1                            MEETING
       2                            OF THE
       4                CALIFORNIA AIR RESOURCES BOARD
       9                        SUNSET VILLAGE
      10                    COVEL COMMONS BUILDING
      12                          THIRD FLOOR
      13                       330 DE NEVE DRIVE
      14              LOS ANGELES, CALIFORNIA  90095-1492
      17                   WEDNESDAY, JUNE 16, 1999
      18                           9:25 A.M.
      23    REPORTED BY:  
      24    Caroline Jetter
            CSR No. 11568
      25    Our File No. 1-55942


       1                          APPEARANCES
       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. Peter Kennedy 
            Mr. Peter Mathews, Office of the Ombudsman
      11    ASSESSMENT:  
      12    Dr. George Alexeeff, Deputy Director for Scientific
      13    Dr. Melanie Marty, Senior Toxicologist
            Dr. James F. Collins, Staff Toxicologist
            Mr. Paul H. Gosselin, Assistant Director
      16    Dr. Nu-may Ruby Reed, Staff Toxicologist
      17    ALSO PRESENT:  
      18    Dr. Keith Pfeifer

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       1                             INDEX  
                                  AGENDA ITEMS                  PAGE
       4    1.     Overview presentation on draft report:  
                   Air Toxics Hot Spots Program Risk 
       5           Assessment Guidelines, Part III.  
                   Technical Support Document for
       6           Determination of Noncancer Chronic 
                   Reference Exposure Levels.                    4 
            2.     Review of draft report:  The Evaluation 
       8           of Methyl Parathion as a Toxic Air 
                   Contaminant                                  84

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       1                  CHAIRMAN FROINES:  June 16, 1999.  Rapidly
       2    approaching the millennium.   
       3                  DR. FUCALORO:  Another year and a half.   
       4                  CHAIRMAN FROINES:  Unless somebody on the
       5    Panel has any comments, I think we should go directly to
       6    the presentation.  
       7                  Melanie, are you going to be the lead? 
       8                  DR. MARTY:  Yes.   
       9                  CHAIRMAN FROINES:  Please.  
      10                  DR. MARTY:  Today we're going to talk about
      11    another one of the Air Toxics Hot Spots Risk Assessments
      12    Guidelines documents.  
      13                  CHAIRMAN FROINES:  Your mike isn't on. 
      14                  DR. MARTY:  How about that?  Can you hear
      15    me now?  He said it's unusual that he couldn't hear me.  
      16                  Okay.  Today we're giving an overview
      17    presentation of our technical support document for the
      18    determination of chronic reference exposure levels for
      19    airborne toxicants.  
      20                  This is the third part of a four-part
      21    series of technical support documents that OEHHA has
      22    produced for the risk assessment guidelines program of
      23    the Air Toxics Hot Spots.  
      24                  Next slide, Jim.  
      25                  This briefly -- an overview of the Air

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       1    Toxics Hot Spots Information and Assessment Act.  The
       2    purpose of the act is to evaluate emissions from point
       3    sources.  
       4                  And the act provided a specified list of
       5    substances that need to be evaluated.  The facilities
       6    subject to the act provide emissions inventories of those
       7    specific substances.   
       8                  If the district deems that there is a
       9    potential for public health risk, then those facilities
      10    must write a risk assessment in which they assess both
      11    the short-term and long-term health risks to those who
      12    are exposed.  
      13                  OEHHA's role in all of this is to provide
      14    guidance for the risk assessment documents and to
      15    actually review the risk assessments for accuracy and
      16    completeness.  
      17                  Next slide, please.  
      18                  We wanted to stress that the Air Toxics Hot
      19    Spots technical support document review process is an
      20    open public process.  The document that you see before
      21    you has undergone a public comment period when it was
      22    initially released in October of '97.  
      23                  There were also public workshops on the
      24    document in both the north and the southern part of the
      25    State.  We have evaluated public comment and reviewed all

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       1    of the comments given to us and responded to them in
       2    writing.  And the response to comments was provided to
       3    the Panel along with the document.   
       4                  The Scientific Review Panel represents the
       5    formalized peer review for our Hot Spots technical
       6    support documents.  And the statute actually states that
       7    the Scientific Review Panel shall evaluate the guidelines
       8    and recommend changes and additional criteria to reflect
       9    new scientific data or empirical studies.  
      10                  Once the Scientific Review Panel has
      11    provided us with their evaluation, we would revise the
      12    document and eventually adopt the guidelines.  And that
      13    is done at the discretion of the OEHHA director.   
      14                  This is part 3 that we're evaluating today. 
      15    The Panel members have already reviewed part 1, the
      16    technical support document for acute reference exposure
      17    levels.  They have also evaluated part 2, which described
      18    available cancer potency values.  And today we're going
      19    to be talking about part 3.  
      20                  Next slide.  
      21                  For those members of the audience who are
      22    interested in obtaining the document, you can download it
      23    off the Internet at the OEHHA home page listed on the
      24    first line.  We are running a comment period at this
      25    moment.  It started June 11 and will go through July 11.  

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       1                  Any inquiries concerning technical matters
       2    can be addressed to Dr. Jim Collins at the telephone
       3    number above.  Jim is sitting over there with the
       4    overheads.  And written comments would be addressed to
       5    myself. 
       6                  At the beginning of the effort to develop
       7    the chronic RELs, we had several general principles that
       8    we intend to follow and have followed.  One of them is to
       9    get input from external stakeholders which we did with
      10    the public comment period and the workshops and with the
      11    existing public comment period now.  
      12                  The other is to have formalized peer
      13    review.  And the Panel -- the Scientific Review Panel
      14    represents our formalized peer review process.  We also
      15    realize we need to balance the level effort in developing
      16    reference exposure levels with the importance of the
      17    chemical in California.  
      18                  The selection of chemicals for review in
      19    this document is based primarily on the extent of
      20    emissions information from stationary sources that is in
      21    the Air Resources Board's Air Toxics Emissions Database.  
      22                  Other things that came into play were
      23    concerns --  
      24                  CHAIRMAN FROINES:  Excuse me.  Is that
      25    information available?  

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       1                  DR. MARTY:  The ATEDS is on -- now on their
       2    web site.  And I could supply the Panel members with
       3    basically a summary which is the chemicals listed in
       4    ATEDS and their emissions in pounds per year if that
       5    would be useful.   
       6                  CHAIRMAN FROINES:  Probably would be
       7    useful.  
       8                  DR. MARTY:  Okay.  
       9                  CHAIRMAN FROINES:  Because both here and on
      10    the Carcinogen Identification Committee the problem, as
      11    you well know, is always one of to what degree do these
      12    represent a problem.  
      13                  And so having the Panel be aware of what
      14    looks significant would be important.  I'm assuming that
      15    the chemicals here are not simply HAPs but may -- are
      16    they all HAPs, or are there others that are not HAPs?  
      17                  DR. MARTY:  The actual list that -- of
      18    chemicals subject to the Hot Spots Act includes the HAPs
      19    but also there's about 300 or so other chemicals that
      20    actually had emissions information.  And then there's
      21    another 400 chemicals which have no emissions
      22    information.  
      23                  So it does include the HAPs.  The chemicals
      24    in this first batch of 40 I'd have to go back and check. 
      25    But they're probably largely HAPs.    

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       1                  CHAIRMAN FROINES:  So we have a total
       2    database of 900 chemicals?  
       3                  DR. MARTY:  It's actually -- I believe
       4    there are 750 on the list, and about 450 of those, I
       5    think, have had some reported emissions in the State
       6    which can vary from little itty-bitty amounts to very
       7    large amounts.  
       8                  CHAIRMAN FROINES:  So the Panel knows what
       9    their workload -- what it's going to look like in the
      10    foreseeable future.  
      11                  DR. MARTY:  Other issues that came into
      12    play in the selection of chemicals were whether or not
      13    the chemical was of concern to risk managers.  For
      14    example, some of the Air Pollution Control districts may
      15    have had a significant source of emissions that they are
      16    responsible for permitting and evaluating.  
      17                  And it may be that overall statewide the
      18    actual emissions were not all that great.  But from a
      19    specific source, they were rather large.  So -- hexane is
      20    one example that comes to mind.  There are some very
      21    large site-specific sources.   
      22                  And also the toxicity information
      23    available, of course, had to come into play.  For
      24    example, dioxanes are emitted in the State but in
      25    relatively minute quantities compared to, say, for

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       1    example, toluene.  
       2                  However, the toxicity of dioxane is so
       3    great that we considered it in this first batch of
       4    chemicals.   
       5                  We did try to coordinate our efforts with
       6    USEPA.  We made use of available risk assessment
       7    information for chemicals in their IRIS database and in
       8    fact have proposed adoption of the several of the USEPA
       9    RfCs as our chronic reference exposure levels.   
      10                  We also heard a lot of concern that we
      11    should consider effect severity.  And we have done that
      12    by incorporating intermediate uncertainty factors for
      13    mild or rarely encountered effects.  
      14                  Additional research, however, is needed to
      15    implement more sophisticated approaches to this problem. 
      16    And lastly, we made a substantial effort to use human
      17    health effects data when it were available -- when the
      18    data were available.   
      19                  I mentioned that we have listed substances
      20    of concern to ARB are in this document, current emissions
      21    in California, adequate toxicity data and also that the
      22    chemicals not currently undergoing full-blown TAC review
      23    or had already done so.  
      24                  For example, I believe we have
      25    perchloroethylene, acetaldehyde and diesel exhaust

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       1    particles.  We have a chronic reference exposure level
       2    already because they've already gone through the Panel
       3    and the whole Tanner process.  
       4                  The initial phase of the Hot Spots program
       5    required risk assessments as early as about 1990, 1991. 
       6    The California Air Pollution Control Officers Association
       7    came out with risk assessment guidelines to use in the
       8    program.  
       9                  This was prior to the statutory amendment
      10    that required OEHHA to develop risk assessment
      11    guidelines.  In those guidelines, there were about 95
      12    substances with chronic reference exposure levels. 
      13    However, they were from various sources and used a wide
      14    range of methodologies.  
      15                  In comparison, the document that you have
      16    before you we attempted to be consistent in our
      17    methodologies.  We used the USEPA RfC methodology with
      18    some minor modifications.  There are about 118 to 120
      19    substances that we actually have evaluated.  
      20                  But this Panel is going to see them in
      21    batches.  So right now there's 40 in the first round. 
      22    And that's -- those are all in the documents that you
      23    received.   
      24                  The reference exposure level is really the
      25    concentration at or below which no adverse health effects

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       1    are anticipated.  We base the reference exposure level on
       2    the most sensitive adverse health effect that is reported
       3    in the literature.  
       4                  These are designed to protect most
       5    sensitive individuals in the population.  However, we
       6    have to say that for idiosyncratic responses, some
       7    individuals may not be protected by these reference
       8    exposure levels.  
       9                  Exceedence of the reference exposure level
      10    in the ambient air may or may not lead to an adverse
      11    health effect.  It really means erosion of the safety
      12    margin that we have built in by using uncertainty
      13    factors.   
      14                  I should also mention that carcinogenicity
      15    is not considered here.  It was considered in the potency
      16    factor document.  So some of these chemicals are
      17    carcinogens, and they have potency factors, but we're
      18    also evaluating potential for chronic noncancer health
      19    impacts.  
      20                  Our reference exposure level method is
      21    essentially modeled on USEPA risk assessment methods. 
      22    The EPA developed guidelines for assessing chronic
      23    exposures and the adverse health effects associated with
      24    those exposures in the early 90's with a final document
      25    which was considerably expanded from the original in

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       1    1994.  
       2                  USEPA has RfCs for about 50 chemicals.  And
       3    actually, it's more now.  OEHHA has adopted the USEPA
       4    approach with some minor modifications which we made for
       5    consistency.  
       6                  A primary difference is that OEHHA has not
       7    incorporated a database uncertainty factor, which is an
       8    additional uncertainty factor on top of the typical ones
       9    that EPA uses when there are not a lot of studies for the
      10    chemical.  
      11                  The criteria for using this factor were not
      12    clearly presented by USEPA.  In fact, when you look at
      13    it, it seems to be somewhat erratic use.  And so we
      14    decided that we were not going to use that additional
      15    uncertainty factor.  
      16                  CHAIRMAN FROINES:  Melanie, on -- go back
      17    to the -- on the 50 or whatever it is RfCs that EPA has
      18    developed, I assume that none of the 40 that we're going
      19    to have will have EPA RfCs or --
      20                  DR. MARTY:  There are actually a number of
      21    RfCs in that first 40 batch that we are proposing to use
      22    as chronic reference exposure levels.  
      23                  CHAIRMAN FROINES:  So in a sense we would
      24    be evaluating what EPA did?  
      25                  DR. MARTY:  Yes.   

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       1                  CHAIRMAN FROINES:  So that's the
       2    determination that we'll be making, whether the EPA
       3    approach was effective and adequate.  
       4                  DR. MARTY:  Yes.   
       5                  CHAIRMAN FROINES:  And there's sufficient
       6    data for that.  
       7                  DR. MARTY:  There should be sufficient
       8    description of their methods in the methodology section
       9    and then a sufficient amount of information in each
      10    chemical toxicity summary to let you evaluate that.  
      11                  The development of the chronic RELs was a
      12    several-step process.  I already discussed a little bit
      13    about prioritizing the chemicals to be evaluated.  We
      14    then conduct an extensive literature search and review.  
      15                  We select the most appropriate study
      16    emphasizing human data where they are available and
      17    identify the critical endpoints from the study.    
      18                  Since the noncancer health impacts are
      19    generally evaluated under the assumptions that there's a
      20    threshold concentration below which you would not see
      21    adverse health effects, we need to somehow estimate that
      22    threshold concentration for effect; and as in the acute
      23    reference exposure levels, we use the no observed adverse
      24    effect level.  
      25                  Where that wasn't available, we used the

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       1    lowest observed adverse effect level or a benchmark
       2    concentration instead of the NOEL or LOEL approach.  
       3                  We made two basic types of adjustments to
       4    the concentration, the experimental concentration.  One
       5    is a temporal adjustment where -- which adjusts from the
       6    discontinuous exposure typical of both occupational and
       7    toxicological experimental studies to a 24-hour
       8    concentration.  
       9                  We also did some dosimetric adjustments
      10    which are using the USEPA methodology for human
      11    equivalent concentrations.  And I'll get into that in a
      12    moment.  
      13                  And finally, uncertainties in the data were
      14    addressed with the use of uncertainty factors, and they
      15    are pretty typical of the uncertainty factors used in the
      16    acute reference exposure level document.  
      17                  Some for lack of human data, where we'd
      18    have to extrapolate for animals -- from animals, lack of
      19    lifetime exposure, we very frequently have subchronic
      20    toxicity studies but not chronic.  And then lack of data
      21    from sensitive subgroups we applied an uncertainty factor
      22    for intraspecies variability.   
      23                  CHAIRMAN FROINES:  I'm sorry.  Go back to
      24    that last one.  
      25                  DR. MARTY:  Jim, could you go back? 

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       1    Thanks.  
       2                  CHAIRMAN FROINES:  What was the last
       3    sentence that you just said?  
       4                  DR. MARTY:  That we used an uncertainty
       5    factor to count for intraspecies variability in the human
       6    population.  
       7                  CHAIRMAN FROINES:  Intra?  
       8                  DR. MARTY:  Intra.  So if human --
       9                  DR. BLANC:  Sensitive populations.  Let's
      10    say a group of workers.  There was a no -- a lowest -- a
      11    no effect level of 10 parts per million.  So they'd say,
      12    "Well that doesn't include" -- "take into account that
      13    there might be more sensitive individuals."  So we divide
      14    by ten.    
      15                  CHAIRMAN FROINES:  No.  I understand all
      16    that.  I thought she said, "intraindividual."  You 
      17    mean -- you really mean interindividual variability.  
      18                  DR. MARTY:  Interindividual and
      19    intraspecies.  
      20                  DR. BLANC:  Intraspecies instead of
      21    interspecies.  
      22                  DR. MARTY:  The documentation -- 
      23                  CHAIRMAN FROINES:  So you're using a -- for
      24    interindividual variability, you were using a safety
      25    factor.  

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       1                  DR. MARTY:  Yes.  
       2                  CHAIRMAN FROINES:  And it is 10?  
       3                  DR. MARTY:  Generally tenfold.  I have a
       4    discussion of that coming up.  But it's generally
       5    tenfold.  
       6                  The chronic reference exposure level
       7    documentation in the technical support document consists
       8    essentially of several sections.  One is a summary of the
       9    chronic reference exposure level.  Another section
      10    follows with physical and chemical properties including
      11    information on, for example, volatility and water
      12    solubility.  
      13                  There's a section -- a brief section on
      14    occurrence and use.  And we describe the typical uses of
      15    the chemical and where it would likely be found.   
      16                  Then under the adverse effects in humans,
      17    we have brief discussion of any pharmacokinetic or
      18    metabolic information that may be relevant.  And studies
      19    are described in some detail providing information on the
      20    study design, study population, the exposure
      21    concentration and the exposure duration and whether that
      22    was a continuous exposure or discontinuous, the duration
      23    of the study and methods used to test for adverse effects
      24    as well as the adverse effects noted.  
      25                  Similarly, we have a section on adverse

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       1    effects in animals that includes all of those things.  
       2                  We have a section which described the
       3    derivation of the chronic reference exposure level, and
       4    as in the acute reference exposure level document, we
       5    presented the information in tabular form.  
       6                  And then finally we have a reference
       7    section.  The question arises what do you do with the
       8    reference exposure levels?  And again, we apply a hazard
       9    index approach.  This is an approach that has been used
      10    in noncancer risk assessment for some time now.  
      11                  And it is a method for evaluated potential
      12    for noncancer health impacts.  Essentially, a hazard
      13    quotient, here depicted as HQ, is the ratio of the ground
      14    level concentration which in the Hot Spots program is
      15    generally a model rather than a measured concentration
      16    divided by the reference exposure level, and the ground
      17    level exposure concentration represents an annualized
      18    average from air dispersion modeling.  
      19                  Where you have chemicals that impact the
      20    same target organ, total hazard index is a sum of those
      21    hazard quotients for each of those chemicals affecting
      22    the same target organ.  Of course this does make the
      23    assumption that the effects are additive.  It also
      24    ignores any synergistic or possibly antagonistic effects
      25    also.   

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       1                  For the chemicals that we have evaluated,
       2    we have several target organs including --
       3                  DR. FRIEDMAN:  Can I interrupt?  
       4                  DR. MARTY:  Yes.  
       5                  DR. FRIEDMAN:  You -- in other words, you
       6    may have a hazard -- I'm looking at the hazard index. 
       7    Some of these hazard quotients.  So you might have --
       8                  DR. MARTY:  Jim, could you put that slide
       9    back up?  Thanks.  
      10                  DR. FRIEDMAN:  Pardon?  So you might have,
      11    say, a hazard quotient 1 on them being one and a half and
      12    another being, say, 2.  You just add those and get three
      13    and a half?  
      14                  DR. MARTY:  Exactly.  
      15                  DR. FRIEDMAN:  I think the usual way of
      16    dealing with additive risk is to subtract out one from
      17    each so that you have 50 percent extra.  And then the
      18    other one might be 100 percent extra.  So you get 150
      19    percent.  
      20                  I'm not absolutely sure of that.  But it
      21    doesn't seem -- just on the face of it, adding those
      22    ratios does not quite seem the way it's usually done. 
      23    But maybe if it works and you have examples of that --
      24                  DR. MARTY:  Yeah.  That is how we've been
      25    doing noncancer health risk assessment at least in the

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       1    environmental toxicology arena.  I'm not sure what other
       2    areas of study have done.  I don't know if that's -- if
       3    that comes from pharmaceutical research or -- 
       4                  DR. FRIEDMAN:  I'd like to -- I guess I'm
       5    the lead person on this.  I'd like to -- when we discuss
       6    other things about this, I'd like to discuss that with
       7    you further and make sure I understand it.  
       8                  DR. MARTY:  Certainly.  Okay.  
       9                  CHAIRMAN FROINES:  I understand what he's
      10    saying is he wants to add up the excess risk basically as
      11    opposed to a value --  
      12                  DR. FRIEDMAN:  Right. 
      13                  CHAIRMAN FROINES:  -- one.  
      14                  DR. ALEXEEFF:  George Alexeeff with OEHHA. 
      15    Yeah.  This is an approach which will be discussed
      16    actually in our fifth document; right?  Or is it in the
      17    exposure assessment?  I think it's actually in the fifth
      18    document.  So if there is -- are some concerns about this
      19    approach, this would be a good time to try to work them
      20    all out.  
      21                  So when we actually make the final document
      22    on how we're going to really use these numbers -- this is
      23    our current operating procedure on how we use them.  But
      24    if there's some ways of modifying them, then that would
      25    be great over a time to figure out.  

