1                            MEETING                   2                            OF THE                   3       SCIENTIFIC REVIEW PANEL ON TOXIC AIR CONTAMINANTS                   4                CALIFORNIA AIR RESOURCES BOARD                   5                       6                       7                       8                       9                        SUNSET VILLAGE                  10                    COVEL COMMONS BUILDING                  11             UNIVERSITY OF CALIFORNIA, LOS ANGELES                  12                          THIRD FLOOR                  13                       330 DE NEVE DRIVE                  14              LOS ANGELES, CALIFORNIA  90095-1492                  15                      16                      17                   FRIDAY, JANUARY 15, 1999                  18                           9:45 A.M.                  19                      20                      21                      22                      23    REPORTED BY:                    24    Caroline Jetter            CSR No. 11568      25    Our File No. 1-52124                                                       1                          APPEARANCES                   2                       3    MEMBERS PRESENT:                     4    Dr. John Froines, Chairman            Dr. Paul Blanc       5    Dr. Gary Friedman            Dr. Anthony Fucaloro       6    Dr. Craig Byus            Dr. Roger Atkinson       7    Dr. Stanton Glantz                    8                REPRESENTING THE CALIFORNIA AIR RESOURCES BOARD:         9                Mr. Bill Lockett, Deputy Ombudsman, Northern California      10    Mr. Peter Mathews, Office of the Ombudsman                  11                REPRESENTING THE OFFICE OF ENVIRONMENTAL HEALTH HAZARD      12    ASSESSMENT:                    13    Dr. George Alexeeff, Deputy Director for Scientific            Affairs      14    Dr. Melanie Marty, Senior Toxicologist                  15                REPRESENTING THE DEPARTMENT OF PESTICIDE REGULATION:        16                Mr. Paul H. Gosselin, Assistant Director      17                      18    ALSO PRESENT:                    19    Dr. James Collins                  20                      21                      22                      23                                24                      25                                 BARNEY, UNGERMANN & ASSOCIATES  1-888-326-5900       1                             INDEX                     2                                      AGENDA ITEMS       3                       4    1      Continuation of review of draft report:                     The Determination of Acute Reference        5           Exposure Levels for Airborne Toxicants -                    Office of Environmental Health Hazard        6           Assessment, staff                   7    2      Review of findings for                   S,S,S-tributylphosphorotrithioate (DEF)        8           as a toxic air contaminant - SRP members                   9    3      Update of draft report:  The Evaluation                    of Methyl Parathion as a Toxic Air       10           Contaminant - Department of Pesticide                    Regulation, (DPR) staff      11                4      Continuation of discussion of the       12           proposed agenda for an SRP workshop                    entitled: 'Pesticides in the Air' -       13           SRP and DPR staff                  14                      15                      16                      17                                                          18                      19                      20                      21                      22                      23                      24                      25                                 BARNEY, UNGERMANN & ASSOCIATES  1-888-326-5900       1                  CHAIRMAN FROINES:  I think it's Friday                   2    January 15.  It's a little bit after 9:30, and let's call                   3    the meeting to order formally.  Everyone has a copy of                   4    the agenda.  I wanted to say at the beginning happy new                   5    year to everybody but more importantly to welcome Roger                   6    Atkinson to the panel.                     7                  We have very major needs on this panel for                   8    exposure assessment issues, atmospheric chemistry                   9    questions and so Roger is a more than distinguished                  10    scientist in U.C. Riverside, and we're very, very pleased                  11    to have him with us.  Thank you for accepting the                  12    position.                    13                  And I'll just say on a substantive note                  14    that in doing risk assessments on pesticides, which is                  15    what's taking up a lot of our time lately, since the risk                  16    assessment is to a large degree also dependent upon the                  17    levels of exposure in the environment, that the exposure                  18    assessment question becomes absolutely paramount to our                  19    deliberations so that your being on the panel is going to                  20    be really important in that regard.                    21                  And I think that one of the things we're                  22    going to want to talk about, as we move forward through                  23    some of the workshops, is how to develop protocols for                  24    characterizing atmospheric concentrations so we have                  25    confidence in the numbers when we actually do the                                                                                   4                 BARNEY, UNGERMANN & ASSOCIATES  1-888-326-5900       1    calculations and determine what the levels of risk are so                   2    that they -- so your role is really important.  And we've                   3    been blessed having Tony Fucaloro on the committee.                     4                  So that means we really have two people who                   5    have ongoing responsibility for some of the exposure                   6    questions.                     7                  Let's go directly to the agenda, and we'll                   8    go to the issue of the changes that have been made in the                   9    acute reference exposure document.  And, I guess, is                  10    Melanie going to lead that?                    11                  DR. MARTY:  Yes.                    12                  CHAIRMAN FROINES:  Melanie, do you want me                  13    to discuss the results of our discussion last night and                  14    this morning, or do you want to -- how do you want to                  15    proceed on that?                  16                  DR. ALEXEEFF:  My name is George Alexeeff                  17    with the Office of Environmental Health Hazard                  18    Assessment.  I think you can discuss it now what you                  19    suggested to us this morning.  That's fine.  Or you can                  20    wait until we've made our presentation and then discuss                  21    where you want to go from there.                    22                  CHAIRMAN FROINES:  Well, why don't you go                  23    ahead, and we'll come back to the issue of the specific                  24    chemicals.                    25                  DR. ALEXEEFF:  What we thought we would do                                                                                   5                 BARNEY, UNGERMANN & ASSOCIATES  1-888-326-5900       1    today -- we met on the acute document -- was it in                   2    December 2, I believe.  And we discussed it to a certain                   3    extent for several hours, and there were several                   4    suggested changes by the panel to the document.                     5                  At the same time we have received comments                   6    from the public up until a couple of days before the                   7    Scientific Review Panel meeting, and we hadn't had time                   8    to incorporate it in that document at that time.                     9                  So what we've done thus -- for today is                  10    we've reviewed the comments that it's been submitted up                  11    until December 2.  We've provided some responses to the                  12    comments, and we'll -- I know we've provided it to the                  13    panel, and we'll also put it on our web site.                    14                  And we've also made proposed changes,                  15    proposed revisions both based upon comments made that                  16    were submitted and comments by the panel.                    17                  So what we're going to do today is discuss                  18    the changes that are being proposed from the last version                  19    to bring you up to date what the suggested changes were                  20    and also a couple of issues that came up at the last                  21    meeting.  We'll be discussing those in a little more                  22    depth today.                    23                  CHAIRMAN FROINES:  Roger, do you have the                   24    document?                    25                  DR. ATKINSON:  I have the document.                                                                                     6                 BARNEY, UNGERMANN & ASSOCIATES  1-888-326-5900       1                  CHAIRMAN FROINES:  You got it this morning.                    2    So if you can --                   3                  DR. GLANTZ:  Can I just ask one --                   4                  CHAIRMAN FROINES:  As you go through, try                   5    and give a little bit of background as you go so Roger                   6    gets up to speed.                     7                  DR. ALEXEEFF:  Okay.  And I can --                   8                  DR. GLANTZ:  Can I just ask one question.                    9    You gave us this Response to Comments document.  Have the                  10    changes that you talked about in here been incorporated                  11    into the text?                    12                  DR. ALEXEEFF:  Yes.                    13                  DR. GLANTZ:  So what are the changes?                    14                  DR. ALEXEEFF:  We will be presenting those                  15    changes.  Now, since that time, there were some                  16    additional changes that have come up over time --                  17                  DR. GLANTZ:  Okay.                    18                  DR. ALEXEEFF:  -- that we'll mention here.                   19    Either typographical errors that we have subsequently                  20    found or someone has pointed out to us or some other                  21    changes that we felt we found better data on which to                  22    base the numbers.  There is a couple like that.                    23                  DR. GLANTZ:  Okay.  But I just want to be                  24    clear because, when I read this and looked at the                  25    document, it looked like all these changes had already                                                                                   7                 BARNEY, UNGERMANN & ASSOCIATES  1-888-326-5900       1    been incorporated.                     2                  DR. ALEXEEFF:  That's correct.                     3                  DR. GLANTZ:  You're talking about some                   4    other changes.  Okay.                   5                  DR. FUCALORO:  What?                     6                  DR. MARTY:  Okay.  I guess I'll launch into                   7    the presentation then.  Next slide.                     8                  I'm Melanie Marty of the Office of                   9    Environmental Health Hazard Assessment.                   10                  There were some suggestions that were made                  11    by SRP members at the December 2 meeting.  One of them                  12    was to change the uncertainty factor for extrapolating                  13    from a lowest observed adverse effect level to a no                  14    observed adverse effect level to 6 for mild adverse                  15    effects.                    16                  We had been using 3 for mild irritation                  17    based on analysis by Alexeeff and coworkers, and at that                  18    meeting, the last meeting, we took another look at that.                   19    It was suggested to us to use a 95th percentile of that                  20    analysis, which was 6, and to apply it to not just a mild                  21    irritation but to all of our mild adverse endpoints.  So                  22    we have done that.                    23                  Also the SRP suggested that at this meeting                  24    we discuss issues related to specific chemicals.  So I do                  25    have lots of slides pertaining to that.  These are the 15                                                                                   8                 BARNEY, UNGERMANN & ASSOCIATES  1-888-326-5900       1    chemicals which we received public comment.  I do have                   2    slides that cover all of these issues.  We don't -- if                   3    you want to go through them, we will.                      4                  CHAIRMAN FROINES:  Let me just say since                   5    this issue of the chemicals -- specific chemicals came                   6    up, that I should tell the panel that, based on a                   7    discussion last night and this morning, that we think                   8    that we have to divide up the chemicals into groups and                   9    have the panel -- have members of the panel actually do a                  10    review for the next meeting so that we can actually say                  11    that the panel has read the document in its entirety as                  12    opposed to the panel having only read what is essentially                  13    10 percent of the document with the appendices, which                  14    represent 90 percent not having been read.                    15                  So in order to reduce the workload, we'll                  16    have to break it down, and Tony has asked that we break                  17    it down in teams of two, which isn't going to work out                  18    quite perfectly because there aren't -- it doesn't work                  19    out to do that.                    20                  But we'll come back to it.  But just to                  21    alert the panel that I think we're -- in order to meet                  22    our obligation, we really do need to -- that is, to read                  23    the entire document, we're going to have to look at the                  24    individual chemical.                    25                  DR. BLANC:  We have to give preferences on                                                                                   9                 BARNEY, UNGERMANN & ASSOCIATES  1-888-326-5900       1    the ones we'd like?                     2                  DR. FUCALORO:  If no one has preferences                   3    except you, the answer is yes.                     4                  CHAIRMAN FROINES:  If you want to sit there                   5    and develop a list of preferences that you would like,                   6    feel free to.                     7                  DR. BLANC:  How many is it going to be per                   8    person?                     9                  CHAIRMAN FROINES:  Well, there                   10    are -- essentially Tony and Roger, I think, are going to                  11    be the two exposure people who would not necessarily take                  12    chemicals, but they'd be working with the rest of the                  13    people.  So it's one, two, three, four, five of us, and                  14    Peter would be --                  15                  DR. BLANC:  For how many?                    16                  CHAIRMAN FROINES:  6 into 51.                    17                  DR. FUCALORO:  6 times 8.                    18                  DR. BLANC:  So 7 or 8.                    19                  CHAIRMAN FROINES:  Hopefully it can go very                  20    quickly because the methodology has been laid out.  Let's                  21    come back to it.                    22                  DR. GLANTZ:  Do I get any credit for                  23    working on the methodology?                    24                  DR. BLANC:  No.                    25                  DR. MARTY:  As I mentioned, there are a                                                                                   10                 BARNEY, UNGERMANN & ASSOCIATES  1-888-326-5900       1    number of revisions to the document which you have before                   2    you.  Some are based on using the suggested LOAEL to                   3    NOAEL uncertainty factor of 6 for mild adverse effects.                    4    And I listed the chemicals in there which changed as a                   5    result of that decision.                     6                  Some were based on public comments that we                   7    received, and we changed the reference exposure levels                   8    accordingly.  We also have additional suggestions today                   9    for chloropicrin and methyl bromide also based on public                  10    comments.  Those last two changes are not in the document                  11    that you received in December.                     12                  CHAIRMAN FROINES:  Usually when there's a                  13    part "A" and part "B" document, the part "A" deals with                  14    the "exposure."  Are we -- do we have a sense that there                  15    is exposure to these chemicals -- to all 51 of these                  16    chemicals in California?  In other words, is the part "A"                  17    requirements met?                    18                  DR. MARTY:  We -- what we have is                  19    information from the ARB's air toxics emissions database,                  20    and we did look at that database before we developed                  21    reference exposure levels for these chemicals to see if                  22    they were emitted in California.                    23                  The emissions vary widely.  Some of them                  24    are much more important than others.  And also                   25    what -- the other thing that weighed in was whether or                                                                                   11                 BARNEY, UNGERMANN & ASSOCIATES  1-888-326-5900       1    not we had information to develop a reference exposure                   2    level.                     3                  CHAIRMAN FROINES:  So you can                    4    say -- the ARB can tell the panel that every one of the                   5    51 chemicals that people are going to read has some                   6    measurable concentration in the environment.                     7                  DR. MARTY:  You can say they're reported as                   8    emitted under the AB 2588 program.  So you would assume                   9    that there is some exposure near a source at a minimum.                   10                  Again, though, it varies widely.  We can                  11    look at the ATEDS database, and we can look at the most                  12    current update and see if there are some chemicals that                  13    are less important.  If you want us to do that, we can do                  14    that.                    15                  CHAIRMAN FROINES:  I think it would be good                  16    for the panel to know which chemicals people actually                  17    think are important in the state --                  18                  DR. MARTY:  Okay.                    19                  CHAIRMAN FROINES:  -- if it's not too                  20    inconvenient.                    21                  DR. MARTY:  Yeah --                  22                  CHAIRMAN FROINES:  Am I not loud enough?  I                  23    feel like I'm screaming.                    24                  DR. MARTY:  Let me talk with the ARB                  25    emissions inventory branch and get the latest                                                                                   12                 BARNEY, UNGERMANN & ASSOCIATES  1-888-326-5900       1    information, and then what I can do is send it to you.                    2    Now, the information is in pounds per year.  It's not in                   3    concentrations at any specific receptor.  So --                   4                  CHAIRMAN FROINES:  I should say to the                   5    panel that this is an issue which is coming up now                   6    frequently with the Carcinogen Identification Committee                   7    under Prop 65, and that is the question of whether or not                   8    we are identifying carcinogens on that committee that are                   9    actually used or have any potential exposure in                  10    California and in many cases their laboratory                   11    curiosities -- there's just no use.                    12                  And I think on this panel we should only be                  13    dealing with chemicals for which there is an issue and                  14    not simply -- we don't want to get trapped in the kind of                  15    tyranny of lists where people are doing work that isn't                  16    essential and so that's why it's an important issue                  17                  DR. ALEXEEFF:  Genevieve just mentioned to                  18    me that the information on the exposure should be in the                  19    compound summary volumes that ARB has prepared.  So we                  20    should probably give Dr. Atkinson a copy.  The other                  21    panel members have received it.                    22                  Remember the large volumes of the TAC                  23    summary information?  So that exposure information should                  24    be in there as well.                    25                  The other thing -- the difference between                                                                                   13                 BARNEY, UNGERMANN & ASSOCIATES  1-888-326-5900       1    these compounds and those that we have been discussing                   2    under the Toxic Contaminant Program is these are already                   3    listed.  So these are already required to take some sort                   4    of action on as opposed to the TAC process, which has to                   5    develop the basis for listing.                     6                  CHAIRMAN FROINES:  Just for the panel to                   7    note, the reason they're already listed is because                   8    they're hazardous air pollutants under the Clean Air Act                   9    amendments.                    10                  DR. ALEXEEFF:  That is one of the reasons.                   11    Either they are hazardous air pollutants, or they could                  12    be Proposition 65 chemicals, or there could be other                  13    reasons that they're on this list, the hot spots list.                   14    But most of them are on there because they are hazardous                  15    air pollutants or most of them are hazardous air                  16    pollutants.                    17                  CHAIRMAN FROINES:  One of the things we                  18    don't need to take up today but we'd like to begin to                  19    think about reconciling the chemicals on Prop 65 with the                  20    chemicals here so that, if it's here, it should be on                  21    Prop 65.  If it's on Prop 65, it should be here.  So                  22    that's something to talk about at some future date                  23                  DR. ALEXEEFF:  Well, Proposition 65 is                  24    limited to two types of health effects -- reproductive                  25    developmental and carcinogenicity.  So this arena that                                                                                   14                 BARNEY, UNGERMANN & ASSOCIATES  1-888-326-5900       1    we're talking about now includes other health                    2    effects -- neurotoxicity and immunotoxicity.  So this                   3    list is bound to be larger than the other list.                     4                  What has been done here is that the                   5    original hot spots list has been divided into two lists.                    6    One is chemicals that are on the big list which is over                   7    750 chemicals, and the other one is those chemicals for                   8    which the emission information is required to be                   9    obtained.                    10                  So this -- the chemicals we're talking                  11    about are those that the emission inventory has required.                   12    So this is already a sublist of the big list.  So there's                  13    substances that are on the Proposition 65 list for which                  14    we do not believe there's emissions in California.  So                  15    they're not taken care of in this program.                    16                  We've already cut those out.  Most of those                  17    would be -- for our program most of those would probably                  18    be pharmaceuticals that -- for which we don't expect air                  19    emissions.                    20                  DR. MARTY:  Okay.  I thought I'd just                  21    briefly go over this LOAEL to NOAEL extrapolation                  22    uncertainty factor.  Previously we had for mild                  23    irritation an uncertainty factor of 6, and now we have                  24    for all mild adverse effects an uncertainty factor of 6.                   25                  Previously it was 3.  I'm sorry.  Now it is                                                                                   15                 BARNEY, UNGERMANN & ASSOCIATES  1-888-326-5900       1    6.  This is based on an analysis of 112 acute inhalation                   2    studies which identified LOAELs and NOAELs so we could                   3    get the ratio of the LOAEL to the NOAEL for mild adverse                   4    effects.                     5                  For the lowest LOAEL reported to the NOAEL                   6    in the same study, for that ratio, a SAS analysis                   7    indicated that the 50th percentile is 2.2.  The 90th is                    8    5, and the 95th is 6.2.  And that's where we get the 6.                    9    We added an appendix, Appendix F, to the document which                  10    has the analysis in it.                    11                  DR. FUCALORO:  And a 10 is, I guess, the                  12    99th percentile?                    13                  DR. MARTY:  Yes, 10 is the 99th percentile.                    14    The time extrapolation defaults were also of concern to                  15    the SRP.  We had a question last time regarding why, for                  16    the Haber's Law equation, we use a default value for the                  17    exponent "N" of 1 when we are extrapolating from less                  18    than one hour to one hour.                    19                  At the same time we're using a default                  20    value of 2 for that same exponent when extrapolating from                  21    greater than one hour to one hour, and basically, the                  22    answer is that it's a more health-protective approach to                  23    use in the absence of data indicating otherwise.                    24                  And just a very simple example, Haber's Law                  25    is right there.  CNT equals K.  If the concentration of                                                                                   16                 BARNEY, UNGERMANN & ASSOCIATES  1-888-326-5900       1    the NOAEL is 2 at ten minutes, if you use an exponent of                   2    2, then your extrapolated concentration at 60 minutes                   3    would be 0.8.                     4                  If you use an exponent of 1, your                   5    concentration allowable -- or however you want to term                   6    that -- at 60 minutes is equal to 0.3.  The difference                   7    does get larger with shorter and shorter durations of                   8    exposure.                                   9                  So if you do that extrapolation from a very                  10    short exposure, you get a rather large difference between                  11    the one hour extrapolated values for different values of                  12    "N."                  13                  Overall, for a greater than one-hour to                  14    one-hour extrapolations, we decided to use 2, which was                  15    the midpoint of the range of empirically derived values                  16    for the exponent "N" provided in table 12 of the                  17    document.                    18                  DR. ALEXEEFF:  So I'm wondering -- you                  19    know, we're happy to discuss this point some more right                  20    now, if it makes sense to do so.  So our -- what we've                  21    derived in the document are one-hour values, but the                  22    information that we often have in the literature may be                  23    either greater than one hour or less than one hour.                    24                  If there is data to show exactly how to                  25    extrapolate, we will use that empirical information in                                                                                   17                 BARNEY, UNGERMANN & ASSOCIATES  1-888-326-5900       1    the calculation.  But when there is no data, we have a                   2    default procedure.  And the procedure depends on if we're                   3    going from a short time to one hour or a long time to one                   4    hour.                                   5                  And the calculation that we've provided                   6    there shows that -- you know, how much difference there                   7    can be in this calculation.  And that's why we chose                   8    that.  And we've done an analysis of -- in the document                   9    there is a table which discusses all the empirical "N"                  10    values we've been able to find in the literature and                  11    derive.                                  12                  And we did a brief sort of distributional                  13    sort of analysis on that, and the values of 1 and 2 are                  14    kind of, you know, surrounding the two sides of the 50th                  15    percentile there.  So depending upon which way one wants                  16    to extrapolate, it's important to look at                   17    the -- you know, to choose one of those two.                    18                  And both of those two can fit to a certain                  19    extent.  Maybe I didn't exactly describe the distribution                  20    aspect of it, but in any case, there is a table on table                  21    12 which shows all the different values, and you can see                  22    that in many empirical cases it could be 1, and in many                  23    empirical cases it could be 2 or slightly greater.                    24                  And we haven't been able to derive on the                  25    empirical evidence any sort of clear rule, you know, or                                                                                   18                 BARNEY, UNGERMANN & ASSOCIATES  1-888-326-5900       1    decision-making process as to -- on an effect basis as to                   2    when to use 1 or when to use 2.                     3                  Like, the thought originally was that maybe                   4    with irritants it would be closer to 2.  But if you look                   5    at the table, that's not the case.  So we have -- we're                   6    hoping over time maybe to come up with some sort of                   7    better empirical basis on maybe certain types of                   8    mechanisms might have a different extrapolation                   9    procedure.  But at this point we haven't been able to                  10    resolve that.                    11                  DR. MARTY:  I think I need to add in one                  12    other issue and that is that the examples in table 12 for                  13    which "N" was derived are based on lethality.  So they                  14    were not studies just looking at the irritation.                    15                  There aren't any available.  So that's why                  16    we choose to use these.  And there's a large number of                  17    irritants that were given at exposure concentrations that                  18    produced lethality, and I might add that some of them                  19    have an empirically derived value of "N" very close to 1.                   20    Okay.  I --                  21                  DR. GLANTZ:  Could I just ask one other                  22    question about that.  This may reflect -- it's been a                  23    while since I read the comments, but as I recall,                   24    the -- some of the commenters are raising the issues of                  25    repeated dosages versus a single dose.  Could you                                                                                    19                 BARNEY, UNGERMANN & ASSOCIATES  1-888-326-5900       1    just -- that's relevant in terms of this Haber's Law                   2    issue; right?  Or am I getting something mixed up?                     3                  DR. MARTY:  Yes, it is.                     4                  DR. GLANTZ:  Could you just comment -- you                   5    know, kind of explain what the issue is and briefly, you                   6    know, kind of summarize what the commenter said in your                   7    response to it?  Because I think that's an important                   8    point.                     9                  DR. MARTY:  Okay.  I'll cover this a little                  10    bit --                   11                  DR. GLANTZ:  When I read it, it seemed                  12    reasonable, but I forget.                    13                  DR. MARTY:  I'll cover this a little bit in                  14    some of the later slides on specific chemicals.                    15                  DR. GLANTZ:  Okay.  Well, if you'd rather                  16    do that --                  17                  DR. MARTY:  No.  I can do it right now.                   18                  DR. GLANTZ:  Okay.                    19                  DR. MARTY:  Many commented that we should                  20    not use repeated dose studies to generate a one-hour                  21    reference exposure level.  