1                             MEETING

 2                              OF THE









11                   255 SOUTH AIRPORT BOULEVARD






                    WEDNESDAY, FEBRUARY 10, 1999
                              9:30 A.M.





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



 1                           APPEARANCES


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

     Mr. Bill Lockett, Deputy Ombudsman, Northern California
10   Mr. Peter Mathews, Office of the Ombudsman


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


16   Paul Goesslin, Assistant Director


18   Bill Jordan










 1                              INDEX

 2                                                           PAGE
     1    Initial workshop presentation on "Pesticides         3
 4        in the Air".  US Environmental Protection Agency

 5   2    Continuation of review of draft report:             74
          "The Determination of Acute Reference Exposure
 6        Levels for Airborne Toxicants".  Office of
          Environmental Health Hazard Assessment (OEHHA)
     3    Discussion of margin of exposure and reference
 8        exposure level (REL) approaches.  Department of
          Pesticide Regulation and OEHHA
     Adjournment                                             180
     Certificate of Reporter                                 181

















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

 2             CHAIRMAN FROINES:  Let's get started.

 3             I have a letter from Jean-Mari Peltier, which I

 4   have misplaced in my packet of materials, but I'll find it

 5   before the meeting is over, but she suggests that the pace

 6   that they had anticipated at 12 pesticides in the year isn't

 7   going to happen, and gives an altered schedule, which I

 8   think is a reasonable schedule, and so I'll get that to you

 9   as I find it.

10             The other issue is that the work on the April

11   workshop is going ahead and we're going to try and finalize

12   ideas for that and get back to you shortly.  It may be that

13   we'll look at the issue of plasma versus blood versus brain,

14   et cetera, cholinesterase issues.  And I'm told that US EPA

15   has a position paper developing on that, and that that might

16   be a useful document for us.

17             So that's the second piece of background

18   information.

19             DR. GLANTZ:  What's the dates for the workshop?

20             CHAIRMAN FROINES:  10th of April.

21             The third piece of information is that we spent a

22   lot of time on the DEF findings at the last meeting.  We

23   haven't quite finished the DEF findings.  They should be

24   finished this week to be circulated to the panel.  So that

25   we had to go back over the transcript, because there were so



 1   many suggestions that were being made, we couldn't keep

 2   track, and so now we have been back over the transcript and

 3   so we're going to finalize them and we'll send them out to

 4   you this week and Paul Gosselin, I think, will be happy to

 5   move forward.  And I think if he says anything today he's

 6   going to say he has some materials ready to go forward from

 7   when he gets our findings.

 8             So those are the three kind of announcements that

 9   we have.

10             There is no meeting in March.

11             There is a meeting April 10th.

12             Bill, do we have a May meeting date?

13             MR. LOCKETT:  Mr. Chairman, I think it's April

14   13th is the meeting date and there is no March meeting

15   scheduled at this time.

16             CHAIRMAN FROINES:  So April 13th, Stan.

17             DR. GLANTZ:  Is there a May date?

18             CHAIRMAN FROINES:  Is there a May date?

19             MR. LOCKETT:  No.  We're going to poll the panel

20   again to get some dates beyond April.

21             CHAIRMAN FROINES:  My assumption is that we will

22   have a May and June meeting, given what I've heard this

23   morning from Paul Gosselin from DPR, that they'll have two

24   compounds basically ready for May and June.

25             Then I would suspect we wouldn't have a July



 1   meeting.

 2             So it will be fairly intense for about three

 3   months.

 4             And July we go on strike unless they raise our

 5   salaries.

 6             The first speaker --

 7             DR. GLANTZ:  Was that a dignified comment?

 8             DR. FUCALORO:  Why would you expect one?

 9             CHAIRMAN FROINES:  Anyway, so that's more or less

10   the schedule.

11             At this meeting we've invited Bill Jordan from US

12   EPA to come and talk with us about how pesticides are

13   handled under FIFRA, developments at EPA on pesticides and

14   in general to bring the panel information about how US EPA's

15   approaching pesticides issues as a regulatory matter and as

16   a policy matter.

17             Bill is not a technical person, so he's going to

18   focus more on the regulatory and policy and historical

19   issues, I think.

20             So, Bill Jordan, welcome.

21             MR. JORDAN:  Thank you very much.

22             I want to first of all express my thanks to you,

23   Dr. Froines, and to Bill Lockett for inviting us to be part

24   of this and for your hospitality.

25             Feel like I've got a job that ought to be either



 1   fairly easy or fairly hard, I can't tell which.

 2             I heard a little bit from Mr. Lockett about the

 3   distinguished credentials that all of you brought, and I've

 4   got to say I'm not sure I can keep you fully engaged, but

 5   I'll do my best, to tell you a little bit about what is in

 6   some ways a different kind of environmental regulation that

 7   EPA does with respect to pesticides.

 8             As you've heard, I'm not a scientist, I'm not a

 9   nontechnical person, but I have been at EPA for over 20

10   years, and hope to tell you a little bit of what I've

11   learned in the course of that time.

12             I have prepared a package of materials, and each

13   of you should already have it.  I'm going to take a moment

14   or two to fill you in on what is in the package, and then

15   work from the outline that constitutes the first two pages.

16             CHAIRMAN FROINES:  Bill, let me interrupt you for

17   just a second.

18             Just so everybody is aware, I think this

19   discussion will probably run two hours, is what we've talked

20   about.  And then we're going to go immediately into the

21   discussion of the RELs, because Gary Friedman has to leave

22   at 12:30.  So Gary will be the first up about 12:00 o'clock

23   and we'll go from there.

24             Go ahead, Bill.

25             MR. JORDAN:  I'm planning on talking for about



 1   half an hour, but if you want to interrupt in the course of

 2   that, and change it into more of a dialogue, that is

 3   perfectly fine with me, ask questions or if you see

 4   something that you think ought to be covered in more depth,

 5   please stop me and I'll try to respond to your interest.

 6             The first document is a paper that's dated October

 7   16th, '98.  It's about 14 pages long.  It is the notes that

 8   our group within EPA, the pesticides office, used to provide

 9   a briefing for our new deputy administrator who knew very

10   little about pesticides.  And so it is a survey of a lot of

11   different aspects of the regulatory program that's run at

12   the headquarters level.  I don't intend to go into all of

13   it, but I thought it was one of the more current useful

14   descriptions of what we do.

15             After you get through that paper, there are three

16   pages from the Code of Federal Regulations.  It is the

17   toxicology data requirements for pesticides and they are

18   tables in table format, and I'll be talking in considerable

19   depth about the types of data that EPA routinely requires

20   for a pesticide product.

21             The next document is one page, and it is also from

22   the Code of Federal Regulations.  It is the table of

23   contents for the Good Laboratory Practice Standards, which

24   are one of the sets of rules that we have in place to

25   address quality control, quality assurance kinds of issues



 1   with the data that we get.

 2             And then the last document is entitled the Users

 3   Guide to Available Information on Assessing Dietary Food

 4   Exposure to Pesticides.  While I realize that the focus here

 5   is on airborne exposures to chemicals, some of the

 6   principles that we use in the dietary area are very relevant

 7   to our approach to the exposures through air, and it was a

 8   useful primer, if you will, on the dietary exposure approach

 9   and provides some points which I'll also be referring to

10   later on in the discussion.

11             Let me ask you to turn to the first one, Pesticide

12   Regulation in a Nutshell, and look at page two, the one that

13   is entitled, We Are Unique.  Obviously every regulatory

14   program wants to impress the boss that we are special and we

15   deserve more money and all that sort of thing and this was

16   our pitch to try to make that case to our new boss.

17             But it also, I think, sets out some important

18   differences between the way that pesticides are regulated,

19   as opposed to other types of environmental products or

20   environmental pollutants.

21             The first point that's made is that pesticides are

22   products, as opposed to pollutants.  They're not a

23   byproduct, a manufacturing waste product from some other

24   activity.  Pesticides are produced and deliberately released

25   into the environment in order to achieve controls of the



 1   bugs or the weeds or the fungus, or what have you, that are

 2   considered to be a problem for society.

 3             They are, therefore, have some benefits and they

 4   also have considerable potential to cause harm in the

 5   environment.  And that product regulation basis is one that

 6   leads to some different kinds of approaches, as opposed to

 7   the way that water pollutants or waste, hazardous waste

 8   materials, might be regulated.

 9             There are two laws and I'll be talking in more

10   depth about each of them, but they are -- they regulate

11   different kinds of things.

12             The first is called the Federal Insecticide

13   Fungicide and Rodenticide Act.  And I notice the court

14   reporter looking over at me.  I will tell you, just as I'm

15   sure that this transcript will not have a problem that I saw

16   in one earlier transcript in which it was recorded as the

17   Federal Insecticide, Fungicide and Genocide Act.

18             DR. FUCALORO:  It will now be recorded.

19             MR. JORDAN:  But FIFRA, as any law with such a

20   long name, has to have an acronym.  We call it FIFRA.  Of

21   course there was the lawyer who kept calling it Flicka.  He

22   liked to ride horses.

23             FIFRA is the law under which we regulate the

24   product, the bag, the bottle, the can of pesticide.  And

25   through that law we control the entry of those products into



 1   the marketplace.  No product that is a pesticide may be sold

 2   or distributed in commerce unless it has first been reviewed

 3   and given a registration or a license by EPA.

 4             In the course of licensing it, we set constraints

 5   on the way that the product may be used.  And it is a

 6   violation of federal law and state law to use a pesticide

 7   product in the manner inconsistent with the instructions on

 8   the label of the product.

 9             The other law -- and let me back up.  That law is

10   a risk-benefit balancing standard.  It recognizes the fact

11   that people use pesticides because they get benefits, but it

12   also recognizes the fact that pesticides have risks and it

13   says to EPA, make sure that from a societal point of view

14   the benefits outweigh the risks.

15             The other law is the Federal Food, Drug and

16   Cosmetic Act.  The acronym is FFDCA.  It doesn't have a

17   funny story about it.

18             But it is the one that is associated with the

19   residues of pesticide in food.  And it's under that law that

20   we set a tolerance or an upper limit on the amount of

21   residue that may remain in food, and it has a public health

22   emphasis or a public health standard.  It is not a

23   risk-benefit balancing standard.

24             The two laws need to work together.  It makes no

25   sense whatsoever for government to say it's okay to use a



 1   pesticide if the consequence of using it would create food

 2   that's adulterated.  So we have said as a practical matter,

 3   and the statutes now recognize this, you can't get a FIFRA

 4   registration unless you have the necessary Food, Drug and

 5   Cosmetic Act tolerances.

 6             CHAIRMAN FROINES:  I have a question.

 7             Isn't there a third law that you then enforce as

 8   well, because you have authority for occupational exposure

 9   to pesticides as well.

10             MR. JORDAN:  That's part of the FIFRA

11   considerations.

12             There is a law that was passed in 1996, called the

13   Food Quality Protection Act, which amended both FIFRA and

14   the FFDCA, and put us into some new kinds of

15   responsibilities, and I'll be talking about those.

16             So we're a licensing program.

17             One of the things that I think also distinguishes

18   the federal pesticide program from other environmental

19   efforts is that we have the authority to collect data, not

20   just collect it, but to require the regulated community to

21   generate the studies.  If EPA says to ourselves we need a

22   particular kind of study to be done on a pesticide in order

23   to tell what its health effects might be, we can write a

24   letter to the companies that hold a registration and that

25   company or those companies are obliged to perform the study



 1   and send the results to the agency, or if they don't, they

 2   lose the registration.  They are off the market.

 3             CHAIRMAN FROINES:  Does that same authority exist

 4   in California?

 5             MR. JORDAN:  I'm not familiar with California laws

 6   in that regard.

 7             CHAIRMAN FROINES:  Could California request a

 8   study through you?

 9             MR. JORDAN:  If California thought that it would

10   be helpful to have a particular kind of data, they could ask

11   EPA to do that.  I know that we and California Department of

12   Pesticide Regulation work together on doing some of the risk

13   assessments, and that's one of the options that we would

14   certainly put on the table.  I don't remember any specific

15   instances where that's happened, however.

16             So what that means is that with regard to

17   pesticides, EPA is pretty data rich, compared to what I've

18   seen in a lot of other parts of the agency.

19             The next tick indicate that the label is the law.

20   What's on the can or the bag or the bottle of pesticides is

21   the way in which we establish the limits of the pesticide

22   use.  That is different from the way, for example, OSHA

23   regulates workplace, where they may require engineering

24   controls.  We say you can use it in this situation, you

25   can't use it in any other situation.  We set limits on how



 1   much may be used, on what kind of equipment people may use

 2   when they're applying it, but we do not set, for example,

 3   ambient air concentrations that have to be met in terms of

 4   amounts as a consequence of the use.

 5             The states, and generally it's the State

 6   Department of Agriculture, although here in California it's

 7   the California Environmental Protection Agency, have the

 8   responsibility for enforcing the use, proper use, of the

 9   pesticides.

10             And then the last two points, again, we were

11   bragging to our boss, we're the largest headquarters

12   operation.

