1                             MEETING

 2                              OF THE










12                       500 PARNASSUS AVENUE

13                    SAN FRANCISCO, CALIFORNIA





                      TUESDAY, FEBRUARY 1, 2000
                              9:00 A.M.




24   Janet H. Nicol
     Certified Shorthand Reporter
25   License Number 9764



 1                           APPEARANCES


 3   Dr. John Froines, Chairman
     Dr. Roger Atkinson
 4   Dr. Paul D. Blanc
     Dr. Craig Byus
 5   Dr. Gary Friedman
     Dr. Anthony Fucaloro
 6   Dr. Stanton Glantz
     Dr. Peter S. Kennedy
 7   Dr. Hanspeter Witschi

     Mr. Jim Behrmann, Manager
10   Mr. Bill Lockett
     Mr. Peter Mathews

     Dr. George Alexeeff, Deputy Director for Scientific Affairs
14   Dr. James Collins, Staff Toxicologist
     Dr. Melanie Marty, Senior Toxicologist
15   Dr. Andrew Salmon, Chief, Air Toxicology and Risk Assessment


17   Mr. Paul Gosselin, Assistant Director
     Dr. Andrew Rubin, Staff Toxicologist
     Ms. Elinor Fanning, UC Berkeley








 1                              INDEX

 3   1    Continuation of Consideration of Draft Report:       1
          Air Toxics Hot Spots Program Risk Assessment
 4        Guidelines, Part III:  "Technical Support
          Document for Determination of Noncancer Chronic
 5        Reference Exposure Levels"

 6   2    Update to the Scientific Review Panel on the        22
          Air Toxics Hot Spots Program Risk Assessment
 7        Guidelines

 8   3    Discussion of Possible Topics for Future            39
          "Pesticides in the Air" Panel Workshops
     4    Continuation of Consideration of Draft Report:      55
10        "The Evaluation of Methyl Isothiocyanate (MITC)
          as a Toxic Air Contaminant
     Adjournment                                             162
     Certificate of Reporter                                 163















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

 2             CHAIRMAN FROINES:  Welcome, everybody.

 3             This panel has had approximately a two-month

 4   break, so that everybody should be really raring to go.

 5             Melanie doesn't want to hear that.

 6             DR. GLANTZ:  I just thought of a wise crack, but I

 7   won't make it.

 8             CHAIRMAN FROINES:  The first item, there's no

 9   other information I think that's particularly relevant at

10   the beginning, so we might as well just go right into the

11   agenda.

12             So we're going to continue to consider the draft

13   report, 23 of the first 43 compounds.

14             DR. MARTY:  I'm Melanie Marty from the Office of

15   Environmental Health Hazard Assessment, and we're going to

16   present today the revisions made to the document based on

17   the panel's comments from the last three meetings or so.

18             Today we're talking about the technical support

19   Document for the determination of chronic reference exposure

20   levels for airborne toxicants.

21             This slide presents the definition of the chronic

22   REL.  Essentially the chronic REL is the concentration in

23   air at or below which no adverse health impacts are

24   anticipated following long-term exposure.  It is meant to

25   protect most people, including sensitive individuals,



 1   although we are obviously unable to account for

 2   idiosyncratic responses.

 3             Exceedance of this REL does not necessarily result

 4   in adverse health consequences, until you reach a high

 5   enough level to see adverse health connections.  I think

 6   that's important that people understand that.

 7             We made a number of revisions in the document.

 8   This slide summarizes the revisions in the introduction.

 9             We changed the uncertainty factor for interspecies

10   extrapolation when you're using primate data to three from

11   ten.  This was based on comments from the panel that they

12   felt primates were close enough to people that perhaps we

13   shouldn't have lumped them together with rodents.

14             We added a brief discussion of hyperplasia as a

15   toxicological endpoint.  That's on page 17 of the

16   introduction.

17             We also reworded our discussion of the benchmark

18   concentration approach on page 19 and in particular talked

19   about the difference between how US EPA does benchmark

20   concentration and how we have proposed to use it.

21             The difference being primarily that they are

22   looking for a benchmark which is the 95 percent lower

23   confidence limit on the dose that produces a ten percent

24   response rate.  We felt that was closer to a LOAEL rather

25   than a NOAEL.  We would rather use the 95 percent lower



 1   confidence limit on the dose that produces a five percent

 2   response rate.  So that's one difference between our

 3   approach and their approach.

 4             We added an equation for unit conversion from ppm

 5   to milligrams per cubic meter.  That's on page 30.

 6             We also on page 30 clarified our discussion of the

 7   use of US EPA RfCs.  Essentially what we have stated is that

 8   we have a evaluated the US EPA RfCs.  In many cases we agree

 9   with the choice of the key study, but we have somewhat

10   different approaches to the use of uncertainty factors and

11   we're also more consistent with what we describe as a

12   chronic toxicological study.  So we actually have criteria

13   for the duration of the exposure.

14             We also made a number of generic revisions to the

15   toxicity summaries in the RELs.  We responded to all the

16   panel members' comments.

17             We added emissions information from the air toxics

18   emissions database, which is the Air Toxics Hot Spot

19   Program's database of emissions reported by the air

20   districts and facilities.

21             We also added, where available, ambient

22   concentration data, which we intend to update to whatever we

23   can -- the latest year from the Air Resources Board.  I

24   doubt they have their '99 all pulled together, but at least

25   we'll get the '98 emissions in.  I'm sorry.  In '98, the



 1   ambient concentration data.

 2             We added more description of key studies, and that

 3   was in response to most of the panel members' concerns about

 4   us not describing enough the information that was available.

 5             We added comparison reference exposure levels

 6   where you could have chosen one study or another with some

 7   discussion of why the study we chose we chose.

 8             We also added a section, strengths and limitations

 9   of the data, and essentially organized some material that

10   was already in there into that section so it was easy to

11   find and describe, and we bolstered that section in a number

12   of cases.

13             The panel had directed us to go back and look at

14   our US EPA RfCs that we proposed just adopting.  So we did

15   do that.  And in fact with a number of the studies we agreed

16   with the choice of the study made by US EPA, but we would

17   have applied different uncertainty factors.

18             One of the things we did was drop the modifying

19   factor that EPA uses in a number of their RfCs.  This

20   changed the chronic REL for ammonia, EGME, mercury and MTBE.

21   In general it went up, because they added an additional

22   modifying factor of three, which they of course divide

23   through by.  And we removed that modifying factor so the

24   numbers went up a little bit.  With rounding it ends up

25   being about a twofold, depending on the numbers.



 1             In the case of mercury, we actually used different

 2   uncertainty factors than US EPA.  We dropped the modifying

 3   factor, but we actually used a different uncertainty factor

 4   so the number changes, it actually drops.

 5             DR. FUCALORO:  Can I ask a question?  How does

 6   three round to two?  I'm not quite sure.

 7             DR. MARTY:  If you go through the calculation and

 8   then round the final number, we rounded it to one

 9   significant figure, so it ends up if you do the calculation

10   and round the final numbers, the difference isn't quite

11   three.

12             DR. SALMON:  Like ammonia was 70 and 210.  Went

13   from 70 to 210, so we rounded 70 up and 210 down.

14             DR. MARTY:  Other changes --

15             DR. GLANTZ:  Where is the limitations section?

16             DR. MARTY:  It's section 7 of each toxicity

17   summary.

18             DR. GLANTZ:  Okay.

19             DR. MARTY:  I'm sorry.  It's not in the

20   introduction.  The last section, before the references.

21             DR. GLANTZ:  I see them.

22             DR. MARTY:  Other changes that were made in

23   response to our re-review of some of these issues, for

24   chlorine we used a benchmark concentration approach.  This

25   approach we discussed quite a bit and essentially most



 1   everyone agrees it's better than just using the NOAEL, LOAEL

 2   divided by uncertainty factors approach.

 3             In so doing, the reference exposure level changed

 4   from .06 to .2 micrograms per cubic meter, and we did use a

 5   benchmark concentration for a five percent response rate.

 6             In the case of ethylene glycol monoethyl ether,

 7   we actually read some studies that were suggested by

 8   Dr. Blanc.  They were human studies.  They indicated to us

 9   that the interspecies uncertainty factor should really be

10   higher than what we had initially proposed.  So this dropped

11   the reference exposure level to 70 micrograms per cubic

12   meter.

13             The original number was an EPA RfC.  We used the

14   same study and kept the key study, but rather than using an

15   interspecies uncertainty factor of three, we used ten, even

16   though we had a human equivalent concentration adjustment.

17   And that's basically as a result of us evaluating a series

18   of studies by Welch and Cohn, which couldn't themselves be

19   used because of uncertainties in the information, but

20   indicated that humans might actually be pretty sensitive to

21   the reproductive toxicology effects.

22             Ethylbenzene is another chemical that was

23   suggested we go back and look at the new chronic NTP

24   bioassay, which came out in the middle of last year.  We did

25   that and revised the REL using that study.  And the REL



 1   changed from .2 to .4 parts per billion.  The original

 2   proposed REL was an EPA RfC based on developmental toxicity.

 3             If we had used the EPA study and done our

 4   methodology, we actually would have had an even higher

 5   number.  So we're not uncomfortable that -- we think we're

 6   protecting against developmental effects.

 7             In the formaldehyde summary we added a table with

 8   comparisons of the REL, which was based on a human study to

 9   RELs based on 13 animal studies.  And essentially they

10   bracket that human REL.  Some of them are lower, some are

11   higher.  So it just strengthens the argument for the use of

12   those studies.

13             For hydrogen chloride we updated the RGDR from

14   what was originally in the document.  Originally we proposed

15   to use an EPA RfC and, when we evaluated it, the RGDR was

16   changed and we also changed the low observed adverse effect

17   level uncertainty factor from ten to three in the process,

18   so the REL changed from seven to nine micrograms per cubic

19   meter.

20             In the case of methyl ethyl ketone, we went back

21   and looked at a study which I believe Dr. Blanc had

22   suggested us to look at it.

23             Mitran et al, 1997, is a study of exposed cable

24   factory workers and we replaced the rat study which we had

25   used, which in essence was actually a subchronic study.  And



 1   the REL changed.  It actually dropped from 10,000 to 500

 2   micrograms per cubic meter.  So this was a significant

 3   change and we were impressed by that and thought it would

 4   have been much better to use that human study in this case.

 5             In this case these workers were only exposed to

 6   MEK.  They did not have other solid exposures, and the

 7   exposure assessment seemed to be relatively good for a human

 8   study.

 9             DR. FUCALORO:  Curiosity on that, I mean, that's a

10   20 to 1 change.  Now, the US EPA has any data?  I mean, how

11   did they handle methyl ethyl ketone?  I mean, something is

12   that big a change, I mean it's -- you have to understand

13   what that -- what other people think of that change.

14             DR. MARTY:  The RfC for methyl ethyl ketone that

15   was developed by EPA in '92 has been withdrawn, and we

16   don't -- they don't have any number.

17             DR. FUCALORO:  What was theirs and why was it

18   withdraw, by the way?

19             DR. MARTY:  I think the methodology changed

20   between when they had developed it.

21             The original study that we proposed for the REL

22   was a rat study with whole body inhalation for 90 days, and

23   the toxic endpoint noted was increased liver weight and

24   relative kidney weight in the male and female rats.

25             In contrast this Mitran et al study, which looked



 1   at people, was looking at neurotoxic endpoints.  They had a

 2   battery of neurobehavioral tests which obviously has some --

 3   there are problems in interpretation of those tests, but in

 4   addition they conducted motor nerve conduction velocity

 5   tests, which are not subjective, at least near to the degree

 6   that the neurobehavioral battery tests are.  And they got

 7   significant decreases in measured nerve conduction velocity

 8   in three nerves.

 9             So we felt that that was important information.

10   The Cavender study really didn't look at neurotoxicities, so

11   they have been missing the more important endpoint in this

12   case.

13             CHAIRMAN FROINES:  I'm sorry.  Where is that

14   described?

15             DR. MARTY:  Page A-182, methyl ethyl ketone

16   derivation of chronic reference exposure levels.

17             And then the Mitran study is described on page

18   180.

19             CHAIRMAN FROINES:  I'm sorry, Melanie, which is

20   the study with the nerve conduction velocity change?

21             DR. MARTY:  That was Mitran et al, 1997.  It's

22   described under effects of human exposure on page A-180.

23             These were relatively long-term exposures.  The

24   average length of exposure was 14 years.

25             CHAIRMAN FROINES:  Did they control for alcohol?



 1             DR. MARTY:  Jim is looking at the study.

 2             They did have 41 exposed workers and 63 controls,

 3   which they say were matched for age, physical effort at

 4   work, work shift and socioeconomic factors.

 5             I'm not sure that they specifically addressed

 6   alcohol.  You would have to assume, though, that the alcohol

 7   usage was different in the 41 subjects and 63 controls if it

 8   were to impact the results.

 9             CHAIRMAN FROINES:  The historical problem with

10   neurobehavioral occupational studies is always this problem

11   of alcohol, not controlling for alcohol consumption.

12             DR. SALMON:  That isn't such a big problem now

13   with the neuroconduction velocities studies.

14             CHAIRMAN FROINES:  I understand.

15             DR. SALMON:  Which was one of the reasons why we

16   focused on that endpoint rather than the neurobehavioral

17   studies, because, as you correctly point out, the number of

18   variables and confounding factors which need to be taken

19   care of.

20             CHAIRMAN FROINES:  It's also true that hexane

21   produces a distal axonopathy, as you know, and that myelin

22   changes are a late stage of that process, and so motor nerve

23   conduction velocity changes are in fact late stage change in

24   hexane exposures.  So it may be that because you've got 14

25   years' exposure, you've got myelin damage as well as axonal



 1   damage.  That's the assumption, I assume.

 2             DR. MARTY:  Yes.

 3             CHAIRMAN FROINES:  Tony, question?

 4             DR. FUCALORO:  No, I'm done.

 5             DR. MARTY:  In the case of PGME, we originally

 6   used a subchronic study for the REL, and there was a

 7   submission to us from industry of a chronic toxicity

 8   oncogenicity, two-year bioassay, that we read and have

 9   incorporated into the document.  And the result is that we

10   used it as the basis of REL rather than the subchronic

11   study, and the result is that the REL went from 0.6 to 2

12   ppm.

13             CHAIRMAN FROINES:  The record should show that

14   Dr. Friedman is here now.

15             DR. COLLINS:  The original study was subchronic

16   and the new study was chronic.

17             DR. MARTY:  Correct.

18             For phosphoric acid we originally had an EPA

19   number which was based on a benchmark concentration, but the

20   benchmark concentration used again the 95 percent lower

21   confidence limit on the dose for ten percent response rate.

22   We went back and calculated that using the LCL on a five

23   percent response rate.  The result was the REL changed from

24   10 to 7 micrograms per cubic meter.

25             That's it for the changes to the document.



 1             I did want to -- maybe I should wait if there are

 2   any questions.

 3             I did want to talk about the next steps for this

 4   document to clarify that, at least what we're thinking.

 5             Okay.  We will --

 6             CHAIRMAN FROINES:  The panel sees this as our rock

 7   of Sisyphus, you know.

 8             DR. GLANTZ:  What's the rock of Sisyphus?

 9             DR. BYUS:  It keeps rolling.  Roll it up there and

10   it comes back down.

11             CHAIRMAN FROINES:  Who was condemned to roll the

12   rock up the hill, he gets it to the top of the hill, it

13   rolls back down, and he has to start over again.

14             And the chronic REL document has some of the

15   qualities of that.

16             DR. GLANTZ:  I was actually going to speak to

17   that, but not as eloquently.

18             DR. MARTY:  We need to incorporate any additional

19   comments that we get from the panel today and finalize the

20   methodology section and these first 23 chemicals.

21             We will then address the rest of the first batch

22   at the March 7th SRP meeting, so the panel will be receiving

23   the last 16 of the first 40 chemicals and with changes that

24   we have made pursuant to all the comments that has gone on

25   for the last three meetings.  So you should be receiving



 1   that very shortly.

 2             CHAIRMAN FROINES:  Help me.  This next 16 are

 3   chemicals that we have already discussed, you've made

 4   changes?

 5             DR. MARTY:  Correct.

 6             CHAIRMAN FROINES:  And then they'll be coming back

 7   to us again?

 8             DR. MARTY:  Correct.  Just like this first 23.  We

 9   wanted to get all 40 to you, but December got in the way.

10             DR. GLANTZ:  I had asked Melanie about this before

11   the meeting, why we didn't just get all 40 back, and I was

12   told that, as she just said, that they just didn't have time

13   to integrate the comments from the last meeting.

14             So what I would like to suggest is that subject to

15   any further discussion we approve the document as it's

16   before us, which is a method, a basic methodology in the

17   first 23, and then the rest of the 16 or 17 that they didn't

18   get to will just come in and maybe be incorporated as an

19   addendum, but appropre of the rock of Sisyphus, I'd like to

20   approve this document.

21             And unless people have -- I read through it.  I

22   thought it was fine.

23             And so the subsequent chemicals that we will deal

24   with would be treated as additions to an approved document,

25   rather than hold the document up.  Because this is going to



 1   go on for a long time as we add more and more compounds.

 2             CHAIRMAN FROINES:  We have 80 more to go.

 3             DR. GLANTZ:  Yeah.  But I'd like to have this be

 4   finished and approved so they have a finalized document and

 5   then we'll just add chemicals to it.

 6             CHAIRMAN FROINES:  Do you want us to then take up

 7   the 16 at a subsequent meeting?

 8             DR. GLANTZ:  Yeah.  I mean, what she just said is

 9   that they'll bring the rest of those back to us at the next

10   meeting, and I would expect that since they were discussed

11   at length already, hopefully it will be like -- at least

12   when I reviewed the document, I looked at it and said, yes,

13   they made the changes we suggested.  I couldn't think of

14   anything else, so I'd like to approve it, unless someone

15   else found anything they wanted to do.

16             Then as the additional chemicals come, the next 16

17   we would take, approve unless there's still a problem, and

18   that would be treated as an addendum to this document.  But

19   this document would be done and then the third batch or the

20   second batch and the third batch, as those come to the

21   committee and are discussed and dealt with would simply be

22   added to the approved document, rather than have the

23   document continue to wait.

24             CHAIRMAN FROINES:  So you're basically proposing a

25   two-vote sequence?



 1             DR. GLANTZ:  Well, I'm proposing that we vote,

 2   unless people have objections to it.  I have no concerns

 3   remaining with this document.  That we approve this and

 4   finalize it.  And then as additional chemicals come to us,

 5   that when those are approved they be added to the approved

 6   document, rather than holding the document until all 120 or

 7   however many there are compounds that will be dealt with.

 8             CHAIRMAN FROINES:  Comments on that?

 9             DR. FUCALORO:  I have no problem.  There are a few

10   things that almost fall into the category of typos that I

11   can talk to her later about.

12             DR. GLANTZ:  If other people have problems, then,

13   fine, but I don't personally have any problems with the

14   document as it stands now.  If they do, they should be dealt

15   with.

16             DR. WITSCHI:  I have a question about the future

17   of this document.  What's the mechanism or the process?  If

18   new data become available, which should be used to modify

19   what's already in it, because, you know, I've seen a few

20   examples where like this 1999 stuff which you didn't have

21   the last time, so as things -- if we approve it, you know,

22   as times move along, what's the mechanism to take care of

23   new developments?

24             DR. MARTY:  We intend to keep relooking at these

25   chemicals as time goes on, for that very reason.  There are,



 1   as you pointed out, a number of examples in here where we

 2   found new studies.

 3             DR. WITSCHI:  Yes.  Will you bring those changes

 4   before us?

 5             DR. MARTY:  Yes.  We have to bring the chemicals

 6   and the revisions before the panel.

 7             CHAIRMAN FROINES:  I guess I would suggest that if

 8   you are going to make revisions that you make the revisions

 9   over a period of time and bring as a block of chemicals.

10   The last thing I think we want to see is a chemical

11   dribbling in here and there.

12             DR. COLLINS:  Chemical of the month problem.

13             DR. GLANTZ:  Could be the pebble of Sisyphus.

14             DR. MARTY:  That makes a lot of sense to us too.

15   Bring it in batches.

16             CHAIRMAN FROINES:  I think that this then it does

17   begin to feel like an endless process.

18             DR. WITSCHI:  Won't it give some mandate to them

19   to -- OEHHA gives us an update every year, every two years,

20   something like this.

21             DR. COLLINS:  An annual update.

22             DR. WITSCHI:  At one of the meetings.

23             CHAIRMAN FROINES:  That make sense?  That's good.

24             So, Melanie, I think you're still -- this is a

25   little bit -- should have come at the end of your



 1   presentation rather than here, so why don't you go ahead.

 2             DR. MARTY:  Okay.

 3             CHAIRMAN FROINES:  Unless you are finished.

 4             DR. COLLINS:  We have no objection.

 5             DR. GLANTZ:  I actually thought she was finished.

 6   I'm sorry.

 7             CHAIRMAN FROINES:  No, no.

 8             DR. MARTY:  I'm almost finished.  I have four more

 9   bullets.

10             As Stan noted, I talked to him a little earlier,

11   we wanted to address the rest of the first batch on March

12   7th, and then I think it's a great idea to have that added

13   as addendum.

14             We have to review the public comments on the

15   second batch of 40.  We started that process, but we need to

16   keep going and make changes to those second batch of 40

17   based on the public comments, and also on the panel's

18   comments from the last several meetings.  So in other words

19   all the things that we changed in these chemicals, we've got

20   to go back to the second batch and make those similar

21   changes.  And then we were hoping to bring them to the panel

22   for review in June.

23             Then we have the third batch which has not even

24   gone out for the second public comment period yet, so that's

25   down the line.



 1             CHAIRMAN FROINES:  Now, the panel may not remember

 2   this, but the chemicals have been assigned to the various

 3   members of the panel.  And I guess I'll ask Peter to make

 4   sure everybody has that so they're reminded.

 5             DR. GLANTZ:  Why don't you give them, since some

 6   of us have short memory, I guess -- no jokes, I'm sorry.  He

 7   can just give them to me again.

 8             This is the current set.  Okay.  I can remember

 9   this.  I was going to say, as we get -- you haven't assigned

10   the second or third batch, have you?

11             CHAIRMAN FROINES:  The second are assigned.

12             DR. GLANTZ:  I thought my memory had completely --

13             CHAIRMAN FROINES:  The second are assigned.

14             DR. GLANTZ:  The second are.  Okay.  Maybe what

15   you should do is when we get the report from OEHHA on the

16   second batch, maybe you should send the assignments around.

17             CHAIRMAN FROINES:  I'll redo it.

18             Peter or Jim, we've sent the assignments out, but

19   let's redo it.

20             DR. GLANTZ:  For the second batch.

21             CHAIRMAN FROINES:  For the second batch.

22             DR. GLANTZ:  Why didn't you send that out

23   concurrently when you send the second batch out.

24             DR. MARTY:  Okay.  That's it for talking about

25   this document.



 1             I have three more overheads, but it's actually

 2   going to the second agenda item.

 3             DR. GLANTZ:  Let's finish with this before we go

 4   on.

 5             CHAIRMAN FROINES:  You're moving -- the last

 6   overheads are for the second agenda item?

 7             DR. MARTY:  Yes.  These last three are really the

 8   second agenda item, updating the panel as to where the rest

 9   of all the hots spots guidelines are.

10             DR. GLANTZ:  Let's finish this.

11             CHAIRMAN FROINES:  In that second -- we had talked

12   on the telephone about you're talking about the implications

13   of what we've all done and that's what's coming?

