



 1   contaminants.  The original legislation, AB 1807, addresses

 2   by somewhat distinct processes non-pesticide chemicals, of

 3   which the panel has much experience, things like

 4   trichloroethylene, dioxins, tetrachlorodibenzo dioxins,

 5   lead, et cetera.  And also pesticides by somewhat distinct

 6   processes, as I mentioned.

 7             As the lead agency for pesticide registration,

 8   regulation and assessment, the Department of Pesticide

 9   Regulation, a department of California EPA, has the lead

10   role in the consideration of pesticides as toxic air

11   contaminants.  So a lot of our program today will involve

12   presentations by the staff of the Department of Pesticide

13   Regulation, or DPR.

14             I might comment also that the evaluation of

15   pesticides as a candidate TAC is in a good position to move

16   forward considerably as a result of the day's meeting.

17             Since ethyl parathion was brought before the panel

18   in the 1980s, there has not been a formal decision required

19   of the panel relative to AB 1807.

20             There has been a lot of informal discussion --

21   well, at the meetings formal discussion, but not leading to

22   a decision on things like methyl bromide, toluene, and DEF,

23   and of course DEF is a chemical about which we'll hear a lot

24   in today's meeting.

25             There's also been a discussion in previous SRP



 1   meetings of DPR's prioritization scheme for bringing

 2   pesticides before the panel for consideration as TACs, for

 3   DPR's proposed tiered process for evaluating candidate

 4   chemicals, and the desirability of holding a workshop

 5   organized by the Department of Pesticide Regulation to

 6   basically inform the process so we can all make better

 7   decisions on the question of pesticides as toxic air

 8   contaminants.

 9             So most of these items will also be on the agenda

10   for today.

11             Now, we're aiming for a early afternoon end time,

12   if possible, so at this point I think we ought to get

13   rolling and get into the main agenda items.

14             Our first presentation this morning will be by

15   DPR, Jean-Mari Peltier and Doug Okumura, and we'll let them

16   decide between them how they'll make that presentation.

17             And I think the presentation will address how

18   DPR's timetable looks.  It's really a reminder for us, we've

19   heard some of this before, on bringing reports and fact

20   sheets before the panel over the next several months.

21             Is that correct?

22             MR. OKUMURA:  That's correct.

23             Can you hear me?

24             Good morning, Mr. Chairman, members of the SRP.

25             I have for you a handout here, or I guess it's



 1   being handed out now, the schedule.

 2             Basically, we are on schedule with mostly every

 3   item.  I think we have two exceptions with that we'd like to

 4   share with you.

 5             The first one would be for azinphosmethyl -- or

 6   excuse me, for MITC.  What we're planning on doing, because

 7   we're anticipating the workshop being in January, we're

 8   looking at potentially moving the MITC item back to the

 9   February calendar, because of the workshop being held in

10   lieu of the committee meeting.

11             And the other one would be benomyl and we have a

12   staff recommendation that we're putting forward to

13   management.  On that one, as a result of the first meeting

14   we had several months ago, we've determined that we are

15   recommending that this item could potentially be pulled from

16   the calendar based on the fact that looking at the historic

17   pesticide use report data and looking at the sampling, it

18   does not appear that the sampling, the timing and the place

19   of sampling didn't match up with the historic pesticide use

20   reporting data.

21             This was not a restricted material under our

22   restricted materials system, and so when we looked at the

23   use report data we were finding that timing and place of the

24   samples was probably not the most appropriate to determine

25   whether it's an air toxic or not.



 1             So we're looking at pulling that one and having

 2   the Air Board resample that one.

 3             Those are the two items that we feel we have to

 4   make some changes to the calendar on.

 5             The other thing would be is that if at any time we

 6   bring these items forward then and the committee and members

 7   here, we do not get to a decision point and it carries over

 8   to other meetings, that potentially could impact the

 9   calendar.

10             Other than that, we feel that the calendar looks

11   pretty good and we're pretty solid on most of those items.

12             DR. SEIBER:  Okay.  Just a couple of questions.

13             Did I hear you mention azinphosmethyl?

14             MR. OKUMURA:  Yeah.  That was a mistake on my

15   part, though.  I meant to say MITC.

16             DR. SEIBER:  Then methyl parathion should be

17   fairly early on the agenda.

18             MR. OKUMURA:  That is on schedule, that is

19   correct.

20             DR. SEIBER:  And we all have copies of methyl

21   parathion, I think that was provided to us a week or so

22   again.

23             MR. OKUMURA:  That is correct.

24             DR. SEIBER:  Okay.  Any questions or comments on

25   the time table, fellow panelists?



 1             By the way, while they're thinking about that, I

 2   forgot an announcement, and that is Dr. John Froines, who is

 3   the chair of our panel, was unable to be with us this

 4   morning, so I am sitting in his stead.

 5             But Dr. Froines has been in contact.  He's

 6   provided some input and we'll bring that up in due course.

 7             MS. PELTIER:  Dr. Seiber, I thought I'd stay here

 8   and invite Dr. Lisa Ross up to the table to talk about the

 9   second agenda item as well, which is the workshop.

10             You'll recall that -- let me start again.  Good

11   morning.  My name is Jean-Mari Peltier and I'm the chief

12   deputy director of the Department of Pesticide Regulation.

13             You'll recall that beginning in, I believe June of

14   this year, the Department of Pesticide Regulation began

15   having discussions with members of the SRP exploring the

16   possibility of putting together a workshop on pesticides for

17   the committee.

18             And the agenda for that workshop has undergone a

19   bit of a metamorphosis.  One of the interests was in

20   providing, especially new members of the panel, an outline

21   of the regulatory framework in which pesticides are

22   regulated by the Department of Pesticide Regulation in

23   California.

24             We have prepared for you two different option

25   papers, which I believe have been circulated to the



 1   committee, both of which have as a morning component a

 2   review of the regulatory program in California.  First, with

 3   opening remarks by John Dunlap, or rather the new chair of

 4   the ARB, since this will be held in February of '99, and

 5   Dr. Froines as the chair, and then with Director Wells of

 6   our department walking through an introduction to the

 7   California program, and inviting a representative of US EPA

 8   to talk in particular about the provisions of the Food

 9   Quality Protection Act and how the assessment of aggregate

10   risk at the federal level will impact the way they're

11   assessing exposures to pesticides and their tolerance

12   assessment program.

13             And then further to walk through our registration

14   and enforcement programs here in the State of California.

15             Then the afternoon programs you have two different

16   options before you, and I would call on Dr. Ross to walk

17   through those two options with you.

18             DR. LISA ROSS:  Well, in discussions with

19   Dr. Seiber about the kinds of things that the SRP would like

20   to hear about and hear more discussion on, we came up with

21   these two alternatives.  One is more focused on groups of

22   pesticides, if you will.  The other more focused on

23   scientific, specific scientific issues.

24             Alternative one focusing on some of the case

25   studies that you've already seen, DEF, methyl parathion and



 1   1,3-D representing different groups of chemicals and

 2   discussions can center around those types of chemicals.

 3             And in the first case we talk about the

 4   defoliants, basically DEF, and some of the issues

 5   surrounding DEF in that report that came up in the review of

 6   that report.

 7             The second item being organophosphates, methyl

 8   parathion would be an example of that group of chemicals,

 9   which presents different issues than the DEF chemicals would

10   present.

11             And then finally fumigants, such as 1,3-D, which

12   is also in the process of being produced, the report, and

13   which may have other types of issues surrounding that kind

14   of chemical.

15             And the second alternative basically would be to

16   address specific issues, scientific issues and questions

17   that have come up on why we do what we do.

18             For instance, issues surrounding exposure

19   assessment and how those are done.  There are a number of

20   things that could be discussed under that category.

21             Issues surrounding neurotoxicological end points

22   that are chosen for the reports, and issues, other

23   additional issues that the Scientific Review Panel might

24   like to hear about.

25             So actually at this point we'd like to solicit



 1   some of your ideas, since this is a workshop for you, and

 2   try to take some notes.  And if Dr. Seiber would like to

 3   lead that discussion, I'd appreciate it, so I can take some

 4   notes and get some ideas back.

 5             We would like to try to get an agenda set up by

 6   the end of this month, so if at this point you don't have

 7   ideas that you'd like to bring forward, but would like to

 8   comment to me later, I'd like to take those ideas by the end

 9   of the month and put it together so we can get the proper

10   moderators and speakers set up so that we can have a good

11   discussion.

12             Jim.

13             DR. SEIBER:  Thank you very much, Dr. Ross.  And

14   thanks for putting the effort in to get the workshop

15   organized and give us some clear alternatives to choose

16   from.  I think that is a useful way to begin the discussion,

17   but we would like to get the panel input on the workshop

18   now.

19             And, Dr. Witschi, do you have a comment?

20             DR. WITSCHI:  Yes, I'm confused.  You mentioned

21   about DEF and organophosphates.  I thought DEF was an

22   organophosphate.

23             DR. LISA ROSS:  No, I don't believe so.

24             Is DEF an organophosphate?

25             DR. SEIBER:  It's an organophosphate, but it's not



 1   one of the cholinesterase, the more aggressive

 2   cholinesterase-inhibiting organophosphates.

 3             DR. WITSCHI:  It produces neuropathy.

 4             DR. BYUS:  It's cholinesterase.

 5             DR. WITSCHI:  It produces neuropathy.

 6             DR. SEIBER:  That's true.  I guess the difference

 7   is it's an herbicide as opposed to an insecticide, but it's

 8   an organophosphate.

 9             DR. LISA ROSS:  What we're trying to do with a

10   defoliant category is address some specific issues that came

11   up surrounding DEF and other herbicide types defoliants that

12   may have some similar actions.

13             DR. SEIBER:  Go ahead.

14             DR. LISA ROSS:  Well, DEF could be a specific

15   category in and of itself.  I think that --

16             DR. WITSCHI:  The reason I'm bringing this up is

17   to me they look the same.  I'm just looking at the DEF

18   document.  The concern I have, and we discussed this to some

19   extent on the phone call we had last week, is cholinesterase

20   inhibition, and also some other concerns with CFR, the

21   neurotoxicity.

22             That's the reason why I definitely would favor

23   alternative two in which we go to the toxicology, the end

24   points, rather than discussing the different components,

25   which are definitely divided and not -- I mean, you just



 1   can't have DEF and organophosphorus compounds.  They are the

 2   same and they have similar processes.

 3             So that's why I would really favor alternative

 4   two.

 5             DR. SEIBER:  Yeah.  The two alternatives, let me

 6   just put it in a little bit of perspective, we're after the

 7   same kind of information by two different mechanisms.  One

 8   is to use case studies to surface the issues and as examples

 9   of the issues, and the second is to go straight for the

10   issues and then bring chemicals in to kind of exemplify the

11   issues.

12             So it's just kind of a how you approach the

13   subject, what's the best way to get that information out.

14             DR. WITSCHI:  What I definitely think is the

15   pressing issues would be much more important, because I

16   think the panelists have a big experience in some things

17   like cancer, chronic toxicity, which are concerns,

18   pesticides, as far as I'm concerned, but we do not have

19   really much experience how to handle neurotoxicity.

20             DR. FUCALORO:  And I will agree with you,

21   Hanspeter.  For example, on the exposure assessment, I'd

22   like to see that broken out as a special topic, personally,

23   and I think that would -- so I would support your suggestion

24   at this point, unless someone can convince me otherwise.

25             DR. SEIBER:  Personally, I tend to support the



 1   issues-driven workshop.  We've started out, this workshop

 2   has gone through several evolutions.  It started out as a

 3   fumigant workshop.

 4             DR. FUCALORO:  That idea stunk.

 5             DR. SEIBER:  Well, let's just say it was not the

 6   right time for the fumigants.

 7             Now, I'd like to hold the fumigants option open

 8   for a future workshop if we decide we need it, and that may

 9   be in the spring or summer or some later time.

10             But this is clearly not a fumigant workshop.

11             And then we went through the evolution of using

12   case studies.  Well, the problem with the case study

13   technical problem is that we'll have already talked about

14   DEF here in this meeting and perhaps the next one, and so

15   that will be passe.  What new issues could we bring up with

16   DEF?

17             So that's why we were leaning more towards an

18   issues driven workshop, but again with this battery of

19   examples that we can pull forward to illustrate the issues.

20   Not these three, plus others.  There's other chemicals that

21   should be brought in as examples.

22             So I tend to agree with you on the issues driven,

23   but let's hear some other comments.

24             DR. BYUS:  Well, I agree with the neurotoxicology.

25   I mean, it was my impression from reading the DEF document



 1   if a significant number of these pesticides are

 2   neurotoxicological agents, is that true?  So if that is the

 3   case, then I would really like to have -- hear somebody who

 4   is an expert on neurotoxicology, particularly as it relates

 5   to acetylcholinesterase inhibition and the serum inhibition

 6   and serum design versus the brain enzymes, what does it mean

 7   when you inhibit the brain enzyme by 30 percent.  I mean

 8   there's statements in the DEF document that says that that's

 9   not something we should necessarily worry about.  I question

10   whether that's the case or not.

11             But, I mean, but I'm not an expert in that, but I

12   am a pharmacologist, so I would think that would be a very

13   important issue to discuss.

14             I also would like to see something about exposure

15   assessment.  I mean, I think that is very important.  We all

16   have questions about that.  There seems like every time we

17   discuss the pesticides we spend a lot of time having you

18   explain to us what was done, and it would be nice to do it

19   all at one point at one time.

20             But I also do think that getting right to the

21   cases is, you know, the speedy way to get going here too.

22   We don't want to necessarily waste a lot of time, but if

23   there are other issues, they're the two I do agree that I

24   would like to hear about from other people.

25             MS. PELTIER:  The discussion topics that you



 1   brought up, Dr. Byus, especially with regard to choice of

 2   neurotoxicological end point, the kinds of issues that you

 3   maybe were struggling with a little bit are the same kinds

 4   of questions that have been brought to the scientific

 5   advisory board back with US EPA and discussion of use of

 6   acetylcholinesterase inhibition as an end point in and of

 7   itself is very much a part of the discussion under the Food

 8   Quality Protection Act, as US EPA struggles with how to deal

 9   with pesticides that deal with the common mechanism of

10   toxicity.

11             So the discussion is very timely and I know that

12   it's been something that has been confounding the debate at

13   the national level as well.

14             DR. SEIBER:  The idea of having invited experts, I

15   think, is consistent with either one of these models and

16   that's the sort of thing that we've had in mind from the

17   beginning.  We were open very much to suggestions as we

18   plan.  And in fact the more panel buy-in to this workshop,

19   the better.

20             So if you have ideas of people, any of you, that

21   could make presentations that might inform us, inform the

22   process, then you're certainly welcome to do that.  This is

23   a good time to do it.

24             Dr. Ross will be apparently taking the lead and

25   organizing this.



 1             If we are aiming for a January workshop, which it

 2   sounds that we are, we need to get moving fairly rapidly on

 3   getting outside experts to schedule them.

 4             Okay.  Other comments on the workshop?

 5             We received a letter, all the panelists have

 6   gotten a copy of the letter, from Cal PIRG, a public

 7   interest group here in California, and as near as I can

 8   tell, the comments are good and I think they're consistent

 9   with what we have in mind.  We appreciate the comments from

10   Cal PIRG and I think we'll take those into consideration as

11   we plan the workshop.

12             Is that correct?

13             MS. PELTIER:  Yes, Dr. Seiber.  I would suggest

14   that most of those questions should probably be answered in

15   the first component of the session, the morning session, in

16   which we're walking through the way we coordinate with ARB

17   and tying back to use reports such as was just covered by

18   Doug Okumura on the issue of benomyl and so I think that we

19   welcome the opportunity to walk through those questions.

20             DR. SEIBER:  Okay.  You'll notice that in

21   alternative two, by design, issues three, four and five are

22   left blank.  So we're after other issues that could be

23   addressed here, and so far I think we've all bought into the

24   exposure assessment and the identification of toxic end

25   points.



 1             And I'm assuming issue two is more general than

 2   just neurotox end points.  It may be that we need an issue

 3   on other toxicological end points.

 4             How do you feel about that?

 5             DR. BYUS:  The non-cancer the ones, that we --

 6             DR. SEIBER:  Well, it could be either.

 7             DR. BYUS:  Could be either.

 8             DR. SEIBER:  Cancer is pretty well defined.  We

 9   don't have a lot of options there.  If a chemical is a

10   carcinogen, we're driven in that direction and we've had

11   lots of experience with it, so I'm not sure we need to spend

12   a lot of time on that end point.  But other end points --

13             DR. BYUS:  Unless it's something like diesel

14   exhaust and lung cancer, which was a very complex issue that

15   required, I think, a lot of expert consideration.

16             But I do agree with not generally the cancer end

17   points, unless it's an unusual cancer phenomenon.

18             DR. SEIBER:  One of the issues that seems to come

19   up and is a cross-cutting issue is what's a legitimate

20   source of toxicological data.  We've got registrants, that

21   information.  There's information in the let's say the gray

22   literature, the unpublished reports and so forth.  And then

23   there's the published peer reviewed information.

24             I don't know whether that's worth discussing, but

25   it seems that it's been important in our considerations to



 1   the present.

 2             So how do you feel about something on what types

 3   of data should be considered, particularly toxicological

 4   data, but I think that could extend to exposure data as well

 5   in these risk assessments?

 6             DR. FUCALORO:  Yeah.  I was impressed with the

 7   information we received from OEHHA on the data from the

 8   diesel exhaust study and laying it out for the nonexpert.

 9   I'm not a toxicological expert, and laying it out, what is

10   likely to be very reliable, what's not and so on.  I thought

11   that was helpful.

12             I mean, my area of expertise is not toxicology, so

13   I found the presentation and the experience they have in

14   presenting that information to us very convincing and

15   compelling.

16             So maybe they may wish to make a presentation.  I

17   don't know if that's a good idea or not.

18             DR. SEIBER:  So a presentation from OEHHA on

19   sources of information.

20             DR. FUCALORO:  If you wish to go in that

21   direction, which I have no problem with, because I think

22   that is always an issue, but what I'm saying from my

23   experience with what OEHHA provided to us on that particular

24   study, I found that to be excellent and it helped me tie all

25   the issues together and to make the decision that I made



 1   when I voted.

 2             DR. KENNEDY:  As the nonexpert's nonexpert, my

 3   major concern is to help us to find biases and sources of

 4   error in evaluating the material, and who can help us with

 5   that?  Can OEHHA do that?

 6             DR. SEIBER:  So variability and uncertainty, that

 7   type of thing, as a generic?

 8             DR. KENNEDY:  We can get lost in non-peer reviewed

 9   information for years.  That's a distinctly different thing

10   from measured information, which will see the observations

11   and assessments, but I think helping us to be able to define

12   and understand the intrinsic sources of error and bias

13   within the presentation of those data would be helpful.

14             DR. LISA ROSS:  So it's actually the collected

15   data, the exposure assessment data that you're -- or

16   actually variability and how the values are then massaged

17   and put into a model.

18             DR. SEIBER:  I think could be exposure, but also

19   you were talking about the --

20             DR. KENNEDY:  I'm talking in general, yeah.

21             DR. WITSCHI:  But I don't think we should get hung

22   up in this particular case on something has been published

23   in the peer review literature or not, as far as pesticides

24   are concerned.  After all, these are pretty toxic chemicals,

25   and before they can be sprayed around they probably go



 1   through a review process, which is much much more stringent

 2   than anything being published in the open literature.

 3   That's a no-brainer, essentially.  Otherwise, they wouldn't

 4   see the market.

 5             So I'd be much more happy if you would get a very

 6   good briefing on the process, a new pesticide or a pesticide

 7   has to go through before it can be used, because I think

 8   that there is some review process which involves anything

 9   that ever appears even in the best scientific journals,

10   because those things, as far as I know, people who look at

11   those things they look at the original data, which you never

12   do if you review the paper.

13             MS. PELTIER:  Exactly, Dr. Witschi, and that's the

14   part of the presentation we'd really hoped to lay out more

15   clearly through the morning session with both the

16   representative of US EPA and California DPR through our

17   registration process to walk through the kinds of reviews

18   that those pesticides undergo before they're ever allowed to

19   be introduced into the environment in California.

20             DR. SEIBER:  I think it would be good to go over

21   it in the morning, but there's still a question whether

22   maybe there should be a special session.  One of the issues

23   should be on how those studies are conducted.

24             And as an outside expert we can even consider

25   getting someone from industry who supplies that information



 1   to say, okay, here's what they tell us we have to do and

 2   here's how we do it and why we do it and here's what we're

 3   looking for in the final product.  And that's information

 4   that goes to the regulatory agencies which, of course, can

 5   be used, I'm assuming it's used in things such as the TAC

 6   evaluation process.

 7             MS. PELTIER:  It is through our hazard ID

 8   component, yes.

 9             DR. SEIBER:  And that's different from the generic

10   chemicals that we -- you know, the benzenes and so forth.

11   Sometimes we have that kind of information, but it tends to

12   be more peer review literature information.  So I think

13   there is a difference here with economic poisons.

14             So I would --

15             MS. PELTIER:  So preference would be to add an

16   additional component.  Maybe right after the first session

17   where we talk about the data generation and bring in a

18   registrant.

19             DR. SEIBER:  It could be there or it could be one

20   of the issues that are left blank.  So we can work on that,

21   I think, as we try to finalize the program.

22             MS. PELTIER:  Okay.

23             DR. SEIBER:  But any suggestions, again, would be

24   very welcome in this regard.