13             And I want to say a word or two about the other

14   claim that's made on the bottom, we're on the cutting edge

15   of science.

16             I don't necessarily say that we are doing research

17   quality science.  We were a regulatory scientific

18   organization at EPA.  But some of the kinds of questions

19   that we need to answer as we carry out our responsibility

20   are things that are more at the cutting edge, we believe,

21   than some of our colleagues in the Superfund program or the

22   water program, particularly with regard to how to model, how

23   to use probabilistic exposure assessment techniques, how to

24   aggregate exposure from multiple uses of pesticides, and how

25   to do cumulative risk assessments where we're trying to take



 1   into account multiple chemicals that have a common mechanism

 2   of toxicity.

 3             All of those are things that really have come out

 4   of the Food Quality Protection Act in the last three years

 5   and are pushing us in new directions.

 6             So that's a little bit of a survey, if you will,

 7   of the pesticide area.

 8             What I want to do is return to the outline and go

 9   through it in a little bit more depth.

10             CHAIRMAN FROINES:  Bill, let me just make one

11   comment to the panel.

12             Last night we were talking about the issue of

13   science, and one of the things that people should recognize,

14   I think, is that FIFRA, under FIFRA they collect an enormous

15   amount of data on toxicity through studies mandated to

16   industry, and but the nature of that -- the nature of those

17   studies are relatively defined by the regulatory

18   requirements that they engage in.  So that whereas an

19   academician who is interested in underlying mechanisms of

20   toxicity would be approaching things from a wholly different

21   standpoint, and it's important for us to recognize that

22   while EPA collects important information, that there are

23   limits on the scope of that research, and so we need to

24   keep, always keep in mind the balance between the kinds of

25   work that goes on in academics study versus in a regulatory



 1   context.

 2             MR. JORDAN:  Right.

 3             Looking at the outline, the types of risks that we

 4   address are very broad.  We look at the risks that derive

 5   from the presence of pesticide residues in food, and we have

 6   very extensive, elaborate process for estimating those

 7   risks, which I'll discuss in more detail.

 8             We also look at the presence of pesticide residues

 9   in water, and add those to the risks from pesticides in food

10   to come up with a dietary exposure estimate.

11             Dr. Froines mentioned occupational exposure.  When

12   you apply a pesticide, there is potential for exposure, and

13   we are in the business of trying to estimate the risks there

14   and to put in regulatory controls to make sure that those

15   are acceptable.

16             In addition, there is potential for bystander

17   exposure.  Bystander is probably a poor term to describe a

18   whole host of potential scenarios that might arise.  For

19   example, agricultural workers reentering a field that has

20   been treated, people living in apartments or homes near

21   places where a pesticide has been applied, children going to

22   school where pesticides have been applied for cockroach

23   control or rodent control kind of programs.

24             So the bystander issues are another type of risk

25   on which we ask for data.



 1             And then, finally, we also pay attention to

 2   wildlife risks, what happens to the birds, fish, mammals.

 3   We also worry about plants and insects that might be

 4   affected by the use of the pesticide in the environment.

 5             The programs that we bring these things up in are

 6   identified in the next heading under the outline.

 7             Registration is the process of looking at new

 8   products that are being presented for market entry.  As I

 9   mentioned, every pesticide product must be registered, and

10   to the extent that it represents something new that we

11   haven't looked at before, it undergoes a thorough risk

12   assessment, and we decide whether or not to grant the

13   registration.

14             Reregistration, as the name suggests, is going

15   back and doing that over again for the products that have

16   already been admitted to the market.

17             Beginning in 1972, and then in a succession of

18   amendments to the law, EPA has been directed to go back and

19   reexamine all of the decisions it's made in previous years

20   to determine whether or not against the contemporary

21   scientific standards and contemporary standards of

22   acceptable risks, the decisions will come out the same way.

23   If they don't, then EPA is directed to change, to ask for

24   more data to change the conditions of registration so that

25   the products would be considered up to date.



 1             DR. FUCALORO:  How many products have you

 2   reregistered to date?

 3             MR. JORDAN:  It's probably helpful to define some

 4   terms here.

 5             Pesticides are a mixture, generally, of a number

 6   of different chemical ingredients.  The active ingredient is

 7   the element that achieves the pesticidal effect and it is

 8   the focus of the -- primary focus of our regulatory efforts.

 9             The inert ingredients, the emulsifiers, the dyes,

10   the perfumes, the extenders, the stickers, also are looked

11   at and have to be approved, but, I will tell you, we do not

12   do nearly as an in-depth assessment of them.

13             That whole product gets registered after we have

14   looked at the active ingredients.  And we have looked at, of

15   the roughly 400 active ingredients, we've looked at

16   something like 200 of them, and reregistered the products

17   containing those active ingredients.  And I don't remember

18   exactly what the count is.  I think it's somewhere around

19   4,000 or 5,000 out of the 20,000 products that are

20   registered.

21             But by volume of pesticide use, I think we're

22   somewhere in the neighborhood of 75 percent of the poundage

23   of active ingredients that are used in the United States

24   that have been looked at in those first 200.

25             I should put a footnote down that chlorine is by



 1   far the largest use of any pesticide active ingredient.

 2             DR. FUCALORO:  I guess what I was trying to get at

 3   is when you go through the process of reregistering, have

 4   you found that mistakes were made the first time where more

 5   information made you change --

 6             MR. JORDAN:  Sure.

 7             DR. FUCALORO:  -- usage?

 8             MR. JORDAN:  Almost every single product, every

 9   single active ingredient, has had both new data requirements

10   imposed on them, and has had to undergo some sort of changes

11   with respect to the uses that are allowed, the conditions

12   which under those products may be used.

13             DR. FUCALORO:  Substantially new conditions?  I

14   mean, what I guess I'm trying to get at is if -- this is a

15   lot of work, it seems to me.

16             MR. JORDAN:  Sure.

17             DR. FUCALORO:  Certainly, I don't mind work,

18   especially when you're doing it, but what --

19             MR. JORDAN:  You're paying for it.

20             DR. FUCALORO:  Is it a good expenditure of energy

21   to do it at, say, at the schedule you currently have, is it

22   worth doing it?

23             MR. JORDAN:  Is it resulting in real changes out

24   there in the world?

25             DR. FUCALORO:  That's what I'm asking.



 1             MR. JORDAN:  In the eye of the beholder.

 2             I think from our point of view, we're seeing, we

 3   think, that there are significant changes.  A lot of the

 4   older products, companies looked at them and basically said,

 5   you know, when we handicap the chances of getting through

 6   the process, and we add in the cost of generating the data

 7   to satisfy EPA that our product should get through the

 8   process successfully, we think we are probably better off

 9   abandoning it.

10             A large number, we started off with 600 active

11   ingredients that we were looking at, about 200 of them

12   disappeared --

13             DR. GLANTZ:  How many?

14             MR. JORDAN:  -- on that basis.

15             About 200.

16             Now, some of them were, admittedly, small things

17   that had niche markets that just wouldn't support the

18   economics of doing the new testing, but others of them were

19   bad actors that people said, you know, we'll throw in the

20   towel now and not put up much of a fuss.

21             For the ones that we have gone through, and I

22   wasn't counting that 200 that kind of disappeared, for the

23   ones that we've gone through, it's very common for companies

24   to change application rates and cut them substantially, to

25   agree to put on requirements for closed systems that would



 1   limit occupational exposure or add protective equipment, to

 2   change the method of application such that it would reduce

 3   drift, for example, things like that.  And in some cases get

 4   rid of uses that are associated with particularly high

 5   risks.

 6             Now, I will tell you that there are certainly

 7   environmental and consumer advocacy groups that say EPA

 8   didn't go far enough on some of those products, but other

 9   people say we went way too far.

10             DR. FUCALORO:  When you are criticized from both

11   sides, you have a sense that you are right.

12             MR. JORDAN:  Or that we're really wrong.

13             DR. FUCALORO:  That's right.

14             CHAIRMAN FROINES:  When you're going through this

15   process or when you're requiring industries to do studies,

16   how do you validate that those studies and those reviews are

17   done effectively?  I mean, when you basically ask the fox

18   to, you know, do the study to determine that he's safe, you

19   have to worry about that.

20             That's a very bad analogy, I know, but it's the

21   best I can think of.

22             MR. JORDAN:  An appropriate analogy.

23             DR. GLANTZ:  Install an alarm system on it.

24             MR. JORDAN:  Let me direct your attention to the

25   Roman numeral II C, which is quality control measures, on



 1   the outline, and I'll go down through those and I'll hope

 2   they'll answer some of your questions.

 3             CHAIRMAN FROINES:  If you want to wait and defer

 4   it until you get there, go ahead.  Don't let me --

 5             MR. JORDAN:  Might at well do it now.  That's

 6   okay.

 7             We've got a lot of different programs in place to

 8   assure that the data are high quality and reliable.

 9             The first is good laboratory practice rules.  And

10   in the package of material that I put together and that you

11   all have, there's one sheet from the Code of Federal

12   Regulations, it's page 127, that describes all of the good

13   laboratory practice standards that EPA has for performing

14   tests that come into the agency.

15             There are -- they are modeled on and consistent

16   with the FDA good laboratory practice standards that were

17   developed following some scandals in the drug arena, I think

18   by Searle Company, although I'm not positive about that,

19   that raised some serious questions about the ability of

20   government agencies to identify fraudulent dry lab

21   information.  And so these measures are put in place to

22   diminish the chances that that might happen.

23             Every laboratory has to have a fixed protocol for

24   performing the study.  It has to have an independent quality

25   control group.  It has to maintain scrupulous records of how



 1   the study was performed.  It has to document its standard

 2   operating proceeds for calibration of equipment, for

 3   collection of data.  It has to have animal care protocols in

 4   place to assure that the animals are handled in a way that

 5   won't compromise the reliability of the data.

 6             Similar procedures with regard to the assurance of

 7   the quality of test material and so on and so forth.

 8             And you can see and get a sense from looking

 9   through the good laboratory practice standards regulations

10   headings here, some of the things that those are -- that

11   those regulations deal with.

12             In addition to those standards, we have a

13   laboratory audit program, which is a program of inspections,

14   both random and targeted to the laboratories that are

15   submitting data to the agency.

16             EPA inspectors usually trained in the fields of

17   doing these kinds of, particular kinds of studies, will go

18   out to the laboratory and pick a test and go through the

19   paperwork in depth and in detail to see whether or not the

20   company has accurately reported what it did and that what it

21   reported matches up with the records that the company, the

22   laboratory, is required to maintain.

23             And if there are violations, then those

24   laboratories are subject to modest penalties under the law,

25   but more importantly we tell the pesticide companies that



 1   they are in peril of having to do tests over again.  And if

 2   you've heard the word that you might have to repeat a

 3   million dollar cancer study or $2 million cancer study, I

 4   forget what the going rate is these days, the pesticide

 5   companies start to look seriously and create a lot of

 6   pressure on the laboratories to do it right for the first

 7   time.

 8             DR. FUCALORO:  Your 20 years of experience tells

 9   you what, are they generally in compliance with these

10   things?

11             MR. JORDAN:  I think that the agricultural

12   chemicals and the toxicology field compliance is very high,

13   and the quality of the lab data coming to us are very good.

14             There are some other areas where the standards are

15   not as rigorous.  In particular, area where I used to work

16   in the antimicrobials efficacy testing, there have been some

17   abuses, and it worries us and --

18             DR. FUCALORO:  Incompetence or deceit?

19             MR. JORDAN:  Say again.

20             DR. FUCALORO:  Incompetence or deceit?

21             MR. JORDAN:  A little bit of both.

22             We're trying to weed out those bad apples as best

23   we can.

24             In addition to the laboratory audit program, we

25   are -- we have a test guidelines program, which is basically



 1   writing out almost protocol level directions about how to

 2   perform different types of studies.  And the guidelines are

 3   not necessarily binding, but they represent a very strong

 4   encouragement that when you do a particular kind of study,

 5   this is the -- these are the ways that you ought to do it,

 6   this is a number of dose levels, this is the number of test

 7   animals, this is the frequency of performing various kinds

 8   of clinical symptoms, this is how often to weigh the

 9   animals, these are the organs you necropsy post mortem, and

10   that sort of thing.

11             Those guidelines are developed in consultation

12   with other parts of EPA, other federal agencies, undergo

13   external peer review, undergo public comment, are published.

14   They have been used as the basis for international

15   guidelines development.  To the extent that international

16   organizations are developing them, we try to harmonize with

17   them.

18             So I think they have a very very wide basis of

19   support in terms of the scientific examination and consensus

20   around them.

21             DR. ATKINSON:  Does that include guidelines for

22   environmental degradation?

23             MR. JORDAN:  It does.

24             In addition to the test guidelines, we have

25   developed standard reporting formats.  We tell the companies



 1   who have done a study and send the study to EPA, this is how

 2   we want the data to be formatted, and these are the data

 3   that we expect to appear in the report, so that we will be

 4   in a position to review the data for quality purposes, as

 5   well as substantive purposes, to figure out what it tells us

 6   about the action of the chemical.