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       1                  DR. FRIEDMAN:  Yeah.  I'd like to go back
       2    to some of the basic epidemiologic references about
       3    adding risk and make sure that either this is compatible
       4    with that or that -- if there's some difference that we
       5    both understand what effect that it might have.   
       6                  CHAIRMAN FROINES:  What would you do if you
       7    had methyl ethyl ketone and hexane?  Would you add a
       8    factor for potentiation?  
       9                  DR. MARTY:  We have not done that in the
      10    past.  And we recognize that that is a gap, as you have
      11    just brought up one example where there is known
      12    potentiation.  
      13                  This is just a listing of the target organs
      14    that we have come across in the evaluation of our 120 or
      15    so chemicals.  I'm going to talk a little bit now about
      16    how we derive our chronic reference exposure levels. 
      17                  Essentially, we start out with what we term
      18    here a low risk estimate which is either the no observed
      19    adverse effect level from a study.  If that is
      20    unavailable, it's the lowest observed adverse effect
      21    level or possibly even a benchmark concentration if
      22    enough data are available to evaluate that.  
      23                  We use here, what we're calling here,
      24    extrapolation factors which account for the temporal
      25    differences in exposure and also any dosimetric

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       1    differences and then divide those through by uncertainty
       2    factors.  
       3                  The no observed adverse effect level is
       4    defined as the exposure level with no biologically or
       5    statistically significant increase in the frequency or
       6    severity of the adverse health effects in the exposed
       7    population relative to the controls.  
       8                  CHAIRMAN FROINES:  So you would never use a
       9    NOEL for --
      10                  DR. MARTY:  I don't think we have ever used
      11    an NOEL.  Of course, all of this needs to be tempered by
      12    appropriate statistical interpretations in the words of
      13    Dr. Glantz.  And again, if NOAEL is not identifiable in
      14    the available literature, then we move to the LOAEL.  
      15                  The LOAEL is extrapolated to a NOAEL using
      16    uncertainty factors.  We generally use an uncertainty
      17    factor of 10 for that extrapolation.                
      18                  However, we have in this document proposed
      19    some intermediate -- an uncertainty factor of 3 if the
      20    effect is mild and of low incidence, indicating that it's
      21    actually closer to the NOAEL than a LOAEL, where more
      22    severe and higher incidence effects are noted. 
      23                  I will describe the benchmark concentration
      24    in a little while again.  It's basically identical to
      25    what you have seen already in the acute reference

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       1    exposure level document.   
       2                  I mentioned earlier that there are two
       3    types of adjustments, these extrapolation factors that
       4    were in that previous equation to the exposure
       5    concentrations in the studies that we have used.  
       6                  One is a temporal adjustment.  It adjusts
       7    for the discontinuous exposure in studies.  For example,
       8    a typical toxicology study.  The animals are exposed
       9    maybe five or six hours -- up to eight hours per pay,
      10    five days per week.  
      11                  What does that mean in terms of 24-hour
      12    continuous exposure?  We have a adjustment for that which
      13    is essentially a time-weighted average adjustment.  I
      14    will actually get back to those in more detail in a
      15    second.  
      16                  And then the human equivalent concentration
      17    extrapolation is a method of looking at dosimetric
      18    differences between the experimental animal and humans. 
      19    Those adjustments have been used by USEPA in their RfC
      20    approach.  So I have slides on all this.  And we'll get
      21    back to them in a little more detail in a moment.   
      22                  In the case of looking at chronic reference
      23    exposure levels, we sometimes have to use a subchronic to
      24    chronic uncertainty factor.  Frequently, the adverse
      25    health effect studies generally involve less than

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       1    lifetime exposure.  
       2                  So commonly encountered exposures would be,
       3    say, five to twenty years in occupational study or
       4    approximately 10 percent of the lifetime in a typical
       5    rodent study.  
       6                  The EPA has incorporated this also in their
       7    methodology.  And they used factors of 1 to 10.  But
       8    their rationale for selecting that was not very clearly
       9    presented.  
      10                  So in order to implement it in a more
      11    systematic fashion, OEHHA is proposing that, if the
      12    exposures are greater than 12 percent of the expected
      13    life, then we would not use a subchronic uncertainty
      14    factor.  
      15                  In other words, it would be 1.  If the
      16    exposures were from 8 to 12 percent of the expected
      17    lifetime, then we use an intermediate uncertainty factor
      18    of 3 to extrapolate from that length of exposure to a
      19    lifetime.  
      20                  If the exposures in the study were less
      21    than 8 percent of the estimated lifetime, then we used
      22    the full uncertainty factor of 10.    
      23                  DR. FUCALORO:  It's certainly clear and
      24    systematic, but on what basis is it assigned?  
      25                  DR. MARTY:  Well, I think that what we did

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       1    was looked at EPA documents and other documents that
       2    describe what they considered to be chronic exposures
       3    experimentally.  And pretty much everybody was consistent
       4    that 12 percent -- greater than 12 percent of the
       5    lifetime is considered a chronic exposure in experimental
       6    studies.  
       7                  And less than that, there was disagreement
       8    about where you could call it a chronic versus a
       9    subchronic exposure.  So it's basically the perception of
      10    toxicological investigators that drive the choice of
      11    those values.  
      12                  DR. BLANC:  But then almost in the
      13    occupational -- chronic occupational study, you wouldn't
      14    be using an uncertainty factor then.  
      15                  DR. MARTY:  I think for most of them you
      16    wouldn't.  But for some of them what we did, I -- if I'm
      17    remembering correctly, we took the mean duration of
      18    exposure.  
      19                  So if that mean was less than 12 percent of
      20    70, then we would use one of those uncertainty factors,
      21    either 3 or 10, depending on how much less.  There
      22    probably are examples where we didn't use one because the
      23    mean was greater than 12 percent of the 70 years.  
      24                  DR. BLANC:  So five years -- can I just get
      25    a number on that then?  Then a five -- in an occupational

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       1    study where the mean exposure was five years --
       2                  DR. MARTY:  We would use --
       3                  DR. BLANC:  Three.  
       4                  DR. MARTY:  Three.  
       5                  DR. BLANC:  And if the mean exposure was --
       6                  DR. MARTY:  Eight years or greater I think
       7    it is, then we would use one.    
       8                  DR. BLANC:  I guess I would say that that's
       9    not convincingly conservative just thinking about what
      10    one's sort of offhand take would be on a chronic
      11    occupational study.  
      12                  If you think about -- I don't know if it
      13    was driving your thoughts in this, but if you -- it is
      14    true in general to enter into cancer epidemiologic cohort
      15    for occupational exposure.  Often people will require a
      16    minimum of five years of exposure to then follow someone
      17    through risk.  
      18                  But if I were thinking of -- you're talking
      19    about noncancer health effects and, you know, I was
      20    thinking about coal miners and chronic lung disease.  
      21                  And you know, eight years isn't so
      22    convincing either.  I don't know what the right number
      23    would be.  But it doesn't -- it's -- it strikes one as
      24    not being perhaps conservative enough.  
      25                  I don't know whether one would say, if

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       1    there's 20 years on average, then that's the equivalent 
       2    of -- you don't have to make an adjustment.  
       3                  John, what would be your take on that?  
       4                  CHAIRMAN FROINES:  I think it's very
       5    unclear how you choose --
       6                  DR. BLANC:  A cutoff?  
       7                  CHAIRMAN FROINES:  A cutoff point.  Because
       8    somebody asked -- I guess Tony asked Melanie for why they
       9    did that.  And she said that because EPA does it that
      10    way.  And so the answer to the question is what's the
      11    underlying basis for the EPA approach?   
      12                  DR. FUCALORO:  You see these often in these
      13    things.  1, 3, 10.  And anyone who knows mathematics,
      14    these are people dealing with logs, but that doesn't
      15    necessarily mean that it has any connection to reality of
      16    a good scientific basis.  
      17                  I don't know what to do.  I mean perhaps
      18    it's not as efficiently conservative maybe once you look
      19    at that.   
      20                  DR. FRIEDMAN:  I'm having a little trouble
      21    differentiating the discontinuous exposure extrapolation
      22    from the subchronic uncertainty factor.  In other words,
      23    you get a time-weighted average to try to get what the
      24    continuous exposure would be when the studies have been
      25    based on discontinuance.  

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       1                  Why don't you just extend that
       2    time-weighted average to 70 years of a lifetime?  What
       3    are you adding here?  What new concept is being taken
       4    care of by this subchronic uncertainty factor?  
       5                  DR. MARTY:  Well, when you do the
       6    discontinuous exposure adjustment, you're really looking
       7    at a daily -- sort of a daily dose idea.  So if it were
       8    eight hours out of 24, and only five days out of the
       9    week, then you would adjust the concentration for a
      10    continuous 24-hour exposure.  
      11                  This is an additional adjustment for
      12    duration of the experiment essentially.  
      13                  DR. FRIEDMAN:  Why don't you just build
      14    that into the life -- you know, just have a time-weighted
      15    lifetime exposure, you know, extrapolating from that
      16    experiment?  
      17                  DR. MARTY:  So in other words -- well,
      18    it's, I guess, easier said than done.  If you're dealing
      19    with different species of animal, the lifetime is
      20    different.  You could, if it's a rat, choose two years
      21    for the -- I guess really your denominator.  
      22                  DR. FRIEDMAN:  So these are always -- these
      23    always -- the subchronic uncertainty factors always refer
      24    to animal studies, not human --
      25                  DR. MARTY:  No, no.  We would use it also

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       1    in an occupational study if the mean duration of the
       2    exposure of the workers was less than 12 percent of the
       3    lifetime or actually 12 percent or less.  
       4                  DR. BLANC:  Maybe another way of coming at
       5    this is how many roughly -- having worked with these 40,
       6    the initial 40, what percentage of them would you say are
       7    driven by human occupational studies?  Because 
       8    most -- I would say almost all of the ones that it's a
       9    human study it's an occupational study; is that right?  
      10                  DR. MARTY:  Yes.  
      11                  DR. BLANC:  By and large?  And would you
      12    say half of them are driven by occupational studies?  Two
      13    thirds?  
      14                  DR. COLLINS:  Less than half.  
      15                  DR. MARTY:  I think it is less than half
      16    for the chronic.    
      17                  DR. FRIEDMAN:  Well, I don't know if I want
      18    to take the Panel's time with this.  But again, this is
      19    something I would like to spend time with you on because
      20    I don't really understand it.   
      21                  DR. MARTY:  Okay.  
      22                  DR. ALEXEEFF:  George Alexeeff.  There is a
      23    difference in the way it's adjusted for humans for
      24    chronic exposure versus cancer -- the cancer risk
      25    estimate.  And that's partly -- might be partly the

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       1    confusion.  Because in the cancer documents, when we do
       2    those adjustments, we basically do the exposure
       3    adjustment over a lifetime.  
       4                  So if the person was exposed for eight
       5    years, we sort of average it over a lifetime and 
       6    then -- and do our calculations from there.  
       7                  Here in this case -- and it's in part the
       8    convention -- and I think not really just copying 
       9    USEPA -- but it's kind of the convention that's grown out
      10    of this whole field, both us and USEPA, is we annualize
      11    it.  
      12                  And then depending upon how long the study
      13    was, we add an uncertainty factor.  So it's a slightly
      14    different kind of approach trying to get at the same
      15    issue here.  And the reason for coming with these
      16    percentages was simply -- they are not really cast in
      17    stone.  
      18                  In fact, we've had internal review here. 
      19    There was a number of discussion and changes on some of
      20    these.  Some don't actually fit this paradigm of these
      21    percentages.  
      22                  But this is basically the starting place
      23    that our staff worked with in terms of percent of
      24    lifetime and what uncertainty factor they would use just
      25    to try to have everybody think about it the same way. 

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       1                  CHAIRMAN FROINES:  George --
       2                  MR. ALEXEEFF:  Yeah.  
       3                  CHAIRMAN FROINES:  -- if I understand what
       4    Paul was saying -- and he'll correct me if I'm 
       5    wrong -- part of the problem is that, if you have a study
       6    which is only 12 percent of the estimated lifetime, I'm
       7    assuming that you're worried about not detecting
       8    long-term chronic effects.  
       9                  And so one should adjust for that
      10    uncertainty and, assuming that you find everything you
      11    are likely to find at 12 percent, it's worrisome. 
      12    Certainly in cancer studies we would worry a great deal
      13    about that.  
      14                  DR. MARTY:  You know, there's another sort
      15    of issue that comes into play and that is the concept
      16    that cancer -- carcinogens should be treated as having no
      17    threshold versus the phenomenon of a threshold for
      18    adverse effects for noncancer health endpoints.  
      19                  So the extrapolation over a 70-year period
      20    is really a result of treating the carcinogen as not
      21    having a threshold so that even a very small effect is
      22    associated with possibly a very small risk.   
      23                  Whereas at some point, if you try to take 
      24    a -- say, a two-year exposure looking at a noncancer
      25    health endpoint and divide that by two seventieths,

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       1    you're likely to be pretty far below the threshold for
       2    that effect.  
       3                  So that I think is another reason why it's
       4    approached the way it is rather than what you're used to
       5    seeing in terms of averaging out over a lifetime for
       6    cancer.  
       7                  CHAIRMAN FROINES:  But mechanistically
       8    speaking, this notion that you've overwhelmed homeostasis
       9    in a noncancer effect is clearly historical and
      10    simplistic.  And that there are obviously more
      11    complicated mechanisms for chronic effects from chemicals
      12    and so that we need to be careful to understand that
      13    chronicity may occur over a long period of time and is
      14    not necessarily simple -- the way people traditionally
      15    view noncancer effects -- 
      16                  DR. MARTY:  Yes.  Especially if
      17    pharmacokinetics is not considered then -- for chemicals
      18    with very long half-lifes in the body, that approach is
      19    probably too simplistic --
      20                  DR. ALEXEEFF:  Yeah.  We're not arguing
      21    with -- I think, Dr. Friedman, you have a very good point
      22    about trying to think this through some more.  This is as
      23    far as we've gotten in trying to deal with this issue. 
      24    And so that -- so we just tried to clarify why we got to
      25    where we are.  

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       1                  But I think it's -- a lot of it has to do
       2    with just the convention and how we thought about some of
       3    these different chemicals.  It could be, when we get to
       4    some of the chemicals, especially some of the human ones,
       5    we may want to adjust this and say, you know, it doesn't
       6    seem to work.  
       7                  And we're open to that.  But we're just
       8    saying this is the basis for how we did the chemicals and
       9    so, when you actually look at the document, if you could
      10    think about this issue and any help you can give us on
      11    either further research or ways of improving this
      12    procedure, that would be very helpful.   
      13                  DR. FRIEDMAN:  Well, I feel already helped
      14    a lot by Melanie's discussion of the threshold idea and
      15    with John's addition about how you may not achieve
      16    chronicity of some of these long-term effects even for a
      17    long duration.  You're just not certain that, if you
      18    couldn't -- hadn't had a longer exposure, some new thing
      19    would have appeared.   
      20                  DR. ALEXEEFF:  I think there's -- there
      21    could also be the issue of whether or not the substance
      22    is bioaccumulating and causing an effect or whether or
      23    not it's the pathology that's accumulating.  And I don't
      24    know.  That could differentiate how you might want to
      25    choose your factors.  We haven't been able to resolve

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       1    that.  
       2                  There could be some different 
       3    mechanistic -- basic mechanistic approaches that force us
       4    to slightly adjust this but --
       5                  CHAIRMAN FROINES:  Well, we assume that
       6    things like liver cirrhosis, emphysema and
       7    atherosclerosis are all chronic cumulative irreversible
       8    processes.  
       9                  And so those are three examples of 
      10    where -- what you mean by chronicity starts from day one
      11    and proceeds until you have a clinical manifestation.  
      12                  So we need to take those kinds of chronic
      13    cumulative and irreversible -- theoretically irreversible
      14    effects into this consideration.  
      15                  DR. MARTY:  So what I'm hearing is we
      16    better look at whether or not the chemical has a long
      17    half-life.  I think that might argue against using just 3
      18    rather than 10.  
      19                  The examples that Dr. Froines just gave
      20    with the endpoint of toxicity -- whether that's
      21    essentially viewed as a progressive nonirreversible
      22    problem and look at our chemicals again from that
      23    standpoint.  
      24                  There was a third thing which I just
      25    forgot.  

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       1                  CHAIRMAN FROINES:  I want to make a point. 
       2    And I'll -- I think we should go ahead because I don't
       3    want to overstate it.  I think that, when we write
       4    sections in these documents on toxicokinetics, they need
       5    to be written in a way that just doesn't review the
       6    literature.  And a lot of that happens.  
       7                  You read these endless studies about uptake
       8    and distribution and what have you.  I think
       9    toxicokinetic studies should -- when we write these
      10    documents -- should really be directed to the
      11    relationship between the toxicokinetics and the health
      12    outcomes that we later talk about.  
      13                  So you know where -- when you do carbon 14
      14    work, where the compounds end up.  Do they end up in the
      15    target organs?  What are the half-lifes of the compounds? 
      16    So on and so forth.  So they're always in a context so we
      17    understand the toxicokinetics in terms of the health
      18    effects rather than the special section which everybody
      19    kind of glosses over.  
      20                  And so it's -- I think that's something to
      21    think about for the future document.  
      22                  DR. MARTY:  Okay.  We also use the low
      23    observed adverse effect level uncertainty factor where we
      24    have been unable to identify a NOAEL.  And we did this
      25    again in the acute reference exposure level document.  

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       1                  We have proposed here where, if you have a
       2    NOAEL, then obviously you don't need a LOAEL
       3    extrapolation factor.  So that would be one.  
       4                  If you have a LOAEL, the effect is mild and
       5    we define that as low severity USEPA grade 5 or below,
       6    and that information is in the document and that the
       7    effect was observed in less than 50 percent of the
       8    subjects.  Then we would apply an intermediate LOAEL to
       9    NOAEL uncertainty factor of 3.  
      10                  Where those two criterion were not readily
      11    applicable, then the LOAEL to NOAEL uncertainty factor
      12    would be 10.  
      13                  DR. FRIEDMAN:  I thought, from reading the
      14    document, that you thought there was more uncertainty
      15    when there was a low incidence or mild effect.  Maybe I
      16    misread it.  
      17                  But I thought that made it harder to tell
      18    what the truth was.  Whereas if you have a high incidence
      19    severe effect, it's pretty obvious what's going on.  The
      20    uncertainty may be less.  And I thought that's what the
      21    document said.  Maybe I misread it.  
      22                  DR. MARTY:  It may have said that.  And I'm
      23    not sure what we were exactly talking about in there. 
      24    But when you think about extrapolating from a LOAEL to a
      25    NOAEL, what you're trying to do is figure out how close

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       1    the LOAEL is on the dose response curve to the NOAEL. 
       2                  And our interpretation, valid or not, is
       3    that, if you have a mild effect with relatively low
       4    incidence, you're probably closer to that NOAEL than if
       5    you're up in frank toxicity where you have moderate to
       6    severe effects with relatively high incidence.  
       7                  So we felt that that extrapolation factor
       8    could be decreased from 10, and we pick 3 because we
       9    think in logs.  It's 3.14, but we just round it to 3. 
      10    And that's the reasoning behind using this intermediate
      11    uncertainty factor.  
      12                  You are correct in the sense that, if your
      13    dose response slope is relatively shallow, then you may
      14    have a pretty long distance between that mild low
      15    incidence effect in the true population threshold.  
      16                  And that's -- that's one of the problems
      17    with the NOAEL, LOAEL uncertainty factor approach is you
      18    have not incorporated any information on the slope of the
      19    dose response curve which is why we like benchmark
      20    concentration because you are allowed to use that
      21    information.    
      22                  DR. BYUS:  Craig Byus.  You're
      23    extrapolating to a point where there's no effect.  You
      24    really don't know what that is or the slope is not good
      25    at all.  

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       1                  DR. MARTY:  Right.  Right.  Well, when you
       2    think about it, the no observed adverse effect level is
       3    something you take from a study which essentially sampled
       4    the population of concern or maybe even just a rat or a
       5    mouse study.  
       6                  DR. BYUS:  They might have chosen the wrong
       7    doses.  
       8                  DR. MARTY:  Right.  Exactly.  So you can't
       9    infer that that NOAEL is actually a threshold
      10    concentration for the population because you really don't
      11    know that, and you'll never know that.  
      12                  DR. BYUS:  But that's what -- 
      13                  DR. MARTY:  And actually, there's been a
      14    few analyses in the literature where a NOAEL really
      15    probably represents anywhere between a 1 and 10 percent
      16    incidence response rate.  But you just can't see it
      17    because you don't have the statistical power.  
      18                  DR. BYUS:  That's why I'm more a -- go
      19    along with the tenfold.  I'm a little less comfortable
      20    with interpreting the intensity of the effects and only
      21    using a factor of 3.  If you don't even incorporate the
      22    slope in the study if it was there and then because of
      23    the significance of it.  And the power of these animal
      24    studies are usually not that great to detect those small
      25    changes.  That actually makes me more uncomfortable than

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       1    the previous argument which I am more comfortable with
       2    than I am for this LOEL to NOEL extrapolation.  
       3                  Because it winds up being a -- used as the
       4    threshold almost sort of information --
       5                  DR. MARTY:  I think it's safe to say that
       6    we would hopefully use some judgment based on the
       7    information available about what that slope looks like.   
       8                  CHAIRMAN FROINES:  I was just going to make
       9    a comment about -- everybody -- it's popular to say that
      10    you don't take the dose response relationships into
      11    account, and that's true.  But it's also true that at the
      12    lower dose levels where the processes tend to be
      13    diffusion driven, you probably expect some level of
      14    linearity in the low dose region.  How you deal with high
      15    dose nonlinearities I think is a different issue.  And so
      16    you have that problem.  
      17                  But I don't think that we -- I think we
      18    have to be a little bit -- everybody says we don't take
      19    into account dose response.  But in fact there's some
      20    science that actually goes along with the shape of those
      21    curves.  
      22                  And it's not -- I don't expect major
      23    nonlinearities occurring at very low dose levels around
      24    the threshold.  So I think you'd have to show me a case
      25    where that actually occurred.  It would be interesting to

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       1    see.   
       2                  DR. BLANC:  Can I see the wording on this
       3    for a second again?  
       4                  DR. MARTY:  Jim?  
       5                  DR. BLANC:  I mean maybe one of the things
       6    that -- this is probably just more semantic than
       7    anything.  But there's no one from a -- from a public
       8    health or epidemiologic point of view that would think
       9    that incidence of 40 percent -- 40 percent is a low
      10    incidence.  
      11                  So maybe just think about how you're
      12    wording this because it's a little -- that's one of the
      13    things that's kind of jarring about it too.  
      14                  DR. MARTY:  Okay.  
      15                  DR. BLANC:  I mean maybe you have a reason
      16    for saying -- you know, if you said, "mild effect on low
      17    incidence, less than 10 percent," you know, then I -- we
      18    would be arguing about the rationale more globally.  But
      19    then there's something so jarring about saying, you know,
      20    this low incidence of 45 percent.  It's like --
      21                  CHAIRMAN FROINES:  It's a full-blown
      22    epidemic.  
      23                  DR. FUCALORO:  Wipe out a whole city.  
      24                  DR. MARTY:  Okay.  Point --
      25                  DR. BLANC:  So --

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       1                  DR. MARTY:  -- well made.  
       2                  DR. BLANC:  What's the rationale here? 
       3    What are they thinking?  
       4                  DR. MARTY:  Right.  
       5                  DR. BLANC:  Why do they think this is a low
       6    incident?  So anyway.  
       7                  DR. MARTY:  These next two uncertainty
       8    factors you should be somewhat familiar with from the
       9    acute reference exposure level document.  Basically we
      10    used an interspecies uncertainty factor when we're
      11    extrapolating from animal studies to the human situation.  
      12                  That factor would be 1 if you're actually
      13    starting on this human data.  If you're starting with
      14    animal data, it's generally 10 except where we have
      15    accounted for dosimetric differences using the human
      16    equivalent concentration calculations which I'll get to
      17    in just a second.  
      18                  There we use a factor of 3 and the
      19    rationale is that, although you may have accounted for
      20    dosimetric differences, you have not accounted for
      21    pharmacodynamic differences or differences in response
      22    between the different species.  
      23                  And then of course we mentioned already the
      24    intraspecies or interindividual variability uncertainty
      25    factor.  If you have a human study, but the study

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       1    population was not a particularly known sensitive
       2    subpopulation for that particular chemical, then you
       3    would apply an interspecies uncertainty factor of 10. 
       4                  However, as in the acute REL document, if
       5    you had a human study where you were actually evaluating
       6    the sensitive or an identified sensitive subpopulation
       7    for that particular chemical, then we did not apply an
       8    interspecies uncertainty factor.  That is, it's equal to
       9    1.   
      10                  CHAIRMAN FROINES:  What does HEC stand for?  
      11                  DR. MARTY:  I'm sorry.  HEC is the human
      12    equivalent concentration adjustment factor.  We mentioned
      13    here the modifying factor because the United States
      14    Environment Protection Agency has used this in the
      15    development of their RfCs.  
      16                  And I mentioned that earlier in the talk. 
      17    This is the modifying factor that they apply because of
      18    what they considered database uncertainties.  So it's
      19    generally 1, 3 or 10.  
      20                  We could not find a reasonable description
      21    of when to use the study in the USEPA documents.  And so
      22    we were unwilling to use this because it did not appear
      23    to be particularly objective.  
      24                  And, of course, then the cumulative
      25    uncertainty factors range in our OEHHA proposed chronic

                 BARNEY, UNGERMANN & ASSOCIATES  1-888-326-5900


       1    RELs from 1 to 3,000.  And 1 would be where you actually
       2    have a human study in a sensitive subpopulation.  
       3                  3,000 is the highest that we have used. 
       4    That would have come from an animal study with a variety
       5    of uncertainties that we ended up using certainty factors
       6    for.   
       7                  In the case of the EPA RfCs that we have
       8    looked at, their range of cumulative uncertainty factors
       9    is 30 to 3,000.  
      10                  DR. BLANC:  Why don't they go up to 30,000? 
      11    Because they have this factor of 10 that you don't have. 
      12    Is there a factor that you have that they don't have that
      13    I missed in the discussion?  
      14                  DR. COLLINS:  They put a ceiling arbitrary
      15    at 3,000.  
      16                  DR. MARTY:  Thank you.  
      17                  DR. BLANC:  So actually, theoretically it
      18    could have gone up to 30,000.  
      19                  DR. MARTY:  Right.  But they decided that
      20    that seemed inordinately high.   
      21                  DR. BLANC:  And why is it -- which is the
      22    factor that can only get as high as 3 for you that makes
      23    it not go to 10,000?  Suppose you had a --
      24                  DR. MARTY:  I don't know if it couldn't go
      25    up to 10,000 or if -- 