25             Other issues that could be addressed in the



 1   workshop?

 2             DR. BYUS:  Maybe we'll have a better idea after we

 3   go through DEF today and maybe at the next meeting, which

 4   isn't that far away, and we can think of something.  I'm

 5   sure something will come to us as we start doing these

 6   discussions.  We have to get started, obviously, and you

 7   have to sort of start somewhere and have this -- it's

 8   difficult to know what exactly you want in the workshop.

 9   After we do this for a while we'll know exactly what we

10   want.

11             MS. PELTIER:  Where the holes are.

12             DR. BYUS:  So we have to plan it now, so we're

13   sort of in a little bit of a catch 22 there.

14             MS. PELTIER:  If there's agreement with the core,

15   we can at least, Dr. Ross and the rest of the staff, can

16   start working on that core and lining up speakers for those

17   components and then if after we walk through DEF or walk

18   through methyl parathion if something else comes jumping out

19   at us, we can add that as an additional module at the end.

20             DR. BYUS:  If there is any other non-cancer

21   toxicological end points in any of these chemicals that are,

22   I hate to say the word unusual, but they're unusual to us,

23   not necessarily unusual to you, but that might be useful as

24   well.

25             DR. SEIBER:  Do you mean for example the butyl



 1   mercaptan issue that we'll --

 2             DR. BYUS:  Yeah.  Or any kind of maybe there's a

 3   immunotoxicological issue that's unusual.  I don't know,

 4   because I don't know what's in them.  I don't even know what

 5   they all are, but if there is an another toxicity that's

 6   different than cancer, that that would be good.

 7             DR. SEIBER:  Well, I'm kind of torn between kind

 8   of the academic viewpoint to workshops to say I'd love to

 9   have somebody come in and talk about chemicals in the

10   atmosphere and what happens to them, how long do they last,

11   whether they degrade, how fast they degrade and what's known

12   about chemical dynamics in the atmosphere.

13             Maybe Dr. Fucaloro and I could relate on a topic

14   like that.  I'm not sure.

15             How do you feel?

16             But it's kind of abstract in a way and, yes, it

17   does deal with what we need to consider, but not head on.

18             DR. FUCALORO:  Of course there's complex issues of

19   gas phase kinetics and in fact heterogenous kinetics with

20   particles and so on.  It's a very interesting topic.

21             Couple of years ago a couple of fellows won the

22   Nobel prize with high atmosphere with heterogeneous

23   catalysis.

24             So, yeah, it would be interesting, because it's

25   certainly an issue in this one, in DEF, that the



 1   environmental fate of these chemicals in the atmosphere, I

 2   think, is an issue when we have to look at them.

 3             DR. SEIBER:  So would you be in favor of at least

 4   considering that as a --

 5             DR. FUCALORO:  Yes.

 6             DR. SEIBER:  And maybe an invited expert --

 7             DR. FUCALORO:  Sure.  Of course, I'm tempted

 8   because I also find that a scientifically intriguing topic,

 9   and that may override my responsibilities here to find where

10   we're considering health issues.  But I think they are

11   related to health issues and if other people think that that

12   would be important enough to warrant a particular section, I

13   would certainly go along with that.

14             DR. SEIBER:  Okay.  Any other comments for now on

15   the workshop?

16             As Dr. Byus suggested, if we can come back and

17   revisit after we've gone through the DEF.

18             But we appreciate what you've done so far.  You've

19   given us some good alternatives to choose from.  And thanks

20   for the presentation.  And I think we're on track.  Thank

21   you very much.

22             MS. PELTIER:  Thank you very much.

23             DR. SEIBER:  Our next agenda item is staff of the

24   DPR presentation of the issues, the DEF report.  Paul

25   Gosselin, who is with DPR, will lead off.



 1             I believe you have a team of people with you to

 2   make parts of the presentation.  So we're essentially going

 3   to turn it over to you and maybe in about a half an hour or

 4   so, if we get to a logical break point we'll take a break.

 5             MR. GOSSELIN:  Great.  Thank you.

 6             I do have a team of DPR scientists here who are

 7   going to give presentations similar to what was given a year

 8   ago.

 9             And it is kind of a pleasure to be here.  I think

10   this is my fourth or fifth time coming here, and this is --

11   previously it's been a lot of presentation on process and

12   prioritization and sort of the plans on pulling our

13   documents together.

14             But today I think is kind of a very important time

15   because we actually do have a document for your official

16   consideration today, which I think has been quite some time

17   since we've actually reached this point.

18             DEF is, as I mentioned, is a document we had

19   pulled together largely from a risk assessment that we had

20   been working on for a number of years.  It's presented today

21   in a format that you're used to seeing for other toxic air

22   contaminants in the split-out volumes.

23             As I said, we are focused on completing a full

24   risk assessment on DEF and are nearing completion on that,

25   that are going to account for all exposures, particularly



 1   focused on occupational exposures, but today the main focus

 2   of the document and presentation is going to be on the

 3   ambient air components of that, which is fairly on has a lot

 4   of compelling issues with it.

 5             The basis of the hazard identification, the

 6   toxicology of the material, is consistent with both risk

 7   assessments, so that's a major piece of it.

 8             One thing I did want to give some introductory

 9   comments on.  I'm not going to get into any of the details

10   on the DEF presentation.  Staff is going to do that.

11             But there had been a number of discussions that

12   we've had with the panel members that I just wanted to

13   clarify.

14             One was actually going to be the subject of the

15   workshop, but also the choice of studies.  It's kind of been

16   sort of a contentious issues that we sort of give preference

17   to the official FIFRA or GLP generated studies over the open

18   literature.

19             And really the fact of the matter is all of the

20   studies, all the available information, not just the DEF,

21   for all our risk assessments, are taken into account and

22   essentially given equal weight.

23             We do full literature searches.  We have a

24   contract with UC toxicology library to run literature

25   searches for us that go into our risk assessment.



 1             And really what it comes down to is that based

 2   upon the entire weight of evidence, what the entire set of

 3   data show, really drive how our risk assessments go.

 4             And one thing that really weighs more than the

 5   open literature is that the details that we get from the

 6   required studies actually sort of paint a more clear picture

 7   in many cases, not all cases, of what the toxicology and

 8   mechanisms of action really are on whole.

 9             And I think we'll hear about that in DEF and

10   probably get into more details in the workshop, but I wanted

11   to just clarify that there isn't disregarding of open

12   literature.

13             Another issue is how we actually craft the

14   documents.  We have, and I think one of the things that

15   we've really looked at was through the risk assessment

16   advisory committee is internally and externally conducting

17   peer review.  We've actually set up a number of different

18   levels internally to have different staff review the data,

19   characterize the data.  That's all compiled.

20             And then we actually have an internal team of

21   senior toxicologists and scientists actually go over and

22   peer review the end points and make an end point selection

23   and actually internally peer review the documents before

24   they're even sent out for external peer review.

25             And we use OEHHA and ARB for toxic air



 1   contaminants and OEHHA and US EPA for our full risk

 2   assessments, prior to actually completing them.

 3             And this document had gone through that process.

 4             One of the things that is going to be a focus here

 5   today is that the document you have today is by and large a

 6   lot of the same information that you heard, but since the

 7   past year there have been a number of changes that we're

 8   going to focus in on.

 9             One issue is the comments that were raised at last

10   year's meeting.  Those comments were brought back and some

11   changes to the document were made.

12             We did get some additional comments from OEHHA.

13             And actually conducted additional literature

14   searches.

15             So all that information was brought back into this

16   document and going to be highlighted.

17             The third piece that is very important, and I

18   think timely, is EPA has released their draft risk

19   assessment for DEF, and that's something that -- and that

20   was over the past four to six weeks they actually issued

21   that.  So even though we, our staff, coordinate and consult

22   EPA all the time, now we actually have their draft document

23   that's up for comment.  So that's actually going to create a

24   nice contrast piece to our risk assessment.

25             So without going into any more overview, I wanted



 1   to just kind of give those sort of background pieces.  And

 2   what I'm going to do is invite the staff up who are going to

 3   give presentations.  And I think typically you -- it's

 4   pretty much open question during each presentation.

 5             The one thing, too, is we are very interested in

 6   the comments you have.  I think there are going to be a

 7   number of compelling issues particularly in n-butyl

 8   mercaptan and a limited tox database on that.

 9             And also some discussion on how we actually chose

10   the critical tox end points, particularly the cholinesterase

11   inhibition.  And I think that's going to be a major topic

12   we'll talk about today.

13             And again, with that I won't get into the details.

14             Although we focus in principally on clinical

15   symptoms and rank cholinesterase, we don't out of hand

16   disregard plasma cholinesterase inhibition.  It's viewed as

17   sort of a total weight on all the studies and really what

18   they show is causing adverse effects.

19             So it's something we'll get into more discussion,

20   not only today, but I think as sort of a general policy on

21   how we view all the studies and actually try to get to the

22   best critical end point for toxicological standpoint will be

23   the focus.

24             With that, if there aren't any other general

25   questions --



 1             DR. SEIBER:  Do we have general questions at this

 2   point for Dr. Gosselin?

 3             DR. WITSCHI:  I have just one general question.

 4             Among the reports which are submitted by industry

 5   and then DPR deposited, how accessible are they?  Are they

 6   accessible to anybody?

 7             MR. GOSSELIN:  They're accessible to other state

 8   agencies and to the panel.  There is some level of

 9   confidential business information associated with it but --

10             DR. WITSCHI:  If I wanted to read one of those, I

11   could?

12             MR. GOSSELIN:  Yes.  It's specifically designated

13   as allowed to access that, so any time you want to make

14   arrangements to come and view them, we'll do that and set

15   that up.

16             DR. SEIBER:  Could you, Paul, can you give us a

17   little more on this EPA draft document on DEF?  What the

18   status is, what time table, why was it prepared, how does it

19   fit in to the overall?  Is this a reregistration related

20   activity?

21             MR. GOSSELIN:  It's somewhat tied to

22   reregistration, but it's also principally focused and came

23   out of FTPAs.  Jean-Mari mentioned that's one of the major

24   driving forces with EPA and one of the areas that we've been

25   increasing our consultation with them on our risk



 1   assessments.

 2             The FTPA focused their attention on particularly

 3   eso carbamates and they've issued recently a series of nine

 4   and then seven risk assessments in draft form out for public

 5   comment.  I believe this DEF document was in the second

 6   round of that, and comments are due, I believe, in November

 7   on the draft risk assessment.

 8             They do have them listed and available for review

 9   on their Internet site.

10             So I'm not sure honestly their time table on

11   bringing closure to that, but it's something that I'm sure

12   they're going to be getting a lot of comments on those risk

13   assessments.

14             DR. SEIBER:  I'm assuming EPA would have copies of

15   your product too?

16             MR. GOSSELIN:  Yeah.  Most all the risk

17   assessments, like I said, we do send not only to OEHHA for

18   peer review, but also to US EPA, and they provide peer

19   review comments to us on most of them.

20             Recently because of the time frames and workload

21   that they have been under, they've been mostly focused in on

22   the ones that they already have on their plate, because

23   they're under a pretty tight time frame to complete risk

24   assessments under FTPA.

25             But this one and another one that we're both



 1   jointly working on, staff throughout the process converse

 2   e-mail and over the phone and on draft, because in the end

 3   what we've typically in an ideal sense try to do is try to

 4   coordinate when we do have to regulate, put additional

 5   regulations on, we'd like to coordinate that jointly between

 6   us and US EPA.

 7             DR. SEIBER:  Thank you.

 8             Any other general comments before we get into the

 9   specifics of the documentation before us?

10             Okay.  Thank you.

11             MR. GOSSELIN:  I'm going to sit here and then

12   invite staff up.

13             And the first presentation we have, Nita Davidson

14   from environmental monitoring is going to go over the

15   environmental use portion of the document.

16             DR. DAVIDSON:  I have overheads.

17             DR. SEIBER:  You'll need a microphone probably.

18             DR. DAVIDSON:  Sorry about that.  Can you hear me

19   now?

20             Okay.  DEF is a defoliant applied to cotton plants

21   toward the end of the growing season to encourage leaf drop,

22   which makes harvesting the bolls easier.

23             The chemical name for DEF is S,S,S-tributyl

24   phosphorotrithioate, and the active ingredient is used for

25   two products, DEF and Folex.



 1             DEF and Folex are identical.  Both contain 70.5

 2   percent of the active ingredient, but DEF is manufactured by

 3   Miles, and Folex by Rhone and Poulenc.  Both are

 4   emulsifiable concentrates.  To simplify things I'll refer to

 5   both products as DEF.

 6             Before the mid 1980s, DEF and Folex were two

 7   different active ingredients.  DEF was the oxidized version

 8   of Folex and Folex was phosphorotrithioite.

 9             Almost immediately upon exposure to air,

10   trithioite converts to DEF and gives off two smelly

11   conversion products, n-butyl mercaptan, which is skunky

12   smelling, and dibutyl disulfide, which smells like rotten

13   eggs.

14             n-Butyl mercaptan is also a side product of the

15   synthesis of trithioite.

16             The old Folex is no longer registered, although

17   the name Folex has been retained.

18             And I'll get into some regulations affecting this

19   later.

20             DEF is practically insoluble in water and

21   therefore it's formulated as an emulsifiable concentrate.

22   It has an extremely low vapor pressure, which implies little

23   volatilization.

24             Henry's Law constant is the relationship of vapor

25   pressure to solubility and because of DEF's low vapor



 1   pressure, Henry's Law constant also implies that DEF does

 2   not volatilize quickly.

 3             Both n-butyl mercaptan and dibutyl disulphide have

 4   high vapor pressures, so they do volatilize readily.

 5             The physical chemical characteristics indication

 6   that following an application of DEF, aerosol particles

 7   remain close to cotton plants and soil.

 8             During an application, air currents transport the

 9   vapor created by evaporating aerosol particles.

10             And also because of DEF's low volatility,

11   particles may attach to airborne dust and be transported

12   that way.

13             Because DEF is applied during warm weather, the

14   atmosphere is thought to be a major sink for volatilized DEF

15   both following and during an application.

16             By eliminating cotton leaves, cotton is much

17   easier to harvest mechanically.  Also, main leaves clog the

18   harvesting equipment and stain cotton fibers.

19             Defoliants enable the plants to dry quickly and

20   the mature bolls open faster and this reduces the potential

21   for boll rots.  And it reduces the damage from fiber

22   staining insects such as aphids and white flies.

23             DEF defoliates by causing an abscission layer for

24   scar tissue to form between the skin and the petal.  The

25   leaf drops off within four to seven days.



 1             The DEF and Folex label specify .75 to 2.25 pounds

 2   per acre, depending on the type of defoliation, whether it's

 3   intended to be complete or an initial thinning type, called

 4   bottom defoliation.  And bottom defoliation is used more for

 5   pima type cotton and also harvesting the cotton seed.

 6             80 percent of DEF is applied aerially, 20 percent

 7   by ground.

 8             There's an important reason to hasten ripening of

 9   bolls.  All cotton within the southern San Joaquin Valley

10   must be harvested or destroyed by the end of December to

11   meet an early plow down date.  This is a cotton-free window

12   from January to March to prevent pink bollworm moths and

13   boll weevils from overwintering.  Although the pink

14   bollworms are weak flyers, they get blown up from storm

15   fronts to the San Joaquin Valley from Southern California.

16             So if you drive through the Central Valley from

17   January through March, or, well, I guess it's just January

18   and February, you shouldn't see any cotton in the ground.

19             This table shows the use of DEF from 1984 to 1995.

20   And in 1986 the least amount of DEF was used, about 756,000

21   pounds on 425,000 acres.  And note that in 1984, 1988 and

22   1990 these were years of highest use.

23             From 1992 through 1995, approximately 82 percent

24   of DEF was applied within the counties of Fresno, Kings and

25   Kern.



 1             Less than four percent was used on the Colorado

 2   Desert counties of San Bernardino, Riverside and Imperial.

 3             Less than two percent was applied to cotton grown

 4   in the Sacramento Valley, Colusa, Glenn and Yolo.  But

 5   cotton acreage in DEF use in this area has increased every

 6   year since 1992.

 7             This table shows acres of cotton harvested and

 8   percentage of acres treated with DEF.

 9             To summarize, the use of DEF in 1995, 97 percent

10   was applied in the San Joaquin Valley counties.  And you can

11   see the first six counties add up to 97 percent.  98 percent

12   of all cotton grown in California was grown in these same

13   counties.

14             I'm going to briefly discuss seasonal use.

15             In the southern San Joaquin counties where DEF has

16   the highest use, most is applied during September and

17   October.  In 1994 these counties, almost 99 percent was used

18   during these months, and in 1995, 98 percent was used.

19             We contrast this with Imperial County.  In the

20   Imperial Valley counties the phonology of cotton is a little

21   earlier and the peak application time is August through

22   September, and primarily August.  The duration of DEF

23   application is the same as in the San Joaquin Valley,

24   approximately 60 days.

25             This table shows how the use of DEF compares to



 1   use of other defoliants.

 2             In 1995 DEF was used on 47 percent of all

 3   harvested cotton acreage and this is cumulative acreage, so

 4   these numbers do not add up to 100 percent.

 5             Many of these -- many of these herbicides are used

 6   more than once and many are tank mixed.

 7             Sodium chlorate and paraquat are used on 77

 8   percent, and 62 percent of all acreage.

 9             Some other examples of specific use.  Let's see,

10   Dropp is recommended for total defoliation to prevent heavy

11   regrowth of the cotton plant and Prep and Harvade are at the

12   bottom are both plant growth regulators, and they're often

13   added to the tank mixture to speed up boll opening before

14   harvest.

15             Harvade was recently registered and actually its

16   popularity is increasing.

17             And one thing I should mention is that cotton

18   growers really see the harvest time as a continuum of the

19   whole process, so what they're trying to do is defoliate the

20   plants and also desiccate the plants, dry them out as much

21   as possible, but encourage them to put their energy into

22   maturing the cotton bolls so they can get maximum harvest.

23             I'm going to say a few words about the two

24   regulations that affect DEF.

25             One is the buffer zones, and in 1978 California



 1   adopted a regulation establishing buffer zones for

 2   application of DEF and the old type of Folex.  DEF cannot be

 3   sprayed within one-half mile of residential areas or any

 4   school in session or due to be in session within 24 hours.

 5             And also you cannot apply DEF within one-eighth of

 6   a mile of any school, whether it's in session or not.

 7             And as far as odor goes, in 1983 California

 8   adopted another regulation directed toward DEF and the old

 9   type of Folex, the n-butyl mercaptan content of DEF and

10   Folex was limited to a tenth of a percent.  And soon after

11   this regulation was adopted, Rhone-Poulenc switched from

12   trithioite to trithioate formulation, and also changed their

13   Folex product to their new Folex product.

14             I'm going to say a little bit about the contracted

15   study that DPR got scientists at UC Davis to do, including

16   Dr. Seiber, who is here, and this was a study done to

17   monitor DEF concentrations in ambient air.  They monitored

18   ambient levels of DEF at four rural sites in Fresno County

19   during September and October of 1987.  This was a year of

20   average DEF use.

21             The study was conducted during the defoliation

22   season, but it didn't monitor specific applications.  So, as

23   I mentioned, it was meant to be ambient monitoring.

24             The graph shows that during September the highest

25   concentrations of DEF occurred at the sites closest to



 1   cotton fields.

 2             Over 90 percent of all samples were above the

 3   minimum detection level.  The study also monitored

 4   background samples in Fresno and Bakersfield and the amount

 5   of DEF detected was much lower.  And less than 20 percent of

 6   these samples recovered were above the minimum detection

 7   level.

 8             Well, to conclude, DEF is a cotton defoliant used

 9   primarily in August and September in the Imperial Valley and

10   September-October in the San Joaquin Valley, and it's used

11   only on cotton and in a given year only for a 60-day

12   duration.

13             In 1995 cotton growers applied 866,000 pounds of

14   DEF to a little over 600,000 acres, and they harvested about

15   1.3 million acres.

16             Two types of buffer zones were established in

17   1978.  And I know that Tareq Formoli, who will come after

18   me, will go into more detail about this.

19             But growers cannot apply DEF within one-half mile

20   of residential areas or any school in session, and they

21   cannot apply it within an eighth of a mile of any school.

22             And, last, air concentrations in Fresno County

23   near cotton fields in DPR's contracted ambient monitoring

24   study in 1987 ranged from zero to 29.2 parts per trillion.

25             DR. FRIEDMAN:  How far from the cotton fields were



 1   those measurements made?

 2             DR. DAVIDSON:  I believe within 20 meters.  Maybe

 3   Dr. Seiber remembers, but --

 4             DR. SEIBER:  What was the question?

 5             DR. FRIEDMAN:  I just wondered in your study how

 6   far from the cotton fields were those measurements made?

 7             DR. SEIBER:  The ambient -- they weren't right

 8   next to cotton fields.  They were inside of the little

 9   towns, usually on public buildings like on the rooftop of

10   schools and city hall and wherever we could gain access.  So

11   there is some mapping that was done, it's part of the report

12   to show you where the nearest field was, but they're not

13   right next to fields.

14             DR. FRIEDMAN:  They're always outside of that

15   buffer zone?

