BEFORE THE 

                            SCIENTIFIC REVIEW PANEL

                                     OF THE

                         CALIFORNIA AIR RESOURCES BOARD

                          MARIAN MINER COOK ATHENAEUM

                             385 EAST EIGHTH STREET

                             CLAREMONT, CALIFORNIA

                          WEDNESDAY, NOVEMBER 17, 1999

                                   9:44 a.m.

           Kathleen Knowlton, CSR

           License No. 11595

                 BARNEY, UNGERMANN & ASSOCIATES  888 326-5900

                                MEMBERS PRESENT

           Dr. John Froines, Chairman

           Dr. Stanton Glantz

           Dr. Craig Byus

           Dr. Roger Atkinson

           Dr. Anthony Fucaloro

           Dr. Paul Blanc

           Dr. Hanspeter Witschi

           Others Present:

           Jim Behrmann, ARB

           Peter Mathews, ARB

           Paul Helliker, DPR

           Randall Segawa, DPR

           Dr. Gary T. Patterson, DPR

           Lynton Baker, ARB

           Pamela C. Wales, DPR

           Dr. Thomas Thongsinthusak, DPR

           Dr. Andrew G. Salmon, CEPA

           Dr.Martha Sandy, CEPA

           Dr. Melanie Marty, CEPA

           Dr. Andrew Rubin, DPR

           Dr. James F. Collins, CEPA

                 BARNEY, UNGERMANN & ASSOCIATES  888 326-5900

                                   I N D E X

                                     * * *


           Proceedings                                 1

           Call to Order                               1

           Opening remarks by Chairman Froines         1

           AGENDA ITEMS:

           Item 1 - Presentation on Monitoring         4

                    for Multiple Chemicals   

           Item 2 - Discussion of Revisions of Draft  23

                    Document 11-15-99

           Item 3 - Presentation of MITC              43

           Item 4 - Discussion of Methyl Tertiary     83

                    Butyl Ether 

           Item 5 - Assessment of MTBE's Human       130

                    Health Effects

           Item 6 - Discussion of REL                157

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        1                         PROCEEDINGS

        2                            * * *

        3                CHAIRMAN FROINES:  Shall we call the meeting 

        4  to order?  We have a quorum.  One person who will be 

        5  missing today, oh, is -- Peter Kennedy is unable to come 

        6  because of a health problem.  But Gary Friedman, I assume, 

        7  is going to be here?  Gary Friedman and Peter Kennedy will 

        8  not be here.

        9                The first thing I'd like to do on the agenda 

       10  is introduce the panel to Paul Helliker who's the director 

       11  of -- the new director of the Department of Pesticide 

       12  Regulation.  And so I ask Paul to say a few words.  But we 

       13  welcome you, appreciate your coming to the meeting, and 

       14  look forward to be working with you.

       15                MR. HELLIKER:  Thank you.  It's a pleasure 

       16  to be here.  I assume this is the right spot to speak 

       17  from.  I apologize for not having been able to participate 

       18  in the Scientific Review Panel meetings to date, but I'm 

       19  glad that I'm able to be here today, since I've been able 

       20  to review the draft findings that you've made, and look 

       21  forward to having a final document from you about the 

       22  workshops we've been having.

       23                But let me just give you a little bit of 

       24  background.  I have a -- an opportunity to meet with      

       25  Dr. Froines early on in my tenure and pointed out to him, 

                 BARNEY, UNGERMANN & ASSOCIATES  888 326-5900

        1  I think we've been marking some good progress over the 

        2  past year, and I want to see that progress continue in 

        3  getting a good collaborative, working relationship going 

        4  with the Scientific Review Panel.

        5                And I think that's going to set a good 

        6  foundation for how we go forward with responding to the 

        7  recommendations you have with what sort of prioritization 

        8  plans that we implement at the department for bringing 

        9  additional compounds to your attention.

       10                So I think part of the background that has 

       11  generated some of the controversy might be when we 

       12  evaluate pesticides, we have the ability to move fairly 

       13  quickly, and we have in the past.  So I think that might 

       14  have been some of the source of the discussion or the 

       15  difference in approach that we have with ARB.

       16                But my goal is to make sure that we go 

       17  through the similar process to what the Air Resources 

       18  Board does, and make sure that all of our decisions about 

       19  toxic air contaminants are decisions that merit by the 

       20  input from this panel.

       21                Because I look to you as being one of our 

       22  primary guiding organizations when it comes to our 

       23  scientific decisions.  So I won't take much more time than 

       24  that.  But look forward to the discussions today.  And I 

       25  did want to point out I did sign yesterday the 

                 BARNEY, UNGERMANN & ASSOCIATES  888 326-5900

        1  recommendation or the decision to list methyl parathion as 

        2  a toxic air contaminant.  So thank you for your 

        3  recommendations on that.  And I look forward to the 

        4  additional ones in the future.

        5                CHAIRMAN FROINES:  Thank you.  Everyone has 

        6  a new record.  That's great.  Just great.  And thank you, 

        7  Craig Byus, for the effort that went into methyl 

        8  parathion.  I think that is, Paul, a good example of 

        9  interaction.  Craig and Ruby Reed worked very closely and 

       10  worked very effectively.  And I think that Craig is a real 

       11  advocate for Ruby.  And so that -- that seems to me to be 

       12  a great model for how we can work effectively together.

       13                 So without further ado, we're going to -- 

       14  we have -- the problem we have today is a problem we have 

       15  normally.  It's with Stan.  I'm not supposed to make 

       16  jokes, because he makes them back.  But we'll cool it.

       17                DR. GLANTZ:  Let the record indicate that 

       18  Dr. Froines made me get up very early this morning to get 

       19  here.  Actually, the problem is with Dr. Froines.

       20                CHAIRMAN FROINES:  Stan actually has to 

       21  leave early.  And so we are going to try and move 

       22  relatively quickly, so we can at least get through item 3 

       23  before he leaves.   He's finished item 4 from his 

       24  compound.  So -- so we have some tension about working 

       25  through items 1 through 3.

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        1                Any case, so the first item on the agenda is 

        2  the case study of multiple pesticides sampling.  And I 

        3  don't know who's presenting.  This is, in essence, a 

        4  continuation of a workshop on prioritization and exposure 

        5  monitoring.  So this will complete that small workshop. 

        6                MR. SEGAWA:  Good morning.  I am Randy 

        7  Segawa.  Yeah.  We're trying to get the lights fixed 

        8  there.  I'm Randy Segawa with Department of Pesticide 

        9  Regulation.  And this is a -- pretty much a continuation 

       10  of a workshop we had a couple months ago that got cut 

       11  short.  And I will be presenting some case studies or 

       12  hypothetical examples on how we could possibly monitor for 

       13  multiple chemicals.

       14                First off, I'd like to point out that this 

       15  is a hypothetical exercise.  Department of Pesticide 

       16  Regulation and the Air Resources Board have had a series 

       17  of meetings to discuss the different alternatives and 

       18  options for monitoring multiple chemicals, but we haven't 

       19  settled on a concrete plan yet.  So right now we're just 

       20  still in the discussion stage.

       21                For this particular exercise, I put a couple 

       22  limitations on -- on how we might accomplish this.  One, 

       23  I -- for this exercise, I wanted to come up with some sort 

       24  of objective criteria for grouping and prioritizing the 

       25  different chemicals that we might be monitoring.

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        1                The other restriction I had placed on it, is 

        2  that I set up the examples so they fit within the current 

        3  resources available to DPR and the Air Resources Board.  

        4  And the other factor I consider -- or did not consider, 

        5  actually, is the risk assessment and mitigation.  Those 

        6  factors did not play any role in determining the groupings 

        7  and priorities that I'll be discussing.

        8                I'm going to present three separate examples 

        9  on how we might group for multiple chemicals.  And the 

       10  first example I'll look at a crop-type grouping using 

       11  cotton as an example.  In this second example, I've done a 

       12  chemical-family-type grouping using organophosphates as an 

       13  example.

       14                And then finally I'll present a county or 

       15  month-type group where we've looked at the highest county 

       16  and highest month for the various counts of pesticides and 

       17  group them together.  For this exercise I've included 157 

       18  pesticides, both candidate toxic air contaminants as well 

       19  as those chemicals currently on the toxic air contaminant 

       20  list.

       21                 I've used our current priority system, 

       22  DPR's report 9601, which was published back in '96.  And 

       23  so is somewhat outdated, but we are working to revise 

       24  that.  But for this exercise, I've used that for all the 

       25  candidate scores.  And then for those chemicals that are 

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        1  currently toxic air contaminants, I assigned an arbitrary 

        2  score of 15.

        3                A lot of this exercise, the priorities have 

        4  to do with the pesticide-use data.  And I've used the 1996 

        5  through 1998 data for these examples.  So for each of the 

        6  157 chemicals that we want to try and monitor for, I've 

        7  selected four different factors.  I've looked at the crop 

        8  of highest use for each of a hundred fifty-seven.  We 

        9  determined the chemical family each of the hundred 

       10  fifty-seven belonged to.

       11                From the pesticide-use data, we determined 

       12  the county of highest use for each of the hundred and 

       13  fifty-seven.  And we've also determined the month of 

       14  highest use for each of the hundred and fifty-seven.

       15                So our first example, the crop grouping -- 

       16  what we've done is taken, for each of the 157 chemicals, 

       17  the highest crop for each of those chemicals.  And cotton 

       18  actually came out on top where 23 of the chemicals had the 

       19  highest use on cotton.  Structural pest control was second 

       20  with 14 chemicals at highest use for that particular site.  

       21  And then almonds was number three.

       22                DR. GLANTZ:  Structural pest control is like 

       23  termites and things like that?

       24                MR. SEGAWA:  Correct.  Yes.  And so if you 

       25  look at the list of chemicals there, there are 23 that are 

                 BARNEY, UNGERMANN & ASSOCIATES  888 326-5900

        1  used on cotton, used throughout, mainly, the Central 

        2  Valley.  You see that Fresno and Kern County are probably 

        3  the highest for virtually all those chemicals, which you 

        4  expect, since those are the largest cotton-growing areas 

        5  in the state.

        6                DR. BYUS:  Are they -- pardon me.  Are --  

        7  you're not saying that 23 are used on -- all 23 are used 

        8  on one cotton field, are you?

        9                MR. SEGAWA:  No.

       10                DR. BYUS:  You're just saying between all 

       11  the cotton?

       12                MR. SEGAWA:  Correct.  Correct.  Yes.

       13                CHAIRMAN FROINES:  One other question --

       14                DR. BLANC:  But your house did have 14 

       15  chemicals applied prior to your purchase.

       16                CHAIRMAN FROINES:  And xylene you have 

       17  listed as a pesticide.  Is that considered a pesticide on 

       18  cotton?

       19                MR. SEGAWA:  It's both considered an active 

       20  ingredient as well as an inert ingredient in many 

       21  products.

       22                DR. FUCALORO:  Solvent?

       23                MR. SEGAWA:  Correct.

       24                DR. BLANC:  Why would it be considered an 

       25  active ingredient if it's a solvent?  Because it has 

                 BARNEY, UNGERMANN & ASSOCIATES  888 326-5900

        1  health effects, but not because it has pesticidal --

        2                MR. SEGAWA:  It does have some pesticidal 

        3  effects for cotton.  I'm not sure exactly what pest they 

        4  are trying to get with xylene.

        5                DR. BLANC:  But actually, I guess I should 

        6  ask the question more clearly.  Because, do you know from 

        7  a regulatory point of view, is a toxic additive to a 

        8  pesticide which is not pesticidal considered inert?  Does 

        9  the term "inert" designate a non-pesticidal component or 

       10  does it imply nontoxic component?

       11                MR. SEGAWA:  It implies non-pesticidal 

       12  component.

       13                DR. BLANC:  So theoretically an insert 

       14  ingredient can still be toxic to humans?

       15                MR. SEGAWA:  Correct.

       16                CHAIRMAN FROINES:  I was on a National 

       17  Academy of Science Committee that actually discussed this 

       18  issue.  And you find there are a lot of compounds listed 

       19  as inert that are by no means inert.  And that's a problem 

       20  at some level that hasn't received attention, although 

       21  there has been some focus on it at some points.

       22                DR. BLANC:  And a follow-up to that 

       23  question.  Do you know whether inert -- other inert -- 

       24  well, do you know whether there are other solvents which 

       25  are considered inert?  It seems that xylene is not 

                 BARNEY, UNGERMANN & ASSOCIATES  888 326-5900

        1  considered inert.  That would reason I ask specifically 

        2  about solvents, because of their volatility, clearly they 

        3  would be of interest to this panel as potentially toxic 

        4  air pollutants.

        5                MR. SEGAWA:  If I understand your question 

        6  correctly, yes, there are solvents which we may consider 

        7  toxic.  But our list is as inert ingredients in pesticidal 

        8  products.

        9                CHAIRMAN FROINES:  He's asking a different 

       10  question.

       11                DR. BLANC:  I'm asking, how -- would we end 

       12  up ever hearing about them at this panel?  For example, 

       13  suppose there was a hypothetical pesticide that was very 

       14  widely used, which had a significant inert percentage of 

       15  the solvent dioxane, theoretically.  Would that be 

       16  something that would ever enter into our inventories?  Or 

       17  we ever hear about or that would appear in the -- 

       18  otherwise on our radar screen?

       19                MR. SEGAWA:  I'm not real sure.  I know that 

       20  under some of our regulatory authority -- for instance, 

       21  our groundwater program, we do have the authority to look 

       22  at inert ingredients as potential groundwater 

       23  contaminants.  I'm not sure we have the same authority for 

       24  toxic air contaminants.

       25                DR. BLANC:  Can somebody from the ARB 

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        1  comment on that?

        2                MR. BAKER:  I didn't hear the question.  I'm 

        3  sorry.

        4                CHAIRMAN FROINES:  Paul is asking the 

        5  question, there are compounds that are listed as active 

        6  ingredients and inactive ingredients.  There are times 

        7  when the inactive ingredients are toxic.  And if they're 

        8  volatile, that has potential significance for the 

        9  designation of those compounds as toxic air contaminants.

       10                And the question is, would that ever come 

       11  before this panel?  And he's, I think, not entirely sure.  

       12  I think that -- and so the reason ARB comes into it is 

       13  because, if there was an inert volatile compound that 

       14  might be considered a toxic air contaminant, then that 

       15  might come -- well, ARB, I think, 1807 lists pesticides, 

       16  and that would be the role of DPR.

       17                So I think their authority would be -- with 

       18  respect to DPR would be with respect to pesticides.  But 

       19  inert ingredients might be with ARB.  I don't know.  

       20  That's the question.

       21                MR. BAKER:  This is Lyn Baker from the Air 

       22  Resources Board.  I would assume that solvents are 

       23  carriers that might -- might fall under this category that 

       24  would be toxic, but would not be pesticidal -- would not 

       25  have pesticidal activity.

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        1                That the Air Resources Board might look at 

        2  compounds like that under our toxic air contaminant 

        3  process, but not as carriers for pesticides.  If they were 

        4  solvents, we would probably be viewing them from 

        5  industrial sources, and might have regulated in that way 

        6  rather than as a -- as an inert, pesticidal ingredient.  

        7  Jeannette, would that -- 

        8                MS. BROOKS:  That's correct.

        9                DR. BLANC:  But let's say a pesticide came 

       10  before this panel in the process that we were embarking 

       11  on.  And we're going to come back to this subject later.  

       12  But let's take our grouped --

       13                Suppose that our suggestion to group the 

       14  cholinesterase inhibiting -- suppose our proposal to group 

       15  the cholinesterase-inhibiting organophosphate pesticides 

       16  goes forward and we receive risk assessment on 35 

       17  organophosphates.  Are we going to be assured that as they 

       18  are marketed, none of those organophosphate pesticides 

       19  perforce also include volatile, toxic-air-contaminant 

       20  solvent carriers?  

       21                Because if something is marketed in a 

       22  particular way, which means that when it's used there will 

       23  be release of a toxic air contaminant solvent then we 

       24  should -- I would assume it would be our obligation to 

       25  designate that pesticide a toxic air contaminant, even if 

                 BARNEY, UNGERMANN & ASSOCIATES  888 326-5900

        1  it's not on the basis of its active pesticidal component. 

        2  But rather on the basis of its inert solvent carrier, 

        3  unless it's reformulated to exclude that solvent carrier.

        4                MR. BAKER:  That would certainly make sense, 

        5  Dr. Blanc.  But the Air Resources Board doesn't have 

        6  regulatory authority over pesticides.  So to -- we would 

        7  not have the authority to regulate or to -- 

        8                DR. FUCALORO:  Is there any group, I mean, 

        9  within the state that is looking -- is this slipping 

       10  through the cracks, I guess is what Dr. Blanc is referring 

       11  to.  That if you have a series of solvents that are used 

       12  to deliver pesticides, is there anyone paying attention to 

       13  those solvents?  

       14                I'm given to understand that xylene shows up 

       15  on this list, because the pesticidal action rather than 

       16  its use as a carrier or solvent.  So between the two -- 

       17  the two organizations, there anyone looking at these?  I 

       18  mean, that's a fair question, and maybe you can get back 

       19  to us.

       20                MS. BROOKS:  Well, in the case of xylene, 

       21  xylene is already listed.  It's a hazardous air 

       22  pollutant.  So it's already a toxic air contaminant.  And 

       23  Melanie was reminding me, there are some other solvents 

       24  that would be the same.

       25                And the only -- at the Air Resources Board, 

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        1  we do have a consumer products program where this would be 

        2  the public being able to go in and buy off the shelf Raid 

        3  or something like that.  And we're limiting the volatile 

        4  organic content of those.  And a lot of the carriers are 

        5  what we're regulating, trying to get as low as we can, 

        6  close to zero BOC.

        7                And we know, too, those products are 

        8  labeled.  If these carriers are toxic like xylene, and 

        9  maybe toluene, they have to be labeled for Proposition 65.  

       10  So there is at least a warning.  But I know what you're 

       11  saying as far as control measurement development.

       12                DR. FUCALORO:  Yeah.  Clearly if a carrier 

       13  were benzene, it would raise red flags all over the place.  

       14  I understand that.  But suppose, for example -- I'm just 

       15  following up what Dr. Blanc is saying.

       16                Suppose there is a solvent that is really 

       17  not being considered in any way as no one's done any 

       18  investigation of it, and a manufacturer uses a carrier 

       19  that uses a solvent that no one has investigated, is there 

       20  any mechanism within the state to say, this is something 

       21  we ought to be looking at?  I assume it's the ARB.

       22                MS. BROOKS:  Under our toxics program, in a 

       23  consumer product that's sold, we can do a toxic control 

       24  measure for a toxic air contaminant.  And in fact, we have 

       25  a branch at the board that's looking at break cleaners and 

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        1  engine degreasers that contain perchloroethylene right 

        2  now.  And they're planning to take a control measure to 

        3  the board next year.

        4                So I think for a commercial product where 

        5  the Air Resources Board has authority, we could develop a 

        6  controller measure.  And, in fact, we are.  For a 

        7  pesticide that's used on application at a farm, I don't 

        8  think we could control the xylene content.

        9                DR. GLANTZ:  Could DPR?

       10                MS. BROOKS:  We have to double-check on 

       11  that.

       12                MR. BAKER:  I would think that would fall to 

       13  DPR.

       14                CHAIRMAN FROINES:  I'm going to cut this 

       15  off, because we are way off what this session is about. 

       16                DR. BLANC:  Sorry.  My fault.

       17                CHAIRMAN FROINES:  No, nobody should 

       18  apologize.  It's a very important discussion, and we 

       19  should take it up at a later date.  We've now certainly 

       20  raised it, and so let's leave it for the moment.  I'll 

       21  just, as Chair's prerogative, will say this last word on 

       22  it. 

       23                DR. GLANTZ:  This is part of Dr. Froines' 

       24  effort to always shorten discussions.

       25                CHAIRMAN FROINES:  Under AB 1807, compound 

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        1  is listed as a toxic air contaminant.  The law then says 

        2  that a risk-management process will follow.  It doesn't 

        3  say, "only for these uses, compared to these uses."  

        4                So if there is a toxic air contaminant, say 

        5  xylene, then it seems to me that the issue is what is the 

        6  appropriate, regulatory-management strategy that you would 

        7  follow for that compound, for any and all of its uses.  

        8  And so it would be up to ARB to determine those uses and 

        9  to determine strategies for control.

       10                MS. BROOKS:  That's correct.

       11                CHAIRMAN FROINES:  That's, I think, what the 

       12  question is.  And this is obviously something that hasn't 

       13  come up before, so we can talk about it later.  Thanks.  

       14  Thank you.

       15                MR. SEGAWA:  Okay.  This figure here shows 

       16  the use for all the 23 chemicals that we were just 

       17  discussing.  As you can see, that the San Joaquin Valley 

       18  has the highest use for chemicals used on cotton.  And of 

       19  course, that is where most of the cotton is grown.

       20                But you can also see that there is use of 

       21  these chemicals throughout much of the state down, in the 

       22  Imperial County and southeast desert region, as well as 

       23  even far up north in the Modoc County area as well.

       24                And don't forget, while these chemicals may 

       25  have highest use on cotton, cotton would not be their only 

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        1  use.  They would also be used on other crops.  Okay.  

        2  Moving on to -- 

        3                CHAIRMAN FROINES:  Not much of those, do you 

        4  think, of the 20 -- we know xylene's organophosphate.  But 

        5  how many of the others do you think are organophosphates?

        6                MR. SEGAWA:  Organophosphates?  Phorate is 

        7  an organophosphate.  Chlorpyrifos, of course, 

        8  methamidophos, naled, def, and ethephon. 

        9                CHAIRMAN FROINES:  I only ask that question 

       10  because, clearly, where you have a common mechamism of 

       11  action, you would want to look at the compounds with 

       12  common mechanism of actions collectively, if one were able 

       13  to.

       14                MR. SEGAWA:  And that's a good segue into 

       15  the next slide.  Because the second example does deal with 

       16  the chemical-family-type of grouping.  Again, for the 157 

       17  candidate and TAC chemicals that we're looking at in this 

       18  exercise, 20 of them are organophosphates.  And they came 

       19  out highest in the priority score in the grouping.

       20                Organochlorines came in second.  There are 

       21  eight chemicals in that group.  And carbamates is third 

       22  with nine chemicals.  And so if you look at the list here, 

       23  these are all organophosphates used on variety of crops.  

       24  And you can see, used at a variety of locations and 

       25  throughout most of the year.

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        1                DR. ATKINSON:  So it looks as though at 

        2  least three of these are also organochlorines.

        3                MR. SEGAWA:  That's probably true, yes.  And 

        4  then as a third example, we took the 157 chemicals and 

        5  determined the combination of county a month of highest 

        6  use.  So that if we were to try and monitor for multiple 

        7  chemicals, it's, of course, ideal to be monitoring at the 

        8  same time in the same place for multiple chemicals.

        9                And in this type of grouping, Fresno in July 

       10  came out as the highest -- scoring with seven chemicals in 

       11  that group.  Fresno in June was second with five 

       12  chemicals.  And Fresno in August was third with four 

       13  chemicals.

       14                And the drawback to this type of grouping, 

       15  as you can see, is that the chemicals in the highest 

       16  group, the Fresno in July, are different groups of 

       17  chemicals.  And so they would require several different 

       18  sampling and analytical methods to try to get them all at 

       19  the same time.

       20                After looking through these various 

       21  exercises, we came to several conclusions regarding the 

       22  shortcomings and problems.  Number one, it's difficult to 

       23  monitor the complete groups, whichever the three groupings 

       24  we chose.  It requires monitoring in several different 

       25  seasons, as well as several different areas, and using 

                 BARNEY, UNGERMANN & ASSOCIATES  888 326-5900

        1  several different types of monitoring methods.

        2                While this is, maybe, a good approach for 

        3  the ambient monitoring, it probably does not work for the 

        4  application monitoring, since in most application 

        5  monitoring, one to three chemicals would be applied at the 

        6  same time, not groups of 20 or more.

        7                And of course, risk-assessment factors have 

        8  not been addressed in this exercise.  And it's very likely 

        9  that, to do the risk assessment for multiple chemicals, 

       10  particularly outside the chemical-family grouping, would 

       11  be very difficult.  Any questions?

       12                DR. FUCALORO:  Yeah.  I guess you were 

       13  looking at some sort of intersection of these lists; is 

       14  that correct?

       15                MR. SEGAWA:  Correct.

       16                DR. FUCALORO:  And looking at the monitoring 

       17  multiple chemicals, county look, the month group, it seems 

       18  to me that quite possible that you don't need an 

       19  intersection.  I missed the original pesticide workshop, 

       20  so I'm a little unclear as to what's going on.  But what 

       21  you consider, the list under Fresno in July, probably 

       22  Fresno in June and August, too, as being a candidate for 

       23  multiple testing.

       24                MR. SEGAWA:  Yes, you're correct, that if we 

       25  were actually to follow this type of scheme, that we would 

                 BARNEY, UNGERMANN & ASSOCIATES  888 326-5900

        1  probably be monitoring in June, July, and August, yes.  

        2  And the list would expand as well, of course.

        3                DR. FUCALORO:  I'm not encouraging people to 

        4  go in Fresno in June, July, and August.  In fact, I would 

        5  discourage them.

        6                CHAIRMAN FROINES:  I make just one comment.  

        7  That list of compounds, the seven chemicals -- 1, 2, 3, 4, 

        8  5, 6, 7 -- in terms of your '96 priorities, they -- we 

        9  have here the first compound the highest priority, the 

       10  fifth highest priority, the seventh highest priority, the 

       11  39th highest priority, and 42nd, 58th and 63rd.

       12                So it represents, actually, a relatively 

       13  important cross section of compounds that your priority 

       14  document identified.  And in fact, one would say, these 

       15  are all candidates that are worth taking a look at, given 

       16  their priority in the DPR '96 document.  Has -- has Lyn -- 

       17  have you and Lyn talked about the actual analytical and 

       18  sampling methodology required to look across -- 

       19                MR. SEGAWA:  We did ask Air Resources Board 

       20  to take a quick look at these various lists and come up 

       21  with a ballpark estimate as to how many methods are  

       22  required, and how they would go about doing it.  In this 

       23  particular case for the seven chemicals in the 

       24  county-month grouping, they thought it would take two or 

       25  three methods.

                 BARNEY, UNGERMANN & ASSOCIATES  888 326-5900

        1                CHAIRMAN FROINES:  Two or three?

        2                MR. SEGAWA:  Yeah.

        3                DR. BLANC:  That sounds technologically 

        4  feasible.

        5                MR. SEGAWA:  Uh-huh.

        6                DR. BLANC:  I think from some of this, 

        7  probably be tempered by logistical considerations also.  

        8  But one advantage I think you may have, given the weather 

        9  and pesticide-use patterns, is that even for certain other 

       10  areas outside of Fresno County that you might be 

       11  interested in, the time frame when you would need to 

       12  sample would be a different time of the year, thus making 

       13  it, you know, physically possible for the staff to 

       14  contemplate sampling.

       15                For example, you know, there's a -- there 

       16  certainly is a heavy concentration of use in -- probably 

       17  in Imperial County at certain times of the year, and 

       18  similarly in Salinas Valley which may differ from Central 

       19  Valley.

       20                MR. SEGAWA:  I would agree, yes.

       21                DR. BLANC:  So therefore, there would be 

       22  things that you -- sampling there, even if they -- they -- 

       23  so I guess, another thing I would suggest, in addition to 

       24  the very excellent analysis, would be an analysis where it 

       25  was divided up by agricultural region, and you saw what 

                 BARNEY, UNGERMANN & ASSOCIATES  888 326-5900

        1  was the time at which the most number of chemicals were 

        2  used in Imperial County.  So that you leave aside the 

        3  issue of, how does Imperial County rate compared to 

        4  Fresno.

        5                It's going to be clear that areas in the 

        6  Central Valley are going to be the heaviest pesticide 

        7  use.  But there may be very real issues in some of these 

        8  other geographic agricultural areas, because the types of 

        9  pesticides used are likely quite different.

       10                MR. SEGAWA:  Yes.  My guess that 

       11  meteorological conditions would be different in those 

       12  areas as well.

       13                DR. BLANC:  I would suggest that you do that 

       14  analysis as well.  I would like to see that analysis for 

       15  three or four of what you would imagine would be key 

       16  areas.  And I guess, those key areas would be the North 

       17  Central Valley as opposed to Fresno and Kern, Salinas 

       18  Valley, Imperial, and then perhaps, based on your map 

       19  here, probably certain other hot spots. 

       20                CHAIRMAN FROINES:  Comments?  Thank you very 

       21  much.  This is a really nice piece of work.  And I think 

       22  it just raises a lot of interesting questions.  So 

       23  hopefully we can pursue it over time.  I think it's really 

       24  well done and thought-provoking, as you can tell.  Have 

       25  you ever done -- never mind.  I'll ask another time. 

                 BARNEY, UNGERMANN & ASSOCIATES  888 326-5900

        1                MR. SEGAWA:  Okay.  Thank you.

        2                DR. GLANTZ:  Can I just ask one quick 

        3  question?  So where are you planning to go next with this 

        4  in terms of -- I mean, I agree with the others who said -- 

        5  I think it's real interesting.  I mean, are you going to 

        6  further develop these ideas and come back again to us or 

        7  work with ARB?  What's the sort of next -- what's the plan 

        8  over the next couple three months?