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       1                  DR. FUCALORO:  I thought you said --
       2                  DR. MARTY:  Out of our chemicals, those 
       3    are -- the 3,000 is the highest that we have applied 
       4    and --
       5                  DR. BLANC:  Let's walk this through.  If
       6    you had a study which was less than -- what was it?  Less
       7    than 10 percent?  Less than 8 percent of the lifetime in
       8    animals only, then that would get you 10,000?  
       9                  DR. MARTY:  That would get up to 10,000.  
      10                  DR. ALEXEEFF:  We also limited our maximum
      11    uncertainty factor total up to 3,000.  And the reason for
      12    that is because of the RAAC report that was done.  This
      13    is the Risk Assessment Advisory Committee that reviewed
      14    our risk assessment guidelines.  
      15                  And they mostly evaluated the -- since we
      16    didn't have uncertainty factors in the air program, they
      17    were evaluating the uncertainty factors in the water
      18    program.  And at that point they had recommended, I
      19    think, a maximum of 1,000 to 3,000 for total uncertainty
      20    factors.   
      21                  So we're basically adopting that
      22    convention.  So at some point we -- you know, if the
      23    uncertainty is so great, we either decide that we need
      24    another study or maybe that chemical can't be evaluated
      25    or the information is unclear.  So we limited it to 3,000

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       1    like USEPA did.  
       2                  DR. FUCALORO:  Did you come across a case
       3    where, if you didn't have that -- what seems to me an
       4    arbitrary limitation of 3,000 -- would have gone above
       5    3,000 in any of the cases you can think of?  
       6                  DR. MARTY:  Jim, can you --
       7                  DR. COLLINS:  I don't know offhand.  
       8                  DR. ALEXEEFF:  I know we have in the water
       9    programs.  We've often come across that situation where
      10    basically you're -- what happens in that case is you're
      11    using a low effect level from a subchronic study.  And
      12    that will just add in a factor, an animal study.  And
      13    that just adds enough right there.  
      14                  DR. MARTY:  One of our staff people who
      15    actually was a key person on the document is in the
      16    audience.  Dr. David Lewis.  He just told me that there
      17    is one chemical where we could have gone to 10,000 and we
      18    limited it to 3,000.  
      19                  DR. FUCALORO:  Is it a secret?  
      20                  DR. MARTY:  Dave, I can't hear you from
      21    here.  
      22                  It's not a secret.  But I couldn't hear
      23    which one he said.  
      24                  124 trinitrobenzene.   
      25                  DR. BLANC:  And does it say in the document

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       1    that you did that?  
       2                  DR. MARTY:  It's not in the first batch of
       3    40, is it?  
       4                  (No audible response.)
       5                  DR. MARTY:  Okay.  So we didn't do it.  We
       6    ended up discarding it because we felt that the data 
       7    were too uncertain to develop a REL.  
       8                  DR. ALEXEEFF:  So there was just the
       9    chemical that would have made it, but instead we didn't
      10    do the assessment for that substance.  
      11                  CHAIRMAN FROINES:  I think the compound is
      12    actually found in the environment from explosives.  
      13                  DR. ALEXEEFF:  I think that is a question
      14    that, you know, maybe after we finish this chronic
      15    document review that you -- that the Panel could give us
      16    some guidance on because we're basically stuck in a
      17    situation where, if a substance -- whether it's used or
      18    not used -- if there's limited data, we basically don't
      19    develop a factor, a level for it.  
      20                  If we don't develop a level for it, it's
      21    generally not measured in the environment and therefore
      22    just kind of stays off of the radar screen.  We have no
      23    way of tracking to see what the levels are, if it's an
      24    issue.  
      25                  So it's a little bit of a -- what we would

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       1    consider a catch-22 situation where we don't go up a
       2    level.  The districts don't monitor for it.  We have no
       3    idea if it's a concern or not.  
       4                  Except we would have possibly some
       5    information on whether or not how many pounds have been
       6    released from the ATEDS database.  That would be the one
       7    thing that would trigger us that would tell us, maybe
       8    would try to force us to try to come up with a level.  
       9                  CHAIRMAN FROINES:  The -- one of the 
      10    things -- I'll just say this, then we should move ahead. 
      11    I could argue and will, in fact, that one should -- could
      12    consider using an uncertainty factor of 10,000 for methyl
      13    parathion so that it's not totally out of one's stream of
      14    consciousness.   
      15                  DR. ALEXEEFF:  I'm sorry.  George Alexeeff
      16    again.  In the -- in the water program, it's not really
      17    uncommon for us to use it, a 10,000-fold factor if it's 
      18    a -- you know, a borderline carcinogen because basically
      19    there's another factor you can add that's used in the
      20    water program for -- if it's -- if there's genotox data
      21    and maybe one borderline cancer study.  
      22                  But there's not enough to do a real risk
      23    assessment.  You might add another factor for potential
      24    carcinogenicity.  
      25                  And in fact, that was done in our MTBE

                 BARNEY, UNGERMANN & ASSOCIATES  1-888-326-5900


       1    document.  So --
       2                  DR. MARTY:  Okay.  This next slide which
       3    should say "methods for temporal adjustments" just
       4    describes the calculations used to account for
       5    discontinuous exposure.  
       6                  Essentially for -- in an animal study we
       7    would adjust the concentration observed to produce an
       8    effect or not produce an effect, whichever -- if you had
       9    a NOEL or a LOEL -- by the hours per 24 hours that the
      10    animals were exposed and by the days per seven days that
      11    the animals were exposed.  
      12                  In an occupational study, that traditional
      13    adjustment is a little bit different.  Here you multiply
      14    by assuming -- multiply by a factor of 10 over 20,
      15    assuming that of the total 20 cubic meters per day that
      16    you breathe, 10 of that is breathed in the occupational
      17    setting.  
      18                  And then of course by the number of days
      19    per week which is usually five out of seven.  So that
      20    adjustment is done a little bit differently.  It's trying
      21    to account for the amount of air consumed while you are
      22    being exposed over the total amount you're consuming a
      23    day.  
      24                  MR. FRIEDMAN:  In other words, normally you
      25    would think of an eight-hour workday which would give you

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       1    a lower ratio.  But you assume that people at work are
       2    breathing more than they are elsewhere?  
       3                  DR. MARTY:  Exactly.  
       4                  DR. FRIEDMAN:  Okay.  
       5                  DR. MARTY:  So that is -- rather than a
       6    time-weighted average -- is more of an
       7    inhalation-weighted average approach.   
       8                  This slide described our method -- and
       9    actually, it's not our method.  It's USEPA's method for a
      10    dosimetric adjustment.  And it's called the human
      11    equivalent concentration or HEC method.  This method is
      12    published in a document.  In 1994 it did receive some
      13    external peer review and review by ARB -- excuse me. 
      14    USEPA's signs advisory board.  
      15                  And essentially the two most common
      16    adjustments used adjust for the relative minute volume to
      17    relative surface area for the lung region of concern for
      18    what are called type one gases.  
      19                  And these are highly water soluble and
      20    reactive compounds that generally may have respiratory
      21    effects but don't end up having much of a systemic effect
      22    in terms of noncancer.   
      23                  The other commonly used adjustment is for
      24    type three gases which are the less water soluble gasses. 
      25    They enter the bloodstream and are basically -- the

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       1    concentration is basically perfusion limited.  
       2                  And here the adjustment is to look at data
       3    on the blood, gas partition coefficient in animals
       4    relative to the blood gas partition coefficient in
       5    humans.  
       6                  So the average exposure concentration is
       7    then multiplied by this factor which is termed a regional
       8    gas dose ratio.  And a regional gas dose ratio is derived
       9    by looking at the differences in minute volume and
      10    surface area for the water soluble reactive gases.  
      11                  And in the second case it's derived by
      12    ratioing the blood gas partition coefficient.  I'd have
      13    to say in that second case, generally, you don't have
      14    that information except for in a couple of instances. 
      15    And so the assumption is made that that ratio is 1.   
      16                  DR. FUCALORO:  Wouldn't it in a sense be
      17    deriving human equivalent concentrations -- I'm sorry. 
      18    These are from animal studies.  
      19                  DR. MARTY:  Right.  Right.  
      20                  DR. FUCALORO:  And you're just ratioing the
      21    surface area of the lungs versus the volume -- in other
      22    words, that's dosage.  That's a dosage --
      23                  DR. MARTY:  Exactly.  It's a dosimetric
      24    adjustment.  
      25                  DR. FUCALORO:  And the other is the ratio

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       1    of the partition coefficient that's based on sometimes
       2    octanal studies; is that right?  
       3                  DR. MARTY:  Well, it's actually -- in this
       4    case you're looking for studies where they actually did
       5    look at the blood gas ratio.  
       6                  DR. FUCALORO:  Right.  
       7                  DR. MARTY:  The idea there is it's a
       8    perfusion limited system.  And there might be some
       9    differences in the blood gas partitioning between an
      10    animal and a human.  
      11                  My guess is -- and maybe Dave Lewis can
      12    chime in here -- is that that number is not usually too
      13    far from 1.  
      14                  DR. BLANC:  I guess what surprises me about
      15    this for the second one more than maybe for the first
      16    case -- although the first case somewhat is -- because
      17    this then yields an interspecies uncertainty factor of 3
      18    rather than of 10.  This is what you -- you by yourself
      19    with this; is that correct?  
      20                  DR. MARTY:  Right.  
      21                  DR. BLANC:  That it's saying that what
      22    drives our uncertainty, when we extrapolate from rodents
      23    to humans, for example, is as much uncertainty about the
      24    delivered dose as it is uncertainty about the many
      25    variations between an inbred small animal and humans.  

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       1                  DR. MARTY:  That's --  
       2                  DR. BLANC:  And that surprises me because I
       3    would think that most of the uncertainty and variability
       4    is not related to dose so much as it's related to all of
       5    the other things that are quite difficult to measure in
       6    terms of metabolism and in terms of implications of
       7    inbred genetic strains and their narrower response even
       8    when we're not talking about sensitive subpopulations
       9    which we take into account with a factor of 10.  
      10                  Is this use of the -- this adjustment
      11    something that your staff internally feels that
      12    comfortable with?  
      13                  DR. MARTY:  Actually, I never asked them
      14    that question.  But it is -- we are modeling it 
      15    after -- we're essentially wholesale adopting USEPA's
      16    approach to doing that.  
      17                  And I think it can be argued -- and you
      18    have just argued it -- that uncertainty factor of 3 for
      19    essentially pharmacodynamic differences might be much
      20    bigger than 3 in reality.  
      21                  And unfortunately we don't know that
      22    because that kind of information is just not available. 
      23    Some people argue that actually that should be a factor
      24    of 10 and the pharmacokinetics should also be a factor of
      25    10.  And we should really be using a total factor of 100. 

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       1                  So it has been argued in all directions. 
       2    And also a dosimetric adjustment does not account for
       3    other toxicokinetic factors.  So that also argues against
       4    using just a factor of 3 when you have done a HEC
       5    calculation.  
       6                  I think all of those things, you know, we
       7    realize are out there as sort of, you know, the elephant
       8    in the room kind of thing.  
       9                  But at this point, we're starting out with
      10    this proposal, and we're, of course, willing to change it
      11    if it doesn't appear to be health protective enough.   
      12                  DR. ALEXEEFF:  George Alexeeff.  It goes
      13    back in part to our methylene chloride document that we
      14    discussed -- I don't know.  Was it ten years ago?  And at
      15    that time -- I think also Lawrence Rhomberg discussed it
      16    at the last SRP meeting.  
      17                  Sort of the issues surrounding this
      18    interspecies uncertainty factor and the 
      19    issue -- originally it was mostly justifications and the
      20    thought process behind the difference was -- had to do
      21    with surface area differences and metabolism differences
      22    and things like that.  
      23                  So the whole focus of research was to try
      24    to identify the differences in metabolism because that's
      25    how some of the first examples that came up

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       1    toxicologically were examples of the metabolism
       2    differences.  And so that's how it all came out.  
       3                  But then since that time, and I think
       4    methylene chloride was probably -- at least for this
       5    Panel and for me personally -- was probably sort of the
       6    defining point where then the pharmacokinetics
       7    information was really getting better.  
       8                  But then all a sudden the area
       9    pharmacodynamics came out and said, "Wait a second. 
      10    There's a lot of response variation."
      11                  And I think what could happen is you could
      12    have the kinetics being similar between the two species
      13    but the dynamics being tenfold different and vice-versa. 
      14    You could have the dynamics being the same but the
      15    kinetics being tenfold.  
      16                  And I don't think we've learned how to
      17    resolve that.  So in the interim, we're kind of saying,
      18    if we understand -- let's say, if we understand the
      19    kinetics better, which is what this is purporting to do,
      20    then we can reduce the uncertainty factor and then simply
      21    worry about the pharmacodynamics which at this point
      22    we're suggesting is 3.  
      23                  But clearly there would be incidents where
      24    that's not the case.  But I don't know if we've
      25    identified any.  But there's just bound to be some. 

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       1                  So I think we're kind of agreeing with you. 
       2    And I think we're saying this -- it looks like this
       3    probably works most of the time but we're not sure how
       4    often it's wrong.  
       5                  DR. MARTY:  Also just another comment on
       6    the tenfold interspecies uncertainty factor.  There have
       7    been a couple of investigators who have looked at how
       8    good that is using data on -- the two I'm thinking of are
       9    Freireich back in the 60's and then Curtis Travis and
      10    Hatte Mer-Fry looked at the chemotherapeutic agents
      11    maximum tolerated dose in people -- where they actually
      12    had people data and also in animals -- and looked at what
      13    an appropriate scaling factor would be.  
      14                  And essentially, it's anywhere between two
      15    thirds and three quarters on average.  But the error bars
      16    are huge which translates to about a sixfold to
      17    twelvefold difference depending on if you're talking
      18    about rats or mice in dose scaling.  
      19                  So I don't know if that provides any
      20    insight into this.  But a tenfold has been argued that it
      21    probably is reasonable for most chemicals.  But you're
      22    always going to find -- you're always going to find
      23    outliners.  And whether that is toxicokinetics or
      24    toxicodynamics is really blurry and messy at this point.   
      25                  DR. ALEXEEFF:  George Alexeeff.  But you

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       1    know, I think that's -- whenever we use, of course, the
       2    animal interspecies factor we're also using the human
       3    one.  
       4                  And there's been a number of arguments that
       5    we've heard that there -- that the two factors are not
       6    independent.  That there is some interdependence and
       7    that, therefore, by multiplying them together to come up
       8    with 100, you're actually overprotecting.  
       9                  But I think, in fact, what's happening,
      10    though, there are these types of issues that you've
      11    raised where we're really not necessarily overprotecting
      12    because there's these other underlying issues that -- or
      13    the dynamics and the kinetics can vary so much.  
      14                  And the interindividual variability can
      15    vary so much that I don't think we're necessarily
      16    overprotecting even though there is some interdependence
      17    between those two factors.  
      18                  But I think it's a whole area -- I 
      19    think -- that's probably going to sort of -- it's really
      20    growing right now in research and trying to resolve this. 
      21    We ourselves are trying to think through how could we
      22    evaluate this better to get a better grasp on it but --
      23                  DR. MARTY:  Show us the money.  
      24                  DR. ALEXEEFF:  Yeah, I think that, you
      25    know, hopefully, like if we're -- I think what we would

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       1    get concerned about -- if we used a threefold factor for
       2    interspecies and another threefold factor for
       3    intraspecies, then we would start -- the staff then start
       4    getting queasy on certain things because we're 
       5    not -- we're feeling we're not totally covering all the
       6    uncertainties.  
       7                  DR. MARTY:  Next slide, Jim.  Are we ready
       8    for the next slide?   
       9                  CHAIRMAN FROINES:  We have gotten to slide 
      10    21.  And we have to go to slide 35.  
      11                  DR. MARTY:  Yes.  
      12                  CHAIRMAN FROINES:  So we should try and
      13    probably move along.  
      14                  DR. MARTY:  Okay.  The other slides after
      15    these should go much faster.  The USEPA also developed a
      16    method for deriving human equivalent concentrations for
      17    particles.  
      18                  And this is a bit more data intensive than
      19    the method applied to gases, and again, they have these
      20    two categories where the primary effect is respiratory
      21    and not systemic or where the effective concern is
      22    systemic.  
      23                  And essentially they have developed a
      24    computer program, the USEPA RDDR program.  And the RDDR
      25    is the regional deposited dose ratio.  And we used their

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       1    program when we had information available to do that for
       2    adjusting human equivalent concentrations.   
       3                  The type of information that goes into the
       4    program are -- is information on the particle size
       5    distribution characterized by the mass median aerodynamic
       6    diameter in the geometric standard deviation thereof.  
       7                  Also what goes into the program is the
       8    identity of the experimental species because information
       9    on minute volume and lung surface area by region of the
      10    lung is incorporated into the program.   
      11                  So what you're really doing is accounting
      12    for the relative ratio of minute volumes to surface areas
      13    times the fractional deposition in the regional lung of
      14    concern.  That would be for a respiratory effect.  
      15                  For a systemic effect you want to look at
      16    the total fractional deposition because the assumption
      17    there is there is absorption and then distribution to
      18    distal sites to produce the effects.   
      19                  We had talked a bit about the benchmark
      20    concentration earlier.  And basically, it's the same deal
      21    as was in the acute reference exposure level document
      22    with a couple of twists.  We ourselves did not use the
      23    benchmark concentration for any of the chronic RELs we
      24    generated de novo.  
      25                  However, USEPA used this methodology for

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       1    some of the RfCs which we have proposed to accept for use
       2    as chronic reference exposure levels.  And again, the
       3    advantages are that it incorporates dose response
       4    information better than the NOEL method does.  
       5                  You can use multiple studies to define your
       6    dose response curve using models to extrapolate downwards
       7    such as the Weibull model or log-probit model.  
       8                  It allows you to estimate a NOAEL where it
       9    was not experimentally observed.  In essence, the USEPA
      10    defines the benchmark concentration as the 95 -- it's not
      11    percentile.  95 percent lower confidence limit for a 10
      12    percent response rate.  
      13                  The model used at the BMC 10 is less
      14    critical than if you're trying to define the 95 percent
      15    lower confidence limit on dose for a 5 percent response
      16    rate.  
      17                  And that is the reasoning that USEPA uses
      18    for choosing the 10 percent response rate.  So you get
      19    less model uncertainty.  They then take this BMC 10 as
      20    the point of extrapolation.  
      21                  And this figure -- just to visualize what
      22    they're doing, here they've taken -- this is just a
      23    generic figure where you have dose response points, and
      24    it could be for more than one study.  
      25                  And in this case it was a log-probit

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       1    modeling of the dose response data.  Then you take 95
       2    percent lower confidence limit on that line.  And in our
       3    case we would pick the BCO5, which would be the 95
       4    percent lower confidence limited dose to produce a 5
       5    percent incidence.   
       6                  The BCO5 and the BC 10 have been used by us
       7    and by EPA respectively. 
       8                  DR. FRIEDMAN:  Are you saying -- you see an
       9    effect at the level at which you're taking the BMC 10,
      10    and I don't quite understand why taking the lower
      11    confidence level will get you the no effect.  
      12                  DR. MARTY:  Okay.  That does not get you to
      13    the no effect level.  What that does is tell you what the
      14    lowest dose is that you have confidence in could possibly
      15    produce a 5 percent incidence.  
      16                  So what you're doing is you're -- rather
      17    than taking the maximum likelihood estimate, which would
      18    kind of give you more of an average number, you're
      19    actually lowering that point from which you extrapolate
      20    downwards using uncertainty factors.  
      21                  And what that does is it takes care of some
      22    of the intraindividual variability and response.  So you
      23    really -- you want -- it basically functions as an
      24    uncertainty factor.  
      25                  DR. FRIEDMAN:  But then it says it allows

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       1    estimation of the NOAEL.  We're not experimentally -- 
       2                  DR. MARTY:  Okay.  
       3                  DR. FRIEDMAN:  How do you get to the NOAEL
       4    from that number?  
       5                  DR. MARTY:  You would apply uncertainty
       6    factors.  And actually, a NOAEL really is not a NOAEL in
       7    terms of if you had a huge study population, you would
       8    not see an effect.  
       9                  It really is around a 5 percent incidence
      10    rate.  So I think that's probably -- that's probably what
      11    we were talking about when they made that bullet.  
      12                  DR. FUCALORO:  Don't you mean once you have
      13    a BMC you really don't derive a NOEL -- a NOAEL, you just
      14    use the benchmark?  
      15                  DR. MARTY:  Right.  You just use --
      16                  DR. FUCALORO:  That's why I think you might
      17    be confused.  The second bullet says "allows" -- on the
      18    previous --
      19                  DR. MARTY:  Yes, it does.  
      20                  DR. FUCALORO:  "Allows estimation of NOAEL
      21    where not experimentally observed."  And in fact, I think
      22    what you're saying is you forgo a NOAEL and just get a
      23    bench -- a BMC.  And that's --
      24                  DR. MARTY:  Yes.  
      25                  DR. FRIEDMAN:  And it's safe?  Benchmark is

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       1    safe?  Is a safe level?  
       2                  DR. MARTY:  It's a point that you use it in
       3    instead of the NOAEL, and you apply uncertainty factors
       4    to the BMC instead of the NOAEL.  I would hesitate to
       5    call that a safe level because generally you're targeting
       6    a 5 to 10 percent incidence rate.  
       7                  So that's not really a safe level.  But
       8    it's a point of extrapolation.  And the idea is that a
       9    NOEL is also probably somewhere between a 5 and 10
      10    percent incidence rate.  
      11                  DR. FRIEDMAN:  So you take this BMC and
      12    then apply a bunch of uncertainty factors and get down to
      13    a much lower level in terms of the reference for the REL? 
      14    Is that what you do?  
      15                  DR. MARTY:  Right.  Right.  
      16                  DR. ALEXEEFF:  Yeah.  Really, I mean the
      17    NOEL could be considered the limited protection of that
      18    experimental system that you're looking at and then
      19    you're applying uncertainty factors.  
      20                  So what this is doing in benchmark dose,
      21    it's defining the limited detection for the experimental
      22    system a little bit more rigourously in a more systematic
      23    way.  
      24                  Because if you only had fewer dose groups,
      25    you could see where the NOEL or the LOEL might be way up

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       1    there in terms of a 25 percent response rate.  And then
       2    if it's simply a factor that you only have five animals
       3    per dose group there, then you could be missing, you
       4    know, 20 percent of your response or over 15 percent of
       5    your response.  
       6                  So this is just a more systematic way of
       7    starting -- the starting point for then applying the
       8    uncertainty factor saying that's limited detection of
       9    your experimental system.  
      10                  DR. MARTY:  We have now a couple of
      11    examples for you looking at three different bases for
      12    deriving the chronic REL.  The first is formaldehyde.  In
      13    this case we have a human NOAEL.  
      14                  The studies used were Wilhelmsson and
      15    Holmstrom, '92 and Holmstrom and Wilhelmsson, '88.  These
      16    investigators studied people working in chemical plant
      17    exposed to formaldehyde.  There were about 66 subjects in
      18    all.   
      19                  The occupational exposures were a ten-year
      20    average and actually ranged from 1 to 36 years.  The
      21    critical effects were essentially related to the
      22    irritancy of formaldehyde, nasal and eye irritation,
      23    nasal obstruction, lower airway discomfort.   
      24                  They did use a control group which actually
      25    was also exposed but to a much lower concentration.  And

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       1    what was done here is we essentially described the
       2    control group which did not have these symptoms as the
       3    NOAEL, and they were exposed to a mean of about .09
       4    milligrams per cubic meter.  
       5                  The exposure continuity was eight hours per
       6    day, five days per week.  And the five days per week is
       7    an assumed number just based on a typical workweek.   
       8                  We adjusted the occupational concentration
       9    by the 10 cubic meters over 20 cubic meters adjustment
      10    and 5 days per 7 to arrive at an average exposure of .03
      11    milligrams per cubic meter.  And --
      12                  DR. BLANC:  Can you stop there -- sorry. 
      13    Can you stop there for a second.  The 10 over 20 again? 
      14    What is that?  
      15                  DR. MARTY:  That is assuming that you
      16    breathe about half your total intake of air while at work
      17    over a whole day.  So if you assume that the person
      18    breathes 20 cubic meters over a whole day, you make the
      19    assumption that half of that was inhaled while at work. 
      20                  And it accounts for, when you're sleeping,
      21    your respiratory rate drops and usually, when you come
      22    home, the average person is a couch potato.  So their
      23    respiration rate drops.  
      24                  DR. BLANC:  So rather than, let's say,
      25    conservatively saying that a third of your exposure

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       1    occurs in 8 out of 24 hours, you're saying that half of
       2    your exposure occurs.  
       3                  DR. MARTY:  Right.  
       4                  DR. BLANC:  And that's what you do
       5    consistently through the document?  
       6                  DR. MARTY:  Yeah.  Right.  Where we have
       7    the human studies.  
       8                  DR. BLANC:  And you're assuming that people
       9    work 52 weeks out of the year?  
      10                  DR. MARTY:  The yearly adjustment doesn't
      11    come into play here because that's accounted for by the
      12    subchronic to chronic extrapolation --
      13                  DR. BLANC:  No.  I'm asking a different
      14    question.  Because you're assuming that over the time
      15    that they were exposed they were exposed for 5 out of 7
      16    days a week and that they never missed a day of work in
      17    52 weeks.  
      18                  DR. MARTY:  Yeah.  That assumption is
      19    implicit, yes.   
      20                  DR. BLANC:  And you're 
      21    assuming -- and -- that one breathes half of their air in
      22    their eight-hour day is based on what kinds of
      23    occupations?  What certain level of manual occupations?  
      24                  DR. MARTY:  It's really based on the
      25    assumption that you're more active while at work than you

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       1    are at home --
       2                  DR. BLANC:  How much more active is that
       3    assumption?  
       4                  DR. MARTY:  -- and sleeping.  
       5                  DR. BLANC:  This is a major adjustment
       6    factor for the studies that use human -- for your
       7    calculations that use human subjects because it's a
       8    difference between .5 and .3.  
       9                  So I'm fixating on this a little bit
      10    because it's going to have a, you know, 20 percent effect
      11    or something on your calculations for all of the ones
      12    that are --
      13                  DR. FUCALORO:  But isn't it an allowance
      14    that has built in -- make it conservative.  I mean if you
      15    go to .3, and you get a number that's not as --
      16                  DR. BLANC:  No.  You get a lower --
      17                  DR. FUCALORO:  -- protected --
      18                  DR. BLANC:  No.  You get a lower number.  
      19                  DR. MARTY:  Right.  It's a denominator.  
      20                  DR. FUCALORO:  Okay.  Right.  Right.   
      21                  DR. BLANC:  I'm just pointing that out as
      22    an issue.  The other issue I would -- to come back to my
      23    earlier question, the previous -- slide 23.  Ten years
      24    average of these people who worked 1 to 36, do you mean
      25    the mean years of exposure was ten?  