 7             We have standard evaluation procedures, which are

 8   instructions for our scientific reviewers, about what it is

 9   they are to look for in their examination of a study report,

10   both for the quality and substantive purposes.

11             And then that also gives them directions about

12   what they are to put in their study reviews.  Our study

13   reviews are standardized so that we feel like one reviewer

14   can go and pick up another reviewer's work and read through

15   it and understood what happened with that particular study.

16             DR. GLANTZ:  Do you guys go out and do spot checks

17   of the laboratories or audits?

18             MR. JORDAN:  Sure do.

19             DR. GLANTZ:  Do they know you're coming or do you

20   just show up?

21             MR. JORDAN:  They know that we are coming with

22   regard to when we want to do a records check.  And the

23   reason is, we've discovered that sometimes the records are

24   stored someplace other than where the laboratory's

25   conducting its day-to-day business, and we need to give them



 1   enough advance notice so that they can get the records.

 2             DR. GLANTZ:  I wasn't thinking so much about the

 3   paper, I was thinking of going in there and actually seeing

 4   that there are rats in cages and that they are doing the

 5   protocols the way they say they are.

 6             DR. FUCALORO:  They send in undercover.

 7             DR. GLANTZ:  Yeah.  No, but I mean I'm serious.

 8   Do you guys go in there announced or unannounced?

 9             MR. JORDAN:  They are usually announced, I think,

10   about a week in advance.  We think for these laboratories

11   that it's hard to create a lab in seven days.  So it's not

12   enough advance notice that they could sort of fix

13   everything.

14             DR. GLANTZ:  What were you saying, there are

15   rent-a rats, you say?

16             DR. FRIEDMAN:  Rats on rats.

17             MR. JORDAN:  And then the last thing I want to

18   talk about is something Dr. Froines and I discussed last

19   night, which is the scientific peer review.  Not only do our

20   data reviews undergo peer review within the agency, but when

21   a particular study is key to what we're doing from a

22   regulatory point of view, we also seek external peer review.

23             We have a group called the Scientific Advisory

24   Panel at EPA, which is comprised of scientists in the

25   relevant disciplines, and they examine our work and give us



 1   feedback on it.

 2             These Scientific Advisory Panel meetings are

 3   public, under the Federal Advisory Committee Act, and

 4   members of the public are also invited to comment and

 5   critique EPA's process.

 6             You can be sure that, because of the stakes, that

 7   the chemical companies look at it very closely and give us

 8   comments on it.

 9             We also get comments from environmental groups.

10             When we are working on something that's also being

11   reviewed at the California Department of Pesticide

12   Regulation, we work with them and exchange reviews and

13   expertise.

14             So we get a lot of different types of review over

15   the course of working through our stuff to make sure that we

16   come out with scientifically defensible material.

17             CHAIRMAN FROINES:  I have an announcement of a

18   meeting.  It's the FIFRA Scientific Advisory Panel open

19   meeting on February 23rd and 24th.  And it looks to me as if

20   they're going to be dealing with three issues, sediment

21   toxicity and the fate of synthetic pyrethroids, time

22   sensitive reversible -- reversibility of aldicarb-induced

23   cholinesterase inhibition as a factor in acute dietary risk

24   assessment, and, third, consultation on development of draft

25   aggregate exposure assessment guidance documents for



 1   combining exposure from multiple sources and routes.

 2   Crucial issues.

 3             MR. JORDAN:  They are.

 4             DR. FUCALORO:  We'll be talking about those;

 5   right?

 6             CHAIRMAN FROINES:  And my question is not to put

 7   Paul Gosselin on the spot, but --

 8             DR. GLANTZ:  We never would to do that.

 9             DR. BLANC:  Is that the same spot where he's been

10   previously?

11             DR. FUCALORO:  It has his name on it.

12             CHAIRMAN FROINES:  Having said that --

13             DR. GLANTZ:  Dignified, now.

14             CHAIRMAN FROINES:  Dignified.

15             Will this be a meeting that DPR would attend and

16   participate in?

17             MR. GOSSELIN:  Yes.  Actually, one of our

18   scientists have been contacted to participate on the third

19   item.  They occasionally, the SAP, brings in, my

20   understanding from the standing members, they will bring in

21   scientists from different disciplines on specific topics and

22   have been asked to participate on the third topic.  So we're

23   going to be there.

24             CHAIRMAN FROINES:  It seems to me that the third

25   topic is really crucial.  Just to tell you again, it's



 1   consultation on draft aggregate exposure assessment guidance

 2   document for combining exposures from multiple source and

 3   routes, and clearly that's a major issue in California, and

 4   one that this panel will presumably take up at some point,

 5   because the issue of multiple pesticide exposures is clearly

 6   an important issue.

 7             So I think that we would like to be aware of these

 8   kinds of meetings in case anybody wanted to attend, and also

 9   to be at some point when somebody comes back from a meeting

10   like that to learn more about what actually happened.  So

11   we're kind of abreast, because this is really cutting-edge

12   policy and science, and so it's really quite important for

13   California to be an active participant, and even for the

14   panel if they wanted, somebody from the panel wanted to go

15   at some point.

16             But I just say that, because I think that these

17   things come up and we're generally not aware of it.  I just

18   happened to get it from a friend of mine, who is one of the

19   advisory board people.

20             MR. JORDAN:  A couple of things to add.

21             The first is that the documents that will be

22   discussed at that meeting of the Scientific Advisory Panel

23   are available on the World Wide Web, EPA pesticide site,

24   including a lengthy paper on the aggregate exposure

25   assessment.



 1             And, secondly, when the panel has reviewed, held

 2   one of these meetings, reviewed documents, they write

 3   comments, which are also posted at the same Web site.  And

 4   our previous issue papers and SAP comments on them are

 5   maintained there for a year or so.

 6             DR. BYUS:  You also -- I'm on one of the panels,

 7   you also e-mail -- if you're interested, they will e-mail

 8   you regularly about everything that's going on.  You don't

 9   have to look for the postings, it just shows up on your

10   e-mail with attached documents describing everything that's

11   going on, for as much detail as you're interested in.

12             MR. JORDAN:  Right.

13             CHAIRMAN FROINES:  I think that we're still in

14   something of a learning curve on pesticide, so the more

15   input, the more time it takes to read it, but I think the

16   better overall it will be for all of us.

17             MR. GOSSELIN:  Might I suggest, I'll talk to Bill

18   about getting the address for that list server, and that

19   might be a source, because I was thinking otherwise we can

20   track the topics as they come out and sort of give you a

21   synopsis of the topics, but if they have a list server

22   already built in, that might the these easiest source, if

23   you don't mind getting those things occasionally.

24             CHAIRMAN FROINES:  Everybody can just create a

25   filter that goes into the file.



 1             MR. JORDAN:  Okay.  Let me try to get back and

 2   finish up the first heading.

 3             Tolerance reassessment is this process of looking

 4   at the tolerances side of the pesticides that are already on

 5   the market.  It is noteworthy, because unlike

 6   reregistration, there are some fairly specific deadlines for

 7   EPA to review the tolerances, and it also gives us

 8   priorities about what we are doing.

 9             From that new mandate, EPA has focused in on the

10   organophosphate insecticides as being among -- the shorthand

11   term we use is worst first, among the groups of pesticides

12   that we could have looked at that, the ones that seem to

13   have associated with them the greatest potential dietary

14   risk.

15             And we are deeply into the review of those

16   organophosphates and making the preliminary risk assessments

17   and refined risk assessments available to the public.  Over

18   the next six months or so we will be moving through the

19   process of having refined our risk assessments and making

20   regulatory decisions about what needs to be done to mitigate

21   the risks, not only the dietary risk, but also the worker,

22   bystander and wildlife risks that are identified with the

23   use of the organophosphates.

24             I think that is going to be critical for a variety

25   of reasons.



 1             The first is that the organophosphate insecticides

 2   are very important to agriculture, and so a lot of people

 3   are interested in those decisions for that reason.

 4             The second is that the decisions themselves will

 5   set precedents about EPA approaches questions like

 6   cholinesterase inhibition, application of the aggregate

 7   exposure assessment techniques, how we're going to use

 8   probabilistic exposure assessments and so forth.

 9             So the next nine months are going to be very very

10   busy for us.

11             I think it was Dr. Atkinson who asked about the

12   types of data that EPA collects.  The next Roman numeral

13   identifies the broad areas.  Product chemistry is what's in

14   the product, down to contaminants and impurities at the .1

15   level of the product.

16             Toxicity data, the three pages that I attached

17   from the Code of Federal Regulations, called toxicology data

18   requirements, are the data requirements show the different

19   types of data that EPA fairly routinely requires.  And you

20   will see that there are six or seven different acute tests,

21   a battery of subchronic testing by different routes of

22   exposure, feeding, dermal and inhalation, and then a number

23   of chronic studies, two sort of general chronic toxicity

24   studies and a rodent and nonrodent oncogenicity data in two

25   different rodent species, two different studies for



 1   developmental teratogenic effects, a two-generation

 2   reproduction study, a battery of mutagenicity testing

 3   requirements, and then we also require a metabolism study

 4   and on special occasions a dermal penetration study.

 5             Those data requirements have been in effect since,

 6   oh, the early '80s.  We have -- since then we haven't

 7   updated this regulation, but since then we have begun

 8   requiring other types of toxicity data, particularly

 9   immunotoxicity and developmental neurotoxicity.

10             There's a battery of studies, schedule operant

11   behavior and so forth, and I don't remember all the names of

12   them, that we require when there is some indication that

13   there may be effects on the nervous system, particularly of

14   the developing organisms that warrant further investigation.

15             And we are currently considering making it a

16   routine data requirement for any pesticide that has food

17   uses or has other exposure profiles that would involve

18   exposure to children or infants.

19             So that's the set, the suite of toxicity studies

20   that are required to be submitted to the agency on pretty

21   much every pesticide these days, every major pesticide.

22             It's possible that something used in flume water

23   for paper making might not have that full set, but those are

24   by far the exception.

25             Yes, sir.



 1             DR. BLANC:  One of the problems that we have run

 2   into in terms of making the transition from documents

 3   prepared for California pesticide use, as opposed to what we

 4   need for our purposes, has been related to comments from the

 5   California Department of Food and Agriculture, or pesticide

 6   unit, that they have discounted the results of a particular

 7   test because it was inconsistent with FIFRA guidelines.  I'm

 8   paraphrasing.

 9             But it's caused some consternation to this panel,

10   because it has led to data within the document which would

11   otherwise be of concern for us from a public health point of

12   view to somehow be discounted from California food --

13   California ag point of view, because it was considered by

14   them not as relevant to their perceived pesticide regulation

15   requirements.

16             Would you comment on that?  What could it possibly

17   mean if a test in ten dogs would show that they started

18   falling over at 10 parts per million, didn't meet FIFRA

19   guidelines, what is the code word for it?

20             MR. JORDAN:  Well, when I was discussing the

21   quality control measures, I talked about the test

22   guidelines, and that is the reference that I suspect Cal DPR

23   is talking about.

24             If you look at the toxicology table, you'll see in

25   the far right-hand column, guidelines reference numbers.



 1   Those are the -- there is a guideline for each particular

 2   kind of study.  It tells -- as there is for almost every

 3   other type of study in each of the other disciplines that we

 4   examine.

 5             What we say at EPA is we have to have a

 6   scientifically sound study that addresses all of the aspects

 7   that a particular study requirement is intended to evaluate.

 8             For example, if an oncogenicity study were

 9   performed and looked only at five or ten organs, and it did

10   not include histopathological examination of the list, I

11   think now about 25 organs in tissues that need to be looked

12   at, in post mortem, then we would say that doesn't satisfy

13   our requirement that we have in oncogenicity study.

14             It does not mean, however, in our view that the

15   study is scientifically useless.  That study may well be

16   very reliable for the kind of information that it contains.

17             DR. BLANC:  Therefore you would use it?

18             MR. JORDAN:  We would use it for whatever

19   information it contained.

20             DR. BLANC:  Well, I think that cuts to the heart

21   of the matter, because, to me, part of this is the parallel

22   to the criticism that one inappropriately gets on a research

23   paper where someone says you found these results which are

24   very -- two things are very highly correlated, but your

25   sample size was small, therefore these are not reliable



 1   results.

 2             Well, the small sample size might keep me from

 3   seeing a relationship or being able to reject a null

 4   hypothesis when I should, but if there's a very potent

 5   relationship that does cause me to reject a null hypothesis,

 6   then small sample size is, in that sense, irrelevant,

 7   because it impacts my error in the other direction.

 8             And, to me, this is a key issue when -- Paul, I'd

 9   like you to take this into account in your documents, that

10   if -- to me, it will not be an argument that I will accept

11   that a study didn't meet FIFRA guidelines if there is in

12   fact a finding which does show a toxic endpoint.

13             To me it's more of an issue if toxic endpoint has

14   not been seen, then perhaps we should discount falsely

15   attributing a no effect level at those --

16             MR. GOSSELIN:  I'd like to keep this general,

17   because I think there are some specific issues that we're

18   talking about that you're bringing up, but what Bill

19   described largely mirrors the position we have.  I know that

20   there have been cases where specific studies have been sort

21   of --

22             DR. BLANC:  Downplayed.

23             MR. GOSSELIN:  Downplayed.

24             DR. BLANC:  Or downgraded?

25             MR. GOSSELIN:  And part of the reason was the



 1   guideline issue to put up.