        9                MR. SEGAWA:  We can do that.  We of course 

       10  need additional discussions with Air Resources Board to 

       11  see which approach we do want to take.  If it's possible, 

       12  can go with our current resources, and we can come back to 

       13  the panel with a more updated recommendation.

       14                CHAIRMAN FROINES: I should tell you, by the 

       15  way, that I have a Ph.D. student who's doing a study of 

       16  multiple-pesticide exposures in Mexico.  She's looking at 

       17  about ten pesticides, and she's doing the analytical 

       18  chemistry herself.

       19                And she's also looking at soil, water.  

       20  She's doing a multi-media, multi-environment and looking 

       21  at -- also at urinary metabolites, and looking at what 

       22  families and children of workers and applicators are 

       23  getting.  So we will keep you informed of what that data 

       24  looks like, because it's very parallel, in some respects.

       25                DR. GLANTZ:  Getting back to the earlier 

                 BARNEY, UNGERMANN & ASSOCIATES  888 326-5900

        1  point, though.  I hope that at some reasonable time they 

        2  can come back with a sort of next iteration on this.

        3                CHAIRMAN FROINES:  So we should define an 

        4  action item.  What's a good action item of a report in 

        5  three months for this?  What's a good reasonable time 

        6  frame for you?

        7                MR. SEGAWA:  We can do that in three months.

        8                CHAIRMAN FROINES:  That good?  Thank you.

        9                MR. SEGAWA:  Thank you.

       10                CHAIRMAN FROINES:  The second item on the 

       11  agenda is the prioritization -- B and C we'll take 

       12  together, is a discussion of the prioritization and air 

       13  monitoring document that we wrote up.

       14                If you'll remember -- if the panel will 

       15  remember at the September meeting, Stan and Paul, in 

       16  particular, recommended that the Chair write a document 

       17  that could be sent to DPR with our recommendations and 

       18  conclusions from the mini-workshop.  And I said that I 

       19  would -- wanted to have input from the panel.

       20                So we went ahead and wrote a document which 

       21  you all had for, I think, a reasonable period of time to 

       22  read and review.  I know we've had comments from       

       23  Roger Atkinson up to this point.  And what we would like 

       24  here is, on a discussion with the agencies -- this is 

       25  really an internal matter to the panel.

                 BARNEY, UNGERMANN & ASSOCIATES  888 326-5900

        1                Basically what I need is for you to give us 

        2  final recommendations and suggestions so we can then take 

        3  this document or modified version, send it to           

        4  Paul Helliker at the agency for their consideration.  So I 

        5  think the best way to handle this would be to go around 

        6  the room and get people's comments.

        7                DR. GLANTZ:  Well, I -- I think -- I think 

        8  it's basically quite good, actually.  I think -- and I --  

        9  the revised draft, which I got a couple days ago, I agreed 

       10  with many, but not all of the changes.  Because I think 

       11  that some of the changes, while perhaps toning it down a 

       12  little bit and making it a little bit more palatable 

       13  politically, have made it less clear.

       14                And I just like to go through the specific 

       15  things that I would suggest we -- I'm working not off the 

       16  one that we were just handed, but the one that you 

       17  E-mailed around.  Has a red-line, strike-out format.

       18                So if you look under part A, number 1, I 

       19  actually think the original statement that prioritization 

       20  for the SB50 program has overshadowed -- or no.  The 

       21  original thing which is shown as struck out, "DPR has not 

       22  used the AB 1807 prioritization method," was -- is just 

       23  clearer, I think.  So I would suggest going back on that 

       24  one.  And the same -- let's see.  I want to make sure I 

       25  didn't -- 

                 BARNEY, UNGERMANN & ASSOCIATES  888 326-5900

        1                DR. BLANC:  How about "not appropriately 

        2  used"?

        3                DR. GLANTZ:   Well, I don't think they've 

        4  used it.

        5                DR. BLANC:  They may have used it in some 

        6  instances.  I don't know.  I mean, they may have in some 

        7  kind of ad hoc way.  I don't know, but -- 

        8                DR. GLANTZ:  This was discussed endlessly 

        9  over many years.  And we were told over and over and over 

       10  again that the SB950 program took -- was more important.  

       11  Maybe if you wanted an intermediary, you could say, "DPR 

       12  has used SB950 over AB 1807."  But I think that's the 

       13  statement of fact which is correct.  And I mean, the 

       14  other -- the statement -- 

       15                CHAIRMAN FROINES:  Stan -- Elinor, can you 

       16  try -- we'll get the transcript.  Can you try and write 

       17  down what is being said?

       18                DR. FANNING:  Yeah.  I'm, like, making 

       19  notes.

       20                DR. GLANTZ:  I don't feel violently about 

       21  any of these things.  Let me just think here.  And then 

       22  number two, I think that the original statement, 

       23  "Prioritization for SB950 does not necessarily reflect the 

       24  likelihood of being a toxic air contaminant," is also a 

       25  clearer statement than -- 

                 BARNEY, UNGERMANN & ASSOCIATES  888 326-5900

        1                DR. BLANC:  I'm sorry.  Which one is that?

        2                DR. GLANTZ:  This is number two.  I think 

        3  that was a clearer statement.  For number three, I have a 

        4  third wording.  I would say, "The process used to select 

        5  pesticides for active risk assessment at DPR has not 

        6  generally taken into account TAC candidate status."

        7                CHAIRMAN FROINES:  Is that -- 

        8                DR. GLANTZ:  That's number three.  Huh?

        9                CHAIRMAN FROINES:  Did you write that?

       10                DR. GLANTZ:  Yeah.

       11                CHAIRMAN FROINES:  So you'll give that to 

       12  us?

       13                DR. GLANTZ:  Yeah.  I mean, these are -- and 

       14  then let's see.  With number five, I just had a question 

       15  about that.  I think that original statement, "In the 

       16  past, pesticides selected for monitoring did not reflect 

       17  TAC priorities," is true.

       18                The alternative wording, that it "better 

       19  reflects TAC priorities than in the past," is also true.  

       20  But in the past, they didn't seem to be paying much 

       21  attention to them at all, to me.  So I would be a little 

       22  meaner, I guess.

       23                The number six, I think the original 

       24  wording, "DPR does not routinely consider USEPA risk 

       25  assessments," is a clearer statement than the thing which 

                 BARNEY, UNGERMANN & ASSOCIATES  888 326-5900

        1  has been reworded.  I think that was it.  Let me just 

        2  look.

        3                The other changes that were made were all 

        4  fine.  Oh, and then, if you go to number -- page -- what 

        5  is my -- page 10, number 4, the -- where we -- it had 

        6  said -- the original wording was, "DPR should supplement 

        7  monitoring data," and it was changed to "could."  And I 

        8  prefer "should."  So -- 

        9                DR. FUCALORO:  Just want to subtract the 

       10  power of the subjective.

       11                DR. GLANTZ:  What?  Whatever.  I think we 

       12  want to make it affirmative recommendations here.  You 

       13  know, because I think that one of the things that I think 

       14  came out of the workshop was, you know, trying to 

       15  couple -- you know, get a better job of getting a handle 

       16  of what's actually going on.

       17                And -- and so, I think we should say 

       18  "should" there.  But those are my -- the rest of it is 

       19  fine.  The rest of the changes were fine.  So I don't know 

       20  if you want to discuss that or just go around the table.

       21                CHAIRMAN FROINES:  I think if anybody has 

       22  comments as to what your recommendations are -- 

       23                DR. GLANTZ:  I'm keeping Dr. Blanc awake.

       24                DR. BLANC:  I don't feel strongly about the 

       25  things you said.  I mean, it's fine.  Only thing I would 

                 BARNEY, UNGERMANN & ASSOCIATES  888 326-5900

        1  say is, that I would defer to the Chair's discretion.  If 

        2  after having heard your concerns, he still chooses in 

        3  certain of the instances to temper the tone of some of 

        4  these things, since you're closer on the ground to the 

        5  likely effectiveness of the document and how it might be 

        6  impactive, depending upon specific wording.

        7                But I think that Stan's general direction of 

        8  trying to be as explicit as possible, assuming that it 

        9  wouldn't be counterproductive, is a good general 

       10  guideline.  But you have final responsibility.

       11                CHAIRMAN FROINES:  And Paul Helliker has 

       12  heard both comments.  He understands that the context -- 

       13                DR. BLANC:  Right.  I have some specific 

       14  questions.  On page 2, point 2 -- 

       15                CHAIRMAN FROINES:  Well, let's go around.  

       16  Craig?

       17                DR. BYUS:  Okay.  I agree with what Stan 

       18  said.  I'm not totally strong about it, but I think the 

       19  stronger language is probably the better choice.  I just 

       20  would like to echo the point 2 here about considering a 

       21  vast approach relisting high priority organophosphates.

       22                I really think this is an excellent idea, 

       23  considering how many organophosphates there are, and the 

       24  fact that they all do work by a common mechanism.  So I 

       25  really think this is an excellent idea.  The 

                 BARNEY, UNGERMANN & ASSOCIATES  888 326-5900

        1  possibility -- likely -- high likelihood of multiple 

        2  organophosphates being used on the same crop is, in fact, 

        3  likely.

        4                So I pretty much like the document as it's 

        5  written.  I would like to add, though, that I think that 

        6  some -- pardon me.  Pardon me.  That some examination or 

        7  incorporation of the food residue -- we have all this data 

        8  somewhere.  There is somewhere a lot of data about what 

        9  pesticides actually are on foods.

       10                Now -- and so this could really be a guide 

       11  for which pesticides are used together.  I mean, clearly 

       12  they had to be used on the same crop.  Now, clearly, it 

       13  wouldn't incorporate all pesticides, because some might be 

       14  less stable and maybe wouldn't show up in food residue.  

       15  But there's a lot of multiple-pesticide-use data in the 

       16  food-residue data somewhere.

       17                It could -- could be used to guide 

       18  prioritizations for -- in terms of multiple risk for 

       19  multiple pesticides, when they were applied.  I tried to 

       20  find out about some of that information, but I -- when I 

       21  was doing methyl parathion.  But it became just too 

       22  cumbersome to try to do it.  I do think there is a lot of 

       23  information there about it -- about multiple pesticide use 

       24  in the food-residue data.

       25                CHAIRMAN FROINES:  That sounds almost like 

                 BARNEY, UNGERMANN & ASSOCIATES  888 326-5900

        1  an academic research project.

        2                DR. BYUS:  It does.  It does.  But that's 

        3  all.

        4                CHAIRMAN FROINES:  Which would be good.

        5                DR. BYUS:  Yeah.  Oh, sure. 

        6                DR. ATKINSON:  Well, talking -- I'd like to 

        7  also echo the -- that I like the batched approach for 

        8  listing of chemicals.  Certainly makes sense from an 

        9  environmental-type of approach, as well.  Certainly 

       10  organophosphates, since there isn't a lot of data, they'd 

       11  be much more easily dealt with as a whole batch.

       12                Another thing is, I'd like to -- I certainly 

       13  endorse the controlled applications, that DPR should do 

       14  controlled applications for site monitoring, rather than 

       15  preferably to spending time and energy doing ambient 

       16  monitoring. 

       17                CHAIRMAN FROINES:  I think that's a very 

       18  important recommendation.  And I think it was made 

       19  particularly clear by Bob Spear's presentation.  And from 

       20  the standpoint -- again, from the standpoint of 

       21  identifying a compound as a toxic air contaminant, ambient 

       22  monitoring has different implications for risk-management 

       23  purposes.  And that's also -- 

       24                DR. ATKINSON:  Yes.

       25                DR. FUCALORO:  As you know, I wasn't at the 

                 BARNEY, UNGERMANN & ASSOCIATES  888 326-5900

        1  September workshop.  I couldn't make it.  But I did read 

        2  this document and noted a few things that some of you 

        3  noted.  The -- the monitoring -- the regulated monitoring, 

        4  that was a good one.  Of course grouping the 

        5  organophosphates is another one.

        6                The one thing I noted --  and I wasn't, 

        7  again, part of this discussion.  This is on page 9, 

        8  number-one recommendation.  Says, "DPR should consider 

        9  basing TAC listing on application site monitoring results, 

       10  and using ambient primarily in the risk-management 

       11  phase."  I was just wondering, if that really meant TAC 

       12  priority listing or does it just mean -- 

       13                DR. BLANC:  I think that was the intent.  I 

       14  circled the same thing.  Because they don't actually list 

       15  something as a TAC. 

       16                DR. FUCALORO:  That struck me.

       17                DR. BLANC:  We recommend that something be a 

       18  TAC; right?

       19                CHAIRMAN FROINES:  Yes.

       20                DR. BLANC:  So that wording needs to be 

       21  changed to be clearer.  It implies that the DPR is 

       22  identifying -- is from a regulatory point of view listing 

       23  something as a TAC.  Whereas what you're saying is how to 

       24  do their listing of priorities for consideration as a 

       25  TAC.  Something -- I don't know that being too.

                 BARNEY, UNGERMANN & ASSOCIATES  888 326-5900

        1                DR. FUCALORO:  Well, their priority list -- 

        2  I think that's become a common language with ARB and DPR, 

        3  the priority list in which chemicals are used and go to 

        4  next in order to see if we are going to designate them as 

        5  TACs.

        6                CHAIRMAN FROINES:  Well, the -- this goes 

        7  back in history to the -- to the debate that we've had 

        8  with DPR since the mid '80s where we have always strongly 

        9  disagreed with DPR on -- on the MOE as the basis for a TAC 

       10  listing.

       11                We've always taken the position that a 

       12  compound should be designated as a toxic air contaminant 

       13  based on its toxicity.  And that's different than the DPR 

       14  position.  So that this recommendation for application 

       15  site monitoring is, in essence, to -- to -- is in essence 

       16  saying, if you're going to use the MOE, then we think 

       17  application site monitoring is the most appropriate 

       18  approach to that for purposes of identifying TACs. 

       19                DR. FUCALORO:  And this highlights the 

       20  difference of what I think ARB does and DPR, on the other 

       21  hand.  ARB will look at potency factors in some way and 

       22  designate something a TAC, and then use exposure as part 

       23  of mitigation; right?  

       24                Whereas DPR brings exposure in also --  

       25  exposure and potency factors, whatever they are, cancer or 

                 BARNEY, UNGERMANN & ASSOCIATES  888 326-5900

        1  noncancer effects, and then uses that as a basis for 

        2  designating something a TAC.  But both, organizations as 

        3  far as I understand, use both of those in order to set up 

        4  a priority list.  I think -- I think I have -- I think I 

        5  have that right.

        6                CHAIRMAN FROINES:  The problem, of course, 

        7  with the ambient monitoring, leaving aside the variability 

        8  issue is, you can go back to the data that is available 

        9  for us to review on methyl parathion and the actual 

       10  monitoring data that was available was very limited.  So 

       11  we ended up, I think, used Jim Seiber's data, which was 

       12  one study from the '80s.

       13                I mean, it's -- it's really, when you base 

       14  major policy and scientific decisions on one study done in 

       15  1988, 1987, and that forms the basis of whether 

       16  something's a TAC or not, you realize the limitations of 

       17  that approach.

       18                So if we had lots of data that dealt with 

       19  variability, that's a different issue.  But in any case, 

       20  to the degree that we continue this approach with the MOE, 

       21  then application site monitoring becomes obviously the 

       22  preferred approach, at least from the standpoint of this 

       23  panel.  Paul?

       24                DR. BLANC:  I have a number of text changes  

       25  I'll just pass on to your colleague.  But let me ask you 

                 BARNEY, UNGERMANN & ASSOCIATES  888 326-5900

        1  my substantive questions.  In page 2, point 2, the last 

        2  line, "Further, the SB950 process does not use a 

        3  quantitative ranking scheme."  

        4                CHAIRMAN FROINES:  Where are you at?

        5                DR. BLANC:  The last line of section 2, on 

        6  page 2, you know, "The criteria used to prioritize SB950 

        7  differ from those articulated by DPR."  In that section, 

        8  the last line.  "Further, the SB950 process does not use a 

        9  quantitative ranking scheme."  I just wanted to be clear 

       10  on that.  Do you mean you're not referring therefore to 

       11  their priority list, which did have some kind of rank?

       12                CHAIRMAN FROINES:  No.  They have this 

       13  committee, remember?

       14                DR. BLANC:  Right.

       15                CHAIRMAN FROINES:  And the committee 

       16  basically defined the priority, and that they're not, in 

       17  essence, using this document for prioritization.  This is 

       18  the quantitative document that effectively is not being 

       19  used. 

       20                DR. BLANC:  Okay.  And when they -- you --  

       21  you -- I think it was a little confusing, because they --  

       22  they rank things in three groups or something; right?  So 

       23  it is -- it's very roughly a semi-quantitative.  But it's 

       24  not the -- there's no process to it.  It's two separate 

       25  issues to me.

                 BARNEY, UNGERMANN & ASSOCIATES  888 326-5900

        1                And the stronger one is not that they -- not 

        2  so much that they group things in the three groups, you 

        3  know -- bad, very bad, and better -- but that there is no 

        4  rationally articulated process by which they do that.  And 

        5  I thought that needed to be stated more clearly.

        6                And I wondered, in fact, if on -- and this 

        7  is the related point, I think, in terms of recommendations 

        8  on page 5, where it says -- current language is -- the 

        9  third point is, "Develop a policy for coordination of 

       10  priorities under different programs that require DPR to 

       11  prepare risk assessments for pesticide."  That's getting 

       12  at this process; right?  

       13                And what I would rather explicitly say, that 

       14  they need to delineate explicite criteria for ranking, 

       15  rather than the currently used ad hoc procedure.  Because 

       16  of all of the things we heard, that was, for me, the most 

       17  disturbing, was that there could not -- maybe they have 

       18  something.  But they could not explain it to me in a way 

       19  that sounded coherent.

       20                That there was actually -- so I don't mean 

       21  that they have to prepare a 500-page document.  But they 

       22  need to have a clearly delineated process.  And I think we 

       23  need to say that.

       24                CHAIRMAN FROINES:  Does everybody agree with 

       25  that recommendation?

                 BARNEY, UNGERMANN & ASSOCIATES  888 326-5900

        1                DR. BLANC:  I mean, I wouldn't make it as a 

        2  new point, necessarily.  But I think that's the point I'm 

        3  trying to get at.  I also thought that -- going back 

        4  earlier, back to page 2 on point 3 where it says -- the 

        5  point that has to do with, "The process used to select 

        6  pesticides for an active risk assessment does not 

        7  necessarily take into account TAC candidate status."  And 

        8  I would say that the decision -- 

        9                CHAIRMAN FROINES:  I'm sorry.  Where are 

       10  you?

       11                DR. BLANC:  Point 3, on page 2.  And I would 

       12  say that the problem is not that they don't seem to be 

       13  guided by a specific policy approach.  I think they're not 

       14  guided by a coherent policy.  It's not the lack of 

       15  specificity that bothers me so much, it's that it's 

       16  incoherent.

       17                And similarly, on point 4 on the next page, 

       18  it's not that the process used to select pesticides for 

       19  air monitoring has been distinct from the risk assessment, 

       20  it's been disconnected from the risk assessment.  I notice 

       21  you use the word "disconnected" later, but I really think 

       22  that that's -- 

       23                On page 4, point 6.  Well, after point 6. 

       24  These six points summarize the information which was 

       25  presented in that first part.  And you get into this in 

                 BARNEY, UNGERMANN & ASSOCIATES  888 326-5900

        1  the second half.  But the fact that the changing-use 

        2  patterns are not incorporated in a timely fashion to 

        3  priority setting, it's emphasized a lot in the sampling.  

        4  But I thought it was a critical issue that came up 

        5  relevant to the priority setting, as well.

        6                Now, going on to the next section.  In terms 

        7  of the -- the next set of -- next set of recommendations, 

        8  on the batching the organophosphate pesticides, this is a 

        9  technical question -- two technical questions.  One is, do 

       10  we need to specify cholinesterase inhibiting 

       11  organophosphates?  

       12                The reason I ask, I know there are 

       13  carbamates which are not cholinesterase inhibiting and are 

       14  used for other purposes.  Are there any --  technical 

       15  question for DPR.  Are there any organophosphates which -- 

       16  whose principal means of action is something other than 

       17  cholinesterase inhibiting?

       18                CHAIRMAN FROINES:  Well, there is the issue 

       19  of -- 

       20                DR. BLANC:  I'm going to get to the -- 

       21  just -- 

       22                DR. PATTERSON:  I'm Gary Patterson from 

       23  DPR.  And, no.  It's -- organophosphates by nature are 

       24  cholinesterase inhibitors.

       25                DR. BLANC:  So unlike the carbamates, some 

                 BARNEY, UNGERMANN & ASSOCIATES  888 326-5900

        1  of which -- 

        2                DR. PATTERSON:  Diatomic carbamates usually 

        3  are not.

        4                DR. BLANC:  Right.  Okay.  Fine.  But I do 

        5  think we may need this -- this section to say something 

        6  about organophosphates with delayed neurotoxicity.  

        7  Because in the batching process, we're certainly going to 

        8  have to take into account whether within those 

        9  organophosphates, any of them have delayed neurotoxicity.  

       10  Thanks.

       11                And I thought that point 3 is really what 

       12  you really -- what we're really trying to say.  They need 

       13  to delineate specific criteria for ranking rather than the 

       14  currently used ad hoc procedure.  I think I said that 

       15  already.  Okay.  In Dr. Spear's comments -- 

       16                CHAIRMAN FROINES:  What page are you on?

       17                DR. BLANC:  Page 8.  Under the heading, 

       18  "Ambient monitoring may not result in useful 

       19  characterization of population exposure."  You have here 

       20  his critique of the ambient air monitoring, but not 

       21  necessarily alternatives that he also suggested.

       22                And since you've come back to that in the 

       23  recommendations, invoking him.  I guess, one question that 

       24  I have is, aside from the comment and discussion about 

       25  sampling in control applications, didn't Dr. Spear also 

                 BARNEY, UNGERMANN & ASSOCIATES  888 326-5900

        1  talk about the importance of modelling -- of theoretical 

        2  modelling exposure?

        3                CHAIRMAN FROINES:  Yes.

        4                DR. BLANC:  And there's no recommendation 

        5  here in -- A -- A, it's not described here.  But B, 

        6  there's no follow-up recommendation that says that, in 

        7  addition to these other things, models of exposure should 

        8  also be used in estimating.

        9                DR. ATKINSON:  Point 5, the last sentence 

       10  has -- computer modelling is mentioned.

       11                DR. BLANC:  Where is that?

       12                DR. ATKINSON:  Same page.

       13                CHAIRMAN FROINES:  Last sentence of number 

       14  5.  Page 8, last sentence.

       15                DR. ATKINSON:  That's just mentioned.

       16                DR. BLANC:  I'm sorry.  Page 8, point 5?

       17                CHAIRMAN FROINES:  Last sentence.

       18                DR. BLANC:  Under "Currently proposed 

       19  changes to the ambient monitoring program may increase the 

       20  time required."  Maybe -- page 8.

       21                DR. ATKINSON:  Page 8, point 5.

       22                CHAIRMAN FROINES:  Last sentence in the 

       23  paragraph under 5.

       24                DR. FUCALORO:  It says -- starts with "Other 

       25  ideas under consideration."

                 BARNEY, UNGERMANN & ASSOCIATES  888 326-5900

        1                DR. BLANC:  (Reading.)  Well, I think you 

        2  should -- I think it got lost in the shuffle, because I 

        3  thought it warranted being a separate --

        4                CHAIRMAN FROINES:  Yeah, I think it could be 

        5  made more explicit.  Take your results of application site 

        6  monitoring and use dispersion models for predicting 

        7  ambient concentrations.

        8                DR. BLANC:  Okay.  Those were my -- 

        9                CHAIRMAN FROINES:  It's all good.  

       10  Everybody's fine with that?  Peter?

       11                DR. WITSCHI:  Yeah.  Not much to add, except 

       12  I picked up on Spear's point which says, "very limited 

       13  value."  So first question must come to mind, why are we 

       14  doing it at all?  The second one comes -- comes out like 

       15  Mark Twain in the weather, everybody complains about it, 

       16  but nobody's really doing something.

       17                And I think what's really missing is some 

       18  overall master plan or great view of how the whole 

       19  exposure assessment could be improved so that it can serve 

       20  the purpose we would like things, and that's the 

       21  health-risk assessment.

       22                Because the way I've seen -- this includes 

       23  this morning's presentation, that was very good.  But we 

       24  are going to monitor more and more without really having a 

       25  clear view of what is going out to be, and for -- 

                 BARNEY, UNGERMANN & ASSOCIATES  888 326-5900

        1                CHAIRMAN FROINES:  Well, I think that DPR 

        2  has requested that we assign a panel member or more to 

        3  work with them on -- on these recommendations.  And 

        4  certainly the issue of exposure-assessment monitoring 

        5  would be one of the question features.

        6                Now, what I did was to propose that 

        7  Elinor -- Dr. Elinor Fanning, who's working with the 

        8  panel, and who has more time than the panel members to 

        9  work with them.  But I -- but I think that we need to 

       10  assign at least one or two people to work with DPR to 

       11  address precisely the kinds of questions that you're 

       12  raising.

       13                And so, if I can use your comments -- I wish 

       14  Stan were in the room.  We -- it would be good to have a 

       15  volunteer or two to agree to work with DPR on the issues 

       16  that arise out of this document.  And I think that the two 

       17  people who are missing are not the appropriate people for 

       18  this.  I think it takes people who have some more 

       19  knowledge of exposure-related issues.

       20                So I think this group here today is actually 

       21  the best.  And if nobody wants to volunteer, I'll just 

       22  take that as -- take that silence as silence and then 

       23  we'll work it out outside, you know, the lights of the 

       24  meeting.  Or we can assign Stan, because he's not in the 

       25  room. 

                 BARNEY, UNGERMANN & ASSOCIATES  888 326-5900

        1                DR. BLANC:  And he's leaving early.  So he 

        2  should be punished.

        3                CHAIRMAN FROINES:  So hearing no volunteers, 

        4  we'll take it up after the meeting.  Anyway, go ahead, 

        5  Peter.

        6                DR. WITSCHI:  That's about all.  I'm still 

        7  puzzled.  I still do not see any good way how the human 

        8  data can be used for human health-risk assessment.  And I 

        9  also see that we are doing more and more, which is going 

       10  to be less and less useful for this purpose. 

       11                CHAIRMAN FROINES:  Well, this is a specific 

       12  example of a major problem, as you know, about how 

       13  monitoring data is used in air pollution exposure 

       14  assessment.  It's one of the -- it is one of the -- it 

       15  is -- it is basically the first-stated priority by the 

       16  National Academy of Scientists, committee on Particulate 

       17  Matter.  So it's a key issue.

       18                So I think that we're finished with this.  

       19  We'll take all these suggestions -- we'll take all these 

       20  suggestions and develop a final document and send it off.  

       21  I don't know, Paul, if there's anything that you heard 

       22  this morning that makes you want to comment now or you 

       23  want to just wait till you receive the actual, formal 

       24  document.  But it's your call. 

       25                MR. HELLIKER:  My make of it is, I think 

                 BARNEY, UNGERMANN & ASSOCIATES  888 326-5900

        1  this is an excellent document, and it will help guide us 

        2  as we go forward.  And as you just mentioned, there are 

        3  some fundamental problems that we face.  And we will seek 

        4  your input and your assistance in helping to make a 

        5  reasonable choice as we go forward in all of our 

        6  regulatory programs.

        7                But, I appreciate this.  And certainly it 

        8  reflects some of my impressions, as I've come into the 

        9  department, that we do need to be clearer in defining for 

       10  you, as well as for other stakeholders out there, as what 

       11  our processes are, that we've gone through in making 

       12  decisions about the prioritization about different 

       13  monitoring and different risk assessments.  So I'm looking 

       14  forward to responding to this.

       15                CHAIRMAN FROINES:  Thanks.  Okay.  Do we 

       16  want to take a break?  Don't you?  Just for everybody, got 

       17  a note from Peter that Stan was on the phone.  We'll take 

       18  a ten-minute break. 

       19                       (Brief recess taken.)

       20                CHAIRMAN FROINES:   The next item on the 

       21  agenda is MITC.  This will be a staff report from DPR.  

       22  The panel will not take up the document today for 

       23  discussion purposes.  That doesn't mean that we can't ask 

       24  questions as the presentation is made.  And you're welcome 

       25  to do that.

                 BARNEY, UNGERMANN & ASSOCIATES  888 326-5900

        1                But in terms of our formal -- a formal 

        2  discussion of the document, that will happen at our next 

        3  meeting, and we will have the benefit at that time, also, 

        4  of the OEHHA comments, which we currently don't have.  And 

        5  we'll also have the benefit of Peter Witschi's final --  

        6  final review.

        7                So those two things are -- because they're 

        8  still outstanding, I want to not try to take it up.  Also 

        9  the -- before we start on MITC, I have overlooked saying 

       10  something at the beginning that I want to catch up and say 

       11  thank you very much to Tony Fucaloro for hosting us here.

       12                DR. FUCALORO:  Actually, the thanks goes to 

       13  the staff of Athenaeum.  They are very competent and very 

       14  helpful.  I'll transmit that thanks to them.

       15                CHAIRMAN FROINES:  If you have any comments 

       16  you want to say about the history and anything else,  

       17  please feel free.