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       1                  DR. MARTY:  Right.  
       2                  DR. BLANC:  Because I would argue very
       3    strongly that what matters is what's the median years of
       4    exposure.  
       5                  If I have two or three people who worked 40
       6    years in that plant driving up that mean to 10 years but
       7    actually the median exposure of that group was 6.5 
       8    years --
       9                  DR. MARTY:  I'm not sure we have
      10    information on the shape of that distribution.  What
      11    you're essentially doing is assuming it's a normal
      12    distribution if he used the mean rather than the median.   
      13                  DR. BLANC:  What I'm saying is that, if
      14    most of the people in the factory weren't exposed
      15    chronically but were exposed for five years, then -- and
      16    it's a cumulative effect, you may have a couple of people
      17    that you saw the effect because they actually were
      18    exposed long enough, and most of the people weren't.  
      19                  And therefore, saying that you can
      20    extrapolate because this is more than 12 percent of a
      21    lifetime becomes even more tenuous.  That's all I'm
      22    saying.  
      23                  DR. FRIEDMAN:  Could I ask how this study
      24    was done?  Was it -- they asked these workers who have
      25    been working there a long time "Do your eyes and nose

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       1    ever bother you?"  
       2                  And the workers who said no had an average
       3    exposure of .09, and the workers who said yes had an
       4    average exposure of .26?  Is that what I'm understanding?  
       5                  DR. MARTY:  In a nutshell, what they did
       6    was look at nonatopic workers who were -- and they did
       7    survey them and ask them if they experienced general
       8    nasal discomfort.  
       9                  They also looked at incidence of lower
      10    airway problems such as cough, wheeze and symptoms of
      11    bronchitis in this study population and eye irritation. 
      12                  So then they examined people in these two
      13    different exposure categories and looked at the
      14    differences in incidence of those things amongst those
      15    two groups of people.  
      16                  So it's not to say that there were zero
      17    symptoms in the NOAEL group but that the incidence was
      18    considerably less in that group.  For example, 6 percent
      19    in the NOAEL group said that they had eye irritation
      20    while at work.  
      21                  And 24 percent in what we have termed the
      22    LOAEL group had eye irritation.  66 percent of the
      23    workers in the LOAEL group experienced what they called
      24    general nasal discomfort compared to 17 percent in the
      25    NOAEL group.  

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       1                  So that's how we ended up -- that's how the
       2    study was designed, and we were somewhat constrained by
       3    the study design, and that's how we ended up breaking it
       4    out and describing the low exposure group essentially as
       5    a NOAEL.  
       6                  DR. FRIEDMAN:  Isn't it troublesome,
       7    though, to -- when -- you know, a reasonable percentage
       8    has these symptoms unless you have some kind of totally
       9    unexposed control group who you would ask about the same
      10    symptoms, isn't it unreasonable to call that no adverse
      11    effects?   
      12                  DR. BLANC:  Well, it's what the EPA did.  
      13                  DR. MARTY:  Well, I think, you know, we
      14    didn't have a study that we could use that identified a
      15    group of people who had absolutely no effects.  
      16                  So all we could do is differentiate between
      17    these two groups.  And that's why we set it up the way we
      18    set it up.  It's problematic.  I mean that is one of the
      19    uncertainties in there.  
      20                  And the problem is that we don't have a
      21    nonexposed group to ask the same questions of to use as a
      22    true control as -- and actually, I 
      23    prefer -- formaldehyde.  I'm not sure if there is a
      24    nonexposed group anywhere.  
      25                  DR. ALEXEEFF:  I think, when we actually

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       1    get to the chemical, you know, and discuss it, maybe we
       2    could look at that NOEL group -- NOAEL and see if it is a
       3    NOAEL group or if it's a LOAEL group.  And if it's a
       4    LOAEL group, how severe is it?  And would it have to be
       5    adjusted like a threefold factor or something like that?  
       6                  I mean I think one could look at that when
       7    we look at the study and whoever the lead is can actually
       8    look at it, you know, very carefully.  But 
       9    that's -- we're basically using the data that's given to
      10    us in the literature.  
      11                  And so this is some of the constraints and
      12    pitfalls we come up with.  So I think, when we look at
      13    that, that's a good point to look at.  
      14                  DR. FRIEDMAN:  Do the authors call that a
      15    no effect level, or do they not try to --  
      16                  DR. ALEXEEFF:  They called it the control
      17    group.  And so that's what we interpreted as the NOAEL. 
      18    I mean -- so they may have felt that that was reflecting
      19    background incidence of response.  
      20                  But until -- you know, we should probably
      21    go back and look at those studies and be more confident. 
      22    We will review this chemical individually later on.  
      23                  CHAIRMAN FROINES:  This is one of our 40;
      24    right?  
      25                  DR. MARTY:  Right.  

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       1                  CHAIRMAN FROINES:  So we should go on.  
       2                  DR. MARTY:  And the next slide just
       3    indicates the rest of the NOAEL calculation.  We did not
       4    use a LOAEL uncertainty factor or a subchronic
       5    uncertainty factor because the mean exposure duration was
       6    ten years.  
       7                  And of course, we don't need an
       8    interspecies uncertainty factor because we're dealing
       9    with humans.  So the cumulative uncertainty factor is 10. 
      10    And it is consistent -- comprises solely of the
      11    intraspecies uncertainty factor of 10.  
      12                  Then the inhalation reference level then is
      13    2ppb or 3 micrograms per cubic meter.    
      14                  DR. BYUS:  Melanie, if you had used the
      15    LOEL uncertainty factor, what would the number have been
      16    if you -- you see what I'm saying?  Was it 10 or
      17    threefold?  What was it?  Would it be accurate based on
      18    the data?  
      19                  DR. MARTY:  I think it would be subject to
      20    interpretation of whether those effects were mild.  
      21                  DR. BYUS:  That's right.  That's why I'm
      22    asking.  So you see what I'm -- 
      23                  DR. MARTY:  We probably would consider
      24    those mild effects and so it would be threefold lower
      25    than that.  So it would be one microgram per cubic meter

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       1    essentially if we consider the NOAEL to actually be a
       2    LOAEL.   
       3                  DR. BYUS:  If you took the LOEL data 0.26
       4    and divided it by 3, you would get pretty close to 0.09,
       5    which is what -- which is what the study showed.  
       6                  So this -- am I doing this incorrectly? 
       7                  DR. MARTY:  I see what you're saying.  
       8                  DR. BYUS:  Do you see what I'm saying?  
       9                  DR. MARTY:  Yeah.  Okay.  
      10                  DR. BYUS:  I'm just saying apply those
      11    uncertainty factors here where you actually have the
      12    data.  And do they actually come out to be correct?  
      13                  DR. MARTY:  It comes out fairly close.  
      14                  DR. BYUS:  It comes -- in this case it
      15    does.  So that's good.  
      16                  DR. MARTY:  Serendipity.  
      17                  CHAIRMAN FROINES:  What percentage of the
      18    40 chemicals are benchmark dose?  
      19                  DR. MARTY:  It's only the USEPA RfC because
      20    we -- it's two out of the 40 --
      21                  DR. ALEXEEFF:  Two out of 40 --
      22                  DR. MARTY:  Two out of this first 40. 
      23    Okay.  I'm sorry.  It's one out of this first 40 and two
      24    out of all the ones that we've looked at.  And those are
      25    both USEPA RfCs.  

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       1                  CHAIRMAN FROINES:  The Crumps paper was
       2    written in '86?  
       3                  DR. COLLINS:  '84.  
       4                  CHAIRMAN FROINES:  '84?  We're really
       5    moving along rapidly, aren't we?  In terms of adopting
       6    new approaches.  
       7                  DR. ALEXEEFF:  Well, for the chronic
       8    exposures, first of all, the data is less likely to be
       9    useful for that.  
      10                  Also we've had some problems in doing the
      11    calculations because I think in part sometimes the dose
      12    response curves are shallow, and the calculation
      13    procedure kind of blows up on us.  So that's been the
      14    problem.  
      15                  I think the ones that were used were on
      16    developmental data, and that's a fairly defined procedure
      17    for benchmark dose.  But that is definitely something
      18    that we would like to do more.  But it's one 
      19    that's -- we've had difficulty on the chronic side of
      20    really nailing down what the procedure should be.  
      21                  CHAIRMAN FROINES:  Why don't we go 
      22    ahead -- do we really need to do propylene and do
      23    phosphoric acid today?  
      24                  DR. MARTY:  No.  We can do phosphoric acid
      25    which is an example of a benchmark concentration. 

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       1    However, it's not in the first batch of 40.  It's going
       2    to be --
       3                  CHAIRMAN FROINES:  Let's just do propylene,
       4    then go on.  
       5                  DR. MARTY:  Okay.  
       6                  CHAIRMAN FROINES:  We'll do phosphoric acid
       7    later then.  
       8                  DR. MARTY:  Okay.  So propylene is an
       9    example where you have a LOAEL from an animal study.  In
      10    this case the study was of rats, 50 rats per group per
      11    sex.  And it was whole body inhalation, six hours per
      12    day, five days per week for a two-year lifetime.  
      13                  The critical effects observed all were
      14    related to the epithelium of the respiratory system. 
      15    There were squamous metaplasia in both sexes, epithelial
      16    hyperplasia in females only and inflammation in the males
      17    of the nasal cavity.   
      18                  (A short break was taken.)
      19                  CHAIRMAN FROINES:  Let's call it back to
      20    order.  So we're going to go through propylene and then
      21    give whatever concluding remarks you want to make.  
      22                  DR. MARTY:  Right.  
      23                  DR. FUCALORO:  The responsible people are
      24    already here.  
      25                  DR. MARTY:  In this study a no observed 

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       1    adverse effect level was not identified.  So we started
       2    with the lowest observed adverse effect level which is
       3    about 5,000 ppm.  The temporal adjustments result in an
       4    average experimental exposure of 890 ppm for the LOAEL
       5    group.  
       6                  We then applied the human equivalent
       7    concentration adjustment for a gas with extrathoracic
       8    respiratory effects -- basically upper airway effects.  
       9                  The regional gas dose ratio was 0.2 based
      10    on the body weight of a rat of 3.5 grams and then a
      11    volume of .2 on liters per minute, the surface area of 15
      12    square centimeters.  These would have been the ratio, of
      13    course, to the minute volume and surface area of the
      14    human.   
      15                  Since the exposure was a two-year rodent
      16    study, that's a lifetime exposure.  So we did not apply a
      17    subchronic uncertainty factor.  We had a LOAEL that we
      18    considered based on the EPA severity classifications to
      19    be of low severity.  So we used a LOAEL uncertainty
      20    factor of 3 because we had applied the human 
      21    equivalent --
      22                  CHAIRMAN FROINES:  Why is that considered a
      23    low severity?  
      24                  DR. MARTY:  In table -- I think it's 2 of
      25    the document, there is a description of severity

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       1    categories.  We followed those severity categories in
       2    deciding whether an effect was of low or moderate or
       3    severe.  Severe severity.  So this is from a USEPA
       4    document --
       5                  CHAIRMAN FROINES:  What page?  
       6                  DR. MARTY:  Page 18.  I'm sorry.  The
       7    severity levels run from 0 to 10.  And anything that was
       8    below a severity level of 5 we considered a low severity
       9    effect.  So the hyperplasia and inflammation were
      10    considered of low severity.   
      11                  CHAIRMAN FROINES:  Well, Paul's here, but
      12    Witschi isn't.  I'm not sure I'd consider squamous cell
      13    metaplasia as -- what do you call it?  A --
      14                  DR. MARTY:  Low severity?  
      15                  CHAIRMAN FROINES:  Low severity.  
      16                  DR. MARTY:  Okay.  
      17                  CHAIRMAN FROINES:  I mean you're on your
      18    way to cancer, I think.  And that's the significance, the
      19    hyperplasia and metaplasia.  It's not just a noncancer
      20    finding.   
      21                  Anyway, let's not -- we can look at it a
      22    little bit more later.  
      23                  DR. MARTY:  Yeah.  Okay.  Because we had
      24    done the human equivalent concentration adjustment, we
      25    used an interspecies uncertainty factor of 3.  We applied

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       1    an intraspecies or interindividual variability
       2    uncertainty factor of 10.  
       3                  And the cumulative uncertainty factor then
       4    is 100.  So the chronic reference exposure level for
       5    propylene comes to 2 parts per million.  
       6                  DR. BLANC:  Why isn't it 900?  
       7                  DR. MARTY:  Why isn't it 900?  Because the
       8    3 is actually the half log.  So if you multiply the two
       9    of them together, you get 10.  3 is rounded from 3.14, I
      10    think.   
      11                  DR. FUCALORO:  It's 90.   
      12                  DR. BLANC:  Thanks.  Because I saw that
      13    throughout, and I was confused.  
      14                  DR. MARTY:  Right.  That's why.   
      15                  DR. BLANC:  There's a note somewhere in
      16    your general methods that clarifies that, I believe; is
      17    that right?  
      18                  DR. MARTY:  I think so.  If there isn't,
      19    we'll add one in.  
      20                  DR. ALEXEEFF:  There is.  
      21                  DR. MARTY:  So in summary the document
      22    describes the methodology used to develop the reference
      23    exposure levels.  We have proposed values for 40 out of
      24    the 120 substances that we've looked at.  
      25                  And these substances in this first batch

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       1    were selected based on -- primarily on emissions
       2    inventory information, toxicity information and relative
       3    importance to risk managers.  
       4                  We attempt to use a more consistent
       5    methodology than has been used either in California in
       6    the past or by USEPA in some instances to develop the REL
       7    values.   
       8                  Use of the tenfold defaults were adapted to
       9    intermediate threefold factors in some instances.  We
      10    have suggested adopting some of the USEPA RfCs.  
      11                  And finally, the overall methodology for
      12    OEHHA derived chronic reference exposure levels is fairly
      13    comparable to USEPA's reference concentrations.  
      14                  There are a number of research needs that
      15    we see and some of which were already mentioned.  The
      16    need to, first of all, develop more chronic RELs for
      17    additional chemicals of concern.    
      18                  It would be very beneficial to have better
      19    chronic toxicity data for some of these chemicals and
      20    better data and models to estimate the effective human
      21    dose.  
      22                  We really need to develop a consensus
      23    approach on the dose response modeling procedures such as
      24    the benchmark concentration.  
      25                  We were just trying to follow USEPA in

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       1    their development of the benchmark concentration
       2    methodology as they were applying them to their chronic
       3    RfCs.  And they had not yet reached consensus on certain
       4    aspects or assumptions in the models.  
       5                  And that is one of the reasons why you
       6    don't see more benchmark concentrations coming from
       7    OEHHA.   
       8                  And then, of course, lots of research needs
       9    to go into development of databased factors to replace
      10    the default uncertainty factors.  And we did already talk
      11    a little bit about that.  
      12                  The next steps in our process are to have
      13    the document reviewed by the Panel and address SRP
      14    comments and concerns and incorporate those changes.  
      15                  We also are running a concurrent public
      16    comment period right now, a 30-day public comment period. 
      17    So we will be looking at those comments, responding to
      18    them and incorporating any appropriate changes to the
      19    document.  We'll then bring the document back to the SRP
      20    for endorsement essentially.  
      21                  And finally, after the SRP concerns have
      22    been incorporated, then we would be able to release the
      23    final version.   
      24                  CHAIRMAN FROINES:  Gary?  
      25                  DR. FRIEDMAN:  John, do you plan to do what

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       1    you did for the acute -- what we did for the acute
       2    exposure levels and divide up the specific chemicals
       3    among us so that each of us gets a few to look at?    
       4                  CHAIRMAN FROINES:  Yeah.  If that's okay, I
       5    was going to propose that I pick which chemicals go to
       6    which person only -- if anybody has any things that they
       7    would prefer to do, should let me know.  But otherwise
       8    I'll pick sort of people's expertise and -- so I'll give
       9    you the ones that were more human-based.  
      10                  And Paul would have more respiratory and 
      11    things of that nature.  So we won't do that today.  I'll
      12    send an E-mail so we don't take the time to do it, if
      13    that's okay with everybody.  
      14                  And I assume that -- that we'll divide up
      15    between Tony and Roger the chemicals although there
      16    really is no exposure data in here.  So it's not entirely
      17    clear.  
      18                  DR. FUCALORO:  I've looked at the -- all
      19    the chemicals, and I have about 15 comments on some of
      20    the physical chemical properties.  Now, I don't know if
      21    you want to do it now.  
      22                  I think it -- it shouldn't take too long. 
      23    But then again, we are pressed for time.  Again, I have
      24    them outlined here.  
      25                  CHAIRMAN FROINES:  So it seems to me that

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       1    Roger and Tony's contribution would be more looking at
       2    the document from the standpoint of the methodology
       3    around the exposure issues and any dosimetric questions
       4    that they may want to address.  
       5                  I wanted to go back to propylene.  Is
       6    propylene a carcinogen?  Animal carcinogen?  
       7                  DR. MARTY:  I don't believe it has tested
       8    positive.  Andy?  
       9                  I know there is a concern that it could be
      10    metabolized to propylene oxide --
      11                  CHAIRMAN FROINES:  But the point is you're
      12    basing your endpoint on squamous cell metaplasia and
      13    hyperplasia.  You talk in your document about long-term
      14    carcinogenicity study in mice and rats.  And you don't
      15    give the results of that study.  
      16                  So that when you finish this document, you
      17    have a -- two paragraphs or one paragraph on the cancer
      18    study with no outcome.  So the reader doesn't know
      19    whether or not to say, "Why don't we just look at this as
      20    a carcinogen and forget the" -- "some of the pathologic
      21    changes or" --
      22                  DR. MARTY:  Yeah.  Okay.  We need to fix
      23    that.   
      24                  CHAIRMAN FROINES:  And you have a whole
      25    section in which you talk about propylene oxide as a

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       1    known carcinogen, experimental animals and so on and so
       2    forth.  So that this document could be a surrogate for a
       3    carcinogen discussion of propylene except you don't give
       4    us the results.  
       5                  DR. MARTY:  Okay.   
       6                  CHAIRMAN FROINES:  That's not a criticism. 
       7    It's just a -- 
       8                  DR. MARTY:  Yeah.  We got to fix that.  
       9                  DR. ALEXEEFF:  Yeah.  This is George.  It's
      10    not considered a carcinogen.  We'll clarify that in the
      11    document.  
      12                  CHAIRMAN FROINES:  Well, it's not
      13    considered a carcinogen?  Animal carcinogen?  
      14                  DR. MARTY:  Right.  
      15                  DR. ALEXEEFF:  No.  At this point --
      16                  DR. MARTY:  No.  It hasn't been positive in
      17    any animal studies.  
      18                  DR. ALEXEEFF:  But we'll clarify 
      19    whatever -- you know, we'll clarify that in the
      20    documents.  It raises the issue because this -- it would
      21    be the chronic level that would be the driver for chronic
      22    exposure, the chronic -- this number would be the driver
      23    not the cancer risk number.  
      24                  CHAIRMAN FROINES:  So that would be
      25    essentially a toxicokinetic argument that the GST is so

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       1    fast that the propylene oxide doesn't sit around and do
       2    anything but react with GST instead of DNA?  
       3                  DR. ALEXEEFF:  I think at this point it
       4    just might be an empirical argument -- whatever the
       5    studies are showing.  But we'll take a look at it.  
       6                  CHAIRMAN FROINES:  Because ethylene oxide
       7    is a IARC human carcinogen.  And all we've done is add a
       8    methyl group here.   
       9                  DR. MARTY:  Right.   
      10                  CHAIRMAN FROINES:  George, I have a
      11    question for you and Melanie for the September meeting
      12    when we take this up again.  So we'll take this up in
      13    September.  
      14                  EPA is about to test 2,800 high production
      15    volume chemicals.  And I've read the list of tests that
      16    they're going to do.  And what I'd like you to do, since
      17    you're doing acute and chronic and cancer, is to look at
      18    the tests that EPA is going to do and comment as to
      19    whether or not that data would be sufficient for the
      20    purposes of what you have done in these three documents.   
      21                  DR. ALEXEEFF:  Okay.   
      22                  CHAIRMAN FROINES:  And I have a bias I
      23    think by the way I'm asking the question.  But I think
      24    the danger is, if you do testing but you don't get the
      25    answers you need, you better look at your testing.  