The idea is, of course, that a                  22    repeated dose study usually involves four to eight hours                  23    per day and maybe in some cases, you know, up to five to                  24    ten days.                    25                  And how do you rationally extrapolate that                                                                                   20                 BARNEY, UNGERMANN & ASSOCIATES  1-888-326-5900       1    back to an endpoint that you think might occur after one                   2    hour of exposure?  So we did use repeated dose studies                   3    for reproductive and developmental toxicity endpoints,                   4    and part of the reason is we're trapped in that the                   5    standard protocol for repro tox study is to use repeated                   6    dose exposures because you don't know where in gestation                   7    the developmental or the reproductive effect may occur.                     8                  So we're pretty much stuck.  If we're going                   9    to look at reproductive developmental toxicity as an                  10    endpoint, we're stuck with these types of studies that                  11    use repeated dose exposures.                    12                  There were a few other instances for                  13    different tox endpoints that we ended up using repeated                  14    dose studies.  In one case that I can think of, the                  15    effective concern happened after the first day of                  16    exposure.                    17                  So we were fairly comfortable that it was                  18    okay to use that six-hour exposure and extrapolate that                  19    back to 1.  In the other case that I can think of off the                  20    top of my head, benzene, which I'm going to get to right                  21    now -- Jim, can you put the slide up.                    22                  We were criticized for using repeated dose                  23    studies of immunotoxicity, and this was an infectivity                  24    model in the mouse.  We ended up agreeing with the                  25    commentator that this probably was not the best thing to                                                                                   21                 BARNEY, UNGERMANN & ASSOCIATES  1-888-326-5900       1    do.  So we changed the basis of the REL for benzene.                     2                  DR. GLANTZ:  Well, now, when you do -- when                   3    you're going from the repeated dose studies to your one                   4    hour, let's say I gave -- I exposed a rat or something                   5    four hours a day for a week or for five days, would you                   6    consider that a four-hour exposure or a twenty-hour                   7    exposure?                      8                  DR. MARTY:  We did -- we considered it a                   9    four-hour exposure.  We took -- particularly justifiable                  10    in the case, I think, of reproductive and developmental                  11    endpoints.                    12                  We did receive comment that perhaps we                  13    should have gone for the cumulative 20 hour, and that                  14    example would have been.  But the problem with that is                  15    you can assume for endpoints other than repro tox and                  16    developmental tox that there is a little bit of recovery                  17    in between those four-hour exposures.                    18                  So it's some justification for just using                  19    the one day's worth of exposure to extrapolate back to                  20    one hour.                    21                  DR. ALEXEEFF:  I can clarify a little bit.                   22    You know, our desire is to pick the most appropriate                  23    study to a one-hour exposure.  That's our ideal.  The                  24    closer to one hour that has a sensitive endpoint in                  25    humans or sensitive humans, that's what we'd want.                                                                                     22                 BARNEY, UNGERMANN & ASSOCIATES  1-888-326-5900       1                  And the ideal in this document -- there's a                   2    few substances like sulfur dioxide where you can do that.                     3                  We're basically -- have to use the                   4    information that is published in the literature.  And in                   5    cases where there are repeated dose studies, there's a                   6    couple different types that occur.                     7                  In some cases there is information -- let's                   8    say, it's a ten-day study, and in the report it will say                   9    "After the first day there was" -- "were signs of                  10    irritation.  After the fifth day the animals were having                  11    convulsions."                   12                  So under that circumstance, we had only                  13    used the information under the first day, and we would                  14    just take that out and make all the calculations assuming                  15    that symptom.                    16                  So in other cases, particularly in the                  17    occupational environment studies, they would say "We                  18    conducted a study, four exposures on four different days                  19    within a two-week period on these controlled subjects,                  20    and the subjects indicated" -- "expressed headache."                  21                  But they wouldn't tell us in the article if                  22    it was the first day or the -- you know, anytime during                  23    the period or every time.  So under those circumstances,                  24    we may have had to just make the assumption that it could                  25    have occurred on the first day.                                                                                     23                 BARNEY, UNGERMANN & ASSOCIATES  1-888-326-5900       1                  Now, the example that those are -- there's                   2    not that many of those types of studies.  And then the                   3    example that Dr. Marty gave is the developmental study.                    4    In those cases, there's a very standard protocol for                   5    gestation days.  Usually 6 to 15 animals are exposed, and                   6    that's the data that's provided.  They don't provide                   7    information usually after one -- day one or day two or                   8    anything like that.                     9                  And there are guidelines that have been                  10    developed for reproductive toxicity by the U.S.EPA, which                  11    we feel we are following, and there are also the                  12    guidelines that we operate under in our department, which                  13    is that a one-day exposure could have caused the                  14    developmental effect unless there's some information                  15    which says it didn't happen, and that's because of the                  16    critical period that occurs in the gestation period.  So                  17    that's what we did here.                    18                  So if it was a 6 to -- the most common                  19    comment we received were on developmental studies.  So it                  20    stays 6 to 15, 6 or 7 hours per day exposure.  So we used                  21    that 6 or 7 hours, converted it into one-hour exposure,                  22    and that's the dose that we used.                    23                  DR. MARTY:  Okay.  We made some changes --                  24                  CHAIRMAN FROINES:  Just one quickie.  When                  25    you have a study like four days of certain concentration,                                                                                   24                 BARNEY, UNGERMANN & ASSOCIATES  1-888-326-5900       1    you also, I assume, look at the toxicokinetics to look                   2    and see what you know about elimination clearance and the                   3    AUC overall.                      4                  DR. MARTY:  If that data are available.                     5                  DR. BYUS:  In that regard, if the drug has                   6    a long half-life, it clearly has accumulated over the                   7    time and so the concentration is going up if the                    8    exposure --                   9                  DR. ALEXEEFF:  Right.                    10                  DR. BYUS:  More frequent than the                   11    half-life --                   12                  REPORTER:  I'm sorry?                    13                  DR. BYUS:  Than the half-life.                    14                  DR. ALEXEEFF:  Yes.  If we had the                  15    information like that, then it would be considered                  16    inappropriate to do that calculation.  I mean it would                   17    be -- if we knew that the chemical accumulated and that                  18    the effect was basically an accumulation because the                  19    half-life was so long, then we would not do that                  20    conversion using a one-day study.                    21                  CHAIRMAN FROINES:  So the problem is you                  22    really don't have the data to -- go ahead.                    23                  DR. MARTY:  We did make some changes to our                  24    proposed benzene reference exposure level.  Again, this                  25    is -- the comment was not to use repeated dose studies of                                                                                   25                 BARNEY, UNGERMANN & ASSOCIATES  1-888-326-5900       1    immunotoxicity for the reference exposure level, and we                   2    agreed that for the infectivity model, repeated dose                   3    studies are problematic for extrapolating, for                   4    extrapolating to one-hour exposures.                     5                  We changed to the reproductive and                   6    developmental study that formed the basis of the level                   7    protective against severe adverse effects and this then                   8    becomes the reference exposure level.                     9                  In so doing, that change resulted in a                  10    change of the reference exposure level from 0.24 to                   11    1 ppm.  So it was not a huge change anyhow.  We provide                  12    that information in this revised document.                    13                  This just -- the next few slides just go                  14    over the study that was used.  Coate, et al. (1984),                  15    where there was inhalation exposure to benzene of                  16    pregnant female rats, and the lowest effect measured was                  17    the decreased fetal body weight.                    18                  Next slide, Jim.                    19                  In this case the exposure duration was six                  20    hours per day for five days, and we just used one                  21    six-hour exposure to extrapolate to a one-hour                  22    concentration using Haber's Law and an exponent of 2.                   23                  Since there was an identified no observed                  24    adverse effect level, we did not need an uncertainty                  25    factor to extrapolate from the LOAEL.  We did use                                                                                   26                 BARNEY, UNGERMANN & ASSOCIATES  1-888-326-5900       1    interspecies and intraspecies uncertainty factors of 10                   2    for a cumulative uncertainty factor of 100.                     3                  This resulted in our REL of 1 ppm.  This is                   4    in the document, and it previously served as the level                   5    protective against severe adverse effects, and that has                   6    now become the reference exposure level.                     7                  We also are suggesting changes to the EGBE                   8    reference exposure level.  We received a comment that                   9    EGBE is not a reproductive or developmental toxicant.                   10    And we agreed with the position of the commentator.                    11                  In essence, the study we had used was                  12    problematic because of lysis of the red blood cells that                  13    was seen in the rabbit -- the mother rabbits.                    14                  Instead we used two human studies on                  15    irritation of the eye and nose as the basis for the                  16    revised reference exposure level, and the REL changed                  17    from 2.5 to 2.8 ppm.                    18                  This next slide goes over a little bit of                  19    the data that we ended up using.  There were essentially                  20    two studies that pointed to a no observed adverse effect                  21    level.  One of them was Carpenter, et al. (1956), in                  22    which two subjects were exposed to 113 parts per million                  23    EGBE, and they experienced nasal and ocular irritation.                   24                  However, this study in and of itself we                  25    didn't think was sufficient since there were only two                                                                                   27                 BARNEY, UNGERMANN & ASSOCIATES  1-888-326-5900       1    subjects and only one exposure level.  There is another                   2    study, however, Johanson, et al. (1986), in which seven                   3    healthy adults were exposed to 20 parts per million for                   4    two hours.  There was no irritation observed in these                   5    seven healthy adults.                     6                  This level can, therefore, be identified as                   7    what we would call a freestanding NOAEL on which to base                   8    the REL.  It's freestanding because there were not other                   9    concentrations used in the experiments, and we cannot                  10    figure out where the low observed adverse effect level                  11    might have been in that study.                     12                  After time extrapolation to one hour and                  13    the application of an intraspecies uncertainty factor of                  14    10, the REL is 2.8 ppm.                    15                  DR. BLANC:  Can I just clarify something                  16    again with the lowest observed effect level and the no                  17    observed effect level.  You're basing the RELs on the                  18    uncertainty factor -- you just lost me for a second.                   19                  Because I know sometimes we're using the                  20    lowest -- could you just repeat?  I know you've gone over                  21    this before.                    22                  DR. MARTY:  Okay.  That's fine.                    23                  DR. BLANC:  I just want to be crystal                  24    clear.                    25                  DR. MARTY:  Sometimes the best available                                                                                   28                 BARNEY, UNGERMANN & ASSOCIATES  1-888-326-5900       1    studies do not identify a no observed adverse effect                   2    level.                     3                  DR. BLANC:  They just have the lowest                   4    effect level.                     5                  DR. MARTY:  All you have is the lowest                   6    level tested that had an effect.                     7                  DR. BLANC:  Right.  And then you use an                   8    uncertainty factor.                     9                  DR. MARTY:  Correct.                    10                  DR. BLANC:  When you actually have the no                  11    observed effect level, then what do you do?                    12                  DR. MARTY:  Then we use that level --                  13                  DR. BLANC:  Without an uncertainty factor?                    14                  DR. MARTY:  Without an uncertainty factor.                    15                  DR. BLANC:  Except for the intraspecies.                    16                  DR. MARTY:  And inter.  Inter- and                  17    intraspecies may be applicable.  If it's people, there's                  18    no interspecies extrapolation, but if it's an animal                  19    study, we use --                  20                  DR. BLANC:  A 10.                    21                  DR. MARTY:  Right.                    22                  DR. BLANC:  If it's human, there wouldn't                  23    be an uncertainty factor, or there would still be                   24    an -- within humans.                    25                  DR. MARTY:  There is a within humans                                                                                   29                 BARNEY, UNGERMANN & ASSOCIATES  1-888-326-5900       1    uncertainty factor.                     2                  DR. BLANC:  Okay.  So suppose I have -- if                   3    I have a no effect level of 1 in humans, 1 part per                   4    million, then your level would come up to be .1 because                   5    you'd always use 10.                     6                  DR. MARTY:  Unless --                   7                  DR. BLANC:  It was done in asthmatics.  And                   8    then you wouldn't use anything.                     9                  DR. FUCALORO:  Excuse me.  That's a .1 for                  10    an REL.                   11                  DR. BLANC:  For an REL.  For your RELs.                    12                  DR. MARTY:  Correct.                    13                  DR. BLANC:  If you had a lowest observed                  14    effect level in a mouse, can you just walk through what                  15    happens then?  A lowest --                  16                  DR. MARTY:  A lowest observed effect level,                  17    we would use -- if it were a mild adverse effect level,                  18    we would use an uncertainty factor of 6 to try to define                  19    the no observed adverse effect level.                    20                  DR. BLANC:  And then you'd do 10 and 10.                    21                  DR. MARTY:  Yes.                    22                  DR. ALEXEEFF:  So that the total                  23    uncertainty factor in that case would be 600.                    24                  DR. BLANC:  The most it can be is a                  25    thousand if it was a serious effect because then you'd do                                                                                   30                 BARNEY, UNGERMANN & ASSOCIATES  1-888-326-5900       1    10, 10 and 10.                     2                  DR. MARTY:  Correct.                     3                  DR. BLANC:  So depending on the study                   4    number that you have, the difference between the REL and                   5    the number you're actually working with can be anywhere                   6    from 1,000 to 1.                     7                  DR. MARTY:  Correct.                     8                  DR. BLANC:  Is that --                   9                  DR. FUCALORO:  It can't be 1, can it?                     10                  DR. BLANC:  It can be 1 if it was a study                  11    in asthmatic humans.                    12                  DR. FUCALORO:  That would give you a NOAEL,                  13    an N-O-A-E-L; correct?  Say, of -- then you'd still put                  14    another factor on it to get the REL; correct?                    15                  DR. MARTY:  If we had a no observed adverse                  16    effect level in asthmatic humans and we know that                  17    asthmatics are identified sensitive subpopulation for                  18    that chemical, then we would not apply an additional                  19    uncertainty factor.                    20                  If we were -- if the study was done in                  21    asthmatics but asthmatics are not particularly sensitive                  22    relative to general population, then we would have to                  23    apply another uncertainty factor.                    24                  DR. ALEXEEFF:  If you turn in the document                  25    to page 43, there's a table of all the uncertainty                                                                                   31                 BARNEY, UNGERMANN & ASSOCIATES  1-888-326-5900       1    factors that we've used, on page 43, table 9, for each                   2    substance.  And it tells you when we've had to apply                   3    uncertainty factors and then how large the uncertainty                   4    factors are.                     5                  DR. BLANC:  Right.                     6                  DR. ALEXEEFF:  In that table you can see                   7    that, for example, carbon monoxide, the total uncertainty                   8    factor is 1.  For ammonia the total uncertainty factor is                   9    3 and then the next level is 60 for dioxane.  The total                  10    uncertainty factor is 60.  Then it goes to 100 and then                  11    600 and then 1,000.                    12                  CHAIRMAN FROINES:  If I can make just one                  13    comment just for the panel, this means that, if the                  14    endpoint were reproductive or developmental, that the REL                  15    or the value that you calculate could differ than the                  16    value that would be calculated near Prop 65 since under                  17    Prop 65 it is required to use a safety factor of 1,000.                   18    So that the value that OEHHA has for developmental                  19    reproductive toxins in Prop 65 could differ considerably,                  20    in fact, from the value between the 1807 and Prop 65.                    21                  DR. ALEXEEFF:  Generally the Proposition 65                  22    value would be more stringent by a factor of 10.                    23                  DR. MARTY:  We also made changes to the                  24    hydrogen sulfide reference exposure level.                    25                  CHAIRMAN FROINES:  One could argue -- I'm                                                                                   32                 BARNEY, UNGERMANN & ASSOCIATES  1-888-326-5900       1    sorry.  I'm sorry for prolonging this, but one could                   2    argue that we should modify that factor of a thousand                   3    because it's what was in the law.  It's not based on any                   4    science.  But that's --                   5                  DR. BLANC:  Thank you for sharing that with                   6    us.                     7                  DR. GLANTZ:  Let the record show that the                   8    chair was hoping to expedite the meeting.                     9                  CHAIRMAN FROINES:  Let's go ahead.                    10                  DR. GLANTZ:  And told me I wasn't allowed                  11    to talk.                    12                  CHAIRMAN FROINES:  I never said that.                    13                  DR. MARTY:  Okay.  We made some changes to                  14    the hydrogen sulfide REL.  This is, again, based on                  15    public comment.  We received comment that hydrogen                  16    sulfide odor detection can be accompanied by headache and                  17    nausea and that the Ambient Air Quality Standard is not                  18    solely based on odor detection.                    19                  We were provided documentation of                  20    complaints of headache and nausea by the Air Districts,                  21    and we decided to return to the original proposal to use                  22    the Ambient Air Quality Standard, which is set for a                  23    one-hour exposure in the state.                    24                  The acute reference exposure level then                  25    becomes 42 micrograms per cubic meter based on the                                                                                   33                 BARNEY, UNGERMANN & ASSOCIATES  1-888-326-5900       1    Ambient Air Quality Standard.  The documentation for that                   2    Ambient Air Quality Standard indicates that the primary                   3    study that was the basis for the Ambient Air Quality                   4    Standard consisted of a panel of 16 people.                     5                  They exposed these individuals to hydrogen                   6    sulfide at increasing concentrations until the odor was                   7    detected.  To some the odor was accompanied by adverse                   8    physiological responses.  So we are terming the                   9    critical-effect physiological response to odor, namely                  10    headache and nausea.                    11                  And again, the Ambient Air Quality Standard                  12    used the geometric mean of the odor threshold, which is                  13    0.03 parts per million.  I should probably add that we                  14    did receive comment after the public comment period that                  15    in actual fact the H2S Ambient Air Quality Standard is                  16    0.025, which would mean that it's 35 micrograms per cubic                  17    meter.  Somewhere along the line it was rounded up.  So I                  18    think we're going to stick with what we have here.                    19                  We did also in deliberating the hydrogen                  20    sulfide issue -- initially our proposed reference                  21    exposure level was for respiratory irritation.  So the                  22    endpoint has actually changed.  This number will not be                  23    used to evaluate impacts on respiratory irritation --                  24    impacts of respiratory irritation from hydrogen sulfide                  25    in a risk assessment.                                                                                     34                 BARNEY, UNGERMANN & ASSOCIATES  1-888-326-5900       1                  It's almost -- in fact, it is at this point                   2    in a category all its own.  That's physiological response                   3    to odor.                     4                  We also made changes to the xylene                   5    reference exposure level based on the comment that more                   6    data were available on irritation than was used in our                   7    document and that these studies had more appropriate                    8    exposure durations.                     9                  We agreed with the commentator and ended up                  10    using Hastings, et al. (1986), with support from two                  11    other studies, Carpenter, et al. ('75), and Nelson, et                  12    al. (1943).  Initially, we had used Nelson, et al.                  13    (1943), which had a three- to five-minute exposure                  14    duration and had extrapolated to a 60-minute exposure                  15    duration.                  16                  And as I mentioned earlier, the shorter the                  17    duration, the more important the choice of that exponent                  18    "N" in Haber's Law becomes when you're extrapolating up                  19    to 60 minutes.                    20                  So this change using Hastings et al.                  21    allowed a lesser time extrapolation.  So we went from 30                  22    minutes to 60 minutes, rather than from 3 minutes to 60                  23    minutes.  The result is it changed the reference exposure                  24    level from .5 to 5 parts per million.                    25                  Just a brief comment on the studies for                                                                                   35                 BARNEY, UNGERMANN & ASSOCIATES  1-888-326-5900       1    xylenes.  Nelson, et al. (1943), exposed ten subjects for                   2    three to five minutes to 100 or 200 ppm.  There was no                   3    irritation noted by the subjects at 100 ppm.                     4                  In Carpenter, et al. (1975), one of seven                   5    subjects reported nose discomfort at 106 ppm for a                   6    15-minute exposure.  But this same individual did not                   7    report nose discomfort at higher concentrations to which                   8    he was exposed.  So the authors considered 106 ppm to be                   9    a no observed adverse effect level for a 15-minute                  10    exposure.                    11                  CHAIRMAN FROINES:  Do you agree with that?                    12                  DR. MARTY:  We agree with that.                    13                  CHAIRMAN FROINES:  Wow.  Why                   14    isn't -- why -- perhaps you get some saturation                  15    phenomenon on a higher concentration and that the value                  16    of 106 was actually an occurrence that had -- that was                  17    meaningful.                    18                  DR. MARTY:  I think taken in context of the                  19    rest of the available data, it points to 100 ppm as a                  20    NOAEL.  In also reading the study, the individual who                  21    reported nose discomfort, the way he put it was that he                  22    thought maybe his -- he had some irritation in the nose,                  23    but it wasn't so striking as to be called irritation.  So                  24    he called it discomfort.                    25                  CHAIRMAN FROINES:  So how do you get to 5                                                                                   36                 BARNEY, UNGERMANN & ASSOCIATES  1-888-326-5900       1    parts per million?  Because you're adding an interspecies                   2    variability term -- I mean an interindividual variability                   3    term of 10 and then a factor of -- you're not assuming a                   4    LOAEL.  You're assuming it's a NOAEL.  So you don't have                   5    6.                     6                  DR. MARTY:  Right.  The way it gets to 5 is                   7    because we extrapolate from 30 minutes in the Hastings                   8    study to 60 minutes using Haber's Law.  Hastings had                   9    exposed 50 individuals to 100, 200 or 400 parts per                  10    million of mixed xylenes for 30 minutes to evaluate eye,                  11    nose and throat irritation.                         12                  The percent of subjects reporting eye                  13    irritation was not different from controls at 100 ppm.                   14    Thus these three studies together point to 100 ppm as a                  15    NOAEL for at least 30-minute exposure durations, and                  16    that's what we ended up choosing.  It is -- it does point                  17    to the fact that we would like to have a stronger data                  18    set to develop a lot of these reference exposure levels.                    19                  CHAIRMAN FROINES:  These issues become                  20    important depending upon the levels of aromatics and                  21    gasoline.  So it's not a trivial issue.                    22                  DR. MARTY:  I think that covers it for the                  23    changes that we made to a reference exposure level based                  24    on public comment except for two more that are coming                  25    down the line.  Maybe I should do those first.                                                                                     37                 BARNEY, UNGERMANN & ASSOCIATES  1-888-326-5900       1                  Jim, it's the chloropicrin slide.                      2                  DR. GLANTZ:  While you're digging it out, I                   3    have -- I read through all of the comments and the                   4    responses, and I think OEHHA was very responsive.  I                   5    think when the commenters brought forward reasonable                   6    evidence for a change.  It was made in the cases where                   7    they didn't change something, and I thought they had                   8    pretty good reasons.                     9                  DR. MARTY:  In the case of chloropicrin?                    10                  DR. GLANTZ:  No.  These are the new ones.                   11    We haven't seen --                  12                  DR. MARTY:  Right.  I'm going to go over                  13    the two new ones right now.  It would be chloropicrin and                  14    methyl bromide that the panel has not seen.                    15                  We did receive comment on the chloropicrin                  16    reference exposure level.  One of the comments was that                  17    we should not time extrapolate for trigeminal nerve                  18    mediated irritants.  There is evidence for some irritants                  19    that irritation may be more concentration dependent than                  20    time dependent.                    21                  And so certain individuals in the                  22    scientific community think it's inappropriate to use                  23    Haber's Law to extrapolate.                                  24                  However, we cannot find data to quantitate                  25    this phenomenon and particularly for chloropicrin here.                                                                                    38                 BARNEY, UNGERMANN & ASSOCIATES  1-888-326-5900       1    There is also a comment that we should have done or could                   2    have done a benchmark dose approach.                     3                  So we are now suggesting using a                   4    benchmark-concentration-type approach and applying                   5    appropriate uncertainty factors, but we are also                   6    continuing to use time extrapolation.  The reference                   7    exposure level would change from 1 to 4.4 parts per                   8    billion.                     9                  DR. GLANTZ:  That's if you do the                   10    benchmark --                  11                  DR. MARTY:  Right.                    12                  DR. GLANTZ:  So I'm unclear, though.  What                  13    is it you're recommending?                    14                  DR. MARTY:  Okay.  The next couple slides                  15    will show that.  We use the same study we used before.                   16    That is a study of the RD50 by Kane, et al. ('79).  