 2             But each case is very specific.  And I know of

 3   cases in risk assessments, some that haven't been brought

 4   here, where the body of evidence, some of it non-FIFRA

 5   studies, have been used or actually contributed to the

 6   weight of evidence.

 7             So I think largely it's going to come down to the

 8   specific circumstance, but I think to categorically say that

 9   we would totally discount and not look at what a non-FIFRA

10   guidelines study shows us, is not opposition if it's brought

11   out that way.  That's really not what we're looking at.  It

12   might have been presented that way, but that isn't sort of

13   the course of business we've been doing.  There might be

14   specific circumstances where there's some scientific

15   disagreement about those studies, and that, I think, we

16   could probably get into on the specific compounds when they

17   come out.

18             DR. BLANC:  Two other areas, I think, of

19   importance.

20             One is related to the specific guidelines for

21   inhalation studies, and it might, because frequently from

22   within a myriad of studies that California has done with

23   just as your agency does, the one which is most relevant to

24   some of our deliberations may be the inhalation studies, and

25   then there have been issues that have come up related to



 1   whether or not the test animals could have been dosed

 2   through grooming, in addition to inhalation and so forth.

 3             And I think it may be helpful to get a sense in

 4   more detail as to what you're -- what the EPA approach is in

 5   the inhalation studies specifically, and you may want to

 6   transmit some -- if there's a written protocol that you have

 7   in discussion from the EPA, I think that -- I think that

 8   would be useful for this panel particularly.

 9             And the other issue that's come up more recently

10   is the interpretation of the neurotoxicity studies in the

11   hen, since it's our understanding that in fact the hen is

12   the only reliable animal test for delayed peripheral

13   neuropathy or the most reliable with test chemicals,

14   particularly organophosphates that are likely to cause that

15   effect, and yet we seem to have gotten into a bit of a

16   paradox where precisely because it was in the hen, the data

17   were discounted in an odd way, or potentially discounted.

18             And, John, correct me if I'm wrong, but that was

19   an area of discussion at our last meeting.

20             CHAIRMAN FROINES:  Can't use it for risk

21   assessment.

22             DR. BLANC:  What's that?

23             CHAIRMAN FROINES:  Can't use the hen data for risk

24   assessment, was the argument and that was --

25             DR. BLANC:  Shot down.



 1             CHAIRMAN FROINES:  Well, we just said basically if

 2   it is the best model, then that seems the most appropriate

 3   model for risk assessment, if you can do the species to

 4   species.

 5             DR. BLANC:  Right.  So we were kind of curious

 6   about how EPA handled that specifically.

 7             MR. JORDAN:  I'm probably out of my depth

 8   technically.  I know that the hen study is one that is

 9   listed here as a data requirement and that --

10             DR. BLANC:  So it seems that you would be using

11   the risk assessment --

12             MR. JORDAN:  -- the details say it's for

13   organophosphates and carbamates, I think.

14             And it's been on the books for a long time.  I

15   remember hearing about it in the '70s and knowing that EPA

16   was using it.

17             The latest thinking about how EPA evaluates

18   substances that inhibit cholinesterase is described in one

19   of a series of papers that we released and asked for the

20   public to comment on.  And I don't remember it saying

21   anything one way or the other about using the hen as a test

22   species.  I'll go back and see if we have any information

23   that might be responsive on that.

24             DR. BLANC:  Then in terms of the ones, the

25   pesticides that have to go back to be recertified, that you



 1   were discussing, and that's in process currently?

 2             MR. JORDAN:  Yes, sir.

 3             DR. BLANC:  I would hope that the OEHHA group is

 4   in contact with you on any of the substances from their

 5   document for which there were not a good acute inhalation

 6   toxicity animal data, because that was the limitation for

 7   some of the chemicals here and some of them may overlap with

 8   FIFRA requirements and maybe there is some acute inhalation

 9   data that's coming down the pike.

10             I'm thinking specifically about chloropicrin and

11   chlorine and phosgene.  Phosgene wouldn't be a pesticide,

12   but chloropicrin and chlorine would come under those.  There

13   may be others that by chance have dual uses.

14             MR. GOSSELIN:  Typically, if I can answer, we

15   mirror the same FIFRA requirements for data, and those are

16   the data sets we have and OEHHA does contact us for not only

17   the hot spots program and also Prop 65 to see what data,

18   FIFRA-generated data, we would have.  Nine times out of ten

19   the studies we have here in California are the same data

20   sets that EPA has back in DC.  So OEHHA routinely does that,

21   and we'll go through a bibliography to see what we have that

22   might support their efforts.

23             CHAIRMAN FROINES:  I think there's another issue

24   too, following up on Paul's comments, which is if you go

25   through the molinate document, you know, I can point out all



 1   sorts, any number of studies which are listed as not

 2   acceptable, and any number of those studies actually have

 3   positive findings.

 4             So on the one hand you have positive findings

 5   showing toxicity.  On the other hand you have

 6   nonacceptability.

 7             And so, one, it's good to hear that the data isn't

 8   thrown out, although I think that's still a question mark.

 9             But the second question then becomes, to the

10   degree that a study is found not acceptable, then it seems

11   to me one should go back to the company and have them redo

12   the study, because otherwise -- with MTBE recently at the

13   Carcinogen Identification Committee, industry

14   representatives came in and argued that the studies were

15   flawed that looked at carcinogenicity.  Well, these were the

16   studies that the industry had used.  So we were, by then,

17   rejecting the studies and rewarding the person doing them.

18   And I think that's a position we have to be careful to

19   avoid.

20             MR. GOSSELIN:  Some of the context, because we are

21   dealing with two issues dealing with study reviews, similar

22   to what EPA does is we're reviewing studies as a requirement

23   for the registrant to either maintain or get registered a

24   pesticide.  It's sort of what you just described as ensuring

25   that they have met the appropriate guidelines and those



 1   studies are complete and adequate.

 2             Many instances we will have, and those studies are

 3   described in the risk assessment documents, studies that

 4   don't meet the guidelines, we wouldn't give the company sort

 5   of the break on accepting it, because they haven't followed

 6   the rule, but those studies were probably done in a way that

 7   we could assess the risk.  But, still, they need to clear

 8   that regulatory hurdle of having a guideline acceptable

 9   study.

10             So there two things.  And, again, speaking from

11   our regulatory hat of things, that they need to get in sort

12   of the study that has all the bells and whistles and the I's

13   crossed -- the I's dotted and T's crossed, but also all of

14   that is used to assess the risk.

15             So there two actual aspects of us looking at data.

16             CHAIRMAN FROINES:  So when we take a document like

17   this, which in the back in the appendices has all these

18   nonacceptables, we will then expect, however, to see

19   evaluation of the data from the nonacceptables in the front.

20             MR. GOSSELIN:  All of those studies that are

21   referenced are summarized in there.

22             And then I think in the description as to how

23   we've characterized the risk should be in the

24   finally-accepted document, fully explained on the rationale

25   as to how we reached the conclusions we did and the



 1   rationale behind that.

 2             DR. BLANC:  I think all John is saying is that

 3   there will be great resistance on this panel to having the

 4   rationale be for not taking a positive study into account

 5   that it didn't meet FIFRA guidelines.  I think that's all

 6   that we're saying, is that you should be prepared for great

 7   resistance on that front, that it better be some other

 8   rationale for not taking positive findings into account.

 9   For example --

10             MR. GOSSELIN:  Largely, I wouldn't disagree with

11   that.

12             DR. GLANTZ:  I think just to hammer on that a

13   little bit and go back to Paul's --

14             MR. GOSSELIN:  Stan, I was agreeing with you.

15             DR. GLANTZ:  I know.  Well, just for the record,

16   I've been sitting here quietly.

17             I think the whole idea of having these guidelines

18   is to keep people, to force people to do quality studies, so

19   they won't miss a positive finding because of a poorly

20   designed study.  So if you have a relatively weak study that

21   comes up positive, in a way that's stronger evidence for an

22   effect than a stronger study coming up positive.

23             Anyway.  But I appreciate that you agree with me.

24   But you are on the spot.  We need to keep wearing the

25   carpeting down.



 1             DR. BLANC:  Where we were?  Sorry.

 2             CHAIRMAN FROINES:  That position is, if you looked

 3   at everybody's heads around the room when that was -- when

 4   Paul said that, I think that you'll find that that's a

 5   pretty unanimous view.  I think, unless somebody wants to

 6   quarrel with that.

 7             MR. JORDAN:  Okay.  Back to types of data.

 8             Environmental effects are effects on birds and

 9   fish, primarily.  Nontarget plants and insects are -- that's

10   pretty self-evident.

11             Environmental fate.  When a chemical is used

12   outdoors, we routinely try to understand what happens to the

13   chemical, how does it degrade, how fast, what are the

14   factors, is it hydrolysis, is it photolysis, is it microbial

15   mediated, that sort of thing.

16             It's important to us to understand not only what

17   the parent is, but also what the metabolites are.  And that,

18   incidentally, is something that we look at in the mammalian

19   metabolism study as well.

20             So we are trying to see not only -- well, try to

21   see where the parent goes, but also what the metabolites

22   are.

23             Residue chemistry is the whole section of

24   information related to residues in food.

25             DR. ATKINSON:  Excuse me.  Any chance of getting a



 1   copy of the guidelines for the environmental degradation?

 2             MR. JORDAN:  Certainly.  Sure.

 3             CHAIRMAN FROINES:  When you identified degradation

 4   products, does that trigger some kind of toxicity review?

 5             MR. JORDAN:  Yes and no.  There is a group within

 6   our science division that looks at metabolism issues, and

 7   one of the things is that sometimes the environmental

 8   degradates are also formed in vivo through mammalian

 9   metabolism and in those cases we figure that the toxicity

10   tests will evaluate the impact of the metabolites.

11             Now, I recognize that's not always the case

12   because of sites, and so forth, but that's a sort of general

13   first rule of thumb.

14             The second is that if -- we've got chemists who

15   look at the metabolite and say, gee, does this look like

16   it's got the active moity in it or is it breaking down to

17   carbon dioxide or other substances, essentially say we feel

18   fairly confident it's not a problem.

19             If there is a metabolite that is formed

20   environmentally, that is not evaluated through the testing

21   of the parent active ingredient, then on a case-by-case

22   basis the agency can require, although I'd be candid, it's

23   not often done, can require that that metabolite be tested

24   independently.

25             DR. FUCALORO:  And you use the criteria,



 1   biological plausibility, is that correct?  You look at the

 2   compound and say I think this might be a dangerous thing or

 3   it might not be?

 4             MR. JORDAN:  Right.

 5             DR. FUCALORO:  That doesn't always work, of

 6   course.

 7             MR. JORDAN:  Granted.  But one could easily

 8   exhaust the capacity of the world testing various metabolic

 9   breakdown products.

10             DR. FUCALORO:  It's also a welfare program for

11   scientists.

12             MR. JORDAN:  And a worthy thing to do.

13             There may be other more valuable ways to use their

14   time.

15             Human exposure assessment is an area that we also

16   require monitoring, both monitoring of exposure substrates

17   like sampling of residues on foliage in a field that's been

18   sprayed with a pesticide or monitoring of pesticide residues

19   in dirt or air or that sort of thing, coupled with

20   characterization of the human activity patterns that would

21   lead to contact with the chemical in the environment.  For

22   example, how often -- how much time do children typically

23   spend crawling on the lawn such that their contact with a

24   pesticide-treated lawn might lead to exposure.

25             We also have provisions for biological monitoring



 1   of human volunteers to evaluate internal dosage, coupled

 2   with the mammalian metabolism studies, it gives us a picture

 3   of internal dose and helps us to correlate external

 4   environmental exposure with internal dose.

 5             That's an area which we're working on.  I think

 6   it's got a lot of room for improvement, but still where we

 7   are is trying to push the envelope in those areas.

 8             Spray drift evaluation is another special area

 9   where pesticides are applied through helicopters or

10   airplanes or ground sprayers.  The spray may drift off

11   target.  And this is a body of data that actually are not

12   chemical specific, but much more related to the

13   characteristics of the spray and how it's delivered.  We've

14   discovered that things like droplet size, height of the

15   equipment, orientation of the nozzle, through-put of the

16   amount of water or other diluent put through the spray

17   system will eventually wind up driving the amount of

18   material that will drift off-site.  So this is a series of

19   data requirements that help us to evaluate that.

20             CHAIRMAN FROINES:  Do you do that yourself, is

21   that done by contract, does the -- do the users do it or how

22   is it -- how do you handle that procedurally?

23             MR. JORDAN:  That's a perfect segue into the

24   next -- most of the data we get come from the pesticide

25   companies.  It seems to us and sort of in broad policy point



 1   of view that we ought not to ask the American taxpayer to

 2   pay for developing the data to evaluate the safety of the

 3   products that will provide financial returns to the

 4   companies that make those products.  So the burden is put on

 5   the pesticide company to generate a database which will be

 6   sufficient for EPA to evaluate the safety of the products.