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       1                  So it would be helpful if you looked at
       2    that.  Because I looked at two or three chemicals, and
       3    when you were finished, you would not have learned about
       4    the toxicity of the three chemicals I looked at as
       5    examples.  So it's an important issue it seems to me.  So
       6    thank you, Melanie.   
       7                  DR. MARTY:  You're welcome.  
       8                  CHAIRMAN FROINES:  Great.  Okay.  Paul
       9    Gosselin and Ruby Reed.  
      10                  Paul, I've just been handed the OEHHA
      11    findings.  That means that the Panel has not seen the
      12    OEHHA findings.  So Peter's going to hand those out now.  
      13                  MR. GOSSELIN:  What may be helpful is over
      14    the last couple of months, a lot of effort has been put
      15    in by Dr. Reed and my staff and the Panel.  
      16                  I'm making improvements to the document,
      17    incorporating new information that was received at the
      18    workshop we had, I believe, in January on the document. 
      19    And OEHHA had prepared findings based upon the November
      20    document, the original draft that was presented to the
      21    Panel.  
      22                  And this reflects the changes and additions
      23    and modifications to the document.   
      24                  CHAIRMAN FROINES:  Well, here's -- nobody's
      25    going to be able to read this before we go into this.  So

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       1    I think George or Melanie or whoever, you maybe want to
       2    comment on what's in this document for the Panel because
       3    the Panel hasn't had an opportunity to read the document,
       4    your findings.  
       5                  I mean not now.  Let's go through it, and
       6    you can come back later.  In the future we would rather
       7    this didn't happen.  The Panel should always be able to
       8    have the document ahead of time to read before coming to
       9    the meeting.  
      10                  MR. GOSSELIN:  What we wanted to do today
      11    was bridge off of -- even though November was a 
      12    long -- fairly long time ago, it was to focus in on the
      13    changes to the document that has occurred since then and
      14    focus on that.  And so with that, I would turn it over to
      15    Ruby.   
      16                  DR. REED:  As per mentioned, my focus would
      17    be to highlight the substantive changes that I've made
      18    since November.  But I was talking to Dr. Byus this
      19    morning.  And he thought it would be good for me to go
      20    over very briefly some key slides that I have presented
      21    in November.  
      22                  So I shall do that.  But accept my apology
      23    for not making copies of that for you because I was not
      24    planning for it.   
      25                  Methyl parathion is an organophosphate

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       1    insecticide.  
       2                  Next slide, please.  
       3                  It is readily absorbed through oral,
       4    inhalation and dermal routes.  The pharmacokinetic
       5    information that we have indicated that the absorption
       6    from oral and inhalation are fairly complete, and it's
       7    comparable.  We assume that it's at 100 percent.  
       8                  The distribution into various compartments
       9    in the body is fairly rapid.  In some of the data it
      10    indicated that within an hour or so.  And it crosses a
      11    brain barrier, and it crosses the placenta.  It can
      12    measure or detect methyl parathion in fetuses and also in
      13    the brain.  
      14                  Methyl parathion is activated into methyl
      15    paraoxon through oxidation.  And it's detoxified through
      16    dearylation and demethylation.  And it's excreted in the
      17    urine as paranitrophenol.  
      18                  Next slide, please.  Next slide, please. 
      19                  The measured key endpoint is neurotoxicity
      20    for methyl parathion.  And the observations that were
      21    made regarding its neurotoxicity are clinical signs and
      22    symptoms of cholinergic abundance and brain
      23    cholinesterase inhibition in addition to plasma and RBC
      24    cholinesterase inhibition and neurobehavioral effects and
      25    nerve degeneration demyelination.  

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       1                  It shows genotoxic potential that there is
       2    no clear evidence of oncogenicity in the chronic rodent 
       3    bioassays.  There's reproductive developmental effects as
       4    a result of methyl parathion treatment to experimental or
       5    lab animals.  
       6                  The key endpoints for reproductive
       7    developmental effects are reduction in pup body weight
       8    and pup survival and deviation from normal ossification
       9    in fetuses.  
      10                  Methyl parathion did not show any effect of
      11    delayed neuropathy.  It has some indication of
      12    suppressing the immune system although the database,
      13    especially a more recent study that I've added into this
      14    version, show that the effect or the potential for
      15    effecting the immune system seems to be weak.  
      16                  Methyl parathion also effects the
      17    hematological parameters, a decreased RBC, hemoglobin and
      18    hematocrit.  
      19                  Next slide, please.  
      20                  I will go right into reviewing the exposure
      21    assessment because in the highlight portion, where you
      22    have the transparencies, I will go more into the
      23    toxicological database especially in light of the new
      24    submissions that we've received in October.  So I will
      25    skip that part and then come back to it.  

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       1                  The exposure assessment was estimated based
       2    on the rice field application scenario.  In Colusa county
       3    the ambient air exposure monitoring conducted in Colusa
       4    county and also the off-site air measurement from rice
       5    field application, also 17 and 20 yards away from the
       6    application site.   
       7                  In our calculation of exposure, we
       8    routinely take into account the difference of body weight
       9    and breathing rate.  And this is sort of close to the
      10    RDDR calculation that Melanie was presenting in terms of
      11    adjusting for the breathing rate and body weight ratio. 
      12                  And in doing so then -- and children -- or
      13    infants and children in general would have higher
      14    exposure.  So we take that into account.  
      15                  However, at the end we do not make an
      16    adjustment of the uncertainty factor for interindividual
      17    differences.  So we're still using an uncertainty factor
      18    of 10 rather than 3.  I think Dr. Blanc mentioned this
      19    point too.  
      20                  That was something to be considered.  In
      21    addition, we also take into account the coexistence of
      22    methyl paraoxon in the air together with methyl
      23    parathion.  
      24                  And so in terms of the toxicity, relative
      25    toxicity between paraoxon and parathion, we look at the

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       1    acute toxicity data.  And that's the only data that we
       2    have.  It looks like within the animal studies comparing
       3    the LD50 and 50 percent cholinesterase inhibition would
       4    come up to be about four to about eightfold difference
       5    between the methyl parathion and methyl paraoxon, methyl
       6    paraoxon being more effective or more toxic in that
       7    sense.  
       8                  So we're applying the tenfold toxicity
       9    equivalency factor.  We're saying that methyl paraoxon
      10    can be ten times more toxic than methyl parathion.  
      11                  And so in the exposure calculation, we take
      12    that into account.  And in terms of the proportion
      13    between parathion and paraoxon, the monitoring data seems
      14    to indicate that in general there's about -- methyl
      15    paraoxon, about 25 percent of methyl parathion show up in
      16    monitoring data.  
      17                  Of course, there's a time factor.  I mean I
      18    think that ratio would change as degradation occurred
      19    more or prior to degradation.  But the data could only
      20    bring to us that point of 25 percent of methyl parathion
      21    compared to methyl paraoxon.  
      22                  So we take that into account too.  And in
      23    the document the absolved daily dose and seasonal daily
      24    dose and annual daily dose were calculated as such for
      25    the ambient air exposure and for the off-site 17 yards

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       1    exposure.  
       2                  Off-site exposure is not calculated per
       3    seasonal and annual exposures because it was considered
       4    that there is no such a scenario that a person would be
       5    right next to the field for a long period of time on a
       6    daily basis  
       7                  Next slide, please.  
       8                  In the risk characterization, the risk 
       9    of -- potential risk of methyl parathion is calculated
      10    based on nononcogenic effects.  Prior to consideration
      11    into this is sort of elaborated in the discussion about
      12    the discrepancies between the genotoxicity and the
      13    oncogenicity bioassays, where there's some indication of
      14    general toxic potential.  
      15                  But the two-year bioassays in rodents does
      16    not show a clear evidence of oncogenicity.  And so I will
      17    go a little bit into that in the -- highlighting the
      18    revision.   
      19                  But the risk is calculated as marginal
      20    exposure which is the ratio of no effect level divided by
      21    the exposure.  And the MOE in these slides apparently 
      22    have been changed because there's a change in acute NOEL
      23    from this version versus the one that I've used
      24    previously, and I will go over that too.  
      25                  Next slide, please.   

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       1                  In calculating the reference concentration,
       2    I show these equations in the document by way of
       3    explanation.  In the first equation, the exposure -- we
       4    calculate in general the exposure whether it's from
       5    animal studies or in humans.  
       6                  In general it's the concentration times
       7    intake rate.  And in this case, it's through inhalation
       8    exposure.  So the intake rate is breathing rate per body
       9    weight.  
      10                  This is similar to oral exposure.  For
      11    example, you have concentration times and intake rate if
      12    it's through dietary intake, how much people eat -- in
      13    this case how much people breathe.  
      14                  So using that equation to solve the
      15    concentration, trying to figure out the reference
      16    concentration, it would be to determine what exposure
      17    level that will be acceptable and then back calculate
      18    using the same equation.  
      19                  So therefore, it's expressed in the second
      20    equation.  So the reference exposure will be the no
      21    effect levels divided by the margin of exposure that one
      22    would consider as health protected.   
      23                  And I'm writing out this equation in the
      24    third equation using the consideration for body weight
      25    and breathing rate in that sense.  

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       1                  Is there any question before I go into 
       2    the -- highlighting the changes?  
       3                  (No response.)
       4                  DR. REED:  Okay.  In the following slides,
       5    I will highlight the changes that I made since last
       6    November.  And as I said, one measure addition or
       7    revision to the document will be because we have four new
       8    studies.  
       9                  Next slides, please.   
      10                  I would only focus on changes that actually
      11    impact the final conclusion of this document.  Well,
      12    first of all, we have replaced the Roman numeral headings
      13    at the request of Dr. Byus.  So there is no more section
      14    VII, VII.  It's all in numbers now.   
      15                  I mentioned that there's four new studies. 
      16    There was a chronic rat toxicity study from which I have
      17    derived a chronic NOEL of 0.02 milligram per kilogram
      18    day.  That one had not been changed.  
      19                  However, there's a submission of a
      20    reevaluation of that study, rereading of these slides in
      21    the tease nerves.  The reevaluation did show that there's
      22    a higher -- much higher incidence in the controls and,
      23    therefore, makes it hard to tell where the NOEL is.  
      24                  However, we reviewed the study.  And we
      25    judged that the reevaluation of the pathological

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       1    preparations was really not according to the standard
       2    reevaluation procedure in that following the NTPs
       3    recommendation or the procedure that they follow.  
       4                  You would have to convene at three -- a
       5    Panel of three pathologists.  And the pathologists would
       6    have to read the slides blind.  This is not the case with
       7    the reevaluation.  
       8                  So we have not accounted for that.  And we
       9    retain the original no effect level that shows in the
      10    previous version.  So there was no change in the final
      11    conclusion based on that summation.  
      12                  DR. BLANC:  You're talking about the table
      13    neurohistopathological findings?  
      14                  DR. REED:  Yes.  Table 6.  Yes.  Thank you.  
      15                  DR. BLANC:  And when you -- on these page
      16    citations are going to be the page citations from the old
      17    document, not from the new document?  
      18                  DR. REED:  It should be the new document. 
      19    Oh, it's page 50, not 51.  
      20                  DR. BLANC:  Page 50.  And table 5 obviously
      21    doesn't follow table 6.  
      22                  DR. REED:  You're right.  I'm sorry about
      23    that.  I apologize.  Yeah.  I must be following one of my
      24    drafts.  I apologize for that.  
      25                  DR. BLANC:  I just wanted to make sure I

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       1    was understanding which table you were referring to.  
       2                  DR. REED:  Yes.  That's good.  And there is
       3    also a submission of one-year chronic dog study.  The
       4    data I've presented in table 5 which is on page --  
       5                  DR. BLANC:  48.  
       6                  DR. REED:  48, yes.  Thank you.  And that
       7    did not result in any change in the final conclusion
       8    either.   
       9                  The acute neurotoxicity study does.  And
      10    the table or the data that I have is in table 20.  Now,
      11    I'm not sure if the page number is correct.  
      12                  DR. FRIEDMAN:  Excuse me.  I think the page
      13    numbers refer to the text that describes the table.  
      14    So -- not where the table is.  So I think -- 
      15                  DR. REED:  Thank you very much.  Yeah.  I
      16    appreciate that.  I don't even remember what I did
      17    myself.  I appreciate that.  
      18                  But yeah.  Paul is right.  I should have
      19    also included the page number for the tables.  Yeah.  I
      20    apologize.  
      21                  In the acute neurotoxicity study, if you
      22    look at the database in table 20, it's fairly clear that
      23    you're seeing quite a bit of effect.  There is essential
      24    effect of 7.5 milligram per kilogram day.  
      25                  I have in the document discussed about

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       1    whether there is a possibility of raising -- or the real
       2    NOEL might be higher than 0.025 because of the 300-fold
       3    difference between the NOEL and LOEL.  
       4                  But this had to be looked at also in the
       5    context of the fact that, if you look at the
       6    demyelination data, it looks like there's some appearance
       7    in increase in incidence of 0.25.  
       8                  However, in general, a neuropathologist
       9    would consider this as not an effect because of the way
      10    that it's difficult to read these slides and come to a
      11    clear conclusion when you have such marginal effects.  
      12                  This is when I talk to people who are more
      13    experienced.  This is how I was told.  There seem to be
      14    no great difference in opinion between a USEPA and our
      15    review people in that sense.  
      16                  But in terms of how firm that NOEL is, I
      17    think both factors had to be taken into account, the
      18    distance, the 300-fold distance between NOEL and LOEL but
      19    also sort of marginal indication that something is going
      20    on here at 0.025.  
      21                  This one does change the final conclusion,
      22    and I will go a little bit into that in the next slide. 
      23    But let me go through this slide first.  
      24                  The subchronic neurotoxicity did not change
      25    the final conclusion in terms of overt toxicity. 

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       1    However, it does have a new NOEL for blood cholinesterase
       2    inhibition.  And I will go over that again about
       3    cholinesterase inhibition endpoints.  
       4                  Next slide, please.  
       5                  As I said, the acute neurotoxicity study
       6    now would have the new NOEL for acute endpoints.  In the
       7    previous version I have the NOEL as 0.1 milligram per
       8    kilogram day.  
       9                  And that was estimated based on
      10    extrapolating from LOEL to NOEL using an uncertainty
      11    factor of 10.  And it is more uncertain.  In this case
      12    0.025 milligram per kilogram days now used to calculate
      13    the risk.  
      14                  In the revision, one of the key additions
      15    to the presentation is the inclusion of plasma, RBC
      16    cholinesterase as an endpoint and then, of course, the
      17    inclusion of the NOELs based on these two endpoints. 
      18                  And so what I did was I went back to the
      19    database and made sure that I had all the statistical
      20    analysis added to it.  Since it's going to be used as an
      21    endpoint.  And so that was revised in -- especially
      22    tables 4 and 5, the subchronic and chronic.   
      23                  You notice that in the chronic table in
      24    table 5, there's more data than what I have presented
      25    before even though there is no more studies.  The reason

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       1    I'm adding more data to it is because in chronic toxicity
       2    studies, there's lots of interim measurements of
       3    cholinesterase activities.  
       4                  And so I went and extract those numbers out
       5    too so that I could use it to gauge the subchronic NOELs
       6    for plasma and RBC cholinesterase inhibition.  So the
       7    table got longer.  And we have more information, and it
       8    makes the estimation of NOEL more supportive.   
       9                  NOELs were determined for acute subchronic
      10    chronic exposure durations for the two new endpoints. 
      11                  Next slide, please.  
      12                  I've also added two new sections to it
      13    because of the neurotoxicity and because of the
      14    importance of the endpoint that would impact the
      15    conclusion.  
      16                  I've pulled out the two neurotoxicity
      17    studies that are published in the open literature and
      18    then add the two newly submitted studies and created
      19    Section 13.  
      20                  I've also added a discussion on endocrine
      21    disruption potential methyl parathion in Section 17.  I
      22    would just go over briefly on that subject to say that
      23    the current database would suggest that there is a
      24    possibility of endocrine disruption potential with methyl
      25    parathion.  

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       1                  However, the method for testing -- the sort
       2    of ways to assess endocrine disruption potential has been
       3    other discussion.  And there's still some sort of issues
       4    that people cannot so far come to some consensus about
       5    it.  
       6                  I think we're moving along in the right
       7    direction.  We're not there yet to have a thorough
       8    evaluation of the endocrine disruption potential of a
       9    chemical.  
      10                  However, a couple of things that are
      11    important.  One is that, if you look at the reproductive
      12    and developmental effects and if you've seen some of
      13    these effects, one could say, "Well that is an indication
      14    of endocrine disruption potential."  But not necessarily. 
      15    It depends on the mechanism by which these effects
      16    occurred.  
      17                  For example, delayed ossification.  I'm not
      18    sure what to call it -- whether it's an indication of
      19    endocrine disruption potential.  And that's why -- and
      20    that's why -- so far people are still trying to think of
      21    this whole issue in terms of how are we going to define
      22    mechanism in order to make a thorough determination.  
      23                  The other thing encouraging is that for
      24    study guidelines, in the past for developmental toxicity
      25    studies -- I'm sorry.  Excuse me.  Reproductive toxicity

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       1    studies.  There is not an emphasis on male, female
       2    reproductive type of effect that could provide
       3    information for endocrine disruption potential. 
       4                  And the new protocol for reproductive
       5    studies would put a lot more emphasis on that.  So in the
       6    future we might begin to see something that we could use
       7    for this purpose.  
       8                  I have expanded discussions mostly in four
       9    areas.  One is to address the disparity between the
      10    genotoxic potential and the oncogenicity -- negative
      11    oncogenicity evidence.  
      12                  And Dr. Byus and I talked about this.  And
      13    we thought it would be good to add a discussion on the
      14    possibility of the study protocol that have been used for
      15    years in rodent studies in which rodents can eat whatever
      16    amount of food they want.  
      17                  And it constitutes sort of an overfeeding 
      18    situation.  And actually, many problems come out of
      19    overfeeding in rodents -- shortened life span, increase
      20    in body weight and an increasing incidence of some
      21    spontaneous tumors and also shorten the latency of some
      22    spontaneous tumors.  
      23                  And so I edited a discussion for that. 
      24    However, looking at -- specifically at methyl parathion
      25    database, there's not a clear correspondence between the

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       1    change of body weight at the high dose and the incidences
       2    that were seen or not seen at the high dose.  However,
       3    there is a discussion on that.  
       4                  Another expansion that I edited was a
       5    discussion about cumulative exposure.  And this is not
       6    just as an issue under Food Quality Protection Act.  But
       7    it is known that more than one OP had been present in our
       8    environment.  
       9                  And since OPs generally have the same
      10    mechanism of toxicity at least for cholinergic toxicity,
      11    this is an important issue.  So I edited a discussion on
      12    that sort of -- not qualitative assessment but
      13    quantitatively express how possible or how probable the
      14    scenario would exist.  
      15                  And actually, I was still working on this
      16    last night.  And Craig and I were talking about this this
      17    morning.  And we would like to add another sort of
      18    additional -- sort of evidence that might affect the way
      19    people look at the monitoring program.  
      20                  And I would just go ahead and read to you
      21    right now.  What I have here is something to add to page
      22    124 -- at the end of the first paragraph of page 124. 
      23                  "Data are not available for showing the
      24                  presence of multiple OPs in the air
      25                  because samples have not been routinely

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       1                  analyzed for more than one pesticide. 
       2                  However, the occurrence of OPs is
       3                  evident in foods.  Nationwide, USDA
       4                  pesticide data program or PDP has the most
       5                  extensive data on pesticide residues in
       6                  agricultural commodities."
       7                  The program is designed specifically for
       8    generating data risk assessment, and samples are analyzed
       9    for multiple OPs.  The PDP data show that of the
      10    commodities sampled in California during 1995 and 1996,
      11    peach had a high frequency of methyl parathion detection
      12    in a total of 177 samples during these two years.  
      13                  Approximately 80 percent of the 47 samples
      14    that showed a detected amount of methyl parathion contain
      15    two to four OPs.  
      16                  And so we thought it strengthened the
      17    discussion or the presentation of the reality of multiple
      18    OP exposure.  
      19                  And the Panel might want to consider
      20    something of that, about the sample monitoring program,
      21    to send samples through multiple OP screen instead of
      22    just analysing for one OP at a time.   
      23                  I have also edited a paragraph on the
      24    limitation of the exposure data that we model for this
      25    assessment.  I think it was ARB who brought up this

                 BARNEY, UNGERMANN & ASSOCIATES  1-888-326-5900


       1    subject in that especially for the off-site exposure, the
       2    exposure assessment model after the application scenario
       3    to the rice field.  
       4                  And it was noted that the rice field
       5    application rate -- maximum application rate to rice is
       6    not the highest application rate for methyl parathion. 
       7    Stone fruits would have, I think, maximum of three pounds
       8    of active ingredient per acre.  While the rice
       9    application is only .75 pounds.  
      10                  However, a quantitative comparison cannot
      11    be made because there are different formulations.  In
      12    general the stone fruits would use microencapsulation
      13    formulation where the rice would use emulsifier for
      14    concentrate.  
      15                  So we don't know how to sort of bridge the
      16    two and say that one would be higher than the other. 
      17    However, that was pointed out in terms of the difference
      18    in application rate that the rice application is not the
      19    highest application rate scenario and also the
      20    dissipation may be different from the water versus the
      21    air.   
      22                  In this document, I've also added in places
      23    where USEPA's reregistration eligibility decision
      24    document, RED document, their decision -- or the decision
      25    pertaining to both the NOEL selection and also their

                 BARNEY, UNGERMANN & ASSOCIATES  1-888-326-5900


       1    consideration for uncertainty factors.  
       2                  One key consideration for uncertainty
       3    factors is the additional safety factor to protect
       4    infants and children based on the possibility of a higher
       5    sensitivity for free and postnatal exposures.  And USEPA
       6    is currently asking for developmental neurotoxicity
       7    study.  
       8                  And they felt at this time, before the
       9    study comes in, that they should go ahead and implement
      10    the FQPA's safety factor of 10.  And that is in addition
      11    to the 10 -- factor of 10 for interindividual differences
      12    factor of 10 for interspecies differences.  
      13                  DR. FUCALORO:  So this has the 
      14    consequence -- I'm sorry.  I was out.  This has the
      15    consequence of bringing the threshold for a designation
      16    of a TAC and an MOE -- using an MOE, if that's in fact
      17    the way to do it, from 100 to 1,000?  Is that -- is that
      18    as you understand it?  
      19                  DR. REED:  It's --
      20                  MR. GOSSELIN:  It's adding an additional 10
      21    uncertainly factor.    
      22                  DR. FUCALORO:  And this would be for any
      23    pesticide or for just the ones that have this --
      24                  MR. GOSSELIN:  They have generally two
      25    areas.  One is under the log.  And it's a judgment call. 