16             DR. SEIBER:  Absolutely.

17             DR. WITSCHI:  I have a question.  I don't

18   understand those two buffer zones, because the second one,

19   one-eighth of a mile within any school is much more

20   stringent than the first one, which is half of a mile of a

21   school.

22             DR. DAVIDSON:  The one-eighth of a mile is a

23   buffer zone for any school at all.

24             DR. WITSCHI:  That's right.  But then when the

25   first one, because half a mile school, the second one is



 1   much more stringent.

 2             DR. DAVIDSON:  Right.  The half a mile one is a

 3   wider buffer zone.  When the school --

 4             DR. WITSCHI:  That's my question, which one of

 5   those two buffer zones applies, because they don't make

 6   sense.

 7             DR. DAVIDSON:  Well, for example, in the summer

 8   when no one is at the school it's one-eighth of a mile, but

 9   where --

10             DR. WITSCHI:  But when the school is in session,

11   it's a half of a mile.  That doesn't make sense.

12             DR. DAVIDSON:  It would be a wider buffer zone, so

13   think of it as being a barrier around the school.

14             DR. WITSCHI:  Okay.  I see.

15             DR. FUCALORO:  They move the school.

16             DR. KENNEDY:  May be a dumb question, but what

17   happened to the other 600,000 acres?  They don't need DEF,

18   they don't use it?

19             DR. DAVIDSON:  No.  There are other defoliants.

20   For example, sodium chlorate is much cheaper and it's

21   preferred by many cotton growers except that it's not as

22   effective.  So growers tend to -- if you think of all of the

23   list of all of those herbicides as being a cocktail that

24   they mix up and use, there are many products that are

25   pre-made tank mixes, for example, of two or three of those.



 1   So they're all kinds of combinations, and one might be a

 2   better desiccant, like paraquat, and another may be better

 3   for making the leaves die.  And DEF seems to be one of the

 4   best ones, but it's also expensive, so it's not used as

 5   much.

 6             DR. SEIBER:  But I think there's a growing market

 7   in organic cotton, and I'm assuming that organic cotton

 8   growers would not use --

 9             DR. DAVIDSON:  They do not use DEF, no.  And

10   actually they would use -- they would turn off irrigation at

11   a certain point, which is also what conventional growers do.

12   They also use salt-based fertilizers like magnesium chloride

13   and zinc sulfate.  So they have a different regimen.

14             DR. SEIBER:  There's some interesting anecdotal

15   questions about some of the early defoliants like magnesium

16   chlorate and some of the others, since they're oxidizers and

17   the plant is pretty dry, occasionally the fields would

18   actually combust, would burn up.  So there's down sides on

19   some of these nonorganic types too.

20             DR. KENNEDY:  You got to get in there quick.

21             DR. DAVIDSON:  If there are no further questions

22   then --

23             DR. FUCALORO:  I do have one question.

24             The monitoring for the photochemical products, the

25   captan, and that's clearly not much of that was done, is



 1   that correct?  The n-butyl mercaptan?

 2             DR. DAVIDSON:  Not in this contracted study.

 3   There are other studies that have been done that did

 4   monitory for n-butyl mercaptan, but it's not an ambient

 5   monitoring study.

 6             DR. SEIBER:  Just as a very quick review, the DPR

 7   identifies the chemical and then the Air Resources Board

 8   goes out and designs the monitoring study and then they

 9   contract it with like UC Davis or whoever does the work and

10   in that case the butyl mercaptan was not part of the

11   monitoring plan.  I think that's correct.  We have

12   separately gone out and looked for it in separate studies,

13   but it wasn't part of the contracted study.

14             DR. FUCALORO:  But certainly it's an issue in this

15   study, of course, to the extent that n-butyl mercaptan and

16   disulfide have toxicological imports.  I'm not an expert in

17   that area.  We really need to know what the exposure is and

18   the various acronyms, N-O-E-L, and so on for these

19   chemicals.

20             DR. SEIBER:  Absolutely.  Are you going to present

21   any data on the disulfide or mercaptan as part of your

22   presentation?  It is considered in the reports.

23             MR. GOSSELIN:  And maybe this might be a good

24   segue into Tareq Formoli's presentation on the exposure.

25             While Tareq is getting ready to come up, I think



 1   that some of this also reflects the evolution of science and

 2   exposure assessment too on looking at some of the breakdown

 3   products in monitoring.

 4             DR. SEIBER:  While we're getting ready to change

 5   speakers, I'd like to welcome Dr. Glantz to the panel.

 6             And do you have any words of wisdom before we

 7   proceed?

 8             DR. GLANTZ:  No.

 9             DR. SEIBER:  Not yet.

10             DR. GLANTZ:  Not yet.

11             MR. GOSSELIN:  We did cover all your concerns

12   before you got here.

13             DR. GLANTZ:  Good.  That's always reassuring.

14             MR. FORMOLI:  Good morning.  My name is Tareq

15   Formoli.  I'm the author of the exposure assessment part of

16   the DEF document.

17             I have some overheads that I would like to start

18   with.  First one Jim is going to help me.

19             My colleague already talked about the products and

20   usage of DEF.  I would like to reemphasize the restrictions

21   that we have in California for use of DEF, which is half a

22   mile buffer zone from residential areas and schools in

23   session and one-eighth of a mile buffer zone from any

24   school, even when they are not in session.

25             We also have a limit for n-butyl mercaptan level



 1   not to exceed .1 percent in formulated product.

 2             We looked at several studies of DEF and ambient

 3   air.

 4             The first study, Stanley et al, looked at DEF in

 5   the ambient air in Mississippi.  They found an average of 16

 6   nanogram per cubic meter.

 7             They also looked at urban Fresno and Riverside in

 8   California and they did not detect any DEF.

 9             The next study was Arthur et al.  This study was

10   also in Mississippi and the maximum level they found was 16

11   nanograms per cubic meter for DEF.

12             The other study was Oshima et al.  They looked at

13   ambient air in Mendota and Dos Palos and they did not detect

14   DEF.

15             Next.

16             The CDFA study is an executive summary that we

17   found and they monitored for DEF in Coalinga, Dos Palos,

18   Lemore and Mendota, and they found very little amount of DEF

19   in the ambient air.

20             In this study they also looked for n-butyl

21   mercaptan in Coalinga, Dos Palos, Lemore and Mendota.  And

22   the levels they found were from 1.9 to 28.6 microgram per

23   cubic meter.  But that range is for the positive samples.

24   And six percent of all samples were positive.  I don't have

25   the limit of detection for the study.  It was not included



 1   in the executive summary.

 2             The next study --

 3             DR. BYUS:  When during the year were these ambient

 4   air monitoring done?  Does it correlate when it was sprayed?

 5   Was it the same two months of the year or was it just any

 6   time?

 7             MR. FORMOLI:  Yes.  This study was done during the

 8   month of October, which is the season for DEF.

 9             The Kilgore et al study, which is somewhat more

10   detailed study, they looked at several rural areas in Kern

11   County and they also looked at the City of Bakersfield for

12   DEF.  The highest level they found in rural Kern County was

13   81.8 nanogram per cubic meter.  And the seasonal average was

14   33.7.

15             In urban area, which was the City of Bakersfield,

16   the highest level was 36.5 nanogram per cubic meter and the

17   seasonal average was 25.7 nanogram per cubic meter.

18             The way this study was conducted, they monitored

19   before -- first they monitored before the new season

20   started.  Then they monitored during the peak application

21   period.  Then they also monitored one week after the peak

22   application and the last one was several weeks after the

23   application, peak application.

24             Next, please.

25             This is the area that I'm going to talk about, the



 1   last study, Seiber et al study, the areas that were

 2   monitored was City of Fresno, San Joaquin, Five Points,

 3   which is shown in this map as UC Westside, and I believe

 4   Huron.  Yes, Huron at the bottom right there.

 5             Let's go to the next.

 6             DR. FRIEDMAN:  That map doesn't really help us in

 7   terms of showing where the stuff would be sprayed.  I mean,

 8   could you, in terms of a suggestion for improving the

 9   report, could you show also on that map where the cotton --

10   or where this would be sprayed so we have some idea of how

11   that relates to the locations where the sampling was done?

12             MR. FORMOLI:  From this study, this study was done

13   in 1987.  This study describes that the cotton fields were

14   pretty close to the monitoring sites.  From close, from ten

15   to 400 meters.  However, there is no information if those

16   fields were actually treated with DEF.  So we don't know if

17   those fields were treated or not.

18             But the buffer zone, the buffer zone is still half

19   a mile from the residential areas and these sites, the

20   monitoring sites were in residential areas.  So we assumed

21   that DEF, the application occurred beyond the buffer zone.

22             DR. FRIEDMAN:  It could be a mile away or five

23   miles.  And I don't know that this is scale of distance on

24   that map.  I just don't have a feel for how those monitoring

25   sites relate to where DEF might have been applied.



 1             DR. KENNEDY:  We don't know how much was applied.

 2             DR. FRIEDMAN:  Right.

 3             DR. SEIBER:  That area is, as I recall, and it's

 4   been a long time, there's cotton fields all around these

 5   towns, and they're -- we could possibly reconstruct some of

 6   the field to sampling by going backward just remembering,

 7   and we had pictures of some of the sites, so it might be a

 8   little more information we can milk out of it but --

 9             Lyn Baker is here from ARB.  I believe, Lyn, you

10   were in charge of the design of that study.  Somebody from

11   ARB.

12             MR. BAKER:  I was and I actually have my notes

13   from 1987.  They're kind of faded now.

14             DR. BYUS:  They don't smell, do they?

15             MR. BAKER:  The paper is kind of faint.

16             But I thought this might be helpful to you with

17   regard to this discussion.

18             Again, as the gentleman pointed out, we don't have

19   information on where DEF was applied to these cotton fields,

20   but I do have information for the monitoring sites on how

21   close they were to the cotton fields that could have been

22   applied.  Maybe that will help you a little bit to address

23   your question.

24             The Huron site was about 150 yards from the

25   nearest cotton field, but it was in a residential area, so



 1   with the half-mile buffer zone, the closest that

 2   applications could have occurred would have been a half-mile

 3   from that site.

 4             The Five Points location at the UC Westside field

 5   station was not a residential or school location.  There was

 6   cotton approximately a quarter of a mile to the north of

 7   that monitoring site and that cotton could have received

 8   DEF.  So that would have been only a quarter of a mile.

 9             The Tranquility site also was not a residential

10   location.  It was at a fire station south of town.  There

11   was a school about a quarter of a mile north of that.  So

12   this -- although that site was within 20 meters of cotton on

13   all sides, that fire station still probably couldn't have

14   had cotton applied within a quarter of a mile, because it

15   was about a quarter of a mile to a school, so for that

16   half-mile buffer.

17             And the San Joaquin site was at a school.  There

18   was cotton within a couple hundred yards to the east of that

19   site, but again it was at a school, so it would have

20   probably have to have been at least a half a mile to the

21   nearest possible DEF application.

22             DR. FUCALORO:  This is not -- I'm sorry.

23             DR. FRIEDMAN:  No.

24             DR. FUCALORO:  The Fresno County study, actually

25   there was measurement, certain times, certain -- a time



 1   certain after spraying.  Did you do that study, the one in

 2   Fresno, where they were downwind 45 meters and they found

 3   145 parts per trillion?

 4             MR. BAKER:  No.

 5             DR. FUCALORO:  Four hours after application.

 6             MR. FORMOLI:  No.  Actually, I think you're

 7   referring to some site application monitoring.  This is

 8   ambient air monitoring.

 9             DR. FUCALORO:  Okay.

10             DR. BYUS:  Could you just -- the purpose of the

11   ambient air monitoring is -- what was the purpose of

12   collecting this data, the rationale behind collecting it?

13   Maybe if you can explain that to us this would make a little

14   more sense.  What was it supposed to be used for, what was

15   it supposed to represent, was it --

16             MR. GOSSELIN:  For DEF in particular, and I think

17   one of the sort of advantages, if you will, because as

18   you've seen you have such a tight narrow application, such a

19   focused application period in a very select area.  It does

20   sort of counterbalance some of the data that in retrospect

21   we would have liked to have maybe collected.

22             But the ambient air scheme that was set up was to

23   try to characterize during this application time period the

24   peak area during the highest use time, what is -- what is

25   sort of the ambient levels of DEF in the atmosphere during



 1   the typical practice of applications during this time

 2   period.

 3             So that's why even back to the site selection on

 4   some of the schools and residential areas, people in these

 5   towns just adjacent to the main application areas, what sort

 6   of levels would they typically be exposed to.  And even

 7   though we don't have the site specific locales where those

 8   fields are or the amount used, if you look through the

 9   table, the use is fairly consistent levels year to year.

10   And Fresno, this area in particular is the principal area of

11   use.  So by and large, given the history of usage, this is

12   where you would find the predominant amount of use and

13   probably the highest ambient exposure.

14             DR. FUCALORO:  Words have meaning, of course, and

15   some are really laden with meaning, like ambient.  And one

16   gets the impression reading the word like that, and I think

17   this is the way you mean it, over the two-month period in

18   which there is spraying, one expects not much variation or

19   expects some sort of gradual or some sort of sloped curve

20   that would give you some idea of that.

21             And of course on the site application then of

22   course you really get wide variation, very short periods of

23   time.

24             So I read -- when he was talking about how far it

25   was from the cotton field, I get the impression that you



 1   were talking about a site study, but this is the ambient

 2   study and presumably the numbers generated here are

 3   certainly within an order of magnitude well within, I

 4   suspect, in order of magnitude what the range that one would

 5   expect during that time period.  At least that's the

 6   assumption I made.

 7             Now, I have to be -- you have to verify that

 8   assumption for me.  And you're not nodding, so I assume you

 9   are verifying.

10             MR. GOSSELIN:  Are you talking about the

11   comparison between the off-site application monitoring and

12   the ambient?

13             DR. FUCALORO:  I'm talking about the ambient right

14   now.  The numbers you have during a two-month period,

15   there's not much variation in that, that that number is

16   pretty solid year to year.

17             There you go.

18             MR. GOSSELIN:  I'll let Tareq continue.

19             But one of the things we tried to focus in on was

20   the choice of the best study, because the studies that he

21   had just summarized had really a range of data supporting

22   them and background information.  So again this is trying to

23   use all the information and see what the total weight, what

24   kind of picture it shows for exposure.

25             But, Tareq, maybe if you want to continue.



 1             DR. SEIBER:  Before you get back to that, let me

 2   just add one other perspective separately.  We've had air

 3   monitors literally right next to an actively sprayed or

 4   field that was sprayed a few hours before and those numbers

 5   will go up to maybe a thousand to 1500 nanograms per cubic

 6   meter, if that helps anyone's perspective.

 7             DR. BYUS:  I just think you need to define the

 8   word ambient in this context.  I mean it's unusual in a

 9   sense of how this is applied and seasonal and geographical

10   location, and in a sense it's more like a hot spot

11   phenomenon, but you're using the word ambient in relation to

12   the data you collect while you're spraying it, when you know

13   how much is applied.

14             So I mean I think you just need to define the word

15   ambient in this context of what it is you were trying to do

16   and what you know about application and what you don't know.

17   It's just a matter of defining the words and laying it out

18   for what it means initially, before you present it.

19             So you -- just that's all.  Is that -- would that

20   be helpful?

21             DR. FUCALORO:  I think here the graphic explains

22   ambient, or at least a definition of ambient.  I think it's

23   pretty clear.  There is more variation than I thought, but

24   that's fine.  That's what the data show, that's what the

25   data show.



 1             I remember this graph now that I see it.  It was

 2   in your report.

 3             DR. SEIBER:  Dr. Glantz.

 4             DR. GLANTZ:  Do you have any idea how much DEF was

 5   used in this area at the time of this study, even if you

 6   don't know exactly when it was applied, do you know how much

 7   was applied?

 8             MR. FORMOLI:  We do have data for the year that

 9   study was conducted.  I believe this data could be

10   available, but since at that time the collection of the use

11   report was not as detailed as we have right now, that

12   probably would take a while to gather that kind of

13   information.

14             MR. GOSSELIN:  It's my understanding it's one of

15   the things we're going back and trying to look at the tapes

16   and derive to see if we can pull that out.  Obviously, if we

17   were using the data we have today, it would be a lot easier,

18   but it's something we're going back trying to piece through

19   the old records.

20             DR. SEIBER:  The previous presenter showed county

21   use for those exact years, so in that regard the amount used

22   in those counties where these towns were located, that is

23   known.

24             But that's the best resolution you had in those

25   cases; is that correct?



 1             MR. FORMOLI:  Based on that information, more than

 2   50 percent of all DEF use was in Fresno County.  And the

 3   areas that it was monitored, that's the cotton growing areas

 4   in Fresno County.  So we believe that would be the worst

 5   case scenario for the use of DEF.

 6             While we also have another study, Kilgore study

 7   that I showed previously, that was conducted in Kern County,

 8   Kern County is another county of high use, but Fresno County

 9   is much -- has more than 50 percent of use, total use.

10             DR. BYUS:  You should put that in here, just those

11   statements.  I mean, if you -- just makes your case much

12   stronger.

13             MR. FORMOLI:  Very good.  I believe that is

14   included in the environmental fate section, but it would be

15   helpful to put it in the exposure assessment also.

16             As we see in the City of Fresno and Bakersfield,

17   the levels were mostly nondetect except for two days in

18   Bakersfield and four days in Fresno, City of Fresno.  And

19   that ranged from the 2.3 to 12 nanograms per cubic meter.

20             The levels in the cotton growing rural areas are

21   shown in that figure, and it basically shows that peak

22   concentrations are sometimes between mid-September to

23   mid-October.

24             And Five Points had the highest level of DEF.

25   Huron had the lowest level.  When we calculated exposure



 1   that I would show later that we use all four sides, but Five

 2   Points was used as the exposure of concern.

 3             Next, please.

 4             This is the same, basically the same sheet, except

 5   I showed that parts per trillion opposed to nanograms per

 6   cubic meters.

 7             So let's go to the next one.

 8             This is where we show how we calculated exposure

 9   to humans.  We divided humans in three subgroups.  We chose

10   children of six years old as the group with the highest

11   potential for exposure.  That is because they have the

12   highest rate of inhalation per unit of body weight as

13   compared to other children and adult.

14             And the other group is adult male and adult

15   female.  The grouping is because of the difference in the

16   inhalation rate.

17             We also divided the exposure into three types

18   also.  Acute exposure was shown as absorbed daily dosage,

19   seasonal exposure was shown as seasonal average daily

20   dosage, and annual exposure was shown as annual average

21   daily dosage.

22             The way we calculated the dosage or the acute

23   exposure, we used the 95th percentile of the concentration

24   of DEF in the ambient air.

25             For seasonal average daily dosage we used mean



 1   ambient air concentration during the entire season.

 2             And for the annual absorbed daily dosage, we used

 3   mean -- ambient air concentration over 60-day period in a

 4   year, or 365 days.

 5             Next, please.

 6             DR. FRIEDMAN:  That is the 60 days that the

 7   spraying took place, September and October?

 8             MR. FORMOLI:  Yes.  Based on the figure that I

 9   showed previously, it shows that most of the exposure,

10   actually most of the exposure occurs in September and

11   October.  And the graph pretty much shows that a good curve

12   within those two months.

13             Based on the Seiber et al study, the absorbed

14   daily dosage ranged from 94 nanograms per kilogram per day

15   for an adult female, to 304 nanogram per kilogram per day

16   for a child.  Seasonal average daily dosage ranged from 38.1

17   nanogram per kilogram per day for an adult female, to 123

18   nanogram per kilogram per day for a child.

19             And annual average daily dosage ranged from 6.3

20   nanogram per kilogram per day for adult female, to 20.2

21   nanogram per kilogram per day for a child.

22             That's at Five Points.  That's where the highest

23   levels of DEF was detected.

24             And Huron at the lowest levels of the exposure

25   shows lower for Huron.



 1             Next, please.

 2             Table 4 shows the estimate of the exposure based

 3   on Kilgore et al study, and again based on this study in

 4   rural Kern County the estimate of exposure was 16.29

 5   nanogram per kilogram per day for an adult female, to 52.2

 6   nanogram per kilogram per day for a child.

 7             Seasonal average daily dosage ranged from 7.1 to

 8   22.8.

 9             And annual average daily dosage ranged from 1.2 to

10   3.7 nanogram per kilogram per day.

11             Urban Bakersfield, the level of exposure is lower

12   than the rural Kern County.

13             I just would like to briefly talk about some

14   assumptions I made during this exposure assessment.  We

15   assumed that inhalation uptake in absorption would be 100

16   percent, and usually the outtake is less than 100 percent

17   for most of the chemicals, so we believe this is a

18   conservative assumption.

19             We also assumed that DEF indoor concentration

20   would be as much as outdoor concentration.  And since the

21   source of ambient air is outdoor, and people, most people,

22   spend most of their day or most of their day indoors,

23   actually 80 to 85 percent of the day people spend indoor,

24   that includes children, so we believe that's also a

25   conservative assumption.



 1             And the last meeting we had there was a concern

 2   about dermal exposure from the concentration in the ambient

 3   air.  There is no data to show that kind of exposure, but we

 4   believe that kind of exposure is, if there is any, would be

 5   minor.

 6             In addition to that, clothing can serve as a

 7   protective measure for that kind of exposure, just

 8   long-sleeve shirt and long pants could reduce exposure by 90

 9   percent.