14             DR. MARTY:  That we should do now.  That we should

15   do now.

16             What's coming is where is Part 4, where is part 5

17   in the process.

18             CHAIRMAN FROINES:  No.  But I mean these three

19   overheads.

20             DR. MARTY:  Yeah.  That's basically what else we

21   have to do for the Air Toxics Hot Spots Risk Assessment

22   Guidelines, but it's not the discussion of how you use the

23   numbers in this.

24             CHAIRMAN FROINES:  Let's follow Stan's -- let's go

25   to Stan.  Does that make sense?



 1             DR. MARTY:  Yes.

 2             Unless you wanted to talk about issues of the

 3   hazard index approach and how we used the numbers, some

 4   issues have come up with the panel.

 5             CHAIRMAN FROINES:  Let's -- but that doesn't -- we

 6   can have a discussion after we've actually approved the

 7   document.

 8             DR. MARTY:  That's fine.

 9             CHAIRMAN FROINES:  Let's do that.  So I guess the

10   thing to do is to ask panel members if they have comments on

11   anything that's been presented or changes that have been

12   made.

13             Let's start out with Stan.

14             DR. GLANTZ:  No, I'm happy with the document.

15             CHAIRMAN FROINES:  Gary.

16             DR. FRIEDMAN:  I have no suggestions.

17             CHAIRMAN FROINES:  Peter.

18             DR. WITSCHI:  No problems.

19             DR. ATKINSON:  I have three minor changes on the

20   physical and chemical properties, if I can just give you

21   those.

22             DR. BYUS:  That's fine.  Very good.

23             DR. FUCALORO:  I have some changes, but they're

24   minor.

25             DR. GLANTZ:  Just for the record, these changes



 1   that Roger and Anthony mentioned, those are just minor

 2   editorial corrections, there's nothing substantive; is that

 3   correct?

 4             DR. ATKINSON:  There is a wrong vapor pressure in

 5   one of them.

 6             DR. FUCALORO:  There's one -- is that

 7   formaldehyde?

 8             DR. ATKINSON:  Yeah.

 9             DR. FUCALORO:  Formaldehyde is clearly wrong and

10   the number hasn't changed.

11             DR. ATKINSON:  Yeah.

12             DR. FUCALORO:  Other than that, they're mostly

13   typos.

14             DR. ATKINSON:  Typos.

15             DR. GLANTZ:  Well, then, I'd like to move that we

16   approve this document and finalize this document.

17             DR. KENNEDY:  Second.

18             CHAIRMAN FROINES:  Is there any further

19   discussion?

20             Then all in favor.

21             (Show of hands.)

22             DR. GLANTZ:  It's unanimous.

23             CHAIRMAN FROINES:  So the rock is tilting, holding

24   in place.

25             DR. MARTY:  Okay.  The next --



 1             DR. GLANTZ:  This is, by the way, a very nice

 2   piece of work.  And I think it continues the very

 3   high-quality work that you guys have brought before us,

 4   after we make you suffer appropriately.  But it is very very

 5   well done and it's just a massive undertaking.

 6             DR. MARTY:  That it is.

 7             DR. GLANTZ:  Very well done.

 8             CHAIRMAN FROINES:  I also think the panel gets

 9   credit, though, for having been very thorough in their

10   review of this.  That's been, I think, important so that the

11   public has trust in the deliberation that results in these

12   numbers being solidified.

13             Why don't you tell us what the meaning of all this

14   is.

15             DR. MARTY:  I can go through these slides and that

16   will help focus that discussion.

17             Basically what we just approved today was Part 3,

18   the determination of chronic reference exposure levels.  And

19   we will, as the discussion reflects, be adding chemicals as

20   we move along in over time.

21             We also have -- Judy, can I have the next slide.

22             As we just discussed Part 3, what we're going to

23   be doing, Part 4 is the technical support document for

24   exposure assessment and stochastic analysis.

25             And Dr. Glantz is the lead on that document.  He



 1   has received a copy and is plowing through it now.

 2             The panel will receive the document mid February,

 3   along with our responses to the comments.  The public

 4   comment period occurred a couple of years ago and then the

 5   document sort of got -- well, we lost a lot of staff and

 6   diesel exhaust got in the way.  So we are now getting back

 7   to the -- we responded to the comments.  Everything is ready

 8   to go, but we didn't want to give it to you before this

 9   meeting to avoid a paper blizzard.

10             We intend to make an overview presentation of the

11   document and some discussion of the changes that were made

12   since the last version, which was presented by OEHHA to the

13   panel in March of, I think it was 1997.

14             So we had an overview of the document already

15   given to the panel.  There was some discussion at that

16   meeting.  And then we have made quite a few changes since

17   then to that document, so we'd like to just re-present the

18   document and talk about some of the key changes.

19             And then we anticipate that by the time the May

20   meeting rolls around the panel will have had enough time to

21   look at the document and we can start discussion by the

22   panel.

23             CHAIRMAN FROINES:  In March?

24             DR. MARTY:  In May.  March 7 we'll present an

25   overview, but you folks will only have had the document a



 1   couple of weeks at that point.

 2             DR. GLANTZ:  We're not meeting in April?

 3             DR. MARTY:  I don't know.  I looked at my latest

 4   notes indicating no April meeting.  So that I'm just

 5   throwing May out there, because I didn't realize there was

 6   an April meeting.

 7             CHAIRMAN FROINES:  Jim.

 8             MR. BEHRMANN:  The next meeting date beyond March

 9   has not been set yet.

10             DR. GLANTZ:  I would think, I mean, I'm about a

11   half, a third, or halfway through the revised document, and

12   I would think that it could be discussed.  I think it's a

13   long, complicated document, but it's, I think if there's a

14   presentation in the March meeting, then it would be

15   reasonable to have a discussion in the May meeting or rather

16   at the next meeting, whether it's in April or May.

17             I think that there have been a lot of changes to

18   the document.  This is the one where they're trying to model

19   population variability, and rather than looking at single

20   numbers, take into account variability of breathing rates,

21   variability of how much dirt you eat, all of that sort of

22   variability, weather conditions, and there are a lot of, you

23   may recall, political problems with the document before

24   where there was some modeling going on, and as far as I am

25   able to detect it's now back to being based on science.



 1             And but I have not had a chance to go through the

 2   public comments.  And I was just looking at the document,

 3   but it is about three inches thick, three or four inches

 4   thick.

 5             Because there's a methodology is laid out and then

 6   they go through, it's sort of like what we've been doing

 7   with these chemicals, except looking at different biological

 8   parameters and there are a series of studies discussed and

 9   distributions involved.

10             But I think it's like the one we just approved,

11   it's going to represent a substantial contribution to

12   improving the quality of these risk assessments.

13             But I think that the plan, since it is

14   complicated, to have it presented at one meeting and give

15   people some time to think about it before we actually

16   discuss it is a good idea.

17             But I have, in going through it so far, I haven't

18   found any major problems, although I'm not finished.

19             DR. MARTY:  Okay.

20             CHAIRMAN FROINES:  Can I ask you one question

21   before we go on.

22             One of the issues that emerges when you do

23   stochastic modeling and you've looked at the population

24   distribution of risk, that gives you a whole series of data

25   which you then use in your ultimate risk management



 1   determinations.

 2             Here we come up with 3 times 10 to minus 4 for

 3   diesel, and then unfortunately, in my view, people tend to

 4   use that as a bright line.

 5             Now, with stochastic modeling, you come up with a

 6   wide range of values, based on the different distributions,

 7   and then somebody has to decide what is the level of

 8   protection that you should afford the public, given those

 9   distributions.

10             And so it would be very useful when we actually

11   get around to discussing it, I don't want -- the panel can't

12   get into the risk management issue, but if you can give us

13   some sense about how you developed this mass of data, how

14   people are going to interpret it for public health

15   consideration and control use, because if you have 25

16   numbers or ten numbers or one number or hundred numbers,

17   somebody still has to decide what is the -- what do you use

18   when you make decisions.

19             And so at some level just because you can do

20   stochastic modeling doesn't mean that things get necessarily

21   better, unless you have a clear, coherent policy framework

22   to offer.  So it seems to me it would be useful to have some

23   sense for the panel to have some sense of that, so they have

24   a sense of how you're actually going to use that

25   information.



 1             DR. GLANTZ:  I'll let Melanie talk here, since she

 2   wrote the document, but that's in there actually.  You know,

 3   where they in fact have some discussion of when it's worth

 4   the trouble or suggestions on how to decide whether or not

 5   it's worth the trouble to use this more complicated modeling

 6   approach.  I don't recall anything about where you should

 7   draw the line.

 8             DR. MARTY:  Right.  We actually presented tiered

 9   approach in there to risk assessment, with four tiers.  The

10   first being just a deterministic approach where you have one

11   input value for an exposure parameter, and that would be the

12   simplest form.

13             And what we did was we used our analyses of the

14   distributional characteristics of the data, for example, for

15   breathing rate, to say where we think those point estimates

16   should lie and we present a mean or a central tendency

17   estimate and a high end estimate, which in this case is the

18   95th percentile on the distribution.

19             And then we do have discussions of when it makes

20   sense or doesn't make sense to do a more complicated risk

21   assessment using the full distribution.

22             We do -- we don't have anything in there about how

23   the risk manager then chooses where on the distribution

24   they're going to protect people.  And we did that in a sense

25   on purpose because we're trying to just look at the science



 1   and say this is the 50th percentile, this is the 75th, this

 2   is the 90th, this is the 95th, rather than getting into the

 3   risk management end of things.

 4             However, both the Air Board and several of the

 5   districts have had some discussion about this issue and I

 6   anticipate a lot more discussion in the next six months or

 7   so of what to do with the numbers.

 8             In essence to have the distributional

 9   characteristics better defined helps the risk managers,

10   because right now the deterministic methodology is based on

11   estimates that might be a combination of the 50th percentile

12   and the 75th and the 95th here and maybe the 99th there and

13   you really don't know where you are on the distribution

14   without doing a really thorough analysis.  So that's one of

15   the issues that we tried to address in this document.

16             CHAIRMAN FROINES:  Go ahead.

17             DR. MARTY:  Okay.  And then Parts 1 through 4

18   represent the technical support documents, with lots of

19   information that eventually gets distilled into Part 5,

20   which is risk assessment guidance manual.  The guidance

21   manual is just that, it's a step-by-step incorporates all

22   the information from Parts 1 through 4 and gives

23   instructions for conducting site-specific health risk

24   assessments in the Air Toxics Hot Spots Program.

25             And we have worked with ARB on this and will



 1   continue to do so and also with the California Air Pollution

 2   Control Officers' Association.

 3             We're hoping that the manual is ready by this

 4   summer.

 5             There was some discussion about the role of the

 6   panel, but we think that the panel needs to look at the

 7   manual.

 8             That's all the overheads that I had.

 9             DR. GLANTZ:  That's all the work you have for us?

10             CHAIRMAN FROINES:  So panel will see the manual

11   this summer?

12             DR. MARTY:  Yes.

13             DR. COLLINS:  Jim Collins, OEHHA.

14             I'd like to say that some of the acute RELs are

15   already being used now in risk assessments that the

16   districts are submitting to OEHHA, so the numbers that were

17   approved last March have been actually used in actual risk

18   assessments or as an index or acute index.

19             CHAIRMAN FROINES:  So, Melanie, you were going to

20   say?

21             DR. MARTY:  There were some concerns on a couple

22   of the panel members regarding the use of the chronic

23   reference exposure levels.  And I don't have overheads for

24   this, but I think I wanted to talk through it.

25             In particular, since some of these chronic



 1   reference exposure levels are fairly close to measured

 2   ambient concentrations in the South Coast Air Basin, the

 3   question arose, well, what does the risk manager do with

 4   that.

 5             The hazard index approach, as you'll recall, is

 6   where you ratio the modeled ground level concentration from

 7   what you estimate using modeling the air dispersion of

 8   chemicals from a specific site.  You ratio that to the

 9   reference exposure level.

10             If that number is one or less, then the typical

11   risk management decision has been that the facility is fine

12   and it poses no public health risk.

13             It's when this number goes above one that flags

14   get raised.  Different risk management, just different risk

15   managers will use that number in different ways.  The 35 air

16   pollution control districts all have to have a regulation as

17   to what they do for the hot spots program when that number

18   goes above one.

19             In the notification provisions of the statute, the

20   district can require facilities to notify the surrounding

21   community of their emissions and what those emissions are,

22   what the potential health impacts are.

23             It's up to the district whether they notify and

24   who notifies.

25             The ARB back in '92, I think, came up with a



 1   notification guidance, and in the guidance they recommend

 2   that OEHHA be contacted if the hazard index goes above one.

 3   And there was a lot of discussion and still is a lot of

 4   discussion about what to do when the hazard index goes above

 5   one.  And the primary issue is, well, there's uncertainty in

 6   those numbers.  Those numbers are meant to protect basically

 7   everybody, so when you start exceeding those numbers, how

 8   much do you have to exceed them before you actually have

 9   endangerment of the public health.

10             Of course we have included information in there to

11   protect sensitive subpopulations.

12             So there have been many instances where the

13   districts have a facility where a hazard index is above one

14   and they've called us and said what is the uncertainty in

15   this number and we've walked them through the derivation of

16   the reference exposure level.

17             If we have an uncertainty factor of a thousand and

18   the hazard index is two, that doesn't give me very much

19   heartburn and generally doesn't give the risk managers very

20   much heartburn.

21             If you have a hazard index of two or three or four

22   and your uncertainty factor was only cumulative uncertainty

23   factor of ten, then in most instances most districts would

24   require that facility to notify.

25             So it's not hard and fast.  Some districts have --



 1   at least one district, Sacramento Air Quality Management

 2   District, the hazard index has to reach ten before they

 3   require notification.

 4             I don't personally necessarily agree with that,

 5   because that erases all of the uncertainty factor for some

 6   chemicals, but for others that may be adequate.  So therein

 7   lies the rub of how to use these numbers.

 8             DR. FUCALORO:  So the reporting of a number, of

 9   course, is one-dimensional object element.  Why not report

10   numbers with uncertainty factors?

11             DR. GLANTZ:  They are.

12             DR. FUCALORO:  They do that?  So they say contact

13   you and ask you what the uncertainty factor is.  It seems to

14   me they should have the information --

15             DR. GLANTZ:  It's in the documents.

16             DR. MARTY:  They have the documents.  They have

17   the documents.  It's just usually a question, it's an

18   engineer who is calling and they're unsure of the meaning

19   and the toxicology of the compound and want to know a little

20   more.  That's generally what happens.

21             DR. FUCALORO:  Also I mean an argument for a

22   case-by-case basis, not only knowing a number and an

23   uncertainty factor, also the toxic endpoint is important.

24             DR. MARTY:  Yes.

25             DR. FUCALORO:  If it's sneezing, it's one thing.



 1   If it's something neurological damage, it's quite another.

 2             DR. MARTY:  Yes, yes.  I think most risk managers

 3   get a little more nervous if we're talking about

 4   developmental toxicity and irreversible impacts, versus eye

 5   irritation.

 6             CHAIRMAN FROINES:  But there's also the issue of

 7   variability versus uncertainty.

 8             DR. FUCALORO:  That's a good point.  That's a good

 9   point.

10             DR. MARTY:  Yes.

11             DR. GLANTZ:  And the stochastic model or document

12   goes on in some length about that, actually.

13             CHAIRMAN FROINES:  So is there -- do the local

14   districts -- let's assume if the local districts then have

15   the company or whoever notify the public who are quote,

16   "overexposure," is there any other legal requirement for

17   control to reduce that level?

18             DR. MARTY:  Yes.  There is a requirement that the

19   districts, if they deem the health risk to be significant

20   enough, institute risk reduction audits and plans, so the

21   facility has to go back and look at their process and decide

22   where they can reduce emissions.

23             To my knowledge, there have been very very few

24   facilities in this state that have had to do risk reduction

25   audits and plans, and it's always been based on the



 1   carcinogenicity, or the carcinogenic risk from the

 2   emissions.  I'm unaware of any risk reduction plans that

 3   have been triggered by a hazard index exceeding one.

 4             DR. COLLINS:  They could be.

 5             DR. MARTY:  Yes, they could be, but I'm unaware

 6   that that has happen.

 7             I think in most cases they have a different

 8   trigger level, so, for example, the notification, the

 9   trigger level might be a hazard index of two or five, but

10   the risk reduction trigger level is much greater than that.

11   They've done that also with the cancer risk estimates from

12   facilities.  Most facilities have to notify when the cancer

13   risk is above ten to the minus five, but risk reduction

14   doesn't kick in until the cancer risk is above ten to the

15   minus four.  There's a parallel.  Each district has their

16   own regulation, so I don't know what all the regulations

17   are, but there's a parallel process for the hazard index.

18             DR. COLLINS:  The South Coast is currently looking

19   at revising the hazard index, get your hazard index below

20   five, and now they're thinking of getting it below three, so

21   that's part of the rule 1402 that we're looking at right

22   now.

23             CHAIRMAN FROINES:  Well, it's interesting --

24   Peter.

25             DR. WITSCHI:  These are great documents.  Are they



 1   are going to be available in some electronic form?

 2             DR. MARTY:  Yes.  They'll be posted on our Web

 3   page, so people can just download them from the Web page,

 4   from OEHHA's web page.

 5             DR. WITSCHI:  Are they going to be searchable in

 6   these form?

 7             DR. MARTY:  Are they going to be circulated?

 8             DR. WITSCHI:  Searchable.

 9             DR. MARTY:  Searchable.

10             DR. WITSCHI:  The reason I'm bringing this up, I

11   once came across documentation which was on a disk, but it

12   was in pictures.  It was totally useless, because you

13   couldn't search it.

14             DR. MARTY:  You know, I have to ask our Web

15   master.

16             Andy says there is a search tool on our Web site,

17   but I personally never tried it, so I don't know how good it

18   is.

19             DR. SALMON:  It's a basic text search function at

20   the moment.  I think they're looking into getting more

21   sophisticated database type structure built into the site,

22   but it's not there at the moment.

23             DR. WITSCHI:  Because the data you have in those

24   documents, they really could be used to do some very

25   interesting research and reexamination, re-evaluation of



 1   some of the assumptions, because we have so many data on

 2   them.

 3             DR. SALMON:  It's a basic long-term objective to

 4   get all these numbers into a database format, so it would be

 5   actively searchable off the Web site, and that's something

 6   which they're working on at the present time.

 7             DR. MARTY:  I think there's another issue to sort

 8   of tie it in there, what do you do when your reference

 9   exposure level is pretty close to ambient measured

10   concentrations.  And it's really parallel to if you look at

11   the criteria air pollutants we do have some RELs for the

12   criteria air pollutants, basically they're the ambient air

13   quality standard.  And many times they're exceeded in the

14   basin.

15             Some years back, the districts required facilities

16   to also in this program look at their criteria air

17   pollutants emissions and add them into the hazard index

18   approach, and in the South Coast Basin that almost always

19   kicked people over one for respiratory and eye irritation,

20   so the district made the decision not to require people to

21   notify based on a criteria air pollutant emission if that

22   exceeded that, the ambient air quality standard.

23             And part of their logic was, well, we have other

24   ways of dealing with that, we don't need to deal with that

25   through the Air Toxics Hot Spots Program.  There's a whole



 1   nother program that deals with criteria air pollutants.

 2             So in the case of formaldehyde there may be for

 3   this chronic REL, it's fairly close.  It's actually the

 4   ambient levels measured in '98 are right on top of what

 5   we're proposing as the chronic reference exposure level.

 6             So it may turn into an issue for the risk manager

 7   of whether they want to do something about that or not.

 8             CHAIRMAN FROINES:  I have just one more question,

 9   which is let's assume that you have a plant that's using

10   toluene diisocyanate, which is a strong sensitizer, that the

11   effects are very low levels and so on and so forth.

12             How does anybody know that plant X, which used the

13   TDI, and how does anyone know what that dispersion

14   concentration is?  In other words, how does one determine

15   the numerator in your hazard index, and how is -- are the

16   local districts responsible for determining that those

17   values for industrial sites and so they have to know what

18   chemicals are being used?  I don't understand how it all

19   works, frankly.

20             DR. MARTY:  The districts are required to obtain

21   information on emissions from the facilities themselves that

22   are under their purview.  And there are cut points in terms

23   of if the facility emits greater than 25 tons per year of

24   criteria air pollutants than they were in the first phase.

25   And there's the first phase, the second phase and the third



 1   phase, basically go by size of the facility.

 2             The districts generally have gone by which

 3   facilities have permits.  So that's how they've tracked

 4   facilities down.  They work with the facility operator to

 5   come up with the emission estimate, and they're responsible

 6   for making sure that the emissions estimates from each

 7   facility are accurate.

 8             For a small district that's a small workload.  For

 9   the South Coast Air District that's been a huge workload.

10             If the facility is required to conduct a risk

11   assessment, and only those that fall within a certain

12   category in the district's prioritization are actually

13   required to write a risk assessment, for those facilities

14   the risk assessment uses an air dispersion model to estimate

15   what the ambient concentrations are in a grid surrounding

16   the facility.  That air dispersion model is reviewed by the

17   local air district engineers and approved.

18             So and also the Air Resources Board is sometimes

19   called in for some of the more -- the larger facilities that

20   had to use fancier modeling.

21             So that's how the numerator is derived.  It's

22   basically based on estimates of emissions and air dispersion

23   modeling.

24             CHAIRMAN FROINES:  Further questions?  Are there

25   further questions for Melanie?



 1             Okay.  Thank you.

 2             Can we take a ten-minute break before we switch

 3   over to pesticides.

 4             (Thereupon a short recess was taken.)

 5             CHAIRMAN FROINES:  Everybody has a copy of the

 6   January 5th letter to Paul Helliker and Mike Kenny that

 7   transmitted the findings from our two -- our workshop that

 8   had two parts, one on prioritization and one on exposure

 9   estimation.  And so you've had that before, so this is just

10   give it to you again.

11             It seems to me that that process worked out very

12   very well.

13             So the point of this part of the agenda is for a

14   discussion to see if the panel has ideas for any subsequent

15   workshop activities that we might consider to further

16   improve our addressing of pesticide-related issues.

17             And I think that the other part of this would be

18   for Elinor to work with DPR staff to further develop ideas

19   and generate suggestions.

20             And I think what she's going to mention this

21   morning is not a direct result of a conversation with DPR,

22   but in a sense her own activities.  But that one of the

23   things we did was to ask Elinor to work with staff at DPR to

24   develop workshop ideas so that we're all in sync on this.

25             She has some suggested ideas for future workshops,



 1   the dates of which are to be determined.

 2             And basically she thought that we never completely

 3   finished the issues surrounding organophosphates.

 4             So, Elinor, why don't you talk about the things

 5   you've been thinking about?

 6             DR. FANNING:  Do you want to start directly with

 7   the organophosphate idea, or do you want to open for a more

 8   general discussion of more a brainstorming for future

 9   workshop topics?  We can do it either way.

10             CHAIRMAN FROINES:  Either way.  Go ahead.

11             DR. FANNING:  Okay.  I had via Jim Behrmann for

12   input before today's meeting from either panel members or

13   agency staff for ideas for future workshops.

14             I think perhaps the time was a bit short, and I

15   haven't heard a lot of feedback yet.

16             But we can have a general brainstorming session

17   today in which we can identify topics that might be helpful

18   to discuss in a workshop format.  And I think the idea is if

19   we can anticipate the issues, scientific issues, that are

20   likely to arise in the evaluation of documents that are

21   coming to the panel, then I can work to develop an agenda

22   and identify some speakers who can address those topics and

23   get to some consensus and clarification before we actually

24   get into long snarls with various documents.