 7             CHAIRMAN FROINES:  You know the problem with that

 8   is the database that we use in this room, that George uses

 9   on a daily basis, by and large comes often from the NTP

10   bioassays that were done in the '70s and '80s.  That's the

11   database which is used on an international basis around

12   toxicity.

13             We don't have an equivalent EPA database, because

14   that information is often not available to us.  So that our

15   entire view of carcinogenicity is driven by the five or six

16   hundred chemicals that NTP tested in the '70s and '80s, 600,

17   I think.

18             And if we have five or six hundred chemicals from

19   EPA, that would be an additional major source of

20   information.

21             And one of the problems with that philosophy,

22   which I fundamentally disagree with, you have to call a

23   spade a spade.  We need information on toxicity and if it's

24   not available to us, then it doesn't serve the broader

25   public interest.



 1             So that I understand the point of view, because I

 2   was on the NTP committee when I was in Washington, but it is

 3   a problem, because we don't have access to information that

 4   would benefit everyone in that process.

 5             So that the data from the companies is all well

 6   and good, but if nobody else has knowledge of it, then it

 7   doesn't serve the public need, I don't think.

 8             And that's not a criticism of you.  It's just a

 9   comment.

10             MR. JORDAN:  We are doing more in the arena of

11   trying to make our data available.  Let me just say a little

12   bit about that process.

13             I was checking through our reference material

14   here.  We've received over 27,000 studies in response to our

15   reregistration program and data call-ins, and not all of

16   them are toxicity studies, by a long shot.

17             But all of those data, with the exception,

18   probably, of product chemistry, are available for anybody to

19   request through the Freedom of Information Act.  And we

20   routinely release studies in response to that.

21             To ask for a study, you've got to have at least

22   some sort of clue as to what it is, and that's not the best

23   way to make things available, but we are trying to improve

24   on and expand on that.

25             When we do a reregistration decision, we write a



 1   document that's called a reregistration eligibility

 2   determination or decision, and that document, much as Paul

 3   described, summarizes all of the data relating to a

 4   particular active ingredient that we have in our possession

 5   in all of the different disciplines -- environmental fate,

 6   product chemistry, toxicity, residue chemistry, ecological

 7   risks, and so forth -- and identifies the studies through an

 8   identification system that would allow somebody to write and

 9   say I'm interested in the teratology study in rabbits in

10   chemical X, and we would say, fine, here's the study, we can

11   also provide our scientists' review of it and so forth.

12             The reregistration eligibility decisions are

13   available through the World Wide Web, through NTIS, National

14   Technical Information Service, available through the FOIA

15   system, and hope and expect that DPR has copies of those

16   documents.

17             They are supposed to be living, such that if we

18   got a new study in, we would update the reg, but we haven't

19   quite got that system up and running the way we want to.

20             Eventually we will have a system where the studies

21   themselves the scientists reviewed, the disciplinary reviews

22   that integrate for a particular field, all of the studies,

23   and show how it fits into our risk assessment, our risk

24   assessments, all of that will be available through the Web.

25   But we're not there yet.



 1             So at this point the reregistration eligibility

 2   decisions is the primary vehicle for getting it out to the

 3   public.

 4             And it will capture not only the chemical

 5   company's data, but also whatever we might happen to have

 6   available from literature sources or other agencies and the

 7   other sources that we've got.

 8             CHAIRMAN FROINES:  I think we need to figure out a

 9   way to have an interface between what you're talking about

10   and calling ourselves the educated public to those people,

11   because it sometimes seems like a black hole at EPA and, you

12   know, we've heard -- and so that having some sense of how

13   you find information becomes really, I think, crucial,

14   because a lot of the information may be there, but it's just

15   not -- whenever I want to go look for something at EPA, it

16   scares me.  And I think I'm not the only person that's ever

17   had that feeling.

18             MR. JORDAN:  It scares me too sometimes.

19             We have a book that's called How to Get

20   Information from EPA, and we'll send that to you.

21             CHAIRMAN FROINES:  That would be good.  I think

22   that would be useful.

23             MR. JORDAN:  To Mr. Lockett.

24             But I think probably the best course is for when

25   you've got identified specific chemicals that you want to



 1   work on, either through DPR or through Bill Lockett or

 2   something like that, we can -- we can make that information

 3   available, what information we have or summary documents

 4   available to you all and then you can follow up with

 5   specific requests about studies and reviews.

 6             So that's the foundation of what we have for

 7   making our risk assessment.

 8             And depending on how you want to do things, I can

 9   keep plowing ahead and talk a little bit about our risk

10   assessment process, or if you want to take a break.

11             In the realm of risk assessment we look at

12   primarily acute and subchronic exposures for the general

13   population.

14             For workers and occasionally for bystanders we

15   will look at a less than lifetime or subchronic exposure

16   scenario.

17             The Food Quality Protection Act that was passed in

18   '96 said that we need to pay attention to aggregate

19   exposure.  Aggregate exposure is a term that means to us

20   looking at all of the different ways that the general

21   population may be exposed to a single chemical.  So that

22   means pesticide residues in food, pesticide residues in

23   drinking water, exposure that people might get in their

24   homes or their workplace as a consequence of pesticide use

25   in and around those places where people live.



 1             It also means paying attention to nonpesticidal

 2   uses of chemical.  For example, I mentioned I used to work

 3   in the antimicrobials area.  A large number of antimicrobial

 4   pesticides are also used in drug context.  Chemical called

 5   triclosan, for example, has recently been added to

 6   toothpaste.  The brand is Colgate Total and it was approved

 7   under Food and Drug Administration as a plaque-fighting

 8   substance.

 9             And when we evaluate triclosan for its

10   antimicrobial uses, we'll also take into account the fact

11   that people may be exposed from brushing their teeth.

12             So that's the aggregate exposure notion.

13             DR. FUCALORO:  I don't use that, because it

14   actually comes through my tap water.

15             MR. JORDAN:  There you go.  And we look at the tap

16   water exposure too.

17             DR. GLANTZ:  They put toothpaste in your tap

18   water?

19             DR. FUCALORO:  I knew you wouldn't understand it.

20             DR. GLANTZ:  How does it get into your tap water?

21             CHAIRMAN FROINES:  I think it was a joke.

22             DR. GLANTZ:  It was a joke?

23             MR. JORDAN:  It's used in water treatment.  I

24   won't go into that whole thing.

25             Cumulative risk is something that has been on the



 1   books for a long time, but it's something that EPA really

 2   hasn't done until really the passage of the Food Quality

 3   Protection Act.

 4             Cumulative risk means exposure to multiple

 5   different chemicals that operate on mammalian systems

 6   through a common mechanism of toxicity.

 7             So this is not interactive effects.  This is not

 8   synergisms or antagonisms.  This is looking to see if you're

 9   exposed to malathion and fenamiphos, two organophosphates

10   that both effect cholinesterase, what's the impact of the

11   exposure to those two chemicals as opposed to looking at

12   them singly.

13             So not only do we need to add up all the risks

14   that might be associated with the presence of a chemical on

15   everything from apples to zucchini and water and

16   residential, but also every one of the other chemicals that

17   might share mechanism of toxicity with that chemical.

18             DR. GLANTZ:  Well, that's, I think that's very

19   good.

20             MR. JORDAN:  I think it's very hard.

21             DR. GLANTZ:  You took the words out of my mouth.

22   It's very hard.

23             I have a couple of questions.

24             One is how do you decide when to do that and what

25   to include?



 1             MR. JORDAN:  Okay.

 2             DR. GLANTZ:  And the other question, which sort of

 3   grows out of that, in the work we've been doing so far, we

 4   really haven't done that.  And the question is what guides

 5   did you have for us in terms of how?  Because I think it's a

 6   very logical thing to do.  Could you give us some guidance

 7   on what you think we ought to be looking for to try to

 8   incorporate those kind of considerations into what we're

 9   doing.

10             So they're kind of related questions.

11             MR. JORDAN:  The first question, I think there's

12   something that can be said that may be helpful.  The second

13   question is more difficult, at the moment at least.

14             On a week ago Friday, EPA published its science

15   policy statement describing how we would approach the

16   decision to group a pesticide with other chemical substances

17   for purposes of a cumulative risk assessment.

18             And as a layperson, I read through the guidance,

19   and I think it was helpful, but far from providing a road

20   map or a recipe about how to make the decision.  It

21   primarily describes the types of information and defines

22   some terms about what we mean when we say common mechanism

23   of toxicity, and then basically says collect all the data,

24   look at the data and make a judgment, using variety of

25   different sources of information, particularly metabolism



 1   data.

 2             The agency has reached a conclusion with regard to

 3   the organophosphates that they operate through a common

 4   mechanism of toxicity, but it is not enough to say that

 5   chemical A and chemical B have LD 50s, they're in the sort

 6   of same range and therefore those two chemicals ought to be

 7   grouped.  It's not enough just to cause the same endpoint or

 8   have the same even carcinogenic effect on the same organ.

 9   Liver carcinogens are not necessarily going to be grouped

10   together.  But at a fairly refined commonality of metabolic

11   pathways is what we're talking about in this arena, such

12   that if you get one chemical you would expect it to

13   reinforce what another chemical is already doing in the

14   body.

15             DR. GLANTZ:  So do you routinely, as you're

16   looking at chemical A, when you define the metabolic

17   pathways, then go out and do a search to see what other

18   things have that same pathway?  I mean, I'm just trying to

19   get some sense of where the boundaries are, because it's

20   potentially a gigantic task.

21             MR. JORDAN:  It is.

22             We are working through it, focusing primarily on

23   pesticides.  And we've got a variety of kind of screening

24   approaches that we use.

25             For example, we look to see common modes of



 1   pesticidal action.  If the pesticides are chiten inhibitors

 2   or anticoagulants, for example, as a number of rodenticides

 3   are, then we would group those together for further inquiry.

 4   We look to see if they have the same toxic endpoint.

 5             We would look at liver carcinogens, I expect, to

 6   see which of those might have a common mechanism of

 7   toxicity.  We look for structural similarities.  Triazine

 8   pesticides, for example, would be grouped together.

 9             Having established those broad categories and

10   putting most of our focus on the universe of pesticides,

11   then we would go through and screen them and if in the

12   course of doing that we found information that suggested

13   there were a veterinary drug or an industrial chemical that

14   would with general population exposure, then we would also

15   include those in our consideration.  But we don't every time

16   we get a new chemical go through this whole process.

17             The second question you asked was once you decide

18   that you've got a group of chemicals that need to be

19   considered collectively for their cumulative risk, how do

20   you do that.

21             And the short answer is we're working on trying to

22   do that for the organophosphates.  There's a certain element

23   of learning by doing, with regard to them.

24             We are concurrently writing guidance that is being

25   developed and will be made available for public comment,



 1   will be presented to the Scientific Advisory Panel at a

 2   future meeting.

 3             Our schedule calls, I believe, for May or early

 4   summer for the first draft of the cumulative risk assessment

 5   guidance to be put out.

 6             It will clearly, in my mind at least, have to

 7   build on the aggregate exposure assessment approach.  I

 8   think it will more likely than not be probabilistic in its

 9   approach, but there's certain limitations on the database

10   about how often a person is exposed to chemical A and

11   chemical B and sufficient proximity in time to make it

12   appropriate to add the exposures together.

13             It will probably have some elements of the

14   toxicity exposure factor which attempts to normalize

15   toxicity across chemicals to take into account the fact that

16   different amounts are needed to produce the same measure of

17   adverse effect in the test species.

18             Beyond that, I can't say a whole lot more.  I

19   think we'll continue to work through it and see where we

20   get.

21             DR. GLANTZ:  Could I just ask, Paul, and then

22   I'll -- what do you guys think about all this?  Because

23   obviously it's not something -- I mean, I think it's

24   something we need to be doing.  What do you think about it

25   and how would you operationalize it?



 1             MR. GOSSELIN:  From my perspective, just being

 2   sort of in this field for a number of years, that these were

 3   questions that have routinely been raised over the years

 4   and, frankly, we didn't have -- the stock answer was that

 5   our scientific knowledge and expertise hasn't brought us

 6   there yet, and we're focusing in on trying to keep pace on

 7   the evolving science on trying to regulate each pesticide on

 8   their own.

 9             I think the enormous task that EPA had to

10   undertake, looking at these issues, was something that we're

11   in one respect was looking at, yes, however this comes down

12   is going to answer a large set of questions that have been

13   lingering out there for a number of years.  We've been

14   working with EPA as they've been going through this and

15   going through a series of issue papers and outside panels

16   that have been pulled together trying to sort these issues

17   out and, frankly, trying to assist as we can in helping them

18   reach the end product and in the end see where they come out

19   and see how that translates to how we operate.

20             So, you know, they do have a daunting task before

21   them.