10             And also skin can serve as another barrier for

11   absorbed dosage.

12             DR. FRIEDMAN:  May I ask a question about the ADD

13   and SADD?  Do I understand correctly that the ADD is just

14   the 95th percentile of exposure over the season, whereas the

15   SADD is the mean?

16             MR. FORMOLI:  Yes.  The ADD is based on the 95th

17   percentile of the concentration in the air, and the seasonal

18   exposure is based on average.

19             DR. FRIEDMAN:  But the 95th percentile for the

20   whole season?

21             MR. FORMOLI:  For the whole season, yes.

22             This document was reviewed by OEHHA, Office of

23   Environmental Health Hazard Assessment, and also by ARB.

24   OEHHA didn't have comments on this part of the document, the

25   exposure assessment part.  ARB's comments were minor and



 1   mostly editorial.

 2             We looked at the EPA's re-registration eligibility

 3   document for DEF also.  Basically, they do not believe that

 4   there is any residential risk from the use of DEF, because

 5   DEF is a restricted material and it's there is no use by

 6   residents.

 7             DR. SEIBER:  Okay.  We'll take questions now.

 8             Is this the end of the exposure part of the

 9   presentation?

10             MR. FORMOLI:  Yes.

11             DR. SEIBER:  So maybe a few questions, and then

12   we'll take our break after that so our court reporter can

13   rest her hands.

14             I guess as the lead person on exposure, and having

15   reviewed the documents and being somewhat familiar with

16   them, the only comment that I had was let's add in those

17   tables that were supplied later on.  I don't think they're

18   in the documents yet that show the use by month by county.

19   I think that was provided and we all had copies of that as

20   part of the correspondence.

21             MR. FORMOLI:  We should add it to the exposure

22   assessment document?

23             DR. SEIBER:  Either that or there's two documents,

24   one on chemistry and, I'm not sure where the appropriate

25   place is, but it ought to be in there somewhere.



 1             DR. GLANTZ:  I would think it should go in the

 2   exposure document.

 3             DR. SEIBER:  Any other questions or comments on

 4   the exposure?

 5             DR. BYUS:  When do we talk about the n-butyl

 6   mercaptan?  Is that in the next section?

 7             MR. GOSSELIN:  Next section we'll talk about

 8   toxicology and risk assessment, so it actually pieces a lot

 9   of it all together.

10             DR. BYUS:  I don't know whether -- the documents

11   have some n-butyl mercaptan data here.  You have some in the

12   next, in the environmental fate section, some in exposure

13   section.  You have some pseudo epidemiology health effects

14   in the exposure assessment document.  I mean, it's just a

15   little bit --

16             DR. SEIBER:  Right.  There is some n-butyl

17   mercaptan data in the exposure section, but you want to hold

18   that over for the next part?  Is that okay?  We'll wait

19   until we --

20             DR. BYUS:  That's fine.  I was just asking where

21   we were going to discuss that.

22             DR. GLANTZ:  Yeah.  Just picking up on this, this

23   isn't real substantive, but I was a little surprised to find

24   some of the health effects stuff in the exposure document.

25   And I think unless there's a reason for it, which I'm open



 1   to hear, but if there's no specific reason, I think it would

 2   be better if you consolidated all the health effects stuff

 3   in one place.  It's easier for people like me.

 4             DR. SEIBER:  Okay.

 5             DR. GLANTZ:  I had one procedural question and

 6   that was were these documents sent out for public comment

 7   the way the other ones are?  The only comment we got back

 8   was the one from the manufacturer.

 9             MR. GOSSELIN:  Right.  We did solicit public

10   comments approximately a year ago.  It was around the same

11   time we made the presentation to you.  We had a public

12   workshop, I believe it was in November of '97.  And, you

13   know, we might hopefully get more interest as we have other

14   workshops.  We have methyl parathion coming up next week, a

15   public workshop and announce that it's open for public

16   comment.

17             DR. GLANTZ:  Okay.  But the question was, this

18   document, I mean normally when documents come to us at this

19   stage there's a public comment period right before they come

20   to us.  Did you do that?

21             MR. GOSSELIN:  Well we had hoped that that public

22   comment period a year ago was going to be right before we

23   brought it to you, but here we are a year later, so.

24             DR. GLANTZ:  Is the document that you've sent out

25   for comment then substantially the same as the one that



 1   we're looking at now?

 2             MR. GOSSELIN:  Except when I introduced it there

 3   were some issues looking at some new literature.  You had

 4   some comments, the panel had some comments a year ago.  We

 5   had some supplemental comments also.  And also we took a

 6   look at US EPA's draft risk assessment that had come out

 7   about four or six weeks ago.  And most of those new issues,

 8   new from the last meeting, are going to be presented in the

 9   next presentation.

10             DR. GLANTZ:  Okay.  Well, I think, I mean as

11   someone who has nagged DPR for a long time to move the

12   process along, I don't want to slow this one down, but I

13   think as we move into processing these other chemicals, I

14   think you ought to have a public comment period immediately

15   approximate to when it comes to the panel, because that's

16   when people usually are paying more attention.

17             And I think the public -- I always find the public

18   comments very helpful and I think it would be good to let

19   the public see the same documents which are being provided

20   to the panel for a couple, it's usually only a couple of

21   weeks.  And that the comment period would close a couple of

22   weeks before the meeting, so that we wouldn't have the usual

23   forwarding faxes the night before.  I'm a slow reader.

24             MR. GOSSELIN:  Methyl parathion is going to kind

25   of follow exactly that kind of scheme because we're going to



 1   close the comment period next week, and then we're scheduled

 2   to come in November 11.  So that would really -- we're

 3   nervous about that tight time frame, but it will make it

 4   more timely, as now we actually start to have the process

 5   start to go.  Exactly that's our intent also.

 6             DR. GLANTZ:  As I understood, you said you're

 7   having a workshop on parathion.

 8             MR. GOSSELIN:  We're having both.  We've announced

 9   that it's open for public comment and open period.  There

10   was -- we did mailers and people had sort of put themselves

11   on a list to get these documents as they were ready.  So we

12   have a mailing list already set for public comments.

13             And then we wanted to have sort of a presentation

14   for the public to come in and voice their comments also.

15             DR. GLANTZ:  Okay.  It's just I -- again, I don't

16   want to slow the process down, but I'm very interested in

17   seeing what people have to say about the document that's put

18   before us.  I mean, if there's minor changes or a little bit

19   of added literature or something, that's not worth going

20   back out, but I think it's important that the public get to

21   see the report, which is substantively -- I mean what's

22   coming to us.  I mean, as I understand it, may be George can

23   correct.

24             George, don't go away.  You can correct me if I'm

25   wrong.



 1             I think what would happen is the documents would

 2   come to us and go out for public comment, but you would

 3   provide -- you might revise the document in accordance with

 4   the comment before the final when it came to us, right?

 5   Isn't that how the ARB documents work?

 6             And then we would get the document with the

 7   comments and the list of the changes it had made.

 8             DR. ALEXEEFF:  This is George Alexeeff, with

 9   OEHHA.

10             With the toxic air contaminant documents there

11   were usually several comment periods.

12             DR. GLANTZ:  I'm talking about the last comment

13   period.

14             DR. ALEXEEFF:  In the last one, what would happen

15   is actually in the statute, and I'm not sure if it governs

16   this part of the pesticide portion of it, but there is a

17   timed release as to when it is sent to the SRP and when you

18   have to deliberate on it.  So there is a comment period when

19   we sent it out to the SRP, but there's really not enough

20   time within that mandatory time frame to actually usually

21   revise the document.

22             DR. GLANTZ:  Right.  But --

23             DR. ALEXEEFF:  Usually just at that last one we

24   come with the document, the final comments and we orally

25   provide testimony explaining --



 1             DR. GLANTZ:  Well, then I'm talking about the one

 2   before that.

 3             DR. ALEXEEFF:  The one before that.

 4             DR. GLANTZ:  How does the one before that --

 5             DR. ALEXEEFF:  The one before that works by there

 6   are public comments and we review the public comments and we

 7   respond to them, summarize them and respond to them in a

 8   document.  And then that part is part of the report we sent

 9   to you.  So really what happens right before the SRP meeting

10   there is kind of an option or a chance for the public to

11   rebut the way we've responded to their comments.

12             DR. GLANTZ:  Okay.  Well, I think that's a good

13   process, and I would hope that as this thing gets rolling

14   you model it on that.  It's sounds like you're pretty close.

15             MR. GOSSELIN:  We're trying.

16             DR. GLANTZ:  Again, I don't want to get into

17   recursive comments, so that we end up going on forever, but

18   I think it is troubling to me that the public comment period

19   on this document was a year ago.

20             DR. SEIBER:  Okay.  Good comment.

21             Shall we take about a 15-minute break.  Let's try

22   to make it 10, knowing that it will be 15.

23             (Thereupon a short recess was taken.)

24             DR. SEIBER:  We'd like to go ahead and get

25   started, so, Paul, do you want to continue with the



 1   presentation?

 2             MR. GOSSELIN:  Next presentation will be given by

 3   Carolyn Lewis.

 4             MS. LEWIS:  Rather than give another overview of

 5   my document, I decided to go through Part C and discuss the

 6   changes that were made in response to the SRP and OEHHA


 8             I should insert here that the document that you

 9   saw had these changes already incorporated into it and there

10   hasn't been any significant changes based on the public


12             Changes to the executive and technical summaries

13   will not be discussed because these merely reflect changes

14   in the main body of the report.

15             In addition, I will not discuss minor changes to

16   the document that were made due to changes made to the other

17   risk assessment I am working on for DEF, addressing worker

18   and dietary exposure.  These changes are mainly information

19   added for clarity.

20             In the acute toxicity section, based on a comment

21   from the SRP, additional information was added regarding

22   particle size to an acceptable inhalation LC 50 study for

23   DEF, technical grade DEF.

24             In addition, an explanation was added as to why

25   the acute studies for the formulations were not used for an



 1   acute NOEL.  The formulation as tested is not how the

 2   general public would be exposed to DEF.  For one, it's

 3   diluted at least 15-fold in water before it's applied and,

 4   two, the inert ingredient in DEF is a solvent which probably

 5   dissipates before DEF reaches the general public.  These

 6   changes were made in response to a comment from OEHHA.

 7             In the subchronic toxicity section, additional

 8   particle size information was added to two inhalation

 9   studies.

10             In addition, acute effects were identified in

11   these two inhalation studies and in a dermal toxicity study.

12             Acute NOELs were identified based on these acute

13   effects.

14             And in the 90-day study the acute NOEL was

15   selected for the critical acute NOEL in the final risk

16   calculation.

17             And because of this, I added a table to this

18   section showing the incidence of the effects in the study.

19             In the chronic toxicity section I elaborated my

20   explanation on why the slight brain cholinesterase

21   inhibition in males at the lowest dose in the mouse

22   oncogenicity study were not considered toxicologically

23   significant.

24             One, the brain cholinesterase inhibition was less

25   than ten percent, and there were no signs.



 1             When the dose was increased fivefold, there was

 2   still only a slight increase in brain cholinesterase

 3   inhibition to 13 percent, and still no signs.

 4             With a 25-fold increase in dose, the brain

 5   cholinesterase inhibition increased to 38 percent.  However,

 6   only mild cholinergic signs were seen.  This included

 7   perineal staining and loose stools.

 8             That comment was a change based on the previous

 9   comment from OEHHA.

10             In the oncogenicity section OEHHA had questioned

11   the discussion of possible threshold mechanisms for

12   oncogenicity with DEF because there was a lack of supporting

13   data.

14             And because this was speculative, I moved this

15   discussion from this section, and also from the hazard

16   identification section, and limited it to the risk appraisal

17   section, which discusses the uncertainties in the risk

18   assessment.

19             The SRP had questioned why the parenteral NOEL

20   from the reproductive toxicity study was not used for the

21   subchronic NOEL.  So I reexamined the data to try to

22   understand the sex-related differences in this study that

23   were not seen in others.

24             I discovered that the females consumed nearly

25   twice as much DEF during lactation as compared to gestation



 1   and the premating period, and this was right before they

 2   were sacrificed, and possibly contributed to the

 3   significantly greater brain cholinesterase inhibition that

 4   was seen in the females.

 5             Previously I had expressed the compound intake as

 6   the average for both sexes during premating, since there did

 7   not appear to be any sex-related difference in intake at

 8   that time.  However, I've changed that and the compound

 9   intake is now expressed as the time weighted average for

10   each sex.

11             Also I have added to the section a discussion of

12   blood cholinesterase inhibition data that was taken during

13   the premating period, which showed that the sex-related

14   differences were more pronounced after lactation.

15             The neurotoxicities is probably the more

16   controversial part of this document, and it would have been

17   easier for me if I had used the NOEL from the Abou-Donia

18   study to evaluate seasonal exposure to DEF, because of the

19   comments from both the SRP and OEHHA.

20             However, I feel very strongly that this is not the

21   most appropriate study to use for this route of exposure,

22   and so I didn't change it.

23             Instead, I have elaborated my discussion of this

24   study in this section and in the hazard identification

25   section to help clarify why it was not used.  And I decided



 1   to present some of the data from the study today to make

 2   this point clear.

 3             I have summarized the incidence of the

 4   histological lesions in the spinal cord and peripheral

 5   nerve, since histology is critical in verifying the presence

 6   of OPIDN, or delayed neuropathy.

 7             In the Abou-Donia study, he exposed hens by either

 8   the oral or dermal route.

 9             With oral exposure, five hens per dose were

10   administered DEF at doses ranging from .1 to 80 milligrams

11   per kilogram day.  And you'll notice on this table there is

12   no data for the lowest, .1, or the controls, and this is

13   because Abou-Donia did not include this in his report.

14             With dermal exposure three hens her dose were

15   administered DEF at only 20 and 40 milligrams per kilogram

16   day.

17             If you compare the responses with oral and dermal

18   exposure at 40 milligrams per kilogram day, you can see that

19   no hens given DEF orally developed unequivocal lesions of

20   OPIDN, and only one had an equivocal lesion.

21             However, with dermal exposure, all three hens

22   developed unequivocal lesions for OPIDN.

23             The equivocal lesions were ones that Abou-Donia

24   suggested were early signs of delayed neuropathy, but

25   because they occasionally were observed in controls, he



 1   could not be certain.

 2             If you look at the incidence of the equivocal

 3   lesions with oral exposure, you can see that there is no

 4   dose response relationship in the incidence, and more likely

 5   these lesions are age related because the birds in the study

 6   were relatively old.

 7             DR. WITSCHI:  Can I ask you a question?

 8             MS. LEWIS:  Yes.

 9             DR. WITSCHI:  Do you know who did the

10   neuropathologic --

11             MS. LEWIS:  I can't say off the top of my head.

12             DR. WITSCHI:  Because Abou-Donia is not a

13   neuropathologist.

14             MS. LEWIS:  Yeah.  Yeah.

15             At 20 to 80 milligrams per kilogram day, hens

16   developed severe ataxia, some became paralyzed, and all but

17   one died from what Abou-Donia described at late acute

18   effects within the first few weeks of exposure.

19             Abou-Donia suggested that more histological

20   lesions would be seen if the animals had lived longer.

21   However, it stands to reason that if there was enough

22   n-butyl mercaptan formed to kill these hens, there would be

23   significantly less DEF available to produce delayed

24   neuropathy.

25             Because of the lack of the histological lesions of



 1   delayed neuropathy, I suspect that n-butyl mercaptan was

 2   responsible for the severe ataxia and paralysis at the high

 3   doses.

 4             Abou-Donia and others have reported that n-butyl

 5   mercaptan causes muscle weakness and CNS depression and

 6   cyanosis, which can all affect gait.

 7             And if you have any more questions about the

 8   findings in the studies, I have made copies of the table in

 9   Abou-Donia's report, which gives a little more detail about

10   the incidence of ataxia of DEF and histological lesions, and

11   I can pass these out later.

12             DR. SEIBER:  Please pass them around.

13             Will that information be in the final version of

14   the DEF report or is this for our information?

15             MS. LEWIS:  This is for your information.  I was

16   not planning on it.  I could include the table I have here

17   if that would help.

18             DR. SEIBER:  At this point I think we should open

19   this up for comment.

20             Dr. Witschi was our health effects lead on the DEF

21   document, so he may have some comments, and as well as the

22   other panelists.

23             MS. LEWIS:  Could I just maybe summarize the

24   deficiencies that the study reported?

25             DR. SEIBER:  Oh, sure.  I'm sorry.



 1             MS. LEWIS:  To summarize, there are a number of

 2   scientific deficiencies that I see with the Abou-Donia

 3   study.

 4             Foremost, the limited histological evidence of

 5   delayed neuropathy with oral exposure, even at the high

 6   doses.

 7             There's no incidence data provided for the hens at

 8   the lowest oral dose or with controls, making interpretation

 9   of the findings, especially the equivocal ones, difficult.

10             The birds were relatively old, which increases the

11   incidence of age-related lesions, again confounding the

12   interpretations of findings.

13             No NOEL was established with dermal exposure.

14             The size of the treatment groups was small,

15   especially with dermal exposure where only three hens were

16   tested per dose.

17             NTE activity was not analyzed in this study, which

18   would have helped in interpreting the cause of ataxia,

19   especially at the lower dose levels.

20             Cholinesterase activity was also not measured,

21   which would have helped in determining how much of the DEF

22   was reaching target tissues.

23             I don't know if Dr. Witschi wants to say anything

24   about it.

25             DR. WITSCHI:  No.  I trust the authorities was in



 1   the pathology.

 2             Not with regard to this study for the moment, but

 3   we talked about this already last week, and you set the NOEL

 4   from a Root study.  Also Root I know very well, so it's a

 5   well-done study.

 6             But we talked about this, you said NOEL according

 7   to a level which produced significant inhibition of plasma

 8   and red blood cell cholinesterase activity.

 9             MS. LEWIS:  That's correct.

10             DR. WITSCHI:  To some of us, certainly to me, this

11   would look like not certainly a marker of exposure, but I

12   would like to learn a bit more what this shouldn't or

13   wouldn't be considered in adverse health effect.  I think

14   this is really something -- you know, if this was a DNA

15   carcinogen, I wouldn't raise my hands.

16             MS. LEWIS:  I was hoping that we might be able to

17   discuss that further at the workshop or some other time,

18   because I think that's a discussion that could take a day,

19   if you wanted.  EPA has spent some time wrestling with this

20   issue and it affects a lot more risk assessments than this

21   particular one.

22             I can say quickly, though, that there is no known

23   physiological function for blood cholinesterase and so then

24   the significance of its inhibition is uncertain, and it has

25   been DPR's policy because of that not to consider it an



 1   adverse effect in itself when there are no accompanying

 2   cholinergic signs.

 3             DR. WITSCHI:  Isn't that blood cholinesterase

 4   something that's being measured in workers and if it's slow

 5   the flags go up?

 6             MS. LEWIS:  It's because we can't monitor

 7   cholinesterase in neurological tissues.  It's unethical.  So

 8   we use the blood as a way to indicate that they're getting

 9   too much exposure.  It's not that it's necessarily --

10             DR. WITSCHI:  I understand.

11             But my point is, as far as I know in program of

12   pesticide workers, you look at blood cholinesterase.

13             MS. LEWIS:  That's correct.

14             DR. WITSCHI:  And based on the results of this

15   test you move up certain restrictions and these kind of

16   things.  If you do this in people, why don't we look in the

17   animals as this being of no consequence?

18             MR. GOSSELIN:  If part of that, and maybe if I

19   don't get all the points, I'll defer to John Ross, but that

20   program to monitor workers was put in many years ago and

21   part of it has really been valuable to make sure that

22   workers are not exposed to unsafe levels and it is really a

23   safety net for workers exposed to cholinesterase in avoiding

24   pesticides.

25             What we're looking at here, and this predates the



 1   types of full scientific vigorous risk assessments that

 2   we're facing right now, so it does point to some of the

 3   evolution on trying to ensure that we have adequate margins

 4   of safety.

 5             John, I don't know if you have any other

 6   perspective on worker monitoring.

 7             DR. JOHN ROSS:  John Ross, Department of Pesticide

 8   Regulation.

 9             We have historically used blood cholinesterase

10   plasma, as well as RBC, as an indicator of exposure for

11   worker populations and as a marker for withdrawal from

12   exposure in the event that they hit certain triggers.  We

13   have not used it as an indicator of adverse effect.

14             MR. GOSSELIN:  And maybe to look at the other side

15   is that we wouldn't, and this had come up on azinphosmethyl,

16   which is a risk assessment we recently completed, we don't

17   use, let's say the negative findings from workers and not

18   having problems as a demonstration of an acceptable safety

19   level.

20             So because we're looking at -- because even worker

21   exposures in the absence of depressed cholinesterases is not

22   for us not an indication of safety.

23             And I don't know if that kind of puts it into

24   context, but on the other side if you do have high incidence

25   or significant incidence of cholinesterase inhibition in



 1   humans, that's going to far exceed any of the margins of

 2   safety that we would have in a completed risk assessment,

 3   because by and large those levels and that sort of

 4   monitoring predates having risk assessments in place.

 5             DR. GLANTZ:  Yeah.  But this was something I

 6   got -- this is very enlightening to me, because I got

 7   confused by this when I was reading it, because I thought

 8   the NOEL was at the level that you couldn't find anything

 9   happening.  And so I mean so you said, okay, we couldn't

10   find anything happening, and so let's go low, then we'll put

11   a margin of safety in to make up for the level of ignorance

12   we all have.