       18                DR. FUCALORO:  Yeah, but I'll probably get 

       19  it wrong.  It's been told to me several times, and I'm not 

       20  sure I have it right.  But this is a product of one of our 

       21  founding -- one of CMC's founders, Donald McKenna, who 

       22  recalls having students and faculty together for teas and 

       23  dinners at -- when he was a student at Pomona College.

       24                So he tried to get that -- that to happen at 

       25  Claremont McKenna College, and he was successful.  And 

                 BARNEY, UNGERMANN & ASSOCIATES  888 326-5900

        1  under Jack Stark raised money for this -- this building, 

        2  and to raise the funds to endow it.

        3                So four nights a week, for example, we will 

        4  have a something -- we'll have -- similar to what you're 

        5  doing tonight, which we'll have a reception, we'll have a 

        6  dinner, and then a presentation in this main hall.  And 

        7  students and faculty from all the colleges, whether they 

        8  have meal plans or not, eat for free.

        9                And that's all endowed.  And so it's quite a 

       10  program.  Runs four times a week during the academic 

       11  year.  So it's a great facility, and it brings faculty and 

       12  students together.  And it's not a faculty high house --  

       13  high table as you would find at another institution.  

       14  Almost all events, with the exception of a few like this 

       15  one, require students' attendance and student 

       16  participation.  So that's pretty much the philosophy and 

       17  the thinking behind this -- this program -- the Athenaeum 

       18  program.

       19                CHAIRMAN FROINES:  Well, thank you again.  I 

       20  think it's lovely. 

       21                DR. GLANTZ:  Where did the name come from?

       22                DR. FUCALORO:  Well, I was ambushed to give 

       23  a history of this place, and you're asking about -- I know 

       24  there's a city named Athens -- 

       25                DR. GLANTZ:  Okay.

                 BARNEY, UNGERMANN & ASSOCIATES  888 326-5900

        1                DR. FUCALORO:  -- that goes back to 

        2  antiquity and has quit a history.  But beyond that, I'm a 

        3  chemist.  What the heck?

        4                DR. GLANTZ:  Well, would you find out and 

        5  report back at the next meeting?

        6                DR. FUCALORO:  I know there's an Athenaeum 

        7  at Cal Tech -- at Cal Tech.

        8                CHAIRMAN FROINES:  This is not a graduate 

        9  student's oral, and you don't keep asking them questions 

       10  till you find the one he doesn't know the answer to.

       11                DR. PATTERSON:  We only do that to DPR.

       12                CHAIRMAN FROINES:  Okay.  MITC.

       13                DR. PATTERSON:  Again, I'm Gary Patterson 

       14  from DPR.  Paul Goslyn is unable to attend this meeting, 

       15  and he sends his apologies.  And few statements that he 

       16  wanted me to start with was, he wanted me to emphasize the 

       17  importance of your input on MITC, and that it will be used 

       18  to help guide us through the risk-management phase for 

       19  this chemical.

       20                In addition, he's very interested in hearing 

       21  your thoughts on the sensitivity of the end points that 

       22  will be presented today.  And on one side note, we gave 

       23  you a list of four chemicals that we were going to do for 

       24  the year.  We're going to replace naled with 

       25  chlorpyrifos.

                 BARNEY, UNGERMANN & ASSOCIATES  888 326-5900

        1                And with that, then, I'll turn it over to 

        2  staff to make a presentation.  The first person will be 

        3  Pam Wales to do the environmental fate.

        4                MS. WALES:  Good morning.  My name is      

        5  Pam Wales.  I'm with the Environmental Monitoring and Pest 

        6  Management Branch at DPR.  And -- next slide.  I'm going 

        7  to very briefly cover the valuation of MITC as a TAC on 

        8  the environmental fate of this chemical.

        9                The three points that I'm going to cover 

       10  very briefly this morning are:  The fate of MITC and the 

       11  environment, and focusing mostly on the air; the use in 

       12  California; and also cover some air monitoring to 

       13  determine levels of MITC following applications.

       14                When we talk about MITC, we're really 

       15  talking about three pesticides.  MITC, on the bottom of 

       16  the slide, is registered in California for use as a wood 

       17  preservative.  Use in California is about 350 pounds per 

       18  year.  MITC is very volatile.  Its vapor pressure is about 

       19  16 millimeters of mercury, and the Henry constant is at 

       20  1.8 times 10 to the minus 4 atmospheres, cubic meters per 

       21  mole.

       22                 MITC is used to control wood decay 

       23  organisms in large structural timbers.  It's typically not 

       24  used in crop-land setting.  However, there are two other 

       25  pesticides.  One is called Dazomet, and the other 

                 BARNEY, UNGERMANN & ASSOCIATES  888 326-5900

        1  Metam-Sodium, for which MITC is the principal active in 

        2  their formulations.

        3                Dazomet is registered for use in California 

        4  as a slimicide and biocide.  It's used in cooling water 

        5  treatments and also in -- just had a brain fade.  Also, 

        6  one product is used as a pre-plant fumigant.  The use of 

        7  Dazomet is about 20 thousand pounds per year, and it 

        8  breaks down to form MITC.

        9                Metam-Sodium, on the other hand, is 

       10  registered for use as a pre-plant fumigant, wood 

       11  preservative, and also for root control.  And in 

       12  California, in the agricultural setting, almost 16 million 

       13  pounds are used per year.  While Metam-Sodium itself is 

       14  non-volatile, it does break down rapidly to MITC.

       15                Next slide.  As I've said, the primary 

       16  source of MITC in the environment is from the breakdown of 

       17  Metam-Sodium.  Metam-Sodium is applied to a soil either

       18  by soil injection or by chemigation.  It's usually -- 

       19                DR. GLANTZ:  What is chemigation?

       20                MS. WALES:  Chemigation is irrigation -- 

       21  treatment by irrigation.

       22                DR. GLANTZ:  Does that mean put it in the 

       23  irrigation water or they just spray it on?

       24                MS. WALES:  Yes, put into irrigation water 

       25  then spray it out over the field.  When it's applied by 

                 BARNEY, UNGERMANN & ASSOCIATES  888 326-5900

        1  chemigation, after the treatment, a -- enough clear water 

        2  is ran afterwards through the sprinklers to produce a 

        3  one-inch seal of water, and also to drive the Metam-Sodium 

        4  into the soil.

        5                When it's injected by soil-injection 

        6  methods, use special equipment that injects it about 10 to 

        7  12 inches into the soil.  Afterward, the soil is bedded or 

        8  tarped or rolled and compressed.  The purpose of this is 

        9  to keep the Metam-Sodium -- actually, the MITC vapors in 

       10  the soil so they actually do the fumigant activity.

       11                 The conversion in the soil of Metam-Sodium 

       12  to MITC occurs within about an hour.  And conversion 

       13  occurs with 87 to 95 percent efficiency, depending on some 

       14  conditions of soil.  Increased soil temperature, increased 

       15  concentrations of clay or organic materials, and increased 

       16  soil pH, coupled with decreased soil moisture content, 

       17  lead to rapid -- more rapid conversion.

       18                Two other compounds may be formed in the 

       19  soil during that conversion.  One is carbon disulfide and 

       20  the other is hydrogen sulfide.  The generation of those 

       21  compounds really depends on the pH of the soil.  If it's 

       22  more alkaline, hydrogen sulfide is expected to be 

       23  generated.  And in basic soils, carbon disulfide.

       24                About 60 percent of the MITC that's 

       25  generated in the soil volatilizes, leaves the soil and 

                 BARNEY, UNGERMANN & ASSOCIATES  888 326-5900

        1  enters the air.  Once in the air, the main pathway for the 

        2  loss of MITC from the air is through photolysis.  The 

        3  photo decomposition results in a variety of compounds, as 

        4  you can see on this overhead here.

        5                MITC is there on the left.  The activated 

        6  molecule is the one in the middle with the star.  And 

        7  according to Geddes, the major, primary photochemicals 

        8  produced is methyl isocyanide.  About 80 percent of the 

        9  MITC is converted to methyl isocyanide.

       10                That follows some secondary photochemical 

       11  processes and results in methyl isocyanate, and 

       12  methylformamide, and some other compounds which you see 

       13  here.  Geddes proposed that the -- the methyl isocyanate 

       14  may be the -- may be photochemically stable, because he 

       15  observed that it increased over time.

       16                Next page.  Briefly to cover the use of 

       17  Metam-Sodium -- 

       18                DR. BLANC:  Can you go back to the last 

       19  slide?

       20                MS. WALES:   Sure. 

       21                DR. BLANC:  Point out to us which 

       22  formulas -- which moiety -- 

       23                MS. WALES:   I'm sorry.  I can't hear you.

       24                DR. BLANC:  Which chemical structure is 

       25  which?

                 BARNEY, UNGERMANN & ASSOCIATES  888 326-5900

        1                MS. WALES:   If you follow the main pathway, 

        2  that's MITC.

        3                DR. BLANC:  Yeah.

        4                MS. WALES:   That's MITC, the activated 

        5  state.  To the right of that is methyl isocyanide.  To the 

        6  right of that is methyl isocyanate.  A-ha.  This structure 

        7  right here is N-methylformamide.  This right here is 

        8  methylamine.  Methylamine is also generated in this 

        9  pathway.  This is carbonyl sulfide, sulfur dioxide, and 

       10  in this pathway, you also generate the MIC plus hydrogen 

       11  sulfide. 

       12                DR. BLANC:  Thank you. 

       13                MS. WALES:   This is -- this slide shows 

       14  overall Metam-Sodium use in California.  This is, once 

       15  again, in the agricultural setting, from 1990 through 

       16  1998.  As you can see, Metam-Sodium use began to increase 

       17  in 1994.  It is pretty-well stabilized at about 15 to 16 

       18  million pounds a year since then.

       19                The reason for this increase in 1994 was 

       20  largely due to two things.  One was the reduced use of 

       21  telone, 1-3 dichloropropene, which is another fumigant, 

       22  and methyl bromide.  Also, researchers discovered that 

       23  Metam-Sodium was very effective in controlling root 

       24  nematodes in carrots, and also nightshades in the 

       25  nightshade crops.  So they applied -- so use went up to 

                 BARNEY, UNGERMANN & ASSOCIATES  888 326-5900

        1  account for that.

        2                Next slide.  This is the use of Metam-Sodium 

        3  from 1990 to 1998 on a month-by-month basis.  You can see 

        4  that it's used pretty much year round.  However, there are 

        5  couple large peaks.  The first one, right here in February 

        6  through April.  And another peak that occurs in the late 

        7  summer, early fall, from about July through October.  And 

        8  this is throughout the whole state.

        9                As I said, Metam-Sodium is primarily used on 

       10  carrots.  Almost 30 percent of what's applied in 

       11  California is used on carrot crops.  Another 25 percent -- 

       12  23 percent is used on tomatoes, cotton, and potatoes 

       13  account for the major crops.  All the rest of the uses are 

       14  from a variety of crops -- root crops, bulb crops, lots of 

       15  different crops.

       16                When we say that the use is associated with 

       17  a crop, it's actually a pre-plant application.  It's 

       18  applied before the crop is put in the ground.  This map 

       19  shows how Metam-Sodium is used throughout the state.  This 

       20  is from 1998 --

       21                CHAIRMAN FROINES:  Question.

       22                MS. WALES:   Uh-huh.

       23                CHAIRMAN FROINES:  This document that we had 

       24  earlier this morning, Monitoring Multiple Chemicals by 

       25  Crop Root, and he's got the 23 chemicals for cotton.

                 BARNEY, UNGERMANN & ASSOCIATES  888 326-5900

        1                MS. WALES:   Uh-huh.

        2                CHAIRMAN FROINES:  And Metam-Sodium is not 

        3  listed on this list.  So there's a disconnect between your 

        4  11 percent here, and this document.  Which seems -- would 

        5  seem to imply that -- well, they're different.  Anybody 

        6  know the answer to that?

        7                MR. SEGAWA:  I do.

        8                CHAIRMAN FROINES:  Oh, there you are.  I 

        9  keep looking for you.

       10                MR. SEGAWA:  That's because, in the chemical 

       11  listed for cotton, I only listed those chemicals which had 

       12  their highest use on cotton.  And in this particular case, 

       13  you can see that highest use is on carrots.  And so in the 

       14  crop grouping, it would have been grouped with carrots, 

       15  rather than cotton.

       16                CHAIRMAN FROINES:  Okay.  For us, it's 

       17  probably better to know which is the highest pesticides on 

       18  cotton.

       19                MR. SEGAWA:  Yes.  For instance, we could 

       20  have one -- I just put the highest crop use.  I could have 

       21  put highest two or highest three crops, which would have 

       22  been another way to do it.

       23                CHAIRMAN FROINES:  Well -- 

       24                DR. GLANTZ:  Well, no.  I think the 

       25  difference -- I think what you're saying, John, is the 

                 BARNEY, UNGERMANN & ASSOCIATES  888 326-5900

        1  list should have been a list of the -- of the pesticides 

        2  used on cotton, perhaps.  And what he did was, he said, 

        3  let's look -- it was the other way around.

        4                It said, let's look at the pesticides and 

        5  pick the crop that each pesticide is used the most on.  

        6  And those are the -- the ones on the list we had earlier 

        7  were the pesticides where cotton was the most heavily -- 

        8  was the greatest use of that pesticide.

        9                CHAIRMAN FROINES:  But you see the potential 

       10  contradiction?

       11                DR. GLANTZ:  Yeah, yeah.  I just think you 

       12  need to be clear, though.

       13                CHAIRMAN FROINES:  So we -- so the panel, 

       14  you see, doesn't know right now what are the most 

       15  important pesticides on cotton. 

       16                DR. BLANC:  Because -- to follow up on that, 

       17  you could have a pesticide which actually isn't used that 

       18  much anywhere, but the one crop that it is used on is 

       19  cotton; right?

       20                MR. SEGAWA:  Correct.

       21                DR. BLANC:  And another pesticide which is 

       22  used, like Metam-Sodium is -- only ten percent of it's 

       23  used on cotton, but it happens to be one of the most 

       24  widely used pesticides in California.  Therefore ten 

       25  percent of 13 million pounds is still a million pounds 

                 BARNEY, UNGERMANN & ASSOCIATES  888 326-5900

        1  used on cotton.

        2                MR. SEGAWA:  That's correct.

        3                DR. BLANC:  And so, therefore, what would 

        4  probably interest us more would be, of the heaviest-use 

        5  pesticides overall in California, which are -- which of 

        6  them are used in rank order in cotton?  So that if you 

        7  talked about one crop -- 

        8                MR. SEGAWA:  Yes, but then we would have to 

        9  come up with some sort of cut off.  As you say, one 

       10  million pounds -- everything above one million pounds, we 

       11  have concerns about.  Everything below, we do not monitor 

       12  for.

       13                DR. GLANTZ:  Or some reasonable cut off.  

       14  Just show us -- or show us if you use a cut off of one 

       15  million pounds, then you use it to cut off 500 thousand 

       16  pounds.  How does it change?

       17                CHAIRMAN FROINES:  I mean, we're interested 

       18  in the scope of the problem.  And so, if you arbitrarily 

       19  limit that, we're left without a real sense of what --  

       20  what's the pattern of use, basically.  Let's go on.

       21                MS. WALES:   Next slide.  Map of the 1998 

       22  use in California.  This is of Metam-Sodium.  So you can 

       23  see the bulk of the Metam-Sodium is applied, once again, 

       24  through the Central Valley.  Heaviest -- these darkest 

       25  spots are the highest use.

                 BARNEY, UNGERMANN & ASSOCIATES  888 326-5900

        1                The highest use is in Kern County.  This is 

        2  1998 now.  We have Kern County, and then up through 

        3  Fresno, that's quite a bit in Madera area.  And then on 

        4  down here in Imperial County.  But you can see, it's 

        5  also -- it's used pretty much through all the agricultural 

        6  areas.  Including, if you look up at the north part of the 

        7  map there, you'll see some use on the potatoes up in Modoc 

        8  and bulbs, I believe, in Del Norte.

        9                Now, these things that I've mentioned about 

       10  the locations of where it's used and also the soil 

       11  conditions actually played a big part in determining where 

       12  we wanted to do our studies.  The ambient studies were 

       13  designed to measure pesticide concentrations in ambient 

       14  air during the time and region of peak use.

       15                The samplers were placed on roof tops of 

       16  schools, fire houses, and other public buildings.  And for 

       17  ambient studying -- studies, we did not associate the 

       18  monitoring with any specific application.  This was to 

       19  provide an estimate of exposures that people living in 

       20  proximity to pesticide applications might experience.

       21                Three studies were conducted in California,  

       22  and they're summarized in the report.  This is a table 

       23  with the information from the three studies.  I'm not 

       24  going to read this to you in the interest of time.  And 

       25  especially since Tom, who's after me, is going to cover a 

                 BARNEY, UNGERMANN & ASSOCIATES  888 326-5900

        1  lot more of this in exposure assessment.

        2                What I did want to point out to you, was 

        3  that the ambient studies were conducted in Kern County,  

        4  and in Lompoc, and then again, very new study that was 

        5  just published this year in Kern County.  And these were 

        6  conducted in the summertime.

        7                Dr. Seiber's study went from May until 

        8  August, and then the Air Board study was in July.  And in 

        9  Kern County, we have soils in the summertime that are very 

       10  warm.  They're dry.  The pH is a little bit on the 

       11  alkaline side.  And the soil-moisture content is low.  And 

       12  so that would indicate that that's probably the best time 

       13  to find MITC in the air.

       14                These are the positive-sample results.  And 

       15  the number of samples that were taken and then the number 

       16  of samples -- of the positive samples.  This recent study 

       17  by Dr. Seiber did something a little different than the 

       18  others did.  And that was, he put monitors inside 

       19  residential homes, outside residences, very close to the 

       20  external walls of the homes.

       21                And then he also placed monitors on tops of 

       22  roof tops, other public buildings in the Kern County area 

       23  where Metam-Sodium was being applied.  Interesting thing 

       24  to notice is that the positive detections indoors was not 

       25  that much different from the outdoors, and the ambient 

                 BARNEY, UNGERMANN & ASSOCIATES  888 326-5900

        1  studies or ambient samples.

        2                In the wintertime, he took samples in 

        3  January and in March.  And now, those cool air/cool soil 

        4  conditions, and the results are much lower than what they 

        5  were in the summer studies.  This is a map from the study 

        6  that was conducted by the Air Board of 1993.  Hard to see, 

        7  because it's not on the scale here.

        8                But the samplers were placed in Shafter and 

        9  Bakersfield, in Lamont, and Weed Patch.  The red hashed 

       10  marks and checker-board marks that you see here on the map 

       11  are where the applications of Metam-Sodium occurred during 

       12  this study.

       13                As you can see, we had applications 

       14  surrounding all of the areas.  An interesting thing that I 

       15  noted was that at Bakersfield, which was the background 

       16  site, there were positive detections in all eight of the 

       17  samples that were collected.  And the nearest applications 

       18  of Metam-Sodium were approximately six miles to the 

       19  northeast -- or to the northwest, and about seven or eight 

       20  miles to the southeast.

       21                CHAIRMAN FROINES:  On your previous 

       22  overhead -- 

       23                MS. WALES:   Uh-huh.

       24                CHAIRMAN FROINES:  -- you say "ambient air 

       25  monitoring, MITC."  My guess is that you mean 

                 BARNEY, UNGERMANN & ASSOCIATES  888 326-5900

        1  Metam-Sodium.

        2                MS. WALES:   We're monitoring for MITC after 

        3  applications of Metam-Sodium.  Because Metam-Sodium is not 

        4  volatile, we don't expect to find it in the air.  Also, 

        5  because conversion is so rapid, yes.

        6                CHAIRMAN FROINES:  But it's a Metam-Sodium 

        7  application.

        8                MS. WALES:   It's a Metam-Sodium 

        9  application.  One other thing to note, I checked.  There 

       10  was no Dazomet or MITC applied anywhere in Kern County 

       11  during the course of the study.  So all of the results 

       12  would presumably be from the Metam-Sodium applications.

       13                This is from the Lompoc study.  Now, while 

       14  this study wasn't conducted solely for Metam-Sodium, one 

       15  of the chemicals was Metam-Sodium.  There were -- samplers 

       16  were placed at these locations around the city of Lompoc.  

       17  And two applications were made during the study, one right 

       18  here, and the other one is right here. 

       19                DR. FUCALORO:  Just one question.  Came up 

       20  when I was reading the report.  A -- AI, what does that 

       21  stand -- 

       22                MS. WALES:   Active ingredient.

       23                DR. FUCALORO:  Thanks.

       24                MS. WALES:   Okay.  On the application site 

       25  air monitoring studies -- 

                 BARNEY, UNGERMANN & ASSOCIATES  888 326-5900

        1                DR. GLANTZ:  Before you go on, on this 

        2  figure 11-A, I'm a little confused.

        3                MS. WALES:   The Lompoc map; okay.

        4                DR. GLANTZ:  Yeah.  Where -- were the -- is 

        5  this whole gray area where it was applied?  That's the 

        6  city of Lompoc; right?

        7                MS. WALES:   Yeah.  Let's go back to that 

        8  map.

        9                DR. GLANTZ:  So where is the actual -- is 

       10  the actual application a little box sort of on the -- 

       11                MS. WALES:   Yeah, on the map here, it's 

       12  purple.  This is the city of Lompoc.  This is where one 

       13  application occurred.

       14                DR. GLANTZ:  I see.

       15                MS. WALES:   That was the 1,058 pounds were 

       16  applied.  And then this field right here to the -- almost 

       17  due west -- 

       18                DR. GLANTZ:  I see.  Okay.

       19                MS. WALES:   -- is the 952.  For the 

       20  application site monitoring studies, we have five studies 

       21  that were conducted, and they're summarized in the 

       22  report.  Once again, I'm not going to -- on the next slide 

       23  I have a table.  I'm not going to read all this again.

       24                However, two of the studies were from -- 

       25  were based on sprinkler irrigations.  One of them we 

                 BARNEY, UNGERMANN & ASSOCIATES  888 326-5900

        1  monitored for MITC, hydrogen sulfide, and carbon disulfide 

        2  following a sprinkler irrigation application.  And then 

        3  these are the results.

        4                Tom is going to discuss this a lot more 

        5  following me, so I'm not going to say much, other than we 

        6  did detect hydrogen sulfide.  And that could be expected 

        7  because of the alkaline of the soil.  And we did not 

        8  detect carbon disulfide.

        9                Three studies were done following soil 

       10  injection.  One in 1993, one in 19 -- all three -- well, 

       11  two in 1993, and one in 1995.  And once again, following 

       12  the application, MITC was detected in all of the 

       13  samples -- nearly all of the samples in all of those 

       14  studies.  There are no questions?  Tom.

       15                CHAIRMAN FROINES:  Thank you.

       16                MS. WALES:   Thank you. 

       17                DR. BLANC:  Actually, I have one question.  

       18  Sorry.

       19                MS. WALES:   Oh, okay.

       20                DR. BLANC:  Because this may not be covered 

       21  later.

       22                MS. WALES:   Okay.

       23                DR. BLANC:  Your third overhead -- 

       24                MS. WALES:   The third one?

       25                DR. BLANC:  -- where you talked about the 

                 BARNEY, UNGERMANN & ASSOCIATES  888 326-5900

        1  structure of Metam-Sodium and Dazomet.

        2                MS. WALES:   Okay.

        3                DR. BLANC:  So is the -- should I assume 

        4  that each molecule of Dazomet yields two molecules of MITC 

        5  as opposed to Metam-Sodium on the one-for-one basis?

        6                MS. WALES:   According to the manufacturer 

        7  of the one -- of one of the Dazomet products, when Dazomet 

        8  breaks down, there's a ring -- 

        9                DR. BLANC:  Rearrangement?

       10                MS. WALES:   Well, a ring break that occurs.  

       11  And you yield one molecule of MITC, one molecule of 

       12  formaldehyde, one molecule of hydrogen sulfide, and one 

       13  molecule of methylamine, I believe.  And together, that 

       14  whole collection of compounds constitutes the active.

       15                DR. FUCALORO:  In the presence of water;  

       16  right?

       17                MS. WALES:   In the presence of water, yes.

       18                DR. BLANC:  Say it again.  One molecule of 

       19  MITC, one molecule of formaldehyde --

       20                MS. WALES:   Of formaldehyde, one molecule 

       21  of hydrogen sulfide, and one molecule of methylamine, I 

       22  believe.  Let me check to make sure.  Yes.  Formaldehyde, 

       23  MITC, hydrogen sulfide, and mono-methylamine.

       24                CHAIRMAN FROINES:  What is it again? 

       25                MS. WALES:   I'm sorry?

                 BARNEY, UNGERMANN & ASSOCIATES  888 326-5900

        1                CHAIRMAN FROINES:  Say it again. 

        2  Methylamine -- 

        3                MS. WALES:   MITC, formaldehyde, hydrogen 

        4  sulfide and mono methylamine. 

        5                DR. BLANC:  What's the form of formaldehyde?

        6                CHAIRMAN FROINES:  CH2O.  There are two 

        7  formaldehydes.

        8                MS. WALES:   You would get two? 

        9                CHAIRMAN FROINES:  You said methylamine, 

       10  MITC, H2S and formaldehyde.

       11                MS. WALES:   Yes.

       12                CHAIRMAN FROINES:  Seems to me you get two 

       13  formaldehydes.  What am I missing here?

       14                DR. BLANC:  You got to get something 

       15  different, because there's five carbons in this molecule.

       16                CHAIRMAN FROINES:  You get MITC, H2S, 

       17  methylamine -- 

       18                MS. WALES:   And formaldehyde.

       19                CHAIRMAN FROINES:  So you have to have two 

       20  formaldehydes.

       21                MS. WALES:   That could be.

       22                CHAIRMAN FROINES:  Break the bond between 

       23  the -- you look at the sulfur.  You break the bond between 

       24  the two sulfur breaks, break the bond between the 

       25  hydrogen, the methylamine, you can see you take that right 

                 BARNEY, UNGERMANN & ASSOCIATES  888 326-5900

        1  out.  See, the MITC is the right-hand side, so you've got 

        2  two carbons unaccounted for.  So that must mean two 

        3  formaldehyde.

        4                MS. WALES:   That could be.

        5                CHAIRMAN FROINES:  I'm sorry.  Thank you.

        6                MS. WALES:   Is that good?  Thank you.

        7                DR. THONGSINTHUSAK:  My name is          

        8  Thomas Thongsinthusak.  I'm with DPR.  My presentation 

        9  will come -- will cover part B, the exposure assessment of 

       10  the MITC.  Next one, please.  My presentation will cover 

       11  six different topics, starting from estimate production of 

       12  MITC in California and the calculated exposures for adults 

       13  and children.  And so I touch on the production of MIT, 

       14  hydrogen sulfide, and then exposure appraisal.

       15                Next please.  Estimated production of MITC 

       16  in California.  I use the -- use report format and sodium 

       17  from 1992 to 1997 and the amount of Metam-Sodium, MITC are 

       18  shown as million pounds.  The first column, Metam-Sodium 

       19  use in California in 1992, is about 8.6 million pounds.  

       20  And the amount was doubled in about 1995.

       21                This is the column show the MITC generated 

       22  from Metam-Sodium use.  This column here.  I use the 

       23  equation shown in foldout B.  The conversion of 

       24  Metam-Sodium to MITC is about 60 percent by weight, which 

       25  is about one mole of Metam-Sodium per one mole of MITC.  

                 BARNEY, UNGERMANN & ASSOCIATES  888 326-5900

        1  The amount of MITC products used in California is very 

        2  low.  For 1992, it's about 8,500 pounds.  In 1997, it's 

        3  about 400 pounds, only.

        4                In the last column show the total estimate 

        5  amount of MITC produced from '92 to '97.  The last part of 

        6  this slide show the amount of use of the estimate in 

        7  California.  Which is -- California, which is very small 

        8  compared to amount use of Metam-Sodium.

        9                Next slide, please.  This slide show the 

       10  calculation of the exposure estimates calculated for 

       11  adults and children.  The -- first of all, I use the data 

       12  from what Pam mentioned, and then those of amount of 

       13  concentration of MITC were adjusted for molecular weight, 

       14  and application weights, and a percent recovery.

       15                First of all, I use the MITC concentration 

       16  times the maximum application rate, divided by the 

       17  application rate, if known or used in the study, and then 

       18  divided by percent of self-recovery.  I can convert from 

       19  the amount expressed as microgram per cubic meter to parts 

       20  per billion using this equation.

       21                The estimate calculated as an observed daily 

       22  dosage or ADD.  For ADD I use the short-term concentration 

       23  of MITC times adult female ventilation rate and divided by 

       24  body weight.  Short-term ADD concentration, that means 24 

       25  hour times average or closest to 24 hour TWA.  Further 

                 BARNEY, UNGERMANN & ASSOCIATES  888 326-5900

        1  exposure estimates for male -- adult males, I can use the 

        2  factor of 1.5, which is obtained from the ratio of 

        3  ventilation rate and body weight between males and 

        4  females.

        5                The next is the long-term or moderate-term 

        6  exposure estimates for MITC or seasonal average daily 

        7  dosage or SADD.  The ADD that used to calculate the SADD 

        8  is used from the moderate term, ADD concentration of MITC 

        9  times exposure days per season 120-days season.  For the 

       10  exposure days, I used 23 days per season.  Currently DPS 

       11  is working on exposure days for current exposure 

       12  assessment.