25             Maybe it is most effective if we begin with the



 1   one idea that I came up with, and then we can take a minute

 2   afterward to develop this idea further and also see if there

 3   are other topics that people would like to suggest.

 4             So this is the one-page outline that Peter should

 5   have, I believe, handed out to everybody.

 6             Okay.  What this is is essentially an idea to take

 7   a short session, probably just a couple of hours, to follow

 8   up on some of the recommendations that came out of our

 9   earlier workshops held in October in South San Francisco.

10             Specifically from workshop Part A on pesticide

11   prioritization from October, the second recommendation from

12   the panel is to consider a batched approach for listing of

13   high priority or organophosphate pesticides.

14             And the idea there is to see if DPR would consider

15   developing a document similar to what you're seeing for

16   chronic RELs that would essentially address a number of the

17   organophosphate pesticides in one document and thereby

18   streamline the process of evaluation.  Many of these

19   pesticides have similar toxicological properties.

20             So I would envision -- this is just sort of

21   brainstorming of my own, and I think it would be good after

22   I go through it to see if DPR might have some comment on

23   what they think would be most useful out of this.

24             But I envisioned beginning with DPR staff coming

25   with a status report on the organophosphates, going through



 1   which ones are their highest priority for assessment at this

 2   point, which have been monitored in California.  And I

 3   believe the majority of the high-priority organophosphates,

 4   there is some monitoring data available.

 5             Furthermore, there are toxicological and health

 6   effect assessments from US EPA, and we had a speaker come to

 7   our workshop to discuss those tolerance reassessment

 8   documents with us.  So there are quite a bit of background

 9   data that may or may not be useful for the DPR assessment,

10   and I'd have to get DPR to comment on that.

11             And after we began with an identification of which

12   organophosphates might be useful to address in a batch, then

13   I envision that we could go on and discuss some of the key

14   toxicological issues with assessments to these pesticides,

15   perhaps bringing in outside speakers if that is useful.

16             And the toxicological issues that came to my mind

17   right off the bat, first are the issue that we've had

18   several times before of cholinesterase inhibition.  It's not

19   clear to me whether it's completely resolved, how the panel

20   and DPR want to handle evaluation of cholinesterase

21   inhibition data, and whether it might be useful to develop a

22   discussion to develop a standardized approach to those data.

23   Most of these pesticides are cholinesterase inhibitors.  So

24   that would be the first of those issues.

25             We can talk about that a little bit more, what



 1   specifically you'd like to see addressed, and then I can

 2   work to try to identify appropriate speakers for it.

 3             Secondly, I identified metabolism and

 4   toxicokinetics as an area that might benefit from some

 5   workshop type discussion before preparation of a document.

 6   There's quite a bit of information on paraoxonases, enzyme

 7   in humans and interindividual variability due to

 8   polymorphisms in the gene for this enzyme, that may affect

 9   the population distribution of sensitivity to

10   organophosphate pesticides.

11             So I had identified that as a potential area to

12   bring in a speaker and have some discussion.

13             And the third toxicological issue that I have on

14   this relates to a discussion that I believe has also come up

15   with the panel before of acute and reversible health effects

16   versus chronic delayed health effects and how those data

17   would be treated in the risk assessment.

18             Item No. 3 would then progress to sort of a

19   discussion of method, what type of format for a batched

20   document would be most useful for the panel and most

21   efficient for DPR to develop some discussion on how to, what

22   type of outline would be most effective.

23             Then the final issue that I thought we may want to

24   include is some discussion of whether or not it's useful to

25   try to address co-exposure to multiple organophosphate



 1   pesticides in this document.

 2             We had some discussion of multiple pesticide

 3   exposure in our workshop.  We had the follow-up session at

 4   Claremont where Randy Segawa from DPR presented some

 5   alternative ways of grouping pesticides.  And one of his

 6   alternatives was in chemical family types such as

 7   organophosphates.

 8             So we may want to develop that idea a bit further,

 9   but I believe it would require quite a bit of discussion

10   about how to do an exposure assessment for mixed pesticides.

11   We need to look into the feasibility issues there.

12             So that's a brief presentation of the idea that I

13   had for that workshop.

14             And I'd be interested in hearing feedback whether

15   people think it's useful, whether there are issues you

16   particularly like to see.  And I don't know if perhaps DPR

17   might want to comment.

18             MR. GOSSELIN:  Thank you, Elinor.

19             I thought this was a real good outline.  It's

20   consistent with the findings from the workshop from last

21   fall and some of discussions we had.  And I think even

22   thinking about the discussion you just had with the OEHHA

23   documents and how they've gone through a pretty lengthy

24   process and batching of many many compounds for

25   consideration, and given the parameters of what the law



 1   allows us to do and what would meet the scientific

 2   expectations of 1807 could we do something similar.  Because

 3   I think as a finding, grinding out single documents is kind

 4   of a long process.  And if there's a more efficient means

 5   while maintaining a full scientific scrutiny of the

 6   pesticides we're dealing with, we should probably look into

 7   that, and I think this might be a good opportunity to do

 8   that, looking at the OPs.

 9             Another cut on this is that we also have a list of

10   HAPs listed toxic contaminants.  Those are out there, some

11   of which we do have risk assessments completed on, some of

12   which because of their use or potential to get into air or

13   other things that we don't have any activity on, but

14   eventually we may have some air issues with them and should

15   there be a means of us going through a similar process you

16   went through with OEHHA of coming up with a summary document

17   and getting RELs established for those compounds.

18             And almost as a sideline is this project we're

19   working on with ARB, OEHHA and some other agencies down in

20   Lompoc, that's going to expand this spring, we're going out

21   and monitoring for upwards of 50 pesticides in a community.

22             CHAIRMAN FROINES:  15?

23             MR. GOSSELIN:  50.

24             CHAIRMAN FROINES:  5-0 or 1-5?

25             MR. GOSSELIN:  5-0.



 1             The staffs from OEHHA, our staff and DHS and the

 2   county have gone through and using best professional

 3   judgment have come up with sort of preliminary RELs that

 4   would be used as screening levels for these numbers.

 5             So this is almost getting into sort of the cutting

 6   edge where pesticide air exposures are getting to the

 7   communities, looking at multi-residues.

 8             The big advent is going to be that there's going

 9   to be multi-residues screens developed for air monitoring

10   that's going to allow us potentially to use these methods in

11   various places, which is going to necessitate having some

12   scientific notice to evaluate whether we need to take any

13   mitigation measures.

14             But I think with this, whatever choice we make on

15   going with OPs, which is a good one, or HAPs, or some other

16   cut, I think looking at the document you've just gone

17   through and approved is almost a template for us to try to

18   emulate, would be a suggestion on how to go.

19             CHAIRMAN FROINES:  When you say multi-residue

20   screens, are you doing essentially micro-environmental

21   monitoring to look at contamination of soil, contamination

22   of water?

23             MR. GOSSELIN:  The one down in Lompoc is strictly

24   air.

25             CHAIRMAN FROINES:  Air.



 1             It's an interesting issue when you think about it.

 2   If you've identified 50 pesticides that are used in Lompoc

 3   that you can sample for, that gives us some sense of the

 4   scope of this problem we're dealing with.  It would be

 5   interesting to see a protocol for what this is.

 6             MR. GOSSELIN:  Actually, one of the things we're

 7   interested in with this project and the protocol is having,

 8   and this was just discussed at the interagency panel, was

 9   having some external peer review of the work that staff had

10   been doing, so that's real critical.  And if that can be

11   brought forward here to evaluate, at least the methodology

12   on how the monitoring is designed and the thought process

13   and screening levels, I think that would be real helpful.

14             CHAIRMAN FROINES:  On the HAPs, you know what

15   would be useful, it seems to me, would be to have Elinor

16   work with your staff to look at the use patterns for the

17   various HAPs, as well as the chemical structures for the

18   HAPs.  In other words, are there unifying elements that

19   would help pick -- we were talking last night about

20   compounds that contain chlorine and bromine, for example, as

21   one structure issue.  And but I don't know the pesticide

22   HAPs, so it would be useful to do some background to look at

23   structure activity issues and to look at use patterns.

24             DR. FANNING:  Is there a sense of whether it would

25   be -- I think this idea of looking at HAPs or looking at the



 1   group of chemicals being monitored at Lompoc is very

 2   interesting, and is there a sense of whether we would want

 3   to focus on one of those issues first or the organophosphate

 4   groups, or which would be most useful?

 5             MR. GOSSELIN:  There are down in Lompoc it does

 6   capture a lot of OPs used in one of the screens.

 7             DR. GLANTZ:  Why did you pick Lompoc, just for

 8   curiosity?

 9             MR. GOSSELIN:  Given we only have the rest of

10   today, I don't have all the time.

11             DR. GLANTZ:  Can you give us, you know, the

12   classic comic book explanation of why you picked Lompoc?

13             MR. GOSSELIN:  They picked us.  It was a community

14   that had housing right next to agriculture in the Valley,

15   and fairly small community, moderate size, fairly moderate

16   size agriculture in an enclosed valley, right next to

17   Vandenburg Air Force Base.

18             There was a lot of concern about various health

19   concerns in the community and one of the concerns was some

20   pesticide use.  And one of the things that had not been done

21   was very extensive or any pesticide monitoring of

22   agriculture in that area.

23             So it became chicken and egg about which products

24   about the 140 that are used there, what to monitor for and

25   whether they had any direct bearing on the health effects.



 1             And that sort of discussion went on for a while

 2   and then about three or more years ago we ended up forming

 3   an interagency work group with state scientists and brought

 4   in some local people to kind of craft out a consensus on

 5   what they would like to see.

 6             That did go beyond pesticides.  There was a silica

 7   plant that eventually shut down and they were having a lot

 8   of problems and a variety of other things.

 9             And there's a big health survey going on also.

10             CHAIRMAN FROINES:  But my sense is that we can

11   follow that operation going on there, but it seems like that

12   wouldn't be part of something we would do as a workshop

13   unless -- it seems to me like the outline that you came up

14   with for this makes more sense, at least from our

15   standpoint.

16             MR. GOSSELIN:  The cholinesterase policy probably

17   be something very relevant and specific, that we've had sort

18   of our paper written on.  I think EPA has held at least one

19   scientific advisory panel on that, with issue papers.  I'm

20   not sure if they have a report out yet.

21             DR. FANNING:  They do have some kind of risk

22   assessment approach to cholinesterase data.

23             MR. GOSSELIN:  Right.

24             And some of the members that sat on the SAP could

25   come out for that also.



 1             DR. BYUS:  I really like this outline for the

 2   organophosphate.  Lot of these issues we dealt with and are

 3   very important.  It's still not clear that -- I really think

 4   it would be an excellent idea to have a workshop on this, on

 5   the organophosphates.  I don't know what the order would be,

 6   but it's certainly a pressing issue.  There's many of them.

 7   And all of these issues, toxic mechanism, toxicokinetics,

 8   plasma versus red blood cell, versus brain, delayed

 9   neurotoxicity versus immediate, and also the carcinogenicity

10   of these things is complicated.  It's variable.

11             And then the multiple exposure issue, God only

12   knows.  I mean, I think I still say somewhere in food

13   residue is some answer to that question, because at least

14   you know that these were all applied at one point.  If you

15   work your way back from that, in addition from forward from

16   how you've sprayed them, you can work your way backwards,

17   because you know they're actually there.

18             So all of these things are very important and

19   since there's a lot of organophosphates, I think just the

20   science discussion would be very important to the panel.

21             DR. FANNING:  Okay.

22             CHAIRMAN FROINES:  I frankly think this issue, the

23   more I read about pesticides, the more impressed I am with

24   the tremendous challenge that we have, because the data we

25   have to work with is so limited.  We're constantly trying to



 1   ask questions and there's no data because people do science

 2   for regulatory purposes rather than science for NIH.

 3             And so you just don't have the kind of -- I mean,

 4   just look at the database on butadiene or perchlorethylene

 5   or asbestos or lead.  I mean, it's thousands of papers.

 6             And with pesticides, there's just a few papers and

 7   they're not in the peer-reviewed literature.  Relatively few

 8   in the peer-reviewed literature.

 9             We can try and look at all these issues, which I

10   think is good, but part of the problem is what we have to

11   work with is so small.  I wish there was a way to stimulate

12   more research on a lot of these issues, because I think we

13   have a real limiting factor.

14             But having said this, I think there's a third

15   issue that is a little different from what Elinor said,

16   which is I take the issue of chronic health effects from OPs

17   as being different than acute effects as being different

18   than delayed neurotoxicity, and that is the long-term

19   chronic neurological effects from organophosphates,

20   irrespective of the delayed neuro effects is still an issue

21   that is not well defined, I think.  So that's another.

22             DR. FUCALORO:  I'm a little unsure as to what

23   we're supposed to be deciding here.  This looks like

24   basically, it seems to be some agreement, at least from

25   those who spoke, that the document presented to us would be



 1   a good working document for the next workshop, and I guess

 2   you come back with some modifications for our review, I

 3   guess through you, John.

 4             CHAIRMAN FROINES:  I think basically Elinor is

 5   doing her best at trying to get feedback from this panel and

 6   so she's dragging --

 7             DR. FUCALORO:  Well, it's such a well-thought-out

 8   document, it's hard for us to say other than it seems good

 9   and we should proceed.  But actually you heard some


11             DR. FANNING:  Yes, the feedback is useful.

12             In addition, I had hoped to get a sense from Paul,

13   from you, how important this issue was versus other issues

14   that you may have in your minds, other questions, other

15   possible workshop topics that you'd like to address.

16             What I'm hearing, I think, is that most people

17   think this would be a good idea to go ahead with as our next

18   workshop.  Is that --

19             DR. KENNEDY:  Unquestionably.

20             DR. FANNING:  Okay.

21             CHAIRMAN FROINES:  I think the other thing is it's

22   important to get a lot of feedback input from DPR, because

23   there are lots of scientific questions that they've been

24   wrestling with for longer than this panel has and the panel

25   becomes a place in which those questions can be aired and so



 1   it's maybe it's useful to us then, as well as for panel

 2   deliberations.

 3             DR. FANNING:  Exactly.  I anticipate that we'll

 4   work together closely and essentially have DPR staff

 5   identify and help sort of frame these issues in a more

 6   specific way.  So we'll plan to work together on that.

 7             DR. WITSCHI:  You know, you comment about not so

 8   much science, this is science, may be true, but there used

 9   to be a very extant volume and it was called "Pesticides, a

10   Study in Man."  And it was edited by Jake Hayes, who has

11   been dead for about seven, eight years or so.  But I think

12   we should make an effort, because to the best of my

13   knowledge somebody is continuing this work, and that is for

14   our purposes the first thing to look for to get information

15   is what are the data out there about toxicities of

16   pesticides as we can derive from man.  And I would expect

17   that much of the old information might actually still be

18   valuable.

19             CHAIRMAN FROINES:  That's true.  There's been a

20   consistent level of research.

21             DR. WITSCHI:  Yes, yes.

22             CHAIRMAN FROINES:  However --

23             DR. WITSCHI:  I don't know, I think somebody has

24   created this, but I'm not quite sure, but this could be

25   found out.



 1             CHAIRMAN FROINES:  On MITC, the person who is most

 2   often quoted is Dr. Alexeeff.  He has the most references, I

 3   think, of anybody.  So we expect to hear from you today.

 4             Thank you, Paul.

 5             Thank you, Elinor.

 6             I think we're finished on that.

 7             DR. FANNING:  Yeah.  I think so.  We'll work

 8   together and send something around with a more detailed

 9   proposal after we have worked it out and propose a date and

10   see if you have input about speakers or want to help refine

11   the agenda.

12             CHAIRMAN FROINES:  I think that I'm interested in

13   paraoxonase polymorphisms, but I think that you should try

14   and keep the context clear, which is how does the

15   paraoxonase polymorphism or other interindividual

16   variability issues affect the risk assessment process.  So

17   it's not just simply an abstract scientific issue.

18             DR. FANNING:  Sure.  I think as I stated here, the

19   idea is can the data on paraoxonase polymorphisms be used to

20   perhaps adjust or at least provide a reality check on the

21   use of default tenfold interindividual variable protection

22   factor.  Perhaps that would help bracket it a bit.  One of

23   the goals of discussing it is that very concrete risk

24   assessment issue.

25             CHAIRMAN FROINES:  One of the things we might hope



 1   to come out of some of these things is questions that we can

 2   send to US EPA to say we need to know how many people in the

 3   population have this genetic change, and EPA should be

 4   funding work to find that out.  I mean, in other words, it's

 5   not -- we don't necessarily have to see this as a totally

 6   internal process, because if we raise important scientific

 7   questions, then in fact those should go to a place like EPA

 8   for them to think about it.  California tends to be ahead on

 9   this stuff to some extent, rather than behind.

10             DR. FANNING:  Thank you.

11             CHAIRMAN FROINES:  Peter and I, we're talking

12   because we were -- Paul Blanc is doing his -- is on the

13   wards at this point, so he can only be here for an hour or

14   two, because he's actually seeing patients.  And he played a

15   fairly strong role in the last meeting on MITC, so we were

16   hoping to have him here, but I don't think he can be here

17   until 12:30 or 1:00, so I think what we should probably do

18   is start with MITC, take a lunch break and then finish up.

19   So we don't sort of delay everything just to get one person

20   to the meeting.

21             So, Paul, let's do MITC.

22             MR. GOSSELIN:  Staff are getting ready to come up.

23             And, thanks.

24             This is continuation of the discussion on the MITC

25   document.



 1             What we had planned on doing, instead of going

 2   back over the entire document, is do a couple things.

 3             One, just summarize the relevant issues for the

 4   toxic side in the document and also kind of focus on the

 5   issues.  I think Elinor summarized some key issues that were

 6   raised from the last meeting and a couple of the other ones

 7   that have been raised since that time, and also talk about

 8   sort of the status of where we are on looking at what

 9   exposures are occurring out there from the data we have had

10   and data we got in December.

11             And also I think Tom is going to look at

12   adjustments to, possible adjustments, to some of the

13   longer-term exposures based upon new use data.

14             A couple things on the importance of this document

15   are twofold, beyond just the consideration of listing MITC

16   as a toxic air contaminant.  Your review's also going to be

17   used by us as our external peer review to help support

18   formal rulemaking that may need to occur based upon the

19   issues, the scientific issues raised in this document.  So

20   the full review and the consideration of these issues are

21   real critical, not only for the listing process, but also

22   for our regulatory process.

23             With that, and I know there's a lot of issues,

24   I'll turn it over to Andy Rubin.

25             CHAIRMAN FROINES:  Just one comment.



 1             Remember at the last meeting in November in

 2   Claremont, we only got about halfway through, so we haven't

 3   really dealt with the risk characterization and risk

 4   assessment issue and I think we did some work on exposure,

 5   but not enough, I think.

 6             And why don't I stop there.

 7             But the issue of clearly you've seen what Elinor

 8   has raised, but one of the major issues that we need to

 9   decide upon is what goes into our -- what goes into our

10   findings, which will then go to Paul Helliker, and in that

11   regard this becomes -- I just want to say this for the

12   panel, because this is an extremely complicated chemical.

13             We have metam-sodium, which has its own

14   toxicologic properties.  We have MITC, which has its own

15   toxicologic properties.  We have methyl isocyanate, which

16   has very significant toxicologic properties, as everybody

17   knows, because of Bhopal.  We have carbon disulfide, and we

18   have hydrogen sulfide, just to list the ones I can think of

19   off the top of my head.  Plus I have no doubt that there are

20   others.  This is a very reactive compound, series of

21   compounds.

22             So that we're really dealing with a quite complex

23   series of compounds and their breakdown products, and so the

24   panel is going to have to address that particular issue when

25   we send our findings forward.



 1             This is not -- we're not dealing with a chemical

 2   here.  We're dealing with at least five.  And so it's

 3   important for us to think about that as we think about how

 4   we transmit this, whatever we intend to transmit.

 5             DR. RUBIN:  My name is Andy Rubin, and I'm going

 6   to be reviewing the health aspects of the MITC document.

 7             In view of the fact, as Dr. Froines mentioned, we

 8   did start the discussion of the toxicity of MITC at the last

 9   meeting on November 17th, and I gave a fairly complete

10   summary of MITC's toxicity profile, I thought what I would

11   do today was instead of spending a whole hour discussing it,

12   the toxic profile again, I would quickly recap what we

13   discussed there to get us all on the same ground, because I

14   know at least one or two members of the panel weren't there.

15             And then probably the most important slide that

16   I'll show you is to introduce you to some of these

17   difficult, what I call discussion decision points with this

18   chemical, some of which have already been mentioned now by

19   Dr. Froines.

20             Then I'm going to take up probably -- well, the

21   issue that we were discussing back on November 17th when we

22   had to stop, and an issue that Dr. Witschi has encouraged me

23   to look at in a little more detail, and that is whether MITC

24   itself could possibly be considered an oncogen, and I'm

25   going to take a detailed look at that, at that particular



 1   study.

 2             Then we'll go through the margin of exposure

 3   calculations, the reference exposure calculations, hopefully

 4   we can do that fairly quickly.

 5             And then mention some of the toxicity of some of

 6   the other metam breakdown products, in particular methyl

 7   isocyanate, MIC, and hydrogen sulfide.

 8             And then wrap it up.  Okay.

 9             By way of recap, if you remember, MITC reached the

10   public consciousness back in 1991, July, when 19.5 thousand

11   gallons of 32.7 percent metam-sodium were spilled in the

12   Sacramento River, causing a release of gaseous MITC and

13   exposure of many people in the local area, particularly

14   around Dunsmuir, to irritating concentrations of MITC.

15             The conclusions of the several papers that came

16   out of the epidemiology on that spill were that despite the

17   fact there were no good measurements for two or three days

18   after the spill, the estimated levels of MITC in the

19   Dunsmuir area, the high estimates, ranged between 140 and

20   1600 ppb.

21             These levels, whatever they are, sent 705 people

22   to the hospital complaining of eye irritation, nausea,

23   throat irritation, with one -- with a possible long-term

24   sequela of condition known as RADS, or reactive airway

25   dysfunction syndrome, a kind of chemical asthma.



 1             In setting or beginning to set the acute levels,

 2   the acute endpoint levels, we looked to a human eye

 3   irritation study.  This was a study conducted at UC Davis

 4   Medical Center, using about 70 individuals.

 5             We came up with a NOEL value of 220 ppb, a LOEL

 6   value of 800 PPB.

 7             Interestingly, this turns out to be right in the

 8   level, these two values, right in the area of the estimated

 9   values of MITC in the Dunsmuir area after the spill.

10             CHAIRMAN FROINES:  Can I ask a question about

11   that?

12             DR. RUBIN:  Yeah.

13             CHAIRMAN FROINES:  I'd like to come back to the

14   RADS later, but in your document you say the following.

15   Interestingly, complaints of abdominal pain, diarrhea, rash

16   and cough continued after ambient levels had hit below the

17   published reference level of .4 parts per million,

18   recalculated to .5 parts per million in Alexeeff, et al,

19   1994.

20             That report by George, I haven't read, and my

21   question is that would indicate a LOEL of about .5, compared

22   to your NOEL of about 220, which you select.  If you take a

23   LOEL of .5, that gets you down to a NOEL of about .05, so

24   there's a fourfold difference between what your document

25   says George says, and he may want to comment on this, and



 1   this value that you select.

 2             So I couldn't -- the Alexeeff document seems to

 3   suggest significant complaints, abdominal pain, diarrhea,

 4   rash and cough, at levels of .5 parts per billion.