22             DR. GLANTZ:  I mean, one thing you might want to

23   think about, because I like to see us move in this

24   direction.  I appreciate it's not easy.  And, you know, one

25   thing you might want to think about as you prepare the



 1   documents for us is if there are other pesticides in use

 2   that have common pathways, and I think the common pathways

 3   is a reasonable way to start, to at least discuss them in

 4   the document.  To say that, you know, this pesticide is, you

 5   know, is in use and there are these three others that are

 6   often used in the same area or in combination with it or

 7   something, just to start creeping up on the problem.

 8             MR. GOSSELIN:  There are two issues with that.

 9             One is, you know, EPA did dive into this whole

10   undertaking because of a specific federal mandate.  Because,

11   again, this is embarking on new ground that wasn't done

12   through general policy direction to actually justify the

13   going forward.

14             The second thing is to be able to do that you're

15   going to also need the foundation of having assessed, as

16   Bill said, the aggregate risk from the compounds

17   individually.  And EPA have been on a fairly fast track to

18   do that.  It's been almost an unprecedented time scale to

19   get that foundation together before then you can then take

20   each one of those and start doing a cumulative one.

21             And I think the point we're at, even the pace

22   we're picked up on doing our risk assessments and bringing

23   even as part of that document to you, that foundation is

24   going to need to be built first, before we do that, because

25   I think that starting to expect to have some of that



 1   assessment done in a very preliminary way is going to maybe

 2   shortchange some of the real issues we have with the

 3   individual compounds.

 4             DR. GLANTZ:  Well, no.  I understand.  But what

 5   I'm just suggesting -- I'm not suggesting you do a formal

 6   quantitative assessment, but I think it would be useful to

 7   just have a little section in the report that mentions that

 8   there are these other compounds that when you get to doing a

 9   combined assessment, would be the ones who will probably be

10   thinking about and why, without actually trying to put

11   numbers to it, but to at least start bringing the issue into

12   the discussion in a systematic way.

13             I agree with you, I think we're having enough

14   trouble doing the compounds one at a time, but I'd like to

15   start to see the other things at least brought in.

16             I mean, we're getting to that and dealing with

17   things like secondhand smoke and diesel.  We've had to start

18   dealing with mixtures and more complicated things, so we're

19   moving in that direction anyway.

20             MR. GOSSELIN:  I think back to what we're looking

21   at and even the panel and potential workshop issues, too, is

22   looking to what EPA has put together for guidance and some

23   of the groups are put together to look at these issues as

24   sort of a lead for us to kind of go down that path.

25             So we're right behind you.



 1             DR. BYUS:  I've made the discussion with the

 2   organophosphates, one place to start is food residue.  You

 3   have that data and you know then the exposure isn't

 4   necessarily a big issue.  You know exactly -- as far I know,

 5   there are in food residue multiple exposures, some of the

 6   residues have many organophosphates, at a given level.

 7             I mean, and clearly you're going to be exposed to

 8   them at that level.  This doesn't get to the air exposure,

 9   but it gets to the sort of multiple sort of additive

10   approach.  I don't think it's -- I agree, the big question

11   is very difficult, it requires a lot of effort, but the

12   smaller question, for example organophosphates, are

13   primarily -- or they're not completely additive

14   mechanistically.  At least you can get some rough

15   approximation and see if you get a significant difficulty.

16             And, again, food is, I would imagine, would be the

17   place to do it, where you've analyzed food and know what's

18   there.  Don't you do that?  Isn't that -- that is done,

19   isn't it?

20             MR. GOSSELIN:  Go ahead.

21             I mean the database for food residues and the

22   ability to know consumption patterns and in various regions,

23   I mean, that for both EPA and us is pretty well documented

24   is probably the most solid set of data we have than anything

25   else.



 1             DR. BYUS:  And there you have the exposure

 2   information right there.  You don't have to worry about one

 3   versus the other.  You know so much of this, so much of

 4   that.

 5             MR. JORDAN:  I guess I'm going to demur or qualify

 6   that a little bit.  I think we know what kinds of foods

 7   people eat and we know what range of residues occur on

 8   foods, but how those two intersect is the tricky part.

 9             A lot of -- do we assume that the use of the

10   organophosphates are completely independent, or are they, if

11   you use chemical A, it becomes less likely you would use

12   chemical B.  That's where --

13             DR. BYUS:  But it's on the food.  I'm just saying,

14   it's there.  It's there.  How it got there is another

15   question, but at least in terms of potential risk, the food,

16   the chemicals are there at a certain level.  You have the

17   data on consumption, which again is imperfect, but at least

18   it's reasonable and there's a huge background that you've

19   generated for that.

20             Again, I said, relating that to air is another

21   question.  Multiple air exposure, I've got into a little bit

22   with Ruby, and I realize the difficulty of this for

23   organophosphate.  There's hundreds of them.  You're right,

24   using one will supplant the other one and what kind of crop

25   you use and when you spray it and where the people are and



 1   all of it, that it's hard, I agree.

 2             But when it comes back down to it, you could use

 3   the food data almost to tell you where the air exposure is

 4   occurring too, by simply the multiple residues.  You can

 5   make some reasonable extrapolation on that.

 6             All I'm just saying, it struck me that the food

 7   was the place to begin with for additives for

 8   organophosphates.

 9             MR. JORDAN:  I think so too.

10             DR. BYUS:  Not the entire picture, but for

11   organophosphates.

12             MR. JORDAN:  We think so too.

13             CHAIRMAN FROINES:  I need to interject.  Everybody

14   needs to speak into their microphone, because Peter Kennedy

15   is now with us, albeit by telephone.

16             And I was going to avoid that joke.

17             Peter, can he hear?

18             DR. FUCALORO:  Let's all hold hands.

19             CHAIRMAN FROINES:  I just want to make one

20   comment.

21             Everybody in the room has said this is difficult

22   and everybody nods their head, you know, robotically.  And

23   that's true, it is difficult.  We're talking about aggregate

24   exposure, which is in many of it is called

25   microenvironmental monitoring, which is an exposure



 1   assessment question, it deals with how do you measure all of

 2   the different ways something can reach a person.

 3             The second issue is chemicals with a common

 4   mechanism.

 5             And, thirdly, obviously, you have the third factor

 6   where you have different chemicals with different mechanisms

 7   but similar endpoint or where their toxicokinetics can

 8   impact on the toxicity of a particular chemical and that's

 9   what we would loosely call interactive effects.

10             So you have sort of three areas and they're all

11   very large areas, and they're all at some level

12   interrelated.

13             But the problem is that EPA is a regulatory

14   agency, and these are, in many respects, research questions.

15   And what needs to be done is that EPA, or somebody, NIHS, or

16   whoever, needs to begin funding research that can begin to

17   address these questions in an academic environment, so that

18   people will take them on to get them away from being hard

19   questions that nobody ever says anything about.

20             We have $1.2 million to study exposure assessment

21   to multiple chemicals and it's from the Department of

22   Energy.  Well, this should be coming from EPA to --

23             MR. JORDAN:  We think Energy is fine.

24             CHAIRMAN FROINES:  Or nudge Energy to do more.

25             But the point is that the problem with these



 1   issues is that you work at developing regulatory policy for

 2   how to address them, but the fundamental research that will

 3   help people understand how to address them isn't being done

 4   for the most part, and that's a crime, because 20 years from

 5   now we're going to sit around this table, and some of the

 6   people may have changed, but the people saying, oh, boy,

 7   that difficulty of multiple chemicals is really hard.

 8             And unless we actually find a way to fund research

 9   to address it, and there are ways to do it, we're doing the

10   study in Torreon, Mexico, right now on aggregate exposures.

11   It's possible.

12             And so I think that we need to figure out a

13   pathway to turn complaints about difficulty into some kind

14   of working reality and that's what's not happening.

15             DR. FUCALORO:  Can I comment here.

16             As most of you know, I'm not a toxicologist nor

17   biologist, so some of these things are new to me and I've

18   been listening carefully and reading things over the last

19   year, several months that I've been on the panel.

20             I think the criterion employed that there is -- I

21   think I heard you say a demonstrated common biological

22   mechanism, then one can start looking at adding exposures

23   together.

24             Then you said something that you actually require

25   companies to do certain studies.



 1             Is it not possible, and I don't know if this makes

 2   sense to you, I don't know the EPA and I don't know this

 3   business very well, is it possible for the EPA to designate

 4   certain company or groups of companies or group of companies

 5   to look at aggregate results?  I mean, I don't know if that

 6   makes sense.

 7             MR. JORDAN:  Companies are doing that.

 8             DR. FUCALORO:  Okay.

 9             MR. JORDAN:  When --

10             DR. FUCALORO:  Froines can do it, I imagine.

11             That's an ellipsis after that I imagine.

12             MR. JORDAN:  One of the questions is what does

13   doing it look like?  To some extent, what EPA is doing in

14   the aggregate area is to model certain kinds of exposures,

15   model what will happen in terms of surface water

16   contamination through runoff or groundwater contamination

17   through leaching, model what will happen within an enclosed

18   building, in, say, a school or a nursery school or a home,

19   from the use of an aerosol spray to control cockroaches, or

20   something like that.  And then to add those exposures up.

21             Well, there's a leap of faith that the particular

22   circumstances that were modeled for the groundwater will

23   happen to an individual who also is in a building where

24   cockroach sprays were occurring, and also happens to eat the

25   diet that has the residue that was added.



 1             And how those things work together are what do you

 2   do.  Do you -- there's a variety of approaches.  There's

 3   biological monitoring that's been suggested.  It's

 4   expensive.  It's controversial.  It's hard to get

 5   volunteers.  And it's getting humans to participate in those

 6   sorts of things are things that raise an enormous number of

 7   ethical questions that we're acutely sensitive to.  So we're

 8   not encouraging that necessarily.

 9             And so how to go about it, I think, really raises

10   a bunch of cutting-edge science and policy questions that

11   we're grappling with trying to figure out how to deal with.

12             CHAIRMAN FROINES:  We can spend hours on this.

13             MR. JORDAN:  Sure.

14             CHAIRMAN FROINES:  The number one recommendation

15   of the National Academy of Science's report on particle

16   measurement was to develop the linkage between ambient

17   monitoring assessment and personal exposure assessment.

18             And what's been missing for years and years and

19   years is the personal assessment side, which is really

20   important.  It's done occupationally and OSHA does it, and

21   things like that, but even that isn't sufficient.  I mean,

22   his suggestion is, in a sense, to get at the personal

23   exposure issue from multiple chemicals, a very good idea.  I

24   mean, I would fund it.

25             DR. BYUS:  Thank you, John.



 1             CHAIRMAN FROINES:  I mean, so would Tony.

 2             DR. FUCALORO:  Absolutely.  I'm designating on

 3   April 15th some of my tax money to go directly to this.

 4             CHAIRMAN FROINES:  But so it is really quite

 5   crucial to, all due respect to the tradition at EPA to model

 6   everything under the sun, is to actually go to the other

 7   half -- and I say this with Roger on my left, so I have to

 8   be very careful about some of it -- but I want -- I do think

 9   we need to get down to some more looking at things in a

10   more, quote, personal basis.  Biological monitoring being

11   the most expensive extreme of that.

12             We're at 11:30.

13             MR. JORDAN:  I sure haven't finished.

14             CHAIRMAN FROINES:  Why don't you try to draw us to

15   a close at this point, because I think I'd like in the next

16   five or ten minutes, I think we need to get to Gary Friedman

17   and the acute RELs, and I think we need a short break.

18             So how about if we take ten more minutes?

19             MR. JORDAN:  I'll gallop through this.

20             I want to call your attention to the FQPA child

21   protection factor.  That is a statutory provision that says

22   to us at EPA, be particularly mindful of the fact that

23   children may be more sensitive to the effects of pesticides,

24   and they may experience different kinds of exposure

25   scenarios, greater exposure than do adults, and unless you



 1   are really sure that you have -- unless you're sure that you

 2   have really reliable data, to dispense with it, include

 3   routinely an additional 10X factor in your risk assessment

 4   to protect children and infants.

 5             When we do cancer, we use a nonthreshold linear

 6   extrapolation model that develops a population incidence

 7   estimate.  Our benchmark for safety is a lifetime of

 8   exposure should result in a projected or estimate of cancer

 9   incidence no greater than one in a million of the exposed

10   population, when it is general population exposures that

11   we're talking about, such as through the diet or drinking

12   water.

13             For noncancer exposures we use a safety factor or

14   uncertainty factor or margin of safety or margin of

15   exposure, those are all terms that more or less mean the

16   same thing.

17             DR. FUCALORO:  Yeah.  But this question, do they

18   mean the same thing that DPR means them?  This is a question

19   we've had, and I just want to clarify.  They mean exactly

20   the same thing?  Good.

21             MR. JORDAN:  Okay.  Let me attempt briefly to

22   explain what we do.  We look at the toxicity database and

23   identify the studies that are most appropriate to the

24   exposure scenarios that we're trying to evaluate.  If it is

25   an acute exposure, then we look at an acute toxicity study.



 1   If it's a chronic exposure, chronic toxicity study.

 2             There are usually several different toxicity

 3   studies, and we look at the one that identifies the effect

 4   that would occur first through that avenue of exposure.  It

 5   might be reduced weight gain or it might something more

 6   serious than that, but we look for the first effect that

 7   would occur in an exposed organism, and then in that study

 8   identify the no observable -- excuse me -- no observed

 9   adverse effect level for that effect.