The                  17    study was conducted in mice, and the critical effect                  18    measured in the study is decrease in respiratory rate by                  19    50 percent or RD50, and this is the Alarie method.                   20                  So we took -- as a low observed adverse                  21    effect level, we took the RD50.  In the study they                  22    provided a dose response curve and gave the equation that                  23    defines the line.  So we use that equation to get the                  24    RD05, which is 0.79 parts per million.                    25                  This is analogous to the benchmark                                                                                   39                 BARNEY, UNGERMANN & ASSOCIATES  1-888-326-5900       1    concentration approach where you're looking for                    2    the -- you're extrapolating back to the 5 percent                   3    response rate.                     4                  The exposure duration was ten minutes.  So                   5    we did use Haber's Law with an "N" value of 1 to                   6    extrapolate to a 60-minute exposure.  The one-hour                   7    extrapolated RD05, then, is 132 parts per billion.                     8                  Since a NOAEL was identified, we didn't                   9    have a LOAEL uncertainty factor.  We used an interspecies                  10    uncertainty factor of 3, which is what we have been doing                  11    with the benchmark concentration approach because we feel                  12    that we have pegged the 5 percent response rate much                  13    better than if you use the classical uncertainty factor                  14    approach where you're constrained by the investigator's                  15    choice of exposure level.                    16                  I probably should insert here that there                  17    have been some studies -- I think George did one -- that                  18    looked at where on a dose response curve the NOAEL comes                  19    out to be -- if you're just looking at the investigator's                  20    choice of doses, it usually ends up being at about what                  21    you would interpolate as the 5- to 10-percent response                  22    rate.  So this goes back to why we chose benchmark                  23    concentration 05 initially in our benchmark concentration                  24    methodology.                                  25                  We also applied an intraspecies uncertainty                                                                                   40                 BARNEY, UNGERMANN & ASSOCIATES  1-888-326-5900       1    factor of 10 to account for sensitive subpopulations for                   2    a cumulative uncertainty factor of 30.  This gives a                   3    reference exposure level of 4.4 parts per billion.                     4                  DR. BLANC:  So you've gone from 1 part per                   5    billion to 4 --                    6                  DR. MARTY:  Right.  Which rounds down to 4.                    7    1 to 4.                     8                  DR. BLANC:  Although I think that the -- it                   9    was good that you were responsive in the way you were                  10    from a general point of view, I think, being responsive                  11    to the earlier comment from a different group wherein                  12    they called your attention to the fact that chloropicrin                  13    photooxidizes to phosgene, I believe you should stick                  14    with 1 part per billion so that you're consistent with                  15    your level for phosgene so that, even if all of it                  16    photooxidized to phosgene -- I think it would be an                  17    inconsistency in the document if, in fact, you were                   18    less -- you were more generous with the REL for                  19    chloropicrin than for phosgene.                                  20                  I think you have to pick whichever's lowest                  21    and apply it to chloropicrin.  Before it wasn't an issue                  22    because you were at 1 part per million anyway.  But I                  23    think what you should do in your document is say, you                  24    know, we -- if we did this ultimate thing, we might come                  25    out to 4.9, but in this particular case because -- as                                                                                   41                 BARNEY, UNGERMANN & ASSOCIATES  1-888-326-5900       1    it's been pointed out to us, it photooxidizes to                   2    phosgene.                                   3                  We have to use the lower level which we had                   4    achieved by different assumptions anyway.  So actually, I                   5    wouldn't adopt this level.  I would stick with the 1 part                   6    per billion since the kind of exposure scenarios we're                   7    talking about would likely be outdoors where there might                   8    very well be photooxidation, if one can assume.  Is that                   9    a reasonable public health approach?                    10                  DR. ALEXEEFF:  I think it's a reasonable                  11    approach.  We'll look --                  12                  DR. BLANC:  And also one of your                  13    commentators anyway -- you'd be responding to them                  14    anyway.  Because they said, "Well, you have to take into                  15    account that it's broken down to phosgene."                  16                  DR. MARTY:  It's the same commentator.                     17                  DR. BLANC:  Oh, great.  Then you're                  18    perfect.  You're golden.                    19                  DR. MARTY:  Okay.  Then the other change                  20    which you folks haven't seen is the methyl bromide                  21    reference exposure level proposed revisions.                    22                  Our initial -- Jim, I got to use your                  23    slide.  I can't find mine.                    24                  We did receive again comment that we should                  25    not use repeated dose studies for methyl bromide, but                                                                                   42                 BARNEY, UNGERMANN & ASSOCIATES  1-888-326-5900       1    this is the instance where the effects were seen after                   2    the first day of exposure.                     3                  Increasingly severe effects were seen                   4    following further exposure, but we're focusing on just                   5    the one day.  There was also a comment that we should                   6    time extrapolate.                     7                  As you'll recall in the original proposal,                   8    we did not time extrapolate from the seven-hour exposure                   9    of a single day to one hour because there was some                  10    controversy over whether that was something that should                  11    be done based on outside review by Dr. Jerry Last at                  12    U.C. Davis.                    13                  This was review that was requested by the                  14    Department of Pesticide Regulation.  So we had not time                  15    extrapolated it.  We did, however, find in the literature                  16    a computed value for the exponent "N" in Haber's Law.  So                  17    there obviously are some people out there who think that                  18    you can compute empirically a value for Haber's Law.                    19                  The commentator also suggested a different                  20    way of coming to a one-hour exposure level for humans,                  21    and the result of that methodology would be that a                  22    six-hour exposure at 100 ppm in rats is equivalent to a                  23    one-hour exposure at over 2,000 ppm in humans.                    24                  The methodologies counter to the human                  25    equivalent calculations done by U.S.EPA and others, and                                                                                   43                 BARNEY, UNGERMANN & ASSOCIATES  1-888-326-5900       1    we were not comfortable with the commentators'                   2    methodology.  They also did not provide a sufficient                   3    justification for that particular method.                     4                  So we have some suggested changes to the                   5    methyl bromide reference exposure level.  Zwart et al. in                   6    1992 reported empirically derived values of "N" for                   7    Haber's Law for methyl bromide.  Based on the Irish, et                   8    al. (1940) data, the "N" is 1.33.  Using that "N" and                   9    time extrapolating changes the reference exposure level                  10    from 1 to 4.45.                    11                  We used the same study, the Pharmaco LSR                  12    data in dogs where exposures varied from 103 to 394 parts                  13    per million.  Various durations of exposure were used                   14    in this study.  We show one seven-hour exposure.  The                  15    critical effects seen were lacrimation, pulmonary                  16    toxicity and central nervous system toxicity.                    17                  There was a no observed adverse effect                  18    level then of 103 parts per million in this study.  We                  19    extrapolated to the one-hour NOAEL using Haber's Law and                  20    an exponent of 1.33.                    21                  We applied a cumulative uncertainty factor                  22    of 100.  10 for interspecies and 10 for intraspecies                  23    variability.  The resulting reference exposure level is                   24    4 ppm.                    25                  DR. FUCALORO:  But, of course, the work in                                                                                   44                 BARNEY, UNGERMANN & ASSOCIATES  1-888-326-5900       1    Zwart's study, as I pointed out I think before, had an                   2    endpoint of LC50; right?  And you're applying that Haber                   3    Law exponent to a different type of endpoint, but you                   4    think that's valid.                     5                  DR. MARTY:  Yes.  We're doing that, and                   6    we've done it in other cases, and it's a function of the                   7    availability of data.  And we do recognize that that is                   8    an uncertainty.                       9                  CHAIRMAN FROINES:  How many do you have                  10    more?                    11                  DR. MARTY:  We probably have 20 more                  12    slides, 15.                    13                  CHAIRMAN FROINES:  20 more slides.                    14                  DR. MARTY:  Fifteen to twenty.                    15                  CHAIRMAN FROINES:  How much time do you                  16    need on DEF and methyl parathion?                    17                  REPORTER:  Wait.  Could you state your                  18    name, please.                    19                  MR. GOSSELIN:  Paul Gosselin.                    20                  DR. BLANC:  Paul Gosselin in DEF.                    21                  MR. GOSSELIN:  Based upon the discussions                  22    we've had and the comments and seeing some of the edits,                  23    that may take -- I don't know -- half hour.                    24                  CHAIRMAN FROINES:  So you say methyl                  25    parathion stands comment about the panel's time                                                                                   45                 BARNEY, UNGERMANN & ASSOCIATES  1-888-326-5900       1    notwithstanding --                   2                  DR. GLANTZ:  There has to be an uncertainty                   3    factor.                     4                  CHAIRMAN FROINES:  No, no, no.  I'll come                   5    to that.  So you're saying, say, 15 minutes on methyl                   6    parathion and half an hour on DEF, and the panel could                   7    double that.  So that's potentially an hour and a half.                    8    That's, say, an hour you need overall.                     9                  MR. GOSSELIN:  Right.                    10                  CHAIRMAN FROINES:  With some error margins                  11    there.  So we're at -- so essentially we can use up to an                  12    hour, I guess, and my assumption is that I'm checking off                  13    each chemical we're going through.                    14                  So when we assign chemicals to the panel,                  15    I'm assuming that, as we go through each chemical, we can                  16    assume that we don't really need to assign those                  17    chemicals, if that's a fair assumption.  Unless somebody                  18    wants to go back and revisit something we've discussed                  19    here.                    20                  DR. FUCALORO:  That's very good, John.                   21    Because I was going to suggest that we forego doing this                  22    since we're going to review the chemicals individually,                  23    but you've actually turned it around saying that, since                  24    we're reviewing these right now, there's no need to                  25    assign them.                                                                                     46                 BARNEY, UNGERMANN & ASSOCIATES  1-888-326-5900       1                  CHAIRMAN FROINES:  If we can cover 20                   2    chemicals in the next hour, recognize that there may be                   3    problems --                    4                  DR. COLLINS:  Twenty slides.                     5                  CHAIRMAN FROINES:  How many chemicals?                     6                  DR. MARTY:  It's a total of 15.                     7                  CHAIRMAN FROINES:  Okay.  Well, that seems                   8    to me it would cut our out-of-meeting workload down                   9    considerably.  So I would argue that we go ahead and do                  10    it.  And I think we can be out of here about one o'clock                  11    if we do that still.                    12                  DR. MARTY:  We do have a revised proposed                   13    acrolein REL.                     14                  CHAIRMAN FROINES:  Is that okay with                  15    everybody?                    16                  DR. MARTY:  Sorry.                    17                  DR. FRIEDMAN:  I just want to clarify.  So                  18    that this quick review of changes in the RELs is supposed                  19    to substitute for our careful reading of each of these                  20    chemicals?                    21                  CHAIRMAN FROINES:  Well, that's a question.                   22    That's why I was raising it.  If the panel is comfortable                  23    with the discussion that we have on the chemical, then we                  24    would not have to assign them.                    25                  If the panel feels that they would like to                                                                                   47                 BARNEY, UNGERMANN & ASSOCIATES  1-888-326-5900       1    go back and read it more in depth, clearly that would                   2    take precedent.                     3                  DR. FRIEDMAN:  Are there people -- I am not                   4    knowledgeable in this area.  Are there people on the                   5    panel who have studied these individual chemical reports                   6    and feel comfortable with them or -- because I feel a                   7    little bit uncomfortable, if that isn't the case, of our                   8    relying just on this half-minute presentation to make a                   9    judgment.                    10                  CHAIRMAN FROINES:  I think there are                  11    varying -- if I had to guess, I'd say there are varying                  12    degrees of review going from 0 to 100 percent.                    13                  DR. GLANTZ:  Well, I think -- I mean since                  14    I think I'm probably, except maybe for the chair, the                  15    only person who's read the whole report, I think that's a                  16    reasonable procedure, John, with the caveat that, since                  17    we're going to be considering the report again at the                  18    next meeting, that to the extent the members want to go                  19    back and read the rest of it and bring any additional                  20    issues to bear at the meeting on the compounds we talk                  21    about today, that's fine.                    22                  I think -- to me -- I mean the way I've                  23    dealt with this was to concentrate mostly on the                  24    methodology which is the first part, and the whole idea                  25    of this exercise, as we've developed it, was to come up                                                                                   48                 BARNEY, UNGERMANN & ASSOCIATES  1-888-326-5900       1    with a defendable methodology and then systematically                   2    apply it with making exceptions where there was a good                   3    reason to do it, which is, I think, what they've done.                    4                  And then I have to say that having done                   5    that, I've relied pretty heavily on the public comments                   6    and to see when criticisms are raised by the interested                   7    parties, because they know more than I do, and then to                   8    try to judge whether OEHHA had a reasonable response                   9    either in amending the report, as they've done in several                  10    cases, or defending the report.                    11                  So I think the important thing is to see                  12    that -- so effectively what's going on here is they're                  13    going through the compounds that there were comments on,                  14    and I think we could just go through the same exercise                  15    for the rest of them.                    16                  It's -- they're pretty much cookie-cutter                  17    analyses, if you look at them.  I think everyone on the                  18    panel should look at the whole report and bring up any                  19    issues people have to bring up before we include.                      20                  DR. FRIEDMAN:  If we do take that route of                  21    looking at the whole report, then I would appreciate the                  22    subdividing by assignments because that's an awful lot of                  23    work to review this carefully in the time we have, and I                  24    would appreciate to be given assignment of a few of them                  25    to look at carefully rather than having to be responsible                                                                                   49                 BARNEY, UNGERMANN & ASSOCIATES  1-888-326-5900       1    for the whole thing.                     2                  DR. GLANTZ:  No.  I think that's what                   3    John's saying.  The question is should he -- for the ones                   4    which were discussed at the meeting, does he need to                   5    explicitly assign those out or not?                     6                  DR. BLANC:  I would -- I'm sorry.                     7                  DR. GLANTZ:  But I would --                   8                  DR. BLANC:  I would just see that it's a                   9    little bit weighted so that somebody doesn't get all ones                  10    that weren't discussed or something, if that's the issue.                    11                  CHAIRMAN FROINES:  I think that one way to                  12    approach it is to assume that we have gone through these                  13    to a certain degree, and if somebody from the outside                  14    wants to raise a question about a particular chemical,                  15    that can be taken up at some future time.  I mean I think                  16    that with -- the process isn't a closed one.                    17                  I think as a matter of law I asked the                  18    question with -- to OEHHA and to ARB last time, "Does the                  19    panel have to go through every chemical and go through                  20    every number?"                  21                  And I think the legal answer so to speak                  22    was "no."  But we felt that we still should go through                  23    the chemicals because the panel should have read the                  24    document, and we should have that within the context of                  25    our findings.                                                                                     50                 BARNEY, UNGERMANN & ASSOCIATES  1-888-326-5900       1                  So I think we're going one step better than                   2    we have to, but I think we also want to try to minimize                   3    the impact as well.                     4                  So it seems to me that, if we subtract out                   5    the chemicals we're doing here and if there is major                   6    controversy surrounding any of those, we can take them up                   7    again, but that would give us a much lighter load.                     8                  DR. FRIEDMAN:  Perhaps we could -- you say                   9    the two of you have read the full report.  We can regard                  10    you as lead persons as we have with previous reports and                  11    then I would feel more comfortable.                    12                  CHAIRMAN FROINES:  Well, I think the                   13    panel -- we should --                  14                  DR. GLANTZ:  Well, the lead --                  15                  CHAIRMAN FROINES:  -- divide --                  16                  REPORTER:  Wait.  Wait.  One at a time.                   17                  DR. GLANTZ:  The other lead person was                  18    Seiber, who's not here anymore.  But yeah.  I think we                  19    should just go on.  Maybe the compromised position on                  20    this would be to assign out to, you know, divide -- was                  21    it 51 chemicals?  The 51 chemicals up among the members                  22    of the panel but then indicate -- just remind people                  23    which ones we've already dealt with.                    24                  And then the people can go take another                  25    look if they want but concentrate on the ones that                                                                                   51                 BARNEY, UNGERMANN & ASSOCIATES  1-888-326-5900       1    haven't been discussed.                     2                 CHAIRMAN FROINES:  I would argue a little                   3    bit the opposite.  I'd argue that we divide up the                   4    chemicals that haven't been discussed here today --                   5                  DR. GLANTZ:  Okay.                     6                  CHAIRMAN FROINES:  -- and that the two                   7    leads, which are now you and me, that we go back over the                   8    chemicals that have been discussed today to see --                   9                  DR. GLANTZ:  Okay.                    10                  CHAIRMAN FROINES:  -- if there's any                  11    particular problem.                    12                  DR. BLANC:  All right.  Fine.                    13                  DR. GLANTZ:  Okay.  That's fine.                    14                  DR. BLANC:  Can I get back to methyl                  15    bromide for a minute?                    16                  DR. GLANTZ:  Okay.                    17                  DR. BLANC:  Can you comment on the acute                  18    human toxicity in your document where a workplace                  19    concentration of 35 parts per million for short,                  20    unspecified durations induced anorexia, nausea, vomiting                  21    and corrosion of the skin, although the methods of                  22    determination were crude --                  23                  CHAIRMAN FROINES:  What page are you on,                  24    Paul?                    25                  DR. BLANC:  That's on page --                                                                                   52                 BARNEY, UNGERMANN & ASSOCIATES  1-888-326-5900       1                  DR. MARTY:  C-197.                     2                  DR. BLANC:  C-197.                     3                  DR. ALEXEEFF:  Yeah.  What that study                   4    refers to, it was a study of workers involved in dried                   5    fruit fumigation, and the level here is -- of 35 reflects                   6    exceedences over time, over the background.                     7                  So there was some general background                   8    concentration of undetermined measure.  And on occasion                   9    there were spikes up to 35.  So it's not -- it's even a                  10    little more complex than the repeated concentrations we                  11    were referring to before, where you have exposures each                  12    day of a certain concentration.                    13                  In this case, we have some sort of chronic                  14    background exposure and then repeated spikes, and what                  15    was happening, as I recall in this case, the 35 was                  16    occurring when they were opening up the chambers.                    17                  DR. BLANC:  Would they have acute symptoms                  18    at the time of 35 --                  19                  DR. ALEXEEFF:  Right.  They would have                  20    acute symptoms until they instituted new controls.                    21                  DR. BLANC:  And when they instituted the                  22    new controls --                  23                  DR. ALEXEEFF:  The symptoms went away.                    24                  DR. BLANC:  Because if the level is 35 and                  25    you assume that was a one-hour exposure and you used an                                                                                   53                 BARNEY, UNGERMANN & ASSOCIATES  1-888-326-5900       1    inter -- intraspecies of 10, that would be 3.5.  You'd                   2    also -- you'd have to go to a no effect level which would                   3    be a .35, which would be considerably lower than the new                   4    proposal you have of 4.8 parts per million.                     5                  DR. ALEXEEFF:  Yeah.  I think --                   6                  DR. BLANC:  Makes me a little                   7    uncomfortable, I must say.                     8                  DR. ALEXEEFF:  You have a good point.                    9    We'll go back and look at that study again.                    10                  DR. BLANC:  And I just have to say that the                  11    4 parts per million range of methyl bromide makes me                  12    uncomfortable.  It seems to me that, given how potent                  13    that is, I'm surprised the calculations yielded a value                  14    that high.  It just strikes me as being on the high side.                   15                  So and also given the amount of human                  16    exposure experience, it might be worth a recheck of the                  17    literature just to make sure there aren't any human case                  18    reports that you've missed that would be relevant.                    19                  Because if you combined even a couple of                  20    case reports with this old industrial report and if it                  21    seems like you're in a range where 30 parts per million                  22    is causing problems -- in fact, anything that was causing                  23    problems at 100 parts per million, in fact, would get you                  24    back to 1 part per million, wouldn't it?  Because you                  25    have an intraspecies factor of 10, and you need 10 to get                                                                                   54                 BARNEY, UNGERMANN & ASSOCIATES  1-888-326-5900       1    to a no effect level; is that right?                     2                  DR. ALEXEEFF:  Yeah.  For the most part,                   3    you're right.  And we will go back.  We'll look at this                   4    study.  We'll look at the other case reports.  And this                   5    particular study, it's in the document because it's                   6    clearly not strictly a chronic exposure level.  So we're                   7    not talking chronic here.                     8                  DR. BLANC:  Right.                     9                  DR. ALEXEEFF:  But it's not really acute                  10    either.  So we can go back to look to see where it sort                  11    of fits on that continuum and look at that information                  12    again.                    13                  And the interesting thing about methyl                  14    bromide -- I don't really -- it's not really that potent                  15    of a compound.  It's really more insidious that creates                  16    the concern about it in that the type of health effects                  17    that occurs and the fact that these effects can be                  18    delayed and the type of neurological symptoms that occur.                   19                  I think there's sort of some issues like                  20    that and that there's not a clear -- there's not -- it's                  21    what I would refer to as kind of a -- an all or none kind                  22    of effect.                    23                  You're dosing either the animals or the                  24    humans are being exposed, and there's no reported health                  25    impact.  And all of a sudden at a slightly higher dose,                                                                                   55                 BARNEY, UNGERMANN & ASSOCIATES  1-888-326-5900       1    there's dramatic impact in the neurological system.                     2                  And I think that's what makes methyl                   3    bromide kind of an interesting, interesting compound.                    4    But it's really -- if you look at the actual doses that                   5    are used in the animal experiments, it's not really that                   6    potent, I mean, compared to some of the other substances                   7    we're talking about such as phosgene or --                    8                  DR. BLANC:  Well, because you're not                   9    primarily looking at a respiratory irritant.  You're                  10    looking at a neurologic, but still double-check that.                    11                  DR. ALEXEEFF:  We will.  We definitely                  12    will.                    13                  DR. BLANC:  It just makes me --                  14                  CHAIRMAN FROINES:  I think this one is                  15    extremely important to check because there is widespread                  16    use and there's also widespread controversy and so I                  17    think that we want to be very careful on this one.  This                  18    is a high-profile chemical.                    19                  DR. MARTY:  I just wanted to add one other                  20    technical issue that, when we read the Watrous, (1942)                  21    study, and that is with exposure, it -- a little nervous                  22    using exposure data from the study since it is a crude                  23    measurement relative to measurements that we would do                  24    today.                    25                  DR. BLANC:  You think they underestimated                                                                                   56                 BARNEY, UNGERMANN & ASSOCIATES  1-888-326-5900       1    the exposure?  Is that when you say "crude"?                     2                  DR. MARTY:  No.  I think we don't                    3    know -- it's not a very accurate measure of exposure --                   4                  DR. BLANC:  Well, it only matters if it's                   5    accurate in that it was actually 350 parts per million                   6    and they thought it was 35.                     7                  DR. MARTY:  Right.                     8                  DR. BLANC:  If it was 3.5 and they thought                   9    it was 35, it's not a problem.                    10                  DR. MARTY:  Right.                    11                  DR. BLANC:  Except in the other direction                  12    for you.                    13                  DR. MARTY:  Right.                    14                  DR. BLANC:  In using it.  So is it that you                  15    think that it's -- that they underestimated exposure?                    16                  DR. MARTY:  I think we can say we don't                  17    know.                    18                  CHAIRMAN FROINES:  But I think that Paul's                  19    point about 100 gets you down to 1, not 4.4, is also very                  20    relevant.  I mean I don't know anybody in this room who                  21    wants to -- who would say that there aren't effects of                  22    methyl bromide 100 parts per million.                    23                  DR. BLANC:  Yeah.  I mean even if you put                  24    an uncertainty factor upwards that they underestimated                  25    the dose in that study by a factor of 3, it would still                                                                                   57                 BARNEY, UNGERMANN & ASSOCIATES  1-888-326-5900       1    be lower --                   2                  CHAIRMAN FROINES:  Than the value you're                   3    proposing.                     4                  DR. ALEXEEFF:  Yeah.                     5                  CHAIRMAN FROINES:  Blanc gets assigned the                   6    methyl bromide.                      7                  DR. BLANC:  Well, no.  We've discussed it                   8    here.  So actually, no.                     9                  Can I ask another question about methyl                  10    bromide too while we're on the subject in terms of what's                  11    driving the REL or the irritant effects, not the                  12    neurological effects; is that right?  