 5             DR. RUBIN:  Parts per million.

 6             CHAIRMAN FROINES:  Yeah.  As opposed to your NOEL

 7   of 220 parts per billion.

 8             So there's obviously in your own document a major

 9   discrepancy.

10             DR. ALEXEEFF:  George Alexeeff with OEHHA.

11             Actually I would probably agree with Andy Rubin on

12   his assessment of that, because what you said is correct, in

13   terms of .5, .4 parts her billion, and having those effects.

14   However, the exposure occurred over several days.  So

15   actually we have a longer exposure than this particular

16   study conducted.  Okay.

17             So there is one is the length of the exposure.

18             The other thing is the issue that in the actual

19   incident that occurred, people were possibly exposed to a

20   higher concentration at first and then a lower

21   concentration.  So there's that whole exposure, it wasn't

22   .4, .5 over two or three days, it was some higher

23   concentration and then a lower concentration.

24             Then the other thing points again to your previous

25   comment that the issue of are we talking about exposure to



 1   MITC or metam-sodium breakdown products.  And those are two

 2   different questions.

 3             And what happened in the Dunsmuir incident was

 4   exposure to metam-sodium breakdown products, of which we

 5   think MITC is the primary one, but how do those other ones

 6   interact.  And that's another question there.

 7             So this study here is strictly MITC.

 8             So I think it is all consistent, but I think it

 9   also shows the variability that we have on some of these

10   questions, exposure time, the other things that are in

11   metam-sodium breakdown products and how do they interact.

12   The issue that this particular exposure study was eye

13   irritation only with an eye mask versus whole body exposure.

14             But I think, surprisingly, is actually to me I see

15   this as consistent, as opposed to really a big discrepancy,

16   but it just points out the variability in responses.

17             And also you can look at that issue as well as the

18   variability aspects where we have a population exposure

19   versus, I forget the individuals, the college students that

20   were involved in this study.

21             DR. KENNEDY:  You're also looking at physiologic

22   manifestations of possible antecedent injury, which can come

23   after the fact.

24             CHAIRMAN FROINES:  Now, I want to, I really do

25   want to emphasize for this panel to be thinking about what



 1   are we taking up here.  Are we taking up metam-sodium, which

 2   is used at 15 million pounds a year in California, or are we

 3   taking up MITC, which is not used at all, essentially.  So

 4   we have zero versus 15 million pounds.

 5             And what we send forward to Paul Helliker, I think

 6   should reflect the issue, which -- and I'll leave it at

 7   that.

 8             But, George --

 9             DR. GLANTZ:  Can I ask a question about that?  And

10   that is does MITC come from anything but metam-sodium in any

11   amount?  And I remember I think the document addressed that,

12   but I can't remember what it said.

13             DR. RUBIN:  There's, to my knowledge, there's one

14   other pesticide that generates MITC upon breakdown and

15   that's dazomet.

16             DR. GLANTZ:  That's right.  And that's in the

17   document.

18             DR. RUBIN:  Yeah.  That's in the document.

19             CHAIRMAN FROINES:  Very low.

20             DR. RUBIN:  Very low compared to the very high

21   levels of metam that are used.

22             MR. GOSSELIN:  John, if I can clarify.  It's true

23   MITC as an active ingredient is hardly used and is

24   inconsequential across the state.  But the risk numbers and

25   this assessment, the way we're going to use it in regulating



 1   is to look at the sources of MITC principally from

 2   metam-sodium.  So this is actually going to be used by us to

 3   regulate metam-sodium use, because of the principal effect

 4   of its breakdown products, MITC.

 5             CHAIRMAN FROINES:  We're going to have to come

 6   back to that.  This is clearly the fundamental issue for

 7   this panel to address.  There's a high ridicule value of

 8   listing a chemical that's not used, and ignoring a chemical

 9   with 15 million pounds, and so we'll come back to that.

10             DR. GLANTZ:  Just on that point, I mean, given

11   what Paul said, I mean couldn't this issue be, to some

12   extent, resolved by just changing the title of the document

13   to say metam-sodium and the other compound, what was the

14   other one?

15             DR. RUBIN:  Dazomet.

16             DR. GLANTZ:  Dazomet and MITC.

17             CHAIRMAN FROINES:  Well, I think we can -- I would

18   like, my strategy is I would like us to, if we can, to not

19   send the document back for multiple rewrites, so it never --

20   the next time it emerges we'll all be retired.  I'd like to

21   try and see, this is an important chemical, a really

22   important chemical.  It would be nice to move the document

23   forward, but we have to be sure in our findings and in terms

24   of how we title the document, and all we can do is recommend

25   is that we address this issue.



 1             DR. FUCALORO:  Well, I'm not sure if we have legal

 2   constraints or just a matter of title.  I'm not sure about

 3   the legal constraints, but it seems to me we're looking at

 4   MITC from all sources, whether it's directly applied from

 5   metam-sodium or the other one that I can't recall, or in the

 6   future some other brand name comes up which produces MITC at

 7   a very high concentration.  We certainly want this document

 8   to cover that, because MITC is toxicological, and so it

 9   would, barring legal constraints, you can say MITC from all

10   its sources.

11             Is that fair enough?  I don't know.

12             CHAIRMAN FROINES:  Well, no, that's not quite

13   right.

14             DR. FUCALORO:  Okay.

15             CHAIRMAN FROINES:  As we go further into, and this

16   is why we should go ahead and not get into this discussion

17   right now, because the toxicity of MIC is so profound --

18             DR. FUCALORO:  That's where really it really comes

19   from, yeah.

20             CHAIRMAN FROINES:  We're going to have to deal

21   with that in the context of this too.  So MITC breaks down

22   to MIC -- so I'll just -- I still want to follow up George's

23   comment, which I never did.

24             At some level we set a NOEL of 220.  It would be

25   nice, however, to see some language in the document that



 1   said -- but given that the Nesterova work and given the

 2   Alexeeff work, there could be a NOEL that's much lower.  I

 3   mean, the trouble is we set these NOELs as though they are

 4   in stone and in fact there's a hugh uncertainty in these

 5   values, as we know.  They're defined by, as we all know,

 6   from reading Kenny Krump's paper, by the dose choices that

 7   people make in setting up the experiments.

 8             So it's worth thinking about.  It seems to me that

 9   we think about sometimes putting in ranges of potential

10   NOELs, as well as -- and then perhaps do your calculation on

11   the MOE, looking at some values.  In other words, there

12   are -- it doesn't have to be quite so rigid.

13             Go ahead.

14             DR. RUBIN:  I might add to that the other aspect

15   that is very determining in NOEL is the endpoint, and when

16   Russell and Rush, who did the study at UC Davis, chose eye

17   irritation using a set of goggles, that they had made

18   essentially the implicit choice not to expose the subjects

19   via the lungs.

20             So we have -- there's a major uncertainty here

21   that perhaps lung effects could occur at lower MITC levels,

22   not even speaking of any other breakdown products.

23             DR. WITSCHI:  Just in interest of precision, I do

24   not think that it was eye irritation.  I think it was just

25   blinking, which is not the same thing.  And if you sell this



 1   study as having shown eye irritation, you open yourself up

 2   to criticism, because some people question whether increased

 3   blinking rate is an adverse health effect.

 4             DR. RUBIN:  Right.  It was increased blink rate,

 5   as well as subjective sense of eye irritation.  In other

 6   words, people were blinking harder and marking a little bit

 7   higher on the scale as to how well they felt, how well their

 8   eyes felt in relation to a midpoint of how would you feel if

 9   you were cutting an onion.

10             DR. WITSCHI:  I know.  But that's not quite eye

11   irritation as people would look for into these kinds of

12   things.

13             DR. RUBIN:  Okay.  Moving on to perhaps even more

14   troublesome area, which we discussed in detail last time,

15   the setting of a subchronic inhalation level at one ppm

16   based on effects measured at ten PPM in rats, at 12- to

17   13-week rat inhalation study.

18             Here what we're looking at are systemic effects, a

19   decrease in weight gain, a decrease -- or an increase in

20   water consumption, and decrease in serum protein, that might

21   be argued as fairly marginal.  But in the absence of any

22   other data on subchronic or chronic exposures to MITC via

23   the air, we felt that we had to rely on this study and these

24   endpoints.

25             And I covered these in the last meeting.



 1             Chronic effects will -- this issue will take more

 2   significance when we have the chronic exposure values.

 3   There are of course chronic effects of exposure to MITC.  We

 4   have no inhalation exposure, which is where the primary

 5   human exposure is going to come from.  There are fairly

 6   serious effects in the dog, vomiting, very pronounced

 7   toxicity vomiting, salivation, liquid feces, et cetera.

 8             But I want to come back to that when we have

 9   chronic exposure data.

10             Next slide.

11             This I think will accent what Dr. Froines has

12   said.  There are a number of catch points in this risk

13   assessment that we've struggled very hard with, we've made

14   some conditional decisions and we're interested in the view

15   of the panel on these issues.

16             The first, the use of the Russell Rush human eye

17   irritation study, the preferable use of that, over the

18   Nesterova cat study to establish an acute endpoint NOEL.

19   That we discussed last time.

20             Number two, we also discussed last time the use of

21   the rat 12- to 13-week inhalation study to establish the

22   subchronic endpoint NOEL, were the endpoints serious enough

23   to base a NOEL and LOEL determination on.

24             Number three, this issue came up from Dr. Witschi

25   in the last session, is MITC itself an oncogen, and I'm



 1   going to present that data today, and how we're looking at

 2   that.  And I'm actually going -- this is one area where

 3   there actually is some change in our thinking from the

 4   document that you have in your hands.

 5             Number four, this is a big one, metam and MITC

 6   have different toxicologic profiles.  Metam, unlike MITC, is

 7   a pretty frank carcinogen, causes angiosarcomas in male

 8   mice, hemangioma sarcomas in male rats.  They're related

 9   tumors.

10             It is also an embryotoxic and clastogenic, none of

11   which we see in any clear way with MITC.

12             How do we handle this?

13             The way I've handled it up to this point is simply

14   to include the metam risk assessment as an addendum to this

15   document.

16             I've also got a summary of the metam's toxicologic

17   properties in the MITC document.

18             But we're definitely interested in what the panel

19   thinks about this issue.

20             Then some typical risk assessment conundrums.

21             If we're going to calculate chronic MOEs, do we

22   use a subchronic inhalation study, which we have, or do we

23   use chronic oral data?

24             Number six, use of a tenfold default uncertainty

25   factor to establish the chronic REL for MITC from the



 1   subchronic data.

 2             It's been argued that perhaps we should be using a

 3   threefold uncertainty factor, for instance.

 4             And then number seven, the toxicologic

 5   implications of other degradation of products.

 6             These are the big issues.

 7             Okay.  The issue of MITC's possible oncogenicity

 8   came up in the last session.  I had a summary slide at that

 9   time that expressed the neoplastic situation in rats that

10   had been exposed, these are CD Sprague-Dawley rats that had

11   been exposed to MITC through the drinking water.  I had

12   expressed it at that time in terms of benign and malignant

13   tumors.

14             Upon going -- basically I'm going back to the

15   study and reviewing the study in detail, we decided that

16   it's more helpful to look at the actual histological tumor

17   type, instead of just classifying as the registrants or as

18   the contract lab did, by whether they were supposedly benign

19   or not.

20             This study the rats were exposed to zero, 2, 10 or

21   50 PPM MITC in the drinking water.  At the end of two years

22   the survivors were sacrificed.  Most of the animals that

23   died, died during the second year.

24             What caught our attention in this study was an

25   apparent rise in multiple benign tumors of the mammary



 1   gland.

 2             When we went back and looked in detail at the path

 3   report, which is quite voluminous on this study, we found

 4   that almost all of those multiple benign tumors were

 5   fibroadenomas.  Fibroadenomas occur in Sprague-Dawley rats

 6   at levels as high as 50 percent, and in this study as high

 7   as 70 percent.  So this is a tumor type that is pretty darn

 8   common even in untreated animals.

 9             A fibroadenoma is a considered a, quote, "benign,"

10   to use a very non-benign term, a benign tumor by all

11   pathologists.  However, it has the capacity to progress

12   either to carcinoma, which would be epithelial in nature, or

13   sarcoma in rare instances.

14             I think most pathologists take fibroadenomas

15   seriously.  It has the capability of developing into a

16   malignant cancer.

17             What sort of raised our eyebrows on this study was

18   the incidence rate shown at the very top.

19             Something -- I don't know about operating this.

20   Maybe it's too bright in here.

21             What we see in this study is a 23 percent

22   incidence rate in the controls, rising to 40 percent at 2,

23   44 percent and 47 percent in the dosed animals.  A Fisher

24   pair wise comparison at the high dose compared to the

25   control comes out with a P value of .054.  This raised our



 1   eyebrows.

 2             I don't pretend to be a statistician, but when I

 3   see a P value that close to .05, it's interesting.

 4             What I went therefore and did was classify all the

 5   related tumors that I could find.

 6             DR. GLANTZ:  What's the C-A?

 7             DR. RUBIN:  That's a Cochran Armitage trend test.

 8             DR. GLANTZ:  You say greater than .05, was that

 9   like that .051?

10             DR. RUBIN:  In those tests we come up with Z

11   values and it says come up with a Z value above something,

12   it's greater, it's greater than .05, and I hope I don't have

13   to comment on that any more.

14             DR. GLANTZ:  Don't happen to remember what the Z

15   value was?

16             DR. RUBIN:  They're incredibility low in all of

17   these.

18             DR. GLANTZ:  You mean the Z's are like around

19   zero?

20             DR. RUBIN:  Or less than zero.  They come out

21   negative.

22             What that points out is that we can't see any

23   obvious dose relation with this effect.

24             DR. GLANTZ:  Well, it could be.  I mean, you don't

25   want to get carried away with small numbers, although those



 1   aren't really small numbers.

 2             First of all, .054 is close enough to .05 to

 3   bother me, and I do know something about it.

 4             But the interpretation that I would put on that

 5   would be to say that it looks like you get an effect at very

 6   low doses and then it tends to saturate, which may be why

 7   you're not seeing a trend effect, but it may be that you've

 8   still got -- if you get any of this stuff it tends to be

 9   bad, and then maybe there's something in there saturating or

10   something.

11             DR. RUBIN:  Yeah.

12             DR. WITSCHI:  These are endocrinic-dependent

13   tumors, so your point is well taken.

14             DR. FRIEDMAN:  It might helpful to see the actual

15   P value rather than just .05.  If it's a .06 we'd feel a lot

16   different about it than if it was .5.

17             DR. RUBIN:  I think the way to do it would be to

18   put the Z value on this, but I'll go back and look at that

19   and talk to --

20             DR. GLANTZ:  It might be interesting to just pull

21   all of your -- to take zero and everything else and to just

22   pool them.

23             DR. RUBIN:  Right.

24             DR. GLANTZ:  And, you know, and at that point I

25   bet you would get a pretty significant effect of exposed



 1   versus unexposed.

 2             CHAIRMAN FROINES:  Well, there's a couple of other

 3   comments I'll make since you did that.

 4             The second date, they clearly have small numbers

 5   here.  We don't like 20 animals.

 6             DR. WITSCHI:  Group of 50.

 7             CHAIRMAN FROINES:  This is surviving.  In my

 8   laboratory we have a hard time picking up cancers in dead

 9   animals, animals that are found dead.  So there's that

10   problem.  So the numbers are small.

11             The other thing is that the animals clearly didn't

12   like the taste of the water, and so that there's going to be

13   a fair degree of variability, or at least uncertainty, in

14   the amount of water that they actually got in.

15             So when you look at this 40 percent, 44 percent

16   and 47 percent, it's not clear whether the mice, the rats,

17   at 50 parts per million didn't hate the drink taste so much

18   that they weren't drinking as much water and therefore their

19   dose was lower.  So there could be some simply dose-related

20   issues at the three dose levels, given the taste of the

21   water.

22             In our arsenic work right now we have to work our

23   tails off to get the animals to drink the water.  They don't

24   like the taste of the arsenic.  And this is clearly the same

25   kind of phenomenon, so that the trend test, given the



 1   circumstances of the study, I think one has to be careful

 2   overinterpreting that.

 3             DR. RUBIN:  Can I respond to that?

 4             CHAIRMAN FROINES:  Sure.

 5             DR. RUBIN:  I calculated the statistical values

 6   based on the calculated intake of MITC based on the observed

 7   water intake.  It is very true that any time you put metam

 8   or MITC into the water the rats stay away from it.  They

 9   don't like it.  It smells like a rotten egg.  However, we do

10   have water consumption values here, so we do have MITC

11   intakes.

12             CHAIRMAN FROINES:  Well, I agree.  And in the

13   experiments that we're doing currently right now on 400

14   animals and 60 animals per test group, we are collecting

15   water data and the animals knock the water -- they don't

16   like the water, so they knock the bottle, they do all sorts

17   of things.

18             So when you actually do this for a living, you

19   have to have some humility about these water intake numbers

20   that you get.

21             DR. FRIEDMAN:  I'm confused now, because what

22   you're showing across the top is concentration.  It doesn't

23   show the total intakes.  So how do we know that that's the

24   total intake?

25             DR. RUBIN:  It's in the document.



 1             DR. FRIEDMAN:  It isn't the concentration, you're

 2   looking at the total amount consumed?

 3             DR. RUBIN:  What we're looking at here is the

 4   concentration in water in PPM.  We make a calculation and

 5   the register -- the contract lab also makes a calculation of

 6   the amount of MITC that the animals actually consumed, based

 7   on the amount of water that they drank.

 8             So those figures are the relevant figures for

 9   calculating any statistical values, recognizing that there

10   is a big variation in the amount of water intake even within

11   the same dose group.

12             DR. FRIEDMAN:  But it would be helpful to see a

13   table like that based on intake.  Do you have those data?

14             DR. RUBIN:  I have them, but I don't have a slide

15   on them.

16             DR. FRIEDMAN:  Do they show similar finding with

17   sort of the threshold and then leveling off or what?

18             DR. RUBIN:  That's what they show.  I mean, I'm

19   not sure what you're getting at, but the intakes do vary,

20   I'd say 20-fold.  The intakes vary, the mean intakes vary

21   20-fold from the lowest to the highest dose.

22             So it's not terribly skewed to say just present

23   the concentrations, although I would be quite willing to.

24             DR. FRIEDMAN:  The intake was fairly similar

25   across those three?



 1             DR. RUBIN:  Yes.  But they're big big --

 2             CHAIRMAN FROINES:  Big concentration.

 3             DR. RUBIN:  Big.

 4             CHAIRMAN FROINES:  And therefore the data is

 5   probably skewed, so some animals are going to be having a

 6   much higher dose than others or a much lower dose than

 7   others.

 8             DR. BYUS:  Within a group, you're saying?

 9             CHAIRMAN FROINES:  Yeah.

10             So all I'm saying is we need to interpret this

11   data with some caution where you have obvious evidence that

12   the animals had difficulty drinking the test chemicals,

13   that's all.

14             DR. FRIEDMAN:  Another point is that we're

15   focusing on the multiple tumors on the top line, but the

16   second row shows singles where there seems to be no effect

17   at all.  I'm a little bit confused as to how to interpret

18   all this.

19             CHAIRMAN FROINES:  Can you say something about

20   that?  I don't understand this focus on single tumors.  I

21   don't understand the relevance of it.

22             Do you, Peter?

23             DR. WITSCHI:  No.  You can have one tumor or seven

24   tumors.  Look at tumor-bearing animals, not the number of

25   tumors.



 1             DR. RUBIN:  This is tumor-bearing animals.

 2             DR. WITSCHI:  What's the difference between the

 3   rat that has one tumor or three tumors or four tumors?

 4             DR. RUBIN:  I made that division because partly

 5   because the division is made in the data itself.  The way

 6   this experiment is done this is quite interesting.  The

 7   pathologist comes along and he sees a big lump in the

 8   animal.  These fibroadenomas are huge.  And while there's

 9   one lump, there's a single adenoma.  If there are two, it's

10   multiple.

11             The reason I expressed it here was I thought that

12   it might provide -- the reason I went to look at it was that

13   I thought that single fibroadenomas if they were being

14   stimulated by MITC would also show an increase.

15             Perhaps it's irrelevant.

16             CHAIRMAN FROINES:  I would draw the conclusion,

17   I'd say the more potent, the greater the dose, the more

18   tumors you're likely to see.

19             DR. WITSCHI:  You're right.  There are certain

20   systems where tumor multiplicity is really an index of

21   carcinogenic potency.  And in this case I really do -- I do

22   not see any reason to separate the animals in the single

23   ones.

24             DR. RUBIN:  They're all added up.

25             DR. WITSCHI:  If you look at the bottom line,



 1   that's very close.  If you just add up the tumor-bearing

 2   animals, first of all, regardless of whether it's benign or

 3   malignant, I think that when we in science and judgment in

 4   risk assessment there's a statement that you really should

 5   not make a difference between benign tumors or malignant

 6   tumors in evaluating bioassays, because uncontrolled growth

 7   is uncontrolled growth.  And that's where I come from.  This

 8   is for animals.

 9             And then if you really look at the bottom line,

10   that was my point, the ones which have been exposed to have

11   more.

12             Now, you also brought in the historical

13   background.  But, see, there's one thing we do not know.

14   Does a carcinogenic treatment increase tumors proportional

15   to the number of spontaneous tumors or does it add tumors?

16             In other words, if you had a background of ten and

17   you have 20 tumors or an incidence of 20, does this mean the

18   incidence was doubled or if you would have only the percent

19   incidence you would have 11 percent in the treated ones.

20   You do not know what is the proportion to the background or

21   something that's being added.

22             And again we're looking at this from a frankly

23   from a conservative standpoint.

24             DR. RUBIN:  Yeah.  Yeah.  I'm well aware of that

25   and I've --



 1             DR. WITSCHI:  Then the other one, this seems to be

 2   a tricky compound, because if you look at the

 3   hemangiosarcomas in the metam and your rats have exactly the

 4   same phenomenon, you have the paradoxic one, you have a dose

 5   response and you have a small increase.  Knowing the metam,

 6   you actually added the mouse study showed a carcinogenic

 7   response, therefore you said the data in the rats mean it's

 8   a carcinogen, but if you look at table 9 in your metam and

 9   compare it with the human data, they're as good or as lousy

10   as they are --

11             DR. RUBIN:  Oh, yeah.  This is very real-world

12   data.

13             DR. FRIEDMAN:  If we take then the tumor-bearing

14   animals are the criterion, the best criterion to use, then

15   the findings there in the third row are not significant.

16   That's bottom line, the multiple plus single.

17             CHAIRMAN FROINES:  Which one are you at?

18             DR. RUBIN:  In the third row from the top, right?

19             DR. FRIEDMAN:  Yes.

20             DR. RUBIN:  When you add all animals bearing

21   fibroadenomas, at least fibroadenomas that can be palpated,

22   you don't get a statistically significant response, although

23   you do still get a slightly higher response in the dose

24   downs.

25             DR. FUCALORO:  If I understand Hanspeter, you look



 1   at the bottom line, which contains not only the benign, but

 2   the malignant, and the same conclusions I think

 3   statistically at least from my eye, there's not much

 4   response.

 5             DR. KENNEDY:  Has this been done, Hanspeter, in a

 6   strain that does not produce spontaneous fibroadenomas?

 7             DR. WITSCHI:  What?

 8             DR. KENNEDY:  Has a comparable study been done on

 9   a strain of rat that does not have spontaneous

10   fibroadenomas?