10             The term no observed adverse effect level is for

11   all practical purposes synonymous with no observed effect

12   level.

13             That NOEL is then transformed into what some

14   people call an acceptable daily intake, other people call a

15   reference dose, by applying to it factors that reflect the

16   uncertainty of using animal toxicity modeling, animal

17   toxicity data, to model effects on humans.

18             Traditionally, we use two uncertainty factors of

19   ten, so that the combined impact is a hundred.  So 100th of

20   the NOEL is the reference dose, in most cases.

21             If the database is particularly weak because of

22   missing studies, we've got to make a decision on a chemical

23   that was registered many years ago, and for whatever reason

24   the data we have are not up to contemporary standards, then

25   we may increase the size of uncertainty factors.



 1             If we have only lowest observed effect levels as

 2   opposed to no observed effect levels, then that may be

 3   another reason to increase the uncertainty factors.  Things

 4   like that also go into that.

 5             The reference dose may be further modified by

 6   application of the Food Quality Protection Act, child

 7   protection 10X factor.  In other words, it could be a factor

 8   of up ten times lower because of this particular FQPA

 9   consideration.

10             That becomes the safety benchmark for noncancer

11   effects, and we compare that safety benchmark with our

12   estimates of exposure.

13             There are a couple of different ways of doing it,

14   and one of them is to look at exposure as a percentage of

15   the reference dose.  If it's more than 100 percent, it's not

16   the other thing.  If it's less than hundred percent thing,

17   we're likely to regard it as safe.

18             Another way is to look at exposure as compared to

19   the NOEL that was used and look at the margin of exposure or

20   the margin of safety.

21             In that instance, we want to see a margin of

22   exposure or margin of safety that is comparable to the

23   uncertainty factors that we would have otherwise been using.

24   So in a lot of ways it's just a reciprocal kind of

25   relationship.



 1             CHAIRMAN FROINES:  We're going to talk about that,

 2   but when you say the margin of exposure, what is the

 3   exposure that you take into account, the upper 95 percent?

 4             MR. JORDAN:  When we do an exposure estimate,

 5   there are basically two types.  A deterministic estimate

 6   which can sometimes be a means, sometimes be a bounding

 7   estimate, sometimes can be a kind of estimate of what we

 8   think the upper bound is, 95th percentile.  It depends on

 9   lots of stuff that I could go into in more depth, but we

10   don't have time.

11             The other approach that we use is a probabilistic

12   estimate, and we're doing that right now, only in the

13   dietary area, where we cross the databases we have on food

14   consumption with the databases we have on the distribution

15   of pesticide residues, and get a probability distribution of

16   dietary residues.  And in that instance we're looking at the

17   99th -- excuse me, 99.9th percentile of estimated dietary

18   exposure, using real residues and real food consumption, and

19   comparing that to the reference dose.

20             And that's happening on the acute side, I should

21   clarify, acute and dietary food exposures.

22             And all of this may change, and you see on the

23   outline four areas that we are working on.

24             The place that strikes me as a person in the

25   policy area that is probably the weakest and will, for a



 1   variety of reasonings, receive the most attention, is

 2   development of better models and validation of the models

 3   that we do have to improve them to come up with exposure

 4   estimates that we feel reflect reality as accurately as

 5   possible.

 6             CHAIRMAN FROINES:  Questions?

 7             I have one question for you.  Do you do any

 8   post-registration exposure testing to validate

 9   pre-registration testing requirements?

10             MR. JORDAN:  Occasionally, but not often.  We've

11   done that particularly in the groundwater arena where we've

12   said we think this chemical has some chance of getting into

13   groundwater, we've imposed regulatory measures to minimize

14   or we hope eliminate that prospect, but just to be sure

15   we'll require people to go out and monitor the groundwater.

16             In addition to that, through the reregistration

17   and the tolerance reassessment programs, we have the

18   authority to call in data and do call it in, but it's not

19   necessarily tied to validating a pre-registration decision.

20             If you think broadly about, gee, we want to make

21   sure that this registration is okay, then EPA's data call-in

22   authority is a way of validating that, or if the data

23   indicate that there's a problem of telling us where we need

24   to make changes.

25             CHAIRMAN FROINES:  You said that there's a



 1   document that's been released in the last two or three weeks

 2   on -- I don't remember, I didn't write it down -- is it the

 3   aggregate or cumulative risk issue?

 4             MR. JORDAN:  It's how to identify substances that

 5   have a common mechanism of toxicity, such that we should

 6   conduct a cumulative risk assessment on that group of

 7   chemicals, as opposed to doing them only one by one.

 8             CHAIRMAN FROINES:  Okay.  Bill and Paul, can we

 9   get a copy of that?

10             MR. JORDAN:  Sure.

11             CHAIRMAN FROINES:  Well, thank you very much.

12             You're our point person now.

13             DR. FUCALORO:  Did we all have your telephone

14   number, e-mail, fax?

15             CHAIRMAN FROINES:  Why don't we take a five-minute

16   break, and then move into acute RELs.

17             (Thereupon a short recess was taken.)

18             CHAIRMAN FROINES:  Question.

19             At least three people who expressed interest in

20   working, continuing to work through, work through lunch, and

21   stop around 2:00, between 2:00 and 3:00, sometime.  How do

22   people feel about that?

23             DR. WITSCHI:  Very positive.

24             CHAIRMAN FROINES:  Very positive.  Gary's going to

25   be gone.



 1             Stan?

 2             DR. GLANTZ:  That's fine.  How about sandwiches or

 3   something.

 4             CHAIRMAN FROINES:  I think Peter is going to go

 5   across the street and try and do that.  I think he'll bring

 6   back some things.

 7             Does that make sense?

 8             We're going to go on to the RELs, and the first

 9   person will be Gary, on the chemicals that he has to report

10   on.

11             Bill and George, Melanie, I think, I'm assuming

12   that we're going to make it through all 51 chemicals today.

13   I would hope so.  But that depends on, obviously, the

14   questions that people have to raise.

15             My question is, the panel at some point will vote

16   to essentially accept the document, thereby with changes

17   that may be recommended, and that the panel probably does

18   not need findings, Bill, what is it?

19             We don't feed findings.  So we in a sense approve,

20   the panel will approve the document, with modifications and

21   then that will in fact imply that we have reviewed chemicals

22   themselves.

23             And we will say so on the record.

24             Is that what meets our requirements?

25             DR. GLANTZ:  Could I ask one procedural question?



 1             CHAIRMAN FROINES:  Sure.

 2             DR. GLANTZ:  After we do that, if OEHHA wants to

 3   make changes, do they then come back to us to change things

 4   subsequently as they would in the 1807 documents?

 5             DR. FUCALORO:  If they make changes without coming

 6   back immediately, our support for the document evaporates.

 7             DR. GLANTZ:  Well, no.  We have a process for

 8   amending the 1807 documents.  Would the same process apply

 9   here then or--

10             DR. ALEXEEFF:  No.

11             George Alexeeff with OEHHA.

12             The process for this particular area is not as

13   high of a bar as in the TAC program, so approving would

14   definitely meet it, but it even exceeds what's really

15   necessary, although approving is fine.  I'm not saying don't

16   approve it.

17             What the statute says is you have to have reviewed

18   it and provided us your comments.  So as long as the review

19   is completed, and you provided us comments, then we can move

20   on to the next -- our next process.

21             But if you basically have reviewed it and approve

22   it, then that's equivalent.

23             DR. GLANTZ:  Well, no.  I had a slightly different

24   question.  We will review it, approve it at some point,

25   hopefully today.



 1             But let's say next week you decide you want to

 2   make a change to it.  Would that then come back to the

 3   panel?

 4             DR. ALEXEEFF:  If we have decided to change a

 5   level, we would like to bring them back to the panel, at

 6   least as informational items and actually go through the

 7   whole process.  Our thought is once we've gone through these

 8   documents, at some point there will be some additional

 9   updates, either some new chemicals we're adding or some new

10   literature has come out that require us to revise the

11   number.  So there will be some process that we'll be

12   updating it.

13             DR. GLANTZ:  But that could come back through us

14   then?

15             DR. ALEXEEFF:  Yeah.

16             CHAIRMAN FROINES:  As I read the Western States

17   Petroleum comments, they feel, rightly or wrongly, that

18   there is some requirement for, quote, we strongly encourage

19   the SRP to propose a thorough and complete external peer

20   review, which presumably means us, and that the implication

21   is that becomes a requirement, although not mandated

22   legislatively, on this kind of process.

23             So I think we are not required to do that as a --

24   there's no law that says we are required to do that, but as

25   a matter of policy, I think what you're saying is that you



 1   would bring changes back to us if they were to occur.

 2             DR. GLANTZ:  The other thing, then we need to let

 3   Gary get on with his compounds for chemicals, but the other

 4   thing I would suggest, once we have approved this and you

 5   issue the final document, I think it would be worth just

 6   putting a statement in it that says this document was

 7   reviewed and approved by the SRP on February 10th, or

 8   whatever date, because I think that will give it an

 9   additional weight.  That would imply then, I think, if you

10   were to amend the document, we'd have to review or approve

11   the amendments.

12             I think that will give you a stronger document.

13   So okay.

14             CHAIRMAN FROINES:  I think that there's another

15   point that I want to make, George, which --

16             DR. GLANTZ:  Then we got to let Gary go.

17             CHAIRMAN FROINES:  I understand.

18             I really can't let this go.

19             I think what's been done here is very good.  And I

20   think that we can go ahead and approve it.

21             I think we need to see this as a process, as a

22   step in a longer process, because noncarcinogen risk

23   assessment is changing, and we need to move away from what

24   is essentially Food and Drug Administration risk assessment

25   from the 1950s.  We might be able to move a few years past



 1   that at some point.

 2             And that it's important -- I mean, I think that

 3   some of the comments from WSPA were not -- were, in fact,

 4   quite reasonable.  And, for example, where we start -- the

 5   biggest problem, it seems to me, is we're not using dose

 6   response information.  We are not using ED 50s and then

 7   applying factors.  We're not looking at distributional

 8   questions.  We're not looking at uncertainty.

 9             So we're not really doing the most up-to-date

10   kinds of risk assessment that we're capable of.

11             And it seems to me that we should not

12   necessarily -- we need to go to adopt some values so people

13   have things to work with, but then continue to move forward

14   in terms of this kind of risk assessment, because -- and we

15   would all, I think, generally agree that there are changes

16   that need to occur that will improve our understanding of

17   these kinds of issues.

18             So I see this as a work in progress, rather than

19   something that's absolutely final.

20             DR. GLANTZ:  Part of that is some of the issues

21   you're mentioning are in this document are stochastic

22   estimation which I've been working -- I don't even know

23   where it is in process right now, but periodically drafts of

24   it appear.

25             But we should let Gary go.



 1             CHAIRMAN FROINES:  Yeah.

 2             But I think that we need to make clear that this

 3   is -- that there are these limitations and that we do want

 4   to continue to explore them as time progresses.

 5             So having said that --

 6             DR. BYUS:  Do we not want findings then?  Do you

 7   want to make statements, we could have some findings and put

 8   them in there.

 9             DR. GLANTZ:  Let's discuss that --

10             CHAIRMAN FROINES:  Let's let Gary --

11             DR. GLANTZ:  He wants to leave.

12             CHAIRMAN FROINES:  Yeah.

13             DR. FRIEDMAN:  Well, I had, I guess, as most of us

14   did, I had seven compounds to review.  And I generally

15   thought the write-ups were good, but for each one I had

16   questions or concerns about wording that was not clear or

17   other ambiguities or things that I didn't quite understand,

18   and I thought what I would propose doing is just take the

19   first one of these that I had, carbon monoxide, just run

20   through those so you see the level of the concerns that I

21   have.  But I think all these can be worked out with staff,

22   if I could meet with staff through either Melanie or someone

23   else who might be responsible for each of these write-ups.

24   I think that could be done, shouldn't hold up approval, if

25   we could agree to that procedure.



 1             CHAIRMAN FROINES:  Unless there's something about

 2   your question that raises a question about the fundamental

 3   numbers that they come up.

 4             DR. FRIEDMAN:  Right.

 5             CHAIRMAN FROINES:  Then I think you really have to

 6   raise them here.

 7             DR. FRIEDMAN:  Let me run through them and you'll

 8   get a feel for what I had.

 9             Under carbon monoxide, which is page C 59, under

10   Roman numeral I, there's a italicized phrase, critical

11   effects.  And I didn't know what that meant.

12             And then I assume it means the angina and other

13   problems in persons with known cardiovascular, but I thought

14   that the other problems were so vague and general that it

15   didn't have much meaning, and I thought that if you could

16   specify a little more about what other problems you mean, it

17   would be very helpful.  Otherwise it could be anything.

18             The next thing I had was on the bottom of that

19   page you listed various items that in combustion led to the

20   generation of carbon monoxide, and I think I would add

21   tobacco to that too, especially unless you're not concerned

22   at all with indoor exposure, but I think tobacco is a known

23   source of carbon monoxide that a lot of people get exposed

24   to, and that should be included there.