Or --                  13                  DR. MARTY:  Yes.                    14                  DR. BLANC:  And in terms of the mechanism;                  15    is that right?                    16                  DR. ALEXEEFF:  No.  Did you ask if                  17    irritation was driving?  No.  It's the neurological                  18    effects.                    19                  DR. BLANC:  In this model.  In the human                  20    one it would be -- it would be anorexia, nausea and                  21    vomiting.  So it would be a nonneurologic endpoint, for                  22    example, if you use that.                    23                  DR. ALEXEEFF:  I don't know if it would be                  24    or not.  I don't know what the mechanism of those effects                  25    are in this case.  I don't think it's an odor mechanism                                                                                   58                 BARNEY, UNGERMANN & ASSOCIATES  1-888-326-5900       1    that we're referring to.                     2                  DR. BLANC:  No.  I didn't mean -- I meant                   3    odor irritant perhaps.                     4                  DR. MARTY:  I don't know if the nausea and                   5    vomiting would be mediated by the CNS.  I think that's                   6    what we're saying.                     7                  DR. BLANC:  Right.  The reason I ask that                   8    question is because, if part of -- you know, it may very                   9    well be that at the acute lethal effects clearly in                  10    humans are from CNS toxicity and uncontrollable seizures.                   11    In fact, it's a very interesting toxin from that point of                  12    view.                    13                  CHAIRMAN FROINES:  What happens to the                  14    respiratory rate at these concentrations in the animals?                    15                  DR. MARTY:  I don't know.  George may know.                    16                  CHAIRMAN FROINES:  Are they closing down?                    17                  DR. ALEXEEFF:  It's labored breathing, and                  18    I believe it's a reduced rate.                    19                  CHAIRMAN FROINES:  Reduced rate so that the                  20    internal dose may be lower than the measured dose.  When                  21    you think about that --                  22                  DR. BLANC:  Well, the only reason I'm going                  23    down this road is because, if there's two separate                  24    pathways of effects, one is the CNS                   25    lethality -- seizures, et cetera -- but the other is that                                                                                   59                 BARNEY, UNGERMANN & ASSOCIATES  1-888-326-5900       1    it's an irritant.                     2                  It may be an irritant because of the                   3    bromine moiety.  I don't know the chemistry of the                   4    breakdown of methyl bromide.  And so you may have a                   5    wealth of data just on bromine if it does break down to a                   6    certain extent to methyl bromide breaks down to bromine.                    7                  You might want to find that out too because                   8    I think that there's more data in terms of irritant dose                   9    response with bromine.                     10                  DR. ALEXEEFF:  Well, yeah.  Methyl bromide                  11    is metabolized to bromine, but I don't know that that                  12    irritant effect is really operating here.  I'll have to                  13    go back and look at that Watrous study.                    14                  I was just rereading our summary here, and                  15    I notice that there is also skin corrosion.                    16                  And now I'm wondering if I'm confusing it                  17    with a slightly different study where the operators were                  18    collecting methyl bromide in ampules and spilling it on                  19    their hands.  So we'll go back and look at that study                  20    just to be sure that we have it clearly characterized and                  21    see if there's a way -- if this study sheds actually some                  22    light that we need to take into account and look at the                  23    other studies.                    24                  DR. FUCALORO:  When you say the breakdown                  25    metabolically is to bromine or bromide or --                                                                                   60                 BARNEY, UNGERMANN & ASSOCIATES  1-888-326-5900       1                  DR. ALEXEEFF:  Bromide ion.                     2                  DR. FUCALORO:  Well, yeah.  Because I'd be                   3    very surprised if it went to bromine, I think.                      4                  DR. ALEXEEFF:  Yes, we're talking about an                   5    alkylating agent, and once it methylates, the                    6    bromine -- the bromide, excuse me.  Is released.                     7                  DR. FUCALORO:  There's different levels of                   8    irritation between bromine and bromide.                     9                  CHAIRMAN FROINES:  Let's move on.  We'll                  10    certainly revisit this again.                    11                  DR. MARTY:  Okay.  We -- the revised                  12    proposed acrolein REL is up on the board.  Essentially we                  13    revised it because the SRP -- pursuant to the SRP                  14    suggestion of using an uncertainty factor of 6 for that                  15    LOAEL to NOAEL extrapolation for this mild adverse                  16    effect.                    17                  We had previously used an uncertainty                  18    factor of 3.  So what it did was reduce the REL by half.                   19    There's a few issues with the study in that there was not                  20    an identified NOAEL, and the duration of exposure was                  21    short, five minutes.                    22                  And I think that we've already discussed                  23    that that leads to uncertainty in using the                  24    extrapolation.                    25                  We also got comment on acrolein.  One of                                                                                   61                 BARNEY, UNGERMANN & ASSOCIATES  1-888-326-5900       1    the comments was to use the NRC eye irritancy threshold                   2    in an NRC document, 1981.                     3                  However, in looking at the document,                   4    there's no clear basis for the threshold.  And the study                   5    we used, Darley, et al. (1960), showed irritancy below                   6    the threshold cited in the NRC document.  So we were not                   7    comfortable with changing that.                     8                  There also was comment on inability to                   9    measure concentrations that low.  This has no direct                  10    impact on developing the reference exposure level, the                  11    commentator was concerned that it would not be                  12    particularly useful if you couldn't measure it anyway.                    13                  We did get comment on ammonia.  As you'll                   14    recall, we used a benchmark concentration approach,                  15    pooled data from four human studies.  Because we were                  16    using a benchmark concentration approach, an uncertainty                  17    factor of 3 was used to account for intraspecies                  18    variability.                    19                  The commentator discouraged combining data                  20    sets into a benchmark analysis and wanted us to select                  21    one.  However, we believe that one of the positive                  22    attributes of the benchmark concentration approach is the                  23    ability to combine data sets because it allows fuller use                  24    of the data.                    25                  We did receive comment on arsenic.  Our                                                                                   62                 BARNEY, UNGERMANN & ASSOCIATES  1-888-326-5900       1    reference exposure level for arsenic, just to review the                   2    study population, it's a repro developmental tox study in                   3    mice.  Inhalation exposures were -- the exposures were by                   4    inhalation.                     5                  The critical effect was decreased fetal                   6    body weight.  There was no observed adverse effect level                   7    determined in the studies.  So we relied on the lowest                   8    observed adverse effect level.                     9                  The exposure duration was four hours per                  10    day for three days of gestation and only chose the                  11    four-hour exposure to back extrapolate to 1 using Haber's                  12    Law with an "N" value of 2.                    13                  The issue really lies in the fact that                  14    there's a cumulative uncertainty factor of a thousand to                  15    give you a reference exposure level of 0.38 micrograms                  16    arsenic per cubic meter.                     17                  The comment that we received included                  18    comments that we should not use repeated dose studies.  I                  19    think we discussed this earlier.  That it's unavoidable                  20    if you're going to consider repro developmental toxicity.                   21                  We received comment that the uncertainty                  22    factor of a thousand is too large.  However, we don't                  23    have data demonstrating a NOAEL in the study, and that's                  24    the methodology that we're using.                    25                  We also received comment that we should                                                                                   63                 BARNEY, UNGERMANN & ASSOCIATES  1-888-326-5900       1    have separate pentavalent and trivalent arsenic reference                   2    exposure levels.  While there's some merit to that                   3    comment, in the hot spots program, the facilities do not                   4    speciate their metals emissions.  They just report total                   5    arsenic or total nickel or total chromium and so forth                   6    such that we felt compelled to use a reference exposure                   7    level that's based on a more toxic arsenic compound in                   8    order to account for the possibility that it is all                   9    trivalent.                    10                  We also received comment that the arsenic                  11    REL should not be lower than the arsine REL.  Arsine, I                  12    think, people recognize as a potent toxicant.  In this                  13    case it's really a function in the available data and the                  14    methods used.                    15                  There's a large uncertainty factor applied                  16    to the arsenic REL because of the lack of available data.                   17    Of course, the arsine REL has a lower uncertainty factor.                   18    There also -- arsine has a peculiar toxicity in that                  19    lysis of red blood cells occurs following exposure to                  20    arsine gas but not following exposure to arsenic                  21    compounds.                    22                  DR. FUCALORO:  Your argument has been                  23    essentially to take the most prudent course and consider                  24    everything to be trivalent as opposed to pentavalent                  25    because trivalent is, in general, more toxic and then to                                                                                   64                 BARNEY, UNGERMANN & ASSOCIATES  1-888-326-5900       1    use soluble arsenic.  Am I --                    2                  DR. MARTY:  I think the soluble is more of                   3    a nickel issue.                     4                  DR. FUCALORO:  Okay.                     5                  DR. BLANC:  Can I ask a question also about                   6    RELs when it's a reproductive outcome not touching on the                   7    multi-data exposure?  The intraspecies uncertainty factor                   8    is used to account for at-risk populations.                     9                  It's always been my assumption that, when                  10    we talk about at-risk populations, we're talking about                  11    asthmatics or the very young or the very old or                  12    reproductive age.  When your endpoint is reproductive                  13    outcome anyway, what's the rationale for the human                  14    intraspecies variations of 10?  Because you're already                  15    talking -- are you assuming that there are some pregnant                  16    humans that are 10 times more at risk than other -- that                  17    there's an equal variation in risk within the pregnant                  18    population?  Because that seems a bit of a stretch.                    19                  DR. MARTY:  That is the implied assumption,                  20    yes.  I don't think we have data one way or the other.                    21                  CHAIRMAN FROINES:  It's not just a question                  22    of sensitive population, though, in the sense of the                  23    asthma versus nonasthma.  It's also a question of                  24    heterogeneity in general.                     25                  DR. BLANC:  I always thought it was                                                                                    65                 BARNEY, UNGERMANN & ASSOCIATES  1-888-326-5900       1    a -- not an issue of, in fact, a bell-shaped curve but of                   2    a non-Gaussian distribution where there were -- here you                   3    had one peak for normal people and then the asthmatics                   4    were way down here -- yeah.  You couldn't even                    5    assume -- this was not just the 95th percentile issue,                   6    but have I been wrong on that --                    7                  DR. ALEXEEFF:  I think that -- I haven't                   8    seen a good explanation for the justification of the                   9    ten-fold uncertainty factor for intraspecies for                  10    reproductive.  So nothing comes to mind as to what the                  11    implicit assumptions are, and we will -- I'll ask our                  12    reproductive experts to see what is being thought there.                   13    But what does come to mind is --                   14                  DR. BLANC:  Because you don't -- excuse me.                   15    Because you don't use it if it was -- coming back to our                  16    earlier conversation, if this was a study of asthma -- of                  17    asthmatics in humans, you wouldn't be using the factor.                   18                  You wouldn't have an intraspecies because                  19    you'd assume that's our target part of the population.                   20    If you had, in fact, not a study of rats exposed to                  21    arsenic but you had a human reproductive study of arsenic                  22    and showed a reproductive adverse outcome, you wouldn't                  23    use a factor of 10 either, or would you in intraspecies?                    24                  DR. MARTY:  Would use a factor of 10.  That                  25    whole concept is actually very complicated                                                                                    66                 BARNEY, UNGERMANN & ASSOCIATES  1-888-326-5900       1    in -- is people mix up different definitions of sensitive                   2    subpopulation within it.                     3                  I think for a chemical that we know a                   4    sensitive subpopulation is asthmatics and you study it in                   5    asthmatics, then we're fairly comfortable not introducing                   6    another uncertainty factor.                     7                  We actually have a comment that we should                   8    be because the asthmatics studied generally in these                   9    types of chamber studies are not people who are severely                  10    sick.  They're mild to moderate asthmatics.  So --                  11                  CHAIRMAN FROINES:  Paul, I would even                   12    argue -- I'd argue that that in fact to assume no                  13    uncertainty factor within an asthmatic is to oversimplify                  14    the science of --                  15                  DR. BLANC:  Well, I was just trying to get                  16    a concept of what the rationale was, the stated                  17    rationale, whether or not it's -- I'm not suggesting that                  18    you reverse course if this is your standard procedure.                   19    I'm just really trying to get a sense as to what the                  20    underlying rationale was.                    21                  DR. MARTY:  And I think the heterogeneity                  22    concept is really the underlying thread to using                  23    intraspecies variability uncertainty factors.                    24                  CHAIRMAN FROINES:  Yeah.  That's what I                  25    would argue.  Now, one of the interesting things about                                                                                   67                 BARNEY, UNGERMANN & ASSOCIATES  1-888-326-5900       1    this is Dale Haddis has just written a major document                   2    looking at the underlying precepts of this ten-fold                   3    safety factor.                     4                  What I'll do is get a copy from Dale and                   5    make it available to everybody, and we can talk about it                   6    in the meeting, say, in the April workshop and talk about                    7    the -- this particular issue because it is a really                   8    important issue, I think.                     9                  But since Haddis has done a major document                  10    looking precisely at the questions we're talking about                  11    here, it's probably worth having that work to review                  12    before we have a full discussion about it.                     13                  DR. ALEXEEFF:  So in getting back to your                  14    comment, though, the little evidence that I have seen                  15    looking at the comparison of the human response to animal                  16    response, and the example that comes to mind is                  17    thalidomide and the sensitivity of the dose of                  18    thalidomide from animals to humans, it's about two orders                  19    of magnitude in terms of what dose was -- the women were                  20    taking when they were pregnant versus some of the animal                  21    studies.  I think it's the rat.                    22                  It's about 50-fold in that case.  So I                  23    think that in the past what the -- and I will                  24    double-check.  The particular folks have simply looked                  25    that for reproductive effects it appears about two orders                                                                                   68                 BARNEY, UNGERMANN & ASSOCIATES  1-888-326-5900       1    of magnitude from the animals.                     2                  But I don't think they actually thought                   3    through the kind of question you're asking, but I'll see                   4    if they have.                      5                  DR. BYUS:  A comment about thalidomide,                   6    that's a metabolic -- what's the development toxic agent                   7    is the metabolic conversion of thalidomide into something                   8    that causes the developmental toxicity.  It's probably at                   9    the level of metabolism differences between the rat and                  10    the human, both in level of metabolism and then sort of                  11    selectivity of metabolism as well.  I'm sure that's what                  12    the difference is there.                    13                  CHAIRMAN FROINES:  Since we don't know the                  14    mechanism, we're still stuck on that one.                    15                  DR. FRIEDMAN:  May I ask which direction                   16    it -- the 50-fold difference is it?  If you extrapolate                  17    from the rats, is it 50-fold safer or 50-fold more                  18    dangerous?                    19                  DR. ALEXEEFF:  Humans are more sensitive to                  20    the effects.  It requires a much smaller dose.                    21                  DR. MARTY:  We also received comment on                  22    formaldehyde.  In our reference exposure level, a key                  23    study used was Kulle, et al. (1987), and we estimated our                  24    reference exposure level by a benchmark concentration                  25    approach.                                                                                     69                 BARNEY, UNGERMANN & ASSOCIATES  1-888-326-5900       1                  The resulting benchmark concentration from                   2    this analysis was .44 parts per million formaldehyde,                   3    which was time adjusted using an "N" of 2 to a resulting                   4    value of .74 parts per million.                     5                  We applied an uncertainty factor of 3 to                   6    account for individual variation to derive our acute                   7    reference exposure level of .25 parts per million.  We                   8    received comment that we should have used categorical                   9    regression analysis, which was published by Paustenbach,                  10    et al. (1997), and which is the basis of the revised                  11    threshold limit value.                    12                  We did review Paustenbach's paper, and we                  13    continued to recommend our benchmark analysis.  The                  14    threshold limit value does not consider sensitive                  15    subpopulations.  We don't think it was appropriate to                  16    just adopt the results of their analysis.                    17                  DR. BLANC:  What is the TLV?  What is the                  18    value --                    19                  DR. MARTY:  What's the number?                     20                  DR. BLANC:  Yeah.                    21                  DR. MARTY:  I don't remember.                    22                  DR. BLANC:  Is it less than or more than                  23    ten times your ultimate REL?                    24                  DR. MARTY:  It's more than our REL, but I                  25    don't believe it's tenfold.                                                                                     70                 BARNEY, UNGERMANN & ASSOCIATES  1-888-326-5900       1                  DR. ALEXEEFF:  It's in the comments.                     2                  CHAIRMAN FROINES:  There are Swedish                   3    studies that have --                   4                  DR. MARTY:  I think it's 1.                     5                  CHAIRMAN FROINES:  -- acute effects down as                   6    low as a tenth of a point.                     7                  DR. BLANC:  That's a different issue.  I                   8    was just -- I would just suggest that in your response to                   9    the comments, if you didn't say it, I might have missed                  10    that.  That you say, if we actually took your approach                  11    and then added the intraspecies uncertainty factor, you                  12    would actually end up with a lower level than what we                  13    did.                    14                  DR. MARTY:  Okay.  I'm remembering that                  15    it's 1 ppm, but I don't know for positive.                    16                  CHAIRMAN FROINES:  What's the --                   17                  DR. BLANC:  That's an eight-hour TLV?                    18                  DR. MARTY:  Uh-huh.  That's an                   19    eight-hour --                  20                  DR. BLANC:  So you would also have to not                   21    only do that but -- so you'd actually get quite a bit                  22    lower.                    23                  DR. MARTY:  Well, that would counter it.                   24    That would go in the other direction.                     25                  DR. BLANC:  Oh, that's right.                                                                                     71                 BARNEY, UNGERMANN & ASSOCIATES  1-888-326-5900       1                  CHAIRMAN FROINES:  This is distressing.  I                   2    think -- what's your REL?                     3                  DR. BLANC:  .25.  Well --                   4                  CHAIRMAN FROINES:  I'll go over that.                     5                  DR. BLANC:  Yeah.  I mean you had left me a                   6    message too about that.  My point with the NIOSH health                   7    hazard evaluations was not that there was a                   8    well-delineated dose response, but in fact, if you look                   9    at those as a group, the lowest effect level is less than                  10    1 part per million in that they go -- there are a variety                  11    of health hazard evaluations that they have done where                  12    there have been reports of irritation.                    13                  But they are eight-hour-a-day exposures.                   14    So by and large.  Because even if you don't assume that                  15    it's a cumulative effect, do you just say what do people                  16    have by the end of the day?                    17                  So I don't know what kind of number that                  18    would give you, but one of the things I was struck by,                  19    when I was involved in one of those, was that NIOSH kept                  20    going back to different work sites and finding that there                  21    was irritation at less than 1 part per million,                  22    either .25 or .5.                    23                  And then the conclusion would be, well, we                  24    saw these effects, but reviewing the literature, the                  25    threshold for an effect is 1 part per million.  And                                                                                   72                 BARNEY, UNGERMANN & ASSOCIATES  1-888-326-5900       1    rather than saying, well, maybe the literature threshold                   2    is actually incorrect, and they never really synthesized                   3    all those health hazard evaluations.                     4                  So that was my point in looking at those                   5    because I think you'll see a pattern of exposure effects,                   6    and I would agree that John should take a close look at                   7    this because there's quite a bit of --                    8                  CHAIRMAN FROINES:  The Scandinavian studies                   9    are not cited in here.                    10                  DR. BLANC:  It may be that because many of                  11    those studies are shift-long that, when you extrapolate                   12    back --                  13                  DR. MARTY:  You'd end up with a higher                  14    number.                    15                  DR. BLANC:  Can you do algebraically just a                  16    quick back of the envelope calculation what -- if there                  17    was, in fact, an eight hour effected .3 parts per                  18    million, what that would come out to be?                    19                  DR. GLANTZ:  What do you want to do?  You                  20    want to say if there's an effect of how many .3 parts --                  21                  DR. BLANC:  .3 parts per million with eight                  22    hours of exposure using a Haber's consonant of 2.                    23                  DR. ATKINSON:  It would increase by a                  24    factor of about 3.                    25                  DR. BLANC:  It would be less.  The level --                                                                                   73                 BARNEY, UNGERMANN & ASSOCIATES  1-888-326-5900       1                  DR. ATKINSON:  One hour level would go up.                    2    Yes, that's right.                     3                  CHAIRMAN FROINES:  So it goes to what?                     4                  DR. BLANC:  I don't know.  He's doing that.                    5                  DR. COLLINS:  .3 squared would be .09?                      6                  DR. BLANC:  No.  It should go the other                   7    way.                     8                  DR. GLANTZ:  No.  It's the other way.                     9    It's -- hold on.                    10                  DR. COLLINS:  Time 8 is 72; square root                  11    between 72 would be .2 something.                    12                  DR. GLANTZ:  8.  Take the square root of 8.                    13                  DR. FUCALORO:  Number --                   14                  DR. GLANTZ:  That's about .85.                    15                  DR. BLANC:  Okay.  And .85 parts per                  16    million, divided by 10?                    17                  DR. GLANTZ:  Would be .085 parts per                  18    million.                    19                  DR. BLANC:  And divided by -- instead of 10                  20    by 3, if we assume this was a bunch of human studies?                    21                  DR. GLANTZ:  Divide that by 3 -- divide by                  22    3, you get .28.                    23                  DR. BLANC:  What did you have?  You have                  24    .25?  So you make them out to a very similar number,                  25    depending, but I think it warrants.                                                                                     74                 BARNEY, UNGERMANN & ASSOCIATES  1-888-326-5900       1                  CHAIRMAN FROINES:  Okay.  So we're going                    2    to -- formaldehyde's clearly a major, major, major                   3    chemical in this regard.  So let's get it right.  Let's                   4    take a break.                     5                  DR. GLANTZ:  We'll have formaldehyde and                   6    methyl bromide; right?                     7                  CHAIRMAN FROINES:  Pardon me?  Methyl                   8    bromide and formaldehyde are not finished as far as we're                   9    concerned.                    10                  DR. GLANTZ:  Yeah.  Paul will take care of                  11    those.                    12                  DR. BLANC:  No, no.  That's -- you're the                  13    lead people.                    14                  CHAIRMAN FROINES:  Let's take a break.                   15    Let's take a quick ten-minute break.                    16                  (A ten-minute break was taken.)                  17                  DR. MARTY:  For isopropanol we had several                  18    comments.  The study used was Nelson, et al. (1943), to                  19    expose subjects for three to five minutes to 400 parts                  20    per million.  These individuals reported mild irritation                  21    of the eyes, nose and throat and indicated that 200 ppm                  22    "would be tolerable."                  23                  We used the 200 parts per million as an                  24    implied no observed adverse effect level, time adjusted                  25    that to one hour and applied an intraspecies uncertainty                                                                                   75                 BARNEY, UNGERMANN & ASSOCIATES  1-888-326-5900       1    factor of 10.                     2                  We did get comment to wait for a new CMA                    3    study of the irritation threshold --                   4                  DR. GLANTZ:  Who is the CMA --                   5                  DR. MARTY:  It's the Chemical Manufacturers                   6    Association.  Isopropanol panel.  And our response                   7    essentially is we can revisit the reference exposure                   8    level when new data become available.                     9                  We got comment that the REL is considerably                  10    lower than both the TLV and the PEL.  However, such                  11    comparisons are generally not too informative since the                  12    occupational standards are not applicable directly to the                  13    general population.                    14                  We got comment that time extrapolation is                  15    inappropriate.  However, there is a lack of data to                  16    substantiate it one way or the other for this particular                  17    compound.                    18                  We also got comment that it is incorrect to                  19    add in the hazard index approach chemicals that impact                  20    the upper and lower airway.  However, we do have this                  21    relatively simple assumption of additivity in that the                  22    whole organism -- in the whole organism effect may be                  23    additive.                    24                  And while a chemical may impact the upper                  25    more than the lower airway and the second chemical might                                                                                   76                 BARNEY, UNGERMANN & ASSOCIATES  1-888-326-5900       1    impact the lower more than the upper airway, we do                   2    believe that the effects are likely to be additive.                    3    There is some information in literature that supports                   4    that.                     5                  We also got comment on nickel primarily                   6    from NIPERA and INCO, Incorporated.  In the nickel                   7    reference exposure level we use human studies of                   8    individuals with occupational asthma.                     9                  These people were exposed to 67 micrograms                  10    of nickel per cubic meter.  And the critical effects were                  11    measured decreases in FEV1.  There was not a NOAEL                  12    observed in this study.  