11             DR. WITSCHI:  I don't think so, no.

12             DR. KENNEDY:  Clearly could be a hormonal effect

13   rather than a direct effect.  Very interesting to evaluate

14   it.  And one can actually make an argument that the vascular

15   tumors are also at least in part hormonally mediated,

16   because it's angiosarcomas of the breast are rare, but not

17   vanishing, where in humans it occasionally will have

18   receptor-specific hormonal --

19             DR. WITSCHI:  Your point is very well taken, but

20   then we have to answer that question, we have to go into the

21   mechanisms.  They're facing the same situation as we are

22   facing with certain steroid tumors, where we do get more

23   lumps, but it's clearly a non-genotoxic mechanism and it's

24   the MITC only to answer this question.

25             DR. RUBIN:  This is the data for MITC right here.



 1             DR. WITSCHI:  Yes, I know.

 2             DR. BYUS:  I have one question.  There were really

 3   50 animals per group, 26 were live at the end?

 4             DR. RUBIN:  There are 60 animals per group, yeah.

 5             DR. BYUS:  So why are they all dying?  What are

 6   they dying of?  I mean even in the control, the control is

 7   zero, you're saying to me that there are 60 animals in the

 8   group and only 26 of them lived to the end of the study?

 9             DR. RUBIN:  That's right.

10             DR. BYUS:  In my opinion that makes this study

11   virtually useless.  Why are the animals dying?  You don't

12   want more than half your animals dying before the end of the

13   study of something that's not related to the cancer.  I

14   mean, it becomes -- it's a worthless study.  You shouldn't

15   even be, perhaps I'm exaggerating because I didn't read the

16   study, but the last thing you want is animals dying.  The

17   fewer the better, unless they're dying of the cancer, in

18   which case you make -- that pathologist makes that

19   diagnosis.

20             DR. RUBIN:  Right.

21             DR. BYUS:  If the animals happen to die during the

22   study, you autopsy them immediately and hopefully determine

23   what the cause of death was and hopefully it's because of

24   the cancer that you're looking for and not something else.

25             If it's something else, you try to make a



 1   diagnosis if you can.

 2             But I mean to have that many animals dying, this

 3   skews all the data completely.  You can't get any incidence

 4   values that are meaningful out of a study where more than

 5   half are dying.

 6             CHAIRMAN FROINES:  Well, the problem is that when

 7   they do die, unless you can pick them up right when they

 8   die, you know, everything turns liquid in their insides and

 9   so you can't really do pathology.  You can find big tumors,

10   but you can't do as precise a pathology as you could do if

11   you sacrificed them.

12             So you really lose data with these animals that

13   are dying from virus infections or whatever is causing it.

14             DR. BYUS:  It skews the value --

15             CHAIRMAN FROINES:  They are down to a point

16   where -- I have talked at great length with the National

17   Institute of Environmental Health Sciences precisely about

18   this issue, because my current mice are in 16 months and

19   they're dying off, and I wanted to figure out how to deal

20   with this issue.

21             They said we will look at the data down to about

22   20 animals, but below that we won't use it.

23             So that these numbers here are really on the

24   border.  And so one has to worry about interpretation.  So

25   it seems to me that one can say that there are some trends



 1   here, but my concern is that the overanalyzed data, like

 2   looking at single versus multiple, it doesn't help.  It

 3   doesn't tell you anything when you're all finished.

 4             And I'm speaking not now as a scientific reviewer,

 5   but as somebody who actually does this in the lab, as Peter

 6   does, and these are issues that are real, not abstract.

 7             DR. BYUS:  I'm still saying if your mice are dying

 8   of viruses or whatever, something not related to the

 9   chemical, and they have this high of percentage that are

10   dying, it skews -- the data becomes meaningless.  I do the

11   studies too.  And if my animals are dying in this high

12   amount I cancel the study and conclude it, end it.  You

13   don't know why they're dying.

14             CHAIRMAN FROINES:  You must have much more money.

15             DR. BYUS:  I have a very good animal facility.

16             DR. FRIEDMAN:  In human studies we deal with this

17   all the time.

18             DR. BYUS:  But not in animal studies where you're

19   designing an experiment to assess the carcinogen incidence,

20   incidence in a lifetime and you're doing lifetime studies,

21   which are hard to do.  The last thing you want are the

22   animals dying of some other cause other than your chemicals.

23             DR. FRIEDMAN:  If you do, it would --

24             DR. BYUS:  They might have gotten the cancer, they

25   might have not.  They died early from a virus that could



 1   have gone on to develop a tumor.  You really don't know.

 2             DR. FRIEDMAN:  There are statistical methods for

 3   dealing with this when you -- they're censored at the point

 4   that they die and you just take into account the time of

 5   follow-up.  We have in human studies we have life table

 6   analysis and so on to deal with that.

 7             DR. BYUS:  When you are doing large numbers, but

 8   small numbers you cannot do it.

 9             DR. FRIEDMAN:  If you get too small a sample, then

10   you're in trouble, or if you require that they all live to a

11   certain point, then I see that you're in trouble.

12             CHAIRMAN FROINES:  Can I ask you --

13             DR. GLANTZ:  Actually, though, I'm sitting here

14   doing some arithmetic on all your numbers.  But Gary raises

15   an interesting question, why don't you do a life table on

16   these animals, because you can, if they've lived to a

17   certain point and then died from an unrelated cause, that's

18   exactly what a life table analysis is for, is to take

19   advantage of the fact that you've been able to follow them

20   up to some point and --

21             DR. BYUS:  The beauty of doing an animal

22   experiment is it's a controlled experiment.  You're

23   designing it to get rid of all these variables and if you

24   don't get rid of the variables your experiment isn't valid.

25             DR. GLANTZ:  Right.  But if the animal dies of a



 1   viral infection or some unrelated thing, you can still take

 2   advantage of the fact that --

 3             DR. BYUS:  A small number.  Out of a group of 60

 4   you probably would not want more than five die from viruses.

 5             CHAIRMAN FROINES:  No, no.

 6             DR. BYUS:  That's all I ever had.

 7             CHAIRMAN FROINES:  No.

 8             DR. BYUS:  Many lifetime --

 9             DR. WITSCHI:  I would have to take issue with what

10   you said.  In a study like this, you do not necessarily

11   expect the animals to die from your carcinogen, because it

12   makes a difference if the animals dies from the tumor or

13   whether it dies with the tumor.  If it dies with the tumor,

14   that's --

15             DR. BYUS:  The zero group is not getting any

16   chemicals and two-thirds of the animals are dying.  That's

17   not good.

18             DR. WITSCHI:  We don't know if they were dying --

19             DR. BYUS:  It doesn't matter when they died,

20   they're supposed to live a lifetime of two years.

21             DR. WITSCHI:  No, no.  This table doesn't tell you

22   whether the ones who died before terminal sacrifice died a

23   couple of weeks or a couple of months before.

24             CHAIRMAN FROINES:  Anyway, this is the only study

25   we have.



 1             DR. RUBIN:  Right.

 2             CHAIRMAN FROINES:  We don't follow your point of

 3   view and throw it out.  You have to use it for whatever we

 4   can get out of it and the life table analysis is the classic

 5   way that one would evaluate data where you have changing

 6   mortality.

 7             And so that's that.  So I don't think we have

 8   another choice.

 9             And I think that there are a couple of issues that

10   we'll talk about a little bit later.  I mean, one should

11   look at this data precisely because we have metam-sodium

12   data.

13             One has to be thinking about the question of is

14   the MITC the carcinogen, since it is a primary breakdown

15   product, how does its carcinogenicity compare to the

16   metam-sodium carcinogenicity and that's a question that

17   requires some analysis.

18             But I don't understand what the decedents are.

19             DR. RUBIN:  These are the animals that died, most

20   of which died in the second year.

21             CHAIRMAN FROINES:  You're right.  I certainly

22   wouldn't include them.

23             DR. RUBIN:  No.  You can tell, the fibroadenomas

24   are much lower.

25             CHAIRMAN FROINES:  Of course they're dying before



 1   you want the study is over, so you can't look at them in

 2   terms of any kind of trends.  You have to be very lucky or

 3   have a very powerful carcinogen.

 4             DR. WITSCHI:  What really we should do is look at

 5   compared when they died off with other studies.  In very few

 6   studies you get your 60 animals to the ripe age of two

 7   years.  It does make a difference if they died between 18

 8   months or 24 months or if they died between six and ten

 9   months.

10             DR. RUBIN:  Most of the animals died around the

11   90-week level, between 18 and 24 months.

12             I took this, without knowing about this strain in

13   particular, the CD Sprague-Dawley, I took this as the

14   normative life span of these animals and perhaps there was

15   something particularly morbid about their treatment, but I

16   thought it was the normative life span.  Many of them were

17   dying around 90 weeks, 95 weeks, 98 weeks.

18             DR. WITSCHI:  That's pretty far into the

19   experiment.

20             DR. RUBIN:  The experiment is 104 weeks long.

21             DR. FUCALORO:  Can I ask a question?  Is it indeed

22   a fact that they only deal with different types of rats and

23   you have no controlled experiments on them, but this would

24   imply that in the lifetime of this particular rat 50 percent

25   of them experienced tumors?



 1             DR. RUBIN:  That's right.  Spontaneous

 2   fibroadenomas.

 3             DR. FUCALORO:  And that's not surprising results

 4   to people who know --

 5             DR. RUBIN:  That is not surprising at all.  Leslie

 6   Folts in his book "Neoplastic Development," mentions the

 7   Sprague-Dawley rat in particular, and says 50 percent of

 8   Sprague -- as much as 50 percent of Sprague-Dawley rats

 9   develop fibroadenomas.

10             It is my personal position, given the way this

11   pathology is done in this experiment, just by taking lumps

12   and then slicing the lump and doing the histology that way,

13   I think that it's quite possible that every animal in this

14   study that survived had fibroadenomas.

15             The ones that are counted, the ones that are

16   counted are the ones that grew big enough to make lumps.  If

17   you actually look at the mammary histopathology, you

18   occasionally -- and the way they do it in a study like this

19   is just take some normal mammary gland and do a section,

20   boom.  They don't -- these are not step sectioned, they are

21   not quantitative histopathology.  And occasionally you see a

22   normal appearing piece of mammary gland showing a

23   fibroadenoma.  If you took -- how many mammary glands do

24   rats have, eight or ten or something?  If you did

25   quantitative sectioning, my guess is you would see



 1   fibroadenomas in every one of them.

 2             CHAIRMAN FROINES:  Let me make --

 3             DR. FRIEDMAN:  It's not a very good control group

 4   then, because hundred percent are going to get it.  What

 5   chemical would make a difference --

 6             DR. BYUS:  If they live along enough.

 7             CHAIRMAN FROINES:  Here's the thing.  You end up

 8   with 6 out of 26 and can you combine multiple fibroadenomas

 9   and carcinomas, you get 6 out of 26, 9 out of 20, 16 out of

10   32, and 15 out of 32, and clearly there's going to be some

11   statistical significance at those higher values.

12             Now, everybody agrees this is a lousy study.  I

13   think no matter what your point of view we can all agree to

14   that, this was not as well conducted as one would like.

15             But we have to be careful to reward the industry

16   for doing a lousy study.  I mean if somebody is going to do

17   a poor study and they have a vested interest, one, it

18   doesn't necessarily test their integrity, but one has to say

19   we don't want to reward that poor study.

20             So it seems to me that you have to take the data

21   at some level on its face value, and say we don't know

22   whether there is a problem, but there could be.

23             It seems to me that it's clearly not black and

24   white.  It's clearly gray.  It seems to me there may be

25   something here and but we don't really know.



 1             But it doesn't mean that we conclude the opposite,

 2   that there isn't something.  I think that would be an

 3   under-interpretation of the study.

 4             DR. FUCALORO:  Yeah.  But also an interpretation

 5   is that MITC extends the life of the rats, if you look at

 6   some of these.  So one has to wonder.

 7             CHAIRMAN FROINES:  But there are people, lot of

 8   people who do studies like this, like Maltoni, who doesn't

 9   sacrifice the animals at 104 weeks, but actually carries the

10   studies out until a later date when the animals are dying,

11   and actually that's where you actually tend to find more

12   tumors when you go beyond the 104 week, two-year period.  So

13   one could argue that the danger of a shortened study, of

14   course, is that you don't see the cancers, because cancer is

15   a late-stage event.  You pick 104 weeks because that's when

16   they're old.  It's like picking -- it's like waiting until

17   we're 65 and seeing if we have cancer cells.  We might have.

18   We will have more by the time we're 80.  So we do need to be

19   careful about our interpretations.

20             DR. FRIEDMAN:  Can I add one?

21             Stan probably could figure this better than I can,

22   but when I look at this Fisher test you did on the very

23   bottom line that gave you .007.

24             DR. RUBIN:  Yeah.

25             DR. FRIEDMAN:  36 over 60, compared to --



 1             DR. RUBIN:  No.  The way I took the very highest

 2   incident rate, the one that's underlined there, 30 over 60

 3   versus 44 over 60.

 4             DR. FRIEDMAN:  I don't think that's quite cricket

 5   to look at the data and then pick the one you wanted to

 6   test.

 7             DR. RUBIN:  I wanted to give it the most

 8   possibility of seeing something.

 9             DR. GLANTZ:  I think, I'm just sitting here doing

10   a lot of arithmetic, if you take the -- if you look at the

11   top at the terminal survivors and you add the multiple --

12   the thing John said, you add the multiple plus single

13   fibroadenoma with the carcinomas, and you just looked at

14   exposure, versus unexposed, which I think makes more sense

15   when you look at these numbers, that is probably

16   statistically significant.  And, I mean, I think that if you

17   look at the multiple fibroadenoma and you just looked at

18   exposed versus unexposed, that's going to be significant.

19             DR. FRIEDMAN:  Again, you're doing that after you

20   see the data.

21             DR. GLANTZ:  Well, that's true but, you know, hey.

22   That doesn't bother me.

23             DR. FUCALORO:  You've got to make a point.

24             DR. GLANTZ:  I agree, picking out the highest

25   incident rate, you don't want to go do that, but I think



 1   that if you look at the data and you do a test of the

 2   trends, the test of the trends aren't significant, but if

 3   you look at the numbers, the reason it's not significant it

 4   looks like there's a threshold effect that you get exposed

 5   and something happens and if you got even more exposure, you

 6   don't seem to be getting a larger effect.

 7             Now, whether that's because there was some enzyme

 8   that saturates and whether that's because the rats won't

 9   drink the water, you don't know.  But if you just divide it,

10   if you collapse the categories, then the first one will be

11   much more significant, I think.

12             I don't have a statistical table here and this

13   doesn't take a square root, so I was sort of having to guess

14   a little bit.

15             I think if you look at the multiple plus single

16   fibroadenomas, that probably doesn't reach significance, but

17   you'd get a smaller P value than you have there, but if you

18   add the carcinomas with the fibroadenomas, that gives you a

19   Z of like 1.9, which is right on the border.

20             And probably if you do a Fisher exact test it

21   would be significant.

22             So, you know, the interpretation I would put on

23   this stuff is that it looks like you're showing that

24   exposure is associated with an increased tumor rate.

25             DR. FRIEDMAN:  And having seen that in this study



 1   it would be really nice to do another study with that

 2   hypothesis in mind.  If that were at all possible, that

 3   would be wonderful.

 4             DR. RUBIN:  $1.5 million.

 5             DR. FRIEDMAN:  I'm in the wrong business.

 6             DR. RUBIN:  Can I move on?

 7             CHAIRMAN FROINES:  I want to ask --

 8             DR. GLANTZ:  This is turning into a seminar here.

 9   Is this your thesis you're defending here?

10             CHAIRMAN FROINES:  But this is important.

11             Although I don't think that the determination of

12   these compounds as TACs rests on oncogenicity issue.

13             I think this is something that clearly requires

14   follow-up, something that for which there are hints, but for

15   which there is no defined --

16             DR. GLANTZ:  But I think the data here are strong

17   enough to say that's there's, at the very least, a strong

18   suggestion of an effect.

19             DR. BYUS:  I wouldn't say that at all.

20             DR. GLANTZ:  You don't?

21             DR. BYUS:  No.  I would say you cannot say -- I

22   would not say it indicates a strong --

23             DR. GLANTZ:  No, I would say --

24             DR. BYUS:  I would say there is maybe an effect.

25             DR. GLANTZ:  Okay.



 1             DR. BYUS:  It's definitely not a strong effect

 2   from this data.

 3             DR. GLANTZ:  No, no.  I said --

 4             DR. BYUS:  You said strong effect.

 5             DR. GLANTZ:  No, no.  I said strong suggestion.

 6             DR. FRIEDMAN:  I would take out the word strong.

 7             DR. GLANTZ:  Okay.

 8             DR. FRIEDMAN:  It's suggestion of an effect, it

 9   should be followed up.

10             CHAIRMAN FROINES:  If you want, we'll work on this

11   in terms of our findings and we'll have to resolve this

12   strong suggestion versus the suggestion.

13             DR. GLANTZ:  How about a somewhat moderate --

14             CHAIRMAN FROINES:  Somebody in this room, who is

15   very articulate, start thinking of the term between strong

16   suggestion and suggestion.

17             DR. BYUS:  Stan and I can go out of the room.

18             DR. GLANTZ:  No, no.

19             DR. KENNEDY:  Real suggestion.

20             DR. GLANTZ:  A moderate suggestion.

21             CHAIRMAN FROINES:  All right.  We'll come back to

22   that.

23             DR. GLANTZ:  Somewhat stronger suggestion,

24   perhaps, an apparently somewhat strong suggestion.

25             CHAIRMAN FROINES:  Bang, bang, bang, bang, bang.



 1             DR. BYUS:  Where is your gavel?

 2             DR. GLANTZ:  We're not allowed to joke.

 3             CHAIRMAN FROINES:  I have a question.  I want to

 4   get back to science.

 5             The second study, the mouse study, the reason I

 6   want to ask a question about the mouse study is that the

 7   principal findings of angiosarcoma in the metam-sodium is in

 8   the mouse, not in the rat.

 9             DR. RUBIN:  Right.

10             CHAIRMAN FROINES:  Now, in the mouse study here I

11   didn't understand this paragraph.  You said in a two-year

12   oncogenicity, 70 mice, blah-blah-blah, blah-blah, but I

13   couldn't tell what was the size of each group, it looked to

14   me like the size of each group was six.

15             DR. RUBIN:  70 mice per group.

16             CHAIRMAN FROINES:  This says 70 mice per sex, per

17   group, but then on the back you're seeing things like

18   ovarian cysts were increased in 10 of 21 versus 2 of 21, so

19   that without having a table --

20             DR. RUBIN:  That's the death problem.

21             CHAIRMAN FROINES:  I don't know what the size -- I

22   have no idea how to interpret this study, because there's no

23   data.  I see six mice from each group were sacrificed at 26

24   and 52 weeks.  So was the study terminated at 52 weeks?  No?

25             DR. RUBIN:  No.



 1             CHAIRMAN FROINES:  It was terminated at 104 weeks.

 2   These are mice, so how long, 18 months?

 3             DR. RUBIN:  Usually run an 18-month study with

 4   mice.  I suspect the animals were dying and what you're

 5   seeing are the ones that are left.

 6             CHAIRMAN FROINES:  There's really not enough

 7   information in this section to interpret this study, and

 8   it's important precisely because you want to look at this.

 9   Again, the strains are different, conditions are different

10   from the metam-sodium study, but if you want to look at

11   mouse-to-mouse findings, you need to have the information to

12   better understand what was done.

13             You see what I'm saying?

14             DR. KENNEDY:  I see.  I don't think it's going to

15   change the oncogenic --

16             CHAIRMAN FROINES:  I don't think so either.

17             DR. KENNEDY:  -- endpoint.  In terms of animals, I

18   think many strains of mice, if they live long enough they

19   all die eventually.

20             DR. WITSCHI:  No.  I think the question about the

21   mice is very important, because Andy has taken a positive

22   mouse study to ascertain the data which are as weak perhaps

23   as metam-sodium as they are from MITC.  But this was your --

24   made your decision swing.  And he calls metam-sodium a

25   carcinogen with lousy rat data and the positive mouse study.



 1   And he calls the MITC not a carcinogen with lousy rat data

 2   and not positive mouse data.  So they have a good --

 3             DR. RUBIN:  We're whistling a slightly different

 4   tune on the next slide.  I think some of the language I've

 5   heard here is reflected in the next slide as to what the

 6   conclusion of the onco study is.

 7             Here I just list some of the arguments for and

 8   against considering a MITC -- an oncogen based on this one

 9   study.  I don't know if you want me to go through these, but

10   I'll read the conclusion first.

11             There is weak evidence of a possible treatment

12   effect.  However, the data are not sufficiently strong to

13   trigger a quantitative oncogenic risk evaluation.  That is

14   what I mean by that is plugging data like 50 percent versus

15   70 percent into a multistage linear extrapolation program

16   because the data won't mean anything.

17             However, I think we have come to the conclusion in

18   our branch that these data, particularly on fibroadenoma,

19   are possibly consistent with the treatment effect.  And

20   that's all I think you can say at this point.

21             So I am going -- I'm changing the language,

22   because the language in the document, as you have it now, is

23   there's no clear effect of oncogenicity.  I'm going -- I

24   think the language really should be something like what I

25   have here or some other language that you would suggest.



 1             DR. WITSCHI:  I think that's reasonable.  We're

 2   talking about, I mean the data are so expensive, something

 3   seems to be there, but nobody in his right mind should use

 4   this study to a quantitative risk assessment.

 5             CHAIRMAN FROINES:  We just gave Craig his piece of

 6   this action, so it's okay.

 7             DR. RUBIN:  We've discussed everything on this

 8   slide.  I think we can move on.

 9             DR. WITSCHI:  I might remind Craig that absence of

10   evidence is never evidence for absence.

11             DR. BYUS:  Absolutely.

12             DR. GLANTZ:  It's noon, if you expect Blanc to

13   show up at 12:30, maybe we should take lunch.

14             CHAIRMAN FROINES:  1:00.

15             DR. GLANTZ:  1:00, okay.  I'm sorry.

16             CHAIRMAN FROINES:  Why don't we stop about 12:15

17   and we will come back at 1:15.

18             And, you know, I don't want to make too much of

19   having one person, because this discussion has been quite

20   good.  Everybody has participated.

21             DR. GLANTZ:  Yeah, since Paul is going to show up,

22   it would be good not to have him watch us eat lunch.

23             But, anyway, go on.

24             CHAIRMAN FROINES:  I think there's a general

25   consensus, there might be slight wording differences, but I



 1   think there's a consensus here that there is a suggestion

 2   that something is happening.  The data is not sufficient to

 3   use for risk assessment purposes.  And that we all, I think,

 4   agree further work should be done.

 5             So go ahead.  Why don't we proceed.

 6             DR. RUBIN:  Next slide.

 7             Now we'll get to shift gears and come to the risk

 8   characterization part of this document.

 9             Just to refresh your memory, we have split this,

10   these exposure and risk calculations, into acute and

11   subchronic or seasonal exposures and then each of those

12   categories are split into ambient exposures and that would

13   be defined as exposures of the general public in the general

14   area where metam is being applied, so that would be

15   exposures in town, small townships and so forth, versus

16   off-site, or perhaps a better term now, application site

17   exposures, these would be people that are standing right off

18   the field in a particular exposure scenario.

19             And I want to just give you the MOE values, the

20   margins of exposure.  A margin of exposure is defined as the

21   NOEL, in this case for acute we're setting the NOEL at 220

22   ppb, divided by the measured air concentration.  So the MOE

23   is a value which expresses just how close to the NOEL a

24   particular air concentration is.  The lower the MOE, the

25   more reason for concern.