       13                This slide show the ADD for adult females.  

       14  And for B.2, B.7, and B.8, they were from ambient 

       15  monitoring studies.  And the first one, wherever I can, I 

       16  will use the Atkinson concentration as TWA.  And if they 

       17  were not available, I will use the highest exposure --  

       18  highest MITC air concentrations.

       19                In this case, only one applicant from each 

       20  site.  I use the highest concentration.  This study was 

       21  conducted in -- 

       22                DR. GLANTZ:  What was TWA again?

       23                DR. THONGSINTHUSAK:  Times weight of 

       24  average.  This study was conducted in 1993.  B.7 conducts 

       25  in 1997 and '98.  As it's shown earlier, the amount of use 

                 BARNEY, UNGERMANN & ASSOCIATES  888 326-5900

        1  of Metam-Sodium for B.7 in California was about doubled to 

        2  the amount of Metam-Sodium use in 1993.  The range of the 

        3  ADD from .62 to about 5 for B.2, B.7.  They were very 

        4  similar to B.2.  For the study in Lompoc, the ADD was 

        5  about .14 micrograms per kilogram per day.

        6                Next slide, please.  This table show the ADD 

        7  obtained from five studies.  This is application site 

        8  studies.  Contra Costa, B.3, and Kern County.  And B.4 

        9  also in the Kern County.  B.5, Madera.  And B.6, 

       10  Bakersfield.  There will be one more study that will be 

       11  added in the future.  The industry conducted one latest 

       12  study.  I will add that study, once the final report is 

       13  available.

       14                There's a wide range of ADD from application 

       15  site study.  When I say it doesn't say how far away from 

       16  the treated field, it's normally range from 12 to 40 yards 

       17  from the treated field, kilometers.  You can see that the 

       18  farther away from the treated field, pyramid of the ADD is 

       19  lower than the station that is located closer, like five 

       20  meters.  Next, please.

       21                CHAIRMAN FROINES:  Will you then use these 

       22  now for the MOE calculations?

       23                DR. THONGSINTHUSAK:  Next person, Andy 

       24  Rubin, will use these ADD for MOE calculations.

       25                DR. BLANC:  Why do the ranges on these ones 

                 BARNEY, UNGERMANN & ASSOCIATES  888 326-5900

        1  that you have here differ from the ranges on the last 

        2  slide that Pam showed us?

        3                DR. THONGSINTHUSAK:  That Pam show?

        4                DR. BLANC:  Yeah, for the same studies.  For 

        5  example, for the Madera County, she had a maximum -- a 

        6  range of 1.29 to maximum of 435 parts per billion.  And 

        7  you have a series of ranges, but none of them are as high 

        8  as 435 parts per billion.  Whereas, your Kern County one 

        9  there, range -- upper range is higher than the upper 

       10  range.

       11                DR. THONGSINTHUSAK:  Pam's data have not 

       12  been corrected for the maximum application weights and the 

       13  percentage of recoveries.  In my case, before I calculate 

       14  the ADD, I will make adjustment for maximum application 

       15  weight, and the percentage of recoveries.

       16                DR. BLANC:  So your value will always have a 

       17  slightly higher -- 

       18                DR. THONGSINTHUSAK:  Pardon me?

       19                DR. BLANC:  So your values will have a 

       20  slightly higher upper range?

       21                DR. THONGSINTHUSAK:  Yes, in most case, they 

       22  will be higher.  Next is to calculate the seasonal average 

       23  daily dosage.  I will use the ADD concentration from a 

       24  moderate-term air monitoring studies.  In this case, I 

       25  will have more samples like for B.2.

                 BARNEY, UNGERMANN & ASSOCIATES  888 326-5900

        1                For B.2, B.7, and B.8, represent ambient air 

        2  monitoring data.  And I calculate use ADD, multiplies 

        3  exposure days per 120-day season.  And the range is like 

        4  for the B.2 from .02 to about .45.  I will not go over all 

        5  these numbers.  They are in your handouts.

        6                Next, please.  The SADD from the application 

        7  site monitoring studies, five studies all together.  And 

        8  for the first one, B.1, 27.2 micrograms per kilogram and 

        9  per day.  And the numbers vary according to the sampling 

       10  site, based on the distance from the treated field 

       11  kilometer.

       12                Next, please.  Now, there's a question about 

       13  a potential retention of MITC on silica gel drying tubes 

       14  which is placed in front of a charcoal sampling tubes,  

       15  not only in a sampling tray.  There will be section of the 

       16  tubes, the front will be the silica gel drying tube, and 

       17  the other two absorb the excess moisture, and the other 

       18  two will be the charcoal sampling tube.

       19                Normally, there will be two sections.  The 

       20  first section will contain 400 milligrams of charcoal, and 

       21  subdivided by -- and the last part will contain about 200 

       22  milligrams charcoal.

       23                Most studies use just charcoal tubes to 

       24  collect their samples.  But there are two studies that use 

       25  the silica gel drying tubes.  The first one by Wofford in 

                 BARNEY, UNGERMANN & ASSOCIATES  888 326-5900

        1  1994, and the second one by Zeneca -- okay.  They found 

        2  right by -- Wofford found at four out of ten tubes of the 

        3  silica gel, they can retain from zero to four percent of 

        4  the total MITC.  And for the internal two, the retention 

        5  ranged from 58 to a hundred percent.  So there's a 

        6  question there.

        7                Silica gel may retain some MITC, but it 

        8  is -- doesn't seem to be so from the study by the 

        9  industry.  The recovery of MITC range from 71 to 95 

       10  percent.  So in this case, after desorption deficiency 

       11  correction, retention would be -- should be around ten 

       12  percent or less.  Next, please. 

       13                DR. BLANC:  Can you say what the 

       14  implications of this is?

       15                DR. THONGSINTHUSAK:  Pardon me?

       16                DR. BLANC:  And what do you believe the 

       17  implications of these data are?

       18                DR. THONGSINTHUSAK:  The implications?  The 

       19  implications of those data is, it's likely that silica gel 

       20  drying tubes can retain some MITC.  But I have got to have 

       21  some more proof for that.  And most studies accept the 

       22  tube.  Most study does not use silica gel drying tubes.  

       23  So, in general, I do not see any problem for that.

       24                DR. BLANC:  But you said that Wofford used 

       25  silica drying tubes.

                 BARNEY, UNGERMANN & ASSOCIATES  888 326-5900

        1                DR. THONGSINTHUSAK:  Yes.

        2                DR. BLANC:  And the highest values that you 

        3  had were from the Wofford study.

        4                DR. THONGSINTHUSAK:  Yes.

        5                DR. BLANC:  And if the retention was high, 

        6  means that you couldn't remove some of the material, and 

        7  therefore underestimated those very high values; is that 

        8  right?  Did I have the direction of the effect?

        9                DR. THONGSINTHUSAK:  Yes.  If the Wofford 

       10  study did not include MITC in the silica gel tubes, but 

       11  they did.  So they combine MITC from both -- both types of 

       12  tubes.  So there's no problem for that.  But that's 

       13  another study conducted by Zenneca.  They did not analyze 

       14  MITC in the silica gel drying tube.  But from the lab from 

       15  the study, they did not see that that is an important 

       16  issue.

       17                DR. BLANC:  And did you use their data in 

       18  any of your calculations?

       19                DR. THONGSINTHUSAK:  Yes, uh-huh.

       20                DR. BLANC:  Which calculations involved the 

       21  Zenneca study?

       22                DR. THONGSINTHUSAK:  I think B.6.

       23                DR. BLANC:  B.6?  The Bakersfield study?

       24                DR. THONGSINTHUSAK:  Madera, I think.  

       25  Madera.  Would you show the table 7.2?

                 BARNEY, UNGERMANN & ASSOCIATES  888 326-5900

        1                DR. BLANC:  7.2 or 8.2?

        2                DR. THONGSINTHUSAK:  B.5.  Madera.  

        3  Actually, it's ICI.  They used silica gel drying tubes, 

        4  but they did not analyze MITC in the tube.

        5                CHAIRMAN FROINES:  They didn't analyze the 

        6  MITC in the -- 

        7                DR. THONGSINTHUSAK:  Silica gel.

        8                CHAIRMAN FROINES:  So that underestimates 

        9  the overall approach.

       10                DR. THONGSINTHUSAK:  It is possible that 

       11  MITC concentrations were underestimate.  But as I 

       12  mentioned before, from their study, the recovery with or 

       13  without silica -- with a silica gel drying tube was very 

       14  high.  So I assume that it is not their concern, because 

       15  of the their findings.

       16                CHAIRMAN FROINES:  Well, it seems to me, 

       17  this is actually an issue that needs to be resolved.  It's 

       18  not enough to say, "I think it was not important."  

       19  That's --  that's -- I think falls in the category of a 

       20  subjective comment.  I think the issue is, is it important 

       21  on a quantitative basis? 

       22                DR. THONGSINTHUSAK:  I agree.  Thank you.

       23                CHAIRMAN FROINES:  So the point is, if we're 

       24  going to be using silica tubes to remove water, then we 

       25  need to know, one, is there a material being absorbed, and 

                 BARNEY, UNGERMANN & ASSOCIATES  888 326-5900

        1  two, can you -- what's the efficiency of desorption to 

        2  determine the residual? 

        3                DR. ATKINSON:  It should only effect the 

        4  ICI, whether it's analyzed the silica gel.

        5                DR. THONGSINTHUSAK:  The reason I cannot 

        6  make an adjustment for this set of data, because I don't 

        7  have any solid information to make an adjustment.  Because 

        8  from the study by Wofford and her colleagues, it show a 

        9  high and low.  And normally, the temperature or the 

       10  relative humidity will affect that.

       11                But from the two intervals, the relative 

       12  humidity and the temperature are very similar.  So I don't 

       13  know what cause that -- what cause the absorption or 

       14  absorption by silica gel.  Okay.

       15                CHAIRMAN FROINES:  I state -- I only press 

       16  it insofar as goes back to the same old, same old, same 

       17  old, which is, if we're using MOEs to determine toxic air 

       18  contaminants, then these kind of matters become part of 

       19  the uncertainty and the exposure characterization.  They 

       20  therefore become elements in the actual designation of the 

       21  compounds of TAC.  So it actually becomes potentially 

       22  significant, in a broad policy context.

       23                DR. FUCALORO:  It's kind of worse than 

       24  that.  When you talk about uncertainty, you're talking 

       25  about quantitative thinking.  And this is just uncertainty 

                 BARNEY, UNGERMANN & ASSOCIATES  888 326-5900

        1  in knowing what the meaning of the number is.  Can you put 

        2  it -- from what you know, can you put an uncertainty in 

        3  some of these numbers?

        4                DR. ATKINSON:  Must be able to.

        5                DR. FUCALORO:  And then just get -- 

        6                DR. ATKINSON:  If the recovery is between 75 

        7  and 95 percent you can bracket -- 

        8                DR. FUCALORO:  You can bracket, it seems.

        9                DR. THONGSINTHUSAK:  Can you put table 7.2 

       10  back again?  I would like to point out one more thing.  

       11  Lynn Baker pointed out to me, actually.  Under Wofford's 

       12  study, I can say that this is the worst case here, because 

       13  the -- they use the silica gel drying tube.  And you 

       14  compare -- this stands from the five meter to air 

       15  concentration up to 1100.  But the same distance under 

       16  ICI, a hundred and eighty-six.

       17                This seem to represent the worst case.  They 

       18  were -- when we compare the same distance from the field  

       19  parameters.  450, and from Wofford's study, 468.  Similar 

       20  distance from ICI, a hundred and eighteen.  So I assume 

       21  that for the first -- before represents the worst-case air 

       22  concentration of MITC.  This one compared to this one.  

       23  May I move on? 

       24                CHAIRMAN FROINES:  I'm confused, but maybe 

       25  we'll deal with it later.  Did you understand? 

                 BARNEY, UNGERMANN & ASSOCIATES  888 326-5900

        1                DR. BYUS:  Which number are you going to use 

        2  to calculate the MOE?

        3                DR. THONGSINTHUSAK:  Both.  Both.

        4                DR. BYUS:  You're going to use the low one 

        5  and the high one?

        6                DR. THONGSINTHUSAK:  Yes.

        7                DR. BYUS:  Why?  Just out of curiosity.

        8                DR. THONGSINTHUSAK:  We will show the 

        9  worst-case MOE, as well as the MOE for the lower air 

       10  concentrations.

       11                DR. BYUS:  But the lower one could very well 

       12  be due to an analytical error and not getting total 

       13  recovery.  So I mean, in a sense, what Dr. Froines' been 

       14  saying, yes, you could put a value of uncertainty on that 

       15  number based upon your clear understanding of the 

       16  analytical difficulties.

       17                So I would -- I mean, we'll get to this.  

       18  But off the top of my head, I would tend to go with the 

       19  higher values for the MOE, and not even bother calculating 

       20  the lower ones, since you know that there's an analytical 

       21  error, perhaps, in the generation of that number.

       22                DR. THONGSINTHUSAK:  Yes, we can disregard 

       23  this study, because of the deficiencies.

       24                DR. ATKINSON:  Well, the ICI ones could be 

       25  increased by about 50 percent, since they are the recovery 

                 BARNEY, UNGERMANN & ASSOCIATES  888 326-5900

        1  70 percent, apparently.

        2                DR. THONGSINTHUSAK:  But if it's increased 

        3  by a hundred percent, it's still less than half of the 

        4  first one.  That's the worst case.

        5                DR. BYUS:  My understanding, that's kind of 

        6  Wofford's estimation of analytical problem, not 

        7  actually -- 

        8                DR. ATKINSON:  That was ICI.

        9                DR. BYUS:  Was it ICI's numbers?  I just 

       10  don't --

       11                DR. ATKINSON:  That's what I got out of it.

       12                DR. BYUS:  Okay.

       13                CHAIRMAN FROINES:  Let's go ahead.  Let's go 

       14  ahead.  Are you throwing your hands up or do you have a 

       15  comment?

       16                DR. BLANC:  I was wrestling paper.

       17                DR. THONGSINTHUSAK:  I also estimate the 

       18  exposure of children to MITC.  I used the data calculated 

       19  for adult females times a correction factor.  And this 

       20  correction factor is 4.  And correction factor was 

       21  calculated from ventilation rate of children and body 

       22  weight of children versus ventilation rate and body weight 

       23  of adult females.

       24                CHAIRMAN FROINES:  Can I go back and ask you 

       25  a question?

                 BARNEY, UNGERMANN & ASSOCIATES  888 326-5900

        1                DR. THONGSINTHUSAK:  Yes.

        2                CHAIRMAN FROINES:  When -- when these 

        3  determinations are made, whether it be ICI or Wofford or 

        4  Caar, do you have written down somewhere what the 

        5  meteorology is?  Do we know where you're upwind and 

        6  downwind of the application?  I mean, the numbers can vary 

        7  widely depending upon -- 

        8                DR. THONGSINTHUSAK:  Yes, in my document, I 

        9  mentioned that most short-term and long-term, 

       10  moderate-term air concentrations were from downwind MITC 

       11  concentrations.

       12                CHAIRMAN FROINES:  They were downwind?

       13                DR. THONGSINTHUSAK:  Yes.

       14                CHAIRMAN FROINES:  Do you have the 

       15  characteristics of the meteorology?

       16                DR. THONGSINTHUSAK:  There's some data in 

       17  the report.  And then I picked the MITC according to the 

       18  downwind direction.  So that would be a wind direction 

       19  of different directions.  I picked downwind and picked the 

       20  air concentration according to the downwind direction.  

       21  Except two.  I forgot which one.  That they were not in 

       22  the downwind direction.  I mentioned that in the document, 

       23  which one.

       24                DR. FUCALORO:  So you have some description, 

       25  although it's not necessarily very detailed?

                 BARNEY, UNGERMANN & ASSOCIATES  888 326-5900

        1                DR. THONGSINTHUSAK:  Yes, that's right.  So 

        2  whenever I can, I will use a downwind air concentrations 

        3  of MITC.

        4                CHAIRMAN FROINES:  And presumably you've 

        5  calculated the distribution of your data, as well as these 

        6  means.  Because it seems to me that one doesn't want to 

        7  use the mean for an MOE calculation.

        8                DR. THONGSINTHUSAK:  I presented both mean 

        9  and the range.  The range -- the ranges are in the 

       10  parentheses.  So there were too many, so I did not go over 

       11  those ranges.  May I proceed? 

       12                CHAIRMAN FROINES:  Yeah, please.  I'm 

       13  sorry.  I think this issue of distribution is one that we 

       14  want to talk about.

       15                DR. THONGSINTHUSAK:  Okay.  There was some 

       16  concern about a production of MIC, CS2 and H2S, hydrogen 

       17  sulfide.  There were two studies that found MIC and CS2 

       18  and H2S, the first one by Air Resources Board, for MIC 

       19  from the downwind direction, the range of .4 to 2.5 parts 

       20  per billion.  For the overall MIC production of recover 

       21  from range from .3 to 2.5 parts per billion.

       22                This the only study that analyze MIC, as far 

       23  as I know.  For carbon disulfide, 8 out of 16 samples 

       24  detected under the detection limit of 4 parts per 

       25  billion.  For hydrogen sulfide, there are three ranges.  

                 BARNEY, UNGERMANN & ASSOCIATES  888 326-5900

        1  The first one is from 3 parts per billion to 76 parts per 

        2  billion.  This is the sampling from one to four hours.  

        3  From five to seven hours, non-detectable, and from 21 to 

        4  24 hours, non-detectable up to 8 parts per billion.

        5                Next, please.  My final slide shows my 

        6  exposure appraisal.  For the number of exposure days that 

        7  were used to calculate the SADD were obtained from limited 

        8  surveys and other information.  We use currently 23 days.  

        9  But the industry suggested 8 days per season.

       10                I mention number two about silica gel drying 

       11  tube can retain MITC in two of the studies.  The study by 

       12  Wofford combine MITC recovered in silica gel tubes, plus 

       13  MITC recovered in charcoal sampling tube.

       14                Currently there's a technical information 

       15  relating, which is the guidelines for all application 

       16  methods for Metam-Sodium in California.  This is the 

       17  guideline issue by the industry.  And that's the way to 

       18  reduce the emission of MITC from sodium.

       19                Many studies conducted in the past were not 

       20  in compliance with these technical information relating.  

       21  But the exposure, especially those that sampled inside are 

       22  shorter than the buffer zone, maybe overestimate the 

       23  exposure for residences by standards.

       24                DR. GLANTZ:  Well now, is that -- is that 

       25  because of something unusual about this exposure or about 

                 BARNEY, UNGERMANN & ASSOCIATES  888 326-5900

        1  these applications?  Because it would seem to me, just as 

        2  a person who occasionally has used pesticides, that I 

        3  don't always exactly follow the exposures, you know, 

        4  because I'm a clod or something.

        5                And so, I mean, is there any evidence that 

        6  the -- that the exposures that you were monitoring are in 

        7  any way unusual?  Because, if they're not, and given that 

        8  people sometimes don't follow the guidelines -- probably a 

        9  lot of times don't follow them, would seem to me, this 

       10  last conclusion is unwarranted.

       11                DR. THONGSINTHUSAK:  Yeah, that's possible.  

       12  And we still don't know the compliance rate, even though 

       13  this technical information bulletin is attached to product 

       14  labels.

       15                DR. GLANTZ:  Right.  Right.  Well, given 

       16  that, I mean, if you have actual data in the field, I 

       17  would believe that over -- rather than saying, well, we're 

       18  just going to assume that we had a few odd people who 

       19  didn't follow the technical specifications the 

       20  manufacturer produced. 

       21                DR. THONGSINTHUSAK:  That is very likely to 

       22  happen.

       23                DR. GLANTZ:  Yeah.  Well then, that's why I 

       24  would say the last statement you have here about 

       25  overestimating actual exposure, you don't have any 

                 BARNEY, UNGERMANN & ASSOCIATES  888 326-5900

        1  evidence to support that statement. 

        2                DR. THONGSINTHUSAK:  Sorry.  Go ahead.

        3                DR. BLANC:  Go ahead.

        4                DR. THONGSINTHUSAK:  If you think that's not 

        5  appropriate, I would remove that.  I agree to do that.

        6                CHAIRMAN FROINES:  We're going to take up 

        7  the whole document.  So probably don't need to -- should 

        8  avoid -- we should take up major issues and avoid --

        9                DR. BLANC:  Well, isn't a major issue the 

       10  fact that if the application amount has doubled in the 

       11  time since the sampling was done to the present, there 

       12  needs to be some comment in the document on whether or not 

       13  the use patterns in terms of doubling is because of added 

       14  acreage that's used versus added pounds per acre when it's 

       15  applied.

       16                And also whether or not the sampling that 

       17  was done representing certain isolated fields being 

       18  sampled -- being -- having use is really applicable to the 

       19  real-world use where there might be much bigger areas used 

       20  simultaneously.

       21                I don't know the acreage of these little 

       22  plots where the application was.  But if the application 

       23  has doubled -- if it's doubled in a geographic area -- if 

       24  that's consistent across geographic areas, and not simply 

       25  that there are new geographic areas that have been 

                 BARNEY, UNGERMANN & ASSOCIATES  888 326-5900

        1  recruited, then the actual exposure areas would likely be 

        2  twice as high.

        3                DR. THONGSINTHUSAK:  I can double check on 

        4  the area, if it correspond to the amount of use.

        5                DR. BLANC:  But you know what I mean?

        6                DR. THONGSINTHUSAK:  Yes.

        7                DR. BLANC:  If within a three-square-mile 

        8  area of Lompoc five years ago over a two-week period there 

        9  would be, you know, 50 acres where it was applied over 

       10  that time period, and now it's a hundred acres, then the 

       11  exposure would probably be higher or the --  you know, I 

       12  mean, the sampling is very dependent on how many acres -- 

       13  over how many acres applications occurring at the time 

       14  that you're sampling.

       15                CHAIRMAN FROINES:  Stan, what time is your 

       16  plane?

       17                DR. GLANTZ:  Quarter -- I have to leave 

       18  about a quarter to 2:00.

       19                CHAIRMAN FROINES:  If we go to 12:30, break 

       20  for lunch, that's 1:30.  Have 45-minute lunch, that's 

       21  1:15.  We get about a half hour on MTBE with you.  Let's 

       22  go ahead and we're going to try to bring this discussion 

       23  to closure.  May be tight, but we're going to try to bring 

       24  this to closure by 12:30.  I really want Stan to have 

       25  input on MTBE.

                 BARNEY, UNGERMANN & ASSOCIATES  888 326-5900

        1                DR. GLANTZ:  Actually, I was going to 

        2  suggest, because I am a little worried about that.  Maybe 

        3  we could table -- finish this one part of the 

        4  presentation, and maybe do MTBE, and then come back to 

        5  this.  Because I'm a little worried about having to leave 

        6  in the middle of that discussion.

        7                CHAIRMAN FROINES:  Okay.  You want to break 

        8  to lunch and then come straight back to MTBE and then take 

        9  this up?

       10                DR. GLANTZ:  Yeah.  Or work through lunch, 

       11  if people want to do that.

       12                CHAIRMAN FROINES:  Is that okay, Paul?  Or 

       13  who's ever handling this presentation?  I'm very worried 

       14  about not getting to MTBE with Stan gone.  Can -- can we 

       15  defer till after lunch, after the MTBE discussion?

       16                MR. HELLICKER:  Sure.  We're here at your 

       17  disposal today.  We do have another segment to this 

       18  presentation.

       19                CHAIRMAN FROINES:  Yeah.  I think -- I hate 

       20  to hurry that, because we're all the health types, and so 

       21  we're interested in hearing that part.  So -- but I know 

       22  we're -- what's going to happen.  Things -- time drifts a 

       23  little bit more than -- even if I thought we could be done 

       24  by 12:30, you know.  It's -- so let's take a 45-minute 

       25  break for lunch.  Then let's do MTBE.  Then we'll go 

                 BARNEY, UNGERMANN & ASSOCIATES  888 326-5900

        1  straight back to MITC. 

        2                       (Lunch recess taken.)

        3                CHAIRMAN FROINES:   We'll take up MTBE.  And 

        4  I want to quote two sections from the transmittal letter 

        5  from Michael Kenny to me.  He said, 

        6                "This letter is to formally request the      

        7         Scientific Review Panel review the Office of        

        8         Environmental Health Hazard Assessments' enclosed   

        9         documentation on the carcinogenic potency of methyl 

       10         tertiary butyl ether in accordance with the usual   

       11         procedures for peer review of the health values for 

       12         toxic air contaminants."  

       13                So that's the defining question.  Now, say 

       14  more about that in a second.  Secondly in his letter, he 

       15  says the following:  

       16                "On April 26th, 1999, the Air Resources      

       17         Board requested OEHHA to develop health values for  

       18         the air exposure pathway for MTBE.  OEHHA's         

       19         assessments incorporated carcinogenicity            

       20         information already contained in the technical      

       21         support document compiled for the public health     

       22         goal for MTBE in drinking water and the recent      

       23         report on MTBE completed by the University of       

       24         California."  

       25                Because of that request, it means that this 

                 BARNEY, UNGERMANN & ASSOCIATES  888 326-5900

        1  panel is now going to, in part, be reviewing the public 

        2  health goal.  But this letter also includes the recent 

        3  report completed by the University of California, which I 

        4  was responsible for the health-effect section.

        5                So what I have decided to do, to avoid any 

        6  appearance of conflict, I don't want to be in the position 

        7  of defending my document.  And so what I decided to do was 

        8  to transfer the chair for this discussion to Tony 

        9  Fucaloro, who will chair the discussion.

       10                But I also felt that I had no reason to not 

       11  be able to participate in the discussion as a scientist 

       12  who's familiar with MTBE.  So Tony is going to take it 

       13  over.

       14                Last thing I'll say is, came up last time, 

       15  we are basically voting on the following:  We are voting 

       16  to determine that the health effects report is based on 

       17  sound scientific knowledge, methods, and practices.  

       18  "Scientific Review Panel determines that the health 

       19  effects are based upon sound scientific knowledge -- sound 

       20  scientific knowledge, methods or practices," that 

       21  criteria.

       22                DR. BLANC:  Tony, I'd like the record to 

       23  show that there is consensus on the panel that John's 

       24  approach to handling this matter meets with our agreement.

       25                DR. FUCALORO:  Sure.  I think if I -- if I 

                 BARNEY, UNGERMANN & ASSOCIATES  888 326-5900

        1  look around -- ask around the table, I see no problem.  I 

        2  personally would have had no problem with John chairing 

        3  this section.  But I also have no problem -- I have a 

        4  little problem with my chairing.  Means I have to work 

        5  harder.  But other than that, I have no problem with it.  

        6  And does anyone disagree with what I just said?  Speak 

        7  now.  So -- 

        8                DR. GLANTZ:  Is this why -- never mind.

        9                DR. FUCALORO:  I think that certainly 

       10  approved by the panel to follow John's suggestion on 

       11  this.  To refresh your memory -- and I've had my memory 

       12  refreshed on this -- MTBE, methyl tertiary butyl ether, is 

       13  a TAC by virtue of being an HAP.  It's a toxic air 

       14  contaminant by virtue of being hazardous air pollutant 

       15  designate by the U.S. Government.

       16                So -- so it is a TAC.  So what is our 

       17  purpose here?  Our purpose is to validate a document 

       18  prepared by OEHHA, actually applying some risk factors --  

       19  stating some -- some risk factors that they've estimated  

       20  so that MTBE especially -- I mean, important especially 

       21  because of the clean up one anticipates for MTBE in the 

       22  groundwater and vapors that would come from that 

       23  groundwater.  With that in mind, is there a presentation 

       24  from OEHHA at this point?

       25                DR. MARTY:  No, we actually gave the 

                 BARNEY, UNGERMANN & ASSOCIATES  888 326-5900

        1  presentation at the last meeting, so we don't have -- 

        2                DR. FUCALORO:  I do recall.  And the 

        3  document that you are handing out to everyone is a 

        4  document that was handed out at the last meeting.  And 

        5  this is the document which we are to find as being based 

        6  upon sound, scientific principles; is that correct as you 

        7  understand is it?

        8                DR. MARTY:  We sent that document out, along 

        9  with the public-health-goal description to the panel 

       10  members, and I'm recalling the middle of September.

       11                CHAIRMAN FROINES:  This document?

       12                DR. SALMON:  Yes.

       13                DR. MARTY:  Yes. 

       14                DR. FUCALORO:  And -- and Attachment 1 is 

       15  essentially a condensation of that document in terms of 

       16  the -- at least the part that you're interested in, the 

       17  potency factors.

       18                DR. MARTY:  It's a condensation, and also 

       19  the presentation of how we derived unit risk factors for 

       20  inhalation exposure. 

       21                DR. FUCALORO:  Now, we discussed this.  And 

       22  I'm going to call upon the panel members to make comments 

       23  about it.  So I want to give you -- want to give you a 

       24  head's up on that.  But I will -- I will indicate that I 

       25  recall some of this -- I recall a lot of this 

                 BARNEY, UNGERMANN & ASSOCIATES  888 326-5900

        1  conversation, now that I've seen the document.  And one of 

        2  the concerns was that these numbers were based upon 

        3  studies that use very high concentrations of MTBE.