The issues essentially                   13    were -- is the effect of a 15 percent decrement in FEV1                  14    mild or severe?                    15                  And in fact, the study reports those                  16    individuals who had greater than or equal to a 15 percent                  17    decrement.  So we're continuing to call that mild                  18    although, in fact, it may be mild to moderate and                  19    possibly even to severe.                    20                  There is also a comment that the reference                  21    exposure level should not be applied to metallic nickel                  22    or insoluble nickel compounds since the exposure was to                  23    nickel's sulfate hexahydrate, which is a soluble form.                   24                  And, again, this brings us back to the                  25    issue that in the hot spots program, the facilities are                                                                                   77                 BARNEY, UNGERMANN & ASSOCIATES  1-888-326-5900       1    not speciating their emissions.  They're reporting total                   2    nickel.  So we feel it is a health-protective assumption                   3    to use the more -- to use the soluble nickel compounds as                   4    the basis for the reference exposure level.                     5                  We did apply the changed uncertainty                    6    factor from LOAEL to NOAEL extrapolation of 6.  So the                   7    resulting reference exposure level is now 6 micrograms                   8    per cubic meter, and prior to that, it was 11.                     9                  DR. BLANC:  Do you make a comment in                   10    your -- in the body of your summary, if it is available,                  11    of the estimate of the percent of the general population                  12    which is -- has skin sensitivity to nickel?                    13                  DR. MARTY:  I don't think we have that in                  14    here.  I certainly don't remember that.                    15                  DR. BLANC:  I mean it's actually a common                  16    sensitization, but what I don't remember is if people who                  17    are sensitive to nickel in terms of contact dermatitis                  18    are more or less likely also to react with bronchiospasm                  19    if they inhale it.                    20                  DR. MARTY:  We do have a statement that                  21    positive -- out of the seven individuals with                  22    occupational asthma, nickel platers, that positive                  23    reactions to skin testing were found in three of those                  24    individuals, and they also experienced dermatitis in the                  25    workplace.  I'm not sure that answers the question --                                                                                   78                 BARNEY, UNGERMANN & ASSOCIATES  1-888-326-5900       1                  DR. BLANC:  I only bring it up because I                   2    think it is reasonable, in fact, in this particular case                   3    to be thinking about, you know, what would a sensitized                   4    person do when they inhale this stuff.                     5                  Whereas if you were talking about                   6    isocyanates, the probability of there being a significant                   7    number of people in the general population who                    8    were -- are presensitized to isocyanates and, therefore,                   9    if there was a release of isocyanate in Westwood, you                  10    know, would you be worried about the people who would be                  11    having an amnestic allergic response, or do you have to                  12    just worry about the acute irritant response?  It's a                  13    different question.                    14                  So I think it is reasonable to be using the                  15    endpoint that you're using.  I don't know -- if you don't                  16    feel that you need to make that statement more explicitly                  17    in your supporting information, that's fine.  But --                  18                  DR. MARTY:  I think that's an interesting                  19    point.  I would like to add that.                    20                  CHAIRMAN FROINES:  I'm going to take the                  21    chair's prerogative and say that this -- we won't close                  22    nickel off, and we'll ask Paul to review what you've done                  23    on nickel because nickel is a particularly difficult                  24    compound, I think.                    25                  And it's difficult with respect to its                                                                                   79                 BARNEY, UNGERMANN & ASSOCIATES  1-888-326-5900       1    chronic toxicity particularly its carcinogenicity, and                   2    it's difficult in terms of its pulmonary issues.  And for                   3    example, FEV1 changes deserves a look at, I think.                     4                  So let's keep the door open on nickel, I                   5    think, for the time being until the next meeting.                     6                  DR. MARTY:  We have comments on our REL for                   7    phenol, and essentially, to be succinct -- essentially,                   8    we were -- the comment was that we should not rely on a                   9    freestanding NOAEL, which is what we had done from                  10    Piotrowski, (1971).                    11                  Unfortunately that's the best available                  12    human acute inhalation exposure data.  And also the                  13    commenter suggested using a threshold cited in a review                  14    article, but we could not find a clear basis for the                  15    threshold cited.  So it's one of those problems.                   16                  And finally, we got comments on toluene.                   17    In that reference exposure level we used a study by                  18    Anderson, et al. (1983), who exposed 16 men to                  19    concentrations ranging from 10 to 100 ppm for six hours.                   20                  No symptoms were reported at 10 and 40 ppm.                   21    However, at 100 ppm, people had headaches, dizziness, a                  22    feeling of intoxication and slight eye and upper                  23    respiratory irritation.                    24                  We chose the highest NOAEL.  And that was                  25    40 parts per million.  We received comment that the NOAEL                                                                                   80                 BARNEY, UNGERMANN & ASSOCIATES  1-888-326-5900       1    should actually be 100 parts per million according to the                   2    way the commentator read the Anderson study.  We reviewed                   3    the study, and it is clearly -- 100 ppm is clearly not a                   4    NOAEL.                     5                  The commentator also suggested looking at                   6    another study which they believed had a NOAEL of 75 ppm,                   7    which would have been higher than the 40 that we chose.                    8    We had already looked at that study, and the author's                   9    report reflects that 75 ppm.  So that also is clearly not                  10    a NOAEL.                    11                  Finally, we got another comment, not on the                  12    reference exposure level but on the level protective                  13    against severe adverse effects, and it's the same                  14    comment.  Not to use repeated dose repro tox study.  So                  15    we've actually been through that.  That's it.                    16                  CHAIRMAN FROINES:  I missed something.                   17    What's the REL for toluene?                    18                  DR. FUCALORO:  9.8 parts per million.                    19                  CHAIRMAN FROINES:  How many?                    20                  DR. FUCALORO:  Am I right?  9.8 parts                   21    per --                  22                  DR. MARTY:  Parts per million.  We had --                  23                  CHAIRMAN FROINES:  Gary?                    24                  DR. FRIEDMAN:  May I ask a general question                  25    about these exposure studies for volunteers?  Are the                                                                                   81                 BARNEY, UNGERMANN & ASSOCIATES  1-888-326-5900       1    volunteers kept blind, or is there, like, a placebo                   2    period?   You know, in studies of drugs, one always likes                   3    to compare the effects of a drug whether beneficial or                   4    adverse with what -- with a placebo because there is                   5    placebo effects.                     6                  And I'm wondering, you know, are -- the                   7    volunteers said, you know, "Let us" -- you know, "We're                   8    going to put something in the environment.  Let us know                   9    when it bothers you"?  Are there controlled periods where                  10    they -- the volunteers are kept blind and they don't know                  11    whether they're being exposed or not?  How are these                  12    studies done?                    13                  DR. MARTY:  In general, that is how they                  14    are conducted.  So there will be exposures to air only,                  15    say, for example, in an inhalation chamber and then                  16    exposures to whatever chemical at varying levels and for                  17    varying durations.                    18                  DR. FRIEDMAN:  And the volunteers are kept                  19    blind to whether they're being exposed or not to the                  20    chemical?                    21                  DR. MARTY:  Correct.  In some cases, not in                  22    all cases.  But in -- for example, in the toluene                  23    exposure -- they may even jump between -- first they do                  24    air.  Then they'll do a higher concentration in some                  25    group, a lower concentration in some group.  So they'll                                                                                   82                 BARNEY, UNGERMANN & ASSOCIATES  1-888-326-5900       1    bounce around, not even just do it in increasing                   2    concentrations unless they're specifically looking for a                   3    threshold for odor.                     4                  For example, most of the odor threshold                   5    studies to keep on incrementally increasing the                   6    concentration.  I'm sure you can find examples where the                   7    studies were not done with the subjects blinded.                     8                  CHAIRMAN FROINES:  It's interesting, isn't                   9    it, how many studies you cite are at least 50 years old.                   10    It shows you how limited a data we operate with, you                  11    know, and we -- it really is scary that we have such                  12    limited data.                    13                  And we also look at all these things as                  14    though they're -- people aren't exposed to anything else                  15    but the chemicals by themselves, and clearly people are                  16    exposed to mixtures of all these things.                    17                  And so we tend to underestimate or at least                  18    we don't really have a handle on how we assess mixtures                  19    in any kind of context.  It's a sorry state of affairs in                  20    some respects.                    21                  DR. BLANC:  Can I just ask in terms of                  22    toluene vis-a-vis the xylene that we discussed earlier?                   23    It's interesting that the -- the -- in the toluene -- I                  24    mean they're within an order of magnitude, but there is a                  25    difference of almost fivefold between the two levels now,                                                                                   83                 BARNEY, UNGERMANN & ASSOCIATES  1-888-326-5900       1    the two RELs.                     2                  DR. FUCALORO:  Are you talking about                   3    between xylene and toluene?                     4                  DR. BLANC:  Yeah.                     5                  DR. FUCALORO:  You know, also in                   6    carcinogenicity, from what I understand, the difference                   7    between toluene and benzene is great; is that correct?                     8                  DR. BLANC:  Well, that's -- there's a clear                   9    mechanistic reason for that.  Do you -- just from                   10    a -- from a scientific point of view, do you feel                  11    comfortable with that gap between the two?                    12                  Would you have thought they would have                   13    come -- I know it's driven by the data that you have                  14    available to you, but in most respects we tend to think                  15    of xylene and toluene as being quite similar.                    16                  And in fact, there are 5 -- you know, if it                  17    was -- if it was a factor of, you know, 2, I would be                  18    perhaps not even pressing the point.                     19                  DR. MARTY:  It's actually a factor of 2.                    20                  DR. BLANC:  Oh, I'm sorry.  It is a factor                  21    of 2.  I'm sorry.  Well, then nevermind.  Maybe they're                  22    close enough that it doesn't matter.                    23                  DR. FUCALORO:  And then there are three                  24    xylenes.                     25                  CHAIRMAN FROINES:  One of the interesting                                                                                   84                 BARNEY, UNGERMANN & ASSOCIATES  1-888-326-5900       1    things from a standpoint of the SB521, where we did the                   2    reports for the -- on MTBE.  You know, one of the                   3    proposed alternatives to the use of MTBE is to use                   4    reformulated gasoline with significantly higher                   5    concentrations of toluene as the octane enhancer so that                   6    we may find ourselves looking at toluene again if MTBE                   7    becomes not the oxygenated choice so that we ought to                   8    make sure we're happy with the toluene numbers because I                   9    suspect they're going to come back on us, and we're going                  10    to have to think about them again sometime.                    11                  So thank you very much.  These are                   12    really -- it takes a long time to go through all those,                  13    but I think these are really quite good discussions.                   14    They're a much better science -- level of science, I                  15    think, than some times.  And so the pace is slower than                  16    we might like, but I think it's good -- I thought he was                  17    going to make a comment.                    18                  DR. GLANTZ:  No.  Actually, I was going to                  19    agree with you for a change.  I mean I have to say --                  20                  DR. FUCALORO:  Make sure the recorder gets                  21    that.                    22                  DR. GLANTZ:  Right.  Yeah.  Maybe we should                  23    go off the record.  No.  I mean I have to just say, as                  24    the one lead person who's been with us from the beginning                  25    since Seiber isn't on the panel, I mean I feel very good                                                                                   85                 BARNEY, UNGERMANN & ASSOCIATES  1-888-326-5900       1    to have the whole group going through things like this                   2    because, you know, I've done the best that I can with                   3    this.  But there's obviously a lot of expertise here that                   4    I don't have. So I think that -- I mean it's going to                   5    take two meetings, I guess, but it's worth it.                    6                  Because I think the report -- I mean each                   7    interation of this report, I think, is getting better,                   8    and I think it's going to be a very solid document by the                   9    time we're done.                    10                  CHAIRMAN FROINES:  Well, it will also help                  11    us hopefully procedurally and intellectually to deal with                  12    the chronic document which is really going to be a tough                  13    one because there's so many chemicals and so many                  14    different issues to address.                    15                  Paul, sorry we've taken so long to get to                  16    you.                    17                  DR. GLANTZ:  We should go get the whips and                  18    chains now, huh?                    19                  CHAIRMAN FROINES:  Paul, last I -- one of                  20    the issues that came up in our discussions, when Tony and                  21    I and Bill were talking, is we wanted at some point to go                  22    over the whole concept of the MOE because the MOE is                  23    clearly a distinct procedure compared to this REL process                  24    we've just been going through.                    25                  I think for the sake of time to get into                                                                                   86                 BARNEY, UNGERMANN & ASSOCIATES  1-888-326-5900       1    that issue today is probably not timely.  But can we take                   2    it up and have -- at some point have staff come and have                   3    a discussion about the underlying scientific basis for                   4    the MOEs and go from there?                     5                  DR. ATKINSON:  What's an MOE?                     6                  MR. GOSSELIN:  Margin of exposure.  And                   7    actually, we went back and talked to staff, and I think                   8    it would be a good discussion to have, and we actually in                   9    our own internal guidance have similar procedures  that                  10    OEHHA's presented on the RELs and the methodology on                  11    calculating out MOEs.                    12                  I think what you'll see in future documents                  13    is the presentation of the toxicity of the material and                  14    the uncertainty factors and the exposure estimates in a                  15    similar fashion as to what you've been seeing in other                  16    documents.  That will help consistency.                    17                  It will have us go back and change sort of                  18    our standard procedure of doing the MOE calculation, but                  19    essentially, it's all the same data endpoints.  It's a                  20    matter of how -- at what point you do the calculation,                  21    but we can bring that up at -- whenever you want to                  22    schedule that.                    23                  CHAIRMAN FROINES:  Yeah.  I think -- you                  24    know, Roger asked the question.  I'm tempted to explain                  25    it, but I think we'll just get off the track, and I think                                                                                   87                 BARNEY, UNGERMANN & ASSOCIATES  1-888-326-5900       1    maybe, if we actually devote time to it, we can have an                   2    in-depth discussion because it really is quite crucial to                   3    the designation of compounds of toxic air contaminants                   4    based on their noncarcinogenic endpoints.                     5                  And that's what the real issue is, Roger.                    6    It has to do with not some of the carcinogenicity risk                   7    assessments are substantially different.                     8                  DR. GLANTZ:  I actually think it would be                   9    helpful to -- if you could in the new reports to put in                  10    an REL and an MOE because they're basically just                  11    different ways of expressing the same information.  And I                  12    think that would lead to more unity between the different                  13    kinds of reports.                    14                  CHAIRMAN FROINES:  Well, I think the                   15    panel -- I think it's useful to go over the                   16    question -- the assumption that you just made, which is                  17    that they are essentially the same information.                    18                  I don't think that's necessarily true.  It                  19    may be true, but I think it's something -- that's exactly                  20    what we want --                   21                  DR. GLANTZ:  I think having a discussion is                  22    a good idea, but I think in terms of the reports, if DPR                  23    likes the MOE presentation, I don't think there's                  24    anything intrinsically wrong with it, but I think if we                  25    also included in the reports an REL, that would just                                                                                   88                 BARNEY, UNGERMANN & ASSOCIATES  1-888-326-5900       1    allow for greater comparability of the two sets of                   2    documents.                     3                  MR. GOSSELIN:  Yeah.  Our intent is to do                   4    that.                     5                  DR. GLANTZ:  Okay.                     6                  CHAIRMAN FROINES:  It's also precisely the                   7    reason why, when I first introduced Roger in the                   8    beginning, said that how we calculate -- how we determine                   9    exposure becomes so central because it defines in a sense                  10    whether or not a chemical becomes designated as a toxic                  11    air contaminant.                    12                  And this panel -- Roger has disagreed with                  13    DPR on that issue in the past, and let's not, you know,                  14    bring up old wounds.  Let's just go ahead.                    15                  So I think that the panel -- everyone on                  16    the panel has the current proposed DEF findings.  And let                  17    me say that there is still one place where there -- one                  18    of the things the panel doesn't know is that in December,                  19    I guess it was, I went over the OEHHA document, OEHHA                  20    findings, and I went over the panel's findings, the draft                  21    of the panel's findings, and in the draft of the panel's                  22    findings, the numbers between that draft and the OEHHA                   23    draft were quite different.  There was not consistency.                   24                  So we went back and tried to make the                  25    numbers consistent, and we found one place this morning                                                                                   89                 BARNEY, UNGERMANN & ASSOCIATES  1-888-326-5900       1    where the numbers are still not consistent, and George                   2    said that he would go back and make sure that in this                   3    case the problem was -- is with the OEHHA findings.  And                   4    so George said that he would bring the OEHHA findings to                   5    be consistent with our findings.                     6                  Right now our findings have one difference                   7    in -- numerically with OEHHA and so we're going to                    8    end -- we're going to try and end up that the OEHHA                   9    findings on pesticides and our findings are consistent                  10    with one another or unless we have a major disagreement,                  11    which I would assume that we would resolve this.                    12                  So that's the one place where there was a                  13    comment.  Now, it was my understanding that Paul Blanc                  14    had a comment or two.                    15                  DR. BLANC:  Yeah.  At what point do you                  16    want to --                  17                  CHAIRMAN FROINES:  Let's start.  We can go                  18    around the room --                   19                  DR. BLANC:  Okay.  Well, there were a few                  20    places where I think the wording should be clarified, and                  21    I want you to correct me if I'm wrong in my                  22    misunderstanding.                    23                  So just to go through the points as I see                  24    where word changes would help the clarification, on point                  25    number two, "Environmental Fate and Exposure," I assume                                                                                   90                 BARNEY, UNGERMANN & ASSOCIATES  1-888-326-5900       1    implication when the statement is made "Fresno County                   2    receives the largest usage of DEF of California                   3    counties."                    4                  That's the largest usage in pounds?  In                   5    total pounds?  I think it would be helpful to say which                   6    county has the largest per capita usage as well.  Unless                   7    it's a different county.  Unless it's the same county.                    8                  And then I would say it has the largest                   9    usage in pounds and per capita because we've had other                  10    exposures where the pound usage may be less than a                  11    particular county, but it's a very low -- you know,                  12    there's not very many people in the county, and                  13    geographically it's not that big.                    14                  MR. GOSSELIN:  You're talking pounds per                  15    capita population?                    16                  DR. BLANC:  Yeah.  I mean to suggest that                  17    really Fresno is -- you know, is the big issue.  But I                  18    don't know, for example, whether or not, you know,                  19    Imperial County -- it may be actually per capita more                  20    exposure there, if you did it that way.                    21                  DR. FRIEDMAN:  What would that mean,                  22    though?  In other words, if the county was sparsely                  23    populated, the compound may be safer because it's being                  24    put far away from the people.  Yet you'll get a higher                  25    per capita exposure because there's fewer people that                                                                                   91                 BARNEY, UNGERMANN & ASSOCIATES  1-888-326-5900       1    you're dividing the pounds by.  So I'm not sure that                   2    that's a meaningful addition.                     3                  DR. BLANC:  Well, it's probably as                   4    meaningful as saying that most of it is used in Fresno                   5    County.  I don't know what that means either.  Maybe just                   6    deleting the sentence then, if we don't want to go down                   7    that pathway.                     8                  The implication singling out Fresno says                   9    that that's where the public health issue is biggest, and                  10    I'm not sure that's the truth -- I mean the implication                  11    we want to make.                    12                  DR. GLANTZ:  Paul is shaking his head.                   13    What did you want to say?                    14                  MR. GOSSELIN:  I think the only thing we                  15    wanted to point out in that was where the predominant                  16    amount of use occurs, and in the report we listed all the                  17    counties that had usage.                    18                  The one thing -- the way we handle this is,                  19    if we do have an unacceptable exposure based upon, in                  20    this case, data that would have come from the high-use                  21    counties, Kern and Fresno -- I think it was Kern and                  22    Fresno -- those exposures would be used in any of the                  23    counties that DEF is used.                    24                  So it's not -- we don't base this upon                  25    numbers of people being exposed.  It would apply                                                                                   92                 BARNEY, UNGERMANN & ASSOCIATES  1-888-326-5900       1    irrespective to that across the state.                     2                  DR. BLANC:  Well, maybe a better way of                   3    saying it would be "pounds per square mile of county."                    4    Maybe that's the way --                   5                  DR. FRIEDMAN:  Yeah.  I think that would                   6    make much more sense.                     7                  MR. GOSSELIN:  I would still say Fresno                   8    would probably --                   9                  DR. BLANC:  My second point --                  10                  CHAIRMAN FROINES:  Wait.  Wait.                    11    One -- these are our findings.  So we have in or out                  12    whatever we want.  These are not DPR findings.                    13                  DR. BLANC:  Well, if you could get the                  14    information, what I would prefer is a sentence that says                  15    "Fresno County receives the largest usage of DEF in                  16    pounds of California counties; County "X" receives the                  17    largest pounds per square mile of area."                  18                  DR. BUYS:  Even that is semimeaningless                  19    because it's really sprayed on crop lands, and wherever                  20    its use is, is really --                  21                  DR. BLANC:  Well, then I would just --                  22                  DR. BUYS:  I could be confined to                   23    even -- it's undoubtedly fine in much more specific                  24    areas.                    25                  DR. BLANC:  Well, then I would just delete                                                                                   93                 BARNEY, UNGERMANN & ASSOCIATES  1-888-326-5900       1    the sentence about Fresno County then.                     2                  DR. BYUS:  So would I.                     3                  CHAIRMAN FROINES:  My time estimates are                   4    really going to go to hell if we --                   5                  DR. BLANC:  Let's just delete the sentence                   6    on Fresno.                     7                  DR. BYUS:  You're absolutely right, what                   8    you're saying.                     9                  DR. BLANC:  My second point is that --                   10                  DR. GLANTZ:  Who agreed to that?                    11                  CHAIRMAN FROINES:  I don't know.                    12                  DR. BLANC:  Is there any dissent?  Hearing                  13    no dissent, the sentence is deleted.  The second is point                  14    three, which currently states "DEF breaks down (e.g.,                  15    photooxidizes) to n-butyl mercaptan," et cetera, et                  16    cetera.                    17                  Now, my understanding is that DEF is first                  18    activated -- although the exact chemical nature of the                  19    activated moiety is not clear -- and then breaks down to                  20    the n-butyl mercaptan, and this becomes confusing                  21    elsewhere in the document.                    22                  So I would suggest the following wording,                  23    if it's consistent with the science, which would be "DEF                  24    oxidizes to an active moiety which then breaks down"                  25    deleting the parenthetic "e.g., photooxidizes"                                                                                    94                 BARNEY, UNGERMANN & ASSOCIATES  1-888-326-5900       1    to -- because I don't think that's how you get to the                   2    n-butyl mercaptan.                     3                  DR. ATKINSON:  Is that known?  I haven't                   4    seen any data on the atmospheric loss processes of DEF.                    5    Are there any?                     6                  MR. GOSSELIN:  I don't believe so.  Because                   7    that gets back to -- in the human studies that there                   8    wasn't any data nailing down the sulfoxide active moiety.                    9                  DR. ATKINSON:  Okay.                    10                  MR. GOSSELIN:  But it's -- because of the                  11    other studies, they know that there is that intermediate                  12    one that is the cholinesterase inhibiting moiety.  It                  13    just hasn't been analyzed and characterized.                     14                  DR. ATKINSON:  In the atmosphere does it                  15    exist as a gas, or is it particle-associated?  DEF?                    16                  MR. GOSSELIN:  I believe it's a particle.                    17                  CHAIRMAN FROINES:  Isn't it an aerosol?                    18                  DR. FUCALORO:  Its boiling point is 150                  19    degrees at three-tenths of a millimeter mercury.                    20                  DR. ATKINSON:  Yes.  It's what?                   21    Three-tenths at 150 degrees?                     22                  DR. FUCALORO:  Millimeter mercury.  150                  23    degrees, yes.                    24                  DR. ATKINSON:  Yeah.  And I would -- my                  25    guess is that that means it's going to be at least                                                                                   95                 BARNEY, UNGERMANN & ASSOCIATES  1-888-326-5900       1    partially in the gas phase.  In the gas phase it will                   2    react with a lifetime of about an hour with OH.  Nobody's                   3    ever looked at it.  You might expect the oxon to be one                   4    of the products.                     