                 BARNEY, UNGERMANN & ASSOCIATES  1-888-326-5900


       1    In the absence of data, they can make that call on a case
       2    by case basis or, if data supports, adding an uncertainty
       3    factor.  
       4                  DR. FUCALORO:  And you're invoking that
       5    uncertainty factor in this case?  
       6                  MR. GOSSELIN:  No.  EPA is.  
       7                  DR. FUCALORO:  No.  But I mean -- oh, I
       8    see.  But there is -- you said it's a judgment call. 
       9    Would you have -- 
      10                  MR. GOSSELIN:  Yeah.  We have judgment
      11    call.  Mostly it's been based upon what the data shows.  
      12                  DR. FUCALORO:  So in this particular case,
      13    methyl parathion, you're invoking it and making -- is
      14    that correct?  Or am --
      15                  DR. REED:  I did not make that conclusion
      16    in the document because I considered that as sort of a
      17    policy decision and the risk management decision.  So
      18    Paul might want to comment on that whether at the end our
      19    department would --  
      20                  MR. GOSSELIN:  Yeah.  This is -- I think
      21    with some of the discussion here about -- we've pretty
      22    much historically stuck with standard defaults of 10 and
      23    10.  
      24                  And we've gotten into internal discussions
      25    about when do we deviate from that similar to the

                 BARNEY, UNGERMANN & ASSOCIATES  1-888-326-5900


       1    discussion you've heard from OEHHA on some of 
       2    the -- particularly the acute document about severity of
       3    effect and other things that may be seen in the studies.  
       4                  A lot of that's going to have to be
       5    developed in policy because what we want to avoid is
       6    having far reaching subjective calls on having us go too
       7    far afield.  
       8                  But we have seen probably some cases in
       9    some risk assessments coming up where some of the
      10    uncertainty default factors may not be totally
      11    appropriate.  Some of this comes out depending upon the
      12    discussion that comes out, the reviews and the studies
      13    about the likelihood of needing an additional factor. 
      14                  But right now we haven't formally developed
      15    a policy on how to do that and what those factors would
      16    be.  
      17                  DR. FUCALORO:  But in some sense this is a
      18    moot point in this particular case; right?  Since the
      19    MOEs we're talking about are under 100, as low as 20, it
      20    would meet that standard regardless of whether the extra
      21    factor of 10 were incorporated or as our illustrious 
      22    chairman said -- perhaps even another factor of 10 should
      23    be added.  But in any event, it does meet that standard.  
      24                  MR. GOSSELIN:  Yeah.  I think for the
      25    criteria for listing it would -- the data does show

                 BARNEY, UNGERMANN & ASSOCIATES  1-888-326-5900


       1    regardless of additional factors that it's there.  But I
       2    think beyond that, the discussion that comes out of here
       3    and the issues that are raised from the Panel are then
       4    going to be important for us as we go forward the next
       5    step, after it's listed, as to what management steps we
       6    take to deal with air exposures.   
       7                  CHAIRMAN FROINES:  Let me make a comment
       8    about this because I think this -- we're touching on an
       9    important issue.  If you go to USEPA or IARC, IARC 
      10    has -- and EPA have a criteria for a carcinogen A, B2,
      11    B1, et cetera.  Probable, possible, so forth.  
      12                  So there are criteria on levels of
      13    evidence.  So in terms of making qualitative decisions
      14    that people have made some judgment about the evidence
      15    for carcinogenicity and they then ranked that substance
      16    on that basis, that's an important qualitative statement. 
      17                  The law that we have says the food and
      18    agricultural code defines toxic air contaminants as air
      19    pollutants that may cause or contribute to an increase in
      20    mortality or an increase in serious illness or that may
      21    pose a present or potential hazard to human health.  
      22                  So that clearly has a qualitative element
      23    to it as well as a quantitative one.  The problem we have
      24    here is that there is -- in my view, my own prejudiced
      25    view, an overemphasis on what is a semiquantitative

                 BARNEY, UNGERMANN & ASSOCIATES  1-888-326-5900


       1    approach, the approach we've been talking about today,
       2    quantitative approach.  
       3                  And the problem with it is this discussion
       4    about uncertainty doesn't really get taken into account
       5    because we're driven by the MOE calculation.  
       6                  And it seems to me that in defining a
       7    substance as a toxic air contaminant, it is a serious
       8    underestimation of the potential health risk of a
       9    chemical by only basing it on an MOE which oversimplifies
      10    so many determinations about potential health effects and
      11    uncertainties associated with them that we end up missing
      12    some of the richness of the data about health effects for
      13    this specific calculation.  
      14                  And so that he's talking about -- EPA is 
      15    talking about a safety factor of 10.  And you say -- and
      16    he acknowledges -- it doesn't matter.  Even though --
      17                  MR. GOSSELIN:  Well, what I'm saying is it
      18    does matter.  
      19                  CHAIRMAN FROINES:  No.  It doesn't matter
      20    in this determination, the way it's currently
      21    established.  And I hope we can change it.  The way it is
      22    now is EPA thinks that there is a health outcome,
      23    neurobehavioral effects in children and so on and so
      24    forth.  This is an important health outcome, and in this
      25    consideration it is not taken into account.  

                 BARNEY, UNGERMANN & ASSOCIATES  1-888-326-5900


       1                  It sits there and hits you in the face and
       2    Ruby correctly puts it in the document as an issue.  But
       3    in terms of the decision making, it's not -- it's not
       4    considered.  And that's just fundamentally wrong, I
       5    think.  
       6                  I think that you can't ignore scientific
       7    data about potential health effects.  It just doesn't
       8    make any sense to anybody.  If you try to explain it to
       9    the average citizen, they'd say, "What?  Are you crazy?  
      10    If it causes neurobehavioral effects in children, of
      11    course you should consider it."
      12                  But we are wedded to the MOE.  And so that
      13    locks us in.  
      14                  DR. FUCALORO:  Well, I think you point to a
      15    broader problem.  I don't mean to take us too far afield. 
      16    I believe that -- I'm relatively new to this Panel.  But
      17    I believe we've had this discussion regarding what
      18    criteria does -- what criteria does SRP use in
      19    recommending designation -- whether or not we should
      20    recommend is another issue -- designations of TAC.  
      21                  With the Air Resources Board we 
      22    essentially -- and I believe, John, this was your 
      23    point -- looked at toxicity alone, not exposure but just
      24    toxicity in which case this would be a different report. 
      25                  But with the Department of Pesticide

                 BARNEY, UNGERMANN & ASSOCIATES  1-888-326-5900


       1    Regulation, its toxicity folded into exposure.  I mean
       2    that's what an MOE is.  And so this is essentially a
       3    different type of recommendation based not only upon
       4    methyl parathion, which appears to be a very potent
       5    toxin, but we also have to -- we also have to compare it
       6    to the availability in the environment, that is to say,
       7    exposure. 
       8                  So I think it is a difference.  What you
       9    are arguing for here -- it seems to me -- is that the
      10    toxicity -- it's what you've argued before.  That the
      11    toxicity should be viewed independently of exposure and
      12    then exposure brought in for purposes of mitigation; do I
      13    have you right?  
      14                  CHAIRMAN FROINES:  Yeah, absolutely.  And I
      15    think that there's another point which is in you and
      16    Roger's area.  When you go look at the amount of exposure
      17    assessment that has been done upon which we base these
      18    decisions, it's vanishingly small.  
      19                  It is a trivial amount of exposure
      20    estimation.  And so we have years and years and years and
      21    years of methyl parathion use.  And then we have this
      22    little tiny database.  And we say, "Oh, well, that's what
      23    we're going to use to define whether or not this is a
      24    TAC."
      25                  Well, it just doesn't make any sense.  I

                 BARNEY, UNGERMANN & ASSOCIATES  1-888-326-5900


       1    mean if we went out and did monitoring on a continuous
       2    basis the way the Southcoast Air Quality Management
       3    District does and we handled scads of data, then we would
       4    say, well, we have a quite adequate database.  
       5                  But when we make major decisions on whether
       6    a substance is a toxic air contaminant based on the
       7    amount of data that we have on air monitoring, we are
       8    really taking the chance that people would be injured as
       9    a result if we choose to go forward.  
      10                  MR. GOSSELIN:  Everything you described we
      11    agree with.  The uses change in a very dynamic way over
      12    years.  The monitoring we have is a very small slice
      13    snapshot of what's really occurring out there.  
      14                  I think historically the way the documents
      15    have been written, have been written in broad risk
      16    assessment methodologies for risk managers in the
      17    department to make decisions. 
      18                  The document coming before the Panel is
      19    going to have to change.  And we've made commitments to
      20    making the change to reflect what the 1807 process really
      21    speaks to.  And I think the data -- and particularly on
      22    the toxicity -- the hazard assessment is fairly
      23    extensive.  And you can just take a look at the size of
      24    the volumes that just sort of illustrates that.  
      25                  And it's fairly rich and well thought out. 

                 BARNEY, UNGERMANN & ASSOCIATES  1-888-326-5900


       1    One of the things that we're sort of bound with right now
       2    is the way -- rightly or wrongly -- the way regulations
       3    were written that sort of guides the director in how 
       4    to -- whether to list or not.  And it is sort of MOE-type
       5    based.   
       6                  That might be something we might want to go
       7    back and revisit and come up with a change on clarifying
       8    how the process is more consistent across the board.  
       9                  But with that, we're still sort of in a
      10    transition taking this document and in particular how it
      11    was crafted and having this go through the process and
      12    still make the changes to make our process more
      13    consistent with what you're used to working with ARB and
      14    OEHHA.  
      15                  DR. FUCALORO:  I think you're correct.  I
      16    think the regulations with DPR actually force you into
      17    looking at exposure.  And perhaps it would be wise -- if
      18    John Froines is correct, and I suspect he is -- that we
      19    should be looking at toxicity.  
      20                  And what comes before us is -- at least
      21    from the ARB, is -- are the chemicals they've decided to
      22    target for consideration.  And that -- and the criteria
      23    to choose those chemicals comes in part from exposure,
      24    how much is out in the environment.  
      25                  So they decide to bring something before us

                 BARNEY, UNGERMANN & ASSOCIATES  1-888-326-5900


       1    that has some concentration out there in the environment. 
       2    And so I think that's perhaps the wisest way to go.  
       3                  MR. GOSSELIN:  Yeah.  And in the larger
       4    context, the monitoring data probably only indicates the
       5    likelihood of the material to get into the air.  To base
       6    firm conclusions on telling the whole story I think would
       7    be a leap.  
       8                  So I think in the broad context, 
       9    leaving -- let's say leaving the 1807 process and having
      10    something listed is sort of largely based on a real
      11    thorough evaluation of the toxicity and sort of the
      12    viewpoint from the data whether the material has the
      13    likelihood to get into air that then would -- similar to
      14    what the districts look at -- a more focused closer
      15    examination as to what exposures are and whether they do
      16    specifically pose health risks.   
      17                  DR. FUCALORO:  Just one more thing for
      18    purposes of accuracy.  George, should I have been saying
      19    OEHHA instead of ARB when I've been using this
      20    designation of TAC's -- ARB was the correct -- correct
      21    designation?  Thank you.  
      22                  DR. REED:  With that, I would just like to
      23    summarize or highlight the conclusion of this assessment
      24    both in terms of the calculated margin of exposure and
      25    also the reference concentration.  

                 BARNEY, UNGERMANN & ASSOCIATES  1-888-326-5900


       1                  If you would turn with me to page 116,
       2    table 29, it summarizes the -- Keith?  There's
       3    transparencies there, I think.  I think it's easier for
       4    you to read it from your document than looking at the
       5    transparencies of a page like this.   
       6                  It has the listed NOEL and also the margin
       7    of exposure.  And I've highlighted the columns for
       8    children six years old because the exposure is higher
       9    because of the higher breathing rate per body weight
      10    basis.  
      11                  And I also have highlighted the seasonal
      12    NOEL of 3 microgram per kilogram day and also 20
      13    microgram per kilogram day.  And then chronic 20
      14    microgram per kilogram day based on brain cholinesterase
      15    inhibition.  
      16                  Those three numbers were estimated NOEL. 
      17    They are not determined from the study.  They're
      18    estimating from LOEL because a NOEL cannot be determined
      19    from these studies.  
      20                  And these studies show a lower NOEL than
      21    other studies.  So you sort of cannot ignore these
      22    endpoints.  And so I used the default extrapolation
      23    factor of 10 to go from LOEL to NOEL.  In a sense, these
      24    values would be less certain or have greater uncertainty.  
      25                  However, I wanted to point out that the 20

                 BARNEY, UNGERMANN & ASSOCIATES  1-888-326-5900


       1    microgram per kilogram day for seasonal NOEL, though it
       2    was extrapolated, you notice that it's also the same NOEL
       3    as the chronic NOEL for neurotoxicity in hematological
       4    effects.  
       5                  And that was determined from two chronic
       6    toxicity studies.  All came up with the same NOEL.  So I
       7    would consider that as fairly consistent.  
       8                  Besides the fact that for seasonal marginal
       9    exposure calculation, we're using subchronic NOELs, and
      10    that usually is up to, like, three month or four month or
      11    so in terms of study period.  
      12                  However, in the exposure assessment, it was
      13    concluded that a season of exposure to methyl parathion
      14    could actually be prolonged and extended to about nine
      15    months.  And so it's reasonable to use the same -- or at
      16    least the NOEL in the same range as the chronic NOEL.  
      17                  So even though that 20 for the subchronic
      18    was extrapolated, I think it's fairly consistent and have
      19    certainties in it, not just uncertainty because of
      20    extrapolation.   
      21                  The chronic NOEL of 20 microgram per
      22    kilogram day for brain cholinesterase was also
      23    extrapolated.  However, that is not the only endpoint
      24    that is used as a basis for that 20 microgram per
      25    kilogram day.  So the uncertainty does not quite impact

                 BARNEY, UNGERMANN & ASSOCIATES  1-888-326-5900


       1    the final certainty of that value of 20.  
       2                  As Tony mentioned, there is marginal
       3    exposure that are below a thousand.  In this case the
       4    acute ambient exposure and also the off-site exposure. 
       5    And there's 150 for the seasonal and 670 for the chronic
       6    using RBC cholinesterase as an endpoint.  
       7                  Next slide, please.  
       8                  Please turn with me to table 30 in page
       9    126.  It presents the reference concentration that I
      10    calculated using the same NOELs for different endpoints,
      11    plasma, RBC, brain cholinesterase and also neurobehavior,
      12    neuropathy effects.  
      13                  The far right columns takes into account
      14    the coexistence of methyl paraoxon based on the toxicity
      15    equivalency factor of 10 for methyl paraoxon.  I've
      16    highlighted the NOEL again for the seasonal exposure
      17    based on plasma cholinesterase inhibition because that
      18    one was the estimated NOEL and so that the subsequent
      19    calculation into 1 ppt for the reference concentration
      20    would have less certainty or greater uncertainty in it. 
      21                  That's all that I have to present.  If
      22    there's any question, I'll be happy to address that.  
      23                  CHAIRMAN FROINES:  Why don't we start out
      24    with the two lead persons now.  What time is it?  
      25                  DR. BYUS:  12:07.  

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       1                  CHAIRMAN FROINES:  12:07.  I think what we
       2    should do is go for a while.  And if it looks as though
       3    it's going to go longer, we'll break for lunch.  
       4                  But for now let's -- unless somebody feels
       5    at this point that they're sufficiently hypoglycemic that
       6    they want to break for lunch now.  
       7                  DR. FRIEDMAN:  Could we do it, say, at
       8    12:30 or --
       9                  CHAIRMAN FROINES:  Yeah.  That's what I was
      10    thinking.  So Tony is the lead on exposure.  And Craig is
      11    the lead on health.  And so why don't we start with Tony.  
      12                  DR. FUCALORO:  Yeah.  I should be very
      13    brief.  We've had discussions on this.  And actually, I
      14    thought we pretty much completed our work last time.  
      15                  The -- I guess we want clarification on the
      16    hydroxyl radical hydroxy irons.  I mean that's no big
      17    deal.  And then the -- although I was corrected, I think
      18    in the main body it was not corrected specific gravity as
      19    units on -- I know it's a hobbyhorse of mine.  But I
      20    think we want to make it clear.  
      21                  I talked about the MOEs I hope to
      22    everyone's satisfaction at least to mine -- to my
      23    satisfaction, and I can support this portion of the
      24    report as written.  
      25                  DR. REED:  Thank you.  And I will make sure

                 BARNEY, UNGERMANN & ASSOCIATES  1-888-326-5900


       1    that those things are clarified and changed in the
       2    document.   
       3                  CHAIRMAN FROINES:  Have you, Tony, had a
       4    chance to look at the findings?  
       5                  DR. FUCALORO:  Yes.  
       6                  CHAIRMAN FROINES:  So we'll come back to
       7    that, I guess.  
       8                  DR. FUCALORO:  Yeah.  And in fact, a lot of
       9    the questions I had with the MOEs had to do with those
      10    findings.  And I've been pretty -- this is the SRP
      11    findings we're talking about --
      12                  CHAIRMAN FROINES:  Yes. 
      13                  DR. FUCALORO:  Yes.  
      14                  CHAIRMAN FROINES:  So everybody's seen the
      15    findings at this point.  
      16                  DR. FRIEDMAN:  The ones that were handed
      17    out?  
      18                  DR. FUCALORO:  No.  That was the DPR.  
      19                  DR. BLANC:  Our findings, not 
      20    the -- a proposed text of our findings, not the --
      21                  CHAIRMAN FROINES:  That was sent 
      22    on June 10 --
      23                  DR. BLANC:  DOEH or whatever it's called. 
      24    COEH.  Whatever.   
      25                  DR. FUCALORO:  Actually, they 

                 BARNEY, UNGERMANN & ASSOCIATES  1-888-326-5900


       1    represent -- I just want to say.  They represent a 
       2    rather -- a large change from the original findings we
       3    had where the recommendation that we designate this
       4    material, the TAC, which originally based upon the cancer
       5    study.  The cancer studies I thought was bad.  Do I have
       6    that wrong or --
       7                  DR. REED:  Could it be DEF?    
       8                  DR. FUCALORO:  Was that DEF?  
       9                  DR. BYUS:  DEF.  You got them mixed up.  
      10                  DR. FUCALORO:  Maybe I did.  Okay.  But
      11    this, I think, had the right -- it was based upon the
      12    right set of data.  
      13                  DR. BYUS:  Let me give you -- the findings
      14    situation's a little confusing, and I'll clarify that for
      15    you.  Partially, it was my fault.  But I'll get back to
      16    it.  
      17                  I reviewed the document last time and asked
      18    Ruby to make a number of changes.  And she did it all
      19    quite well.  A couple of the issues that she's gone over,
      20    I'm pretty -- one is the genotoxicity data.  This
      21    compound looks likes it's genotoxic and should be
      22    oncogenic, and yet it's not.  
      23                  The animal studies -- I mean if you look at
      24    all the invitro genotoxicity studies, you would think
      25    that it would cause mutations in an animal and would

                 BARNEY, UNGERMANN & ASSOCIATES  1-888-326-5900


       1    cause cancer.  
       2                  Yet when they do these studies in animals,
       3    clearly multiple studies have been done -- long-term
       4    studies, high quality studies -- they don't see that as
       5    an endpoint.  
       6                  CHAIRMAN FROINES:  I don't agree.  
       7                  DR. BYUS:  Well, to me --
       8                  CHAIRMAN FROINES:  I'm going to strongly
       9    disagree.  I think it's very dangerous to use the word
      10    "clearly."
      11                  DR. BYUS:  Okay.  I use the word
      12    surprisingly actually.  I've put in the findings.  It's
      13    surprising to me that animal bioassays for tumors or
      14    carcinogen activity don't turn out more positive than
      15    they do.  
      16                  And one of the explanations I thought of,
      17    which she now incorporated into the document, was the
      18    effect on caloric restriction.  In some of these studies,
      19    the animals' weights changed markedly.  If the animal
      20    weights go down one -- if you're feeding something that's
      21    toxic, animal weights go down.  
      22                  One of the best ways to inhibit
      23    carcinogenicity or inhibit tumor formation is to
      24    calorically restrict an animal.  An animal loses weight
      25    significantly during a study.  This can markedly impede

                 BARNEY, UNGERMANN & ASSOCIATES  1-888-326-5900


       1    the formation of tumors and almost eliminate them by a
       2    mechanism that's not clear, worked quite well.  
       3                  Now, okay.  So in any case, that I think 
       4    is -- there is some controversy in that, at least in my
       5    mind.  
       6                  The second was the endocrine disruption
       7    potential.  There's a number of human studies out there
       8    where there's some indication there could be endocrine
       9    disruption.  And she put a very nice discussion of that
      10    in there.  The other thing was the multiple exposure
      11    issue of organophosphates, which she presented.  
      12                  I mean I think it's clear there's many
      13    organophosphates, licensed pesticides.  
      14    It's -- undoubtedly there is going to be some additivity. 
      15    Exactly how much isn't clear.  But based on the food data
      16    and the fact that there are -- even in Colusa County
      17    there are multiple organophosphates licensed and sprayed
      18    at the same time.  It's likely to be a higher exposure
      19    than we have.  
      20                  And then the other thing, of course, is the
      21    issue of the serum versus the red blood cell versus the
      22    brain cholinesterase discussion which we've had
      23    before -- which we haven't -- the Panel I don't think has
      24    discussed extensively.  We haven't really resolved this.  
      25                  It's a very complex issue.  I thought it

                 BARNEY, UNGERMANN & ASSOCIATES  1-888-326-5900


       1    was simpler than it was.  And the more I get into it,
       2    reading about it, the more complicated it becomes.  
       3    But -- so and then she incorporated as all the new
       4    changes with all the new data, and I concur with her
       5    interpretations.  
       6                  Now, about the findings, what I asked her
       7    to do was to draft a series of findings, DPR series of
       8    findings, based on the most recent version of DEF we had
       9    so that, when you are all reviewing the documents, you
      10    had something in front of you you could hang your hat on
      11    rather than trying to read through all the documents.  
      12    And that's what she did.  And I contributed to that -- to
      13    those findings.  
      14                  Now, in the meantime OEHHA, if you had
      15    remembered, had commented on the -- had provided us with
      16    findings way back in November.  But they actually haven't
      17    seen this document until -- the new document with all the
      18    new data until very recently.  So that's one of the
      19    reasons they couldn't get it to us until we showed them.  
      20                  So they took the findings that DPR and me
      21    contributed to, provided and now have given us another
      22    set of findings, which I assume they read what we had as
      23    well as the new document.  
      24                  So that's why there are now really sort of
      25    two sets of findings.  And we can do with them what we

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       1    want because they should be our findings, I believe, is
       2    the correct formula here.  
       3                  But I really wanted the Panel to have a set
       4    of findings from someone when they were trying to read
       5    through the document.  And that's really all I have to
       6    say.  
       7                  CHAIRMAN FROINES:  Roger?  
       8                  DR. ATKINSON:  I have some comments on the
       9    environmental section.  First of all, let me say that
      10    it's a much more detailed and thorough environmental
      11    section for methyl parathion than the DEF document -- I'm
      12    sorry.  
      13                  Comments on one is on page 4-1, which is in
      14    the introduction, the environmental fate.  And the line
      15    is sort of tossed out that methyl parathion is converted
      16    to methyl paraoxon.  And that appears elsewhere in this
      17    thing.  And undoubtedly it does.  I mean there are data
      18    in the literature, ambient data which show that.  
      19                  It would be real nice to see a little more
      20    detailed discussion somewhere, a paragraph maybe, of the
      21    ambient data just pointing out what was done and the
      22    observations.  So that one knows it wasn't done in a
      23    laboratory.  
      24                  It's in ambient measurements which show
      25    that you applied methyl parathion to a specific place and

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       1    down when -- maybe 15 minutes you see in the paraoxon.  
       2                  We really have no idea where that paraoxon
       3    comes from or which particular pathway leads to it.  Is
       4    it particle phase reactions of the methyl parathion, or
       5    is it a gas phase?  
       6                  And we have no idea.  And I don't think the
       7    literature gives you any hint to that.  And that I think
       8    should be pointed out.   
       9                  Let's see.  It would be also -- I would
      10    like to see another table very much like the one that's
      11    got the physical properties of methyl parathion.  Another
      12    one with methyl paraoxon because obviously that is
      13    involved in the toxicity.  
      14                  It would allow the reader to see that
      15    methyl paraoxon, I assume, is less volatile than the
      16    parathion.  And if the octanal water partition
      17    coefficient acquiesce solubility, et cetera, we've given
      18    and vapor pressure -- then that would be useful.  
      19                  On page 4-3, most of my other comments are
      20    on the next couple of pages.  On the atmospheric
      21    reactions, one thing it's labeled a nitrogenoxide
      22    radical, and it's the nitrate radical.  Maybe after that,
      23    you want to put in parentheses "No. 3" so that the reader
      24    would know. 
      25                  And then there's a bunch of stuff about

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       1    personal communication from somebody called Atkinson,
       2    which I assume was me many years ago, the -- those
       3    lifetimes called reconstants which then can be converted
       4    into lifetimes or can all be done off the literature. 
       5                  So literature reference can be given.  And
       6    I can provide you with one readily.  And anybody with the
       7    back of an envelope can crank through them.  So those
       8    could be put on maybe even a lifetime which would turn
       9    out to be about two hours, I believe of a typical OH
      10    concentration.  
      11                  Maybe note in even that during summertime,
      12    at noontime that could come down to less than an hour
      13    maybe.  But this is all guesswork anyway.  And maybe that
      14    should be pointed out as well.  So a little more detail
      15    on some of this part would be good. 
      16                  The other thing is, as I mentioned in the
      17    additions to this document, that there were two studies
      18    on degradation that were obtained but decided not to be
      19    used.  
      20                  But there's no references given, as far as
      21    I know, and maybe it would be nice to have a sentence or
      22    two describing what these particular studies were and
      23    what they showed.  Then stating, okay.  Well, it was a
      24    laboratory study and can't be moved into ambient or
      25    whatever.  And I think that's about it.  