        4                And there was some concern by some members 

        5  on this panel that -- that we were looking at problems 

        6  associated with clearing of the chemical in the mice or 

        7  rats -- that is, mice studies.  And I think that was at 

        8  issue.  Is that your recollection?

        9                DR. MARTY:  I'm recalling that people were 

       10  concerned about the carcinogenistic bioacids using high 

       11  doses.  However, that is not unique to MTBE.

       12                DR. FUCALORO:  I'm not asking to you defend 

       13  it.  That was the issue.

       14                DR. MARTY:  That was one issue that was 

       15  raised.

       16                DR. FUCALORO:  So with that, I would ask if 

       17  there's anyone wants to add to it, because we're going to 

       18  have to vote on this, it seems to me.

       19                DR. GLANTZ:  Well, I -- since I have sort of 

       20  limited time here -- why are you smiling?  The -- 

       21                DR. FUCALORO:  She's grimacing.

       22                DR. GLANTZ:  Okay.  Good.  Good.  Well, my 

       23  understanding of -- and this is a preface to a question.  

       24  But I just want to make sure I understand what you did 

       25  here.  Is that you -- you took the oral data or the data 

                 BARNEY, UNGERMANN & ASSOCIATES  888 326-5900

        1  from drinking water, and you combined that with a 

        2  pharmacokinetic model to get applied dose.  And then you 

        3  used the pharmacokinetic model on a couple of assumptions 

        4  to figure out the equivalent inhaled dose to get the same 

        5  target organs.  And that's where the number -- the error 

        6  number came from; is that correct?

        7                DR. SALMON:  The -- yes, the original 

        8  studies on which the calculation is based -- in fact, 

        9  the -- one of them is an inhalation study.  But there's 

       10  also an oral study.  So what we were doing was using the 

       11  pharmacokinetic models to enable us to compare all the 

       12  data sets we had on a single basis.

       13                And the pharmacokinetic model was actually 

       14  used on the basis of the -- predicting the area under the 

       15  curve for MTBE.  That was the index parameter for the 

       16  model.  And the inhalation calculation for human exposure 

       17  at low dose is related back to that metabolized-dose 

       18  estimate.

       19                So the pharmacokinetic model is basically 

       20  used to tie together, on the one hand, the animal studies 

       21  by either root.  And on the other hand, the human 

       22  exposure.  Which for the PHG, actually, we used both an 

       23  oral number and an inhalation number, because there's 

       24  some, you know, secondary exposure by the inhalation root 

       25  when you have drinking-water contamination.  But in this 

                 BARNEY, UNGERMANN & ASSOCIATES  888 326-5900

        1  particular case for the TAC, we were interested 

        2  specifically and only in the inhalation number.

        3                DR. GLANTZ:  Okay.  Well -- so to me, 

        4  everybody brings their own perspective to these things.  

        5  The model and getting comfortable with the model is really 

        6  the key part of this.  And I had a couple of questions 

        7  about the model.  One of them -- and let me just tell you 

        8  what they are.  Just rattle through them, and then you can 

        9  address them in whatever order makes the most sense.

       10                So if you go to the drinking-water 

       11  document -- I mean, I think from my perspective, and the 

       12  things I know about, if I'm satisfied with the model, 

       13  the -- to go from that to your unit risk for air exposure 

       14  is just arithmetic.  So -- and that all seemed reasonable.

       15                But the questions I have is, if you look at 

       16  table 10 of the drinking-water report, which is on page 

       17  72, you've got -- and this is sort of my standard question 

       18  about these things.  You've got a ton of parameters 

       19  there.  And, you know, how sensitive is the model to those 

       20  assumed parameters?  

       21                How confident are you in the values of those 

       22  parameters, if there are -- because it's -- a lot of this 

       23  is just from one study or one or two studies, and then -- 

       24  and then -- you know, if -- if these are off, how much 

       25  difference does it make and what are the critical ones?  

                 BARNEY, UNGERMANN & ASSOCIATES  888 326-5900

        1  So that's one question I had.

        2                The second question is, in here, you talk 

        3  about using a polynomial model, but it wasn't ever quite 

        4  clear to me exactly what that was or what the 

        5  justification for using the specific model that you had 

        6  was, you know.

        7                Let me just ask all the questions, because 

        8  I'm feeling kind of pressed for time.  And I want to -- 

        9  and you can -- and then the third question is -- and this 

       10  may just be my own not understanding what you wrote 

       11  here -- but if you look at tables 11 and 13, which is on 

       12  page 73 and 75, which is presented as the -- as the 

       13  validation of the model, and you guys say this stuff shows 

       14  that the model works pretty well, as I read it.

       15                And maybe I'm misunderstanding the table.  

       16  It looked -- it didn't look like they worked all that well 

       17  to me.  So the -- especially at the high -- with the 

       18  larger rats.  And so what I'd like to you do is -- and 

       19  then you can deal -- these are three interrelated 

       20  questions -- is, I think it may just be my -- me not 

       21  understanding these two tables.

       22                But I need to be convinced, A, that the 

       23  model parameters are reasonable, and that the model isn't 

       24  overly sensitive to the values that you picked.  B, why 

       25  you used the polynomial model that you used, and what 

                 BARNEY, UNGERMANN & ASSOCIATES  888 326-5900

        1  effect -- how sensitive the results are to those 

        2  assumptions.

        3                And then C, to be convinced or explain how 

        4  to read tables 11 and 13 to draw the conclusion that the 

        5  model actually works pretty well.  So that's what I'm 

        6  looking for.  You can put -- come back to them however is 

        7  most efficient in terms of time.

        8                DR. SALMON:  Okay.  Well, I'll start by 

        9  talking about the parameters in the PBPK model 

       10  simulation.  By the way, the Borgoff Paper and the Row and 

       11  Ginsberg Paper are actually describing previous modelling 

       12  exercises which drew on quite a wide range of different 

       13  data sources.

       14                So in a sense, it's not just two papers that 

       15  are the source of that.  Those are in themselves 

       16  compendiums and evaluations of the data which we choose to 

       17  cite as prior authorities, basically.  The parameters, all 

       18  of which are essentially typical inputs for a PBPK model, 

       19  are things like the compartment volumes and flows fairly 

       20  generic sort of parameters which describe rats, 

       21  basically.

       22                And so those, to some extent, would 

       23  represent sort of consensus values from the modelling 

       24  literature.  Neither we nor Borgoff would have -- you 

       25  know, would have departed very far from the standard 

                 BARNEY, UNGERMANN & ASSOCIATES  888 326-5900

        1  assumed values for those.

        2                The parameters which are a little bit more 

        3  specific to the MTBE case are the partition coefficients 

        4  and the metabolic constants.  And certainly among the 

        5  important issues are the actual values of the partition 

        6  coefficients, which are usually estimated on the basis of 

        7  experimental data.  And we're using for this the 

        8  precedents of the Borgoff paper.

        9                And the metabolism, again, that is usually 

       10  partly, at least, estimated from other experimental data.  

       11  And that, in particular, can be an important one in 

       12  determining how well the predictions of the model fit the 

       13  observed excretion profile of the MTBE.  This is where we 

       14  transfer to tables 11, 12 and 13.  Is that an adequate 

       15  explanation?

       16                DR. GLANTZ:  Well, I understand that's where 

       17  you got them from.  But the concern that I have -- what I 

       18  am interested in, is how sensitive are the results to the 

       19  specific parameter values that you've got here?  And of 

       20  these large number of parameters, what are the important 

       21  ones?  

       22                I mean, some of them aren't going -- I mean, 

       23  we've been through this before with other modelling 

       24  exercises.  And some of the parameters aren't going to 

       25  make much difference at all.  And you can have big errors, 

                 BARNEY, UNGERMANN & ASSOCIATES  888 326-5900

        1  and it wouldn't matter.  And other ones might be highly -- 

        2  where the results might be highly sensitive.

        3                And so, which ones are those, and how can 

        4  you be sure that -- that, you know, that the risk numbers 

        5  you're coming up with aren't highly dependent on parameter 

        6  estimates, which may or may not be reliable?

        7                DR. SALMON:  Well, in terms of the model's 

        8  sensitivity, I think probably the most critical parameters 

        9  would be the V-max and KM values for MTBE.  And the blood 

       10  air and fat-blood partition coefficients.  Those would 

       11  probably be the most critical ones.

       12                The -- as far as the extent to which we can 

       13  validate our choice of the values which we're using there, 

       14  for the purposes of this risk assessment, we are not using 

       15  what I would call the details of the model.  We're not 

       16  trying to say, this is the concentration in the liver or 

       17  the kidney or whatever.

       18                So in a sense, our risk-assessment 

       19  conclusion is not actually very sensitive to the finer 

       20  details of the model.  The only thing which we're actually 

       21  using is the prediction of the -- the metabolized dose of 

       22  MTBE.

       23                One of the things which we did attempt to 

       24  do -- and this I will explain from -- as part of what's 

       25  happening in table 11.  One of the things we looked at was 

                 BARNEY, UNGERMANN & ASSOCIATES  888 326-5900

        1  the question of whether we could use the concentration of 

        2  the metabolite TBA as an index of some perhaps more 

        3  critical exposure than just how much MTBE is around.

        4                The conclusion that we came to was, firstly, 

        5  subjects of various other discussions in the document, we 

        6  really don't have any evidence to suggest directly that 

        7  TBA is the critical metabolite.  So it wasn't safe to base 

        8  a risk-assessment conclusion on that assumption.

        9                And secondly, we do have problems with the 

       10  model in terms of predicting the TBA concentrations.  What 

       11  this shows in table 11 is that the MTBE C-max and 

       12  area-under-the-curve predictions between the -- where 

       13  you've got the observed figures, which are in bold 

       14  italics, those are actual observations which match to the 

       15  theoretical values.

       16                And by the standards of these things, the 

       17  match is considered reasonably good.  I think it may be 

       18  worth commenting that the C-max -- this is the peak 

       19  concentration achieved immediately after dosing -- is 

       20  actually a very difficult parameter to model.

       21                It's highly sensitive to all the inputs.  

       22  And in particular, it's sensitive to details of the exact 

       23  compartmentalization, and things like differential 

       24  absorption, and different regions of the gut, and local 

       25  blood flows, and things like that, which our simple model 

                 BARNEY, UNGERMANN & ASSOCIATES  888 326-5900

        1  simply doesn't accommodate.

        2                So allowing for that known imperfection of 

        3  the complexity of the model that we're using, I think you 

        4  would look at the observed versus predicted concentrations 

        5  as not being too awful for C-max for MTBE.

        6                DR. GLANTZ:  So the observed are in light 

        7  type and the predicted value -- no.

        8                DR. SALMON:  The predicted are in bold.

        9                DR. GLANTZ:  And the observed values are in 

       10  heavy type?

       11                DR. SALMON:  We have predictions at 40 

       12  milligrams per kilograms, which match one set of observed 

       13  values, and predictions at 400 milligrams per kilogram, 

       14  which match the second set of observed values.  And what 

       15  I'm saying is, basically, the C-max is, if we're anywhere 

       16  in the right ballpark, we're actually doing fairly well.

       17                And what we would actually be looking for, 

       18  which isn't easy to show in a table, but if you -- you 

       19  know, I mean, the model produces a fat stack of paper as 

       20  its output.  And if you look through that, what we're 

       21  looking for, in fact, is a reasonable approximation 

       22  between observed and predicted over a time-course type of 

       23  experiment.

       24                And what we're saying is, over that 

       25  time-course experiment, we have a reasonable match.  And 

                 BARNEY, UNGERMANN & ASSOCIATES  888 326-5900

        1  in fact, C-max is probably the hardest point on that curve 

        2  to model.  The other one -- 

        3                DR. GLANTZ:  Well, but if you look, 

        4  though -- I mean, if you look at the 40 milligram per 

        5  kilogram dose, you're saying that -- you're predicting 

        6  .068, whatever the units are here.

        7                DR. FUCALORO:  What are the units?

        8                DR. SALMON:  Minimolar.

        9                DR. GLANTZ:  But what you're observing is 

       10  two or three times that.

       11                DR. SALMON:  Well, if -- 

       12                DR. GLANTZ:  And if you go down to the 400 

       13  milligram per kilogram dose, you're off by -- maybe a 

       14  factor of two, isn't so bad.

       15                DR. SALMON:  I'm saying for C-max, that is 

       16  actually fairly good.  And the -- the match against the 

       17  observed profile will actually probably be quite a lot 

       18  better further out in the curve.  But -- so, yeah.  That's 

       19  exactly what I'm saying.  That C-max within a factor of 

       20  two for that is, in fact, quite reasonable by the 

       21  standards of these things.

       22                The one which is closer to what we're 

       23  actually using for the -- for the basis of the risk 

       24  assessment, is the area under the curve, the units of this 

       25  being millimolar times hours.  And the area under the 

                 BARNEY, UNGERMANN & ASSOCIATES  888 326-5900

        1  curve figures -- as you may notice, the match is still not 

        2  perfect for MTBE.  But it is, in fact, quite a bit closer.

        3                And I think given the -- essentially, you 

        4  could say the parameter we're using for the basis of the 

        5  risk assessment is -- is closely related to that 

        6  area-under-the-curve figure.  And if we're within, you 

        7  know, 20 or 30 percent of the right value, bearing in mind 

        8  that, you know, there's a significant variation between 

        9  the different experimental observations.

       10                So there's quite a bit of uncertainty in the 

       11  data here.  But in a worst case, we're probably all right 

       12  within a factor of 20 or 30 percent.  Which means that the 

       13  uncertainties in this parameter are substantially less 

       14  than the other uncertainties with which we have to deal.

       15                And -- but on the other hand, I would point 

       16  out, as noted in the document, we're not satisfied with 

       17  predictions for the tertiary butyl alcohol metabolite.  

       18  And the reason for this is, there are some 

       19  compartmentalization and further metabolism issues with 

       20  TBA, which we have currently insufficient information to 

       21  make a proper prediction.

       22                And that is one of the reasons why we chose 

       23  to use the relatively unsophisticated model parameter of 

       24  simply looking at thing area under the curve to validate 

       25  the model and predicting the basis -- the dose basis on 

                 BARNEY, UNGERMANN & ASSOCIATES  888 326-5900

        1  total absorbed and metabolized MTBE, which is shown in 

        2  table 12.

        3                The -- these -- so what we're doing is, 

        4  we're looking at the model structure, and we're choosing a 

        5  parameter which we feel we can predict with a reasonable 

        6  degree of confidence across a fairly wide range of doses.

        7                And we can use that as the basis for our 

        8  dosimetry and the risk assessment, without making any 

        9  unsupported assumptions, either about the pharmacokinetics 

       10  or about the mechanism.  That's what we hoped we were 

       11  doing, anyway. 

       12                DR. GLANTZ:  Well, so basically what you're 

       13  saying is, you're within a factor of two.  You think 

       14  that's pretty good.

       15                DR. SALMON:  For the -- for the C-max, I 

       16  think so, yes.  I mean, one of the things is, that's an 

       17  extremely difficult parameter to measure accurately.

       18                DR. GLANTZ:   So -- so how much did you -- 

       19  did you wiggle these parameters around to get that?  Or 

       20  did you -- or did these -- Borgoff and Row and Ginsberg 

       21  wiggle their parameters to get that fit?

       22                DR. SALMON:  We've used a number of 

       23  different combinations of parameters and chosen, 

       24  basically, the parameters here.  The fact that we were 

       25  using it -- the V-max values from Row and Ginsberg, and 

                 BARNEY, UNGERMANN & ASSOCIATES  888 326-5900

        1  also one of the partition coefficients from Row and 

        2  Ginsberg basically reflects the fact that we feel that was 

        3  the combination of available and peer reviewed and 

        4  respectable parameters that -- 

        5                DR. GLANTZ:  Now, were those values -- were 

        6  the data on the observed levels of these parameters, the 

        7  variables and tables 11, 12, and 13 -- were those involved 

        8  in deriving the parameter values in table 10 or did the 

        9  values in table 10 come from independent sources?  You 

       10  plug them into the model, cranked out a set of predictions 

       11  independent of the data -- 

       12                DR. SALMON:  The essence of this is one 

       13  should be using externally derived parameters.  There are 

       14  a couple of things like the -- for instance, the 

       15  gastrointestinal absorption rate, which we simply had no 

       16  data.  So that had to be an assumed parameter, as noted in 

       17  the table.  But -- 

       18                DR. GLANTZ:  Right.  But that's a different 

       19  question, though.

       20                DR. SALMON:  But Borgoff and Row and 

       21  Ginsberg are using externally validated values for their 

       22  parameters.

       23                DR. GLANTZ:  How does that -- how does the 

       24  data in tables 11, 12 and 13 relate to the Borgoff and Row 

       25  and Ginsberg models?  Did they use the data in 11, 12 and 

                 BARNEY, UNGERMANN & ASSOCIATES  888 326-5900

        1  13 to get their parameter values?

        2                DR. SALMON:  They would have used some -- I 

        3  think that they were actually, possibly using a slightly 

        4  different subset of the data than -- I don't have that 

        5  exact information at hand.  Certainly they would have been 

        6  looking at a slightly different combination of inputs.  So 

        7  what we're saying -- 

        8                DR. GLANTZ:  But you took -- I mean, I don't 

        9  mean to be rude.  I'm just feeling kind of pressed for 

       10  time here.  So would I be correct in saying that the 

       11  parameter values in table 10 basically came from the 

       12  literature?

       13                DR. SALMON:  Yes.

       14                DR. GLANTZ:  You took them out of the 

       15  literature, you didn't do anything to them?

       16                DR. SALMON:  We didn't do anything very 

       17  high-handed.  We attempted to make a synthesis.

       18                DR. GLANTZ:  Right.  But in particular, you 

       19  didn't wiggle these parameter values to get the 

       20  predictions?

       21                DR. SALMON:  No.

       22                DR. GLANTZ:  Okay.  Is the data in 11, 12 

       23  and 13, the light numbers -- 

       24                DR. SALMON:  Yes.

       25                DR. GLANTZ:  Were those values in any way 

                 BARNEY, UNGERMANN & ASSOCIATES  888 326-5900

        1  involved in developing the parameter values in table 10?  

        2  Or is that subsets of completely independent data?

        3                DR. SALMON:  Apart from the cases like the 

        4  GI absorption, where it's -- has to be used as a model 

        5  assumption, the parameters of the input and the prediction 

        6  numbers of the output, it isn't an iterative process.

        7                DR. GLANTZ:  Okay.  I don't mean to hammer 

        8  on this.  When you're talking about the GI values, you say 

        9  you assumed those.  Okay.  You didn't adjust those in 

       10  order to -- 

       11                DR. SALMON:  We had to figure out what was a 

       12  reasonable assumption.

       13                DR. GLANTZ:  Right.  But that's -- there's 

       14  two different ways you can do that.

       15                DR. SALMON:  Yes.

       16                DR. GLANTZ:  One way, you can sit down and 

       17  consult your Ouija board or whatever and come up with what 

       18  you think a reasonable value would be.  And then you take 

       19  all the reasonable values, plug them into the model and -- 

       20                DR. SALMON:  See what comes out, yes.

       21                DR. GLANTZ:  And then -- and you do that.  

       22  And you take your blindfold off, and you look at what the 

       23  data is.

       24                DR. SALMON:  Yes.

       25                DR. GLANTZ:  The other way, you can use the 

                 BARNEY, UNGERMANN & ASSOCIATES  888 326-5900

        1  data to help you estimate what values to use.  So would it 

        2  be a correct statement to say that you didn't do that?

        3                DR. SALMON:  We didn't do that.  We -- if we 

        4  found a mismatch between our model output and the 

        5  experimental data, what we would do is realize that we had 

        6  a problem and go back and look for better externally 

        7  estimated model parameters.  Not to mess with the values 

        8  of the physiological parameters in -- inside the model.

        9                DR. GLANTZ:  Well, but that -- that seems 

       10  inconsistent.  See, what I'm trying to get at is how, you 

       11  know -- if you came up with a set of values with a model 

       12  that was defined independently of the data that you've 

       13  shown in 11, 12 and 13, and you plug those numbers into 

       14  this a priori model, and a bunch of parameters that you 

       15  got a priori from the literature, and then you came within 

       16  a factor of two to independently observed data, that's 

       17  pretty good.

       18                DR. SALMON:  That's essentially what we're 

       19  doing.

       20                DR. GLANTZ:  Then you went on and said, if 

       21  the fit wasn't that good, then we went back and 

       22  reconsidered --

       23                DR. SALMON:  We basically, if we saw we had 

       24  a problem, we would have had to have done something about 

       25  it.  I'm not saying that this is quite -- I mean, this -- 

                 BARNEY, UNGERMANN & ASSOCIATES  888 326-5900

        1  as you know, this business of PBPK modeling is somewhat of 

        2  an arcane science.

        3                But we have -- we have consistently tried to 

        4  avoid the process which some modelers have used of 

        5  tweaking the parameters until they get a decent-looking 

        6  fit.  We've tried to use, at all times and whenever 

        7  possible, to use externally derived and validated 

        8  parameters.

        9                DR. GLANTZ:  But the part I'm still -- I'm 

       10  hanging up on, I don't mean to just hammer on this.  But I 

       11  mean, you either did adjust the parameters one way -- 

       12                DR. SALMON:  We didn't adjust them.  We 

       13  selected them.

       14                DR. GLANTZ:  Well, but that's -- that's the 

       15  same thing.  I mean, the thing that I'm concerned about 

       16  is, you've got a huge number of degrees of freedom here in 

       17  this model.  And -- and, you know, you don't have -- 

       18  you're basically trying to predict one number, which is 

       19  the C-max number.  And so I'm a little bit concerned 

       20  that -- that you can, by turning the knobs on the model -- 

       21                DR. SALMON:  Yeah.

       22                DR. GLANTZ:  -- you're going to be able to 

       23  get the fit, and then you're turning around and using -- 

       24  so the model parameters are essentially determined by 

       25  the data you --

                 BARNEY, UNGERMANN & ASSOCIATES  888 326-5900

        1                DR. SALMON:  No, that is not the case.

        2                DR. GLANTZ:  But you told me before, 

        3  though -- this is where you're giving me two different 

        4  answers.  One is you're saying, no, the model is taken a 

        5  priori.  The parameters are taken a priori, and we came 

        6  within a factor of two.  But then you're saying, if we 

        7  looked at it -- 

        8                DR. SALMON:  If it had been out with a 

        9  factor of 10, we would have had to gone back to the 

       10  drawing board and figured out why -- 

       11                DR. GLANTZ:  Did that happen?

       12                DR. SALMON:  No, it didn't.  Borgoff and Row 

       13  and Ginsberg both have previous reasonably successful 

       14  models.  We -- we basically used their prior work and 

       15  selected a combination of what they -- of their 

       16  conclusions, their model structure, and their parameters 

       17  to build what we felt was a good consensus model. 

       18                DR. GLANTZ:  And you did that before you 

       19  looked at the data in tables 11, 12 and 13?

       20                DR. SALMON:  Yes.  Then we would have 

       21  used -- then the process is to validate the model after 

       22  it's being created.

       23                DR. GLANTZ:  Okay.  So the data in 11, 12 

       24  and 13, there were no adjustments made.  Is this a true 

       25  statement?  That after you went through the process of 

                 BARNEY, UNGERMANN & ASSOCIATES  888 326-5900

        1  looking at these published models and coming up with what 

        2  you thought, in your best professional judgment, was the 

        3  right model to use with the right parameters.  So you did 

        4  that, and then you plugged it in, and you cranked out a 

        5  group of predictions.

        6                DR. SALMON:  Yeah.

        7                DR. GLANTZ:  And then after that was done 

        8  and those predictions were then chiseled in stone, and 

        9  those are the numbers in tables 11, 12 and 13; is that 

       10  true?

       11                DR. SALMON:  I believe it's -- 

       12                DR. GLANTZ:  And then after you did that, 

       13  then you went out and looked at the data that's bold 

       14  face -- 

       15                DR. SALMON:  Yes.

       16                DR. GLANTZ:  -- in 11, 12 and 13?  So the 

       17  numbers in 11, 12 and 13, the bold-faced numbers, played 

       18  no role whatsoever --

       19                DR. SALMON:  No, that's axiomatic.  They're 

       20  not input to the model.  That's axiomatic.

       21                DR. GLANTZ:  If that's the case, and now I 

       22  do understand.  I mean, I do understand how to read the 

       23  tables.

       24                DR. SALMON:  I have to say that, running 

       25  these models is a rather messy and approximate kind of a 

                 BARNEY, UNGERMANN & ASSOCIATES  888 326-5900

        1  business.  But one does one's best to make an 

        2  independent -- 

        3                DR. GLANTZ:  Now you're back to kind of 

        4  waffling.  I mean, I -- let me ask -- 

        5                DR. BLANC:  I think, if I could intervene, I 

        6  think your question has been asked and answered.

        7                DR. GLANTZ:  But I don't under the answer.  

        8  Well, tell me the answer, then.

        9                DR. BLANC:  The answer is, they satisfied 

       10  your requirements, and they did not go through an 

       11  intergroup process where they kept choosing a better model 

       12  based on the results that was given.

       13                DR. FUCALORO:  Better -- or tweaking of 

       14  parameters.

       15                DR. GLANTZ:  Is that a true statement?

       16                DR. SALMON:  Yeah.

       17                DR. GLANTZ:  Okay.  I'm happy.

       18                DR. BLANC:  Verging on asking the questions, 

       19  are you still beating your numbers?

       20                DR. GLANTZ:  Sort of.  Every time I thought 

       21  he said that -- 

       22                DR. FUCALORO:  One science.

       23                DR. GLANTZ:  If that's the case -- 

       24                DR. BLANC:  If he said it with a New York 

       25  accent, you would have accepted it the first time.

                 BARNEY, UNGERMANN & ASSOCIATES  888 326-5900

        1                DR. GLANTZ:  I'm not from New York.  Okay.  

        2  If that's the case; okay -- he is.  If that's the case, 

        3  then I'm satisfied with this.  I mean, because I think -- 

        4  I think to get -- to get from -- you know, if the model -- 

        5  to get an a priori model to get within a factor of two is, 

        6  in fact, pretty good.  And I think -- 

        7                DR. FUCALORO:  Almost unbelievable.

        8                DR. GLANTZ:   Well, not necessarily.  I 

        9  think -- and then I think that -- that the -- that going 

       10  from there to the oral -- the oral unit-risk number is 

       11  just pretty straight forward arithmetic at that point.  So 

       12  that to me was the nub of the issue.  So I am satisfied 

       13  with the numbers in the report, then. 

       14                DR. FUCALORO:  Thanks, Stan.  I didn't want 

       15  to seem like a weak chair, but I realized that you had to 

       16  go, so I'm going to give you every minute you wanted.

       17                DR. GLANTZ:  I'm going to have to leave in 

       18  about two minutes.  I think if the discussion, which looks 

       19  like it will go on after I'm -- after I have to leave, in 

       20  terms of the -- my level of expertise and input into this 

       21  process, I am now satisfied.  There may be some other 

       22  things that other people want to raise.

       23                DR. FUCALORO:  Well, Craig is ready.

       24                DR. GLANTZ:  Craig is ready.

       25                CHAIRMAN FROINES:  The important question 

                 BARNEY, UNGERMANN & ASSOCIATES  888 326-5900

        1  for you, though, because I think that within the context 

        2  of this room -- and not to take anything away from anybody 

        3  else -- you're the most familiar with the quantitative 

        4  issues.  And, so remember what I said at the beginning, if 

        5  you consider this, quote, "sound science," then that's -- 

        6                DR. GLANTZ:  Yeah.

        7                CHAIRMAN FROINES:  You need to leave us with 

        8  your views.

        9                DR. GLANTZ:  Yeah, I think it's fine. 

       10                DR. FUCALORO:  Thank you, Stan.  I 

       11  understand.  Craig, did you want to -- 

       12                DR. BYUS:  Yeah, let me go over a few 

       13  things.  I guess I had the most concerns the last time, 

       14  and I still have them.  Just -- and I have another one, 

       15  which I thought of in their intervening time.

       16                My main concern was over the animal 

       17  experiments, themselves.  Although one thing I have 

       18  concern over is the performing of the genetic modelling, 

       19  as well.  I was concerned, there's relatively small 

       20  numbers of animals in most of these studies.

       21                I did have some concern that they were done 

       22  at very high levels, some of them exceeding the maximum 

       23  tolerated dose, some of the studies.  Which overlays a lot 

       24  of toxicities on the interpretations of some of the 

       25  results, particularly the renal toxicity, which I'll get 

                 BARNEY, UNGERMANN & ASSOCIATES  888 326-5900

        1  to in a minute.

        2                Because the compound is a, apparently, quite 

        3  lethal toxic, no matter how it's administered, probably.  

        4  So small numbers of animals, the high doses, again, I know 

        5  that studies are done in high doses.  And I'm going to ask 

        6  you in a minute what was the actual dose extrapolation?  

        7  How many logs did you actually extrapolate down to 

        8  ambient?  Because it's kind of buried in all the 

        9  calculations.

       10                That also gives you some idea of how 

       11  confident you can be in the numbers.  There's the one 

       12  study that has the very sex-specific outcome.  I think it 

       13  was one the leukemias where only female mice got the 

       14  tumors.  And again, that's not totally uncommon.  But 

       15  there was some lack of consistency among the kinds of 

       16  tumors across the experiment.  Some consistency, but there 

       17  was also some inconsistency.