5                  So I think you need a whole new section on                   6    what happens to this stuff in the atmosphere.  There are                   7    data on other organophosphorus compounds, somewhat                   8    simpler ones, both kinetics and products, and some of                   9    that should be in.                    10                  CHAIRMAN FROINES:  What do we do with                  11    paragraph 3?                     12                  DR. ATKINSON:  Paragraph 3 means rewrite                  13    it.                    14                  DR. GLANTZ:  We were kind of hoping to                  15    rewrite it right now.  This has been going on for a long                  16    time.                    17                  MR. GOSSELIN:  Actually, in the                  18    environmental phase section on -- I don't know if people                  19    brought their volume.  But on page 13 --                  20                  DR. ATKINSON:  13 of what?  Okay.  The                  21    document.                    22                  CHAIRMAN FROINES:  I think we should delete                  23    paragraph 3.  Because in the first place, we are -- we                  24    have in here essentially a -- the implication of                  25    paragraph 3 is associated with its atmospheric chemistry.                                                                                    96                 BARNEY, UNGERMANN & ASSOCIATES  1-888-326-5900       1                  Then later we're going to get into                   2    metabolism, and the question is, if we want to put                   3    something about -- in about the fate of DEF, we better                   4    know what that is we want to say.                     5                  DR. GLANTZ:  Yeah.  But as I recall, wasn't                   6    the issue of the n-butyl mercaptan important because                   7    that's potentially very toxic?  Don't we want to point                   8    out that, you know, the DEF turns into that somewhere in                   9    here?                    10                  DR. FRIEDMAN:  Can we do it in sort of a                  11    general way that doesn't conflict with other knowledge?                   12    Just so that it becomes converted to without talking                  13    about what its --                  14                  DR. ATKINSON:  But does anybody know                  15    whether it's converted to that in atmosphere, or this is                  16    just the environment in general?                    17                  CHAIRMAN FROINES:  I think that's what it                  18    means.                    19                  DR. GLANTZ:  What were you going to say,                  20    Paul?                    21                  MR. GOSSELIN:  I'm just trying to read                  22    through the environmental fate section in the studies.                   23    They did from a couple studies monitoring DEF -- did pick                  24    up DEF and the n-butyl mercaptan and n-butyl disulfide.                    25                  And so I think there was some body of                                                                                   97                 BARNEY, UNGERMANN & ASSOCIATES  1-888-326-5900       1    evidence that, yeah, DEF did convert down and break down                   2    to those --                   3                  DR. ATKINSON:  So these are field studies.                     4                  MR. GOSSELIN:  Uh-huh.                     5                  DR. ATKINSON:  Nobody has done any lab                   6    studies on it.                     7                  DR. GLANTZ:  Do we have any more copies --                   8                  MR. GOSSELIN:  There was some laboratory                   9    experiments in 1980.  Photooxidation to --                  10                  CHAIRMAN FROINES:  Well --                  11                  MR. GOSSELIN:  Yes.  Within 11 hours                  12    n-butyl mercaptan and n-butyl disulfide.                    13                  CHAIRMAN FROINES:  What I would suggest is                  14    that the issue of the atmospheric chemistry and breakdown                  15    products of DEF we leave -- hold over and Roger take a                  16    look at it and suggest some language --                  17                  DR. ATKINSON:  I will.                    18                  CHAIRMAN FROINES:  Because right now we're                  19    trying to do something that we're not prepared to do, and                  20    we don't even have documents in front of us.  I hate to                  21    put it off because it would be nice to bring this to                  22    closure.  But I think Roger is raising important points                  23    and unless somebody can easily --                  24                  DR. ATKINSON:  I'll look at that.                    25                  CHAIRMAN FROINES:  See, the problem we have                                                                                   98                 BARNEY, UNGERMANN & ASSOCIATES  1-888-326-5900       1    here is we have three people, myself and Paul and Roger,                   2    who were not at the October meeting when this issue came                   3    up and so there are gaps that I think will continue to                   4    emerge.                     5                  DR. BLANC:  Well, I'm not sure that we need                   6    to hold it over because, you know, Roger is focusing on                   7    the -- as if this just referred to the atmosphere, what                   8    goes on in the atmosphere.  This is a more general issue                   9    of the total environment.                    10                  I think we could have wording that would                  11    subsume the important issues.                    12                  DR. GLANTZ:  Yeah.  What about just                  13    deleting "e.g. photooxidizes"?                    14                  DR. BLANC:  Well, I think the two                   15    things -- that, one, taking rid of that parenthetic                  16    statement and the other is making clear in the same                  17    paragraph that -- because, when I read this, I was                  18    confused by it.                                  19                  The DEF is oxidized to an active moiety.                    20    Just so that that's clear and up front and then say                  21    either DEF directly or through that oxidated moiety can                  22    be broken down to these other two chemicals which are                  23    also important in terms of their effects.                    24                  Because what was confusing about -- I don't                  25    care whether it does other things too, but all the things                                                                                   99                 BARNEY, UNGERMANN & ASSOCIATES  1-888-326-5900       1    that are discussed in the findings either refer to DEF                   2    using that as shorthand for actually what is its active                   3    moiety, which is not clear what it is, or we're talking                   4    about these two other breakdown products.                     5                  But the way that number three is currently                   6    worded, it confused me later on when we started about it                   7    being oxidized to an active moiety.                      8                  CHAIRMAN FROINES:  But we're talking about                   9    two different issues.  We're talking about metabolic                  10    activation in vivo, and we're talking about environmental                  11    chemistry, and those are different issues.                    12                  You see, the active moiety is not produced                  13    in -- an active moiety may be produced in the atmosphere,                  14    but the point is that the compound -- DEF is bioactivated                  15    in the liver presumably or wherever, and that's the other                  16    side of this coin.                    17                  DR. BLANC:  I see.                    18                  MR. GOSSELIN:  I think the main point in 3                  19    is that still may -- what's still important is that there                  20    is data to show, field and laboratory, that DEF does                  21    break down by, you know --                  22                  DR. BLANC:  By whatever means.                    23                  MR. GOSSELIN:  -- by whatever means to                  24    n-butyl mercaptan and n-butyl disulfide.  Those two                  25    components besides DEF may pose some health --                                                                                   100                 BARNEY, UNGERMANN & ASSOCIATES  1-888-326-5900       1                  DR. BLANC:  Okay.  Then I have another                   2    suggestion that I think will solve all these problems.                    3    It's pretty simple.  One is take out the parenthetic                   4    comment "e.g., photooxidizes" because some of it breaks                   5    down through hydrolysis in the environment so that we                   6    shouldn't say that.                     7                  And simply inserting the phrase on the                   8    second sentence where it says "Therefore, the health                   9    effects associated with the use of DEF include the direct                  10    effects of DEF (through its active metabolite) and may                  11    also include the effects of NBM and NBD."                  12                  Because that would highlight to the reader                  13    of that issue.  Because otherwise it was quite confusing                  14    later on when suddenly we were talking about the active                  15    moiety of DEF.                   16                  DR. ATKINSON:  I think it would be best to                  17    put 3 as DEF is transformed in the environment, at least                  18    in part, to the mercaptan and on dimethyl sulfide.                    19                  DR. BLANC:  Okay.  That's fine with me.                   20    Did you get that wording, John?                    21                  CHAIRMAN FROINES:  Yeah.  But I'm relying                  22    on Bill to get the wording.                    23                  DR. BLANC:  Bill, it would read "DEF is                  24    transformed in the environment, at least in part,"                   25    delete parenthetic phrase, "to" -- blah, blah, blah,                                                                                   101                 BARNEY, UNGERMANN & ASSOCIATES  1-888-326-5900       1    blah.  "Therefore, the health effects associated with the                   2    use of DEF include the direct effects of DEF (through its                   3    active metabolite) and may also include the effects of                   4    NBM and NBD."                   5                  CHAIRMAN FROINES:  I think that takes care                   6    of it, but the question still begging is, is there an                   7    atmospheric transformation product of DEF that may itself                   8    have toxicity in it?                     9                  So I would still ask Roger to look at that,                  10    and we can add that if that's the case.  So that                   11    the -- there are still really the two issues.                    12                  DR. BLANC:  Yeah.  I agree with that.                    13    My -- should I keep going on my --                  14                  CHAIRMAN FROINES:  Yeah, please.                    15                  DR. BLANC:  Point number -- skipping to                  16    point number 15.  "Symptoms reported by people                  17    potentially exposed to DEF through occupational exposure                  18    or through ambient air near DEF-sprayed fields included                  19    ocular and respiratory irritation (e.g." -- blah, blah,                  20    blah.                    21                  And the current phraseology is "and                  22    apparent cholinergic effects," parenthesis -- blah, blah,                  23    blah, blah.  And I would say -- I would delete the word                  24    "apparent" because I don't know what that means there,                  25    and I would clarify by saying "and cholinergic effects                                                                                   102                 BARNEY, UNGERMANN & ASSOCIATES  1-888-326-5900       1    consistent with acetylcholinesterase inhibition."  And                   2    then the rest of it.                     3                  DR. GLANTZ:  Then leave the list of the                   4    symptoms.                     5                  DR. BLANC:  Yes.  That's fine.  And on                   6    number 16, the next one, I would delete the word                   7    "symptoms resembling" and replace it with "findings                   8    consistent with" so that it would say "One case report                   9    describes the development of findings consistent with                  10    OPIDN."                  11                  DR. FRIEDMAN:  Is OPIDN ever defined before                  12    that?  Is that abbreviation --                  13                  MR. GOSSELIN:  Number 9.                    14                  DR. BLANC:  Again, and the next one, number                  15    17, I know that you've already changed the wording                   16    but -- based on the bold -- but actually would suggest a                  17    different wording so the last sentence would say "The                  18    inhibition of neural" -- it should be -- it should be                  19    actually just either "NTE" or "neuro-target esterase."                   20    So I don't know why the word "neural" is there.  But                   21    the --                  22                  CHAIRMAN FROINES:  "Neural" should go out?                    23                  DR. BLANC:  Yeah.  Because you never                  24    measure in the nerve.  You measure, I think, usually in                  25    the lymphocytes or some other marker, but "inhibition of                                                                                   103                 BARNEY, UNGERMANN & ASSOCIATES  1-888-326-5900       1    NTE in sensitive species is a biomarker that correlates                   2    with the induction of OPIDN" would be a better wording, I                   3    think, rather than "may be one of the factors."                   4                  Because I don't think there's evidence that                   5    it's the factor.  It's just a good mark for it would be a                   6    more --                   7                  CHAIRMAN FROINES:  We talked about that                   8    this morning, and that language is better.  Say it again.                     9                  DR. BLANC:  So it would say "The inhibition                  10    of NTE in sensitive species is a biomarker that                  11    correlates with the induction of OPIDN."  So those were                  12    the word changes that I caught at least so far.                    13                  CHAIRMAN FROINES:  Gary?  Tony?                    14                  DR. FUCALORO:  Just -- environmental fate.                   15    I just have a question.                    16                  REPORTER:  Move up to your microphone.                    17                  DR. FUCALORO:  Sorry.  Looking at the                  18    document "Environmental Fate," dated November, '98, I                  19    just don't understand this entry at the bottom                   20    the -- "an ultimate property ultraviolet                   21    absorbance" -- which I think is spelled wrong -- "less                  22    than 50 at 300 nanometers."  I mean I don't understand                  23    what that means.                    24                  DR. ATKINSON:  It means "units," for one                  25    thing.                                                                                     104                 BARNEY, UNGERMANN & ASSOCIATES  1-888-326-5900       1                  DR. FUCALORO:  I mean 50 -- if it's -- I                   2    mean if it's absorbance units, I mean, how can                    3    you think it's -- I mean 50 is a number -- you can't                   4    measure 50 absorbance units by no machine I know.  I mean                   5    it's not even -- I don't quite understand that, and I                   6    think absorbance is spelled with an "A," isn't it?                     7    B-e -- b-a-n-c-e?                     8                  DR. ATKINSON:  Absorbance?                     9                  DR. FUCALORO:  Absorbance.  But                   10    that's --                    11                  CHAIRMAN FROINES:  No.  It's "E," isn't it?                    12                  DR. ATKINSON:  I don't --                  13                  DR. FUCALORO:  Could be.                    14                  MR. GOSSELIN:  We can go back and --                  15                  DR. FUCALORO:  I don't understand 50.  I                  16    mean, you know, absorbance is a -- if you have an                  17    absorbance of 2, it means that that 1 part in 100 gets                  18    through.  If you have an absorbance of light, if you have                  19    an absorbance of 3, it's 1 part in 1,000.  There's no                  20    machine that can measure an absorbance of 50 or 20 or 10,                  21    as a matter of fact.                    22                  DR. ATKINSON:  So what you need is the                  23    absorption cross-section and the correct units.                    24                  DR. FUCALORO:  Right.  Which would have to                  25    have been units.  Absorbance is unit less because it's in                                                                                   105                 BARNEY, UNGERMANN & ASSOCIATES  1-888-326-5900       1    a log as an exponent.                     2                  CHAIRMAN FROINES:  I just think we're going                   3    to have a lot of fun with Roger on this committee.  I'm                   4    looking forward to it.  Craig?                     5                  DR. BYUS:  Yeah.  I just think it's nicely                   6    done.  I'm just reading over to make sure that this whole                   7    issue of the serum cholinesterase inhibition and the                   8    calculation of NOELs is adequately illuminated here                   9    relative to the actual appearance of symptoms.                    10                  It appears to me that it is.  I mean are                  11    the lead people happy with this?  I mean this is                   12    the -- you know -- 19.  It's this whole issue of the                  13    subchronic identified NOEL of 2.4 milligrams per meter                  14    squared for DEF based on blood cholinesterase inhibition                  15    is the lowest number, and I -- so what -- the last                  16    sentence in this is that -- so what did you do then?                    17                  The adjusted NOAEL as noted for                   18    the -- could you explain to me the last sentence?  What                  19    that means?                    20                  MR. GOSSELIN:  The adjusted NOAEL?                     21                  DR. BYUS:  Yeah.                    22                  MR. GOSSELIN:  That's taking --                  23                  DR. BYUS:  In other words, how did you                   24    go -- you got the NOEL of 2.4 and the NOAEL of 12.2 and                  25    then you now have the adjusted NOAEL of 4.3.  Just                                                                                   106                 BARNEY, UNGERMANN & ASSOCIATES  1-888-326-5900       1    explain to me --                   2                  MR. GOSSELIN:  It's using the respiration                   3    differences.  We have standards for the rats and then we                   4    have standards for adults and standards for children, and                   5    we calculate both scenarios.                     6                  So this is adjusting -- and I think what                   7    this reference is just the adjusted NOAEL that was based                   8    upon the six-year-old child, which is -- comes out to be                   9    the lowest adjusted NOAEL compared to adults which has                  10    been what we would derive the assessment for general                  11    population.                    12                  DR. BLANC:  And at the October meeting                  13    somebody maybe can clue me in as to -- and I apologize                  14    for not being more familiar with the transcript of that                  15    meeting -- the level of comfort on this committee for                  16    accepting serum cholinesterase as being a marker of an                  17    effect which was not an adverse effect.                    18                  DR. BYUS:  I brought this up with -- this                  19    was at this meeting.  This was one of the big points of                  20    discussions, and it's still perhaps.  It doesn't affect                  21    the methyl parathion as much because the number they come                  22    up with on other studies is actually lower than the serum                  23    cholinesterase value.                    24                  So in a sense it really doesn't matter, at                  25    least so far.  Now, they're still calculating and still                                                                                   107                 BARNEY, UNGERMANN & ASSOCIATES  1-888-326-5900       1    getting more information, but so far the number they                   2    chose is lower than the one where the serum                   3    cholinesterase -- so it's not an issue.                     4                  But it still is an issue here.  My personal                   5    feeling is that, if you're inhibiting your serum                   6    cholinesterase, this is indicative of your brain                   7    cholinesterase must be inhibited also.  I mean it's                   8    simply a matter of affinities in the chemical.                     9                  There's no way you could only inhibit serum                  10    cholinesterase without inhibiting some cholinesterase in                  11    your central nervous system.  Now, whether you see some                  12    adverse effect of that -- in other words, whether that                  13    shows up as lacrimation or these other cholinesterase                  14    symptoms is another question.                    15                  But in my opinion, you don't want to walk                  16    around with your serum cholinesterase inhibited by 20 to                  17    30 percent.  That's indicative to me of some significant                  18    level of exposure.  Your brain cholinesterase has to be                  19    inhibited.                    20                  Now, whether you see symptoms or not is                  21    another question.  There appears to be some threshold                  22    effect -- threshold by which you see these symptoms.  And                  23    we're going to hopefully deal with this question, I hope,                  24    in this workshop.  Because it's a very -- apparently the                  25    EPA -- now, correct me if I'm wrong, Paul.  The EPA                                                                                    108                 BARNEY, UNGERMANN & ASSOCIATES  1-888-326-5900       1    has -- in the past has decided to not to use serum                   2    cholinesterase as an --                   3                  MR. GOSSELIN:  No.  They do.                     4                  DR. BYUS:  But now they've changed it.  I                   5    said in the past.  But now they've changed their mind and                   6    are calculating the risk factors based on the inhibition                   7    of serum cholinesterase.                      8                  CHAIRMAN FROINES:  Paul's asking the                   9    question is plasma cholinesterase inhibition an NOAEL or                  10    an NOEL?  I think that's his question.                    11                  DR. BYUS:  I'm not sure --                  12                  CHAIRMAN FROINES:  The U.S. Supreme Court                  13    is very clear that clinical symptoms are not the criteria                  14    for defining adverse effects.  The inhibition of enzymes                  15    in the -- with -- lead in the association with hemoglobin                  16    levels is an adverse effect.                    17                  The reduction of motor nerve conduction                  18    velocity is an adverse effect.  Enzyme inhibition is an                  19    adverse effect so that one cannot simply say that you                  20    need to -- according to the U. S. Supreme Court, you do                  21    not have to have clinical symptoms to define adversity.                    22                  DR. BLANC:  Well, Paul --                  23                  DR. BYUS:  My point as a biochemist here is                  24    that inhibition of brain cholinesterase would be                  25    considered an adverse effect, but you can't measure that                                                                                   109                 BARNEY, UNGERMANN & ASSOCIATES  1-888-326-5900       1    in individuals without -- certainly in humans without                   2    taking biopsies of their brain or what you can't do.  You                   3    can do it in animals, but you can't do it in humans.                     4                  But you can take serum levels, and you can                   5    measure the serum cholinesterase, which is a different                   6    enzyme, but it has many of the same characteristics                    7    as -- of the brain enzyme, and it has a certain relative                   8    affinity for this chemical as relative and very near what                   9    the brain enzyme is.                    10                  So if you -- my contention is that, if your                   11    serum cholinesterase is inhibited, your brain                  12    cholinesterase must be inhibited by some factor.  Maybe                  13    not by quite as much but by some factor.  It's just that                  14    you can't measure it.                    15                  So what they're saying is you can't measure                  16    it.  You may not see symptoms either.  But you have been                  17    affected.                    18                  DR. FUCALORO:  But you're saying the serum                  19    cholinesterase is a surrogate for measuring enzyme -- the                  20    brain.  But also the issue, as I recall, was that serum                  21    cholinesterase inhibition was also a bad effect in and of                  22    itself; right?  An adverse effect in and of itself, and I                  23    guess once Peter brought up some case --                  24                  DR. BYUS:  The further statement that was                  25    made -- I don't mean to bring up my stuff again, but                                                                                   110                 BARNEY, UNGERMANN & ASSOCIATES  1-888-326-5900       1    since you weren't there, the DPR said -- somebody                    2    on -- the staff person said that there's no known                   3    function of serum cholinesterase, and that's not true.                    4    It does have known functions.                     5                  It does function, for example, in some drug                   6    clearing reactions and so, if you inhibit that enzyme,                   7    you're taking certain drugs, you may have had an adverse                   8    effect on top of that.  It does have known functions.                    9    That is clear.                    10                  It may not have known functions in sort of                  11    the normal etiology of an individual, but certainly, if                  12    you're exposed to other drugs under certain situations,                  13    yes, and if this enzyme were inhibited by                  14    organophosphates, you could have additional adverse                  15    effects.  That's the point there.                    16                  DR. FUCALORO:  Yeah.  I just wanted to                  17    mention that.  Because it was mentioned the last time.                    18                  DR. BYUS:  Exactly.  And so I mean this is                  19    what we went over and discussed, and this is one topic                  20    that we would hope to explore in some detail in this                  21    workshop to really -- and my understanding of -- I had to                  22    come up to a lot of speed on this topic.  But that's kind                  23    of my feeling, what I just said to you.  The last --                  24                  CHAIRMAN FROINES:  Comments on that?                    25                  DR. BLANC:  Well, I have a suggestion                                                                                   111                 BARNEY, UNGERMANN & ASSOCIATES  1-888-326-5900       1    unless there's a statutory requirement to a different                   2    effect and so let me ask my question first.  In our                   3    findings, are we required to comment on both the no                   4    effect level and a no adverse effect level?                     5                  CHAIRMAN FROINES:  We don't have -- there                   6    are no criteria for our findings.                     7                 DR. BLANC:  Then I suggest that our findings                   8    address the no effect level based on 2.4 milligrams per                   9    meter and that we make the calculation for the adjusted                  10    no effect level rather than the no adverse effect level                  11    for the 24-hour respiratory rate in the six-year-old                  12    child, and I assume that the ratio would be the same so                  13    that the ratio 4.3 to 12.2 times 2.4 would give us the no                  14    effect level for the six-year-old child.                   15                  And let us not -- I think it's -- as a                  16    procedural matter it's not fair for me to come in at this                  17    late date and reargue the issue about whether we should                  18    also be calling that a no effect level.  Let's just in                  19    our findings focus on the no effect level rather than the                  20    no adverse effect level.                    21                  CHAIRMAN FROINES:  So are you suggesting                  22    that we use the 2.4 milligram per cubic meter in                  23    calculating the 24-hour --                   24                  DR. BLANC:  Yes.                    25                  CHAIRMAN FROINES:  -- calculating the                                                                                   112                 BARNEY, UNGERMANN & ASSOCIATES  1-888-326-5900       1    adjusted NOEL?                      2                  DR. BLANC:  Yes.  And let's just not                   3    address a NOAEL.  Let's just not --                    4                  DR. BYUS:  This is what Stan                    5    originally -- I don't --                   6                  DR. BLANC:  Because I'll tell you --                    7                  DR. BYUS:  -- suggested.                     8                  DR. BLANC:  -- I could not support                    9    this -- I can't support suggesting that the implication                  10    here is that -- the explicit implication is that                  11    acetylcholinesterase inhibition is not an adverse effect.                    12                  DR. BYUS:  Serum.                     13                  DR. BLANC:  Serum.  And I don't accept that                  14    argument because I think it is as clearly a marker of an                  15    adverse effect as the neuro-target esterase is a                  16    correlate of risk of delayed peripheral neuropathy for                  17    exactly the same reasons.                    18                  DR. FRIEDMAN:  Which adverse effect would                  19    you -- what does -- which adverse effect does it                  20    represent?                    21                  DR. BLANC:  It represents all the                  22    cholinergic adverse effects of having your cholinesterase                  23    inhibited at your nerve endings even though you're                  24    measuring it in the blood and in your CNS as well.                    25                  Both of which we can't measure.  We never                                                                                   113                 BARNEY, UNGERMANN & ASSOCIATES  1-888-326-5900       1    measure nerve ending acetylcholinesterase.  We always use                   2    either RBC or serum cholinesterase.  RBC or serum                   3    cholinesterase -- and as our marker of the presumed                   4    effect at the nerve endings.                     5                  DR. BYUS:  You can measure it with animals.                    6    It's measured in some of the animal studies --                   7                  DR. BLANC:  The brain.                     8                  DR. BYUS:  Right.  Not at the nerve endings                   9    but at the brain.                    10                  DR. BLANC:  Right.                      11                  DR. FRIEDMAN:  Does this get across the                  12    blood brain barrier?                    13                  DR. FUCALORO:  That would be the key;                  14    right?                    15                  DR. BLANC:  Almost all of these do.  That's                  16    why -- one of the reasons why they --                   17                  DR. BYUS:  Peripheral as well.                    18                  DR. BLANC:  Most of the clinical things                  19    that we follow are effects that -- at the peripheral                  20    nerves but --                  21                  CHAIRMAN FROINES:  Autonomic?                    22                  DR. BLANC:  Autonomic and the neuromuscular                  23    junction, but there clearly are CNS effects as well.                    24                  DR. FUCALORO:  Paul, can I ask you a                  25    question.  I think I'm understanding what you're                                                                                   114                 BARNEY, UNGERMANN & ASSOCIATES  1-888-326-5900       1    suggesting.  Your concern with the NOEL -- because you                   2    would actually like to see that as an NOAEL; correct?                     3                  DR. BLANC:  Right.                     