13             And it bothered me a little bit that you're

14   calling something a NOEL when you're actually finding

15   physiological effects.

16             MS. LEWIS:  Actually, the way we use NOEL is

17   N-O-A-E-L.  It's no adverse effect level.

18             DR. GLANTZ:  I know, but this gets into this sort

19   of never-never land of DPR where -- I remember we had a

20   meeting where we spent an hour finding out that you didn't

21   use drift to mean the way normal people do.

22             And I mean I think that I agree with you that

23   there is some broader policy issues that would be worth

24   including in the workshop.  The way this panel has always

25   worked is to deal with these sort of as they come up in the



 1   context of documents.

 2             I mean, I think that you should be using NOEL the

 3   way everybody else uses it, which is no observed effect.  If

 4   you want to say in your risk management that, well, these

 5   effects that were observed are not adverse effects and

 6   therefore we're going to set our risk management levels

 7   higher, then you might base that on a no observed defect

 8   level.  That's the regulator's problem.

 9             But I really think to be consistent with the other

10   stuff that this panel has approved, we should use NOEL the

11   way we've used it in the past.

12             Now, if you want to make other regulatory

13   decisions, that's not our concern, but I think that the

14   NOELs that is used in these documents should be the same as

15   the way it's been used in everything else we've done.

16             Is that sort of the point you were making, because

17   I got all confused when I was reading that part of the

18   document.

19             DR. WITSCHI:  Well, there are two things.

20             The one is really what you said by attributing

21   something that we understand different.

22             The other thing, the whole thing is to some

23   trivial, because probably if you go to the next lower dose,

24   or even two down, in Calhoun study, you would change your

25   conclusion by a factor of two or three at the most.  So it's



 1   we're talking about trivial things, accept I would agree

 2   with Stan not sticking generally accepted definitions.

 3             The other one, the real question is I really would

 4   like to get some education why this doesn't mean anything as

 5   far as human health is concerned.  I'm ignorant about

 6   pesticide.  One of my oldest friends --

 7             DR. SEIBER:  Let's ask Dr. Lewis or some of the

 8   others that are present what is EPA's position on

 9   cholinesterase depression and whether it's a --

10             MS. LEWIS:  They consider blood cholinesterase

11   inhibition as a regulatory end point.  However, they don't

12   consider it adverse effect in itself.

13             What they use it for is a surrogate for peripheral

14   cholinesterase inhibition data when it's not available,

15   which it generally isn't.

16             DR. KENNEDY:  Question.  Has there been any

17   investigation into the behavior and the survivability of red

18   cells in these systems?  Because cholinesterase deficiencies

19   do appear in hemoglobin area, and it's there are a couple of

20   defects there, but it does represent an occasionally a

21   significant clinical addition.  And it would be interesting

22   to know whether the system there's any sort of correlation

23   between survival or activation or some other biochemical

24   phenomenon.

25             MS. LEWIS:  I know there are individuals out there



 1   that are genetically deficient in plasma cholinesterase, and

 2   I can't recall in those, in the studies, if they have done

 3   any where they have shown increased susceptibility to

 4   cholinesterase inhibitors.

 5             DR. WITSCHI:  Oh, yes.  There is a famous example,

 6   which happened in 1956 or so in Switzerland when the king of

 7   Morocco underwent a trivial operation and died because he

 8   was deficient in cholinesterase and couldn't recover from

 9   the anesthesia.

10             DR. BYUS:  I take issue with there's physiological

11   function with plasma cholinesterase.  I believe that is

12   involved in drug metabolism, and even though this is major

13   area, it is involved in metabolism of a number of drugs like

14   succinylcholine which is used during anesthesia as a muscle

15   relaxer.  So if you have an impaired serum cholinesterase,

16   it's very important to calculate in drug doses, and this is

17   probably why -- causes prolonged apnea during an operation

18   and the genetic deficiency is at the level of the KM of the

19   enzymes for succinylcholine.

20             DR. WITSCHI:  That's why the king died.

21             DR. BYUS:  That's why the king died.

22             So it makes no sense for you to say there's no

23   physiological function in the sense that if someone with

24   a -- now, I can be wrong in this, and I'll be the first to

25   admit it if I am -- but if someone has a depressed



 1   cholinesterase, serum cholinesterase level, it could affect

 2   their ability to metabolize succinylcholine and a number of

 3   other drugs, including at the least cocaine.  But my

 4   colleague was out of town when I read this, and I couldn't

 5   check with him.

 6             DR. GLANTZ:  One of your colleagues is a coke

 7   head?

 8             DR. BYUS:  He is a pharmacologist that deals with

 9   this.

10             So I mean this is an important point, and I said

11   this workshop should address that.

12             As a pharmacologist also, and even as far as

13   pharmacokinetics here, if you're using the serum level as a

14   surrogate of the actual level of DEF or the drug that's in

15   the body, it's got to be indicative of a certain level that

16   is present, and it's also a surrogate of the brain

17   inhibition.  I mean there may be a relationship.  Is

18   there --

19             MS. LEWIS:  We have done some review of the data

20   that we have in house.  In fact I was involved in that

21   project.  And what made us come to the conclusion partly to

22   not use the blood cholinesterase inhibition was there was no

23   consistent relationship between the blood and the brain

24   cholinesterase inhibition, that with some chemicals the

25   plasma would be more sensitive, with others the red blood



 1   cell would be more sensitive.  I had one I'm looking at

 2   where they saw brain cholinesterase inhibition before either

 3   blood or red blood cells.  Then it makes interpretation of

 4   its inhibition --

 5             DR. BYUS:  Not necessarily.  I can understand that

 6   if they had -- there's two different enzymes and they have

 7   different affinities for all these --

 8             MS. LEWIS:  Yeah.

 9             DR. BYUS:  It's perfectly reasonable that if you

10   go between analogs or between chemicals that the brain

11   enzyme might have a greater or less affinity for one than

12   another one, but within a single compound, within a single

13   compound there should be a correlation and it should be

14   reasonable.

15             MS. LEWIS:  Even within one compound, and maybe it

16   had to do with the time the blood was collected, and in

17   relationship to the brain, but -- and it may have been a

18   difference in species sensitivities too.

19             DR. BYUS:  See, it says, for example, you say, in

20   general, DPR does not consider plasma erythrocyte

21   cholinesterase inhibition signs or symptoms as adverse

22   effect, because the cholinesterase is in the blood and no

23   known physiological function.

24             And I think that is really, seems to me to be a

25   much more definitive statement that is perhaps --



 1             MR. GOSSELIN:  There's more to that than that

 2   statement.  And I think as Carolyn described --

 3             DR. BYUS:  Plus when you fold on top of that the

 4   fact that you tell people to not be exposed, to minimize

 5   their exposure to the chemical if they have a decreased

 6   serum cholinesterase, it doesn't make any sense to me.  So

 7   that --

 8             MR. GOSSELIN:  Again, that was put in place years

 9   before there was any sort of rigorous scientific program.

10             DR. BYUS:  You would say you would let people

11   continue to be exposed?

12             MR. GOSSELIN:  Absolutely not.  If the

13   cholinesterase is being depressed -- I mean, that program

14   was put in place to pull people out of fields and

15   situations.

16             Conversely when we come up with a risk assessment

17   even using brain cholinesterase inhibition, there are case

18   after case of people who are monitored using the materials

19   that don't show any cholinesterase inhibition which we're

20   expecting, and but because of the risk assessment we have,

21   we put in some fairly stringent restrictions and it does --

22   people, some people are viewing that like doesn't this

23   monitoring show that there isn't any risk.

24             So on the other side, it's not a risk assessment

25   tool per se.  It was a fail safe to make sure that workers



 1   weren't exposed to really high levels.

 2             DR. BYUS:  In this case.

 3             MR. GOSSELIN:  Our choice of end points is I think

 4   one of the big terms is generally.  I know that the staff

 5   toxicologists have spent a lot of time going over a lot of

 6   studies and the details of this to kind of come to some

 7   consistent position on how to choose the end points.  And by

 8   and large it comes down to each compound and sort of the

 9   weight of evidence on what all the data shows on how that

10   compound acts and what the appropriate NOEL is, not to

11   totally disregard plasma cholinesterase inhibition, but how

12   does that plasma cholinesterase inhibition fit into the

13   logic context of what other adverse effects are seen in all

14   the studies.

15             DR. GLANTZ:  Yeah.  But, see, I think that gets

16   back to this issue of the idea of a NOEL is no observed

17   effect level, because there's all these issues that you're

18   raising and all of these gaps in our knowledge and the

19   problems of what do you measure where and different species

20   and this and that.  And at least my understanding of the

21   idea of the NOEL is to say, look, if you look at everything

22   you can think of and you don't find any effect anywhere,

23   then probably you're okay.

24             And I think that for the reasons that you

25   specified, this idea of picking one end point and saying



 1   that's the end point, is silly, because it -- because of all

 2   the things we don't know, which you guys have just been

 3   talking about.

 4             MR. GOSSELIN:  And I think a lot of this

 5   discussion is going -- we could probably spend, and I'm

 6   hoping a lot of time talking about it, but the reason why we

 7   end up choosing an end point and sort of using that with

 8   what exposure data we have, not just ambient, but worker and

 9   everything else, is because they result, or potentially

10   result in some real life restrictions at the place.  So we

11   need to --

12             DR. GLANTZ:  Right.  But you're talking about

13   regulatory issues, and we're talking about what the reports

14   would say and you guys know more about this than I do, but

15   my sense is what the committee is saying to you is we want

16   you to use NOEL the way everybody else does and come up with

17   a NOEL which makes sense, and then what you do with that in

18   terms of regulatory arguments later, if you want to say,

19   well, the SRP was being too prissy and we're going to use

20   some other end point, then you can go fight with the people

21   that don't like that.

22             But I think in terms of the report that we're

23   going to approve, NOEL should be NOEL and you could have a

24   discussion of these other issues if you want, but the NOEL

25   should be a place at which there is no observed effect,



 1   period.

 2             And, I mean, you guys know more about this than I

 3   do, so if you don't agree with me, then change this.

 4             The other thing that I found, this is more in the

 5   nature of an editorial comment, I think, is that you had a

 6   whole bunch of different NOELs for different end points, and

 7   I think the report would be a lot easier to understand if

 8   that stuff was at least consolidated, but maybe even

 9   summarized in a table with the different end points that you

10   were looking at, and then whatever the smallest of those

11   numbers are where you are finding no effect, that becomes

12   the NOEL which we would put forward in the findings.

13             Because I think it's very -- at least to me, was

14   very confusing to have all of these different numbers

15   floating around without them at least being put in some kind

16   of comparative concept.

17             That's more of a kind of editorial comment of the

18   way it's presented, rather than the substantive comment.

19   The substantive comment is NOEL should be NOEL, period.

20             The other thing is when you go through all these

21   different end points, which I think is useful, it could be

22   presented another way.

23             MR. GOSSELIN:  I think as we talked earlier about

24   the definition of ambient, you're probably going to see also

25   as our documents come forward they're going to have somewhat



 1   of an evolution on presentation and content.

 2             DR. GLANTZ:  Right.

 3             MR. GOSSELIN:  And everything else.

 4             DR. GLANTZ:  But what I'm saying is this document

 5   needs to evolve before it's approved.

 6             MR. GOSSELIN:  Well, one thing to also, and I

 7   think we're hearing what you are used to seeing and sort of

 8   the eyes you're viewing it as, what we're doing historically

 9   is these documents have been written principally for

10   regulatory purposes to actually help be the foundation for

11   us to regulate pesticides.

12             DR. GLANTZ:  That's true.

13             MR. GOSSELIN:  That's probably why some of it is

14   written in a different format.  I think over time we're

15   going to get probably in a little better comfort zone on

16   sort of how we've been living in our world and how we can

17   have these documents meet your needs.

18             DR. GLANTZ:  Yeah.  The other thing, just as a --

19   I don't want to get off the subject, but I think the issue

20   about ambient and what somebody said that it's sort of what

21   you're talking about making more of a hot spot, it may be

22   that you should just use that terminology.  I mean, again

23   I'll defer to the atmospheric tempest and the exposure guys,

24   but that was another thing I was confused by in reading the

25   document, because to me ambient means sort of out there,



 1   breathed by the general public.

 2             And then what I thought you might mean, and even

 3   based on earlier discussion, which I missed a little bit of,

 4   but it could mean ambient in Fresno.  And if that's what --

 5   which would be okay, you know.  But I think that should be

 6   clear that this is the ambient level, meaning the level --

 7   to me ambient means the level that the general populous is

 8   exposed to.

 9             And if, I mean, it would make sense to me to talk

10   about ambient level in Fresno or in Kern County or in sort

11   of a broader region rather than sitting -- because to me hot

12   spot means sitting next door to where it's happening.

13             But I think you need -- and I don't want to derail

14   the current discussion, but I think that's something you

15   need to think about to again to try to use the terminology

16   as consistently as other people, but as we have in the past,

17   but it may be because of the difference between pesticides

18   and say pollution coming out of the back end of an

19   automobile, which is spread out all over the place, you

20   might just say by ambient we mean ambient in this county or

21   something like that.

22             Getting back to the other thing, I think these

23   issues -- and we went through all this with OEHHA years ago.

24   I think the issues which are being brought up by the panel

25   do need to be fixed in this document, even though there are



 1   general issues that will be discussed at the workshop.

 2             DR. SEIBER:  It's a good comment.  The ambient

 3   terminology, I think, was adopted when the pesticide

 4   monitoring program was first started 15 years ago without

 5   really much strict definition, and it was to differentiate

 6   what people who weren't involved in spraying might be

 7   exposed to as opposed to an application where your monitor

 8   is right downwind.  So it probably doesn't synchronize

 9   perhaps with the more general ARB terminology.  I don't

10   know.  This is my suspicion.

11             And, you know, Tranquility has got a few hundred

12   people in it and Fresno has got several hundred thousand.

13   Where do you draw the line?  I don't think any of that was

14   thought out.

15             DR. GLANTZ:  I'm not arguing with what you did.  I

16   think what you did, subject to the comments that were made

17   earlier, is reasonable.  I'm just thinking about making sure

18   that it's presented in a way where people don't get

19   confused.

20             DR. SEIBER:  You just want to define your terms

21   and say what they are and what you mean by it.

22             MR. GOSSELIN:  DEF in particular is going to be

23   kind of a unique case, because it is such a narrow window

24   and such a small locale.

25             We are maybe conservatively looking at that term



 1   hot spot, if you will, as the statewide ambient exposure

 2   scenario, which is a conservative view, but that's what that

 3   actually leaves us with.

 4             The other materials, as they come up, because

 5   you're going to see smattering of uses on again and off

 6   again through the year and around the state, that we are

 7   able to do more complicated characterizations of ambient.

 8             DR. GLANTZ:  I don't want -- we should get back to

 9   the toxicology issue.

10             DR. SEIBER:  Let me ask a question as a

11   non-toxicologist here.

12             Dr. Lewis, maybe you can give us some perspective.

13             How much of this discussion about cholinesterase

14   inhibition and whether it's a point at which you should take

15   off as for your risk assessment, how much difference would

16   it make in let's say your margin of exposure calculation if

17   you had used that as opposed to what you did use?  Is this a

18   big deal or is it a small --

19             MS. LEWIS:  It really depends on the individual

20   study and the spacing of the dose groups and the definitive

21   study that it was used for acute and seasonal exposure,

22   there is about a threefold difference between the NOEL for

23   blood cholinesterase inhibition and the NOEL for the other

24   effects that we're seeing.

25             DR. SEIBER:  Threefold?



 1             MS. LEWIS:  Threefold lower.

 2             This would then obviously reduce the margin of

 3   exposure threefold.

 4             However, the lowest acute margin of exposure was

 5   greater than 9,000.  So they would still be greater than

 6   3,000.

 7             DR. SEIBER:  That tells me it wouldn't matter if

 8   your bottom line --

 9             MS. LEWIS:  No.  It wouldn't change the bottom

10   line.

11             DR. SEIBER:  We're talking about a scientific

12   issue and consistency, which I agree with, and we always

13   want to be on the conservative side always, but still even

14   with all that, you're saying that it wouldn't affect.  I

15   think that's kind of important.

16             DR. GLANTZ:  But to me that's a reason to do the

17   things we are talking about, because I think one of the

18   things we're doing with this document is sort of

19   establishing how these things are going to be done.  And the

20   fact it's probably not going to make any difference in terms

21   of risk management isn't really at issue here and in a way

22   makes it easier.

23             MR. GOSSELIN:  As a toxic air contaminant and even

24   the chronic issues too, we'll talk about, but for this piece

25   that you have before you is piece of a larger risk



 1   assessment that involves also characterizing worker and

 2   occupational exposures, which are going to be much greater

 3   than this ambient exposure level.

 4             So because we've tried to integrate our risk

 5   assessment process into one process for efficiency, the

 6   choice of the NOEL will have some significance, regulatory

 7   significance.

 8             But one thing, and even the choice whether we use

 9   brain or plasma, they were going to be significant issues as

10   we complete the risk assessment.

11             The question may be coming back for the document

12   is have we -- does the document describe the range of toxic

13   end points clearly enough and is that a way to kind of get

14   at some of the sort of the full scientific consideration

15   that you need to consider in this document.

16             DR. KENNEDY:  I would like to see and hear, I

17   think it was just suggested, that part of the workshop look

18   at this whole issue of cholinesterase inhibition and the

19   tissue specific significance.

20             I think you tried to address that, but there are

21   holes, and we need to be clearer about the things we don't

22   know and where the correlations don't exist.  I think

23   clarifying that will implicitly and explicitly help to deal

24   with this plan.  And I'm less concerned with terminology

25   than I am with our defining what our knowledge is or isn't.



 1             DR. FUCALORO:  As a non-specialist I redo a lot of

 2   the calculations that you do, because I feel I have to most

 3   often in those areas.  I tend to look at -- I tend to look

 4   at the highest exposures and the most conservative NOELs and

 5   cancer potency factors, and so I get a feeling that this is

 6   a problem or not a problem.  So I've got to feel that the

 7   numbers I'm getting, like NOELs, are reliable and I mean

 8   there's a standard usage, no observed effect is clearly not

 9   the NOEL you meant.  I guess I'm restating what everyone

10   else has stated.

11             So as someone who can contribute, I think, to this

12   whole process, but in certain areas I really have to feel

13   comfortable with numbers or the results I'm getting from

14   other areas, which these gentlemen are more expert in.

15             I was misled in a sense.  I'm telling you honestly

16   I was misled by that and hearing this discussion I probably

17   would review it again after -- is it in three to one?  Yes,

18   it brings it down from the 9,000 margin of safety to its

19   3,000, but I want to take a look at that again so for my own

20   sake, because we're dealing with health problems here and

21   it's a responsibility.

22             DR. SEIBER:  Now, I'm assuming that you still have

23   some more presentation.

24             MS. LEWIS:  I'm only about halfway through.

25             DR. SEIBER:  Are there any other questions at this



 1   point?  Maybe some of these other things will come up as we

 2   continue.

 3             DR. GLANTZ:  Gee, I thought you were done.

 4             MS. LEWIS:  The most significant changes to Part C

 5   were to the hazard identification section.  As I alluded to

 6   earlier, the critical NOEL selected for evaluating acute

 7   exposure to DEF in ambient air was changed to the acute NOEL

 8   from the 90-day study.

 9             The acute NOEL from this study is now the lowest

10   NOEL for acute effects in any study for DEF, regardless of

11   route of exposures.

12             Based on a comment from OEHHA I have moved the

13   discussion of health-related effects attributed to n-butyl

14   mercaptan forward from the risk appraisal section for

15   emphasis.

16             I've also elaborated my discussion of the

17   reproductive toxicity study and the Abou-Donia study and why

18   these were not used for evaluating seasonal exposure to DEF

19   and ambient air.

20             And this is again based on comments from the SRP

21   and OEHHA.

22             I've also added a new section evaluating possible

23   increased pre- and postnatal sensitivity to DEF.  And based

24   on this evaluation, there does not appear to be any

25   indication of increased pre- or postnatal sensitivity



 1   comparing brain cholinesterase inhibition in newborn pups

 2   and 21-day-old pups to the adults.

 3             This change was made based on a comment, partly

 4   based on comment from the SRP, but I should also point out

 5   that we are now adding a discussion of this and other

 6   FQPA-related issues to all of our documents.

 7             I have eliminated a discussion of possible

 8   threshold mechanisms from the oncogenicity section, as

 9   mentioned earlier.

10             In a conference call with Dr. Witschi last week,

11   he asked me if I could express the oncogenic potency in unit

12   risk, which is how the SRP is used to seeing it expressed,

13   so I prepared this table showing oncogenic potency for DEF

14   as unit risk relative to other chemicals that the SRP has

15   previously reviews.

16             By the way, the other chemicals on this table were

17   at one time or another registered as pesticides.  The unit

18   risk estimate for DEF ranged from 9.2 times ten to the minus

19   six for the maximum likelihood estimate, to 1.6 times ten to

20   the minus fifth, for the 95th percent upper bound estimate.