       18                The other thing from last time was my 

       19  concern about the dose-response data.  We discussed this 

       20  briefly.  Within an individual experiment I'm talking 

       21  about.  Within an individual tumor experiment, did you see 

       22  a dose response?  So as you increase the dose, did you see 

       23  more tumors?  And there is some dose-response data in 

       24  here.  But it is relatively minimal.

       25                And this is also overlaid on the fact that 

                 BARNEY, UNGERMANN & ASSOCIATES  888 326-5900

        1  the significances -- the degrees of significance were 

        2  calculated, as we went over last time, one-tailed, as 

        3  opposed to two-tailed.  We can discuss this.  But this is 

        4  a one-tailed analysis, not a two-tailed analysis -- 

        5  okay --  which affects how you want to interpret it.  It's 

        6  not said anywhere in here.  That -- you told me that.  Or 

        7  somebody told me that the last time.

        8                So I just -- just as an indication of 

        9  what --  I mean, about the lack of dose response, you say 

       10  on page 55 -- you disagreed with me about the statement, 

       11  so I'm going to read it to you.  And I think it's the next 

       12  to the last paragraph.  

       13                "Despite the reduced sensitivity of bioacid, 

       14         a statistically significant increase in             

       15         interstitial cell testicular tumors was observed in 

       16         mid and high-dose mammals with a clear dose         

       17         response evident."

       18                Table 8.  If you turn to table 8 and look at 

       19  the bottom, in the testes to the lytic cell, this is not 

       20  what I would call a clear indication of a dose response.  

       21  I mean, I just don't think the data states that.  Okay.  

       22  So that is the kind of concern I had.

       23                Now, the last concern I had, in addition to 

       24  the fact there's no human data and there's no clear 

       25  mechanism.  And again, it's -- you did a very nice job 

                 BARNEY, UNGERMANN & ASSOCIATES  888 326-5900

        1  trying to come through, figure out a mechanism, but there 

        2  really is no clear mechanism.

        3                But my last concern, which I didn't discuss 

        4  last time, has to do with the clearance.  If this is a 

        5  fairly renal-toxic compound -- and according to your 

        6  paper -- I mean, to this document, it's very renal 

        7  toxic -- all treated mammals, both female and male rats, 

        8  had a progressive, chronic nephropathy, all kinds of 

        9  changes in kidney function.  Mid, high dose, is where it 

       10  occurred.

       11                "Mineralization and interstitial fibrosis of 

       12  the kidney, which increases in mild to moderate" -- oh, 

       13  I'm sorry.  Sorry.  

       14                "Mineralization and interstitial fibrosis of 

       15         the kidney while increases in mild to moderate      

       16         glomerulosclerosis, interstitial fibrosis, and      

       17         tubular proteinosis were observed in females."

       18                So my last point is, if this is a really 

       19  renal-toxic compound, which it is, what is happening to 

       20  the pharmacokinetics in these long-term tumor experiments 

       21  at the high doses?  Since this compound is cleared 

       22  both the parent compound and the metabolites by the 

       23  kidney, what's probably happening, as you increase the 

       24  dose and as you give it over time is, the kidney's 

       25  becoming damaged.

                 BARNEY, UNGERMANN & ASSOCIATES  888 326-5900

        1                And so the metabolites might be building up 

        2  to very high levels.  The parent compound might be 

        3  building up to really high levels.  And so you probably 

        4  have a much higher real dose than your externally applied 

        5  dose.

        6                And your pharmacokinetic modelling doesn't 

        7  really take that into consideration.  It takes it into 

        8  consideration, I believe -- and correct me if I'm wrong --  

        9  just for an acutely administered dose, not the chronic, 

       10  two year or year and a half, whatever, where kidney damage 

       11  would be occurring.

       12                So again, I mean, I think the data is 

       13  there.  I do believe that it is a carcinogen that is 

       14  causing cancer in animals, clearly.  But all these 

       15  concerns, you know, I start thinking about a 

       16  threshold-type mechanism, et cetera.  So I mean, there -- 

       17  that's -- I'm done.

       18                DR. SALMON:  Okay.  I will comment on a 

       19  couple of these issues.  And I think I will then hand over 

       20  to my colleague, Dr. Sandy, to address some of the 

       21  others.  If I can take your last point first about 

       22  pharmacokinetic model, it's certainly true that the 

       23  pharmacokinetic experiments are single-dose based.

       24                So if there is accumulating damage, then the 

       25  pharmacokinetic model will fail to reflect that.  I'm not 

                 BARNEY, UNGERMANN & ASSOCIATES  888 326-5900

        1  sure that we can -- I mean, one of the problems, of 

        2  course, is that we're entering the realms of speculation 

        3  as to how substantial that effect might be.

        4                If the -- for the sake of argument, the 

        5  clearance of MTBE were to be reduced by a factor of 2 or 

        6  something like that, then obviously that would be seen as 

        7  fairly significant in terms of an impact on renal 

        8  function.  But I don't think that it would make an 

        9  enormous difference to the -- either the qualitative or 

       10  quantitative conclusions that we would be able to draw 

       11  from the data.

       12                If the impact on kidney function were much 

       13  more severe than that, then it's -- I would imagine that 

       14  you would be getting into the zone where the kidney damage 

       15  would be fatal, which may well have occurred with some of 

       16  the animals.  But of course, at that point, they cease to 

       17  play a part in the study anyway.  So they would not be 

       18  impacting the result.

       19                But I would -- basically what I am saying 

       20  is, I agree with you that this is an uncertainty in our 

       21  conclusion, and we have been at some pains to point out 

       22  that there are a number of considerable uncertainties in 

       23  the conclusion.

       24                But we've done our best to work through what 

       25  information we did have, and could interpret.  And 

                 BARNEY, UNGERMANN & ASSOCIATES  888 326-5900

        1  basically to follow -- follow our guidelines in 

        2  determining an appropriate and public-health-protective 

        3  level, in spite of the uncertainties.  I think that's all 

        4  I'm -- I'll say.

        5                DR. SANDY:  And I'll address a few points.  

        6  Animal bioacids, in general, that are conducted now, for 

        7  example, by the National Toxicology Program, which is 

        8  considered the gold standard for design, it's 50 animals 

        9  per group, per sex.  And that's what was used in the 

       10  inhalation studies for the rat and the mouse, and for the 

       11  Gavage studies, they used 60 animals per group, per sex.

       12                So I would not characterize those as small 

       13  numbers.  Those are -- those are the numbers that we work 

       14  with when we look at animal bioacid data, if we're lucky.  

       15  Small numbers is 20, and that's from historical studies.

       16                We do acknowledge that, in the 

       17  rat-inhalation studies, MTBE was renal toxic.  And, in 

       18  fact, the study pathologist, as well as -- I guess had a 

       19  second pathologist look at the slides, confirmed that MTBE 

       20  seemed to exacerbate the chronic, progressive nephropathy 

       21  seen in rats of both sexes.  So that is something that is 

       22  going on.  You're correct.

       23                There are a number of carcinogens -- kidney 

       24  carcinogens which are also nephrotoxic.  And that's just 

       25  something that we'll have to deal with.  As Andy said, 

                 BARNEY, UNGERMANN & ASSOCIATES  888 326-5900

        1  it's part of the uncertainty.  Let's see.  For the dose 

        2  response, we do see a dose response in the combined 

        3  incidence of lymphomas and leukemias of lymphoid origins 

        4  in the female Dawley rats used in the Gavage study.

        5                The incidence that was reported in the 1998 

        6  pathology review by Belpoggi was 3.4 percent in the 

        7  controls, 13.7 percent in the low dose, and 25.5 percent 

        8  in the high dose.  Now, only the high dose was 

        9  statistically significant.  And we did not do a trend 

       10  test, because this data -- the authors of the paper, they 

       11  did not analyze it using a Fisher exact test.  They 

       12  analyzed it using a log rank test.

       13                DR. FUCALORO:  Using what?

       14                DR. SANDY:  A log rank test.  And that 

       15  entails having time-to-tumor information, which we could 

       16  not obtain, so we could not replicate that analysis.  We 

       17  just took the data and did a Fisher exact test, which is 

       18  one-tailed.  And that is, again, a -- the accepted, common 

       19  way of analyzing animal bioacidic data.

       20                DR. BYUS:  We just repeated this the last 

       21  time.

       22                DR. SANDY:  Well, so -- 

       23                DR. BYUS:  That's okay.  But in any case, 

       24  you should indicate one-tailed versus two-tailed.  It 

       25  should be stated what statistical test you're using, 

                 BARNEY, UNGERMANN & ASSOCIATES  888 326-5900

        1  clearly.

        2                DR. SANDY:  Again, just like to emphasize, 

        3  the data was analyzed by the study authors by another 

        4  method.  And it was also significant, the incidence of the 

        5  high dose.

        6                DR. BYUS:  The incidence of high dose or the 

        7  dose-response relationship?

        8                DR. SANDY:  The incidence of high dose.  In 

        9  the -- the male Fischer rat -- that's the inhalation 

       10  study -- the -- that's table 8.  The tumor incidence for 

       11  testicular tumors, 64 percent of control, 70 at the 

       12  400-parts-per-million dose, 82 at the 300 -- sorry -- 

       13  3,000-parts-per-million dose, and 94 percent of the 

       14  8,000-parts-per-million dose.  I believe that's a dose 

       15  response.

       16                Again, this study had early mortality in the 

       17  mid and high-dose groups.  So you're seeing -- you're 

       18  still seeing a dose response, even those these animals are 

       19  dying sooner. 

       20                DR. BYUS:  I know I would never call that a 

       21  clear evidence of a dose-response effect.  I mean, I would 

       22  say that is very weak evidence if -- at the best.  I 

       23  wouldn't call this a clear-dose response.

       24                DR. MARTY:  Craig, is your concern that high 

       25  incidence in the controls -- is that part of the issue?

                 BARNEY, UNGERMANN & ASSOCIATES  888 326-5900

        1                DR. BYUS:  That is part of it, sure.  Of 

        2  course.  Plus, if you factor all of this in, the 

        3  variability of the control incidence and the cross 

        4  studies, the very incidence of it, which as I said last 

        5  time is -- what you're probably doing is simply affecting 

        6  time-to-tumor, rather than actually affecting the overall 

        7  incidence.

        8                And I don't want to argue -- you know what I 

        9  mean -- about that.  What that means -- what the 

       10  significance is.  But I would not call this a clear 

       11  evidence of a dose response -- tumor-incidence dose 

       12  response.

       13                The reason it's important, of course, is 

       14  whether or not there's a threshold.  I mean, that's the 

       15  point.  That's why seeing a clear evidence of a dose 

       16  response is important, in a sense.  You see what I'm 

       17  saying?  Clear evidence. 

       18                DR. MARTY:  I think it's -- we should point 

       19  out that at the mid and high dose, those were both 

       20  significantly different than control.  So it may -- maybe 

       21  is a semantic issue versus a clear --

       22                DR. BYUS:  I teach pharmacology to the 

       23  medical students.  I also do tumor studies where we try 

       24  and establish a clear dose response.  And that is 

       25  different.  Yes, they may be different than control.  But 

                 BARNEY, UNGERMANN & ASSOCIATES  888 326-5900

        1  it is not indication of a clear dose response, I mean, in 

        2  my opinion.

        3                DR. BLANC:  Well, perhaps what you're trying 

        4  to say, there's a difference in a qualitative statement 

        5  saying that the data can be interpreted as showing a dose 

        6  response, versus the implication that there is statistical 

        7  relationship between the group suggesting a step up, in 

        8  effect, or consistent with it.

        9                And so it sounds, if I see -- hearing the 

       10  difference in the two points of view, you, from a 

       11  qualitative point of view, felt the data consistent with 

       12  the dose response.  But there isn't a statistical test 

       13  that you can state you performed that's consistent.  In 

       14  the one case, said you couldn't do a test of a trend 

       15  because of the way the data was presented.  And in the 

       16  latter case, was there indeed a test for trend?

       17                DR. SANDY:  I think we can and probably 

       18  should have done a trend test.  I would -- 

       19                DR. BLANC:  Because I think -- 

       20                DR. SANDY:  -- hazard to guess it would be 

       21  significant.

       22                DR. BLANC:  Well then, I would suggest you 

       23  do that.  And I think that that -- and then rather than 

       24  get hung up on, you know, one man's meat is another man's 

       25  poison, you simply say that it was a statistical 

                 BARNEY, UNGERMANN & ASSOCIATES  888 326-5900

        1  relationship that was consistent with the trend.

        2                DR. SALMON:  One of the other things is that 

        3  I think, for the purposes of our risk assessment, which 

        4  is, you know, essentially what we're looking at here, we 

        5  were concerned to follow the letter, both of our 

        6  assessment guidelines, and also the Health and Safety Code 

        7  applicable to the TAC program.

        8                And I quote, "Where it can be established 

        9  that a threshold of adverse health effects exist, the 

       10  estimate shall include a appropriate factor."  Our risk 

       11  assessment assumptions would only consider a threshold 

       12  analysis if there was solid evidence for a threshold.

       13                DR. BLANC:  Which there isn't?

       14                DR. SALMON:  Which, I think, regardless of 

       15  which side of the fence you come down on -- I'm sensitive 

       16  to the fact there's a debate here, obviously.  The point 

       17  is, either way you think about that debate, I don't think 

       18  you could argue that there is any substantial evidence for 

       19  a threshold.  Or at least, that was the interpretation 

       20  which we made when we undertook the risk assessment.

       21                DR. BYUS:  It's mainly -- it's mainly the 

       22  language.  It seems -- in my opinion, it seems to be 

       23  overstated in the document.  That's all I'm getting at.

       24                DR. SANDY:  Okay.

       25                DR. BYUS:  I don't disagree with the 

                 BARNEY, UNGERMANN & ASSOCIATES  888 326-5900

        1  conclusion that this is a carcinogen or causes cancer in 

        2  animals, clearly.  I'm just disagreeing with some of the 

        3  language, in my opinion, tends to be overstating the 

        4  animal data.

        5                DR. FUCALORO:  I do want to point out, the 

        6  issue is not whether -- the only issue is not whether it 

        7  is carcinogen -- whether it's carcinogen or not.  What I 

        8  think we are charged to do is to come up with a potency 

        9  factor.  And I think that -- and your comments really 

       10  address that issue.  And I think that's something --  

       11  something we need to discuss.  I don't believe they 

       12  answered your first question regarding how high these 

       13  doses were.

       14                DR. BYUS:  The extrapolation.  How many 

       15  orders of magnitude did you extrapolate?

       16                DR. FUCALORO:  I think you used the words 

       17  "logs."  Orders of magnitude; right?

       18                DR. BYUS:  What is the extrapolation here?

       19                DR. SALMON:  We don't actually make an -- 

       20  such an extrapolation in the document.  Because, of 

       21  course, we're not saying that, you know, there is a 

       22  specific exposure level to MTBE out there, which we're 

       23  trying -- which we're evaluating at this point.

       24                However, I think it would be fair to say 

       25  that, taking the typical ambient levels of MTBE which are 

                 BARNEY, UNGERMANN & ASSOCIATES  888 326-5900

        1  out there at the moment, it's something around 4 or 5 

        2  orders of magnitude, which is not untypical for the sort 

        3  of extrapolation -- 

        4                DR. FUCALORO:  So 4 or 5 orders of magnitude 

        5  greater than what is -- 

        6                DR. SALMON:  Than what is ambient, yes.

        7                DR. FUCALORO:  10 to a 100,000 times more?

        8                DR. SALMON:  I believe that's correct.

        9                DR. BYUS:  We have put that in documents 

       10  before.  First document I ever did, which I can't even 

       11  remember what the chemical is now.  We did, in fact, say 

       12  that we extrapolated 5 orders of magnitude.  It's just 

       13  something that, you know, especially -- again -- 

       14                DR. MARTY:  I think we can add that.  We can 

       15  add that to our attachment, based on the information we 

       16  get from ARB regarding concentration of air.

       17                DR. BYUS:  I know.  And I understand what 

       18  you've done.  And I understand the quantitative risk 

       19  assessment, and what you're trying to do.  But, I mean, in 

       20  a sense, we're talking about mechanism.  In a way 

       21  there's -- you're trying to interpret -- trying to put 

       22  some substance on some kind of mechanism and validity.  

       23  And really the further -- I mean, it troubles me that 

       24  we're extrapolating 5 orders of magnitude for this number.

       25                DR. MARTY:  I would agree.

                 BARNEY, UNGERMANN & ASSOCIATES  888 326-5900

        1                DR. BYUS:  It always troubles me when we 

        2  extrapolate 5 orders of magnitude or 4.  Much better if it 

        3  was one order.

        4                DR. MARTY:  Yes, I don't think we would 

        5  disagree with that at all.

        6                DR. BYUS:  No one would disagree with that, 

        7  I hope.

        8                DR. SALMON:  It's just we don't have the 

        9  means to do anything else.

       10                DR. BYUS:  I know.  I'm not saying you 

       11  should have the means.  It's part of the, in a sense, the 

       12  language here.

       13                DR. SALMON:  Characterizes the uncertainty.

       14                DR. BYUS:  Characterizing the uncertain, 

       15  exactly.

       16                DR. BLANC:  You know, I have a solution to 

       17  this.  Because, if I understand what we're being asked to 

       18  do, we're being asked to make our finding, in light of 

       19  their document -- which once again, I think would be some 

       20  kind of written memorandum, not of great -- or are we just 

       21  being asked to make sentence -- 

       22                CHAIRMAN FROINES:  We're being asked to vote 

       23  on whether what they've done is sound science, period. 

       24  There will be no finding on this.

       25                DR. BLANC:  There's no finding?  Are we 

                 BARNEY, UNGERMANN & ASSOCIATES  888 326-5900

        1  asking -- and the attachment of health effects of exposure 

        2  to methyl tertiary butyl ether, is that the only thing 

        3  we're commenting on or commenting on the entire document?  

        4  How does this relate to the entire document?  As an 

        5  addendum to it? 

        6                DR. MARTY:  Can I -- 

        7                CHAIRMAN FROINES:  We're voting on that 

        8  document.

        9                DR. BLANC:  Not on this.  What is this?

       10                DR. MARTY:  Can I drop in here maybe a 

       11  little bit?  When we were asked to come up with the unit 

       12  risk factor by inhalation exposures by the Air Resources 

       13  Board, we had just completed a document to our public -- 

       14  our Public Health Goal Drinking Water Program.

       15                So we took that document and used the 

       16  information in there, and had to do some more calculations 

       17  to get to the dose via inhalation -- target dose via 

       18  inhalation, and then back to a unit risk factor for use 

       19  with concentrations in air.  That little end piece of it 

       20  is what is attached to the attachment.  In terms of 

       21  commenting on the PHG document, you know, you guys needed 

       22  to see that because -- 

       23                DR. FUCALORO:  This document?

       24                DR. MARTY:  Right.

       25                DR. FUCALORO:  This is the document where we 

                 BARNEY, UNGERMANN & ASSOCIATES  888 326-5900

        1  have to render judgment on whether or not -- 

        2                DR. MARTY:  And you need the bigger document 

        3  in order to understand what we've done in the little 

        4  document.

        5                DR. BLANC:  So this is actually what we're 

        6  commenting on?

        7                DR. MARTY:  Right.

        8                DR. SALMON:  We don't have a mandate to 

        9  modify the PHG document at this point.

       10                DR. MARTY:  Right.  We can't modify this 

       11  document.  But we can address your concerns by putting 

       12  information into that appendix.

       13                DR. BLANC:  But wouldn't that delay the 

       14  whole process?  You have to come back to us again.

       15                DR. FUCALORO:  That was -- I was going to --  

       16  do you need to come back to us again or is it possible for 

       17  to us vote now?  I'm not clear -- I'm not clear on that.  

       18  Craig brought up a lot of -- many points, and there was 

       19  some disagreement and some agreement, I think, on the 

       20  points he brought up.  What do you -- what do you suggest 

       21  at this point?

       22                DR. MARTY:  Well, I would suggest that we 

       23  modify the little document to address the uncertainty 

       24  issue, which is what Craig was getting at.  And then -- 

       25                DR. BYUS:  That's clearly all I'm getting at 

                 BARNEY, UNGERMANN & ASSOCIATES  888 326-5900

        1  is clearer explanation on the uncertainties, not on the 

        2  overall process.  Because you did a very good job.  It's 

        3  just at the level of the uncertainties.

        4                DR. BLANC:  I would say its fine if you do 

        5  that.  I would also say, if I understand the charge to us, 

        6  if the charge to us is to comment on whether what you did 

        7  is consistent with standard and acceptable scientific 

        8  process, then I think, it's about as easy as saying that 

        9  diesel exhaust is toxic air contaminant.

       10                Which is -- that's kind of a no-brainer.  Of 

       11  course it's a toxic air contaminant.  And, you know, yeah, 

       12  you dealt with the uncertainties that we deal with every 

       13  single time you have to do on these exercises.  But what 

       14  you did is what is standardly done.

       15                I really think that the discussion is -- 

       16  because it's so applicable to every single one of these 

       17  cancer-potency things we have to deal with.  But on the 

       18  other hand, I don't think it would, in any way, make me 

       19  say that this wasn't consistent with standard practice.  

       20  All the more so.  So I would certainly feel comfortable 

       21  just calling the question.

       22                DR. FUCALORO:  Well, I think -- jumping 

       23  ahead.  I think, though, I'd like -- I think give everyone 

       24  an opportunity to comment, because we certainly asked Stan 

       25  to comment, and Craig.  And there may be no other 

                 BARNEY, UNGERMANN & ASSOCIATES  888 326-5900

        1  comments.  I mean, I frankly -- I think Craig and Stan -- 

        2  I made my comments, I feel.  Roger?

        3                DR. ATKINSON:  I have no comments.

        4                DR. FUCALORO:  John, did you want to say 

        5  something on this?  Yes, he did.  But he won't.

        6                CHAIRMAN FROINES:  Maybe I'll let it go.  I 

        7  think that the -- I think Craig's comments are very useful 

        8  and valuable.  I think that we have to keep fighting the 

        9  tendency on, where does the burden lie on these things.

       10                And that is, it is not -- the burden is not 

       11  up to the state to demonstrate mechanistically the 

       12  relevance of animal-cancer data to humans.  I take that as 

       13  not being the burden of the state.  I take it as the 

       14  burden of the critics to demonstrate the irrelevance of 

       15  the animal data. 

       16                DR. BYUS:  That's right.  Very good.

       17                CHAIRMAN FROINES:  And there are enormous 

       18  difficulties with MTBE.  There's no question, whatsoever, 

       19  that there are scientific difficulties.  But the 

       20  conclusion that we came to was that we found no evidence 

       21  to demonstrate the irrelevance of lytic cell tumors or 

       22  liver tumors, what have you, even though we didn't like 

       23  lots of stuff about that science.

       24                But it's this notion of who has the burden, 

       25  that I think is really quite important.  The other problem 

                 BARNEY, UNGERMANN & ASSOCIATES  888 326-5900

        1  is, the two inhalation studies were done by industry.  And 

        2  they have the most problems, in many ways, in my view.  

        3  They're the ones with real toxicity problems, so on and so 

        4  forth.

        5                And we find ourself in this very strange 

        6  position of having industry studies, which we criticize.  

        7  And if we don't then accept the positive findings, we, in 

        8  a sense, are rewarding the people who did the bad 

        9  studies.  So that's really contradictory in terms of the 

       10  way we have to look at it, it seems to me.

       11                And the other thing is, that if this was an 

       12  abstract question, we really could debate it.  But it's 

       13  not, because we have 15 percent of the stuff in all our 

       14  gasoline.  So actually we're breathing it as we speak.

       15                So I frankly -- frankly, as far as I'm 

       16  concerned, this is not a quantitative issue.  It's a 

       17  qualitative issue.  I would rather not have this in my 

       18  gasoline, as a qualitative matter.  So I agree that you 

       19  want to do reasons that I don't even understand the 

       20  quantitative risk assessment.  That -- seems to me, that's 

       21  not even the issue here.

       22                The issue is, the government should never 

       23  have pushed this.  We shouldn't be in this position in 

       24  1999 arguing over an EPA decision from 1992.  And this is 

       25  a bad -- was a flawed policy decision to begin with.  It's 

                 BARNEY, UNGERMANN & ASSOCIATES  888 326-5900

        1  still a flawed policy decision.  And I think there's light 

        2  at the end of the tunnel, so we should proceed with it.  

        3  So it becomes, for me, at some level, sort of a 

        4  no-brainer -- 

        5                DR. FUCALORO:  All right.  Paul, did you 

        6  want to comment further?  How about you, Hanspeter?  Then 

        7  I would ask the panel.  This is the pleasure of the panel 

        8  to make a motion that I will suggest in a moment, to 

        9  essentially have closure on this issue.

       10                Is there anyone who objects to that?  If 

       11  not, let me make a suggestion at a motion.  I won't 

       12  move it.  I'll allow someone else to, because I have the 

       13  language here.   

       14                "That the -- this panel finds that this      

       15         document titled, 'Attachment 1, Health Effects of   

       16         Exposures to Methyl Tertiary Butyl Ether, MTBE' be  

       17         found to have sound -- be based upon sound,         

       18         scientific knowledge, methods, and practices."

       19                And the record shows that John Froines is 

       20  still with us.  I need to say that parenthetically for 

       21  matters of quorum.  And that we -- that's finding one.  

       22  And finding two, that we recognize that OEHHA may wish to 

       23  expand upon the document at a future time for purposes of 

       24  clarity; okay, and to introduce more pertinent information 

       25  for the purpose of clarity.

                 BARNEY, UNGERMANN & ASSOCIATES  888 326-5900

        1                Let me stop it there.  That's a motion I 

        2  suggest.  If anyone thinks that's a good motion, I will 

        3  entertain that motion from the floor.

        4                DR. BYUS:  I so move.

        5                DR. FUCALORO:  Is there a second to that?

        6                DR. BLANC:  Second.

        7                DR. FUCALORO:  Is there any further 

        8  discussion on that?  Hearing none, I will take the vote.  

        9  All in favor please indicate by saying aye.  

       10                MEMBERS OF THE PANEL:  Aye.  

       11                DR. FUCALORO:  Opposed?  Anyone wishing to 

       12  be recorded as abstaining?   The motion carries 

       13  unanimously.  With that, I leave, and turn back orders to  

       14  Dr. John Froines.

       15                CHAIRMAN FROINES:  You know, the tragedy of 

       16  this thing is, the -- 

       17                DR. BLANC:  John, I suggest we let our 

       18  stenographer take a break.

       19                CHAIRMAN FROINES:  Let's take a ten-minute 

       20  break. 

       21                       (Brief recess taken.)

       22                CHAIRMAN FROINES:  Okay.  MITC.  We are back 

       23  in business.  And then, Melanie, we're going to get to the 

       24  REL.  We're going to finish.  It will go fast, I think.  

       25  No, no.  They may not.  I don't want to -- I realized 

                 BARNEY, UNGERMANN & ASSOCIATES  888 326-5900

        1  who's doing them.

        2                DR. FUCALORO:  Don't forget it.

        3                CHAIRMAN FROINES:  Forget I said anything 

        4  about it.

        5                DR. BYUS:  He knows too much.  He knows too 

        6  many things.

        7                DR. FUCALORO:  You know too much.

        8                CHAIRMAN FROINES:  Andrew, please go ahead.

        9                DR. RUBIN:  Are we looking at a finishing at 

       10  3:00 o'clock?

       11                CHAIRMAN FROINES:  No, go ahead.  We don't 

       12  have any -- 

       13                DR. RUBIN:  Okay.

       14                CHAIRMAN FROINES:  We'll all try and push 

       15  this panel along.  You work at your pace.

       16                DR. RUBIN:  All right.  First -- first 

       17  slide.  Let me just start, before the first slide, which 

       18  is -- has my name on it, basically.  My name is        

       19  Andy Rubin.  I'm the staff toxicologist at DPR responsible 

       20  for the risk assessment on MITC.

       21                In opening up the subject of the assessment 

       22  of MIT's health effects, I really wanted to be clear from 

       23  the outset that there are some very interesting problems 

       24  in determining the critical end-point values.  These 

       25  relate to the significance of the actual end points.

                 BARNEY, UNGERMANN & ASSOCIATES  888 326-5900

        1                That is, the toxicological effects that were 

        2  observed, the quality of the studies used, the 

        3  availability of the sufficient number of studies, and the 

        4  issue of assigning a subchronic NOEL value that is higher 

        5  than a -- an acute NOEL value.  Which goes against sort of 

        6  standard toxicologic dictum.

        7                And I'd like to ask for and recommend that 

        8  the panel, as you read the document, consider these issues 

        9  that I bring up as we get to them, and as you read the 

       10  document and critique the document.  We're not to the 

       11  slides yet. 

       12                MS. WALES:  Technical problems. 

       13                DR. RUBIN:  The slides are so amazing that 

       14  they've broken the overhead projector. 

       15                DR. FUCALORO:  Is it on? 

       16                DR. BYUS:  It just started.

       17                DR. FUCALORO:  Let the record show it was my 

       18  finger that -- dumb luck.

       19                MS. WALES:  It's on.

       20                DR. FUCALORO:  We'll be impressed with this 

       21  high technology.