4                  DR. FUCALORO:  But as a compromise you're                   5    willing to -- you're just getting rid of some of the                   6    vocabulary but having the same quantitative conclusions?                     7                  DR. BLANC:  No.  The quantitative                   8    conclusion, we would be making the quantitative                   9    calculation for the NOEL that's been made for the                   10    NOAEL --                  11                  DR. FUCALORO:  So we would have a ratio of                  12    6 to 1 or something like that.                    13                  DR. BLANC:  Yeah.  I don't know what -- if                  14    somebody would divide -- no.  It would be -- well, it                  15    would be something like a factor of 3 less than 2.4                  16    because the ratio 4.3 to 12.2 times 2.4 must come out to                  17    be .8 or something.  I don't know.                    18                  CHAIRMAN FROINES:  What we would be                  19    essentially saying, Tony, is, if you look at that, you                  20    see the sentence that starts out "The report identified                  21    an acute air."  We would say "The panel has identified an                  22    acute air NOAEL of 2.4 milligrams per" --                   23                  DR. FUCALORO:  I do understand, yeah.                    24                  DR. BLANC:  Well, I was just going to say                  25    NOEL, and I wouldn't -- I would be willing to go even                                                                                   115                 BARNEY, UNGERMANN & ASSOCIATES  1-888-326-5900       1    further, but as a compromise, I'm willing just to refer                   2    to the NOEL.                       3                  CHAIRMAN FROINES:  But Paul, you can't have                   4    it both ways.  You either call it an NOAEL or otherwise                   5    you can't use it for this calculation.                     6                  DR. BLANC:  Why?                     7                  DR. BYUS:  The crux of the question is do                   8    you believe inhibition of serum cholinesterase is an                   9    adverse effect or not?                    10                  DR. BLANC:  Yes, I do.  But --                  11                  DR. BYUS:  You either do or you don't.  And                  12    I certainly -- I mean I do.                    13                  DR. BLANC:  And I do.                     14                  DR. BYUS:  And you do.                   15                  DR. BLANC:  But I wasn't at the October                  16    meeting.                    17                  CHAIRMAN FROINES:  But the point is that                  18    your compromise -- you can't -- your compromise is trying                  19    to -- it doesn't really work.  You have to say the                  20    adjusted NOAEL is this value of 2.4 adjusted for the                  21    respiratory rate of .68.                    22                  DR. BLANC:  Why can't you just say the                  23    adjusted NOEL is this?                    24                  CHAIRMAN FROINES:  Well, I think you                   25    should -- if we're going to use 2.4, because it's an                                                                                   116                 BARNEY, UNGERMANN & ASSOCIATES  1-888-326-5900       1    adverse effect level, we should call it an adverse effect                   2    level.  We shouldn't try and call it a no effect level                   3    but treat it as an adverse effect level.                     4                  DR. BLANC:  I see.                     5                  DR. GLANTZ:  I think then, what you should                   6    do -- because you do want to have this document or the                   7    findings make some sense in the context of the report.                    8    And we don't want to reopen the report.  I don't think.                    9    Unless Paul wants to.                    10                  MR. GOSSELIN:  No.                    11                  DR. GLANTZ:  So what I would suggest is to                  12    rewrite this slightly, and somewhere -- I mean you talk                  13    about the report identified this -- da, da, da.  And then                  14    somewhere I think we should insert a sentence that says                  15    "The panel believes inhibition of blood alcohol                  16    cholinesterase is an adverse effect."                  17                  DR. BYUS:  I agree.                    18                  DR. FUCALORO:  I think that's good.                    19                  DR. GLANTZ:  And then say, "Based on that,                   20    we" -- "the panel differs with the report and says that                  21    the NOAEL should be" -- whatever.  The 2.4.                    22                  DR. BLANC:  That's fine.  I would be                  23    comfortable with that.                    24                  DR. GLANTZ:  And then continue on --                  25                  DR. BLANC:  I would be comfortable with                                                                                   117                 BARNEY, UNGERMANN & ASSOCIATES  1-888-326-5900       1    that.                     2                  CHAIRMAN FROINES:  Is everybody comfortable                   3    with that?                     4                  DR. GLANTZ:  That way someone who looks at                   5    this and looks at the report, they will at least                    6    make -- they'll understand where these different                    7    numbers --                     8                  CHAIRMAN FROINES:  Can we do this -- Bill?                    9    If we write the language -- and you and I can do this                  10    after the meeting -- we can then circulate it -- can we                  11    circulate it to the panel, and if everybody buys off, we                  12    can just go ahead and send it to Paul and say "Here we                  13    are"?                    14                  MR. LOCKETT:  Yeah.                    15                  CHAIRMAN FROINES:  So we don't have to take                  16    the -- I'd rather not carry this over to another meeting.                   17                  MR. LOCKETT:  What the panel is agreeing                  18    on, they are agreeing on.  And then we're just                  19    memorializing it, and they're confirming what we                  20    memorialized.                    21                  DR. BLANC:  Then I would recommend the same                  22    thing with Section 19, which is parallel.                     23                  MR. GOSSELIN:  And if I was going to -- I                  24    was going to add too I was going through the findings.                   25    They do calculate out both values that, if you were going                                                                                   118                 BARNEY, UNGERMANN & ASSOCIATES  1-888-326-5900       1    to insert that finding on this, that it could be sort of                   2    at the end and generalized all the way through.                     3                  And that's just sort of a procedural                   4    suggestion.  Because at the end, both values are                   5    calculated out, and if you want to put your perspective                   6    on it, you can carry it all the way back.                     7                  CHAIRMAN FROINES:  I'll do it.                     8                  DR. BLANC:  You'll have to go through.                    9    You'll have to modify point 20 in a similar way because                  10    it also derives from the same numbers.                    11                  DR. FUCALORO:  Using just a completely                  12    parallel modification; right?                    13                  DR. BLANC:  Right.  And --                  14                  DR. FUCALORO:  Then we can rely upon you                  15    and Bill to do that.                    16                  CHAIRMAN FROINES:  Well, you'll --                   17                  DR. FUCALORO:  I'll take a look at it and                  18    convince myself that's true, but I think --                   19                  CHAIRMAN FROINES:  Everybody will see it.                   20    So --                  21                  DR. GLANTZ:  And when you show it to us,                  22    could you do it like the changes highlighted for those of                  23    us with failing short-term memories?                    24                  DR. FUCALORO:  Proving that it does make                  25    the blood brain barrier --                                                                                    119                 BARNEY, UNGERMANN & ASSOCIATES  1-888-326-5900       1                  DR. ALEXEEFF:  George Alexeeff.  If I could                   2    just make a comment.  I just wanted to clarify something                   3    in my mind just so that -- and maybe to help clarify the                   4    panel, but it seemed to me, from what was being said, is                   5    that what we have is serum cholinesterase, which we                   6    believe is indicative that probably there's some other                   7    cholinesterase inhibition occurring even though we can't                   8    measure it at this time at important sites.                     9                  So -- but the serum cholinesterase itself                  10    is not in and of itself adverse.  It's simply reflecting                  11    that we think there's other potentially adverse effects                  12    happening.  That's what I wanted to clarify.                    13                  DR. BYUS:  No.  In fact, I started doing a                  14    literature search on this, started to work up this                  15    question, and we are going to hopefully deal with this as                  16    a topic in the workshop symposium.  It's a very -- it's                  17    complex, but it's not that complex.                    18                  The point is serum cholinesterase, I think,                  19    from my reading in the literature looks like it could be                  20    adverse itself but that since -- and, again, the example                  21    I use is it's used in the metabolism of some drugs.  And                  22    so it would be like cocaine.                    23                  I just pick that as an example, but it's                  24    used so that, if you were exposed -- I could be shown                  25    wrong this by an expert, but if you had been exposed                                                                                    120                 BARNEY, UNGERMANN & ASSOCIATES  1-888-326-5900       1    to -- if your serum cholinesterase was altered, inhibited                   2    and you took cocaine, it would -- you know, the levels of                   3    cocaine would reach a higher value because you're                   4    inhibiting metabolism, and you could have toxic effects.                    5    You could even die.                     6                  There's other examples of this too.  Other                   7    drugs, other therapeutic drugs that are given are                   8    metabolized by this enzyme, and you calculate drug                   9    dosages based on metabolic rates, you know, half-life.                   10                  So that if you inhibited that by 50                  11    percent, the half-life may go up by 50 percent.  You wind                  12    up with doubling the therapeutic dose which puts you way                  13    up into the toxic range.                    14                  So yes.  In the normal etiology of things,                  15    people walking around, it may be not a problem.  But it                  16    is in and of -- you know, because you take other drugs                  17    both illicitly and therapeutically.                    18                  CHAIRMAN FROINES:  I argue that it at least                  19    fulfills the criteria of an adverse effect as a surrogate                  20    in the same way that a DNA adduct is a surrogate for                  21    events that may occur subsequent downstream.                    22                  DR. BYUS:  And I cannot see how that cannot                  23    be a case until somebody who's an expert shows me --                   24                  CHAIRMAN FROINES:  Paul's right.  The                  25    neurotoxic esterase is, in fact, a marker.  It's not                                                                                    121                 BARNEY, UNGERMANN & ASSOCIATES  1-888-326-5900       1    a -- well, we talked about that earlier anyway.  So                    2    that -- you comfortable -- you folks comfortable with                   3    that?  Nevermind.  I didn't mean to open the barn door.                     4    Let's just go on.  Let's get the cows back in the                   5    pasture.                     6                  DR. FUCALORO:  Out of the pasture.                     7                  CHAIRMAN FROINES:  Out of the pasture.                     8                  DR. BLANC:  Can I ask about point 25?  In                   9    the last sentence, which reads "This information could be                  10    used to calculate seasonal 'air concentration standards'                  11    to protect against these health effects."                  12                  What would be the implication -- this is a                  13    question for the chair -- of changing the word "could" to                  14    "should"?                    15                  CHAIRMAN FROINES:  That's our prerogative.                    16                  DR. BLANC:  Would then something happen if                  17    we did that?  Would there be a response?  An appendix?                    18    A --                   19                  CHAIRMAN FROINES:  No.  It's advisory to                  20    the --                  21                  DR. BLANC:  Well, then --                  22                  CHAIRMAN FROINES:  -- chair.                    23                  DR. BLANC:  I think we should -- it should                  24    be changed to "should," I think.                    25                  DR. BYUS:  Does anybody know that study                                                                                   122                 BARNEY, UNGERMANN & ASSOCIATES  1-888-326-5900       1    well enough?  I mean this is -- now you're saying this                   2    based on this one study.  I don't -- I remember reading                   3    about it, but I don't remember it enough to say we should                   4    use it.                     5                  You know, that's -- if we're going to say                   6    that, we better know what we're talking about with that                   7    specific study.                     8                  CHAIRMAN FROINES:  Well, I think if                    9    we -- if we write findings based on those -- these                  10    conclusions, then in fact either we stand behind them or                  11    we have to find some other bases to come up with NOELs.                   12                  I mean we're saying the NOEL is "X" value                  13    based on this literature and then you can't go back and                  14    say "Well, I'm not sure the study's any good."                  15                  This is the academic approach where you                  16    don't want to, you know, make it too --                  17                  DR. GLANTZ:  I think we should say                  18    "should."  The other thing I think you should do, when                  19    you're editing this to reflect this discussion --                  20                  DR. FUCALORO:  Actually, Stan, you said,                  21    "the other thing I think you could do."                  22                  DR. GLANTZ:  I think you should do is say                  23    "should."  Okay.  And the other thing that I think you                  24    should do, when you're editing this in light of this                  25    discussion, is the way the document is currently written,                                                                                   123                 BARNEY, UNGERMANN & ASSOCIATES  1-888-326-5900       1    it keeps doing the old NOAEL and the NOEL.                     2                  And we're saying that what used to be                   3    called the NOEL should be called the NOAEL.  So I think                   4    that, after we've made that statement, we should drop the                   5    references to the higher number.                     6                  DR. BLANC:  In point 25.                     7                  DR. GLANTZ:  Yeah.                     8                  DR. FUCALORO:  That's fair.                     9                  DR. GLANTZ:  For consistency.                    10                  DR. BLANC:  Do you understand that point?                    11                  CHAIRMAN FROINES:  Yes.                    12                  DR. GLANTZ:  He should.                    13                  CHAIRMAN FROINES:  When he makes it a                  14    "should," it becomes an order.  So I --                   15                  DR. BLANC:  The other thing that's                  16    inconsistent here in this sentence in that next to last                  17    sentence is that the milligram per kilogram dose for the                  18    rats studied and of .1 milligrams per kilogram per day,                  19    that was a reproductive study, but the endpoint was                  20    ataxia.  Am I reading it --                   21                  MR. GOSSELIN:  No, no, no.  That was -- it                  22    is two studies.  I think that was from the 90-day hen                  23    feeding study.                    24                  DR. BLANC:  Oh, I see.  So it's 1 for the                  25    hen --                                                                                    124                 BARNEY, UNGERMANN & ASSOCIATES  1-888-326-5900       1                  MR. GOSSELIN:  .1.  Right.  For ataxia.                      2                  DR. BLANC:  Okay.  And .4; right?                     3                  MR. GOSSELIN:  Right.  For the rate --                   4                  DR. BLANC:  And what was the actual level                   5    for the neuro-target esterase depression in the hen that                   6    was 30-fold lower?                      7                  CHAIRMAN FROINES:  Oh, Paul, back to this                   8    could and should, before you get into this, because I                   9    think that we've now made the decision that we can't                  10    necessarily do until we deal with this issue.  Because                  11    what this sentence now says is we're going to use the                  12    OPIDN work as the basis for regulatory decision making.                   13    But go ahead.  Do you know what I mean?                    14                  DR. BLANC:  Well, yeah.  That's what I'm                  15    trying to get at.  There is an ataxia outcome in the hen                  16    study.  Let's see if I follow this correctly.  At .1                  17    milligram; right?                    18                  MR. GOSSELIN:  Uh-huh.                    19                  DR. BLANC:  Now, that would be -- is ataxia                  20    not considered an adverse effect?  That's just considered                  21    just an effect?                    22                  MR. GOSSELIN:  No.  Depending on the study,                  23    it would have been considered an adverse effect, but with                  24    both of these, there were probably some other                  25    circumstances in the studies as to -- maybe                                                                                   125                 BARNEY, UNGERMANN & ASSOCIATES  1-888-326-5900       1    inconsistencies in the effect through different doses of                   2    some other variables as to why that wasn't used.                     3                  I think the important thing was -- is that                   4    there were some other effects and other studies but for a                   5    variety of reasons, and I don't have them with me right                   6    now.  Those weren't highlighted.  That was -- if that was                   7    a solid study and there weren't any other                    8    circumstances --                   9                  DR. BLANC:  Okay.  Well, let me take you                  10    where I'm going with this thought, which has to do with                  11    the point 26, which has to do with the neuro-target                  12    esterase in the chicken, and I assume it's the same                  13    chicken study.                    14                  My approach to neuro-target esterase with a                  15    known chemical which causes delayed peripheral                   16    neuropathy such as this, is that it is parallel to an                  17    acetylcholinesterase depression, a serum                  18    acetylcholinesterase depression so that I would not call                  19    neuro-target esterase inhibition an effect for which one                  20    calculates a no effect level, but it's a no adverse                  21    effect level.                    22                  The neuro-target esterase is so correlated                  23    with peripheral neuropathy, it's the only good marker we                  24    have in an animal species.  It doesn't tell us that                  25    that's the mechanism, but it tells us that's the marker                                                                                   126                 BARNEY, UNGERMANN & ASSOCIATES  1-888-326-5900       1    in the same way that plasma cholinesterase is not the                   2    mechanism by which the cholinergic effects are observed                   3    at a regular organophosphate.                     4                  CHAIRMAN FROINES:  Can I -- let me -- this                   5    is the one point I wanted to make.  Can I -- are you                   6    going to get into 26?  Because if you're going to get                   7    into 26, I'll shut up.                     8                  DR. BLANC:  No.  That's where I'm going.                    9                  CHAIRMAN FROINES:  Okay.  Go ahead.                   10                  DR. BLANC:  So therefore, I think that                   11    our -- again, consistent with what Stan said, I don't                  12    think we should ask you to rewrite the document, but I                  13    would strongly suggest that the Scientific Review Panel's                  14    comment be that we do not accept ignoring or -- not                  15    ignoring.  Compartmentalizing the neuro-target esterase                  16    data as a no effect level.                    17                  And, in fact, it, parallel to the other, is                  18    an adverse effect if there are questions with the quality                  19    of study so that it can't be believed.  That's a                  20    different issue which has to be dealt with, but if it was                  21    merely that this was discounted because it's a no -- it's                  22    treated here as a NOEL, and it's really an NOAEL issue.                    23                  DR. FRIEDMAN:  Can I --                  24                  DR. BYUS:  Not really.  Now, as I                  25    understand this, the delayed neurotoxicity doesn't                                                                                   127                 BARNEY, UNGERMANN & ASSOCIATES  1-888-326-5900       1    correlate as strongly with the inhibition of that enzyme.                    2    And the reason -- at least the data that they presented                   3    in support of that and certainly for methyl parathion,                   4    methyl parathion shows no delayed neurotoxicity at all.                    5                  If you survey the various organophosphates                   6    based on compounds, specific delayed neurotoxicities                   7    versus not, some of them show the delayed effects, and                   8    some of them do not, and it doesn't appear to correlate                   9    extremely well with the inhibition of that enzyme.                    10                  Now, I may be wrong about that, but I'm                   11    not -- it was -- the mechanisms there -- the correlation                  12    is less solid -- and at least as I remember reading all                  13    of it -- than it is between inhibition of serum                  14    cholinesterase and peripheral cholinergic effects.                    15                  Is that -- I'm not an expert on this.  We                  16    really need -- you know, that's the other correlation.                   17    It's a difficult --                    18                  DR. BLANC:  Well, the correlation is with                  19    the animal model.  The animal model for delayed                  20    neuropathy is the chicken, and when you have a species                  21    which shows the delayed peripheral neuropathy clinically                  22    and then in that same species you have an effect level                  23    where you show decrease in neuro-target esterase, you                  24    have to assume, until proven otherwise, that that is a                  25    correlate of the adverse effect.                                                                                     128                 BARNEY, UNGERMANN & ASSOCIATES  1-888-326-5900       1                  DR. BYUS:  But do -- say you take 15                   2    cholinesterase inhibitors, does the correlation hold up                   3    in that animal model?                     4                  DR. BLANC:  For ones which there's no dose                   5    response ever for showing the --                   6                  DR. BYUS:  No.  For when there is.  Do they                   7    call -- there's one thing with using one compound and                   8    showing it, but I'm saying cross-compounds.                     9                  DR. BLANC:  My understanding is that the                  10    compounds which cause peripheral neuropathy also inhibit                  11    neuro-target esterase.                    12                  DR. BYUS:  Okay.                    13                  CHAIRMAN FROINES:  There is a                  14    high-structural dependence on delayed neuropathy, and                  15    there is a certain class of organophosphates that produce                  16    it, and those same compounds also inhibit neurotoxic                  17    esterase so that there's a strong structure activity                  18    relationship.                     19                  Gary?                    20                  DR. FRIEDMAN:  I'm trying to -- as long as                  21    we're on point 25, I'm trying to understand that second                  22    to last sentence beginning with "however."  I'm trying to                  23    figure out where the rat reproductive toxicity fits in.                   24    Is brain CH -- cholinesterase inhibition considered                  25    reproductive toxicity?                                                                                     129                 BARNEY, UNGERMANN & ASSOCIATES  1-888-326-5900       1                  MR. GOSSELIN:  No.  But sometimes in                   2    reproductive toxicity studies, early in those studies in                   3    the first day or two, they'll take -- either observe                   4    clinical signs or take various measurements and will                   5    actually in some cases derive some acute or subchronic                   6    values out of them.                     7                  So sometimes it's just sort of an effect                   8    that is seen early on before you get into developmental                   9    effects, and occasionally we use those.                     10                  DR. FRIEDMAN:  I see.  I wonder if that                  11    will be confusing to people.  It seems to -- it isn't                  12    really a reproductive toxicity, but it's a reproductive                  13    toxicity study in which nonreproductive toxicity were                  14    observed.  If everyone's comfortable with that --                  15                  DR. BLANC:  I think you bring up a good                  16    point there.  It would just make the sentence clearer to                  17    delete the word "reproductive."  It's not relevant to                  18    this sentence that there was a reproductive study.                    19                  It could have been a study of inhalation                  20    irritancy and have found this too.  That's not the point.                   21    They found this.                    22                  CHAIRMAN FROINES:  Okay.  So we'll delete                  23    it.                    24                  Paul, go ahead with 26.  We're getting                  25    really tight on time.                                                                                     130                 BARNEY, UNGERMANN & ASSOCIATES  1-888-326-5900       1                  DR. BLANC:  Well, I just think that -- I                   2    don't think -- I actually don't think -- to reverse                   3    myself in earlier comments, I think that Stan's comment                   4    of the general approach where we shouldn't change the                   5    document, we should simply point out where we differ with                   6    it is still the right one.                     7                  The interrelationship between point 25 and                   8    26 is going to take major rewriting.  I don't think we                   9    can do that here.  I am comfortable with seeing a                  10    circulated version.  I don't think you have clear                  11    instructions yet from the committee because I don't know                  12    if we've reached consensus on how to handle neuro-target                  13    esterase.                    14                  It would be my personal view to handle it                  15    in parallel with how we're handling the serum                  16    cholinesterase.                    17                  CHAIRMAN FROINES:  Yeah.  I've been waiting                  18    to get my turn here on this one.  All -- I think that the                  19    point 26 is an extremely important point.  They say and                  20    OEHHA also says these paragraphs are identical in the two                  21    sets of findings.                    22                  They say "First, a cross-route                  23    extrapolation needs to be performed.  Second, this                   24    study" -- "this study" meaning the chicken study, the hen                  25    study -- "suggests an underestimation of risk using the                                                                                   131                 BARNEY, UNGERMANN & ASSOCIATES  1-888-326-5900       1    90-day rat inhalation study."                   2                  In other words, we're not using the hen                   3    study.  We're using the rat study.  There is considerable                   4    uncertainty in quantifying applying the hen study for                   5    inhalation exposure.  I have two points.  One point is                   6    that the sensitive species for delayed neuropathy is the                   7    chicken.  It's the hen.  It's what we use to identify                   8    delayed neuropathy.                     9                  When one test compounds -- as I said,                  10    there's a strong structure activity relationship between                  11    organophosphates and delayed neuropathy.  And so what                  12    people do is, when they have a particular organophosphate                  13    that has the structural characteristics that you think                  14    might lead to delayed neuropathy, they test them in the                  15    chicken because the chicken is the sensitive species.                   16                  So if we have -- if the sensitive species                   17    in the chicken -- is the chicken, then it seems that we                  18    have to be able to develop an ability to conduct a risk                  19    assessment in that species unless somebody can                  20    demonstrate mechanistically why the hen is an                  21    inappropriate model.                    22                  So it seems to me that what I want to do                  23    was to say that OEHHA and to -- the panel recommends to                  24    OEHHA and DPR that further investigation be carried                   25    out -- some language to that effect -- that looks at how                                                                                   132                 BARNEY, UNGERMANN & ASSOCIATES  1-888-326-5900       1    one can make use of the hen data to develop appropriate                   2    risk assessment estimates for delayed neuropathy.                     3                  In other words, we don't say there is -- we                   4    say, you can say there is considerable uncertainty, but                   5    we don't want to leave it at that.  We want to say "Go                   6    out, and figure out how to do it."  Because that's the                   7    model we need to be able to make work because that's the                   8    endpoint that is most relevant for this particular                   9    neurotoxicity.                    10                  And the peripheral neuropathy associated                  11    with delayed neuropathy is much more serious in a chronic                  12    context than -- it's very serious in a chronic context                  13    whereas organophosphate toxicity is obviously more of an                  14    acute nature to some extent.                     15                  DR. FRIEDMAN:  Is it possible that a                  16    substance could produce neuropathy in this very sensitive                  17    chicken and not produce it at all in the human?                    18                  CHAIRMAN FROINES:  That seems to me that's                  19    a question of concern.                     20                  DR. FRIEDMAN:  Because in that case you                  21    might not want to figure -- have some formula for                  22    extrapolating from chickens to people.                    23                  CHAIRMAN FROINES:  But that's exactly what                  24    I'm saying.  