 1             What we have here are the high acute MITC exposure

 2   levels for these various townships and houses and outside of

 3   houses and in the general environment, four or five

 4   different townships.

 5             We get MITC levels.  I think Tom Thongsinthusak

 6   can comment better on this, but we get MITC levels ranging

 7   from .08 ppb all the way up to almost 9 ppb with a

 8   corresponding MOE values ranging from 25 to 2,750.

 9             Since these MOEs are based on human data, the

10   benchmark of concern is an MOE of ten.  So for at least at

11   this point, ambient exposures, that is exposure in town, in

12   a season of metam application, is not ringing a bell, not

13   raising a flag.

14             However, next slide, for the off-site or

15   application site measurements, you get much higher MITC

16   levels if you're standing five to 500 meters from a field

17   where metam is being applied.  Using the same NOEL value of

18   220 ppb, we're getting MOE values less than one in many

19   cases, and certainly all ten or less.

20             These are --

21             CHAIRMAN FROINES:  In the previous slide, the Kern

22   County, I take the '97, '98, that's Jim Seiber's work;

23   correct?

24             DR. RUBIN:  Right.

25             CHAIRMAN FROINES:  Okay.  When he did that, did he



 1   look -- did he estimate the MIC or carbon disulfide or any

 2   other breakdown products?

 3             DR. RUBIN:  I don't think MIC was estimated in

 4   that study, but there might be others.

 5             Our exposure people are saying no.

 6             CHAIRMAN FROINES:  So that we may have half a loaf

 7   here or a ten percent or 90 percent of a loaf.

 8             DR. RUBIN:  We need monitoring data on these

 9   breakdown products.

10             What I'm going to give you here are just MOEs for

11   MITC.

12             CHAIRMAN FROINES:  And the MITC on page nine that

13   you're at now, that also doesn't include MIC?

14             DR. RUBIN:  Apparently not.

15             But even not considering MIC, we're dealing with

16   MOE values that almost certainly indicate that a person

17   standing next to a field when there's spraying going or

18   where there's chem irrigation that is adding metam into the

19   irrigation water or shank injection, that there's going to

20   be at least eye irritation going on out there, and that's

21   what these MOE calculations are telling us.

22             And there could well be pulmonary effects.

23             Next.

24             These are, I'm flooding you with numbers.  You

25   don't of course have to read every number in this chart.



 1             CHAIRMAN FROINES:  When was the previous slide

 2   collected?

 3             DR. RUBIN:  Excuse me?

 4             CHAIRMAN FROINES:  The previous slide, when was

 5   that was data collected?

 6             DR. RUBIN:  These are the off-site acute

 7   measurements.  I have them in the document.

 8             CHAIRMAN FROINES:  I don't want -- I'm trying to

 9   avoid flipping back.

10             FROM THE AUDIENCE:  1993, '94 and '95 --

11             DR. RUBIN:  That's right.  '93, '93, '95, '93,

12   '92.

13             CHAIRMAN FROINES:  And use of metam-sodium has

14   gone up since that time?

15             DR. RUBIN:  It's about doubled.

16             CHAIRMAN FROINES:  About doubled?

17             DR. RUBIN:  Yeah.

18             MR. GOSSELIN:  Also that kind of changes, the use

19   has gone up, but in '94 we started a series of changing use

20   practices, so how this data fits with what's going on now is

21   something we're taking a look at.

22             DR. FRIEDMAN:  Question about similar to my

23   questions about your P values, when you show the MOE, why do

24   you say less than one, why don't you pick the actual value,

25   because .9 would be a lot different than .1.



 1             DR. RUBIN:  Yeah, I can do that.  You're right.

 2   These already when you're dealing with MOE values of one or

 3   less, you're dealing with almost certainly seeing adverse

 4   effects.  So to me it simplified it just to say they were

 5   less than one.  You can do the division right out here.  I

 6   mean, the numbers are, for instance, for site A, injection,

 7   220 divided by 618, so it would be .3, approximately.

 8             Would you suggest that I do that?

 9             DR. FRIEDMAN:  I would think that it would be

10   good.  Shouldn't require the reader to have to do it.

11             DR. RUBIN:  Okay.

12             DR. FUCALORO:  You can also put in the range too.

13             DR. RUBIN:  Yeah, right.

14             CHAIRMAN FROINES:  I think we should break now.

15   This probably is a reasonable time, because it might be good

16   for Paul to see some of this too.

17             It's going very well.

18             (Thereupon the lunch recess was taken.)










 1                A F T E R N O O N    S E S S I O N

 2             CHAIRMAN FROINES:  Go ahead.

 3             DR. RUBIN:  Dr. Froines asked me to go back to

 4   page nine, start up there.

 5             This was the exposure in the MOE calculations for

 6   the application site or off-site measurements, five

 7   different studies, three of them injection studies or

 8   injection applications, and two of them sprinkler

 9   applications.

10             And the point of this slide was to show that when

11   you're standing right off of a field in which metam is being

12   applied, you're very high likelihood of sustaining some of

13   the irritation effects.  The MOEs are less than one.  It was

14   mentioned in the last session that I should perhaps express

15   the exact MOE instead of just less than one.  We'll probably

16   do that.

17             Are there any more questions on this slide?

18             One issue came up, I was told site C, there was

19   MIC monitoring in the site C study.  That's the one study in

20   which there is --

21             DR. ATKINSON:  This was the '95 Kern County one, I

22   assume?

23             DR. RUBIN:  Yes.

24             Okay.  Next slide.

25             Now we move on to the risk characterization for



 1   seasonal exposures.  The NOEL value used here for these MOE

 2   calculations is derived from the 12-, 13-week rat inhalation

 3   toxicity study.  The endpoints were in that study, just to

 4   refresh you, were decrements in weight gain, increased water

 5   consumption and decreased serum protein.

 6             And here these are the ambient MOE levels.  And

 7   you can see that they're not tripping any red flags.

 8   They're all quite fairly high, ranging from low of 708

 9   calculated for children at Lamont, to as high as 17,000 at

10   Arvin, calculated for females.  The Lompoc measurement

11   there, the 3.4 million, I was told that maybe I shouldn't

12   emphasize that.  We're not so keen on the reliability of

13   that data, so I'm going to cut back on that.

14             The next slide finally is the -- are the MOE

15   calculations for off-site exposures for seasonal exposure.

16   And here we get MOEs as low as two, ranging as high as a

17   mean MOE of 236.

18             Now, for MOEs calculated based on animal studies,

19   the benchmark or the convention for tripping a health

20   concern is a MOE of a hundred.  These are clearly coming in

21   below a hundred.

22             DR. BLANC:  Therefore, even if you had

23   overestimated exposure by a factor of five to ten, you would

24   still be triggering --

25             DR. RUBIN:  That's right.



 1             DR. BLANC:  Do you think that is significant?

 2   Does that reassure you that even if there was some error in

 3   the field measurements that even so you would have such a

 4   high margin here in terms of your MOEs that even if you had

 5   overestimated field exposure by a factor of five to ten --

 6             DR. RUBIN:  I would still be concerned, yes.

 7             DR. BLANC:  Right.

 8             DR. RUBIN:  However, I'll just remind you that

 9   there is significant concern about the endpoints in the

10   particular study.  I would love to see this study done again

11   in a properly characterized analytical procedures, the

12   analytical chamber concentrations, all the individual animal

13   data expressed.  We're forced into a corner on this study.

14   We have to go with it.  We don't have anything better at

15   this point.

16             So it is possible that a well-characterized study

17   will come up with a higher NOEL value, in which case these

18   MOE values are going to be higher.

19             DR. BLANC:  Of course, it's also possible a

20   well-characterized study would come up with an even lower --

21             DR. RUBIN:  Yes, certainly is.

22             CHAIRMAN FROINES:  There is some indication that

23   based on George's paper and the Dunsmuir that you might find

24   exposures over time of relatively low levels according to

25   your document.



 1             DR. RUBIN:  Yeah.  There is uncertainty in all of

 2   these calculations and some major uncertainties.

 3             Next slide.

 4             We have calculated reference exposure levels.

 5   These are as --

 6             CHAIRMAN FROINES:  Just one comment.  I think,

 7   Paul, that the other thing that's missing here that you

 8   missed in earlier discussion is none of this includes MIC

 9   carbon disulfide, H2S.

10             DR. BLANC:  That was the case.

11             CHAIRMAN FROINES:  This is only MITC.

12             DR. BLANC:  Yeah.

13             CHAIRMAN FROINES:  So depending upon how much of

14   that would be produced, MOE, however one would calculate it,

15   would be different.

16             DR. RUBIN:  Okay.  Just we have calculated

17   reference exposure levels for acute toxicity since we

18   have -- we're dependent on a human study, eye irritation

19   study, the reference exposure level is calculated by

20   dividing the NOEL by ten.

21             And when you do that, when you divide 220 by 10,

22   you get 22 for a reference exposure level.  And it's quite

23   instructive now to compare that reference exposure level to

24   the actual measurements of MITC both in ambient and off-site

25   studies.



 1             The ambient does not appear to go above the

 2   reference exposure level.  Those, say, in town around in a

 3   season of application.  However, the off-site, the mean

 4   values never go below the REL, so that is an area for

 5   concern.

 6             Okay.  Next slide.

 7             Reference exposure levels for the subchronic is

 8   equal to the NOEL divided by a hundred and that's because

 9   the subchronic NOEL comes from an animal study.

10             CHAIRMAN FROINES:  What happens if you were to

11   calculate in a REL for children?

12             DR. RUBIN:  For acute or subchronic?

13             CHAIRMAN FROINES:  I'm using acute.

14             DR. RUBIN:  What we have made, I don't know

15   whether to call it an assumption, but an irritation -- we've

16   made the assumption that irritation in children, female

17   adults and male adults is going to be the same.  In other

18   words it's not being -- it's not being metabolized, there's

19   no breathing rate considerations here.  So we have assumed

20   that the effect on children of this irritation endpoint is

21   going to be similar to that on adults.

22             DR. BLANC:  Although to the extent that children

23   would be more symptomatic or more sensitive, you're taking

24   that much into account with a factor of ten, even with the

25   human data.



 1             DR. RUBIN:  Right.

 2             DR. BLANC:  It does assume that there are

 3   sensitive subpopulations within the whole population.

 4   Otherwise, you'd have to assume that children were a

 5   separate population and then do another division for

 6   sensitive children.  So that would be an unusual -- it would

 7   not be a standard approach.  The factor of ten is taking

 8   into account that children may be somewhat more responsive

 9   as a subpopulation.

10             DR. RUBIN:  If there are any literature out there

11   that would indicate that children are more sensitive with

12   respect to irritation endpoints, I'd certainly be interested

13   in it.

14             CHAIRMAN FROINES:  There may be to the degree that

15   one thinks about micro-environmental monitoring, there may

16   be some potential to dermal absorption in children that

17   might be different.

18             Go ahead.

19             DR. RUBIN:  Okay.  The reference exposure for

20   subchronic toxicity is the NOEL divided by a hundred.  This

21   is because the NOEL was determined in an animal study, so we

22   have uncertainties of ten for both the human range of

23   sensitivities and going from animals to humans.

24             The way we do this is to calculate from the rat

25   NOEL what I would call a human equivalent NOEL, which takes



 1   into account the different breathing rate of humans, in this

 2   case human children, compared to rats, and amortizes the

 3   data.  This particular experiment the exposures were done

 4   only five out of seven days, and only four hours out of

 5   every 24 hours.

 6             All these modifying factors changed the NOEL, the

 7   rat NOEL, which was one ppm in the rat to a NOEL of 0.1 ppm

 8   in humans, and dividing that further by a hundred gives us a

 9   REL of 1.5 ppb.  This is subchronic REL.

10             And in the document you'll notice that I've also

11   calculated a chronic REL by dividing further the subchronic

12   REL by another factor of ten.  I don't think OEHHA does

13   that, and that I'm very open to comment.  Perhaps a factor

14   of ten is not appropriate.

15             DR. BLANC:  Where did that ten come in again?  I'm

16   sorry.

17             DR. RUBIN:  Because we want to generate a chronic

18   REL value, but we only have a subchronic study.

19             DR. BLANC:  Right.

20             DR. RUBIN:  So there's another factor of ten

21   uncertainty.

22             DR. BLANC:  I see.  I see.  Okay.

23             DR. RUBIN:  So we get a chronic REL of 0.1 ppb.

24             Okay.  I'll finish the talk with just a couple of

25   slides on the alternate or the other breakdown products.



 1             Methyl isocyanate is an extremely toxic compound.

 2   I don't think I need to say that.  It killed on the order

 3   of, say, anywhere from 2500 to 5,000 people at Bhopal in two

 4   or three days, maybe five days.

 5             So this compound has a real good track record for

 6   toxicity.

 7             We have up to this point only one monitoring study

 8   which tracks MIC.  In that study there was one spike of MIC

 9   as high as 2.5 parts per billion, which was about four

10   percent of the MITC that was there.

11             Now, that, I suspect, may be a high estimate of

12   the amount of MIC around, but we definitely need, in my

13   opinion, to have more data on the amount of MIC around when

14   there are metam applications going on.

15             MIC, I've just listed here are the LC 50s in

16   animals 6, 12 and 5 in rats, mice and guinea pigs.  These LC

17   50s are quite a bit lower than MITC.  This is a more acutely

18   toxic compound --

19             DR. BLANC:  By a factor of ten?

20             DR. RUBIN:  Ten to hundred.

21             DR. BLANC:  It's not in here, the LD 50, in this

22   little handout

23             DR. RUBIN:  For MITC, no, it's not in there, no.

24             DR. BLANC:  But it's one to two orders of

25   magnitude?



 1             DR. RUBIN Yeah.

 2             DR. BLANC:  Like two orders of magnitude.

 3             DR. RUBIN:  Yeah.

 4             CHAIRMAN FROINES:  Can I ask you a question?  You

 5   have the acute LOEL of one part per million.

 6             DR. RUBIN:  Yeah.

 7             CHAIRMAN FROINES:  But in the document, for

 8   example, you have a ten-minute study at .5 part per million

 9   found eye irritation, tearing, nose and throat irritation,

10   and so that would seem to indicate that you have a LOEL at

11   .5 part per million and then down here below that in the

12   Allory studies you have certainly a LOEL of 1.3 part per

13   million, increase in respiratory rate, and I didn't look at

14   the paper, but I don't know whether he saw anything in lower

15   dose than 1.3 part per million.

16             But it seems like given this ACGIH information,

17   one could suggest a lower LOEL than one part per million,

18   based on what you have in your document.

19             DR. RUBIN:  I'll definitely go back and look at

20   that.

21             CHAIRMAN FROINES:  I'm just reading what you

22   wrote.

23             DR. RUBIN:  You're absolutely right.

24             DR. BLANC:  Well, another way of asking the same

25   question, I think why John is a little taken aback is



 1   because typically the lethal concentration was six parts per

 2   million, and in five parts per million you wouldn't expect

 3   the LOEL to be one part per million.  It's very steep --

 4   it's possible, but --

 5             DR. RUBIN:  It could be that -- I have to go back

 6   and look.  It could be that those are air concentrations, in

 7   which case they're very different.

 8             DR. BLANC:  That would be more relevant to our

 9   concerns.

10             DR. RUBIN:  Exactly.

11             DR. BLANC:  Do you remember the lethality studies

12   well enough to have a sense of what the curve looked like in

13   terms of mortality?

14             DR. RUBIN:  I couldn't comment on that.

15             CHAIRMAN FROINES:  The document has a LC 50 at 6.1

16   ppm.

17             DR. BLANC:  He's got at the top here 6.1 ppm in

18   rats and 5.4 ppm in guinea pigs.

19             And I don't know whether that's because they saw

20   no lethality at .5 parts per million or -- in other words,

21   if they saw 15 percent mortality at one part per million,

22   you hardly call that a no effect level.

23             So maybe there's some information in the LC 50

24   studies that would be -- would take your LOEL lower than

25   just by looking at it from that point of view.  I don't know



 1   what the studies were.

 2             CHAIRMAN FROINES:  But the ACGIH study did find,

 3   according to this, ten minutes at .5 ppm eye irritation, and

 4   so you may find when you look at that, that data you

 5   described may be awfully limited, would be my guess.

 6             DR. RUBIN:  Yes.

 7             DR. BLANC:  Wasn't there also some modeling data

 8   from Bhopal?

 9             DR. RUBIN:  What the concentrations were?

10             DR. BLANC:  Yeah.  From the various plume radiuses

11   and when they no longer saw any symptoms.

12             DR. RUBIN:  There was modeling data from Bhopal.

13   There are estimates of the concentrations, that the max

14   concentrations that would have been experienced around the

15   factory, but I don't know how sophisticated it was.  I have

16   some of those estimates in this document.

17             DR. BLANC:  Because you want us to make sure that

18   you were being consistent, that it seemed consistent, and

19   you didn't have an estimate that at two miles there's a

20   concentration of .5 ppm and that's where people were having

21   just eye irritation and all that stuff, and then we're sort

22   of arguing against the LOEL.

23             CHAIRMAN FROINES:  The other point I would make

24   here is, and I don't know what you can do with it, if

25   anything, but this data on pregnant mice --



 1             DR. RUBIN:  Yeah.

 2             CHAIRMAN FROINES:  -- where you say that exposure

 3   of pregnant mice for six hours per day on gestation days,

 4   but increased mortalities over control and fetuses at one

 5   and three parts per million.

 6             So you're seeing more lethality, embryo lethality,

 7   at one part per million, but that's an interesting question

 8   about whether you would use a safety factor of ten to get

 9   you to a NOEL, when you have such a profound effect.

10             What would you use?

11             Anyway, let's let it go, because that's a LOEL of

12   one part per million, but that seems pretty high.

13             DR. RUBIN:  Yeah.  That's what I used as the LOEL.

14             CHAIRMAN FROINES:  But to take a factor of ten

15   below that for your NOEL, with that endpoint I'd be nervous

16   about it, frankly.

17             DR. RUBIN:  So you would --

18             CHAIRMAN FROINES:  I think you'd see more

19   lethality -- well, I don't know, it's hard to say.  Again,

20   it's Paul's point about the shape of the dose response

21   curves.

22             DR. RUBIN:  Okay.  Well, using a LOEL of one ppm,

23   I calculated some conditional acute RELs for a one-hour,

24   six-hour, 24-hour exposure, coming up with the numbers you

25   see on the screen, 14.2, 2.4 and .6.



 1             There's a mistake in the document.  I had made the

 2   calculation in the document based on rat breathing rates,

 3   and these are actually mice in the experiment.  So that's

 4   why the numbers look a little different than they do in the

 5   document.

 6             DR. FUCALORO:  These are just purely

 7   proportionate?

 8             DR. RUBIN:  Yes.  These are based on a Haber's Law

 9   proportionality.

10             DR. FUCALORO:  With a exponent of one?

11             DR. RUBIN:  N equals one, yeah.  I used N equals

12   one.  OEHHA in their acute hot spots document lists a number

13   of end values for MIC irritation values.  They range from .5

14   to 1.1.  And I thought just to use one, it will be just a

15   straight proportion, Haber's Law proportionality, and in

16   extrapolating from six to 24 hours and from six to one hour.

17             As I said before, the MIC level, the high MIC

18   level, measured after one metam -- after an metam

19   application i one study, was 2.5 ppb.  Clearly we're in that

20   range just for the acute, for these conditional acute REL

21   values.

22             I just listed some of the NIOSH values here.  The

23   TLV, the eight-hour PEL, based on corrosivity and reactivity

24   of 20 ppb, which is somewhat higher than the values that

25   I've calculated here.



 1             DR. BLANC:  They shouldn't be, because they

 2   intentionally don't take into account any susceptible

 3   populations.

 4             DR. RUBIN:  Right.  These are workers.

 5             DR. BLANC:  If it were any lower than that, you'd

 6   really worry since you will --

 7             DR. RUBIN:  About child labor laws?

 8             DR. BLANC:  You should at least be ten times lower

 9   than that, at least, depending on how it's done, quite a bit

10   lower than that, but at a minimum.

11             DR. RUBIN:  Right.  I don't have any eight-hour

12   type of value here, because -- well, no, take it back.  I do

13   have a six-hour value here and it's getting down toward

14   one-tenth that of the NIOSH value.

15             The other byproduct or degradation product of

16   great concern is hydrogen sulfide.  This we have -- you can

17   fill this room with books written on toxicology of hydrogen

18   sulfide.  It's one of the most, if not the most, toxic

19   industrial gas out there.

20             There's a fair amount known about the levels of

21   sensitivity in human populations, getting respiratory

22   irritation at 100 ppm up to cardiovascular arrest and death

23   at 700 ppm.

24             For these values, I pretty much relied on the

25   ATSDR values that for a minimum -- what's MRL stand for?



 1   Minimal risk level.  An acute minimal risk level of 70 ppb

 2   and subchronic minimal risk level of 30 ppb.

 3             In the monitoring that we've -- that we have so

 4   far, we do see levels rising above those MRLs at one to four

 5   hours, 76 ppb, and then going down with hydrogen sulfide.

 6             I suppose one always has to be worried that there

 7   are other sources, plenty of other sources of hydrogen

 8   sulfide in the atmosphere, so while it does appear to be

 9   going down, perhaps the reason it's coming back up into

10   detectability ranges is that there's some other source

11   there.  I really don't know.

12             The real problem that we're up against here, in my

13   opinion, is how would we go about doing a combined

14   assessment, in other words MITC plus some average or some

15   level, some high level of hydrogen sulfide or MIC, and that

16   I think is quite a cutting-edge issue in risk assessment.

17             I don't have any answers for that right now.  I've

18   based this whole assessment on MITC alone, recognizing that

19   hydrogen sulfide levels are high enough to be of concern and

20   MIC levels are certainly high enough to be of concern in

21   their own right, totally apart from whether they're

22   appearing in conjunction with MITC.

23             There are a few other degradation products,

24   including carbon disulfide, which are monitoring in the one

25   study that I know of, our monitoring has not indicated



 1   detectable levels.  Also carbonyl sulfide and methylamine,

 2   which I don't think we have any monitoring data on.

 3             DR. WITSCHI:  I have a question or a suggestion to

 4   your question about different things being present.  As far

 5   as MITC is concerned, some of the ambient levels of it were

 6   closer about the RELs, right?

 7             DR. RUBIN:  Yes.

 8             DR. WITSCHI:  So these were levels which

 9   presumably, accordingly to our business should have done

10   something, and they can also be assumed that people at this

11   time are exposed not only to MITC, but to MIC and sulfur.

12             Do we have any complaints or do we have any data

13   on people getting sick?

14             DR. RUBIN:  We do have a -- we have a program

15   called PISP, Pesticide Illness Surveillance Program.  And

16   I've got some of that data in the risk assessment as

17   recently as we have it, and there are indeed injuries in the

18   field with metam applications.

19             DR. WITSCHI:  Those data be complete enough at

20   least to give you some clues as to what multiple exposure

21   would mean?

22             DR. RUBIN:  I would say there's probably not

23   enough there to make any conclusions about response --

24             DR. WITSCHI:  Not so much conclusion as

25   hypotheses.



 1             DR. RUBIN:  I'm a good speculator.  Sure.  There's

 2   certainly a possibility here that some of the other

 3   degradation products could be responsible.

 4             DR. WITSCHI:  To say that really strikes me.  This

 5   whole thing is we often construct some hazards or risk

 6   assessments from animal toxicology, but we do not very often

 7   have a chance to verify what the animal tells us about human

 8   data.  And maybe this might be one of those situations.