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       1                  DR. REED:  Thank you.  
       2                  DR. ATKINSON:  And I can provide some
       3    detail -- I mean I can provide those comments in writing,
       4    if you want.  
       5                  DR. REED:  Okay.  
       6                  MR. GOSSELIN:  That's fine.  
       7                  DR. REED:  Yeah.  I think we --
       8                  DR. ATKINSON:  Okay.   
       9                  CHAIRMAN FROINES:  Peter?  Comments?  
      10                  DR. KENNEDY:  I have no additional
      12                  CHAIRMAN FROINES:  Gary?  
      13                  DR. FRIEDMAN:  I have no other comments.   
      14                  DR. BLANC:  Let me -- I have a few
      15    questions for you.  One, the issue of the oxide breakdown
      16    products/metabolites is ten times more toxic than the
      17    parent compound.  Is that on a milligram per kilogram
      18    basis or a molar basis?  
      19                  DR. REED:  Milligram per kilogram basis.  
      20                  DR. BLANC:  So therefore, when you do these
      21    corrections for combined ambient findings where both were
      22    found and both were reported in micrograms per cubic
      23    meter, everything works out okay; right?  
      24                  DR. REED:  Yes.  
      25                  DR. BLANC:  Okay.  Because otherwise you'd

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       1    be underestimating; right?  
       2                  DR. REED:  Yes.  
       3                  DR. BLANC:  So I just wanted to make sure
       4    that the studies that were done and the factor of 
       5    10 -- how sure are you on the factor of 10?  How good are
       6    the data on that?  
       7                  DR. REED:  It's only based on acute
       8    toxicity data.  And that's all there is.  Two types of
       9    endpoint -- one, is DEF as LD50 and the other one is 50
      10    percent inhibition of cholinesterase.   
      11                  DR. BLANC:  And does that carry across by
      12    analogy for other organophosphates which are typically
      13    activated to the oxon for other endpoints?  
      14                  DR. REED:  Yeah.  No.  I have not looked at
      15    database to make that comparison.  
      16                  DR. BLANC:  The reason I bring it up is it
      17    comes back to what Tony and John were talking about is a
      18    lot of the calculations at the end are driven by a very
      19    limited amount of environmental tech data.  
      20                  If the factor were not 10 for the chronic
      21    endpoints but were 12 or were 15, it would dramatically
      22    change your calculations because your calculations are
      23    driven importantly by that factor of 10.  
      24                  So that every microgram of the oxon weighs 
      25    10 times as much, but suppose it should be weighed 15

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       1    times.  So I would say that you might want to look by
       2    analogy, at least the others, and just make sure that 10
       3    is okay.  
       4                  DR. REED:  All right.  
       5                  DR. BLANC:  Because it would be such a
       6    major -- you'd have such a major impact.  
       7                  DR. FUCALORO:  That's a very critical area.  
       8                  DR. BLANC:  There was a passing comment
       9    that 2-PAM does not cross the blood brain barrier as a
      10    treatment?  
      11                  DR. REED:  Yes.  
      12                  DR. BLANC:  Are you -- you're certain about
      13    that?  
      14                  DR. REED:  That seems to be what I read
      15    from the literature.  
      16                  DR. BLANC:  Can you double-check that?  
      17                  DR. REED:  Yes, I will.  
      18                  DR. BLANC:  Because it doesn't really
      19    conform to clinical practice.  
      20                  DR. REED:  Okay.  I will definitely check
      21    on that.  
      22                  DR. BLANC:  I also think 
      23    that -- linguistically that there are times where -- this
      24    is true of the draft of the findings where in certain
      25    places colloquial words are used.  And in certain places

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       1    more medical words are used "fasciculations," "seizures."
       2                  I would try to be consistent in
       3    terminology.  And if you use the more formal terminology,
       4    which is probably -- I recommend if you want to put in
       5    parentheses "convulsions" or something.  But it does
       6    sound a little folky when you stray into some of that
       7    stuff.  
       8                  MR. GOSSELIN:  They probably did that for
       9    my benefit.   
      10                  DR. BLANC:  Another area which I think is
      11    potentially confusing down the road is the issue of the
      12    demyelinating effect that derives certain of the endpoint
      13    for chronicity; is that correct?  Or at least it's an
      14    argument that the -- it appears in several places.  It's
      15    not a trivial outcome that you've looked at? 
      16                  DR. REED:  Right.  It's fairly consistent,
      17    yes.  
      18                  DR. BLANC:  Right.  And there's no -- at
      19    least I didn't see -- well, there's two issues related to
      20    that.  One, it's not clear why that effect would be
      21    related to cholinesterase inhibition.  That's not obvious
      22    to me.  
      23                  DR. REED:  Right.  No.  I don't think there
      24    is a data that would allow that assumption, no.  
      25                  DR. BLANC:  But the -- by not 

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       1    saying -- maybe that uncertainty should be made clearer
       2    or it should be a bit more explicit that in fact this
       3    endpoint -- the mechanism of this endpoint is not
       4    understood but it also needs to be clarified in your
       5    section on delayed peripheral neuropathy.  
       6                  That delayed peripheral neuropathy is a
       7    dying back neuropathy which is not a demyelinating effect
       8    so that somebody who reads this document will understand
       9    that.  
      10                  Otherwise they'll say, "Well, wait a
      11    second.  You just said it caused a chronic neuropathy."
      12    But the chronic neuropathy that you're describing in
      13    those other studies, the demyelinating neuropathy, is not
      14    the chronic neuropathy of the delayed neurotoxicity.   
      15                  Also there was a line in there -- I forget
      16    where, if it's in the findings or in your main document. 
      17    But neuro target esterase is a marker for -- and we
      18    discussed this before in another context -- it is not the
      19    mechanism of -- you can't make mechanistic assumptions.  
      20                  CHAIRMAN FROINES:  Can I -- are you
      21    finished on the demyelination issue?  
      22                  DR. BLANC:  Yeah.  
      23                  CHAIRMAN FROINES:  Can I stay with it for
      24    just a second?  
      25                  DR. BLANC:  Sure.  

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       1                  CHAIRMAN FROINES:  On page 84, the health
       2    effects document, you have a study done in Sprague-Dawley
       3    rats.  And you have at -- in males at a .025 milligram
       4    per kilogram dose, you have apparent demyelination of the
       5    dorsal and ventral roots.  
       6                  And so it seems to me that -- I don't know
       7    that that value would be a LOEL and so the NOEL would be
       8    tenfold less than that.  And yet your lowest NOEL that
       9    you've chosen is .025.  And so this seems to indicate
      10    that -- if you use this as a defining feature -- that you
      11    would have another LOEL and therefore a different MOE.  
      12                  DR. REED:  Right.  I pointed out in the
      13    document -- and I had the same sort of a struggle and
      14    didn't know what to do.  I would certainly appreciate
      15    your comments and direction on that -- is that whether
      16    the effect at 0.025 milligrams per kilogram day is -- is
      17    a clear effect or it isn't a clear effect.  
      18                  And I think there's differences in opinion
      19    even within our own group of people.  It seems to me that
      20    there is some indication.  The argument for and against
      21    is this:  For having that concern as an effect is sort of
      22    the apparent increase of incidence.  You know, for the
      23    dorsal root fibers is zero and then three and four.  
      24                  Though the ventral you have the scoring
      25    numbers for the control also.  The argument or

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       1    consideration for or against considered this as a clear
       2    effect was because the controls also have some
       3    incidences.  
       4                  And I was told that from a
       5    neuropathologist's standpoint, which I'm not.  So I could
       6    only repeat what people told me.  That some kind of a
       7    biochemical indication would have to come before
       8    demyelination.  Not necessarily.  
       9                  I don't think people necessarily are
      10    meaning cholinesterase inhibition although I think in
      11    myself talking to different people I get this mixed
      12    feeling of that.  
      13                  And so the other thing was that the
      14    300-fold difference between the NOEL or the 0.025 and 7.5
      15    in that -- that dose response did not sort of bear out
      16    completely for, you know, a clear dose response at a low
      17    dose group.   
      18                  These are just sort of considerations that
      19    I talked to different people and came up with different
      20    ways in looking at things.  
      21                  I would really appreciate, you know, the
      22    opinion from the Panel to make such a decision in terms
      23    of what is clear and what is not.  
      24                  DR. BLANC:  There were others.  I thought 
      25    he -- maybe not based on this study but the .025 did get

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       1    used by you as a -- 
       2                  DR. REED:  Yes.  As subchronic and chronic.  
       3                  DR. BLANC:  As a NOEL not a LOEL.  
       4                  DR. REED:  NOEL, yes.  
       5                  DR. BLANC:  Not as a LOEL.  Well, you see
       6    you have another problem which is in a way parallel to
       7    what you're saying.  If you look on the same table and
       8    you look at the plasma cholinesterase for male rats, you
       9    have the four values, 100, 78 -- which is 78 percent of
      10    the baseline; right?  Of -- 
      11                  DR. REED:  Right.  Of --
      12                  DR. BLANC:  -- control.  
      13                  DR. REED:  -- percent of control.  
      14                  DR. BLANC:  And then 35 percent and 25
      15    percent.  Then you have two little asterisks which is
      16    comparison -- is it statistically different from the
      17    control; right?  
      18                  DR. REED:  Yes.  
      19                  DR. BLANC:  So you've said, well, 35
      20    percent is statistically significantly different than the
      21    control value of 100 percent.  And 78 percent is not
      22    statistically different.  Therefore, I'm calling that a
      23    no effect level; right?  
      24                  DR. REED:  Yes.  
      25                  DR. BLANC:  That's what you've done?  

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       1                  DR. REED:  Yes.  
       2                  DR. BLANC:  But in fact, that's not
       3    biostatistically -- it's biostatistically reasonable
       4    perhaps to make those series of paired-wise comparisons. 
       5    But it's not the question that you're really asking. 
       6                  Because if you believe that there's a line
       7    that you're drawing, that if you believe there's a
       8    reasonable slope on which 78 percent fits, then in fact
       9    there is an effect at .025.  
      10                  And the question is is 22 percent
      11    inhibition of cholinesterase an effect I'm going to care
      12    about?  That's a different issue.  
      13                  But in fact just because 78 percent isn't
      14    statistically different than 100 percent in that single
      15    pair-wise comparison, doesn't mean that that's a no
      16    effect level.  It just means that you're drawing a line
      17    and -- that we actually see this a lot in -- at least I
      18    saw it in the previous document on a different chemical
      19    that the department was presenting.  
      20                  So I think you have to ask yourself is that
      21    biologically reasonable.  Because you're dealing with
      22    small numbers of test animals in each group, I assume. 
      23                  DR. REED:  Okay.   
      24                  DR. BLANC:   Right?  So --
      25                  CHAIRMAN FROINES:  Which is defining

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       1    whether it's statistically significant or not.  
       2                  DR. BLANC:  In a pair-wise comparison.  But
       3    that's not the question.  The question you're asking is
       4    do those all fall reasonably along the line, and if so,
       5    where is the intercept on that line?  
       6                  DR. REED:  Right.  Or where is the starting
       7    line that you consider -- starting place where you
       8    consider as having effect.  
       9                  DR. BLANC:  Well, that's -- those are two
      10    separate questions.  
      11                  DR. REED:  Right.  Yes.  
      12                  DR. BLANC:  I would say, though, it is
      13    reasonable to think that 20 percent inhibition of
      14    cholinesterase is an effect one we care about, frankly,
      15    because that's an effect that would be associated with
      16    symptoms in humans.  
      17                  CHAIRMAN FROINES:  Well, the point I would
      18    make is that you have 78 in males.  You have 91 in
      19    females and then you have this demyelination.  
      20                  And so you have three -- within that same
      21    study, you have three places where you actually -- there
      22    appears to be something going on.  What exactly it is,
      23    isn't entirely clear.  
      24                  DR. REED:  The other argument, if we're not
      25    considering this -- and I did not bring this up -- is

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       1    that one of the argument was that, if you look at this
       2    study and together with the subchronic neurotoxicity
       3    study, seem to me that the subchronic neurotoxicity study
       4    is not showing this type of picture at the low dose.  
       5                  And so that was one with the argument. 
       6    People would tell me that you're not seeing demyelination
       7    in the subchronic study, and these are comparable study
       8    conducted by the same study director.  So that was also
       9    one --
      10                  DR. BYUS:  Which table is that, Ruby?  
      11                  DR. REED:  We're talking about table 20 for
      12    the acute and then subchronic would be page 21 in 
      13    page 86.  In table 21, I did not show histopath for the
      14    nerves because the study report says that it was just not
      15    outstanding.  
      16                  It was no outstanding findings.  And so the
      17    argument is that the subchronic study actually spend the
      18    same concentration range as the acute study.  But you are
      19    not seeing those effects at all.  So that's another sort
      20    of way of looking at it.  
      21                  DR. BLANC:  I'm not deeply whetted in this
      22    particular study.  But I think it's a generalizable point
      23    because I've seen it in other things.  I guess the 
      24    other -- you wanted me to finish my comments?  
      25                  CHAIRMAN FROINES:  Well, I just -- I think

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       1    that what we should have then is there should be a
       2    discussion of this study of these findings with the
       3    statement that there is evidence, some evidence of an
       4    effect.  And whereas the value won't be used for the
       5    NOEL, one should take it as a point of caution.  
       6                  DR. REED:  I think I have discussion or
       7    that cautionary word -- a sentence in there whenever I
       8    mentioned about this NOEL.  
       9                  CHAIRMAN FROINES:  But part of the problem
      10    with the document is that sometimes things are hard to
      11    find in the documents.  So where you have -- you should
      12    have a section that says -- that actually -- in the
      13    section where you talked about selection of the NOEL, 
      14    it should be -- there should be a paragraph in there that
      15    relates to those studies.  
      16                  And so it's very clear to the reader that
      17    this contradiction -- and it is a contradiction -- that
      18    you don't -- you're not dismissing it but that you're not
      19    going to use it for a NOEL.  
      20                  And it is a matter to be taken into
      21    consideration.  So we don't change the NOEL, but we don't
      22    not acknowledge it either.  
      23                  DR. REED:  Yes.  I will go back to the
      24    document and make sure that it's clear.  Because it is an
      25    important point.  And I -- in writing the document, I 

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       1    did try to make it clear.  
       2                  CHAIRMAN FROINES:  It needs to be in the
       3    back when you're talking about the NOELs that were
       4    selected.  
       5                  Go ahead, Paul.  
       6                  DR. REED:  It's -- in page 99 and the
       7    paragraph under "overt toxicity," that was deciding on
       8    the NOEL.  And at the end of that paragraph I did have
       9    some discussion about weighing the argument of 300-fold
      10    difference between NOEL and LOEL and the fact that --
      11                  CHAIRMAN FROINES:  Well, that -- part of
      12    the problem is you read this -- this little section needs
      13    to be changed.  
      14                  DR. REED:  Okay.   
      15                  DR. BLANC:  The other area that I think is
      16    a challenge -- I don't necessarily know the right way to
      17    handle this -- is this issue of intermediate syndrome in
      18    humans.  
      19                  It's not so important because it doesn't
      20    drive any of your -- you know, any of your decision
      21    making.  But I think that the level of -- there perhaps
      22    could be a little bit more scepticism voiced or quoting
      23    some of the people who have been quite sceptical that
      24    that syndrome as anything other than the undertreatment
      25    of acute toxicity with fat soluble organophosphates,

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       1    particularly fenthion diffusing out and causing further
       2    symptoms.  
       3                  DR. REED:  The intermediate syndrome --
       4                  DR. BLANC:  The intermediate syndrome. 
       5    There's that whole little section -- and I know you're
       6    forced to address it because it's out there in the
       7    literature.  
       8                  I wonder if some of the papers you've
       9    cited, particularly the one in clinical toxicology,
      10    whether or not there wasn't an accompanying editorial
      11    that you might have missed that put some of that in
      12    context.  
      13                  I don't remember if there has been a formal
      14    editorial.  But it seems to me that there might have
      15    been.  It's not a major thing because it doesn't drive
      16    any of your risk calculations.  
      17                  DR. FUCALORO:  Why don't you write one,
      18    Paul?  
      19                  DR. BLANC:  What?   
      20                  DR. FUCALORO:  Why don't you write one?  
      21                  DR. BLANC:  It's not my field.  
      22                  DR. REED:  Okay.   
      23                  DR. BLANC:  It has to do with how the
      24    dosing of the pralidoxime is given and whether it's
      25    efficient.  Because when these people were measured, they

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       1    had -- still had suppressed cholinesterase.  So they were
       2    undertreated --
       3                  DR. REED:  Right.  It seemed to me that
       4    it's a -- the only consistencies that these people were
       5    severely, you know, affected as being poisoned.  And yes. 
       6    The sufficiency of the initial treatment seem to make a
       7    lot of difference on that.   
       8                  CHAIRMAN FROINES:  Done?  What time is it? 
       9                  DR. BLANC:  12:40.  
      10                  CHAIRMAN FROINES:  12:40.  I'll be about 20
      11    minutes, I think.  20 minutes to a half an hour.  And so
      12    we can either break for lunch or drive on through,
      13    depending on what you feel like.  
      14                  DR. FRIEDMAN:  After your 20 minutes to a
      15    half hour, the meeting will be finished then.  Is 
      16    that --
      17                  CHAIRMAN FROINES:  Yeah.  I think what
      18    we'll do, if everybody agrees, that we could agree to
      19    have every body read the findings away from here and then
      20    send in comments.  
      21                  We'll incorporate them and finalize the
      22    findings.  And that way we won't have to discuss them
      23    here because that's a pretty agonizing experience in
      24    trying -- whether you would prefer to stay here -- if the
      25    Panel would prefer to go through the findings and

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       1    finalize them today, then I think we need to break for
       2    lunch.  
       3                  If the Panel -- if we would take the
       4    findings home, go over them, send in the recommendations,
       5    we then put a book together and send it back to you, we
       6    wouldn't have to do it today.  So it's -- either way,
       7    it's whatever way you want to do it.    
       8                  DR. BYUS:  I think that's the best way to
       9    do it.    
      10                  DR. FUCALORO:  Which way?  
      11                  DR. BYUS:  Take the findings home and
      12    everybody contribute their suggestions and we can fix it
      13    up, send it back to you.  We can vote on it at the next
      14    meeting.  Do what you want.  
      15                  CHAIRMAN FROINES:  We can vote on it.  
      16                  DR. BYUS:  We can vote on it today.  
      17                  CHAIRMAN FROINES:  Well, we can vote on the
      18    document and then vote on the findings by -- can we do it
      19    by -- if everybody approves the findings that they get,
      20    then that's presumably a vote on the findings.  We did
      21    that with DEF basically.   
      22                  DR. FUCALORO:  Assent.   
      23                  DR. BLANC:  Go.   
      24                  CHAIRMAN FROINES:  I have a few things. 
      25    Ruby.  The most important comment I wanted to make

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       1    concerns paraoxonase.  And in that respect, I didn't
       2    think the document was adequate in terms of this
       3    discussion of the paraoxonase issue.  
       4                  For those of you that don't know, there's a
       5    genetic polymorphism called PON 1, which is associated
       6    with the detoxification of paraoxon.  And that genetic
       7    polymorphism is actually found in a fairly wide number of
       8    people.  
       9                  And so that if one has the -- that
      10    polymorphism, one is at much greater susceptibility
      11    because you don't basically metabolize the paraoxon out
      12    of the system.  And so there's lack of clearance and the
      13    AUC goes up, and basically, you have greater toxicity. 
      14    So that that polymorphism is particularly important. 
      15                  And, for example, at U.C.L.A. there are
      16    three papers from 1998 that -- in which people reported
      17    on the development of a transgenic mouse of PON 1
      18    knockout mouse in which they looked at the issue and they
      19    found extremely dramatic effects of the -- of the
      20    susceptibility to the animals too that in the transgenic
      21    mouse were clearly highly susceptible to these -- some of
      22    the organophosphates.  
      23                  And so the issue suggests that there is a
      24    significant population of people who have a genetic
      25    polymorphism and who, therefore, are at significantly

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       1    increased risk of toxicity associated with methyl
       2    parathion.  
       3                  Well, having said all that, for example,
       4    there's a paper -- this is all out of 
       5    U.C.L.A. -- genetically determined susceptibility to
       6    organophosphate insecticides and agents developed in a
       7    mouse model for human PON 1 polymorphism and so on and so
       8    forth.  There's a whole bunch of papers.  And I'll give
       9    you the papers.  
      10                  But what that raises is a question about
      11    going -- it goes back to what Tony and I were talking
      12    about earlier which is we are not in any way adjusting
      13    for that genetic susceptibility.  
      14                  And one could argue, I think, that one
      15    needs -- if one is talking about safety factors, one
      16    could argue that one could have a safety factor of 3, 6
      17    or 10 to protect for those genetically susceptible
      18    people.  
      19                  And this is an issue which I talked to
      20    George about.  And George says that how you deal with
      21    genetic susceptibility they haven't dealt with yet.  So
      22    it's not something that everybody has a formula to deal
      23    with.  So it's not trivial.  
      24                  So I'm not necessarily arguing that you
      25    change the NOEL or add additional safety factors or

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       1    anything like that.  But I think that the discussion in
       2    the document needs to be expanded to really address that
       3    this is a major issue with methyl parathion with
       4    parathion and with, you know, chlorpyrifos.  
       5                  And I assume we'll see that down the road. 
       6    So that the issue isn't going to go away.  It's going to
       7    actually get worse.  And most of these papers that they
       8    looked at were chlorpyrifos, and the results were pretty
       9    dramatic.  
      10                  So I think that an expanded discussion on
      11    the issues and in the conclusions, something that really
      12    does acknowledge the need to address susceptible
      13    populations is really quite important.  So that's my
      14    first comment and --
      15                  DR. REED:  All right.  Thank you.  
      16                  DR. BLANC:  But the -- can I just have a
      17    clarification?  The 60 to 1 -- 60 times more sensitive
      18    that's used, is that referring to the same --
      19                  DR. REED:  Right --
      20                  DR. BLANC:  -- genetic --
      21                  DR. REED:  -- it's the same, yes.  
      22                  CHAIRMAN FROINES:  She's using -- but I
      23    think at this point we really don't know what -- because
      24    most of the studies that have been done have been done in
      25    serum.  And so people haven't really looked in livers to

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       1    find out whether you have the same thing going on in
       2    livers that you have in serum.  
       3                  And so that it's clear that, when you look
       4    at the log, a normal distribution of these enzymes, that
       5    there's a susceptible subpopulation associated with the
       6    paraoxonase allele changes and -- so people don't really
       7    know what the magnitude is at this point.  This is to
       8    them literature for only the last ten years, you know.  
       9                  DR. KENNEDY:  Is there any information
      10    regarding prevalence of this at all?    
      11                  CHAIRMAN FROINES:  Prevalence?  
      12                  DR. KENNEDY:  Is there any information
      13    regarding prevalence --
      14                  CHAIRMAN FROINES:  Well, I tried to get as
      15    many papers as I could for this meeting.  And the ones
      16    that I got didn't speak to that issue.  The thing that's
      17    interesting is that the U.C.L.A. people have found that
      18    the paraoxonase genetic polymorphism also creates a
      19    population that are susceptible to atherosclerosis and
      20    coronary heart disease.  
      21                  So it's a major finding that was reported
      22    in nature.  Mice lacking serum paraoxonase are
      23    susceptible to organophosphate toxicity and
      24    atherosclerosis.  
      25                  So it's actually a pretty interesting

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       1    genetic alteration.  And it's only one amino acid.  And
       2    so -- but the point is -- I think for this 
       3    document -- that we could bring our -- keep ourselves at
       4    the highest level of science we can be at.  
       5                  We need to really make sure that we've
       6    covered this kind of issue in some depth and to say, you
       7    know, we're not -- it would be possible that, if one were
       8    to calculate in RfCs, that one would use a safety factor
       9    to address potentially susceptible subpopulations.  
      10                  So that was my second comment.  
      11                  DR. PFEIFER:  Dr. Froine?  
      12                  CHAIRMAN FROINES:  Yeah.  
      13                  DR. PFEIFER:  I'm Keith.  I'm one of the
      14    senior toxicologists of the medical toxicology ring.  And
      15    I supervise the risk assessment group.  
      16                  I appreciate your comments on that, and
      17    believe me, we have had discussions about this very issue
      18    in our group and in our branch.  I mean I know Ruby is
      19    very up to speed on this.  
      20                  And I have had discussions with the author
      21    of the chlorpyrifos document, which is currently being
      22    developed on this issue also.  And as you pointed out,
      23    there's a lot more specific data on chlorpyrifos.  So I
      24    just wanted to assure you that, you know, we are
      25    concerned about this, and we are looking into it.  