I think that the burden now is on OEHHA and                  25    DPR to go back and look at the evidence and say is there                                                                                   133                 BARNEY, UNGERMANN & ASSOCIATES  1-888-326-5900       1    evidence in humans based on the delayed neuropathies in                   2    chickens, and can we develop some risk assessment                   3    approach given the information we currently have                   4    available?                     5                  I'm not presuming that we have to use the                   6    chicken for risk assessment, but I think we have to try                   7    to look at the issues that underlie the most sensitive                   8    species, and somebody has to come back and say why                   9    mechanically we shouldn't assume the chicken may be                  10    relevant.  In other words, you assume that it may be                  11    relevant and then go see if you can disprove its                  12    relevance.                    13                  DR. FRIEDMAN:  Would that be a good topic                  14    for a workshop?                    15                  CHAIRMAN FROINES:  Yes.  Absolutely.  I                  16    think this is a key question because, if every time a                  17    delayed neuropathy comes up, and we're dealing with                  18    pesticides, we simply say it's too hard to deal with.                   19    Then we haven't really met the burden -- our burden.                    20                  So I will rewrite this, and I think this is                  21    a particularly important issue for the panel and for the                  22    agencies because the chicken is in the end the sensitive                  23    species.                    24                  DR. BLANC:  Well, I think, again, that part                  25    of these differences comes up -- you know, traces back to                                                                                   134                 BARNEY, UNGERMANN & ASSOCIATES  1-888-326-5900       1    the regulatory background of your agency and that you've                   2    been used to dealing with FIFRA on EPA.  These -- our                   3    kinds of deliberations are going to differ from that.                     4                  CHAIRMAN FROINES:  Paul and we talked about                   5    this this morning before this meeting, and he's                   6    completely open.  So it's been a very positive                   7    interaction in this.  And so there's no tension between                   8    us and DPR.                     9                  I think that they've been very forthcoming                  10    in terms of their willingness to, you know, hear these                  11    kinds of concerns.  So we appreciate that.  So the good                  12    news is we got through DEF.  The bad news is we're                  13    clearly not going to touch parathion unless you can do it                  14    in five minutes.                    15                  DR. ATKINSON:  What --                  16                  DR. GLANTZ:  What about me?                    17                  CHAIRMAN FROINES:  I'm sorry.  I apologize.                    18                  DR. GLANTZ:  I have a tremendous amount of                  19    stuff.                    20                  DR. FUCALORO:  I thought Paul covered it                  21    all.                    22                  DR. GLANTZ:  No.                    23                  CHAIRMAN FROINES:  Are you sure?                    24                  DR. GLANTZ:  Yeah.                    25                  CHAIRMAN FROINES:  I didn't mean to be                                                                                   135                 BARNEY, UNGERMANN & ASSOCIATES  1-888-326-5900       1    rude.                     2                  DR. GLANTZ:  Yes, you did.                     3                  CHAIRMAN FROINES:  No, I didn't.  On the                   4    contrary.                     5                  DR. GLANTZ:  Okay.  No.  Everything I was                   6    concerned about is somebody else --                   7                  CHAIRMAN FROINES:  Are you sure?                     8                  DR. GLANTZ:  Yeah.  But if you want, I'll                   9    make something up.                    10                  DR. FUCALORO:  He'll have a go at it.                    11                  DR. GLANTZ:  No.  I'm quite happy.  I think                  12    these changes are excellent.                    13                  CHAIRMAN FROINES:  Okay.                    14                  DR. GLANTZ:  I mean they were the kind of                  15    things that I was talking about last time.                    16                  CHAIRMAN FROINES:  You promised that you're                   17    not going to bring this up again sometime.  So you cut me                  18    off at that meeting.                    19                  DR. GLANTZ:  No.  I won't promise that, for                  20    the record.                    21                  CHAIRMAN FROINES:  Please, bring up any                  22    comments right now.                    23                  DR. GLANTZ:  No.  I think the issues that I                  24    had had been aired already.  I think with these changes                  25    it's fine.                                                                                     136                 BARNEY, UNGERMANN & ASSOCIATES  1-888-326-5900       1                  DR. ATKINSON:  I would like to get a copy                   2    of the DPR report for my interest, if that's possible.                     3                  DR. FUCALORO:  Pretty tough to discuss when                   4    your --                   5                  DR. GLANTZ:  One other thing -- I guess one                   6    other thing that I -- I just think that we ought to make                   7    it important.  A point we ought to make for the record,                   8    though, is that in the -- this is the first time we're                   9    going to be issuing findings where we say we're                  10    explicitly differing with a report we already approved.                   11                  And I think we should make it clear that                  12    that is not a reflection of some horrible political                  13    battle with DPR in this case.  It's just simply a                  14    question of expediency and moving the process forward and                  15    to not reopen the report.                    16                  Because I don't think anybody wants to                  17    start reediting the report.  So I think that's an                  18    important point because I wouldn't want somebody to read                  19    the findings and think that, you know, there was some                  20    great deal of bloodshed this time.  That was all in the                  21    past.  But the -- so I just think that's an important                  22    point for the record.                    23                  MR. GOSSELIN:  I think the report's been                  24    crafted in a way that, you know, all the information is                  25    there for the panel and the agency to choose what's the                                                                                   137                 BARNEY, UNGERMANN & ASSOCIATES  1-888-326-5900       1    most relevant endpoint either of concern or to regulate                   2    from and to try to make sure that all the information in                   3    there is presented and factual.                     4                  DR. GLANTZ:  But I would hope, especially                   5    with our change to "should," that in terms we should move                   6    the regulatory process forward.  I think the intent of                   7    the panel to use that sort of endpoint is clearly there.                    8    But I just think it's important that there not be any                   9    misunderstanding, but I think -- I'm quite happy with the                  10    findings as advised.                    11                  CHAIRMAN FROINES:  I think there's another                  12    point which is that I think it's really terrific that we                  13    actually now have brought DEF pretty much to closure.                   14    And so we can all feel good about the fact that we've                  15    overcome that long history.                    16                  And so I think this has been a very                  17    cooperative exchange, and I think the record should                  18    really reflect that, and I think there's a consensus here                  19    that we're moving in the right direction.                    20                  DR. FUCALORO:  You said, "consensus," not                  21    the majority.  Not unanimity.  I'm sorry.                    22                  MR. GOSSELIN:  Do you want me to just --                   23                  DR. GLANTZ:  I think at your next class the                  24    next time you meet here, you should just have your class                  25    come to this meeting.                                                                                     138                 BARNEY, UNGERMANN & ASSOCIATES  1-888-326-5900       1                  DR. FUCALORO:  You did that.                     2                  DR. GLANTZ:  I did that once, yeah.                     3                  CHAIRMAN FROINES:  It was completely                   4    disruptive.  If you'll remember --                   5                  DR. GLANTZ:  But then your students can see                   6    how we regard --                   7                  CHAIRMAN FROINES:  But your students                   8    actually tried to ask questions.  We don't even let the                   9    affected industries ask questions.                    10                  DR. FUCALORO:  One of your students thought                  11    this was Spanish II.                     12                  CHAIRMAN FROINES:  Paul, go ahead.  Do you                  13    want to make --                  14                  MR. GOSSELIN:  Real quickly on methyl                  15    parathion.  I didn't want you folks to forget about that.                   16    Since we made the presentation in November, staff have                  17    gone back, and at the workshop we held the registrar came                  18    in with a number of studies.                    19                  Some of them were voluminous, and staff                  20    have gone through those, reviewed those and are now                  21    incorporating those summaries into the document.                   22    Dr. Byus had some literature references that we've                  23    tracked down and are summarizing, and we also identified                  24    some additional ones for ourselves.                    25                  The other significant issue is that EPA has                                                                                   139                 BARNEY, UNGERMANN & ASSOCIATES  1-888-326-5900       1    issued their draft risk assessment on methyl parathion on                   2    December 18, which is actually a fairly significant                   3    document.  Staffs have been checking all along the way on                   4    risk assessments, and we expect that they're dealing with                   5    the same studies.                     6                  But with that, we're going to need to                   7    review that, actually summarize that like we did with DEF                   8    into the document.  We're hoping to have that done.  Oh,                   9    and there was one other -- the commenter on how we deal                  10    with multiple exposures to OPs, and we need to add some                  11    language into the document on that.                    12                  We're hoping to have that drafted up,                  13    discussed with the leads and circulated probably in the                  14    next two to three weeks and then, hopefully, if all goes                  15    well, we can bring it back before the panel for wrap-up.                    16                  CHAIRMAN FROINES:  Can we -- should we                  17    schedule it for the February meeting?                    18                  MR. GOSSELIN:  I think -- I don't think                  19    we'll be ready for that.  Because I think -- at earliest                  20    we would probably be getting the rewrites out probably                  21    the first week of February, and given everything else,                  22    just the timing, I'd like to make sure that everyone has                  23    a chance to get those rewrites discussed with the leads                  24    so we don't press things.                    25                  CHAIRMAN FROINES:  So we'll schedule it for                                                                                   140                 BARNEY, UNGERMANN & ASSOCIATES  1-888-326-5900       1    the March meeting then.  Okay.                     2                  DR. GLANTZ:  When is the February meeting?                     3                  CHAIRMAN FROINES:  Pardon me?                     4                  DR. GLANTZ:  When is the February meeting?                     5                  CHAIRMAN FROINES:  Bill, I think it's                   6    February 10?                     7                  MR. LOCKETT:  Yes.                     8                  CHAIRMAN FROINES:  February 10.  Now, we                   9    need -- DPR has requested that we designate two lead                  10    persons for MITC.  And when will that -- when                   11    will -- when will documents or when will that                   12    process -- give us some sense of the process.                    13                  MR. GOSSELIN:  The document is in its final                  14    stages.  So probably a week or two.  So as soon as we get                  15    the leads, staff are going to almost immediately start                  16    discussing some of the relevant issues and start to go                  17    over the issues with MITC.                    18                  CHAIRMAN FROINES:  Bill Lockett, at this                  19    point, I think the logical thing would be to ask Roger to                  20    take on the exposure part of that document.                    21                  Who would be willing to take on the health                  22    effects part?  Who had -- currently is a lead person on a                  23    document?                    24                  DR. GLANTZ:  Who is or isn't?                    25                  CHAIRMAN FROINES:  Who is.  You're methyl                                                                                   141                 BARNEY, UNGERMANN & ASSOCIATES  1-888-326-5900       1    parathion.  You're --                    2                  DR. GLANTZ:  Reference exposure level.                     3                  CHAIRMAN FROINES:  Reference exposure.                     4                  DR. FRIEDMAN:  I'm supposed to be on that                   5    chronic toxicity --                     6                  CHAIRMAN FROINES:  Chronic toxicity.  Paul,                   7    are you a lead on -- oh, you're molinate, aren't you?                    8    How could we forget.                     9                  DR. BLANC:  Oh, yeah.                      10                  CHAIRMAN FROINES:  So Peter Witschi.  Is he                  11    a lead on chemical at this point?                    12                  MR. GOSSELIN:  He was on DEF.                    13                  CHAIRMAN FROINES:  Well, that's good.  He's                  14    rotated off, and let's rotate him on to MITC.                    15                  DR. GLANTZ:  Plus he's not here.                    16                  DR. BYUS:  Plus he's not here.                    17                  CHAIRMAN FROINES:  Plus he's not here.                   18    Hearing no objections.  The next meeting -- we also                  19    discussed that we want to find out -- we want to learn                  20    about how EPA is doing acute -- George, how EPA is doing                  21    acute RELs, and we'll talk with you later about -- look                  22    at the comparison between how you're doing it and the                  23    U.S.EPA.                    24                  And then the final issue is the April                  25    meeting.  Bill gave me some dates.                                                                                     142                 BARNEY, UNGERMANN & ASSOCIATES  1-888-326-5900       1                  DR. GLANTZ:  Do we have a March meeting?  I                   2    didn't have a February one on my calendar.                     3                  CHAIRMAN FROINES:  Bill, do we have a March                   4    meeting set up?                     5                  MR. LOCKETT:  We have not scheduled one,                   6    no.                     7                  DR. FUCALORO:  When's the workshop?                     8                  CHAIRMAN FROINES:  April.                     9                  DR. GLANTZ:  Oh, can I bring up one other                  10    issue?                    11                  CHAIRMAN FROINES:  Sure.                    12                  DR. GLANTZ:  Before we -- since it sounds                  13    like we're kind of wrapping it up here, this is the thing                  14    I mentioned to you the hall.  I think now that we're rid                  15    of Pete Wilson, I'd like to suggest that we ask the staff                  16    to finish the job of listing ETS as a toxic air                  17    contaminant which -- in the most expeditious possible                  18    manner, I don't know who we -- how would we go about                  19    getting the ball rolling based on the existing report,                  20    which is my understanding, was written to AB 1807                  21    standards.                    22                  MR. LOCKETT:  I think the next step would                  23    be for the panel to discuss it.                    24                  DR. GLANTZ:  Okay.  We're discussing it.                    25                  CHAIRMAN FROINES:  To discuss Stan's                                                                                   143                 BARNEY, UNGERMANN & ASSOCIATES  1-888-326-5900       1    request or discuss ETS?                     2                  MR. LOCKETT:  No.  To discuss Stan's                   3    request.                      4                  CHAIRMAN FROINES:  Well, we'll put that on                   5    the agenda.                     6                  DR. GLANTZ:  Okay.  We can't just do it now                   7    and be done with it?                     8                  DR. BLANC:  What's Stan's request?                     9                  CHAIRMAN FROINES:  Stan would like -- the                  10    panel would like the ETS report, which is complete, to be                  11    taken to -- taken up by the ARB as a toxic air                  12    contaminant.                    13                  In other words, we would take it to the ARB                  14    and recommend that it be declared a toxic air                  15    contaminant.                    16                  DR. FRIEDMAN:  Hadn't that been done                  17    already?                    18                  CHAIRMAN FROINES:  No.  All we did                   19    was -- the report was prepared.  We reviewed it and said                  20    it was very positive and then --                  21                  DR. GLANTZ:  No.  We said it met                   22    the -- there was a bunch of maneuvering because of                  23    basically political pressure from the governor's office,                  24    but the report says the panel believes -- finds that the                  25    toxic air contaminant -- or says it meets the definition.                                                                                    144                 BARNEY, UNGERMANN & ASSOCIATES  1-888-326-5900       1    I don't remember the exact words.                     2                  So there are findings, but when it was                   3    presented to the Air Resources Board, it was presented as                   4    an information item, not as an action item.  So my                   5    understanding -- I mean I guess our lawyer people aren't                   6    here.                     7                  But what I would hope we could do is have                   8    no further action by the panel necessary other than                   9    making a recommendation that the Air Resources Board take                  10    the report and put out the necessary public notices, hold                  11    the necessary hearing and then vote the identification.                   12                  I think that's all that's left to do.  Do                  13    you disagree -- would you say that's a correct statement,                  14    Bill?                    15                  MR. LOCKETT:  I think that's a correct                  16    statement.                    17                  DR. GLANTZ:  So it would simply mean -- it                  18    would simply mean that the panel requesting that the Air                  19    Board, based on the existing report, take the steps                  20    necessary to form --                  21                  DR. BLANC:  Can we do that at the February                  22    meeting?  Can that be an agenda item there at February?                   23    Stan, I would agree that -- let's just double-check what                  24    we need to do and what we don't need to do.                    25                  DR. GLANTZ:  Okay.  There's a small chance                                                                                   145                 BARNEY, UNGERMANN & ASSOCIATES  1-888-326-5900       1    I won't be here.  That's the only problem.  But okay.                    2    I've waited seven years --                   3                  DR. FUCALORO:  What the heck.  Another                   4    month.                     5                  DR. GLANTZ:  Huh?                     6                  DR. FUCALORO:  Another month.                     7                  DR. GLANTZ:  Another month.  Okay.                     8                  CHAIRMAN FROINES:  Bill, we don't have a                   9    date for the March meeting yet.  So we'll poll the panel.                   10                  MR. LOCKETT:  Well, because you met in                  11    January and February and April, we were trying to reflect                  12    the panel's view that they weren't necessarily wanting to                  13    meet every month.                    14                  CHAIRMAN FROINES:  Hearing no opposition --                  15                  DR. GLANTZ:  Why don't we have Witschi                  16    meet?                    17                  DR. BYUS:  John, I've got one more                   18    comment -- one more statement just in relation to methyl                  19    parathion that's come up, which I think is something we                  20    might want to include in the workshop or discuss more, is                  21    the additive effects of these organophosphates.                    22                  There's hundreds of them used and sprayed,                  23    and they all work in a similar way, and this came up in                   24    Cal PIRG's comments on methyl parathion.  And I think                  25    it's a very good one.  What are the additive effects, the                                                                                   146                 BARNEY, UNGERMANN & ASSOCIATES  1-888-326-5900       1    risk factors if you add all the organophosphates up in                   2    terms of exposure?                     3                  And it's not necessarily an easy question,                   4    certainly for DPR, but it's certainly a very good                   5    question, and it's a very valid question, and it's                   6    something we really should consider for each -- not just                   7    methyl parathion in-depth, but they all work by similar                   8    mechanisms here, and they're all basically sprayed in the                   9    same way.                    10                  So we should really deal with that question                  11    scientifically and really get a good answer to that                  12    question.                    13                  CHAIRMAN FROINES:  Gary is beginning to put                  14    his papers together and so is Tony.  We're really short                  15    on time.  Gary has to leave for the airport.  Let me just                  16    say one thing.  I don't know if anybody's been keeping                  17    track, but the number of issues that have been said we                  18    can deal with this at the workshop means that the                  19    workshop will either have to be broken up into a few                  20    workshops, which I would propose, or we had better plan a                  21    week-long conference to deal with all these issues.                    22                  I think that all of those are very                  23    relevant.  So I think that what we're talking about is a                  24    series of workshops over time.  In each workshop we                  25    should deal with a couple of topics and then try and do                                                                                   147                 BARNEY, UNGERMANN & ASSOCIATES  1-888-326-5900       1    it effectively.                     2                  And what I think it means is that the panel                   3    is changing to some extent from a body where every six                   4    months or every three months -- I mean in the old days,                   5    what would happen is a chemical would come to the panel,                   6    and we would deal with it over a period of three or four                   7    months, and we would then make our findings, and it would                   8    go to the Board, and that would be it.                     9                  Here what we're talking about, and I think                  10    it's not just with the DPR -- so that Paul doesn't need                  11    to feel like a pin cushion -- is that what we're talking                  12    about is the panel saying "We're going to hold workshops                  13    over time to address scientific issues that are relevant                  14    to our work as a panel around the issue of toxic air                  15    contaminants so that we may have two workshops a year or                  16    one a year."                  17                  But what we're really saying is that we're                  18    going to take up some of the content -- scientific                  19    content of these issues and not simply be responsive to a                  20    particular document coming forward, and that's quite a                  21    change in the panel for those of you who haven't been on                  22    for a long period of time.                    23                  And I think it's a good change, but it's                  24    something we need to be aware of that we are doing that.                   25    So this workshop may grow into one or two or three or                                                                                   148                 BARNEY, UNGERMANN & ASSOCIATES  1-888-326-5900       1    whatever workshops over a long period of time.  And I                   2    think that's a very good thing to happen, but it also                   3    means this will take some time commitment associated with                   4    it.                     5                  So we have to -- again, I think not having                   6    a meeting in March is good because it balances out the                   7    load to some extent.  I think I'm talking to this side of                   8    the room.  I think that side of the room --                   9                  DR. BYUS:  They're gone.                    10                  CHAIRMAN FROINES:  -- isn't paying any                  11    attention at all.                    12                  DR. GLANTZ:  While they're not listening,                  13    appoint some lead people.                    14                  DR. BLANC:  Okay.                    15                  CHAIRMAN FROINES:  I think that's it.                    16                  DR. BLANC:  Can I make a plea for the -- if                  17    the workshop be in April, that it be during the first two                  18    weeks of April so that I can be here --                  19                  CHAIRMAN FROINES:  Oh, that's what I                  20    forgot.  I'm sorry, Paul.  The dates are -- I would                  21    propose the dates are the 7th and the 13th.  I think we                  22    need all the time we can get to get the people here and                  23    prepare for it.  So I would argue, if everybody can do                  24    the 13th, that would be the best.                    25                  DR. BLANC:  Let me just look one second.                                                                                    149                 BARNEY, UNGERMANN & ASSOCIATES  1-888-326-5900       1    The 13th is Tuesday.  Yeah.  I'll be here.                     2                  CHAIRMAN FROINES:  Tuesday the 13th.                     3                  MR. LOCKETT:  Dr. Atkinson is the only                   4    person we hadn't polled about those two dates.                     5                  DR. ATKINSON:  I have no idea.                     6                  MR. LOCKETT:  So I gather we will choose                   7    April 13 unless we hear otherwise.                     8                  CHAIRMAN FROINES:  Unless Roger says he                   9    absolutely can't do it.                    10                  DR. FUCALORO:  You checked my office;                  11    right?                    12                  MR. LOCKETT:  Yes.                    13                  CHAIRMAN FROINES:  I think it's absolutely                  14    crucial that Roger attend so that he'll be the --                   15                  MR. LOCKETT:  So I guess my request is for                  16    the members present to put April 13 on their calendar                  17    now, and we'll call you if it's going to change.                    18                  DR. GLANTZ:  Do you know where it's going                  19    to be?                    20                  MR. LOCKETT:  That's a decision not made                  21    yet.                    22                  DR. BLANC:  Palm Springs?  It's not that                  23    time of year.                    24                  DR. GLANTZ:  How about the Ahwahnee Hotel?                    25                  CHAIRMAN FROINES:  Bob Spear just had a                                                                                   150                 BARNEY, UNGERMANN & ASSOCIATES  1-888-326-5900       1    retreat of his Center to Occupational Environmental                   2    Health at the Sonoma Valley Mission Inn.  That was really                   3    something.  I'm sure everybody would agree to that.                     4                  DR. FUCALORO:  Do we have to stay in the                   5    state?                           6                  MR. LOCKETT:  We are trying to be                   7    thoughtful to the folks flying in from the various parts                   8    of the United States, and so it's thought to be either                   9    near SFO or LAX.                     10                  DR. BLANC:  Well, but in fact, I was being                  11    somewhat -- whatever.  In fact, if it's a nice place,                  12    that does actually in April still winter many places.  It                  13    does effectively draw people to come --                  14                  DR. GLANTZ:  I like the Ahwahnee.                    15                  DR. FUCALORO:  It's not winter in the                  16    southern hemisphere --                  17                  DR. GLANTZ:  It's easy to get there.                    18                  MR. LOCKETT:  Are you going to fund that?                    19                  CHAIRMAN FROINES:  Anyway, thank you                  20    everybody.  I think this was a really very useful and                  21    good meeting.  So we'll continue, and we've made it                  22    time-wise, I think.                    23                      24                  (Whereupon the meeting was adjourned at                  25    1:15 P.M.)                                                                                   151                 BARNEY, UNGERMANN & ASSOCIATES  1-888-326-5900       1                       2                             * * *                   3                       4                       5                       6                       7                       8                       9                      10                      11                      12                      13                      14                      15                      16                      17                      18                      19                      20                      21                      22                      23                      24                      25                                                                                       152                 BARNEY, UNGERMANN & ASSOCIATES  1-888-326-5900       1    STATE OF CALIFORNIA    )                                   )  ss.       2    COUNTY OF LOS ANGELES  )                          3                        4                  I, CAROLINE JETTER, CSR 11568, a Certified                   5    Shorthand Reporter in and for the State of California, do                   6    hereby certify:                                                                           7                  That said meeting was taken down by me in                   8    shorthand at the time and place named therein and was                   9    thereafter reduced to typewriting under my supervision;                  10    that this transcript is a true record of the testimony                  11    given by the witness and contains a full, true and                  12    correct report of the proceedings which took place at the                  13    time and place set forth.                    14                  I further certify that I have no interest                  15    in the event of the action.                    16                  EXECUTED this      day of                ,                  17    1999.                  18                           19                                                                              20                          Caroline Jetter, CSR 11568                  21                      22                      23                      24                      25                                                                                       153                 BARNEY, UNGERMANN & ASSOCIATES  1-888-326-5900