21             I've also added US EPA --

22             DR. GLANTZ:  Can I interrupt you?

23             MS. LEWIS:  Oh, sure.

24             DR. GLANTZ:  This is one other thing I think you

25   need to elaborate on in the report.  The unit risk



 1   calculation, which I think was on page 74.

 2             MS. LEWIS:  Actually I don't have the unit risk in

 3   your draft.  This is something I just added based on our

 4   conference call.

 5             DR. GLANTZ:  There was something on page 74.

 6             You had that oncogenic --

 7             MS. LEWIS:  I expressed oncogenic potency in

 8   milligrams per kilogram day to --

 9             DR. GLANTZ:  Well, that was something, maybe again

10   this is what you're used to, but in the risk assessments

11   that we've gotten from OEHHA, they usually go on endlessly

12   about how they get to these numbers.  And you had like one

13   paragraph.

14             And I think that in the final report you need to

15   spell out.  I'm not saying you did it wrong here.  But I

16   think you need to explain in some detail how you got that

17   information.  Which day did you use --

18             MS. LEWIS:  I thought I explained that.  I

19   explained which model I used, which tumors I used, the

20   scaling factor I used.  I'm not sure what else you wanted.

21             DR. GLANTZ:  I don't know.  Maybe it just seems

22   too terse.  Maybe you're just --

23             MS. LEWIS:  Throw some more words in there?

24             DR. GLANTZ:  Maybe.  Maybe you're just not as

25   verbose as OEHHA.  Maybe they should be more like you.



 1             But it just seemed that the -- well, maybe not.

 2   Maybe George can you give you some advice on being verbose.

 3   It just seemed to me not as kind of fleshed out as I'm used

 4   to seeing.

 5             Maybe you're doing a better job than they are.

 6             DR. WITSCHI:  I think it's there, because the way

 7   I understood it you calculated this according to usually in

 8   a feeding study.  That's how you came into your potency,

 9   right?

10             MS. LEWIS:  Yes.

11             DR. WITSCHI:  The number you came up with is the

12   one of oncogenic potencies he uses, this kind of numbering,

13   this kind of --

14             MS. LEWIS:  Yes.

15             DR. GLANTZ:  Am I just displaying my ignorance?

16             DR. FUCALORO:  This is the liver cancer.

17             MS. LEWIS:  Yes.  The liver tumors.  There were no

18   calculations for the other tumors because they were only

19   seen at the high dose level.  In essence you would have

20   gotten meaningless results because you're trying to draw a

21   line through one point and so --

22             DR. GLANTZ:  I figured it would have been good --

23             MS. LEWIS:  That's why there's no other numbers

24   there --

25             DR. GLANTZ:  I'm not saying there's anything wrong



 1   with what you did, but like that would be a useful fact.

 2   Maybe I just missed that.

 3             DR. WITSCHI:  This is a different kind of potency

 4   calculations, which is derived from feeding study, which

 5   goes to say there's more potency and that was just here.

 6             DR. GLANTZ:  Maybe I'm just displaying my

 7   ignorance.  I was just used to sort of a more thrashed out

 8   explanation why you didn't use -- why you chose that one

 9   over others.  The kinds of things you're saying now.

10             MS. LEWIS:  Actually, I think I did indicate in

11   there that I didn't use the tumors in the small intestine

12   and the lung because they had only occurred at the high dose

13   and you get meaningless results --

14             DR. GLANTZ:  I guess I remember reading that, but

15   I guess I just didn't connect it with the risk assessment.

16   It may be just all I'm talking about is adding a sentence

17   just to reiterate that.

18             DR. FUCALORO:  And I have a question.

19             You used the highest AADD for males.  Is that

20   correct?  As the exposure.

21             MS. LEWIS:  Yes, right.

22             DR. FUCALORO:  8.4 milligrams -- nanograms per

23   kilogram per day.  And of course that's calculated from the

24   SADD.  It's roughly one-sixth, 60th out of 365, right?

25   That's calculated from there.



 1             And in spite of that, you get something that's --

 2   I'm no specialist on where you're supposed to -- where a red

 3   flag comes up, you get very close to what I understand the

 4   red flag to be is one excess cancer per million.  Is that

 5   very close?  I mean, the highest level you get is

 6   approximately --

 7             (Multiple speakers at once.)

 8             DR. FUCALORO:  You are using a hundred million and

 9   ten million base, but the standard way is to use a million

10   and it goes --

11             MS. LEWIS:  Yeah.

12             DR. FUCALORO:  And AADD does not include any

13   exposure outside the season.

14             MS. LEWIS:  Right.  It's just that the

15   concentration exposure during the season, but when we look

16   at oncogenicity that we average it out over a lifetime to

17   come up with an exposure dosage.

18             DR. SEIBER:  I appreciate you putting the table

19   together.

20             Ask Dr. Witschi if he has any comments on the

21   table and the other panelists if they feel this would be a

22   useful addition to the document.  This is not something

23   we've always had in our documents in the past and personally

24   I think it would be useful.

25             DR. WITSCHI:  I think the main reason is I asked



 1   for this table because we are, this panel, is used to

 2   thinking in terms of human risk and so on, and I think this

 3   is very helpful, because this puts exactly with perspective

 4   for DEF as all the other agents we were familiar with, and

 5   dealt with at great length.  So I think that is very useful.

 6             DR. GLANTZ:  I agree.

 7             One other little thing.  On the unit risk, I mean

 8   I agree that seven and ten million is .7 and one million,

 9   but I think again for consistency it would be -- you should

10   just present it as .7 per million, just to be consistent

11   with the other things we did.  I mean, it's just what you

12   didn't do wasn't wrong.

13             And I agree with Hanspeter, I think this should go

14   in the report.

15             DR. WITSCHI:  Actually I will include all

16   the toxic air contaminants --

17             MS. LEWIS:  I just didn't want to have a huge

18   table up there.

19             DR. WITSCHI:  No, that's fine.

20             MS. LEWIS:  In the report.

21             DR. WITSCHI:  I mean, all those at one time or the

22   other are grouped as pesticides.

23             MS. LEWIS:  Yeah.  Sometime at -- that's why I

24   selected those.

25             DR. SEIBER:  Why don't we continue with the



 1   recommendation.

 2             MS. LEWIS:  Can I have that table back.

 3             I just wanted to point out that I put US EPA's

 4   classification on there, and DEF is the only one that US EPA

 5   has classified on this table under its new system.  They

 6   classified it as a likely high dose, not likely low dose

 7   carcinogen, and in essence treated it as a threshold

 8   carcinogen.

 9             That was it.

10             DR. WITSCHI:  Is this a new EPA definition?

11             MS. LEWIS:  As far as I understand it, yeah.  This

12   is in line with their new guidelines.

13             DR. WITSCHI:  You can say this for any carcinogen.

14   They're carcinogenic at higher doses and they're not likely

15   at low doses.  Okay.  That's EPA's problem.

16             MS. LEWIS:  I'll let them come here and defend it.

17             ARB noticed in their review of our document that

18   the term off-site had not been used in a consistent manner

19   between Part A and Part C.

20             After some discussion in our department, we

21   decided to use the definition in Part A.  As it turns out,

22   all the off-site or application related monitoring that was

23   done was within the buffer zone, so no exposure dosages were

24   calculated from this data, since people should not be within

25   the buffer zone except for short periods of time.



 1             The Seiber study then was considered ambient

 2   rather than off-site, since all the -- since none of the

 3   monitoring was done in relation to any specific application

 4   and instead monitored four sites over a 30-day period during

 5   the height of the cotton defoliation season.

 6             I'd like to emphasize that the exposure doses in

 7   this section did not change, only how they were identified

 8   in the text and the table.

 9             In the risk characterization section the term

10   margin of safety was changed to margin of exposure.  The

11   formula remained the same.  This was a change that was not

12   based on comments from the SRP or OEHHA, but was made for

13   purposes of harmonizing with the US EPA.

14             Because the acute NOELs decreased significantly,

15   the acute MOEs decreased significantly.  However, they are

16   still greater than 9,000.

17             In addition, the MOEs that were previously

18   identified as off-site have now been changed to ambient.

19             One other significant change to this section was

20   the addition of a discussion of the odor threshold for

21   n-butyl mercaptan and possible odor-related effects.  Much

22   of this information was moved forward from the risk

23   appraisal section, based on comment from OEHHA.

24             The changes in the risk appraisal section

25   generally are the result of changes made earlier in the



 1   report.  The discussion of the reproductive toxicity study

 2   and Abou-Donia study were revised.  The main change was

 3   moving much of this information forward.

 4             The discussion of possible threshold mechanisms

 5   for oncogenicity was elaborated.  General references were

 6   cited for possible threshold mechanism of oncogenicity.

 7             The discussion of possible health-related effects

 8   from n-butyl mercaptan were also revised because much of the

 9   discussion was moved forward.

10             And finally the air concentration standard for

11   acute exposure was revised because of the lower acute NOEL.

12             Since US EPA recently made their draft

13   reregistration document, or RED, for DEF available on the

14   Internet for public comment, my department has asked me to

15   quickly compare this risk assessment to ours.

16             One of the major differences between our two risk

17   assessments is that US EPA used blood cholinesterase

18   inhibition as a regulatory end point and we did not.

19             US EPA does not consider it an adverse effect in

20   itself, but rather a surrogate for peripheral cholinesterase

21   inhibition data when it's not available.  And we've already

22   talked about this at some length, so --

23             DR. BYUS:  What's not available?

24             MS. LEWIS:  What?

25             DR. BYUS:  You said used as a surrogate --



 1             MS. LEWIS:  When it is not available.  When they

 2   have not measured peripheral cholinesterase inhibition.

 3             US EPA did not address exposure to DEF in ambient

 4   air in their risk assessment, so we cannot compare our

 5   exposure estimates.

 6             However, they did evaluate inhalation exposure in

 7   workers using the same 90-day inhalation study that was

 8   critical on DPR's risk assessment.

 9             However, they set the NOEL at .9 milligrams per

10   kilogram day based on blood cholinesterase inhibition.  If

11   we had used their NOEL in our MOE calculations, the MOEs for

12   acute and seasonal exposure would still be greater than

13   3,000 and 7,000, respectively.

14             US EPA had several previously calculated an RFD

15   for DEF using Abou-Donia's study before there were many of

16   the acceptable registrant studies available.

17             In this draft RED, US EPA estimated a new RFD for

18   DEF using a NOEL of .1 milligrams per kilogram day from the

19   one-year dog study, based on plasma cholinesterase

20   inhibition.

21             To comply with FQPA, US EPA recommended a ten as

22   uncertainty factor be retrained for children, not based on

23   available evidence, but based on data gaps.

24             The registrant had not submitted acute and

25   subchronic neurotoxicity studies in rats.



 1             US EPA is also requesting a developmental

 2   neurotoxicity study in rats and a special 90-day study due

 3   to the severe neurotoxicity seen in other studies.

 4             There were a few instances in which DPR was more

 5   conservative than US EPA in its risk assessment.

 6             In the 90-day neurotoxicity study in hens

 7   submitted by the registrant, DPR identified a lower NOEL for

 8   delayed neurotoxicity than US EPA.

 9             US EPA used an MOE approach for protecting against

10   oncogenicity and treated DEF as a threshold carcinogen.

11   Their justification was that tumors were seen only at the

12   high doses where severe toxicity occurred.

13             DPR assumed that there was no threshold for

14   oncogenicity and calculated an oncogenic potency factor.

15             If we had used their approach, the MOEs for

16   oncogenicity would be greater than 10,000 for exposure to

17   DEF in ambient air.

18             That concludes my presentation.  Are there any

19   more comments?

20             DR. SEIBER:  Thank you.

21             DR. FUCALORO:  I have one comment.

22             DR. SEIBER:  Go ahead.

23             DR. FUCALORO:  On page six of your executive

24   summary, Roman VI, the first paragraph under the heading,

25   what are potential acute and chronic non-carcinogenic health



 1   effects of DEF, at the bottom I think you have the units

 2   wrong, but I could be wrong.  I think that -- no, I'm sorry.

 3   Just a minute.  No, I think I'm right.

 4             Where you have, for example, 2.9 milligrams per

 5   kilogram, don't you mean 2.9 milligrams per kilogram per

 6   day?

 7             MS. LEWIS:  I know they're two different ways of

 8   expressing milligrams per kilogram day, and one is

 9   hyphenated and one is slashing it.  It's just --

10             DR. FUCALORO:  But there is no per day in that

11   one.

12             MS. LEWIS:  Where are you looking at?  Where it is

13   talking about acute effects?

14             DR. FUCALORO:  No observed -- you know the

15   paragraph I'm talking about.

16             MS. LEWIS:  The very first one after the question?

17             DR. FUCALORO:  Correct.

18             MS. LEWIS:  You know, I did that.  That's an acute

19   NOEL and I always think of acute NOELs as usually because

20   they're single dose studies, it's always just milligram per

21   kilogram.  I can easily put that per day.

22             DR. FUCALORO:  Only if it's correct put it in.

23             DR. SEIBER:  I think it's correct.  Single dose.

24             MS. LEWIS:  Actually in this study technically it

25   wasn't, because I considered effects up to three days of



 1   exposure as possible acute effects.

 2             DR. GLANTZ:  This is a place where I think you

 3   just need to be real clear about what you did.  I mean, it

 4   sounds like what you did is okay, you just need to say this

 5   was based on a single dose.

 6             MS. LEWIS:  Yeah.

 7             DR. FUCALORO:  I think it does say that actually.

 8   It says say -- okay.  It doesn't quite say that, yes.

 9   Selected for evaluating acute exposure.  So I see where

10   you're getting at.

11             DR. GLANTZ:  I think if you just put in what you

12   just said it would be fine.

13             DR. SEIBER:  I had a question about the 10 X

14   safety factor and my understanding of an MOE calculation is

15   you compare, observe the exposure and your toxic end point

16   to make a ratio of your no effect level, and then you

17   compare it against the standard of 100.

18             MS. LEWIS:  That's correct.

19             DR. SEIBER:  Now, does this mean that if you threw

20   in an extra ten, I assume you'd be comparing it with a

21   factor of 1,000.

22             MS. LEWIS:  Right.

23             DR. SEIBER:  Are you going to do that?

24             MS. LEWIS:  The extra --

25             DR. SEIBER:  Where is that extra factor of ten?



 1             MS. LEWIS:  For FQPA or the listing as a TAC?

 2             DR. SEIBER:  What we're doing right now, any risk

 3   assessment of this type, are we going to as a standard start

 4   to throw in an extra factor of ten, when there's no data one

 5   way or the other, or not.  What's your current thinking?

 6             MR. GOSSELIN:  Right now, no.  We do take a look

 7   at the entire data set if there is data showing the need to

 8   add another level of uncertainty.  We do consider that.

 9             I know EPA is struggling with this right now

10   because they're looking at two ends, one where registrants

11   have provided data that they need to evaluate to consider

12   what the extra 10 X factor is, and the whole issue about in

13   the absence of data retaining this, which is also prompting

14   more studies to come in.

15             So in the end, I think what we're going to be

16   facing is in the next few years, and immediately, more data

17   to better characterize exposures to infants and children,

18   but right now we're not going to automatically default an

19   extra tenfold.

20             DR. SEIBER:  Yes.

21             DR. FRIEDMAN:  I'm not clear on what our role is

22   within, with regard to evaluation pesticides.  In other

23   words, when we look at another toxic air contaminant that is

24   based on presentations from OEHHA, we've always come out

25   with a bottom line, this is a toxic air contaminant.



 1             I didn't find any bottom line here and I'm just

 2   wondering what -- do we have the mission with regard to

 3   pesticides or what?

 4             DR. SEIBER:  Right now we're considering the

 5   validity of the reports that are before us.  Do we agree

 6   with what's in the report or don't we agree.  We haven't got

 7   to the point on final recommendation.  And in fact if you

 8   notice, we don't have a set of findings to react to that has

 9   that bottom line in it.

10             So I think where we're going is let's look at the

11   data today and say fine tune it, feed comments, but between

12   now and the next meeting my assumption is we'll have to come

13   to grips with the findings.  I don't think we can do it at

14   this meeting, because we don't even have a draft to start

15   with.

16             And but what we're kind of just to give you a

17   preview of where I'd like to go with this is to set up a

18   subcommittee.  Couple of panelists, maybe the lead people,

19   it could be an additional probably a maximum that can be

20   involved in that, and the staff, not only from DPR, but we

21   haven't heard yet from OEHHA.  We're going to do that is

22   just a minute.  And put those together into a set of

23   findings, maybe contentious, maybe not.  We hope they'll

24   be -- we can iron out any differences and bring it back to

25   the panel in time for the November meeting, so we can



 1   essentially have a set draft and spend an hour or so, go

 2   over it and then reach a resolution on what's in the

 3   findings in the bottom line, whether we think it should or

 4   should not be recommended as a toxic air contaminant.

 5             That's kind of where I think we're going --

 6             MR. GOSSELIN:  Since it's been ten years since

 7   we've actually reached this point, we had to dust off the

 8   whole process for ourselves and revisit it and one of the

 9   principle issues is for you to let us know whether we've put

10   the adequate scientific rigor into this document for us to

11   make the call on whether they're listed as a toxic air

12   contaminant.

13             We have in regulations listed the criteria for,

14   you know, in the end when this document said this is

15   reasonable with the findings, it does add in an extra

16   tenfold factor beyond what you could use as a regulatory

17   sort of threshold, if you will, to declare as a toxic air

18   contaminant.

19             So the chronic end point, what is it, .7 to 10 to

20   the minus six would be within that range that would prompt

21   us to list it as a toxic air contaminant.

22             DR. FRIEDMAN:  Are we only to consider that

23   decision based on the concentration in, quote, ambient air,

24   is that --

25             DR. SEIBER:  As opposed to worker exposure?



 1             DR. FRIEDMAN:  Yes.

 2             DR. SEIBER:  Yeah.  Normally worker exposure is

 3   considered separately.  I don't think we've ever used worker

 4   exposure as our criteria.

 5             And maybe can you remind us on that?

 6             DR. GLANTZ:  Well, no, we've dealt with ambient

 7   exposure to the public, which given the -- at least the

 8   public in Fresno.

 9             But I think, and I apologize for running out for a

10   second to the facility, but it seems to me there's no

11   question under AB 1807 that we should recommend this be a

12   toxic air contaminant.  It's in the air and it's toxic.

13             And if you go back and read the definition in the

14   law, we've had this discussion endlessly, in the law, we

15   should recommend, we should say this is a toxic air

16   contaminant.

17             It seems to me there's no evidence for a threshold

18   which is the other issue we're supposed to address.

19             That we should come up, based on the discussion

20   that we've had today with the recommended NOEL, which is a

21   real NOEL, and a unit risk, which we seem very close to, and

22   that's what we should find.

23             And then if DPR wants to say, yes, this is toxic

24   air contaminant for AB 1807, but we don't think the risks

25   are high enough to issue regulations, that's up to DPR.



 1             But, you know, to me the definition of a toxic air

 2   contaminant in AB 1807 is pretty clear.

 3             And I think if the department adopted regulations

 4   and were here to regulate as a toxic air contaminant, that

 5   that doesn't override the law's definition of what a toxic

 6   air contaminant is.

 7             So I think -- and I mean there's lots of things

 8   that are in the air, people correct me if I'm wrong, but

 9   there are things we've listed as toxic air contaminants or

10   recommended listing, which the ARB has listed, which they

11   then said, well, yes, it's a toxic air contaminant, but

12   we're not going to regulate it, because there's not enough

13   of it out there or something like that.

14             I think that's where we're headed.

15             What I would recommend, which is just slightly

16   different, only very slightly different than what you said,

17   is I think you should -- I think that we should, since the

18   report is before us and under the law we have to make a

19   ruling, I think we should find the report seriously

20   deficient, which isn't as bad as it sounds.  We've got a

21   lot -- I mean, that's the only choice.

22             DR. FUCALORO:  That's a standard finding.

23             DR. GLANTZ:  We accept it or declare it seriously

24   deficient.  I think the report is pretty close, actually,

25   but pretty close to being done, not -- I think that you



 1   should make the changes in the report in accordance with the

 2   discussion today.

 3             John Froines indicated in an e-mail to the panel

 4   that he had some comments.  You need to get those from him.

 5   I don't think we should wait until the November meeting.  I

 6   think you should find out what he has to say, bring the

 7   finished report back to us with a set of findings that

 8   include the things I just said, and then we can vote on it.

 9             DR. SEIBER:  I think you maybe were out of the

10   room, but I suggested we might want to form a subcommittee,

11   and I would suggest Dr. Witschi and myself as leads, plus

12   Dr. Froines, and then work with the staff of OEHHA and DPR

13   and come up with a draft list of findings that we can bring

14   back to the November meeting.  Fine tune it as we need to.

15             But before, I don't really want to solidify our

16   positions at this point.  I think it's maybe a little early.

17             We haven't heard yet from OEHHA and most of us

18   have got copies of their response to these documents.  I

19   think it's important to hear from them, but first before we

20   do that I want to ask our DPR folks if they completed their

21   presentation, have anything to add at this point.

22             DR. BYUS:  I have quite a few more questions,

23   actually.

24             DR. SEIBER:  That's good.

25             DR. BYUS:  I thought we were discussing here --



 1             DR. SEIBER:  Well, we are -- we also want to hear

 2   from OEHHA, and I was kind of hoping to get them in before

 3   the sandwiches get delivered, but that's just a little --

 4             DR. GLANTZ:  Let Craig ask his questions.

 5             DR. FUCALORO:  Craig has been dying.

 6             DR. SEIBER:  They're not here yet.  Go ahead.

 7             DR. BYUS:  I just have a couple of questions about

 8   the toxicological interpretations.  One about your

 9   interpretation of the significant changes in organ weights.