       22                DR. RUBIN:  I could hold it up, but I don't 

       23  think you can see it.  You actually have copies of it.

       24                DR. FUCALORO:  We actually all have the 

       25  copies of it.

                 BARNEY, UNGERMANN & ASSOCIATES  888 326-5900

        1                DR. RUBIN:  There we go.  There's 

        2  something -- yeah.  Okay.  This is an overview of the 

        3  subjects I'd like to cover.  First, the Cantara Loop 

        4  spill, which I'll explain in a minute.  Little bit about 

        5  the pharmacokinetics of MITC in mammalian systems.

        6                Then on to the acute toxicity, subchronic 

        7  toxicity, chronic toxicity, oncogenicity, and the famous 

        8  DPR margin of exposure calculations, reference exposure 

        9  level concentrations, and the possibility of toxicity due 

       10  to other Metam-Sodium breakdown products.  In particular, 

       11  methyl isocyanate and hydrogen sulfide.

       12                Next.  Any consideration of the potential 

       13  human health impacts of MITC must or should begin with the 

       14  realization that we actually have some real-world human 

       15  toxicity data out there, courtesy of the Southern Pacific 

       16  Railroad.

       17                Back on July 14th, 1991, a train -- a 

       18  mile-long train heading north near -- about six miles 

       19  north of the town of Dunsmuir couldn't quite make it up a 

       20  grade.  Some of the cars skipped the track, and a tanker 

       21  car containing 19,500 gallons of 32.5 percent Metam-Sodium 

       22  went into the river.

       23                 In the hour or two after -- within the hour 

       24  or two -- within the next few hours after that accident 

       25  occurred, it was felt that there was only a breach above 

                 BARNEY, UNGERMANN & ASSOCIATES  888 326-5900

        1  the water line that was soon dispelled -- to dispell 

        2  within 12 hours when it was learned that all 19,500 

        3  gallons had gone into the river.

        4                And this map just -- this, by the way, much 

        5  of the data -- very creditable data comes from OEHHA and 

        6  DHS's assessment of the health effects of this spill.  And 

        7  this map simply shows -- you probably can't seen see it 

        8  too well.  But basically the Sacramento River with the 

        9  railroad running next to it.

       10                And right up at the top there -- do I point 

       11  this or -- okay.  There it is -- is the Cantara Loop, 

       12  which is a -- which is a loop that goes up a grade.  

       13  There's a bridge over the river here.  And that's where 

       14  the spill occurred.  This occurred at 9:39 at night.  By 

       15  9:15 the next morning, the plume of Metam-Sodium -- the 

       16  big green plume had run by the town of Dunsmuir where the 

       17  major exposures occurred.

       18                That's probably the major population center 

       19  near the spill.  Population of about 3,000 people.  Had 

       20  run down and had reached Castle Crags.  Basically by 

       21  the -- by the morning of the 17th, three days later -- two 

       22  and a half days later, say, the plume was emptying into 

       23  Shasta Lake.

       24                The primary human exposures, as I've -- as I 

       25  said, probably occurred in the town of Dunsmuir.  Now, 

                 BARNEY, UNGERMANN & ASSOCIATES  888 326-5900

        1  the -- from a toxicological standpoint, we're very 

        2  interested in what the levels of -- of exposure to MITC 

        3  were in the town of Dunsmuir near the river so that we can 

        4  gauge what kind of levels caused what kinds of effects.

        5                Unfortunately, it wasn't until three days 

        6  after the spill that good, reliable monitoring was in 

        7  place.  Consequently, in the modelling that -- 

        8  consequently, the levels of Metam-Sodium had to be 

        9  estimated based on environmental-fate and transport 

       10  modelling.

       11                Actually, there were a couple of models that 

       12  were used to estimate the air concentrations of MITC 

       13  around Dunsmuir after the spill -- after the spill.  One 

       14  was an environmental-fate and transport model that took 

       15  into account the evaporation rate, the amount of sunlight, 

       16  the wind, the meteorologic conditions and so forth, as 

       17  well as the known physical, chemical properties of Metam 

       18  in water and how it breaks down to MITC, and how fast MITC 

       19  will go from a water phase into a gas phase, and so forth.

       20                Another model relied on measured 

       21  concentrations, concentrations that were measured three 

       22  days later in the river, and compared them to measured 

       23  concentrations in the air.  Basically, a ratio was set 

       24  up.  So there were two -- there were at least these two 

       25  different models, and some variations in between.

                 BARNEY, UNGERMANN & ASSOCIATES  888 326-5900

        1                The only reason I mention this, is that 

        2  there are some estimates of the levels of MITC in the 

        3  Dunsmuir area soon after the spill.  Within -- but please 

        4  recognize that these are only estimates.  These are not 

        5  measured values.  Actually, there are one or two people in 

        6  the room who actually did these studies, and I want to 

        7  recognize that they are here.

        8                In the 4 to 12 hours after the spill, the 

        9  maximum estimates, based on the model and the assumptions 

       10  used, ranged from a hundred and forty to 1600 ppb.  

       11  Between hours 12 -- and these are -- these are levels that 

       12  were at the river.  At hours 12 to 24, we're dealing with 

       13  88 to 200 ppb.  And at 24 to 48 hours, we were dealing 

       14  with 15 to 88 ppb.

       15                These are very important considerations 

       16  in -- in this risk assessment, because we have to consider 

       17  not only -- we have to consider the whole spectrum of 

       18  toxic effects that occurred there.  When we're looking at 

       19  a laboratory assay that may only be measuring one toxic 

       20  effect.

       21                In other words, as you'll see on the next 

       22  slide -- I don't know if I made clear, but the next slide 

       23  shows that there are -- there was a whole plethora of 

       24  toxic effects that were detected, mostly in the town of 

       25  Dunsmuir following the spill.  And this is all from 

                 BARNEY, UNGERMANN & ASSOCIATES  888 326-5900

        1  OEHHA's publications on the issue on the spill.

        2                There were 848 spill-related hospital visits 

        3  from 705 separate individuals in the month following the 

        4  spill.  These are the effects that people were reporting.  

        5  Headache in 64 percent of those visits.  Eye irritation in 

        6  49 percent.  Throat irritation in 42 percent.  Nausea, 46.  

        7  Dizziness, shortness of breath, diarrhea, nasal 

        8  irritation, and chest tightness.  These were the -- I only 

        9  listed on this table the most commonly expressed toxic 

       10  effects.

       11                There were seven hospitalizations, four 

       12  people with respiratory problems.  Two with fainting 

       13  problems.  One person with disorientation and irregular 

       14  heartbeat.  And according to the paper -- one of the 

       15  papers, that person may have received an excessively high 

       16  dose.  None of these are known for sure, though.

       17                There were eight -- we know about eight 

       18  exposed pregnant women.  Two of them were exposed during 

       19  the first trimester, and they opted for abortion.  

       20  Particularly sad outcome to this accident.  Four exposed 

       21  during the second trimester were advised that their 

       22  pregnancies were progressing normally.  I assume that that 

       23  probably came from their doctors. 

       24                DR. FUCALORO:  Follow up -- was there follow 

       25  up on that?

                 BARNEY, UNGERMANN & ASSOCIATES  888 326-5900

        1                DR. RUBIN:  I believe that's the extent of 

        2  the follow up, at least in the published literature.  

        3  There was some evidence for the initiation of or 

        4  exacerbation of asthma over the longer term.  And this is 

        5  a syndrome that was recognized in 1985 associated with 

        6  exposures to other isocyanates.  Syndrome known as RADS or 

        7  Reactive Airways Disfunction Syndrome.

        8                There were, I believe, oh -- there were 

        9  30 -- 30 of 197 adults referred to health practitioners 

       10  for spill-related reasons, were considered positive for 

       11  RADS.

       12                DR. BLANC:  Can you tell me where, for 

       13  example, in the document -- in the draft document those 

       14  data -- 

       15                DR. RUBIN:  Yeah.

       16                DR. BLANC:  Because it's not in the acute 

       17  toxicity piece.

       18                DR. RUBIN:  Right.  It's before it.  The 

       19  acute toxicity deals with the laboratory studies.

       20                DR. BLANC:  It also talks about the Plutara 

       21  incident.  That's why I was confused.

       22                DR. RUBIN:  Maybe I've got things mixed up.  

       23  Page 16, 17 and 18 is the discussion of the Cantara spill.

       24                DR. BLANC:  Okay.  Great.

       25                DR. RUBIN:  So RADS is a syndrome that is a 

                 BARNEY, UNGERMANN & ASSOCIATES  888 326-5900

        1  little more disturbing, because it implies that there may 

        2  be longer term effects from acute exposures.  RADS -- the 

        3  criteria for RADS include onsets of symptoms within 24 

        4  hours of a single exposure, persistence of such 

        5  symptoms -- and by "symptoms," I'm talking about 

        6  asthmatic-types of symptoms, dyspnea, wheezing, air-flow 

        7  obstruction that may be measured in standard spirometry 

        8  assays in a lung-function lab.

        9                And the possibility that there's 

       10  sensitization later on.  In other words, that a person 

       11  who's experiencing this -- this syndrome, may have an 

       12  exacerbation of the syndrome on subsequent exposures to 

       13  much smaller amounts.  I think this is really important.  

       14  But it's not well-characterized in this particular 

       15  incident.  But it is, at least, a possibility.

       16                We know of at least 30 people, however, that 

       17  were positive for this syndrome after the Cantara spill.  

       18  One more issue, and this took a little bit of digging on 

       19  my part.  There were three railroad workers that were 

       20  dispatched into the spill area within a few hours of the 

       21  spill by their employers -- by Southern Pacific.

       22                They came in to pull the -- the salvagable 

       23  part of the train out of there.  And they went in there, 

       24  and they were -- well, let me start this by saying, this 

       25  does not appear in the scientific literature or in the 

                 BARNEY, UNGERMANN & ASSOCIATES  888 326-5900

        1  medical literature.  It appears in a 1997 article in the 

        2  Sacramento Bee.  I did some calling around to some people 

        3  at OEHHA.  And one psychologist that had worked on some of 

        4  the -- 

        5                DR. BLANC:  I hope it wasn't            

        6  Rosemary Bowler.

        7                DR. RUBIN:  It was.  I called her.  She had 

        8  no information about this.  It was simply a Bee article on 

        9  the three guys running a locomotive in there to try and 

       10  pull out this mile-long train, salvage what they could of 

       11  it.

       12                And while this is not something that I would 

       13  perhaps base an entire risk assessment on, a newspaper 

       14  article, I wanted to recognize that there were three -- 

       15  three workers that claim, six years after the spill, to 

       16  have experienced quite a number of symptoms.  Permanent 

       17  neuropsychological damage, RADS, irregular heartbeat, low 

       18  blood oxygen, coughing, depression, coughing fits, 

       19  back-to-back colds, loss of drive, peeling away of mucous 

       20  membranes in the mouth.

       21                I'm not sure how to -- how to assess that 

       22  kind of thing.  But I think it should be brought to the 

       23  attention of the panel, and it's in this document 

       24  referenced, the Sacramento Bee, 1997.  So -- 

       25                DR. BLANC:  Well, I think -- I think what 

                 BARNEY, UNGERMANN & ASSOCIATES  888 326-5900

        1  you'll hear from the panel, is that section should be 

        2  excluded.  And the -- in fact, the most salient and 

        3  documentable issues of the respiratory complaints, at 

        4  least one, and perhaps all three of those people were 

        5  included in the paper by Cohn, et al.  And so you've 

        6  already included the respiratory findings.

        7                DR. RUBIN:  Yeah.

        8                DR. BLANC:  And I would probably also say 

        9  that, I don't disagree with you that the issue of Reactive 

       10  Airways Disfunction Syndrome and irritant-induced asthma 

       11  is an important end point in acute -- 

       12                DR. RUBIN:  Assessment.

       13                DR. BLANC:  -- acute exposure.  And 

       14  acute-exposure outcome, that's important, and very 

       15  well-documented from the Plutara spill.  But I don't think 

       16  you need to include, you know, newspaper account where it 

       17  gets into some of these other very nebulous and probably 

       18  unsupportable issues of subjective, neurological -- 

       19                DR. RUBIN:  Agree.

       20                CHAIRMAN FROINES:  We need to remember that 

       21  this is the day in which we're having a staff 

       22  presentation, and then we're going to have a full panel 

       23  discussion later.  So I -- I'd like to give him -- the 

       24  time is moving on -- to try and move ahead with the 

       25  presentation and not -- 

                 BARNEY, UNGERMANN & ASSOCIATES  888 326-5900

        1                DR. BLANC:  Get into the details.

        2                CHAIRMAN FROINES:  Doesn't preclude 

        3  discussion, but it -- 

        4                DR. RUBIN:  Okay.  Well, let's move on from 

        5  the -- from the Cantara incident to what we know from 

        6  laboratory investigation of MITC's toxic end points.  

        7  First of all, as far as pharmacokinetics are concerned, 

        8  all we have is oral-exposure pharmacokinetics.  That is, 

        9  exposure of rats to label MITC via the oral route.

       10                We do not have exposures via the inhalation 

       11  route.  We can say that using doses of 4.433 milligram per 

       12  kilogram radio label MITC, that 88 to 96 percent was 

       13  absorbed within the hour.  80 to 82 percent was excreted 

       14  in urine, and small amounts were excreted in the feces.  6 

       15  to 15 percent in the expired air CO2, and less than 1 

       16  percent is carboneal sulfide or carbon disulfide within 24 

       17  hours.

       18                There was at the end of a week, 168 hours, 1 

       19  to 3 percent remained bound in tissues.  There -- MITC is 

       20  conjugated and is excreted as cysteine conjugates, about 

       21  which, nothing is known toxicologically.

       22                The acute toxicity and the bulk of the 

       23  toxicity that was observed at Cantara had to do with the 

       24  irritative capacity of MITC.  Oral presentation of MITC to 

       25  animals always or generally results in irritation of the 

                 BARNEY, UNGERMANN & ASSOCIATES  888 326-5900

        1  stomach lining, the esophagus, and so forth.  I'm not 

        2  going to cover those.

        3                What I'm going to concentrate on now is the 

        4  acute toxicity via the air, because that is where we think 

        5  virtually all the exposure to MITC is coming from.  When 

        6  OEHHA did their original risk assessment on the spill -- 

        7  and indeed, when DPR did a conditional risk assessment in 

        8  1994, the only study we had available to assess the 

        9  toxicity of MITC came from the Ukraine, what we call the 

       10  Ukrainian Cat Study by Nesterova.

       11                We feel, and I have felt, that this study 

       12  was so bereft of experimental and analytical detail, that 

       13  it is virtually unusable.  So we got -- we have another 

       14  study.  Another study came along in 1996, an 

       15  eye-irritation study which was a rather careful study that 

       16  characterized the chamber -- exposure concentrations and 

       17  the end points rather carefully.

       18                And I think we can -- well, I will make an 

       19  argument that this is an appropriate, acute end-point 

       20  study.  This was a human study done in Sacramento --  

       21  actually, at UC Davis Medical Center -- in which there 

       22  were 70 subjects, 38 males, 32 females, mean age of 32 

       23  years were the range, from 18 to 67 years old.

       24                And they were exposed to gaseous MITC 

       25  through specially fitted goggles.  Pam, if you put the 

                 BARNEY, UNGERMANN & ASSOCIATES  888 326-5900

        1  next one up there, you get a sense of what it looked like.

        2                DR. SALMON:  That slide's not -- 

        3                DR. RUBIN:  It's not in there?  Oh.  Okay.  

        4  Well -- 

        5                DR. BLANC:  It's okay.  We'll take your 

        6  word.

        7                DR. RUBIN:  They were goggles.  They were 

        8  airtight around the seam.  They were fed by a feeding tube 

        9  and a distribution manifold across the top.  When the 

       10  study was originally commissioned, DPR was approached as 

       11  to what end points they should measure.

       12                They originally wanted to put a mask on the 

       13  subjects.  And what I am told by the person who initiated 

       14  this risk assessment was, "No mask here.  The pulmonary 

       15  end points are serious enough that we don't want human 

       16  subjects breathing this stuff."  So all we have from the 

       17  acute -- from this experiment is an eye-irritation end 

       18  point. 

       19                DR. BLANC:  Isn't there -- just as an aside.  

       20  I hope this doesn't violate your guidelines.  But I always 

       21  understood that one of the issues with the Cantara spill 

       22  and the immediate health-risk assessment was, that it was 

       23  a licensed pesticide, and there was pesticide-toxicity 

       24  data other than just the Ukrainian Cat Study that was 

       25  deposited with the Department of Pesticide Regulation, but 

                 BARNEY, UNGERMANN & ASSOCIATES  888 326-5900

        1  unfortunately, none of that data was available for 

        2  anybody's health review.  Or is that not true?  How did it 

        3  ever get licensed without any submission of any data?

        4                DR. RUBIN:  Well, the spill, I'm -- first of 

        5  all, I'm not sure I can answer that question, as to what 

        6  data were available.

        7                DR. BLANC:  I mean, are there data relevant 

        8  to its pesticide registration which is not otherwise in 

        9  the public domain that you have also evaluated for the 

       10  purposes of this risk assessment?

       11                DR. RUBIN:  Definitely.

       12                DR. BLANC:  Does that predate -- 

       13                DR. RUBIN:  Some of it, yes.  It does 

       14  predate the spill.

       15                DR. BLANC:  Okay.

       16                DR. RUBIN:  In fact, you will notice when 

       17  you read -- I know this has been at issue before the panel 

       18  in the past.  There are very few open literature studies 

       19  on the toxicity of MITC.  There are a few, and many of 

       20  them come from the spill and human -- human exposures.  

       21  But we're dealing mostly with contracted studies.

       22                The human eye irritation study, 70 people 

       23  exposed for -- just to the eyes through goggles for 14 

       24  minutes, 4 hours or 8 hours.  They were sitting at tables, 

       25  and they had a little graph next to them, so that they 

                 BARNEY, UNGERMANN & ASSOCIATES  888 326-5900

        1  could put on the graph a little mark as they felt some 

        2  level of irritation, say between zero and a hundred.  And 

        3  they would put a little mark on.

        4                That is a subjective sort of 

        5  semi-quantitative, at best, level of assessment of eye 

        6  irritation.  That -- that technique is called -- is known 

        7  as the Likert technique or the Likert scale.  It's a 

        8  subjective technique for assessing eye irritation.

        9                There were a number of other end points that 

       10  were used, including blink rate, tearing, visual acuity, 

       11  and photographs of the eye.  By "visual acuity," I mean 

       12  put your hand over your right eye and tell me if you can 

       13  see the chart.  And photographs of the eye meaning, before 

       14  and after, how red were these -- how red were the eyes of 

       15  these people.

       16                Results were, the Likert scale measurements 

       17  indicated there was an irritation response at 800 ppb 

       18  after one hour of exposure.  Blink rate indicated an 

       19  irritation response at 800 ppb after two hours of 

       20  exposure.  There were no -- none of the other three  

       21  parameters exhibited positivity.

       22                The other factor that is of interest is 

       23  that, when the subjects were withdrawn from the stimulus, 

       24  the -- their perception of irritation and their blink rate 

       25  went back down very quickly.  We have -- we have decided 

                 BARNEY, UNGERMANN & ASSOCIATES  888 326-5900

        1  that this was an adequate study to assign a LOEL value of 

        2  800 ppb and a NOEL value at the lowest concentration 

        3  tested of 220 ppb.

        4                CHAIRMAN FROINES:  Why don't you skip to the 

        5  studies that form the basis of the NOEL and LOEL.

        6                DR. RUBIN:  Okay.  This was the first one.  

        7  This is the acute critical NOEL.

        8                DR. BLANC:  This is the acute one.  The next 

        9  one is going to be subchronic.

       10                DR. RUBIN:  I'm actually only going to talk 

       11  about those studies.  Moving on to subchronic.  We're 

       12  dealing here with a 12 to 13 week, 4 hour a day -- 5 days 

       13  a week, nose only, inhalation-exposure experiment.  This 

       14  one came from Germany by Ross Kamp, et al.  First I'll 

       15  tell you a little bit about what they observed.  Then I 

       16  will attempt to go into some of the weaknesses of this 

       17  study.

       18                There were ten rats per sex, per dose 

       19  exposed to 0, 1, 10, or 45 ppm MITC.  Clinical signs at 

       20  the high dose -- and the signs I've listed here in the 

       21  symptoms I've listed here are ones that were observed in 

       22  many of the animals at this dose, not just one animal.  

       23  Included apathy, increased salivation and nasal discharge, 

       24  vocalization -- vocalization we usually take to mean that 

       25  those animals are uncomfortable.  They want out.

                 BARNEY, UNGERMANN & ASSOCIATES  888 326-5900

        1                Also body-weight gain was 37 and 53 percent 

        2  male and females of the sham dose controls.  Turns out to 

        3  be important, because sham dosing itself in this 

        4  experiment is really hard on these animals.  At 10 ppm, 

        5  which is where we assign the LOEL, we're dealing with 

        6  much-less overt toxicity.  We have decreased body-weight 

        7  gain, compared to sham dose controls, 89 and 85 percent of 

        8  sham dose controls in males and females, not statistically 

        9  significant.

       10                However, I felt that, given the much greater 

       11  decrement in weight gain at the next higher dose -- at the 

       12  high dose, that this was a real effect.  It can be argued, 

       13  though, that the lack of statistical significance is 

       14  problematic.  There was also, interestingly, increased 

       15  water consumption at the LOEL dose of 10 ppm, about 15 

       16  percent above sham controls. This was statistically 

       17  significant.

       18                However, at the high dose, there was also 

       19  about a 15-percent increase, but it wasn't statistically 

       20  significant.  And there was no dose response.  So, that's 

       21  possibly a problematic end point.  I have considered it as 

       22  a positive toxicological end point.

       23                There was a slight statistically significant 

       24  reduction in serum total protein.  Those are the three end 

       25  points that we are basing the subchronic risk assessment 

                 BARNEY, UNGERMANN & ASSOCIATES  888 326-5900

        1  on.  So one needs to examine the toxicologic significance 

        2  of these end points, the fact that there's no dose 

        3  response in this for the increase in water consumption, 

        4  the possibility that the effect on serum protein may be 

        5  related to the increased water consumption.

        6                I would say here, parenthetically, that you 

        7  can find when you feed MITC to rats, and their water 

        8  consumption actually decreases, because the water that the 

        9  MITC is in tastes so bad, that they don't want anything to 

       10  do with it.

       11                But under those conditions, you get drops in 

       12  serum protein as well.  Which made me think that it is at 

       13  least possible that the drop in serum protein was not 

       14  related to the increase in water consumption.  There was 

       15  also no histological examination of the nasal cavity.  And 

       16  for an irritant as powerful as MITC, you should be looking 

       17  at the nasal cavity, the trachea, for irritation effects.

       18                Finally, there is insufficient analytic data 

       19  in this experiment.  First of all, there's no report of 

       20  daily levels of MITC.  This is a difficult thing to do for 

       21  13 straight weeks, to put into a -- an inhalation chamber 

       22  exactly the same amount of MITC every day, and to measure 

       23  it, and to express those results in -- in interpretable 

       24  fashion.

       25                What these investigators did was simply add 

                 BARNEY, UNGERMANN & ASSOCIATES  888 326-5900

        1  up all the data that they had, which they did not supply, 

        2  and give us a mean value.  So the implication of that is, 

        3  that we don't really know what the excursions of the MITC 

        4  levels were in those experiments.  And those, say, at the 

        5  high dose where the mean value was 45, maybe it went down 

        6  to 10, and maybe it was occasionally -- and maybe it was 

        7  up at 165, but we just don't know.

        8                And those are some of the weaknesses in this 

        9  study.  When you don't know the daily doses, what those 

       10  animals are daily exposed to, and you don't have daily 

       11  toxicologic data, you can't really tell what the animals 

       12  are responding to.

       13                But -- and here's -- here is one of the 

       14  problems that we're dealing with with MITC.  This is the 

       15  extent -- this is really the extent of the studies that we 

       16  have.  And so I feel that, given the overtness of the -- 

       17  of the response at 45 ppm, and the admitted marginality of 

       18  the responses at 10 ppm, that that is good enough to call 

       19  10 ppm a LOEL dose.  Moving on.  Okay.

       20                DR. FUCALORO:  The LOEL -- the NOEL was 

       21  calculated from the LOEL?

       22                DR. RUBIN:  Yeah.

       23                DR. FUCALORO:  By just doing -- 

       24                DR. RUBIN:  No, the NOEL is a determined 

       25  NOEL.  In other words, those animals were actually exposed 

                 BARNEY, UNGERMANN & ASSOCIATES  888 326-5900

        1  at that dose.   

        2                DR. FUCALORO:  And experienced nothing?

        3                DR. RUBIN:  And experienced no observable 

        4  effects.  So that's our NOEL.  And that's the NOEL that 

        5  we're going to calculate our RELs and our MOEs based on.  

        6  Chronic toxicity.  This is an issue, because it's become 

        7  apparent to us that there is chronic exposure to MITC.  

        8  It's not included in this document.  The data are 

        9  currently being crunched through at DPR to give us 

       10  chronic-exposure data.

       11                But with chronic toxicity, we don't have any 

       12  inhalation experiments.  And I understand that probably 

       13  with -- probably not a very common thing to see 

       14  chronic-inhalation experimental data.  Anyway, but I 

       15  thought I would flash this slide by just to show you that 

       16  we do pick up some chronic effects.

       17                We determine NOELs of 10 -- 10 ppm in the 

       18  water, which is equal to 463 mics per kick per day in a 

       19  rat study.  And 0.4 milligram per kilogram per day in a 

       20  dog study.  Dog study was very problematic, because the 

       21  animals at the beginning of the study were exposed to huge 

       22  doses of corn oil, and they were getting sick on the corn 

       23  oil.  So it's not a real clear study to begin with.

       24                But I want to move on from chronic, because 

       25  we don't really have a study to base anything on there.  

                 BARNEY, UNGERMANN & ASSOCIATES  888 326-5900

        1  Is there a question?  Okay.  The issue of oncogenicity -- 

        2                DR. FUCALORO:  Wait.  I have a question. 

        3                DR. RUBIN:  Okay.

        4                DR. FUCALORO:  Previous slide.  Study 1 and 

        5  Study 2 have essentially the same NOELs and LOELs, don't 

        6  they?

        7                DR. RUBIN:  Yes.

        8                DR. FUCALORO:  Did you note that?  I'm 

        9  sorry.

       10                DR. RUBIN:  Not only do I note that, but 

       11  it's interesting to note that those NOELs and LOELs are 

       12  similar to the subchronic inhalation study. 

       13                DR. FUCALORO:  And I would point out there 

       14  was missing, of course, some signs, vomiting, excessive 

       15  salivation, liquid feces, at -- and the number's missing. 

       16                DR. RUBIN:  Oh, it -- that's at the LOEL 

       17  dose. 

       18                DR. FUCALORO:  Is that the LOEL?

       19                DR. RUBIN:  Yeah.  At 2.

       20                DR. WITSCHI:  Wasn't this on the dog study, 

       21  the .4 milligram per kilo per day produced some signs of 

       22  toxicity?  That's what it says.

       23                DR. RUBIN:  Excuse me?

       24                DR. WITSCHI:  At the .4 milligram kilo dog 

       25  study.  You had -- 

                 BARNEY, UNGERMANN & ASSOCIATES  888 326-5900

        1                DR. RUBIN:  Oh, I'm sorry.  I have that 

        2  wrong.  That's a mistake.  That should be 2. 

        3                DR. WITSCHI:  Oh.

        4                DR. RUBIN:  That should be 2.  It's in the 

        5  report, sloppily.  Okay.  Should I move on?  Okay.  

        6  Oncogenicity, MITC does not appear to be oncogenic in any 

        7  of the three chronic studies where it was looked at.  And 

        8  again, these are oral-exposure studies.

        9                However, I want to bring to your attention 

       10  that in the two-year rat study, the drinking-water study, 

       11  there was an apparent increase in multiple benign mammary 

       12  tumors in terminal survivors.  Consideration -- and I have 

       13  a whole slide of this, if we want to go through this, the 

       14  numbers.

       15                Consideration of incidence rates for single 

       16  benign tumors separately and in combination with the 

       17  multiple benign tumors, as well as the incidence rates for 

       18  malignant mammary tumors favors the conclusion that the 

       19  increase in multiple benign tumors was not 

       20  treatment-related.  It did not achieve statistical 

       21  significance.  And basically, there was nothing else going 

       22  on in the mammary gland with related tumors, single tumor, 

       23  in decedents, in terminal survivors.

       24                We made a judgment that this was not a 

       25  treatment-related effect.  I want to say in passing, 

                 BARNEY, UNGERMANN & ASSOCIATES  888 326-5900

        1  however, that I have included in this document a draft of 

        2  the Metam-Sodium risk assessment, which I wrote.  And with 

        3  Metam-Sodium, you do get clear, frank, oncogenicity, but 

        4  not in the mammary gland.  You get blood-vessel 

        5  carcinomas -- not carcinomas, sarcomas.

        6                And this is something that we should 

        7  recognize, that the parent compound, but apparently not 

        8  the daughter compound, is carcinogenic. 

        9                DR. BLANC:  That was in the same species 

       10  that the -- these studies were negative with?

       11                DR. RUBIN:  In two species, actually.  Rats 

       12  and mice.  This one here, this is a rat study with MITC 

       13  where you get a small blip in mammary.