 9             MR. GOSSELIN:  Maybe this might answer your

10   question.  Is your question have we been seeing incidents

11   from metam-sodium applications where people have been

12   complaining for exposure to -- we're not going to know

13   exactly what they were exposed to.

14             DR. WITSCHI:  Well, yes, my question really was

15   this seems to me, given exposure data and the possibilities

16   of exposure where there seems to be a real possibility that

17   human data are out there which would reinforce what we

18   conclude from the animal studies, and, if so, that could be

19   very very closely looked at.

20             MR. GOSSELIN:  Actually, that's been one of the

21   things we've been chasing for a number of years is incidence

22   from workers and also incidence from off-site ambient air

23   samples.  And it's caused over the years, most specifically

24   since '93-94, alterations to what practices be allowed to

25   happen.  Some of these are occurring from legal applications



 1   and then some are misused, but sort of the effects of the

 2   exposures, what we have the evidence on.

 3             DR. BLANC:  In fact over half of the cases

 4   reported to the pesticide and surveillance network have been

 5   nonoccupational ambient cases; right?

 6             So that's a ratio which I would imagine is higher

 7   than the ratio of ambient to -- or drift, let's say, because

 8   I don't want to say occupation, because a lot of other

 9   pesticides it's not optional, but it is application driven,

10   but that's fairly high ratio it would seem to me, other than

11   the ratio by standard complaints, because of petroleum

12   distillate smells or something.  But that's sort of very

13   strongly supportive of what Hans was saying, the fact you

14   have a lot of evidence that there is a toxic air problem

15   with this, at least in the acute arena.

16             DR. FUCALORO:  Can I follow up on what Hanspeter

17   was saying?

18             When you get something reported in your

19   surveillance program, how much information is reported?  How

20   much are you trying to get?  Do you get, for example, the

21   length of time of exposure, estimated concentrations and the

22   illness or the effect?  In other words, is there something

23   quantifiable, is it possible to get aggregate data and do

24   something quantifiable?  I don't know.

25             MR. GOSSELIN:  There's a wide range of data that



 1   comes through the illness surveillance program.  Some of it

 2   lags a long time because we get what's called doctor's first

 3   reports.  Some of you may deal with that.  If you suspect

 4   it's a pesticide illness or exposure, you're required to

 5   report that in to the Department of Industrial Relations and

 6   we get that and we'll have staff review that and try to

 7   categorize what went on.

 8             Other times there are incidents that are directly

 9   reported to us and we conduct an immediate investigation

10   with the counties to, one, not only categorize what the

11   exposures were and what occurred, but also to determine if

12   there were violations that occurred under our normal

13   enforcement and surveillance program.

14             DR. FUCALORO:  I understand all those things.

15             MR. GOSSELIN:  Here's kind of what you are asking

16   about, looking at sort of trends and issues, what we've

17   found oftentimes, particularly with agricultural workers

18   reentering fields, sometimes there's trends that occur about

19   from a variety of effects that are illustrated in the data

20   showing a certain crop using a certain material and the time

21   that's elapsed before people go in that causes us to go in

22   and have to extend that time to allow the degradation of the

23   material to occur.  That data, that illness data, has also

24   been used to fix some of those problems.

25             DR. BLANC:  In fact, if we go back to the usage



 1   data that we discussed at a previous meeting, where there

 2   was a sharp upswing in pounds applied in 1994, 1995, is that

 3   right?  Do I have the year right?

 4             DR. RUBIN:  My recollection of the data was that

 5   from '91 to '98 the -- well, from '91 to '95 the use rate

 6   doubled, and so that's what we know.

 7             DR. BLANC:  In fact, beginning in 1995 you have a

 8   two- to fourfold increase in the number of reports of

 9   drift-related events?

10             DR. RUBIN:  Right.  And that's directly --

11             DR. BLANC:  Wouldn't that support the -- wouldn't

12   those observations of ecological data support the hypothesis

13   that metam-sodium and its breakdown products are causing

14   ambient air problems in California?

15             DR. RUBIN:  I would definitely agree with that.

16   The use went up and the ambient incidence went up.

17             DR. BLANC:  If you only had the pesticide

18   surveillance program data and none of the elaborate animal

19   data that you have, would that alone be enough to support

20   considering this material toxic as an air contaminant?

21             MR. GOSSELIN:  It --

22             DR. BLANC:  I don't mean from a strictly

23   regulatory point of view, but from a sort of common sense,

24   public health regulatory point of view.

25             MR. GOSSELIN:  I think so.  And I think the way



 1   that a lot of the counties that have been facing incidents

 2   that are occurring, that's the way they have reacted.  You

 3   know, there's been a lot of issues about the eye irritation,

 4   eye blink.  This a traditional toxic effect.

 5             The fact of the matter is regulators are going to

 6   do we need to solve that problem so that the phone calls

 7   don't come in and people don't complain.  I think back in

 8   '97, beyond what things we had put out, '94 Kern County, I

 9   think, moved on their own, any application outside of the

10   city limits, because they went through and started seeing

11   where they were getting complaints historically, it was all

12   within city boundaries, and on their own made a policy, I

13   think, to move everything outside.

14             DR. BLANC:  Is that historical event documented in

15   your human health assessment section?

16             MR. GOSSELIN:  I don't think a lot of --

17             DR. BLANC:  Is that too anecdotal?

18             MR. GOSSELIN:  It gets into, I think, some of the

19   risk management things that have been done out in the field

20   that's probably not captured to a great extent out here, I

21   mean in this document.

22             DR. RUBIN:  I just have a conclusion slide.

23             CHAIRMAN FROINES:  Going back to Bob Spear's

24   presentation about the variability of exposure estimation,

25   it's interesting, because this data here for '95 and '96 is



 1   so striking, recognizing that variability it again goes to

 2   this issue of whether or not MOEs is the way to determine

 3   whether something should be clarified a toxic air

 4   contaminant.

 5             This compound, metam-sodium and its multiple

 6   products, are so toxic that to sort of rely on whether it's

 7   above this value of MOE or this value of MOE is going back

 8   to what Paul said.  Questions one's common sense.

 9             DR. ALEXEEFF:  George Alexeeff with OEHHA.

10             I just wanted to get back to Dr. Fucaloro's

11   earlier question, and actually it's OEHHA that designs the

12   pesticide illness reporting form that's filled out in these

13   cases and then it goes to DPR and to DIR.

14             And we're thinking about trying to improve this

15   reporting form to get more information to help us in this

16   situation.

17             Another responsibility we have is also training

18   physicians on pesticide illness detection and reporting.

19   And one is of course we change the form, we'd have to also

20   train the physicians so they could use it properly.  So

21   we're also thinking of doing that.  We haven't done much in

22   the area of improving the form or in training physicians in

23   the last several years, but at this point we are planning on

24   doing so or actually we started this year.

25             So it's also the other thing we found, for



 1   example, in the metam-sodium incident where we did go to the

 2   field and trained the physicians at that point on detecting

 3   it and trying to report as much information as possible so

 4   we can do retrospective analyses, it's just a hard thing to

 5   do in terms of the exposure concentration for getting those

 6   samplers there.  That's pretty much the hardest thing is to

 7   get the exposure information.

 8             DR. FUCALORO:  I was thinking you'd have certainly

 9   a large uncertainty in exposure, but of course you could get

10   the information about when it was applied and you have some

11   historical understanding of what the concentration does as a

12   function of timing and distance from point of application.

13   I mean, I don't know that that's true.  I hate to say it's

14   fortuitous when someone gets sick from one of these things,

15   but as Hanspeter was pointing out, you have so little

16   information on human subjects that this is a rare

17   opportunity.

18             DR. KENNEDY:  I think your comments about

19   professional education for physicians are fascinating.  It's

20   never ending in my particular practice.  Our primary

21   inhalent is cordite.

22             CHAIRMAN FROINES:  I think that this raises a very

23   important question, Elinor, that we may want to come back to

24   at some point, which is the one thing it's true about

25   pesticides, which we all agree, is that they're toxic.  You



 1   then debate whether they should be toxic air contaminants.

 2             But what we don't have is an -- and we know that

 3   pesticides drift, people have occupational exposure and so

 4   on and so forth, we need to develop a good surveillance

 5   system for addressing pesticide-related health effects.

 6             There is no good surveillance system except for

 7   what you have in terms of your pesticide injury reports, but

 8   the question is is there a way to improve upon that so we

 9   can actually develop more information, because you don't

10   have the kinds of interventions that occur in industrial

11   America out there in the field.  It's a different ballgame.

12             DR. BLANC:  Okay.

13             DR. RUBIN:  Okay.

14             CHAIRMAN FROINES:  Peter's point is really

15   important.

16             DR. RUBIN:  Just to wrap up of some of the things

17   we've talked about.

18             MITC exposure was associated with both short- and

19   long-term effects following the Cantara Loop spill.  That we

20   talked about in detail back in November.

21             The acute MOEs for ambient exposure range from,

22   and these are mean values, range from 25 to 2,750.  The

23   off-sites from less than one to ten.  By our conventional

24   way of thinking, anyway, those off-site MOEs would trigger

25   health concerns because they're based on human data and



 1   they're less than ten and even less than one.

 2             Subchronic MOEs, again, the ambient from 189 to

 3   17,000, the off-site from 2 to 236.  The convention is that

 4   when based on animal studies an MOE less than a hundred

 5   trips a concern.

 6             The acute REL value, this is for children and

 7   adults, is 22 ppb.

 8             The range of acute exposures for ambient is less

 9   than 22 ppb, but if the off-site exposures can be way more

10   than 22 ppb, that would indicate again health concerns.

11             Subchronic REL value of 1.5 ppb for the ambient

12   range of exposure from .13 to 4.09, so that value the REL

13   falls right in the middle of that range.

14             The off-site values are quite far above that REL

15   value.  That would indicate perhaps some concern.

16             We also discussed in great length the oncogenicity

17   study, and I think we probably agree that some change in

18   language from the original draft that you have is in order.

19             And that's all I have today.

20             CHAIRMAN FROINES:  That's very good.  Very good.

21   Thank you very much.

22             DR. WITSCHI:  I would like to really say it's been

23   pleasant to work with Andrew Rubin on this document and I

24   would like to in the name of the panel thank you very much

25   for the really big big effort you put into that.



 1             DR. RUBIN:  Thank you.

 2             DR. BLANC:  Here here.

 3             DR. RUBIN:  I have the feeling we have not heard

 4   the last from MITC, though.

 5             CHAIRMAN FROINES:  I had one question for OEHHA,

 6   George.

 7             OEHHA also had comments that were submitted.  Do

 8   you want to follow up and make any subsequent comments to

 9   Andy's remarks?

10             DR. ALEXEEFF:  Yes.

11             CHAIRMAN FROINES:  Paul and George --

12             DR. ALEXEEFF:  We have somebody from OEHHA that

13   can speak to it.

14             CHAIRMAN FROINES:  Just one comment, due to the

15   high-level policy operatives, in the future, if we could, it

16   would be nice if we could have integration of your points of

17   view, so we don't see this as an agency war, but rather as a

18   collaborative effort.  If that's possible.  I'm joking

19   obviously, but --

20             DR. ALEXEEFF:  We're not really warring at all.

21             CHAIRMAN FROINES:  The point is that we would like

22   to see -- as you bring us comments, we like to see the OEHHA

23   comments, but to the degree they can end up looking similar,

24   because you've come to some common agreement, it's better

25   from our standpoint.



 1             DR. WITSCHI:  What about the public comments?  We

 2   talked about that one.

 3             CHAIRMAN FROINES:  We don't have any public


 5             DR. WITSCHI:  Yes.

 6             DR. KENNEDY:  Request for delay.

 7             DR. WITSCHI:  I would ask Paul that one.  When we

 8   reviewed the OEHHA documents in the halcyon days, which are

 9   past, whenever the SRP or even the lead person got the

10   finished document he also got what many of us considered the

11   most important volumes, these were the public comments,

12   because the public comments sometimes alert you to things

13   you wouldn't spot yourself.

14             I do not recall having seen a document in this

15   case of the MITC, which might have alerted by comments made

16   by interested parties to give a few things a closer look,

17   studies or whatever it was.

18             So my question really is it possible, is it not in

19   your process, that the time being the combined document just

20   OEHHA and from you department and also at this time we get

21   what usually be Part C, the public comments.

22             Because as Stan pointed out if you can get one of

23   those documents, first thing you do is you look at what

24   other people have to say to get your own thinking into gear.

25             MR. GOSSELIN:  Yeah.  We agree.  And I think one



 1   of the things, and actually staff has got together

 2   yesterday, ARB, OEHHA and DPR, to kind of go over what we

 3   have on the plate and we tried to scheduled out in a far

 4   better way so we get the ARB, OEHHA consultation done

 5   earlier on, the public comment period and public comments

 6   and then our response to those is one package, so when you

 7   get it it's not a piecemeal event so this thing can go a

 8   little smoother.

 9             DR. WITSCHI:  Yes.  I really would like to

10   emphasize that.  I would like to see the public comments.

11             MR. GOSSELIN:  I agree.  It should be, as you

12   said, part of the document with our sort of response or

13   acceptance or rebuttal of that, so it's all there for

14   everyone to see.

15             DR. FUCALORO:  We just received one comment that

16   was copied us by a group called the Metam-Sodium Task Force.

17   Did you see that?

18             DR. WITSCHI:  I saw that.

19             DR. FUCALORO:  That's the only thing I received.

20             DR. WITSCHI:  The way I understand the process,

21   the DPR document has to be open for public comments for a

22   certain period of time and people write and I would like to

23   see those letters.

24             DR. FUCALORO:  And the practice here that I've

25   understood, and I see what you're getting at, was that there



 1   would be a response from OEHHA to the public comments.  For

 2   example, this document received from Metam-Sodium Task

 3   Force, some response to what they say.  It's probably a

 4   group of three or four chemical companies that obviously

 5   have an interest.

 6             CHAIRMAN FROINES:  But there is one point that is

 7   very very important and I guess Stan is probably going to

 8   say it.  Go ahead.  If you don't say it, I will.

 9             DR. GLANTZ:  You can say it, whatever it is.

10             Well, no, I'll say what I was going to say and

11   then you --

12             DR. FUCALORO:  You go, Alphonse.  No, Gaston.

13             DR. GLANTZ:  But anyway, we have no sense of humor

14   here.

15             I had a couple things.

16             On the point about the OEHHA comments and getting

17   DPR and OEHHA together, I mean, I think, again, we don't

18   want to have an adversarial relationship.

19             And I also want to second what the other people

20   said.  I think we've really come a long way in what DPR has

21   been doing vis-a-vis this panel.

22             But I think I wouldn't want to like inhibit

23   OEHHA's comments on the draft, but I think the best --

24   because I think it's helpful, but I think the way it would

25   be nice to handle that is sort of this with the public



 1   comments, so that we would get something like the old Part C

 2   document.

 3             The other thing with regard to this Metam-Sodium

 4   Task Force letter, I don't know if this is what you thought

 5   I was going to say, I get real irritated with things like

 6   this.  There is a process and there was public comments on

 7   this document sometime in the infinite past.  And I think

 8   that it's not appropriate for these agencies to send stuff

 9   directly to us.  It should go to DPR or OEHHA, as

10   appropriate, and then be factored into the public comment

11   process, you know, rather than having people come in at the

12   last second and throwing stuff in front of this panel.  This

13   happens from time to time.

14             CHAIRMAN FROINES:  But some time ago, years and

15   years ago --

16             DR. GLANTZ:  Is that what I was supposed to say?

17             CHAIRMAN FROINES:  Yeah.

18             The panel established very clear guidelines about

19   when something would go to the panel.  And I don't remember

20   the dates, Bill Lockett may, but it was something like if

21   somebody is going to submit something and they want the

22   panel to review it, it must be at least two weeks before the

23   SRP meeting, and it may have been even longer than that.

24             Do you remember?

25             MR. LOCKETT:  Not the exact time, but this was



 1   done back in the mid '80s.

 2             CHAIRMAN FROINES:  Yeah.

 3             We set up guidelines and Tom Mack and I sat down

 4   and wrote these way back when, and the idea was that we

 5   would love to see all the comments that people have to

 6   provide us, but it must be within a reasonable time frame so

 7   the panel can read it, consider it and then take it up at

 8   the meeting.

 9             So I would argue that we should -- nothing should

10   be sent to us closer than at least two weeks before the

11   meeting, and if they get it within two weeks -- and because

12   then we were getting Federal Express packages the night

13   before the meeting, which is really insulting.

14             So whatever the date may be, whatever the date the

15   panel wants to have, it seems to me we want to have a window

16   of time between the time we receive a document and the time

17   we consider it at a meeting.

18             And I think otherwise anybody gets to us after

19   that, we don't take it up, period.

20             DR. GLANTZ:  And the other thing I recall is that

21   stuff shouldn't be sent by these people to us.  It should go

22   to the agency and then come to us through the appropriate

23   channels.

24             And, I mean, I don't -- we didn't do that to be

25   bureaucratic, we did it to be fair and have some control



 1   over the process and not get sandbagged.

 2             And but, yeah, that's a related point.

 3             But I think that the point about bringing -- I

 4   mean, I think we did have public comment on the MITC

 5   document, it's just this has been going on a long time.  And

 6   I think that as things speed up, I just think part of the,

 7   you know, when you were talking earlier about batching

 8   chemicals and things like that, and I think as part of the

 9   process you want to have a Part C document.

10             I think that the OEHHA comments on the draft could

11   be handled along with the public comments.  And in fact I

12   think in one or two of the things we've seen that's how you

13   did it and I thought that was completely appropriate.

14             Because, again, the way I use these like everyone

15   else is I read the executive summary to kind of figure out

16   what's going on, and then I read the public comments to see

17   what issues are being raised, and then go read the document

18   itself.

19             So anyway, but I think this other thing in this

20   last-minute letter, that's just not appropriate.

21             CHAIRMAN FROINES:  Can I stop?

22             I think Stan's finished.

23             But I want to stop because I think Paul has to

24   leave in the next 10, 15 minutes.

25             DR. BLANC:  Yes.



 1             CHAIRMAN FROINES:  Before OEHHA makes any

 2   comments, what I'd like to do is get Paul's comments before

 3   he has to leave.

 4             DR. BLANC:  Well, in general what I think I would

 5   say is that although the documents as prepared by the DPR

 6   may not have everything in exactly the form that we would

 7   want in the best of all possible worlds, and there may be

 8   some areas of discussion that could be clarified or

 9   expanded, this is not a doctoral dissertation and we're not

10   the doctoral review committee.

11             I think the way I would recommend as a matter of

12   process the way we handle clarifications and issues of

13   emphasis would be in our written findings.

14             I think the scientific record is sufficient in the

15   material that we've been provided to make reasonable

16   comments on the indications for metam-sodium and its

17   breakdown products to be treated as toxic air contaminants,

18   and that's what we're required to do.

19             And I would say that we approach it that way

20   rather than trying to seek further editorial modifications

21   in the document.

22             I don't think that there's any question that the

23   fundamental information as provided would support its

24   designation as a TAC, and I think that we simply can serve

25   to better clarify the record by emphasizing the key points



 1   as we see them.

 2             For example, the pesticides surveillance data

 3   that's in the document, for example, and data that is

 4   present in the document on the breakdown products and the

 5   distribution and the assumptions in the modeling, which are

 6   essentially conservative, and for every assumption where you

 7   can argue that it could go one way, it could as easily go

 8   the other way.  So either way you would cut it you would

 9   still be saying that it certainly reaches a red flag level

10   consistent with policy for TAC designation.

11             So that's how I would pragmatically approach the

12   problem.

13             DR. GLANTZ:  Are you saying, just to be clear, you

14   think the report is okay?

15             DR. BLANC:  I think we can come to the conclusions

16   we need to come to based on this report.

17             DR. GLANTZ:  So you don't think there's any

18   additional changes they need to make to the document itself?

19             DR. BLANC:  I don't think that that's required.  I

20   think that we can handle the gaps that we have based on

21   clarifications that we can make in our finding.  We can't

22   make a finding based on something that's not even alluded to

23   here.  I suppose, although it's possible, that we could

24   comment on the fact that what Paul was alluding to about

25   Kern County having to ban it in the notes, but even that I



 1   don't know that that's so germane that we'd be forced to do

 2   that.

 3             So I recommend that we just move forward.

 4             CHAIRMAN FROINES:  And Andy has some changes he

 5   wants to make.

 6             MR. GOSSELIN:  Yeah.  Actually Tom was going to

 7   come up and kind of go over some of the exposure numbers he

 8   was looking at in the newer study that will just be an

 9   addition to the report and maybe another look at some of the

10   subchronic.

11             DR. BLANC:  I don't think we need to meet and

12   review your document again.  If you want to give us your

13   final report in the next three weeks or something, in the

14   meantime we could draft our findings.

15             MR. GOSSELIN:  And we've done that, I think, in

16   the past on a couple and make sure the numbers that are in

17   there match up with additional data and everything else.

18             CHAIRMAN FROINES:  Yeah.  And that would mean that

19   we would be basically voting on the document.

20             DR. BLANC:  Pending the stated revisions.

21             CHAIRMAN FROINES:  Pending the stated revisions.

22             DR. BLANC:  Minor revisions.

23             That would be my --

24             DR. WITSCHI:  I would agree.  I would second that

25   one.



 1             DR. GLANTZ:  Then why don't you make a motion.

 2             DR. BLANC:  I move --

 3             DR. FRIEDMAN:  Can I just ask, is that setting a

 4   precedent?  Haven't we always been really careful about

 5   approving every other document to the last detail before we

 6   come up with findings?

 7             CHAIRMAN FROINES:  No.  The DEF document went

 8   through an enormous number of changes to bring consistency

 9   to the numbers and small errors.

10             DR. GLANTZ:  We've never --

11             CHAIRMAN FROINES:  We've never -- we have always

12   made small changes that weren't fundamental changes.  In

13   fact, the closest thing to actually letting OEHHA or DPR or

14   ARB go was DEF where we actually argued right at the end

15   about NOAEL versus NOEL, and God forbid we ever go back to

16   that argument.

17             And there were some major number errors between

18   OEHHA's numbers and DPR's numbers and so I worked with, I

19   forget who, but we worked it all out to make those changes.

20             But by and large we've generally accepted small

21   changes without necessarily going back.

22             DR. BLANC:  I make a two-part motion.

23             CHAIRMAN FROINES:  But we could.  Whatever you

24   want.

25             DR. FRIEDMAN:  I just wanted to raise that



 1   question, because this sounded sort of new to me, even

 2   though we've always been so careful.

 3             DR. GLANTZ:  I think what we're talking -- I agree

 4   that we've always been very careful, but I think at this

 5   point we're talking about small changes to bring consistency

 6   within the report, based on the discussion at the meeting

 7   and correct some errors that have been identified.  I don't

 8   think it's anything fundamental.

 9             CHAIRMAN FROINES:  I think we'll actually -- I

10   think Paul can make a motion and we can second and vote and

11   if something comes up as we discuss it for the rest of the

12   day we can go back and revisit that motion.  It's not cast

13   in stone.

14             MR. GOSSELIN:  I will say there is the -- I think

15   one of the subjects of the letter you got in about the study

16   in December that we are going to incorporate in the

17   document, that Tom is going to talk about, some new

18   information.

19             CHAIRMAN FROINES:  Why don't Paul make the motion

20   and we can go and then if we want to reconsider we can do

21   that.

22             DR. BLANC:  Move that the Scientific Review Panel

23   accept the draft document for -- accept the draft document

24   pending minor revisions.