10   You say at least two sections in here that you don't

11   consider significant changes in organ weights, this is

12   spleen weight and liver weights, as being a significant

13   toxicological end point.

14             Would you explain that to me?

15             MS. LEWIS:  That's usually, if we make that

16   statement, it's usually because there's no histological

17   findings accompanying it, so it makes interpretation of it

18   difficult.

19             DR. BYUS:  But if you give a chemical to an animal

20   and the organ weight goes up or down significantly, and I

21   have no idea what that amount is, because it's not in here,

22   which would make this statement, for example page 23 that in

23   males a significant reduction in liver, relative liver

24   weights were observed and in females a significant reduction

25   in absolute spleen weights were observed, and the reduction



 1   in organ weights was not considered toxicologically

 2   significant, since there were no treatment-related

 3   histological changes in these organs.

 4             I find that kind of a difficult statement.  Again,

 5   the liver, the organ weights are changing.

 6             And there's another place where weights go up --

 7             DR. WITSCHI:  As the pathologist, pseudo

 8   pathologist on this panel, I would disagree with you.  To me

 9   if --

10             DR. BYUS:  It's just so that if the organ weights

11   change significantly, that is not worthy of consideration?

12             DR. WITSCHI:  No.

13             DR. BYUS:  Okay.

14             MS. LEWIS:  Thank you.

15             DR. GLANTZ:  Does anybody else have an opinion

16   about that on the panel?  I mean, I don't.  Does anybody

17   else?

18             DR. FUCALORO:  Never weighed my liver.

19             DR. KENNEDY:  Is this seen with other compounds?

20   Is this a common event?  If that occurs, then it's routine,

21   then I'm okay with it.

22             DR. WITSCHI:  Increased liver weight without

23   consequences whatsoever occurs with quite a few compounds

24   which are recognized as harmless.  So to reduce weight --

25             DR. BYUS:  I wouldn't want significantly reduced



 1   spleen weight.

 2             I'll take your word for it.

 3             I would -- you should put some explanation of

 4   that, because it jumps out --

 5             MS. LEWIS:  It's another sort of policy decision

 6   that's --

 7             DR. GLANTZ:  See, you keep saying policy.  We're

 8   here to do science, so I think you need to -- what Craig is

 9   saying is you need to justify.

10             DR. BYUS:  Just explain it.

11             DR. GLANTZ:  Explain it in the report.

12             MS. LEWIS:  I think the justification was that its

13   meaning, toxicological meaning, is uncertain, therefore we

14   didn't use it as a regulatory end point.

15             MR. GOSSELIN:  You're looking to just put it into

16   general context.

17             DR. KENNEDY:  If that's by conventions, that's

18   simply describe it as that.

19             DR. BYUS:  It wasn't considered significant, and I

20   don't find -- it's just if you knew, explain it to me.  I'm

21   not disputing it.  I just --

22             DR. SEIBER:  You put in a sentence that says

23   what --

24             DR. BYUS:  That's all.

25             DR. SEIBER:  Dr. Lewis just said.



 1             DR. BYUS:  We can skip that.  We can go on.

 2             I do have my -- I have two other sort of

 3   questions.  Both of them, however, deal around the n-butyl

 4   mercaptan.  I mean we haven't discussed this at all.  This

 5   is a big point in my opinion.  I mean, it's -- and correct

 6   me if I'm wrong, it's the DEF is broken down in the air to

 7   the n-butyl mercaptan and it's also metabolized through that

 8   derivative in vivo.  And n-butyl mercaptan is itself a toxic

 9   compound.  And I -- it's very confusing throughout the

10   document, you've spread the information out among various

11   sections, and it's very difficult to follow and make sense

12   out of it, but if you read it carefully enough.  I mean, I

13   did figure it out.  All the information is there, but it's

14   not clearly laid out.

15             Now, I have my one problem has to do with the

16   doses, the dosage differences.  I mean, it looks -- I'm

17   looking somewhere in here to find a comparison of DEF

18   concentrations in the air to n-butyl mercaptan measured at

19   the same time and the same place under the same situation,

20   and I can't find that.  Does it not exist?

21             MS. LEWIS:  Well, somebody may be should answer

22   that --

23             DR. JOHN ROSS:  Yes, it does not exist.

24             DR. BYUS:  That makes it a little more difficult.

25             You can perhaps talk about this, Jim.



 1             And it also looks to me like there is some

 2   inconsistency here.  At the end of the one document you say

 3   there's only a one to two order of magnitude difference

 4   between DEF and n-butyl mercaptan, but from my reading it's

 5   more like three orders of magnitude, even slightly more

 6   n-butyl mercaptan than DEF at any given time.

 7             The one table here has, for example, in Coalinga

 8   as page 27 of the Part A, it has n-butyl mercaptan here, 23

 9   micrograms per meter square, and DEF is in the nanograms per

10   meter square.  We're talking three orders of magnitude at

11   least in differences.  It would be nice if we could actually

12   compare it at some point.

13             So in a great sense -- and somewhere else in the

14   document you try and make a comparative toxicity argument

15   about n-butyl mercaptan, and OEHHA did correct your

16   statement about its -- your comparing LC 50 and LD 50,

17   lethality as opposed to toxic, and that's fine.

18             In terms of lethality, they're not that much

19   difference.  In terms of toxicological potency, again how

20   close are they?

21             Again, for DEF I think the NOEL discussion was all

22   well and good, but it's so far off here, I mean, DEF,

23   however, even if you take the worst case scenario, it's

24   still way way off from being toxic.

25             However, if you take n-butyl mercaptan, multiply



 1   three orders of magnitude more of it at any given time, not

 2   to mention the metabolic differences, which I have no

 3   feeling for whatsoever in reading this document.

 4             What is the effect of n-butyl mercaptan in terms

 5   of DEF toxicity, because really it's there in three orders

 6   of magnitude in itself is toxic, although it's hard to find

 7   out how toxic it really is.

 8             You also when you read this occasionally you talk

 9   about the odor toxicity, the stink from a biochemical

10   toxicity and actually the odor toxicity is kind of why.  It

11   is a toxicity.  You can't say it is not a toxicity.  It is a

12   toxicity.

13             MS. LEWIS:  Yeah.  Do you address that with MOE

14   calculation?

15             DR. BYUS:  I don't know.

16             But it's just not clear in here.  I think this is

17   the major defect in this document is dealing with the

18   n-butyl mercaptan, both at the exposure level and trying to

19   correlate it throughout, because it's certainly on a

20   molarity point of view and certainly on a dose or amount.

21   It's there and minimally three orders of magnitude greater,

22   and that would maybe put it up into a range where you might

23   be concerned about it.  I don't know.

24             DR. SEIBER:  Well, I agree it's an issue.  People

25   that get sick each year, there are people who report getting



 1   sick when the defoliant is used, are probably reacting to

 2   the butyl mercaptan, and it's making them sick, that they

 3   feel it's making them sick.  So that's an issue.

 4             But how do we deal with it in a rigorous sense

 5   when we have so little exposure data and so little -- I mean

 6   we should really go back out and zero in on that one

 7   chemical.

 8             I asked Bill --

 9             DR. BYUS:  To answer that question, though, you

10   have the data in here.  You say the odor threshold in the

11   parts per billion.  The concentrations are in the parts per

12   million.  And correct me if I'm wrong here, I mean, even

13   that's --

14             MR. GOSSELIN:  The ambient?

15             DR. BYUS:  I don't know what the Table 9 here is

16   ambient or what.  It's just there's no way to tell.  I mean,

17   you're not discussing it clearly enough.  I mean, I'm not

18   saying, grant it, we don't have the data, whatever, but you

19   have to really lay out in a way that you can -- right now I

20   can't --

21             MR. GOSSELIN:  I think probably your

22   characterization is probably the same issues we share also

23   about trying to look and find some definitive data to

24   characterize it.  If it's a matter of trying to piece

25   together the n-butyl mercaptan story, if you will, in



 1   relation to DEF --

 2             DR. BYUS:  Yeah.

 3             MR. GOSSELIN:  That might be an issue maybe we can

 4   with the subgroup talk about, because I think it's an

 5   interesting thing to as maybe part of the findings to sort

 6   of I think the logic you put together is an issue.

 7             But, granted, this was sort of the best document

 8   we could put together with the data that was available.

 9   Obviously, having more data on n-butyl mercaptan on

10   exposures would have really helped complete the picture on

11   this.

12             DR. SEIBER:  That was my reaction was when the

13   butyl mercaptan is an issue, and I think it needs to be

14   dealt with in the findings.  It may that be our findings

15   will say we're concerned about butyl mercaptan, we need more

16   information and it may have to point it out as an issue and

17   just kind of leave it go, because we can't gather the

18   experimental data in the meantime.

19             DR. FUCALORO:  I think we need to say is that not

20   only did Dr. Byus come to that conclusion, I think several

21   of us independently -- I flew up with Dr. Byus and I said

22   what about that mercaptan.  And he said I had that on my

23   mind also.  So we also noticed -- most, many of us noticed

24   that there was a problem with the information on mercaptan.

25             I would simply ask the question, again I'm not a



 1   toxicologist, but if someone said to me hydrochlorocarbons,

 2   I'd say, well, there's liver implication.  I mean, what is

 3   generally understood about mercaptans with regard to health

 4   hazards?  I don't know the answer.  As a class of compounds.

 5             I mean, there must be something on it and

 6   certainly the methyl and the ethyl mercaptan, I mean, skunks

 7   and all that sort of stuff, I would imagine people -- heck,

 8   I've worked with them in the laboratory, but it's so long

 9   ago before we were health conscious, as health conscious as

10   we are today, and I'm glad we are, but I'm just wondering if

11   there is something generally known about mercaptans in

12   general with regard to health effects.

13             DR. BYUS:  You put it in here.

14             MS. LEWIS:  There is acute toxicity data.

15             DR. FUCALORO:  Some of it --

16             DR. BYUS:  Acute toxicity data --

17             MS. LEWIS:  That's basically it.

18             DR. SEIBER:  We're going to try to check if that

19   relates somewhat to this to see if any of the mercaptans are

20   on the list of 189 federal HAPs, in which case they're

21   automatically California TACs.  And we don't even know the

22   answer to that right now.  So we're just asking around the

23   room and we'll try to get that information before the

24   meeting ends.

25             DR. GLANTZ:  I have a question.



 1             I mean, would it be -- since the mercaptans are

 2   breakdown products from DEF, is it possible, based on what

 3   you know about the DEF, to estimate what the mercaptan

 4   exposure is, just based on what you know about the

 5   chemistry?

 6             DR. BYUS:  That was my next statement.  In a

 7   sense, you know how much you're spraying, you know what

 8   that -- this is my line, does it all add up?  You know what

 9   you're spraying.  You know that it breaks down with a

10   certain half life.  You can almost make the assumption if

11   it's a certain percentage what the concentration of the

12   mercaptan will be.

13             And then you can -- the kinetics of it all is very

14   confusing.

15             And there's two more things about that before

16   we -- one is I disagree with you that the document doesn't

17   present -- the data is in here, it's just not presented the

18   right way.  So the document is deficient in just sort of

19   organizing that thought process, not in terms of the

20   information.  If you don't have it, you don't have it.  You

21   have to organize it better.

22             And the other thing, there's one more thing about

23   toxicology, and this could be glucose-6-phosphate

24   dehydrogenase inhibition and blood cell lysis, which I

25   believe you say is due to the mercaptan but --



 1             MS. LEWIS:  That's Abou-Donia's research.

 2             DR. BYUS:  But and that is a potentially -- but

 3   you sort of brush it off as not being significant.

 4             MS. LEWIS:  Oh, no.  I think that is highly

 5   significant.  That's what leading to the red blood cell

 6   destruction and that's what's leading to the cyanosis and

 7   it's probably the final cause of death, as far as I can

 8   tell.  That they -- because apparently right before they die

 9   their combs turn blue and they collapse.  So I think it's

10   highly significant.

11             DR. BYUS:  Okay.  That's all.

12             DR. SEIBER:  Okay.  Where we're at right now is

13   we'd like to hear from OEHHA at some point in this

14   discussion.

15             We can do that now, George, if you're ready.

16             Is that all right with the panel?  I don't think

17   the sandwiches are here, not that that should drive us one

18   way or the other.

19             Why don't we go ahead and listen to Dr. Alexeeff.

20   If we get into a really lengthy discussion, we'll maybe

21   break it at that point, but let's just see how it goes.

22             By the way, before you start, George and Melanie,

23   I see Dr. Marty at the table also, maybe you can tell us

24   what the process was.  You got the document when and did you

25   sit down and talk to the staff?  How do you interact on



 1   these things?

 2             DR. GLANTZ:  Can I just say one thing?

 3             Since DPR is going to be producing another

 4   document, I don't want to delay the schedule, but I would

 5   hope that that can be made available for public comment.

 6   Maybe only just along the way, so we can see what, if

 7   anything, people have to say when it comes back to us next

 8   month.  It will be very abbreviated, as you got a fair

 9   amount of work to do, but I would hope that the public would

10   get a chance to at least look at it for a week or something

11   before the meeting and however --

12             DR. SEIBER:  Dr. Gosselin, maybe if you can

13   comment on that, and the one question I would have is can

14   you post it on the Internet?

15             MR. GOSSELIN:  Yeah.  We'll look to do that and

16   put a notice out to the folks to see if there's any comments

17   on that and have that ready also next time.

18             DR. SEIBER:  Meeting is November 11th, which

19   you're right --

20             DR. GLANTZ:  There's not a lot of time.  It would

21   be nice if you can try.

22             DR. ALEXEEFF:  I'm George Alexeeff of the Office

23   of Environmental Health Hazard Assessment.

24             And with me is Melanie Marty.

25             And so I will do exactly what you asked,



 1   Dr. Seiber, in terms of explaining why are we up here right

 2   now.

 3             DR. GLANTZ:  It's because a meeting isn't complete

 4   without picking on you, George.

 5             DR. ALEXEEFF:  The way the toxic air contaminant

 6   program is set up there's a pesticidal compound and the

 7   non-pesticidal compounds.

 8             For the non-pesticidal compounds, OEHHA and the

 9   Air Resources Board prepare the document, and we present the

10   document and that's what we've normally done.

11             For the pesticidal compounds, it's the Department

12   of Pesticide Regulation that has the lead.

13             But the law has some additional responsibilities

14   given to both OEHHA and the Air Resources Board, but I'll

15   just speak on OEHHA's responsibilities.

16             The law states that we're supposed to work in

17   consultation with the Department of Pesticide Regulation in

18   terms of evaluating the health effects and in preparing the

19   report.

20             So in the way that has been done is there are

21   numerous areas that we interact with the Department of

22   Pesticide Regulations on this type of a chemical or other

23   chemicals.

24             And in terms of preparing the report, primarily

25   it's been the Department of Pesticide Regulation that has



 1   prepared the report and then we've gone through a number of

 2   iterations of review and comments and revisions to that

 3   report.

 4             So with this particular report we've reviewed it

 5   at least once or twice, not three times, and there's been

 6   certain amount of changes made to the report over time.

 7             Now, in addition to that evaluation and

 8   consultation, there is a requirement that we prepare

 9   findings to the health effects, a document that becomes

10   ultimately part of this report.  We haven't done that in the

11   past, so this is kind of a new thing for us.  But that is

12   additional, one of the requirements here.

13             So what we will do is we will -- we prepared some

14   findings.  Melanie Marty will go through those findings and

15   we can sort of explain them to you if need be.

16             DR. SEIBER:  And we have a copy of these.

17             DR. ALEXEEFF:  There's copies here and there's

18   copies on the back on the table.

19             DR. MARTY:  You do have copies and you can read

20   along with me, but pay attention because there's a mistake I

21   have to correct.

22             In terms of the environmental fate and exposure --

23   and what I'm saying is all taken out of the DPR documents,

24   so there's nothing new except for one or two points.

25             DEF photooxidizes, as we have already heard, to



 1   n-butyl mercaptan and n-butyl disulphide.

 2             Therefore, the health effects associated with the

 3   use of DEF include the direct effects of DEF and may also

 4   include the effects of the n-butyl mercaptan and n-butyl

 5   disulfides.  There's uncertainty in here which has been

 6   discussed.

 7             There were ambient air exposure monitoring studies

 8   performed in Fresno and Kern counties during the cotton

 9   defoliation season when DEF is applied.  The highest ambient

10   air DEF levels were seen in Fresno County, rural ambient air

11   levels of DEF evaluated at four locations, and we heard,

12   those were in towns close to agricultural areas, near cotton

13   fields, ranged from nondetectable to 548 nanograms per cubic

14   meter corrected for trapping efficiency.  The mean levels

15   ranged from 44 to 182 nanograms per cubic meter.

16             DEF oral absorption in rats has been measured.

17   It's estimated to be about 70 percent.

18             Inhalation absorption data are, however,

19   unavailable.  And it's been assumed to be hundred percent in

20   the calculations that are in the document.

21             After oral administration of the DEF, significant

22   amounts of n-butyl mercaptan are formed, probably both by

23   acid hydrolysis in the gut and by liver metabolism.

24             The proportion of DEF that gets oxidized to the

25   active cholinesterase inhibiting moiety relative to that



 1   that's hydrolized to the S,S,S-dibutyl phosphorotrithioate

 2   and n-butyl mercaptan is unknown, or relative proportions

 3   are unknown for oral and inhalation routes.  So there may be

 4   a toxic effect difference by the different routes of

 5   administration.

 6             The health effects of nBM have been evaluated in

 7   the DEF report, however apparently no toxicity data are

 8   available for the n-butyl disulfides and there's an

 9   uncertainty there.

10             The health effects, briefly, in animals, acute and

11   subchronic exposures to DEF produce cholinergic effects by

12   inhibiting acetylcholinesterase.

13             Acute and subchronic exposures to DEF by gavage or

14   inhalation in hens produces a neuropathy of a mixed type

15   including an organophosphate-induced delayed neuropathy.

16             Acute inhalation exposures to n-butyl mercaptan

17   can result in respiratory irritation, CNS depression and

18   lung, renal and liver damage.

19             Chronic oral exposure to DEF can result in small

20   intestine damage, spleen hematopoiesis, hematological

21   changes, cholinergic effects and ocular damage.

22             DEF appears to be a reproductive toxicant in rats.

23   Oral exposure induced reductions in fertility, birth and

24   viability indices increase the gestation length, reduced pup

25   weight and led to clinical signs and gross pathological



 1   lesions in the pups.

 2             N-butyl mercaptan appears to be a developmental

 3   toxin in mice.  Inhalation exposures result in significantly

 4   increased post-implantation losses and fetal malformations.

 5             Finally, oral exposure to DEF in the diet produces

 6   significant increase in incidents of the following tumor

 7   types in mice, the small intestine adenocarcinomas and

 8   hepatic hemangiosarcomas in males and lung adenomas and

 9   adenocarcinomas in females.

10             The weight of evidence analysis for

11   carcinogenicity was not presented in the document, but the

12   potential cancer potency risks were evaluated.

13             The health effects in humans, symptoms reported by

14   people, and these are the general public, as opposed to

15   occupationally exposed people, potentially exposed to DEF

16   through occupational or through ambient air, excuse me, it's

17   both, near DEF sprayed cotton fields suggests possible

18   ocular and respiratory irritation and cholinergic effects.

19             DR. SEIBER:  Melanie, we have all the things

20   before us.

21             I guess one question would be so far I think all

22   of these are in agreement that it's in the report and you

23   pulled them out and you're summarizing.

24             One suggestion would be to kind of go to any that

25   you feel are significant in terms of our discussion that we



 1   haven't -- wouldn't have already seen in the report.  Is

 2   that reasonable or do you want --

 3             DR. MARTY:  That's fine.  Okay.

 4             We did want to mention that occupational exposure

 5   to DEF results in reduction of neurotoxic esterase activity

 6   in lymphocytes and the reduction of neurotoxic esterase is

 7   believed to be partially responsible at least for the

 8   induction of organophosphate induced neuropathy.  So there

 9   is a concern there for people, at least occupationally

10   exposed.

11             I think you guys have already seen the NOELs and

12   there's been some discussion on that.

13             They're presented also the cancer potency factors,

14   which were based on the angiosarcomas, so that you have

15   discussion of that, and also of the estimated cancer risks

16   being essentially below ten to the minus six.

17             Under potency and range of risk to humans, I just

18   wanted to correct an error under No. 4 where we have stated

19   the report estimated margins of exposure from Fresno and

20   Kern County monitoring data using the air concentration

21   standards.  That should just be using the air

22   concentrations, because the marginal exposure is essentially

23   the adjusted NOEL divided by the air concentration.  So it's

24   misleading the way it's stated.

25             DR. SEIBER:  I gathered that you're in agreement



 1   with the MOE calculation.  I see that in your -- in that

 2   same statement.

 3             DR. MARTY:  Right.

 4             DR. SEIBER:  So no disagreement there.

 5             DR. MARTY:  Air concentration standard per se was

 6   not calculated for n-butyl mercaptan in the document.