       14                DR. BLANC:  Right.  And it was a rat study 

       15  with the angiosarcoma?

       16                DR. RUBIN:  Angiosarcoma, rats and mice.

       17                DR. BLANC:  Well, I think it's going to be a 

       18  problem, and I think it's going to have to be addressed.  

       19  Because it doesn't -- on the face of it, if it's a 

       20  compound which is quickly transformed -- that is to say, 

       21  Metam-Sodium quickly transformed, in an aqueous 

       22  environment quickly broken down, it's hard to believe that 

       23  even in the animal studies where Metam-Sodium was 

       24  associated with angiosarcoma of the liver, it was actually 

       25  the parent compound that was causing angiosarcoma of the 

                 BARNEY, UNGERMANN & ASSOCIATES  888 326-5900

        1  liver.

        2                So the two sets of findings are inconsistent 

        3  with each other, unless it's related to one of the 

        4  other -- well, no.  Even so, it would -- you know, it 

        5  would have to be carcinogenesis-related to hydrogen 

        6  sulfide or something.  It's hard to understand how the two 

        7  findings --

        8                DR. RUBIN:  It is hard.  It is very 

        9  difficult to tease this out. 

       10                DR. BLANC:  And I think it raises a larger 

       11  point, which I don't think we can get into today.  But 

       12  which is, that structuring the document as a health 

       13  assessment of methyl isothiocyanate carries with it a 

       14  certain problem.

       15                Which is, that the real issue that we're 

       16  dealing with is Metam-Sodium, and all of its breakdown 

       17  products, of which methyl isothiocyanate is a prominent, 

       18  but not the only one.  And whether organizing the entire 

       19  document -- I don't mean organizing, necessarily.  But 

       20  titling it as a evaluation of methyl isothiocyanate, I'm 

       21  not sure if that's a help or hindrance.

       22                DR. RUBIN:  Right.

       23                DR. ATKINSON:  The Metam-sodium will not get 

       24  into the atmosphere.

       25                DR. BLANC:  I understand that.  But MIC 

                 BARNEY, UNGERMANN & ASSOCIATES  888 326-5900

        1  does.

        2                DR. ATKINSON:  Yeah.

        3                DR. BLANC:  And the carbon disulfide and the 

        4  hydrogen sulfide does.  And all those are breakdown 

        5  products.  And then if we're dealing with this other 

        6  product, you also have to think about formaldehyde and -- 

        7  and other breakdown products as well.  So I think it's a 

        8  real challenge.  I'm not quite sure I have a solution to 

        9  it.

       10                But I see that there's a real problem in 

       11  the -- I don't know how you're struggling with it with the 

       12  health effects.  But it seems it must be a nightmare.

       13                DR. RUBIN:  This is a very sticky one.  And 

       14  it's part of the reason why I decided to include the draft 

       15  of the Metam-Sodium document, so that it's very clear that 

       16  we recognize that it's positive for carcinogenicity, the 

       17  parent compound.

       18                It is not at all clear to me why the 

       19  daughter compound doesn't register as such.  There could 

       20  be -- there could be any number of explanations.  It 

       21  wasn't stable, it broke down in certain ways.  And how we 

       22  are to assess this in the real world where people are 

       23  exposed to air levels of MITC, but not to Metam perhaps in 

       24  the air, that's something I'm willing to take the 

       25  direction of the panel on how to handle that.  That's a 

                 BARNEY, UNGERMANN & ASSOCIATES  888 326-5900

        1  very sticky problem.

        2                DR. WITSCHI:  I have a question about those 

        3  tables.  You know, I think you really should treat lumps 

        4  as lumps.  And look again at the tumor data.  If you just 

        5  take total number of lumps, regardless of whether they are 

        6  benign and malignant, the total numbers of animals that 

        7  were at risk.

        8                DR. RUBIN:  I think I did that.

        9                DR. WITSCHI:  Not to -- not this slide.  

       10  Then when you do this, you find that the guys on the MITC, 

       11  in all treatment groups, the incidence of tumors higher.  

       12  Now, whether it would be significant, I don't know. 

       13                DR. BLANC:  No-treatment group -- the 

       14  no-treatment group is higher.

       15                DR. WITSCHI:  No, the treatment ones.  All 

       16  three treated groups are higher than the controls.

       17                CHAIRMAN FROINES:  Where are you reading?

       18                DR. WITSCHI:  Can you -- 

       19                CHAIRMAN FROINES:  We have to stop, 

       20  actually.  Let's do this, and then we have to stop.  We 

       21  have to be out of here at 3:45, and we have to finish the 

       22  RELs.

       23                DR. RUBIN:  Okay.

       24                CHAIRMAN FROINES:  Go ahead, Peter.

       25                DR. WITSCHI:  I should see the bottom.

                 BARNEY, UNGERMANN & ASSOCIATES  888 326-5900

        1                DR. RUBIN:  The bottom is the malignant.

        2                DR. WITSCHI:  Okay.  See, if you -- if you 

        3  add up those and those -- 

        4                DR. RUBIN:  Total benign plus total 

        5  malignant?

        6                DR. WITSCHI:  Total benign and total 

        7  malignant in the ones that died before, and the ones that 

        8  were cured.  Then you have 60 at the bottom.  You had 60 

        9  animals at risk.  And in every single group, the sum of 

       10  total tumors is higher than was in the control group. 

       11                CHAIRMAN FROINES:  Thank you very much. 

       12                DR. RUBIN:  That's it?

       13                CHAIRMAN FROINES:  That's it. 

       14                DR. RUBIN:  Okay.

       15                CHAIRMAN FROINES:  Sorry we can't 

       16  accommodate you further, but we had these other items on 

       17  the agenda before we found out this was going to be on.  

       18  Let's go, Melanie.  Let's go, folks.  We've got to be out 

       19  of here.  At 3:45, we're out. 

       20                DR. MARTY:  I think all that we're missing 

       21  for the comments from the panel on the chronic REL 

       22  document is comments from Dr. Witschi.

       23                DR. FUCALORO:  Is he the only -- comments 

       24  only from -- 

       25                CHAIRMAN FROINES:  Okay.  Peter. 

                 BARNEY, UNGERMANN & ASSOCIATES  888 326-5900

        1                DR. WITSCHI:  Okay.  I -- the first one, 

        2  chlorinated dibenzo dioxins, and I worked with the panel 

        3  which reviewed the dioxins assessment of the EPA.  And 

        4  after the EPA had given its presentation, the Chairman 

        5  asked, "Why does the EPA spend so much effort on dioxin?"  

        6  And the EPA administrator said, "Well, because we have a 

        7  large basis of scientific data on dioxin."  And in view of 

        8  those facts, I'm not going to comment on the dioxins.  The 

        9  chloroform, I have a question.

       10                CHAIRMAN FROINES:  You've finished dioxins?

       11                DR. WITSCHI:  Oh, yeah.  I am not going to 

       12  touch this with a pole.

       13                CHAIRMAN FROINES:  Good.

       14                DR. WITSCHI:  No way.  Okay.  In page A-41, 

       15  chloroform; right?

       16                DR. COLLINS:  Uh-huh.

       17                DR. WITSCHI:  You have in the second 

       18  paragraph a human study which showed some effects between 

       19  10 and 995 milligrams per cubic meter.  Now, if you go to 

       20  the -- the previous page, then you certainly would have an 

       21  inserted factor for LOAEL of 10, and an interspecies 

       22  factor of 10.  So you would have an uncertainty factor of 

       23  100.  The animal in the species falls out; right?  Okay.

       24                Then you take the 100 and divide it by 100, 

       25  and you come up either 10 milligrams per cubic meter, and 

                 BARNEY, UNGERMANN & ASSOCIATES  888 326-5900

        1  divided by 100.  And you wind up with the value which is 3 

        2  times lower than the one you derived from the animal 

        3  experiments. 

        4                DR. MARTY:  Correct. 

        5                DR. WITSCHI:  Okay.  So -- 

        6                DR. MARTY:  Why did we not do that?

        7                DR. WITSCHI:  Yes.

        8                DR. MARTY:  As I'm recalling -- and I will 

        9  go back and look.  But the Bomski paper and the Phoon 

       10  paper, part of the issue is, you can't tell who had the 

       11  liver toxicity -- that the people that had the liver 

       12  toxicity, what exactly were their exposures.  So it's an 

       13  exposure-uncertainty issue.

       14                But I do agree that that is one thing we 

       15  should do, is take the bottom end of the range of 

       16  exposures, make the assumption that that exposure was 

       17  associated with hepatotoxicity and create a REL.  

       18                The fact that it's a little -- it's 

       19  three-fold lower, but that's actually fairly close 

       20  agreement, given all the uncertainty.  But the reason we 

       21  didn't focus on that was this exposure issue.

       22                DR. WITSCHI:  Well, it's really the question 

       23  of, if you have human data that are usable, wouldn't we 

       24  rather use them?  I agree it's trivial difference.  It's 

       25  rather question of -- I don't know.

                 BARNEY, UNGERMANN & ASSOCIATES  888 326-5900

        1                CHAIRMAN FROINES:  Your call.

        2                DR. WITSCHI:  I'd go with the human data.

        3                DR. COLLINS:  I think the other problem we 

        4  have is that it's jaundice rather than some of the mild 

        5  effects we deal with.  In fact, how do you deal with a 

        6  seriously adverse effect?  We put a hundred false-safety 

        7  factor instead of a 10?

        8                DR. WITSCHI:  Oh, I see.  No, no.  No, we 

        9  are talking about interspecies difference.  There you have 

       10  to go by the rules.  We have -- in people, we don't assume 

       11  more than 10.  Although, might be, in the case jaundice, a 

       12  larger factor might be appropriate, because of people 

       13  could have preexisting liver disease or there is 

       14  interaction with other things.  I don't know. 

       15                DR. BLANC:  Well, did they -- how did they 

       16  define jaundice?

       17                DR. COLLINS:  I don't know.  I really -- I 

       18  didn't develop -- that's one I have to go back and find.

       19                DR. BLANC:  You need to find out.  Because 

       20  if they were -- you could make the -- for people to be 

       21  clinically jaundiced, they have to have bilirubin that is 

       22  probably more than twice the upper limit of normal.  So 

       23  you could, you know, put in an added factor for that, and 

       24  assume that -- in other words, if what they were doing was 

       25  observe jaundice in humans and not measure bilirubin 

                 BARNEY, UNGERMANN & ASSOCIATES  888 326-5900

        1  abnormalities, you could assume that a level half that 

        2  amount might cause an elevated bilirubin absent clinical 

        3  jaundice.

        4                DR. MARTY:  There was actually a more 

        5  significant issue.  And that is in both studies, the 

        6  workers had viral hepatitis.  So -- 

        7                DR. BLANC:  Oh, never mind.

        8                DR. WITSCHI:  Well -- 

        9                CHAIRMAN FROINES:  That kind of takes out 

       10  the jaundice.

       11                DR. MARTY:  It wasn't sure if it was the 

       12  cart before the horse.  In one of the studies, the authors 

       13  thought that chloroform exposure was a predisposing 

       14  factor.

       15                DR. BLANC:  To viral hepatitis?

       16                DR. MARTY:  To viral hepatitis.

       17                DR. WITSCHI:  See, now considering the fact 

       18  of how much hepatitis is around these days, you might 

       19  start thinking we are not even a sensitive population, by 

       20  the guys who have subclinical hepatitis.

       21                DR. BLANC:  Well, that's your factor of 10.  

       22  I think if the studies are that flawed, then you shouldn't 

       23  use the human studies.  But you should have a           

       24  rationale --

       25                DR. COLLINS:  See, the other thing with 

                 BARNEY, UNGERMANN & ASSOCIATES  888 326-5900

        1  Bomski, we have to throw in a factor of 10 for subchronic, 

        2  was one to four years.

        3                DR. MARTY:  We could take another look at 

        4  the Phoon study.  I have read that paper.  It's been a 

        5  long time.  But I may be mistaken that they initially 

        6  thought it was viral hepatitis, and then attributed it to 

        7  chloroform.  I'll go back and look at that Phoon study in 

        8  '83 and see if it's usable.

        9                CHAIRMAN FROINES:  Why don't you go back, 

       10  look at it, communicate with Peter, and we'll -- we'll 

       11  basically -- if the panel agrees, we'll agree with the 

       12  conclusions that you two come up with.  I don't think we 

       13  need to hold this for some sort of meeting at some point.  

       14  It's not -- 

       15                DR. FUCALORO:  I agree.

       16                DR. MARTY:  Okay.

       17                CHAIRMAN FROINES:  When it gets to 3:30, 

       18  everybody will agree to almost anything.  I'm getting a 

       19  little -- 

       20                DR. FUCALORO:  I mean, that was an honest 

       21  agreement on my part, for the record. 

       22                DR. WITSCHI:  Okay.  Next one?  

       23  Ethylbenzene.  I think on page A-61 I would take issue 

       24  with the term "subacute developmental toxicity study," 

       25  because this would imply -- if you say "subacute 

                 BARNEY, UNGERMANN & ASSOCIATES  888 326-5900

        1  developmental toxicity," this would imply there are acute 

        2  developmental toxicity or chronic developmental toxicity.  

        3  This doesn't exist; okay?  But that's a trivial point.

        4                DR. COLLINS:  I thought just cross the word 

        5  out.

        6                DR. WITSCHI:  That's a trivial point.  My 

        7  question is -- and I don't know if that's come up before.  

        8  On page 60, third paragraph from the bottom, you have what 

        9  looks like a perfectly well-designed study for -- for a 

       10  subchronic study; right?

       11                DR. COLLINS:  Weeks, yeah.

       12                DR. WITSCHI:  Yeah.

       13                DR. FUCALORO:  Is this Clark?

       14                DR. WITSCHI:  That's Clark.

       15                DR. COLLINS:  At least through the 

       16  comparison, we could do that -- 

       17                DR. WITSCHI:  So then, I was wondering 

       18  when -- then going with the developmental study is the 

       19  right thing to do.

       20                DR. COLLINS:  One thing I'd like to say, we 

       21  are going back and looking at everything.  This is an EPA 

       22  RFC.  We're going back and redoing them by our own 

       23  methodology based on what the panel said.  And I think 

       24  this would be to see whether the developmental study agree 

       25  well, for instance, doing our analysis on the Clark study, 

                 BARNEY, UNGERMANN & ASSOCIATES  888 326-5900

        1  do they agree or not.  And as one method, to see whether 

        2  the thing is an outlie or whether it agrees with the other 

        3  data.

        4                DR. MARTY:  We also looked at the NTP 

        5  bioassay.  And it -- it has some information, but it's a 

        6  little hard to interpret.  But if you look at that 

        7  bioassay, and also the subchronic study -- but that was 

        8  done by NTP prior to the bioassay.  The numbers actually 

        9  are in fairly reasonable agreement with the REL we 

       10  developed from the developmental text.  We can actually 

       11  insert that information into the text, so it's clear.

       12                DR. WITSCHI:  Well, yes.  Again, I was 

       13  wondering, because a developmental toxicity studied in 

       14  rats, kind of a special case.  It's a question of 

       15  principle, again.  Whether you go for something which 

       16  would be your run-of-the-mill toxicity study or whether 

       17  you are going for this, a rather special case.  Because 

       18  many things which show up in developmental toxicity 

       19  studies in rats are not really too relevant for a human 

       20  situation, if I am correct. 

       21                DR. BLANC:  Why would you be correct?  Why 

       22  would that be correct?

       23                DR. WITSCHI:  Well -- 

       24                DR. BLANC:  I think it's more of an example 

       25  that, by chance, they happen to have a more sophisticated 

                 BARNEY, UNGERMANN & ASSOCIATES  888 326-5900

        1  study with subtler end points for analysis.  Take lead, 

        2  for instance.  Would you -- you know a lot about lead.  If 

        3  I have a developmental study in rats that show the effects 

        4  of lead, I'd say it's very relevant.

        5                DR. WITSCHI:  I'd say it depends on what you 

        6  looked at in rats.

        7                DR. BLANC:  Their SAT scores.

        8                DR. COLLINS:  What's the rat population here 

        9  at the colleges? 

       10                DR. FUCALORO:  You're looking at them. 

       11                DR. BLANC:  I mean, I'm not sure there's a 

       12  general principle there.

       13                CHAIRMAN FROINES:  Where are we on this 

       14  issue? 

       15                DR. COLLINS:  Where on this?  That we've 

       16  based on a developmental study, we'll go back and make 

       17  some comparison, using some of the other studies and see 

       18  how well they agree.  And then decide whether we have -- 

       19  we can find out -- we have an outlier with the 

       20  developmental study.  Then maybe we are going to have 

       21  to -- 

       22                DR. WITSCHI:  Well, first of all, I would 

       23  take issue with this developmental studies.  Because in 

       24  the rat study, as described, you have control toxicity.  

       25  And we now know these days, if you have a maternal 

                 BARNEY, UNGERMANN & ASSOCIATES  888 326-5900

        1  toxicity, forget about it.  That's not relevant.  So that 

        2  was one of the reasons why I questioned why taking the -- 

        3  not looking at the rat study.  Because I think that's 

        4  pretty well-established, maternal toxicity is a no-no with 

        5  teratology study.

        6                DR. MARTY:  I think that there's maternal 

        7  toxicity in the rats, but not the rabbits in that study.  

        8  We had the same NOAEL.  So I think, you know, we always 

        9  get heart burn about using numbers where you have maternal 

       10  toxicity, because of that whole issue.

       11                But one of the reasons we thought it was 

       12  okay to use this, is because there was also the decreased 

       13  live kits in the rabbits that were exposed to the same 

       14  concentrations.  In fact, it was the same study.  And it 

       15  was also the NOAELs is supported by Clark when you do that 

       16  calculation.

       17                So I do agree that there are uncertainties 

       18  using, first of all, the developmental studies for chronic 

       19  end points.  Although, we have concerns that if you do 

       20  that in your REL is much lower than any other study that 

       21  you use, are you protecting against developmental 

       22  effects.  So we have that concern.  And that's why we have 

       23  opted in some cases to use developmental studies.

       24                CHAIRMAN FROINES:  Yeah.  Except I would 

       25  almost argue -- we've had this discussion before.  I would 

                 BARNEY, UNGERMANN & ASSOCIATES  888 326-5900

        1  almost argue that you should have a category for 

        2  developmental studies and that -- keep that separate from 

        3  a classic chronic toxicity.  Because it is a case in and 

        4  of itself, so to speak.

        5                We've had that discussion.  Because the time 

        6  frame of the developmental studies is different than what 

        7  we normally think about.  So we're also into the issue of 

        8  averaging.  I should say, by the way, he said something 

        9  that made me nervous.  I don't -- yeah, I don't want to be 

       10  taking up compounds and taking this panel's time if you 

       11  are in the process of reviewing those compounds.  Because 

       12  you want to have a state RIR versus a EPA.

       13                We should get to it when you get to where 

       14  you need to go.  We shouldn't be -- I really don't want a 

       15  hundred and twenty compounds coming back to me that you've 

       16  now got new RELs for and have to redo this whole process.  

       17  I mean, everybody will quit.

       18                DR. MARTY:  What we've done is we've -- we 

       19  are responding to -- 

       20                DR. BLANC:  Your request.

       21                DR. MARTY:  -- to the previous instruction 

       22  from the panel to go back.

       23                CHAIRMAN FROINES:  I understand that.  But 

       24  that means that, if we have compounds that we're doing, 

       25  and you've got at least 80 more compounds to give us; 

                 BARNEY, UNGERMANN & ASSOCIATES  888 326-5900

        1  right?  We've only gotten 40.  We've got 80 to go.

        2                DR. BLANC:  John, John, for these first 40, 

        3  one of our comments was, we wanted them to go back on 

        4  certain ones.  And that's what they're doing.

        5                CHAIRMAN FROINES:  I'm not talking 

        6  about that.  I'm simply saying, he said, "We're looking at 

        7  all the compounds that are EPA documented to develop our 

        8  own RELs."  And I'm simply saying, for the next 80 

        9  compounds, subtract out the ones that are EPA that you're 

       10  re-looking at, and don't bring them forward until you're 

       11  ready.

       12                DR. MARTY:  Yes, we don't intend to bring 

       13  them forward until we've done that.

       14                DR. WITSCHI:  Go on?  Okay.  Hydrogen 

       15  sulfide.  The only thing I have, Andy Rubin's

       16  assay at the end of his presentation of some values, just 

       17  make sure that they are about the same, you know, between 

       18  the two agencies.  Okay.

       19                CHAIRMAN FROINES:  Realize, everybody, that 

       20  the levels of -- never mind.

       21                DR. WITSCHI:  No, I know.

       22                CHAIRMAN FROINES:  Of H2 is that of being 

       23  reported with MITC exceed their realm.

       24                DR. MARTY:  Exceeds our proposed realm. 

       25                DR. WITSCHI:  Okay.  The last one I have is 

                 BARNEY, UNGERMANN & ASSOCIATES  888 326-5900

        1  methyl chloroform.  And if you look through these data, 

        2  the way I -- they are described, the gerbil is more 

        3  sensitive as man; right?  And then you take the gerbil 

        4  data and still build in the interspecies factor of 10 in 

        5  an example where man is definitely less sensitive than the 

        6  test animal was.

        7                You have -- on page A-158, you have some of 

        8  NOELs for men, 250 ppm, hundred and -- 345 ppm, 350 ppm, 

        9  almost.  And the gerbil is much lower.  And yet you 

       10  introduce the factor of 10.  It doesn't make sense, to 

       11  some extent.

       12                DR. MARTY:  Well, I think we were concerned 

       13  about the quality of the data that came out of the human 

       14  studies, whether they could actually have found a 

       15  neurological effect.  There were also case studies which 

       16  are not usable in quantitative risk assessment, but that 

       17  indicated that methyl chloroform is capable of producing 

       18  neurotoxicity in humans.

       19                DR. WITSCHI:  I have problems, in view of 

       20  data, where man seems to be five times more sensitive than 

       21  the gerbil, to take the gerbil and make man ten times more 

       22  sensitive.

       23                DR. MARTY:  Well, I guess the only thing I 

       24  would argue, I'm not convinced that humans are much less 

       25  sensitive than gerbils, by looking at the information that 

                 BARNEY, UNGERMANN & ASSOCIATES  888 326-5900

        1  we have, which isn't very strong.  It would take more than 

        2  that to convince me.

        3                DR. WITSCHI:  Okay.  We have this study on 

        4  page 158.  One, two, third paragraph from top.  250 ppm, 

        5  no changes, exposed for more than one year, 150 workers.  

        6  Then -- 

        7                DR. MARTY:  That was cardiovascular, Kramer. 

        8  Am I looking at the right one?

        9                DR. COLLINS:  Yeah, yeah.

       10                DR. WITSCHI:  Then one down, we have 22 

       11  female workers, hundred ten received -- had a ppm 6.7 

       12  years.  Failed to identify neurotoxicity.  I mean; okay.  

       13  What's wrong with those data?  At least the way they are 

       14  presented here, nothing. 

       15                DR. MARTY:  Well, I can go back and look at 

       16  those studies, but I'm -- I'm certain that the person who 

       17  wrote this, the reason they didn't want to use Maroni at 

       18  all, they didn't have a lot of confidence in the study.  

       19  The fix would be to go back and look at it and also to 

       20  explain why we're concerned about using that study.

       21                DR. WITSCHI:  Well, and see -- then the 

       22  gerbil, you take a neurological end point, astrogliosis, 

       23  a-s-t-r-o-g-l-i-o-s-i-s, so -- okay.  I mean -- 

       24                CHAIRMAN FROINES:  It seems to me that 

       25  the -- Peter's right, that the automatic adoption of 

                 BARNEY, UNGERMANN & ASSOCIATES  888 326-5900

        1  ten-fold safety factor, irrespective of the data, is 

        2  something we need to avoid.

        3                DR. COLLINS:  We had an additional problem 

        4  here.  We couldn't use the EPA's RGDR factor, because 

        5  there was not enough data on gerbils to do it.  Otherwise, 

        6  this could have been a 3. 

        7                DR. MARTY:  The interspecies -- 

        8                DR. COLLINS:  Interspecies factor.

        9                DR. MARTY:  Would have been a 3 if we'd 

       10  done -- 

       11                DR. COLLINS:  But there's no basis on which 

       12  to do an OGC calculation on gerbil.

       13                DR. MARTY:  Another thing we could do is 

       14  look again at the body of Maroni and other studies.  And 

       15  if it really appears that way, we can use the Rosengren 

       16  study in gerbils, but don't include the interspecies 

       17  factor, if that makes sense.

       18                DR. WITSCHI:  Now, the thing with man being 

       19  ten times more sensitive than the most sensitive species, 

       20  that's a notion that goes back to about 1910.  But I do 

       21  not think that it's really true.  Actually, I find man is 

       22  remarkably resistant to quite a few things.  So -- 

       23                CHAIRMAN FROINES:  I have a question.  With 

       24  this information -- by the way, the senior author on this 

       25  paper is a fellow named Foa, F-o-a, who's quite a good 

                 BARNEY, UNGERMANN & ASSOCIATES  888 326-5900

        1  investigator.  So it seems to me that this burden to 

        2  demonstrate why this study isn't appropriate.  The second 

        3  question I had, was -- 

        4                DR. MARTY:  Dr. Froines, I don't know where 

        5  you are.

        6                CHAIRMAN FROINES:  I'm talking about the 

        7  Maroni study.

        8                DR. MARTY:  Okay.

        9                CHAIRMAN FROINES:  Senior author -- last 

       10  author is F-o-a, and I know him.  Now, the next paper down 

       11  I'm confused about, because that's the paper that the 

       12  first author is Mattson.  And I may be missing it, but I 

       13  don't see it in here.  Can you help me find it?  I'm sure 

       14  it's me.  I don't see it. 

       15                DR. COLLINS:  It's on page A-159, the third 

       16  paragraph.  

       17                "No evidence of peripheral neuropathy or     

       18         other neurotoxicity was detected in rats exposed to 

       19         200, 620 or 2,000 ppm methyl chloroform six hours   

       20         per day, five days a week for 13 weeks."

       21                CHAIRMAN FROINES:  Yeah, I got it.  I'm 

       22  sorry.  Now, that's a very good group of investigators. 

       23                DR. COLLINS:  That would have a 2,000 ppm 

       24  NOEL. 

       25                DR. WITSCHI:  That's actually referenced is 

                 BARNEY, UNGERMANN & ASSOCIATES  888 326-5900

        1  Spencer -- it's a C, not an S -- in the Mattson reference, 

        2  I guess.

        3                CHAIRMAN FROINES:  Peterson.

        4                DR. MARTY:  Oh, Spencer's name is 

        5  misspelled.  Oh, yeah.  Sorry.  Well, what we try to do, 

        6  if you have animal studies that are conflicting, and you 

        7  have evidence of an effect in one species but not another, 

        8  we would take the more sensitive species to use in the 

        9  case of people.  Because, you don't know where humans are 

       10  on the sensitivity scale.  So that's, you know, something 

       11  that we've always done.

       12                DR. WITSCHI:  Well, that was my point with 

       13  this particular -- I thought we knew where humans are on 

       14  the sensitivity scale.

       15                DR. MARTY:  I guess knowing is a comfort, 

       16  you know.  There's a comfort level there issue.  But I'm 

       17  happy to go back and look at Maroni, and anything else we 

       18  can find to see if that's the case.  And then if it is, 

       19  what interspecies uncertainty factor, if any, needs to be 

       20  applied.

       21                DR. WITSCHI:  Well, that's what I had to 

       22  say.

       23                DR. COLLINS:  Thank you.

       24                CHAIRMAN FROINES:  And you did it with two 

       25  minutes to spare.  You're the first person today to come 

                 BARNEY, UNGERMANN & ASSOCIATES  888 326-5900

        1  in under the time line.

        2                DR. WITSCHI:  I'm Swiss.

        3                DR. FUCALORO:  Well, he sure clocked you.

        4                DR. WITSCHI:  I believe in running trains on 

        5  time.

        6                CHAIRMAN FROINES:  And my watch is two 

        7  minutes fast, so I think you're five minutes ahead.  Can 

        8  I -- can somebody -- I'd entertain a motion.  Shall we 

        9  adjourn?

       10                DR. BLANC:  I make the motion that we 

       11  adjourn.

       12                DR. FUCALORO:  Second.

       13                CHAIRMAN FROINES:  All in favor?  

       14                THE PANEL:  Aye.  

       15                (Thereupon the Scientific Review Panel       

       16                 meeting was adjourned at 3:39 p.m.)

       17                              * * *









                 BARNEY, UNGERMANN & ASSOCIATES  888 326-5900





        5                 I, Kathleen Knowlton, CSR No. 11595, a 

        6  Certified Shorthand Reporter in and for the state of 

        7  California, do hereby certify:

        8                 That the foregoing proceedings were taken 

        9  down by me in shorthand at the time and place named 

       10  therein and were thereafter transcribed under my 

       11  supervision; that this transcript contains a full, true 

       12  and correct record of the proceedings which took place at 

       13  the time and place set forth in the caption hereto.



       16                 I further certify that I have no interest 

       17  in the event of the action.


       19  EXECUTED this ____ day of __________________, 1999.



       22                        ____________________________________
                                           Kathleen Knowlton 



                 BARNEY, UNGERMANN & ASSOCIATES  888 326-5900