25             DR. WITSCHI:  I second.



 1             DR. GLANTZ:  Can I have one point of

 2   clarification?  The final acceptance of the document on

 3   behalf of the panel would be the chair --

 4             DR. BLANC:  I want to make a second motion, so let

 5   me do that.

 6             DR. GLANTZ:  Make your second motion.

 7             DR. BLANC:  First, let's do this one.  You have to

 8   do one at a time.

 9             DR. KENNEDY:  Call the vote.

10             DR. GLANTZ:  Call the question.

11             CHAIRMAN FROINES:  There's no further discussion,

12   then all in favor of that motion.

13             (Show of hands.)

14             DR. GLANTZ:  It's unanimous.

15             DR. BLANC:  My second motion is that the chair of

16   the panel review the revisions and in light of the draft and

17   its revisions, draft findings for the panel to be circulated

18   to its members.

19             CHAIRMAN FROINES:  Well, I would, if I can add to

20   that, I would say if the review indicates significant

21   changes --

22             DR. BLANC:  Certainly.

23             CHAIRMAN FROINES:  -- then I would bring it back

24   to the panel for --

25             DR. BLANC:  Fine.



 1             CHAIRMAN FROINES:  -- reconsideration.

 2             DR. BLANC:  I accept your friendly amendment.

 3             So let me read it to you so you have it, or state

 4   it to you.

 5             The chair will review the revised draft

 6   document --

 7             CHAIRMAN FROINES:  I have a second friendly

 8   amendment.  Sorry.  Sorry.

 9             I'm concerned about meeting Gary's question.  I

10   think it's important.

11             That the chair and the lead person --

12             DR. BLANC:  Who is the lead person?

13             CHAIRMAN FROINES:  Peter.

14             DR. BLANC:  So that resolve then the chair and the

15   lead reviewer will evaluate the revised document and either

16   request further review by the whole panel or draft findings

17   to be circulated for review by the panel.

18             DR. KENNEDY:  Second.

19             DR. WITSCHI:  Thank you.

20             CHAIRMAN FROINES:  I just don't want anybody to

21   say --

22             DR. GLANTZ:  Just a point of clarification,

23   though.  I mean, I think it's clear if there's any

24   substantive changes to the document, then it would come back

25   to the panel.



 1             CHAIRMAN FROINES:  Absolutely.

 2             DR. GLANTZ:  That the review by the chair is to

 3   simply make sure that any changes that are made are

 4   consistent with the views expressed by the panel.

 5             DR. FUCALORO:  I understood it that way.

 6             DR. GLANTZ:  Just for the record.

 7             Call the question.

 8             CHAIRMAN FROINES:  All in favor.

 9             (Show of hands.)

10             DR. GLANTZ:  It's unanimous for the record.

11             You're supposed to say that.

12             DR. FUCALORO:  Since he never does, you always do.

13             DR. GLANTZ:  I know.  It's because I am so

14   meticulous.

15             CHAIRMAN FROINES:  It's always so much fun when

16   you add in your little pieces and everybody enjoys it, so

17   why would I take that away?

18             Okay.  Can we take a five-minute break?  I mean a

19   five-minute break.  We can finish with this fairly quickly.

20             DR. GLANTZ:  We don't have draft findings already,

21   do you?

22             CHAIRMAN FROINES:  No.  I wish we did.

23             Five-minute break and we're going to hear from

24   OEHHA and then the other.

25             MR. GOSSELIN:  We have a short presentation that's



 1   going to be changes to the document and then OEHHA.

 2             (Thereupon a short recess was taken.)

 3             MR. GOSSELIN:  We have ten-minute presentation, or

 4   shorter than that, and then OEHHA is going to wrap up.  This

 5   is just on the exposure monitoring and one new study that

 6   came in that's going to be added to the document.

 7             If we can go right to the overheads.

 8             CHAIRMAN FROINES:  Yeah.  I have a question.  How

 9   long is OEHHA -- does OEHHA want to make any presentation

10   and, if so, how long would it take?

11             DR. ALEXEEFF:  Two minutes.

12             CHAIRMAN FROINES:  Two minutes.

13             You're considering how long?

14             DR. THONGSINTHUSAK:  Ten minutes.

15             CHAIRMAN FROINES:  Ten minutes.  That's 12

16   minutes.  I'm only asking because Peter just said that

17   there's some panel members who can make a 3:45 plane if we

18   finish in time.

19             DR. FUCALORO:  Make that 3:40.  I have to get a

20   car back to the rental.

21             CHAIRMAN FROINES:  If we were to move in that

22   direction, we haven't had a discussion -- the trouble with

23   Paul making his motion is that we have nobody on the panel

24   has had a chance to give comments to DPR on their reading of

25   the document.  So I think --



 1             DR. GLANTZ:  Our reading of which document?

 2             MR. GOSSELIN:  Which document?

 3             CHAIRMAN FROINES:  The documents.

 4             DR. GLANTZ:  I thought we were --

 5             DR. BYUS:  We just voted for it.

 6             CHAIRMAN FROINES:  I'm still saying that we did

 7   vote for it, but nobody has had an opportunity, besides

 8   Paul, we have had a lot of discussion, enormous discussion

 9   during the day, so the question is are there any members of

10   the panel who still would like to raise questions with DPR,

11   so that they get their positions stated?

12             And, if not, we'll go with the -- try to make the

13   airplanes.  I don't mean to create a Hobson's choice.

14             DR. GLANTZ:  I thought that's what we spent the

15   whole morning doing.

16             CHAIRMAN FROINES:  Your plane or your freedom.

17             DR. GLANTZ:  I thought, John, that's what we spent

18   half the morning doing.

19             CHAIRMAN FROINES:  Okay.  I'm just --

20             DR. GLANTZ:  I don't want to shut anybody else

21   down, but I thought --

22             DR. FUCALORO:  Shut us down.

23             CHAIRMAN FROINES:  All I'm --

24             DR. GLANTZ:  Don't say things like that on the

25   record.  We're all going to be arrested and sued.



 1             CHAIRMAN FROINES:  Stan, you don't get it.  He may

 2   have said it, nobody would have noticed.  You just

 3   reinforced it.

 4             DR. GLANTZ:  And you just reinforced me.  It's

 5   been a long meeting.

 6             CHAIRMAN FROINES:  Okay.  A very good meeting.

 7             DR. GLANTZ:  It has been a very good meeting.

 8             CHAIRMAN FROINES:  As long as everybody feels fine

 9   about this process of doing -- excuse me, let me finish my

10   talking.

11             We will go to a final presentation by DPR, a short

12   presentation by OEHHA, and then we will essentially adjourn,

13   unless somebody asks for a reconsideration and wants to have

14   more comments.

15             Is that acceptable?

16             DR. GLANTZ:  Can I just say one thing to clarify

17   the record?

18             I would say the question you should have asked is,

19   Mr. Chairman, does anyone have any additional comments about

20   the document.

21             CHAIRMAN FROINES:  Okay.

22             DR. GLANTZ:  To guide DPR beyond what we've

23   already discussed so far in the meeting.

24             CHAIRMAN FROINES:  Tony?

25             DR. FUCALORO:  No.



 1             CHAIRMAN FROINES:  Peter?

 2             I think he's already voting with his head.

 3             Roger said no.

 4             Craig, I think, is saying no.  He's trying to

 5   reach his coffee.

 6             So let's go ahead.

 7             DR. THONGSINTHUSAK:  I'm Tom Thongsinthusak.

 8             I would like to present the data from the letter

 9   submission from the Metam-Sodium Task Force.  It's an

10   off-site and monitoring studies conducted in 1999.  The area

11   is in Bakersfield, California.

12             Table 1, summary of the air concentrations of MITC

13   from the application of metam-sodium through sprinkle

14   irrigation.  I present the table in two sections.  The

15   middle section is for ADD.  This is for short-term exposure.

16   And the last part is on the right-hand for SADD or seasonal

17   daily doses.  This is for subchronic exposure.

18             For this study, there were four to five sampling

19   stations located 150, 300, 700 and 9700 meters, in the east

20   and the west areas of the treated field.

21             This treated field consists of about four plots of

22   20 acres each.

23             And the maximum application of metam-sodium was

24   applied, and the application was in accordance with the

25   technical information bulletin.  In other words, the



 1   procedure in the application including pre-application

 2   irrigation and after the application it was a water tap to

 3   retain metam-sodium or MITC.

 4             I group them into day one, day two, day three and

 5   day four for short-term exposure.  Start on day one for the

 6   highest, down the road and then for the subchronic, the

 7   average of the four-day concentration, so they can be used

 8   for the subchronic exposure estimates.

 9             Next, please.

10             The second table is similar to the first one, but

11   this is the metam-sodium was applied through shank

12   injection.  The total area is about 79 acres of land.

13             Also there were four sampling stations located in

14   the east and the west of the field.  Also, air

15   concentrations include four different days.  That's for ADD

16   and SADD.

17             CHAIRMAN FROINES:  How do we know -- I'm sorry, I

18   missed something.  How do we know what the wind patterns

19   were for these determinations?

20             DR. THONGSINTHUSAK:  Yes, I will show them on the

21   next table.

22             CHAIRMAN FROINES:  Okay.

23             DR. THONGSINTHUSAK:  This is summary, and the

24   study assume that the sampling station was in the downwind

25   areas, but according to the data I revealed it's not exactly



 1   the way they wanted to see.  Like this stand 150, 300 and

 2   700 sampling stations A, C and A.  Let's suppose that A,

 3   station A, should be in downwind direction, but because of

 4   the wind shifted, the C showed the highest air concentration

 5   in that direction.

 6             So for the short-term exposure I pick the highest

 7   air concentration, I mean the daily air concentration, to

 8   represent the daily exposure for acute risk assessment.

 9             And for the SADD, the sampling station is pretty

10   consistent, when I take the average of the four sampling

11   days, the high always in the A sampling station for 150, 300

12   and 700 meter stations.

13             For the acute exposure at 150 meters from the

14   treated field, the air concentration is 101 parts per

15   million.  For the 300 it's 52.  700 meters it is 31.

16             And air concentration daily dosage represents ADD

17   in term of micrograms per kilogram and per day.  I would not

18   repeat those numbers.

19             For the SADD or the subchronic exposure, the mean

20   I showed the air concentrations as mean, low and high for

21   all three sampling stations.

22             For example at 150 meters, mean value for the air

23   concentration is 55 parts per billion.

24             And for the low, 50, and the high 63, and so on

25   and so forth.



 1             And then I calculate the subchronic exposure in

 2   terms of SADD.  This is for adult female exposures.

 3             For the 150 represents 100, for 486 the low is 5.5

 4   and the high 6.9.

 5             Next, please.

 6             DR. FRIEDMAN:  Can you explain why it's lower for

 7   SADD than ADD?

 8             DR. THONGSINTHUSAK:  Because I take the average of

 9   those four daily exposures.  The first day will be higher

10   than most of the time, the second day, third day and so on

11   and so forth.

12             DR. FRIEDMAN:  So this is one -- there is an

13   application --

14             DR. THONGSINTHUSAK:  Yes.

15             DR. FRIEDMAN:  And then the A is right after the

16   application and then it gradually disperses?

17             DR. THONGSINTHUSAK:  That's right.  That's

18   correct.

19             The format is similar to Table 3 on the previous

20   table, but this is for the shank injection method.

21             Presentation of the data is the same.  The mean

22   for a short-term exposure and the moderate-term exposure at

23   150, 300, and 486 meter sampling stations.

24             I would cite one example for the ADD run from 175

25   parts per billion for sampling at 150; for 300, 106; and 486



 1   meters, 84 parts per billion.

 2             Overall for two different methods, I mean

 3   sprinkler injection and shank injection, the air

 4   concentrations at similar distance from the treated field

 5   were similar.

 6             And in my previous presentation, probably in

 7   November, there's a question about a retention of the silica

 8   gel tubes.  This study has or used similar methods to that

 9   one.  The previous one was conducted by ICI, and they use a

10   silica gel dry tube, but they did not add residues of MITC

11   from the tube to the total MITC residues.

12             I did not have any good answer for that.  But this

13   study can replace the previous one and the air

14   concentrations at the same distance from the treated field

15   was very similar.

16             So I propose that this study be used to replace

17   the previous one, which was conducted by ICI, and there was

18   so many questions about a retention of silica gel drying

19   tubes, and the study did not include the residue in those

20   tubes.

21             DR. FUCALORO:  Are the results of this study

22   significantly different from the one, the one that was in

23   question?  I don't remember.

24             DR. THONGSINTHUSAK:  Very similar.

25             DR. FUCALORO:  Very similar?



 1             DR. THONGSINTHUSAK:  Yes.

 2             DR. FUCALORO:  Okay.

 3             DR. THONGSINTHUSAK:  But we still have some work

 4   to do for this study, because the downwind direction did not

 5   stay put in the same direction all the time, and some MITC

 6   residues at relatively high amount was observed in the

 7   upwind area.

 8             So I assume there was the wind shift, the

 9   direction did not go to the same direction during that four

10   days of study.

11             Since the letter representative the metam-sodium

12   application methods that currently used in California, I

13   assume that in general the study should be more

14   representative than the previous study.

15             CHAIRMAN FROINES:  Where was this study conducted?

16             DR. THONGSINTHUSAK:  Pardon me?

17             CHAIRMAN FROINES:  Where was it conducted?

18             DR. THONGSINTHUSAK:  Where was it conducted?  In

19   Bakersfield.

20             CHAIRMAN FROINES:  Bakersfield.

21             DR. THONGSINTHUSAK:  Yes.  In 1999.

22             This is the last slide.

23             CHAIRMAN FROINES:  How do we know about how much

24   metam-sodium was actually used relative to other studies

25   that have been conducted?



 1             MR. GOSSELIN:  You mean the rates of application?

 2   That should be part of the whole study report is to -- the

 3   method, injection depth or the sprinkler or how long it took

 4   to put the application on and how much material was actually

 5   put out.

 6             And to kind of put that study and these other

 7   studies into context, all those variables, including the

 8   specific weather data and the residues that were found and

 9   everything else were used by staff in a similar way that

10   Melanie described to us taking and doing some modeling to

11   calculate out on either a regional, statewide basis what the

12   air levels would be and make sure that we don't exceed an

13   REL.

14             CHAIRMAN FROINES:  Exceed an REL as opposed to

15   MOE?

16             MR. GOSSELIN:  Depends on --

17             CHAIRMAN FROINES:  All this continues to reinforce

18   this problem and that is that exposures are highly variable.

19             MR. GOSSELIN:  Right.

20             CHAIRMAN FROINES:  And defining decision criteria

21   on highly variable parameters is a problem.

22             DR. THONGSINTHUSAK:  This is the last overhead.

23             The last time I did not show chronic exposure

24   estimates, and this one I estimated chronic exposure from

25   three ambient air monitoring studies.  The first one



 1   conducted in Kern County and the second Bakersfield by

 2   Seiber and his colleague.

 3             And number of potential exposure days, which is at

 4   the bottom as a footnote, it was estimated to be 188 days

 5   per year and the range is 79 to 328 days.

 6             So I only estimated the exposure for these three

 7   because the ambient air concentrations should be more

 8   representative than the application site and monitoring

 9   study.

10             In the last column I represent annual exposure

11   SADD, annual average daily dosage.

12             For example at a Shafter site the range is .001 to

13   .32 and the median is .05.  For B7, Bakersfield, Lamont, in

14   the houses it showed AADD is .32, the range from .02 to

15   1.76, so on and so forth.

16             CHAIRMAN FROINES:  I have a question.  I don't

17   want to hold it up.

18             Why do you have parts per million on one side and

19   ADD in micrograms per kilogram on the other?

20             DR. THONGSINTHUSAK:  The ppb represent the

21   airborne concentrations of MITC.  The AADD represents the

22   absorbed dose.

23             So the risk assessor can use either values.

24             CHAIRMAN FROINES:  The reader will generally find

25   things in similar units to be better, if you can do it.



 1             DR. GLANTZ:  It's fine.  Depends on what you're

 2   trying to do with it.

 3             CHAIRMAN FROINES:  Okay.

 4             DR. THONGSINTHUSAK:  That's all I have, unless you

 5   have questions.

 6             It's been a little bit over ten minutes.

 7             CHAIRMAN FROINES:  That's all right.

 8             DR. KENNEDY:  Thank you.

 9             DR. WITSCHI:  What was the difference between

10   those data and what you showed earlier, summer 1997 to

11   winter 1998?

12             DR. THONGSINTHUSAK:  Sorry?

13             DR. WITSCHI:  In an earlier slide, very similar

14   data for Lamont and Shafter and Seiber identified those Kern

15   County in summer 1997 for Kern County winter 1998.  Is this

16   the same study or is this a different study?

17             DR. THONGSINTHUSAK:  The same study.

18             DR. WITSCHI:  Same study.

19             DR. THONGSINTHUSAK:  It's the ambient air

20   monitoring study.

21             DR. WITSCHI:  Same study?

22             DR. THONGSINTHUSAK:  Yeah. from Lamont.

23             DR. WITSCHI:  The numbers are not the same.

24             DR. THONGSINTHUSAK:  The second one by Seiber,

25   that's a different one.



 1             DR. GLANTZ:  I think rather than replacing what's

 2   in the report with this study, you should just add it.

 3             MR. GOSSELIN:  That's what we're going to do.

 4             DR. THONGSINTHUSAK:  That's right.

 5             DR. GLANTZ:  That's a suggestion.

 6             DR. FUCALORO:  The explanation.

 7             DR. GLANTZ:  Just add it.  Don't take what you've

 8   got in there out.

 9             DR. THONGSINTHUSAK:  Yes.

10             DR. FUCALORO:  Validate the other.

11             DR. GLANTZ:  Yeah.  It's the results are so

12   similar, it actually tends to affirm it.

13             DR. THONGSINTHUSAK:  Okay.  Thank you.

14             CHAIRMAN FROINES:  Further comments?

15             George.

16             DR. ALEXEEFF:  George Alexeeff with OEHHA.

17             I just want to say right off the bat our findings

18   are very consistent with the report, with the DPR report.

19             And we've actually worked very closely with this

20   one, and the major difficulty we had was just keeping up

21   with their revised versions of it and it's something that

22   we're working on to actually improve that so that sometimes

23   our findings are not -- are in sync with the current version

24   that they have as opposed to an older version.

25             But that's pretty much the biggest difference, the



 1   difficulty we had.

 2             We will revise our finding on oncogenicity so it's

 3   consistent with what the panel discussed here today, and

 4   it's more similar to what their older version or their

 5   current document says.

 6             The other thing is that we did a little bit

 7   differently is emphasized a couple things differently in

 8   here, concerns that we had about uncertainties.

 9             One was the concern about RADS, reactive airway

10   dysfunction syndrome.  We kind of emphasized that, that

11   we're concerned about that as an outcome of an extensive

12   exposure.

13             The other one is, and you talked --

14             DR. KENNEDY:  In what regard?

15             DR. ALEXEEFF:  In that spill that occurred of

16   metam-sodium in the Cantara Loop, we think that it would be

17   very likely to -- the health department, we did a study with

18   the health department, Department of Health Services, excuse

19   me, and we think that many of the individuals, about 20 or

20   so, developed reactive airway dysfunction syndrome, as a

21   result of the exposure, which I think is one of the first

22   times an environmental exposure has resulted in that

23   syndrome.

24             DR. KENNEDY:  Sensitization syndrome?

25             DR. ALEXEEFF:  Yeah.



 1             So we think that's something that was important to

 2   us and it could be the MITC, it could be the MIC.  We don't

 3   know.  But we thought it was an important finding.

 4             DR. KENNEDY:  Has there been any -- is there an

 5   ongoing long-term follow-up with those patients for scar

 6   cancers?

 7             DR. ALEXEEFF:  I don't know.  I can ask the lead

 8   physician.

 9             DR. KENNEDY:  Interesting to do over, say, 15

10   years.

11             DR. ALEXEEFF:  Dr. Jim Cohn was the lead on that

12   and he's with Department of Health Services.

13             CHAIRMAN FROINES:  George, I don't see in here

14   something about discussion of RADS.

15             DR. ALEXEEFF:  Yeah, it's in there.

16             CHAIRMAN FROINES:  Where?

17             DR. ALEXEEFF:  It is in our findings.  It's

18   actually the last findings, I think, that mentions it and

19   then the last word of our findings is RADs.

20             CHAIRMAN FROINES:  I saw that.

21             DR. ALEXEEFF:  And there's another finding.

22             CHAIRMAN FROINES:  Where is it?

23             DR. ALEXEEFF:  Finding No. 10.  Our finding No.

24   10.

25             So this was simply a measure of emphasis, and then



 1   also although we agreed with their choice for that human

 2   exposure study, you know, when you look at the -- weigh

 3   everything together, we also just felt it was important to

 4   look at the pros and cons of the animal study and the human

 5   study, because we sort of felt that neither of them are

 6   exactly what we'd like, so we kind of made a big deal about

 7   that in our findings, but just so that everybody understood

 8   the uncertainties of both studies or the pros and cons.

 9             CHAIRMAN FROINES:  There's no harm in using

10   developing numbers from both studies.  It doesn't have to be

11   a bright line.  It can say there are problems with this

12   study, but this gives us these results, there's a problem

13   with this study, this gives us these results and then you

14   have covered your bases.

15             DR. ALEXEEFF:  Yeah.

16             And I guess the last point, and this is not really

17   directly related to the findings, but in response to

18   Dr. Rubin's comments on how to address the multi-chemical

19   situation, we can talk with their staff regarding the hazard

20   index approach, which is what we are developing in the hot

21   spots guidelines, of course the guidance isn't out yet, but

22   we can explain to them what the approach is, the US EPA

23   based approach is, and to see if that sheds any light.

24             CHAIRMAN FROINES:  You say on your finding 24,

25   OEHHA does not include a RAD on human breathing adjustment.



 1             DR. ALEXEEFF:  Correct.

 2             CHAIRMAN FROINES:  And you all need to work that

 3   out.

 4             DR. ALEXEEFF:  Yeah.

 5             CHAIRMAN FROINES:  And come back to us on that.

 6             DR. ALEXEEFF:  I agree.  Paul and I talked about

 7   that one earlier today, and that is something we do want to

 8   try to work out.  It has to do with simply the way staff

 9   have done their work in the different departments, and we

10   need to work a couple of those things out.

11             CHAIRMAN FROINES:  I want to emphasize one thing

12   quickly.  I think the RADS issue is really a major issue.

13   It also goes to the question of chronic disease versus acute

14   disorders.  So it's something I think we should try and

15   follow up on, because I think if we can -- if there's an

16   issue of MITC or MIC producing RADS, that's a major health,

17   potentially important health problem.

18             I think that's what Peter was --

19             DR. ALEXEEFF:  Okay.  That's all.

20             CHAIRMAN FROINES:  Well, I was just going to

21   say --

22             DR. KENNEDY:  You better say it fast.

23             CHAIRMAN FROINES:  Does anybody else on the panel,

24   while you're still within the room, have any further




 1             DR. FUCALORO:  I need to make a few comments with

 2   slides.

 3             DR. GLANTZ:  I'd like to make a comment that we

 4   adjourn.

 5             CHAIRMAN FROINES:  Move that we adjourn?

 6             DR. GLANTZ:  I move that we adjourn.

 7             DR. ATKINSON:  Second.

 8             DR. GLANTZ:  Call the question.

 9             CHAIRMAN FROINES:  The question, all in favor, was

10   unanimous.

11             (Thereupon the meeting was adjourned

12             at 2:45 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 8th day of February 2000.




                                     Janet H. Nicol
17                                   Certified Shorthand Reporter
                                     License Number 9764