 7             What we did was we took the reported acute NOEL

 8   for n-butyl mercaptan of 10 ppm, or 37 milligrams per cubic

 9   meter, from developmental toxicity observed in a mouse

10   inhalation study.

11             And we adjusted that NOEL for breathing rate of

12   humans and got an adjusted NOEL of 25 milligrams per cubic

13   meter.  Using a standard uncertainty factor of 100 that

14   would lead to acute air concentration standard for n-butyl

15   mercaptan of 250 micrograms per cubic meter.  That number

16   could be used to compare to whatever data are available and

17   there are some for measured concentrations of n-butyl

18   mercaptan.

19             DR. BYUS:  What was that number again?

20             DR. MARTY:  250 micrograms per cubic meter as an

21   air concentration standard, and adjusted if you wanted to do

22   the MOE calculation you would use the adjusted NOEL of 68

23   milligrams per cubic meter and divide that by the air

24   concentrations.

25             DR. BYUS:  They say there's 23 micrograms per



 1   meter cubic, so we're off by at least a thousand.

 2             DR. MARTY:  A thousand.

 3             DR. BYUS:  So, I mean, we ought to say, I mean

 4   this is just what I was getting at, this is the calculation,

 5   this is what we need to make, say we make these estimates

 6   and here's what we come up with, and it's still a

 7   thousandfold for developmental toxicity using that as the

 8   end point.  Maybe not the best way to put it.  It's

 9   certainly the only data you have.  That's really what we

10   need to make that clearer.

11             DR. MARTY:  Okay.  We do also in our draft

12   findings state that the information in the hens indicates a

13   30-fold lower NOEL on a milligram per kilogram day basis,

14   relative to what was identified in the report.

15             However, we do point out that, first of all, you

16   have to have a cross route extrapolation to go from the hen

17   study to the rat study.

18             And as we noted earlier, their metabolism may be

19   different by route, so you may have problems doing a cross

20   route extrapolation.

21             Second, we don't have any experience with

22   quantitative extrapolation from hens to people.  So we

23   haven't ever used hen models, although it's my understanding

24   that birds, and hens in particular, are a good model for the

25   delayed organophosphate delayed neuropathy.



 1             So it may be that the NOEL is an underestimate,

 2   when you take it from 90-day rat inhalation study, but

 3   there's uncertainty in quantifying and applying the hen

 4   study for extrapolating to people.

 5             In addition there is a NOEL that is lower from the

 6   feeding study than from the inhalation study in hens, so

 7   that also indicates that there's a route difference.

 8             So that I think to sum it up, we think that a

 9   primary uncertainty is quantitative extrapolation from oral

10   to inhalation.

11             The rat repro study, which was a feeding study,

12   has a sevenfold lower NOEL on a nanogram per kilogram day

13   basis, but there are some uncertainties in using it to

14   establish an inhalation NOEL and the numbers that are in

15   use, the quantitative extrapolation from oral to inhalation.

16             So sometimes you get stuck doing rat-to-rat

17   extrapolation, but in this case there's inhalation study

18   interval.

19             Another point we made in the findings was that the

20   community health impact from n-butyl mercaptan from n-butyl

21   disulphide from DEF usage is uncertain and I think we've

22   already discussed at least the butyl mercaptan on that.  And

23   unfortunately there's not a lot of toxicity information on

24   the n-butyl disulfide.

25             Perhaps if we had odor threshold information that



 1   that might be useful to compare to the air concentration

 2   standards that were developed.  It has pretty low odor

 3   thresholds, so that it might be not be useful.

 4             So we felt that the available toxicity monitoring

 5   data for n-butyl mercaptan and certainly for the n-butyl

 6   disulfide really are not sufficient to fully characterize

 7   the risk, so it just represents an uncertainty in the risk

 8   estimate for DEF.

 9             I don't think we have any other points that were

10   not already brought up.

11             DR. SEIBER:  Just a quick follow-up to that.

12             We did determine that the n-butyl mercaptan and

13   related aliphatic mercaptans are not on the federal HAPs

14   list.  Now, remember, the federal HAPs list was made up not

15   based on toxicity or things of that type, solely, but it was

16   a consensus list, so that means nothing one way or the other

17   except that we don't have a lot of data available to fall

18   back on as we evaluate those types of chemicals.

19             DR. WITSCHI:  If those would be our findings right

20   now, I would have a problem, not a problem, on potency and

21   risk of humans in five -- no, in six.  You just mentioned

22   two counties.  What's the risk for the rest of us then?  I

23   mean, don't we know or have some guess or so?  I don't think

24   we can come down with findings that refer just to two

25   counties.



 1             DR. MARTY:  I think, first, there's a little bit

 2   of confusion that these are not the SRP's draft findings.

 3   It's a different process that we go through for the

 4   pesticides, where OEHHA actually has to come up with some

 5   findings that get attached to the DPR document.

 6             But, yes, I myself have the same question, what is

 7   the risk elsewhere, are we being exposed to DEF in other

 8   parts of the state, and I think it's primarily what I heard

 9   earlier is that it's applied just to cotton, so unless

10   you're in a cotton growing region, I don't think it's used

11   anywhere else for any other purposes.

12             DR. SEIBER:  There's probably no data.  There

13   could be some exposure, cotton garments and so forth, maybe

14   some water contamination, but in general it would be

15   extremely low, and so the major exposure is in those

16   counties where it's used.

17             DR. MARTY:  The only other possibility is if it's

18   actually manufactured in the state, and that I don't know.

19             DR. SEIBER:  Well, anyway, I'm glad you pointed

20   that out.  These are OEHHA's reactions to the report, and I

21   look at it as starting material for the development of

22   findings for the panel, and certainly will be taken into

23   account.

24             DR. KENNEDY:  I have a question about a bit of

25   biological, but it may relate to the blood or red cell



 1   cholinesterase issue.  But splenic hematopoiesis as an

 2   experimental model, did that reflect intrinsic damage to the

 3   bone marrow, or does it reflect the hypertrophy of the

 4   erythron beyond the marrow's ability to compensate?  What is

 5   its significant?  It isn't a normal event.

 6             DR. MARTY:  I don't know.  Maybe Carolyn --

 7             MS. LEWIS:  I'm not a pathologist.

 8             DR. KENNEDY:  In many species, and I don't know

 9   about the dog, which I guess this is where this is from, the

10   spleen is not normally a hematopoietic organ, it takes over

11   when marrow is either nonfunctioning, as myofibrosis or in a

12   situation where the destruction of red cells is so massive

13   that the marrow is not able to function.

14             MS. LEWIS:  I assume it's the later, because of

15   the evidence of the hemolytic anemia.

16             DR. KENNEDY:  That's the sort of the situation.

17   Okay.  Thank you for telling me.

18             It's pretty massive red cell destruction.  That's

19   killer hemolysis, black water fever.

20             DR. SEIBER:  Any other questions or comments for

21   the OEHHA staff members?

22             DR. GLANTZ:  In reading over these, for the most

23   part it's just a summary of the report, but there were two

24   points that I think that were issues raised, and I'd like to

25   get you to elaborate to them, maybe get DPR to react.



 1             One is under animal No. 5, where you say the

 2   weight of evidence analysis or carcinogenicity -- pardon me,

 3   weight of animal No. 7, I'm sorry.  A weight of evidence

 4   analysis for carcinogenicity was not conducted.

 5             Do you think that the report would be better if

 6   they did conduct such an analysis?  You think that's really

 7   not necessary?

 8             DR. ALEXEEFF:  Well, this is one of those

 9   situations where sometimes going through a weight of

10   evidence analysis and a labeling process actually impedes

11   the ability to get to the end of the report.  And so what

12   was, I think it was mentioned by the DPR staff, that in this

13   case what they've chosen, which is what I think is a more of

14   a technical approach, is there is some cancer data, we

15   haven't evaluated whether it clearly is an animal carcinogen

16   per se.  You heard the definition that US EPA gave, high-low

17   type thing.  But regardless of that, they went ahead and did

18   a cancer potency estimate just to see if this was a

19   significant risk, if it was a carcinogen.

20             So they made a presumption without saying, yes, it

21   is a carcinogen or is not a carcinogen, let's assume it is

22   and what is the risk.  So they've taken it that step.

23             So, now, would it be stronger if they went through

24   a detailed analysis and did that?  I don't know.  We can get

25   bogged down.



 1             DR. GLANTZ:  Okay.  You're not criticizing them

 2   for what they did?

 3             DR. ALEXEEFF:  No.  It's not a criticism.

 4             DR. GLANTZ:  It was a reasonable way of handling

 5   it?

 6             DR. ALEXEEFF:  Yeah.  The reason why it's in there

 7   is because it's not labeled a carcinogen by anybody.  I

 8   mean, the reference that was made is to a draft report, in

 9   terms of what US EPA has done.

10             But it isn't on the IARC list, it isn't on the US

11   EPA list, it isn't on the Prop 65 list.

12             So that's what I -- so there isn't a weight of

13   evidence approach, but I think they have done a health

14   protective statement there.

15             And that's consistent with also the developmental

16   sort of approach too.  There's developmental toxins we can

17   label it.  In OEHHA we have the reproductive developmental

18   listing for Prop 65.

19             Without going through is it or isn't it and having

20   all those arguments go forth, you can do a calculation to

21   see, well, if it was, would it be a potential problem.  And

22   those calculations we've done.

23             So I think it's appropriate for this type of

24   document.

25             DR. GLANTZ:  Then the other -- good.  Then the



 1   other one is on the last page, number three, where you're

 2   talking about the hen studies.  And that would give you a

 3   lower NOEL.

 4             I mean, do you think -- do you think that DPR

 5   should be using that, you know, more -- you know, as a

 6   bigger part of the report than they have or is this just

 7   more usual comment?

 8             DR. ALEXEEFF:  I think we're stating it as I think

 9   our staff's opinions have kind of evolved over time on this.

10   And I think that if we were discussing it for an oral

11   exposure situation, that there might be there a different

12   possible conclusion.

13             But I think in terms of the air inhalation issue,

14   where you have the route to route extrapolation, I think in

15   this case it comes down to a quantitative issue.  I think

16   Melanie summed it up where we just think there is some

17   uncertainty, that there could be a risk that's lower.

18             But quantitatively the extrapolation, I think you

19   start adding enough questions, we just don't have enough

20   quantitative experience on this.  And we do have an

21   inhalation study.

22             But I think what it does tell us, first of all, we

23   do know that hens are a good model for this particular

24   effect.  The human data is consistent with the types of

25   effects that can occur.



 1             But in this case the route to route extrapolation

 2   is a big question and in our program for non-pesticidal

 3   situations generally if we had an inhalation study and an

 4   oral study, we would choose the inhalation study, because

 5   it's inhalation the route to route isn't as complicated.

 6             DR. MARTY:  I think also the interspecies

 7   differences between hens and people are an extra

 8   complicating factor, more so than if it was rats.

 9             DR. GLANTZ:  Does that mean people are more like

10   rats?

11             DR. FUCALORO:  Sad statement on humans.

12             DR. SEIBER:  Okay.  I'm ready to make a suggestion

13   as far as our process, if there are no further questions on

14   this list of OEHHA findings.

15             DR. KENNEDY:  I would make one from a oncogenic

16   view.  I have little say in terms of the document, but I

17   think it is necessary to point out that, although tumors are

18   induced in animals, two of these tumors appear to be

19   related, one to an inflammatory response, the other to

20   epithelial turnover.  The third, the hemangiosarcomas that's

21   perceived, that sort of tumor in the animals, hens or rats,

22   radioactive substance.

23             In any case, as has been pointed out, there really

24   are no data whatsoever about cancer induction in man with

25   this compound, and although it's not unreasonable to be



 1   concerned about this, it needs to be pretty clear that this

 2   is on the basis of different critters and that there really

 3   are no control data at all.

 4             DR. SEIBER:  All right.  Here's kind of a summary

 5   of where I think we are right now, and we'll break in just a

 6   minute.  I'm sure at least one person in here would

 7   appreciate the break.

 8             First of all, and let me just say to the audience,

 9   I apologize for taking you away from your lunch.  We have

10   three members of the audience who traveled down from Reno

11   and they're members of our risk assessment at the University

12   of Nevada, and normally we're more sensitive to food in

13   these meetings and the comfort of our audience but -- well,

14   not always.  I wouldn't say normally.  But we're sensitive

15   to the fact that you probably have to eat and might want to

16   duck out and get something to eat.

17             But I think as a summary, very quick summary,

18   we've all agreed that there needs to be revision of the

19   report and Dr. Glantz said considerable -- no.

20             DR. GLANTZ:  Seriously deficient.

21             DR. SEIBER:  That doesn't mean it really is

22   considerably deficient, it just means that it needs to be

23   revised.

24             And that that would be posted on the Internet for

25   public comment, and we've gotten the agreement on that.



 1             We realize we need to prepare findings for our

 2   November meeting, November 11th, SRP meeting, and I've

 3   suggested that we form a subcommittee of Dr. Witschi,

 4   Dr. Froines and myself, working with the staff, but of

 5   course any of the panel that wants input to that, can.  And

 6   we'll try to come up with that draft and we'll use the OEHHA

 7   findings as input to that.

 8             And then at the November meeting we would discuss

 9   the findings and make some kind of determination on the

10   toxic air contaminant recommendation.

11             And then finally we discussed extensively the

12   morning subject of a workshop.  I think we've all agreed

13   that there should be a workshop.  Lisa Ross from the DPR is

14   gathering input on subjects.

15             And this all occurred before you came, Stan, so

16   you might want to get aboard and look at what Lisa has --

17   she's in the back of the room -- put together so far.

18             And anybody else here in this room, I would

19   recommend that give your input to Lisa.  We'll collect all

20   the input and then we'll sift through it and see what's

21   doable.

22             Let's see.  In that regard to the workshop, there

23   ought to be, in case I forget to bring it up later, time for

24   public input, Lisa, as we devise the agenda for that

25   workshop.  We want to have public input, so that needs to be



 1   built into the structure of the workshop.

 2             Okay.  So that's kind of a wrap-up of what we've

 3   done so far.

 4             I'd suggest we take about a 15 or 20 minute break.

 5             And Dr. Byus has agreed to chair the committee to

 6   the completion of the meeting.  We still have a fact sheet

 7   to go over.

 8             DR. GLANTZ:  Can I make a motion, just to be

 9   official?

10             DR. SEIBER:  Sure.

11             DR. GLANTZ:  I'd like to move that we find the

12   report seriously deficient, and basically with the

13   understanding that it will be revised and come back for a

14   final action in the next meeting in accordance with the

15   comments that were made at the meeting today.

16             DR. SEIBER:  Second?

17             DR. FUCALORO:  No flogging?

18             DR. GLANTZ:  No flogging.  Unfortunately, there's

19   no -- there's nothing in the law which is revise and

20   resubmit.

21             DR. BYUS:  Do we have to do it?  Don't --

22             DR. SEIBER:  Have a motion?

23             DR. GLANTZ:  Well, we do, because the report's

24   been put before us and I think, don't we, Bill, we have to

25   either accept it or declare it seriously deficient.  It's



 1   not -- we've declared lots of them seriously deficient.

 2   It's not a big deal.  But I think it's important to act.

 3             DR. BYUS:  I'm not seconding.

 4             DR. FRIEDMAN:  It is labeled a draft.  It's not

 5   labeled as a final report.

 6             DR. GLANTZ:  If you look at it, they all say that.

 7   If you look at the agenda, it was presented to the

 8   committee.  And I think that that -- the reason that I think

 9   this is important is because of the law that says it has to

10   come back within a certain length of time, and that will --

11   while I agree with the comment that we've gone ten years and

12   what's another month, I think it ought to be finished at the

13   next meeting.

14             I mean, this is not a slap at DPR.

15             MR. GOSSELIN:  Actually I think it fits with the

16   way the law calls out for the process.  Otherwise we would

17   be sort of in limbo having the time line drawn and wanting

18   to come back.  So procedurally it makes sense.

19             DR. KENNEDY:  Second.

20             DR. SEIBER:  Do we have a second now?

21             So it's been moved and seconded.

22             And shall we discuss it before we vote?

23             DR. FUCALORO:  Just a point of clarification.

24             Is Stan's interpretation of law as everyone else

25   understands it?



 1             Bill, I think you're actually a lawyer.

 2             DR. SEIBER:  Inform our process --

 3             DR. KENNEDY:  Do we have to put seriously

 4   deficient in red?

 5             DR. FUCALORO:  I was thinking of fatally flawed.

 6             DR. GLANTZ:  That's the way the law is.

 7             MR. LOCKETT:  The panel in the past has used this

 8   way to make it clear that the panel, once having received a

 9   formal submittal from the department and is not ready to act

10   for various changes and additions that they want, that the

11   mechanism provided for in the Food and Agricultural Code, as

12   well as the Health and Safety Code, is to find it seriously

13   deficient and the department goes back and fixes it and

14   brings it back to the next meeting.  So it's an okay motion

15   to do that.

16             DR. SEIBER:  Okay.  Then moved and seconded.

17             Shall we -- any other comment and discussion?

18             All in favor?

19             (Ayes.)

20             DR. SEIBER:  Your hands are raised.  It's

21   unanimous.

22             And any opposed?  Obviously none.

23             Now we'll take a 15 or 20 minute break.

24             (Thereupon a short recess was taken.)

25             DR. SEIBER:  We're back in session.  If everybody



 1   will take their seats.

 2             Now, I think we've covered the first three of the

 3   four agenda items in some detail.  Obviously, we need to

 4   come back to the workshop at some point, not necessarily

 5   today, so in effect that agenda item is completed.

 6             The fourth agenda item was the discussion of the

 7   coumaphos fact sheet that was brought to the panel by the

 8   Department of Pesticide Regulation.

 9             We have a few options before us now.

10             One would be to take some testimony and comments

11   and questions on the coumaphos fact sheet, or we could

12   postpone this until our November meeting.

13             What would you prefer?

14             DR. WITSCHI:  I think we should postpone this,

15   because it's been comments to make that this is irrelevant

16   because coumaphos isn't being used.

17             Is that correct?

18             DR. SEIBER:  Paul, could you come back up to the

19   microphone just -- we don't want to spend a lot of time on

20   this, but is coumaphos used in the State of California?

21             MR. GOSSELIN:  No.  And it's not registered

22   currently either.

23             And one of the reasons I think your point about

24   that sheet being irrelevant is kind of the reason why we put

25   it together.



 1             DR. BYUS:  That was the purpose of it?

 2             DR. WITSCHI:  As a taxpayer, object to the notion

 3   that government agency puts together irrelevant things.

 4             MR. GOSSELIN:  Let me speak to the relevancy of it

 5   and the importance of it.

 6             At the time it was very relevant when ARB and we

 7   actually had the monitoring go out and it was in use and I

 8   think from what we've seen time and time again is some of

 9   the uses that were intended to consider for TAC fell by the

10   wayside and no longer registered.

11             One of the things we wanted to do was to kind of

12   somewhat close the books and bring closure to some of those

13   things, and what we thought was just a quick fact sheet on

14   just sort of status of it.

15             It doesn't mean that we're going to be doing any

16   more analysis on it, nor are we going to be asking you or

17   OEHHA or anybody else, but at least for the books and the

18   official files, so if somebody does need to go back and have

19   sort of a status as to what happened with this, this is a

20   nice reference sheet that can actually -- and even for our

21   staff and ARB and OEHHA, who did work it, that it did come

22   to closure.

23             So those ones it's sort of like real no brainer.

24   Why is it being done, that's like, yeah, that's exactly why.

25             DR. SEIBER:  My recommendation would be if a



 1   chemical's withdrawn, no longer used, it ought to be

 2   withdrawn from the list.  And I don't think we need a fact

 3   sheet to do that, do we?

 4             That would bring it to closure.  Maybe a letter

 5   saying this compound is no longer used, therefore we're

 6   withdrawing it from TAC consideration, and period.

 7             DR. WITSCHI:  I would agree with that one.

 8             DR. SEIBER:  But, anyway, we do want to look at

 9   the fact sheet concept, so what would be your proposal?  Do

10   you want to bring another --

11             MR. GOSSELIN:  I think because originally we sort

12   of inadvertently threw benomyl out, which does need a full

13   document, that anything of substance that has some

14   monitoring data and significant toxicity issues, are going

15   to come back as documents.  We'll have to go back and talk

16   about what other materials may come forward as fact sheets.

17             DR. SEIBER:  So see if you've got another one that

18   fits what your definition is.

19             MR. GOSSELIN:  From the panel's perspective, us

20   even using this as almost the letter of closure to remove

21   some of these non-materials anymore is not really

22   objectionable, just kind of questionable.

23             DR. SEIBER:  Okay.  So does that end that item of

24   fact sheets for now?

25             Okay.  Good.



 1             Is there any other business that anyone would like

 2   to raise now, relative to our current agenda?

 3             If not, that sounds like we've run out of things

 4   to talk about, so I would entertain a motion for --

 5             DR. WITSCHI:  Well, I move for adjourned.

 6             DR. KENNEDY:  Second.

 7             DR. GLANTZ:  Second.

 8             DR. SEIBER:  All in favor.

 9             (Ayes.)

10             DR. SEIBER:  Thank you.  November 11th.

11             (Thereupon the meeting was adjourned

12             at 1:15 p.m.)


















 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 19th day of October 1998.




                                     Janet H. Nicol
17                                   Certified Shorthand Reporter
                                     License Number 9764