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       1                  I mean the ultimate effect could be to
       2    adjust your default interindividual or intraspecies, as
       3    it's called, uncertainty factors, safety factor of 10 to
       4    account for this.   
       5                  CHAIRMAN FROINES:  Well, I think 
       6    that's -- that would be the logical thing.  That's part
       7    of why I don't like the MOE approach because I'd 
       8    like -- it doesn't -- it doesn't get to these issues the
       9    way I think one should -- 
      10                  MR. PFEIFER:  Right.  Well, with the MOE
      11    you just -- rather than require 100, then you'd say it's
      12    300 or 1,000.  Whatever.  
      13                  CHAIRMAN FROINES:  But see, I would argue
      14    that in the document that -- going back to this
      15    qualitative versus quantitative issue I raised earlier,
      16    that one should argue that, given the susceptible genetic
      17    populations -- susceptible population based on the
      18    genetic changes, that this material should -- even though
      19    we're not taking it into account with our MOE 
      20    calculations -- this should be part of the evidence that
      21    the director should take into consideration when deciding
      22    whether to call it a toxic air contaminant or not. 
      23                  It argues for me to call it that even
      24    though it's not in some numerical calculation that we end
      25    up with.  But it says that the prudent person would say

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       1    that this is -- would weigh heavily in the consideration
       2    of the compound as a toxic air contaminant.  And so it's
       3    that kind of thinking that's both qualitative and
       4    quantitative that I think is important.   
       5                  Okay.  Very quickly.  Let me just say a
       6    couple things about genotoxicity and cancer.  By the way,
       7    I think that in the MOEs I don't think we should have the
       8    words at -- the MOE could be "at least this."  The words
       9    "at least this" imply it would be this low or higher.  
      10                  And given the amount of data that we have,
      11    I think it should be "the MOE is" -- boom.  Forget the
      12    "at least."  Or else put in "at least or at most."  I
      13    mean it makes -- it creates an impression that the MOE
      14    will only be this low.  
      15                  It can't be any lower.  But it can be
      16    higher.  And I think to be -- to have some humility, I
      17    think we should just leave the number as it is.   
      18                  I would argue that it would have been good
      19    to see what genotoxicity data there is for
      20    paranitrophenol and paraoxon, methyl paraoxon because you
      21    haven't developed that.  I don't know if there's any DNA
      22    adduct data on any of those three.  But those would be
      23    interesting too.  
      24                  Because if I look at the carcinogenicity
      25    issue, we will say that there are three categories;

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       1    right?  Structure, activity -- four categories. 
       2    Genotoxicity, animals and humans and mechanisms.  
       3                  Okay.  We know that structure activity
       4    would suggest that this compound is electrophilic, and
       5    may bind macromolecules.  And it may have a potential for
       6    carcinogenicity.  
       7                  In terms of genotoxicity, I think that the
       8    data is positive.  I would argue, by the way, that, when
       9    you say that -- that, when something -- when you describe
      10    the genotoxicity, I think that we need criteria for how
      11    we talk about things.  
      12                  Three places in the document that I found
      13    that word "interesting" was used.  And I think putting
      14    the word "interesting" in the document -- something is
      15    interesting when you go to the movies and come out of the
      16    movie and can't figure out what you're going to say about
      17    the movie.  But in a scientific document, it doesn't tell
      18    you anything to say something's interesting.  
      19                  It says in here the overall database, which
      20    is very large, presented above indicates that methyl
      21    parathion has genotoxic potential.  
      22                  I think one should say that it appears that
      23    methyl parathion is genotoxic, has genotoxic potential. 
      24    I don't know what that means.  That means if you study
      25    hard, you're potentially going to be a good student.  

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       1    It -- the data is stronger than that sentence.  
       2                  And I think we have to be careful about
       3    understating or using words that -- because the data is
       4    actually quite strong.  This material is clearly
       5    genotoxic.  
       6                  I mean -- so I think -- it would have been
       7    nice, as I said, to look at the genotoxicity methyl
       8    parathion and paranitrophenol just because those 
       9    three -- those other two compounds are of 
      10    concern -- potentially of concern.  
      11                  Now, I just wanted to just say something
      12    about the cancer data.  And that is that, when you look
      13    at the cancer data, you're right -- I've looked at
      14    thousands of cancer data things, and I know that the data
      15    is limited.  
      16                  But when you look at the data, you have the
      17    one study where you find two of the ten rats had adrenal
      18    cortex adenomas, and you point that out in the document. 
      19                  You also have the adrenal cortex cancers
      20    where you have about 22 percent and then you get into a
      21    discussion that is relatively confusing because, when you
      22    look at the historical range, the historical range is
      23    actually quite low.  
      24                  In fact, the historic -- the zero -- the
      25    range of this person found in the controls was higher

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       1    than what you wrote was the historical control.  
       2                  But then you go over and you say that even
       3    though this fine incidence rate exceeded the historical
       4    range, you have that in a rebuttal to the evaluation by
       5    DPR regarding the reproductive -- the registrant noted a
       6    historical range of 1.6 to 33 percent for conducting
       7    laboratory biodynamic.  The high end of the range was
       8    much higher than the 16.4 recorded in the open
       9    literature.  Unfortunately no further comparison and
      10    validation are possible because the database for the
      11    quoted range was not provided in the rebuttal.  
      12                  Well, that's like saying that somebody from
      13    the industry who is an affected party comes in and says,
      14    "Oh, no.  Your historical controls are actually up to 33
      15    percent.  But we won't give you any data to show you that
      16    that's the case.  And so please accept it."  And then you
      17    accept it.   
      18                  I think that you can't do that.  I think
      19    that if you've got -- if Cheminova comes in and says it's
      20    33 percent, let him bring you the historical data and
      21    show you.  Otherwise, this data should stand.  This data
      22    should stand.  
      23                  And that would be -- that 22 percent then
      24    represents a finding out of the historical range. 
      25    Because you simply cannot let the people who have the

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       1    vested interest, say -- give you unsubstantiated data. 
       2    That's my concern.  
       3                  DR. REED:  Okay.  
       4                  CHAIRMAN FROINES:  So that's that point. 
       5    Then we go down to the -- go back to the previous study. 
       6    And we look at the thyroid adenomas.  And those are
       7    clearly statistically significant.  
       8                  And then we go to the uterine cancers or
       9    the uteral adenocarcinomas.  And there you have findings
      10    of 19.5 percent which is also out of the historical
      11    range.  So as of those three, you're finding basically
      12    two that are nonsignificant and one that is but three
      13    positive findings.  
      14                  Then you go over to the mice, and you look
      15    at the lung alveolar bronchio -- however you say 
      16    that -- in males.  And you have 1. -- 5.3 percent of lung
      17    cancers in the controls.  This is a feeding study.  So
      18    you're not going to get many lung cancers anyway.  But in
      19    the combined you find 16.3 percent.  That's also not
      20    statistically significant.  But in fact, it's not trivial
      21    either.  
      22                  So that, when you look at the data and
      23    there are problems with all of this because, for example,
      24    in the EIBEN study in 1991, he's dosing the animals
      25    clearly below the MTD because the NCI study went up as

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       1    high as 77 parts per million.  And they started out at
       2    125.  And as far as I can tell, we don't know what the
       3    MTD is for these mice.  BC6 -- B6C3F1 mice.  
       4                  And I would say it looks to me like it's
       5    around -- the MTD is around 100 if I was to design the
       6    experiment.  So we have a 77 part per million cancer
       7    study with no mortality in the animals.  
       8                  And you have -- so you don't know if you've
       9    reached the MTD.  So you don't know whether you got the
      10    cancers that you might have found.  And over here in the
      11    EIBEN study you're only at 50 parts per million.  So
      12    clearly you're under the MTD. 
      13                  So you can't even take that study seriously
      14    anyway.  I mean you would toss that study out and say it
      15    doesn't really matter.  If I find something in the NCI
      16    study that goes up to 77 parts per million and I find
      17    nothing at 50, well, I'm not going to expect to find
      18    anything at 50; right?  
      19                  So I mean -- so in the 77 part per million
      20    study, you go from a control of 5.3 percent lung cancer
      21    to a 16.3 percent lung cancer.  
      22                  So when you take the data together, when
      23    you take the adrenal cortex data, when you take the
      24    thyroid data and the uterine cancers and the lung cancers
      25    in two species, there's an indication of a positive

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       1    finding.  
       2                  And unless somebody reads this differently
       3    than I do, I think that it's not -- it is not strongly
       4    positive.  It's not strong enough to do a risk
       5    assessment.  
       6                  I'm not saying any of that.  I'm not trying
       7    to take you to a risk assessment.  I'm simply saying that
       8    the way cancer is dealt with -- and this document is
       9    dismissive, and it shouldn't be because those -- there is
      10    an indication of at least four endpoints that appear to
      11    be significantly -- not statistically significant, but
      12    greater than historical controls.  And one of them is
      13    statistically significant.  
      14                  So it seems to me that, when you have
      15    structure activity, genotoxicity and some indication of
      16    carcinogenicity, you shouldn't conclude that there's no
      17    cancer -- which is what you conclude.  You conclude that
      18    in fact there are indications that should be followed up
      19    more seriously.  
      20                  And so I think that this data isn't as
      21    negative as it's stated.  And when you go look at the
      22    executive summary, it basically says that there's nothing
      23    there.  And unless I'm really off base, I just showed you
      24    four places where there were findings that should be
      25    taken seriously by somebody who wants to be public health

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       1    protective in that sense.  
       2                  And so I think the document should 
       3    reflect -- however, there is no clear evidence of
       4    increased tumor incidence in rats and mice after
       5    long-term exposure.  
       6                  Well, I would say there is limited
       7    evidence.  There is some limited evidence of increased
       8    tumor incidence.  And then you have to talk -- I mean
       9    basically talk about that.  So that's it --
      10                  DR. REED:  Thank you.   
      11                  CHAIRMAN FROINES:  -- for me.  And I'd be
      12    happy to talk with staff further about these cancer
      13    findings because I think that -- I am not suggesting that
      14    these are positive cancer findings.  
      15                  But I'm simply saying that we can't also
      16    just say that there's no finding of any merit because I
      17    think there are some findings and particularly when you
      18    look at the mutagenic potentials or mutagenicity of these
      19    compounds.  
      20                  DR. BLANC:  John, do you think it's useful
      21    to -- in the findings, when it talks about genotoxicity,
      22    to specifically comment on mutagenicity in bacterial
      23    systems as compared to invivo mammalian systems?  
      24                  It seemed as if the findings were more
      25    impressive for the bacterially based bioassays than for

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       1    any of the mammalian studies.  Not for many.  But I mean
       2    if you wanted to characterize them.  
       3                  The findings don't have to be a
       4    recapitulation of the entire document.  So maybe it would
       5    make more sense for it to say it in the parent document. 
       6    But that might be one -- I think that that's where I
       7    would say the biologically reasonable explanation for the
       8    divergence between the findings is.  
       9                  It would be one thing if it was, you know,
      10    consistently genotoxic in the mammalian systems that were
      11    tested.  But it really wasn't.  So --
      12                  CHAIRMAN FROINES:  There was quite a bit of
      13    positive finding --
      14                  DR. BLANC:  There was some.  I'm just
      15    saying that -- maybe it's too much detail to have the
      16    findings.  
      17                  CHAIRMAN FROINES:  Well, the problem -- we
      18    don't want to get into that discussion because obviously
      19    the -- the good thing about the Ames test is that it's
      20    highly sensitive.  
      21                  So you tend to find -- you do the best you
      22    can.  You get the best out of it that you're going to
      23    get.  And everything else has less sensitivity so that I
      24    think some -- I actually would agree with you insofar as
      25    I think it would be useful -- you have these long tables

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       1    in the book.  
       2                  But in the conclusions, it wouldn't be a
       3    bad idea to have a discussion on the carcinogenicity
       4    issue including genotoxicity.  And she could say a little
       5    bit about those -- about what the nature of the findings
       6    were.  
       7                  I mean there was DNA -- there was stuff
       8    where they obviously did some C14 labeling -- I would
       9    guess.  I didn't read the paper -- and found DNA,
      10    presumably adducts or some -- so I mean there is
      11    evidence.  
      12                  And to have some discussion of that
      13    evidence rather than simply saying that there is 
      14    potential -- genotoxic potential in the end doesn't tell
      15    you very much.  So --
      16                  DR. BLANC:  That was just a question.  
      17                  CHAIRMAN FROINES:  So I think anything that
      18    kind of fills out that little bit would be helpful.  It
      19    doesn't have to be a lot but just something to give you
      20    more -- because if you read something that says this 
      21    compound has genotoxic potential, I don't know what you
      22    go away with that with.  More specificity might help.  
      23                  DR. BYUS:  The data is difficult to try and
      24    figure out in relation to the cancer.  It is unusual. 
      25    And it's sort of contradictions and complexity, and that

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       1    is -- you know, it is difficult to figure out.  
       2                  It is not clearly carcinogenic.  It is not. 
       3    There is no clear evidence of carcinogenicity.  That is
       4    what it says.  And it is -- clearly -- I had the same
       5    question about what genotoxic potential meant.  In my
       6    opinion it was sort of clearly genotoxic.  
       7                  But then again if you want to talk about
       8    genotoxic in a mammal, which I think is what -- in a
       9    human being, that's what you were getting at as a
      10    genotoxic potential.  
      11                  DR. REED:  Right.  And that's what we're
      12    referring to as --
      13                  DR. BYUS:  That's what you told me you
      14    meant by that phrase.  But it is clearly -- my reading of
      15    it was -- there -- I sort of tried to understand this
      16    caloric restriction idea because of the weight changes. 
      17                  In a lot of these studies they have
      18    markedly reduced weight gain.  And some of them have
      19    increased weight gain with methyl parathion.  
      20                  So something funny is going on with weight
      21    gain and eating which can markedly alter the outcome of
      22    your cancer experiments.  That's one clear way of doing
      23    that.  
      24                  So there is something unusual going on, and
      25    I would like to see -- you know, it strikes me as someone

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       1    should do a more -- study on methyl parathion in some
       2    other system.               
       3                  CHAIRMAN FROINES:  I'm right now doing a
       4    two-year chronic animal bioassay on arsenic and drinking
       5    water in mice -- C57 black mice that are methyl
       6    deficient.  They're low in folic acid, methionine an
       7    choline.                
       8                  And we have them on a diet which is called
       9    lipotrophic, which is -- produces low levels of methyl
      10    groups.  We're trying to effect their methylation of DNA
      11    and the expression of DNA in combination with arsenic
      12    because we think that's what goes on with arsenic and
      13    cancer.  
      14                  Well, when you put animals on a lipotrophic
      15    diet, you get scads of cancers.  You get all sorts of
      16    spontaneous cancers.  So you can overfeed and get cancer. 
      17    And you can underfeed and get cancer.  And so the issue
      18    isn't quite -- it's not clear.  It depends on basically
      19    the nature of the vitamins.  It depends on the nature of
      20    the facts.  
      21                  DR. BYUS:  Caloric restriction is a
      22    extremely well-defined property in carcinogenicity.  It
      23    is based strictly on calories, not nutrients.  It's not
      24    nutrient.  It is calories only.  If you restrict
      25    calories, you --

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       1                  CHAIRMAN FROINES:  If I take a
       2    Sprague-Dawley rat and I make him folic deficient, they
       3    get cancer of the liver --
       4                  DR. BYUS:  I'm not talking -- I'm talking
       5    calories only relative to ad libitum feeding.  It's one
       6    of the most poorly understood phenomenas in
       7    carcinogenicity right now.  
       8                  Yet it is extremely clear.  I mean Walford
       9    works on this with humans, increases life span, markedly
      10    decreases cancer incidents.  And in an animal study if
      11    you're feeding something or doing something with your
      12    animal so that it doesn't eat enough, it restricts its
      13    own caloric intake.  You can markedly reduce the amount
      14    of tumors that you see.  
      15                  And you can do it artificially -- this is
      16    compared to ad libitum feeding.  So it's -- again, what
      17    that phenomenon is, how it works, the mechanism behind it
      18    is not known.  If the phenomenon works in humans.  It
      19    works in all animals, all rodents in all these aspects --
      20                  DR. BLANC:  This is just a quick aside. 
      21    There's data on other organophosphates that people who
      22    are nutritionally compromised are more sensitive.  Or
      23    animals.  Maybe not with this particular one.  Or am I
      24    inventing that from memory?  
      25                  DR. REED:  I did not do a -- sort of a

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       1    comparison.  I could go and find out --
       2                  DR. BLANC:  Just in terms of the issue
       3    expanding the discussion of human susceptibility or
       4    variability.  It seems to me that there are data for
       5    cholinesterase inhibition in general that nutritional
       6    compromise makes people more sensitive.  
       7                  That's often cited as an example of why,
       8    you know, an occupational standard may not be protective
       9    of children aside from just developing -- so if there 
      10    are -- but I could be --
      11                  DR. REED:  I can look into that and see if
      12    there's --
      13                  DR. BLANC:  Or it could be a statement
      14    people made.  
      15                  DR. BYUS:  The papers I found showed that
      16    nutritional status affects the serum cholinesterase level
      17    rather significantly.  
      18                  So that if you're looking at a population
      19    base and looking at serum cholinesterase as an indication
      20    of toxicity, you have to take that into consideration,
      21    the nutritional status of the group you're looking at in
      22    order to say that they may be exposed to pesticides
      23    relative to having other problems relative to their
      24    nutrition, that's a little different.  
      25                  CHAIRMAN FROINES:  I have one last thing,

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       1    Ruby.  In the two tables, table 7 and table 8, on the
       2    cancer incidences, tumor incidences, the -- judging from
       3    the text, there was some survival issues associated with
       4    those animals, those two studies.                
       5                  And so I don't know whether the
       6    denominators in these two tables represent those animals
       7    that were the actual number of animals that were on tests
       8    or whether they represent the number of animals that were
       9    surviving at the time of the first tumor.  
      10                  DR. REED:  This was animals at risk in
      11    footnote A, in table 7.  That was based on animals that
      12    survived past week 52 because all the tumors were found
      13    beyond week 52.  
      14                  So in this particular case, 52 would be the
      15    cutoff.  But it is -- the denominator is the animals at
      16    risk, not the number of animals started out with.  
      17                  CHAIRMAN FROINES:  But that's not the case,
      18    I think, in the next table.  
      19                  DR. REED:  They all are.  I probably should
      20    have a footnote on that to indicate.  There is a footnote
      21    on table 8, footnote A.  
      22                  CHAIRMAN FROINES:  59 animals on the
      23    adrenal cortex, for example.  Because over here you talk
      24    about 33 to 42 percent survival at the end of 24 months. 
      25    So --

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       1                  DR. REED:  Right.  This is only to 52
       2    weeks, the end of the first year.  The ones that survived
       3    past the end of the first year.  
       4                  CHAIRMAN FROINES:  Yeah.  But when do you
       5    start seeing the first tumors?  
       6                  DR. REED:  I think for the adrenal cortex
       7    tumors, it was fairly late at the life span.  And so
       8    there was sort of an argument about the increase of
       9    incidence all toward the end of it so that it does not
      10    shorten the latency in this case.   
      11                  CHAIRMAN FROINES:  Well, you're giving him
      12    below the MTD.  So I'm not surprised.  But the fact of
      13    the matter is that it would be nice to see the data with
      14    a proper kind of life table in which the denominators
      15    represented the actual animals alive when you're seeing
      16    cancers.  
      17                  And that would -- I bet that would give you
      18    higher percentages.  But it's hard to tell, if you 
      19    don't --
      20                  DR. BLANC:  So John, I move that we
      21    adjourn.   
      22                  CHAIRMAN FROINES:  Not yet.  Let me finish
      23    this point.  So if you have that data, I'd like to see
      24    it.  
      25                  DR. REED:  Okay.  I was following the

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       1    general convention of -- considering what are the numbers
       2    of animals at risk.  It's either at the first appearance
       3    of tumor or surviving past the first year.  And so in
       4    this case the criteria of surviving past the first year
       5    would come before the first appearance of tumor.  
       6                  CHAIRMAN FROINES:  Well, I'd like to see
       7    the data on the first tumor --
       8                  DR. REED:  Yeah.  I will provide you with
       9    that information.    
      10                  CHAIRMAN FROINES:  Okay.  Now we can quit.  
      11                  DR. BYUS:  John, do you want me to change
      12    the findings to reflect our expanded discussion of the
      13    carcinogenicity issue?  We'll do that.  
      14                  DR. FUCALORO:  So as I understand it, we'll
      15    be mailed a new set of SRP findings for our consideration
      16    and then getting -- give instructions on how we can get
      17    back to you with comments or checking off and saying this
      18    is fine.  
      19                  CHAIRMAN FROINES:  Thank you, everybody. 
      20                  DR. PFEIFER:  Dr. Froine, Paul Gosselin
      21    asked me to mention about the next active ingredient from
      22    us that will come before you.  And that would be MITC. 
      23    And the leads for your Panel are Dr. Witschi and I
      24    believe Dr. Atkinson.  
      25                  And Dr. Witschi, I believe, is on

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       1    Sabbatical up in Oregon and the lead person in my group
       2    will send him a draft of that.  I have a revised draft
       3    with me that I can give to Dr. Atkinson.  
       4                  There are some minor changes that have to
       5    be made in part A, which we're going to wrap up.  And
       6    then we'll get the drafts out.  Paul Gosselin indicated
       7    that as a workshop presentation we'll probably do this
       8    the third Friday in July which is our PREC, Pesticide
       9    Review Evaluation Committee, meeting and then come before
      10    you in the September meeting.   
      11                  CHAIRMAN FROINES:  Thank you.  We need -- I
      12    believe that we need to take a vote at this point before
      13    we adjourn that we tentatively accept this report pending
      14    some changes and that we will then develop our -- so
      15    let's vote on accepting the report pending changes and
      16    then we will have fulfilled that task.  And then we can
      17    finish the findings and then we'll go from there.   
      18                  DR. BLANC:  I move that we tentatively
      19    accept this report pending the changes.  
      20                  DR. KENNEDY:  Second.  
      21                  DR. FUCALORO:  Second.  
      22                  CHAIRMAN FROINES:  All in favor?  
      23                  BOARD MEMBERS:   Aye.  
      24                  CHAIRMAN FROINES:  Opposed?  
      25                  (No response.)

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       1                  CHAIRMAN FROINES:  Good.  
       2                  DR. FUCALORO:  Move to adjourn.  
       3                  DR. BLANC:  A second.  
       4                  BOARD MEMBERS:  Aye.  
       6                  (Whereupon the proceedings were adjourned
       7    at 1:20 P.M.)
       9                              * * *

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       2    STATE OF CALIFORNIA           
       5                  I, CAROLINE JETTER, CSR 11568, a Certified
       6    Shorthand Reporter in and for the State of California, do
       7    hereby certify:                                                        
       8                  That the foregoing proceeding was taken
       9    down by me in shorthand at the time and place named
      10    therein and was thereafter reduced to typewriting under
      11    my supervision; that this transcript is a true record of
      12    the testimony given by the witnesses and contains a full,
      13    true and correct record of the proceedings which took
      14    place at the time and place set forth in the caption
      15    thereto.  
      16                  I further certify that I have no interest
      17    in the event of the action.  
      18                  EXECUTED this      day of                ,
      19    1999.
      22                             Caroline Jetter, CSR

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