25             DR. GLANTZ:  I missed that.



 1             DR. FRIEDMAN:  Stan, I'm doing a good job.

 2             DR. GLANTZ:  You are.

 3             DR. FRIEDMAN:  Then on the next, on page 61, I

 4   started running into these abbreviations and at first I

 5   didn't know what they meant and then I discovered that you

 6   had an appendix at the end which lists them.

 7             And I wonder if -- do you ever mention in the

 8   front of the thing that you have this appendix that has the

 9   definitions?  Because --

10             DR. MARTY:  We may not have.  I don't remember.

11             DR. FRIEDMAN:  I would recommend somehow calling

12   this prominently to the reader's attention, that all these

13   abbreviations are defined in the appendix.

14             And then under Roman numeral V, you talk about

15   four-hour LC 50s for rats, mice, and then on the next line

16   you say the lowest reported lethal concentration in dogs.

17   And is the lethal concentration the same as the LC 50 or is

18   it different and it seems like --

19             DR. BLANC:  When one dog dies at a concentration,

20   that would be the lowest.  When 50 percent of the dogs die,

21   that would be the LC 50.

22             DR. FRIEDMAN:  I understand that, but I don't know

23   what lethal concentration means.  Does that mean when one

24   dog dies?

25             DR. ALEXEEFF:  Uh-huh.



 1             DR. FRIEDMAN:  I think you ought to say that.

 2             DR. FUCALORO:  Even if the dog dies from old age?

 3             DR. FRIEDMAN:  Even if it's a little dog?

 4             Then another thing that I did not understand, and

 5   I assume that people who are involved in this technical work

 6   understand all these, but if you want this to be understood

 7   by the general reader, near the bottom of that page, the

 8   third line from the bottom, I didn't know what homing tests

 9   were.  So I think, you know, you need some kind of glossary

10   if this keeps reappearing.  If it only appears here once,

11   then I think you need to define it.

12             On page C 61 on the bottom third, it talks about

13   homing tests.

14             Then I was a little unsure of your derivation

15   under Roman numeral VII, page C 62, you ended up with a

16   reference exposure level of 20 parts per million, which was

17   exactly the same as the NOEL.  Is that just because all

18   these uncertainty factors were one and you multiple NOEL by

19   one?  Is that the general formula, you multiple the NOEL by

20   the various uncertainty factors to get the reference level?

21             DR. ALEXEEFF:  You actually divide.  You divide

22   the NOEL --

23             DR. FRIEDMAN:  Yeah.

24             Then on the third line of the big paragraph on the

25   bottom of C 62, you talk about one-hour exposure would



 1   result in a carboxyhemoglobin level of less than ten percent

 2   in resting individuals.  And I wondered why you base this

 3   level of protective against severe adverse effects in

 4   resting individuals, since I would think many individuals

 5   exposed to carbon monoxide would not be resting.  And

 6   whether maybe a more appropriate base would be people

 7   undergoing some -- engaging in some activity.

 8             So I just raise that as a question.  Why base it

 9   on resting individuals?

10             DR. ALEXEEFF:  Yeah.  That's put in there because

11   that was the data set available.  It's because there wasn't

12   a data set, let's say, where the individuals were heavily

13   exercising, and these parameters were measured.  So in this

14   case that's what there was, but it does give you a sense as

15   to what the uncertainties might be, just like what you

16   indicated that if you're concerned about active individuals

17   or an evacuation or something like that where there might be

18   greater breathing rates in an occupational environment, this

19   may not be appropriate.

20             But that's pretty much all I can tell you.  Since

21   we have no control over what data was reported in the

22   literature, all we can use is what's there.  That's why we

23   specifically noted that it was resting individuals there.

24             DR. FRIEDMAN:  I see.  I wonder if it wouldn't be

25   worth adding the comments on something like the comments



 1   that you just made, that this may not be a real-life

 2   situation where people would be evacuating an area or

 3   walking or engaged in work.

 4             And that was it for that one.  And I think it's

 5   representative of the kinds of things that I raised about

 6   the others, and I don't know if it's worth really spending

 7   the time of the whole panel to go through those.  I would

 8   just propose that I work with staff on them.

 9             DR. ALEXEEFF:  I guess the ones that you provided

10   so far here are clarifications of the text, really, but not

11   something that results in a revision of either the health

12   effect identified or the level.  So I'm just wondering if

13   there's anything that might be affecting the level or the

14   health effect, because that might be worthwhile to bring up

15   now.

16             DR. FRIEDMAN:  No.  I think that they're all sort

17   of clarifications of the text.

18             DR. BLANC:  Can I ask, relevant to the content of

19   this, I think it's inconsistent with your approach elsewhere

20   to define angina as a mild adverse effect.  And therefore I

21   would suggest that you consider that a severe effect, and

22   you can have your other discussion, which is your level of

23   protective against adverse effects as being part of that,

24   but I think it's completely inconsistent with the approach

25   and since all of your uncertainty factors are one, it's not



 1   a question of using six versus ten.  So it doesn't affect

 2   your level.

 3             DR. ALEXEEFF:  Okay.

 4             DR. BLANC:  And I think the only thing you have to

 5   be very cautious about is that you are sure about your

 6   reproductive levels because the affinity of carbon monoxide

 7   for fetal hemoglobin is about ten times that of adult

 8   hemoglobin.  And therefore you should just double check and

 9   make sure that you are not going to be possibly inducing --

10   these are assuming a one-hour exposure, so I guess you have

11   to run out a scenario for a jogging pregnant person, female,

12   I guess she'd have to be, and make sure your numbers come

13   out, don't come out lower that way.

14             DR. ALEXEEFF:  Okay.

15             CHAIRMAN FROINES:  There's a literature that's

16   developing on adverse outcomes, reproductive outcomes,

17   developmental outcomes, associated with carbon monoxide

18   exposure.  Beate Ritz at UCLA just published a paper on

19   reproductive effects in CO levels.

20             DR. BLANC:  Most of those are chronic studies that

21   are very difficult to extrapolate to short term.  It's going

22   to be more relevant to their chronic exposure paper.

23             CHAIRMAN FROINES:  You want to talk about it in

24   terms of the chronic, that's okay with me.

25             DR. BLANC:  I think also you have to be



 1   consistent, this is something here in my comments, in your

 2   sections on medical and chemical risk, I don't care where

 3   you put it, but, clearly, people who are cigarette smokers

 4   are at risk of carbon monoxide and your lowest adverse level

 5   has to assume that the person exposed to carbon monoxide is

 6   starting off with a five percent carbon monoxide from being

 7   a smoker or seven percent carboxyhemoglobin levels.

 8             DR. FRIEDMAN:  That does raise a question in my

 9   mind that I thought there was an inconsistency between this

10   and what was said about methylene chloride, which isn't that

11   the compound that breaks down into carbon monoxide?

12             DR. MARTY:  Yes.

13             DR. FRIEDMAN:  Because I think for that one, let's

14   see, you did mention, you said predisposing conditions, this

15   is on page C 214, predisposing conditions for methylene

16   chloride toxicity, chemical tobacco smokers typically have

17   chronically elevated carboxyhemoglobin levels and may be

18   able to tolerate higher levels of exposures.

19             So one thing I'm not -- first of all, I wondered

20   why you didn't say the same thing for carbon monoxide.

21             And, secondly, I'm not clear on which direction

22   this goes.  If you're exposed to carbon monoxide

23   chronically, are you less susceptible to other exposure to

24   it or are you more susceptible, as Paul points out, are you

25   more susceptible?



 1             DR. BLANC:  I don't think there's any evidence

 2   that you'd be less susceptible relative to an acute

 3   document, certainly.  If what you mean is you might be less

 4   likely to have acute symptoms of headache or something.  I'm

 5   not aware of data that support that statement, since really

 6   the issue is not did you get up to five percent

 7   carboxyhemoglobin, but now have you gone from five percent

 8   to ten percent, that's the issue.

 9             DR. ALEXEEFF:  One of the reasons we thought it

10   would be good for you to look at both of those substances

11   was because we're basing them both looking at CO.  So I'm

12   glad you pointed that out.  We'll go through and we'll make

13   sure they're consistent with what Dr. Blanc was saying, both

14   discussions, because they really now ultimately go back to

15   CO as being --

16             DR. BLANC:  I'm going to make another generic

17   comment that touches on this, but touches on mine as well,

18   so I might as well say it now.

19             I think that if you think about why you have this

20   section on physical properties for each of these chemicals,

21   I mean, perhaps originally it was the outgrowth of just,

22   well, we've got to put in the physical properties, but think

23   about what somebody would care about knowing in a situation

24   where there's a release or an acute exposure.

25             For things which are gases at normal pressure and



 1   temperature, having a specific gravity doesn't make a lot of

 2   sense, but if you are going to report it, then don't you

 3   have to say what the pressure that was done at, not just the

 4   temperature?  Because even at zero degrees, carbon monoxide,

 5   for example, is a gas, so it can't have a specific gravity,

 6   vis-a-vis water.

 7             Now, I thought it was very useful with the

 8   chlorine that we're going to come to that you provided what

 9   the weight was relative to air, so that somebody would know

10   if this would collect in low-level places and I think that's

11   something that you should put for all of the things which

12   are gases or have a very high vapor concentration at normal

13   pressures and so forth.

14             But this is just a generic comment throughout, but

15   there's certainly, I know it depends on where you pull down

16   the data, but for this it's just --

17             DR. FRIEDMAN:  Since I've turned to methylene

18   chloride, I had a couple of other -- I notice in that there

19   are some things that may be of general concern that I should

20   bring up here.

21             On page C 216, in the middle of that big

22   paragraph, you make the statement the LOEL --

23             DR. GLANTZ:  By the way, Gary is looking at the

24   green copy, rather than the yellow.

25             DR. FUCALORO:  I think for the record, the pages



 1   are off by one or two.

 2             DR. FRIEDMAN:  I don't have the yellow copy.

 3             DR. FUCALORO:  But if they refer back to the

 4   transcript, they then know it's one or two pages away.

 5             DR. FRIEDMAN:  Okay.  Well, then I should tell

 6   you, it's in section Roman numeral VII, derivation of acute

 7   reference exposure and it's the big paragraph under that.

 8             And it says the LOEL is equivalent to NOEL for the

 9   purpose of developing a REL.  And that surprised me that you

10   would take the -- something where the lowest effect level

11   would be equivalent to the no adverse effect level.  I

12   never -- I hadn't heard that concept before, and I was

13   wondering about that.

14             DR. ALEXEEFF:  Well, I think the conclusion here

15   is that the LOEL was not considered clearly adverse and

16   therefore it's the level which we're seeing something, but

17   we haven't been able to identify it as an adverse response,

18   but we're indicating that there is something that was

19   measured in the study.

20             DR. FRIEDMAN:  But, you know, I think it's as Bill

21   Jordan mentioned, that LOELs are not equivalent to NOELs, or

22   you would want to base it on a no effect.  I mean, I think

23   what he said was that for all practical purposes, effects

24   are adverse effects.  And I thought that was an interesting

25   concept, and wondered if you really can assume that an



 1   effect is not an adverse effect.

 2             DR. BLANC:  Let's say I'm the forklift driver

 3   called to the scene of the release of methylene chloride and

 4   my task is to haul away the debris for an hour.  And my

 5   impaired -- my performance on the equivalent of dual task

 6   and auditory vigilance is impaired.  Are you saying that's

 7   not an effect which has any adversity associated with it?

 8             It's a mild adverse effect, but it would change

 9   your -- would it change anything, actually?

10             DR. ALEXEEFF:  I think it was the person in our

11   development of this, I think the decision -- I'd have to go

12   back to the original article to double check, but the

13   decision that was made here was that the -- that on the

14   testing procedures that were performed for this, there's a

15   number of these studies where you have these tasks, but it's

16   not clear as to whether or not real performance is really

17   actually effective, and since there weren't any other signs

18   or symptoms of anything being effective, that's why it was

19   considered not adverse.

20             DR. BLANC:  Let me ask it a different way.  The

21   legal basis for why one is driving under the influence of a

22   certain level of alcohol is basically derived from very

23   similar tests.  I mean, this would have the net impact of

24   lowering this by a factor of six, I understand.  That's the

25   implication, right, if I understand the whole process,



 1   because if this was the LOEL for a mild effect, we'd be

 2   using a factor of six lower, rather than a factor of one.

 3             DR. ALEXEEFF:  Correct.  That would be the impact.

 4             We're looking at the study right now, so just give

 5   us one second.

 6             CHAIRMAN FROINES:  While you're looking can I ask

 7   you a related question?

 8             DR. ALEXEEFF:  She'll look.

 9             CHAIRMAN FROINES:  You talk in here in laboratory

10   animals, and I quote, persistent myocardial arrhythmia and

11   decreased cardiac output were observed in anesthetized

12   open-chested dogs following a five-minute inhalation

13   exposure to 25 parts per million methylene chloride, 1977.

14             If you take that study in animals and go through

15   the various calculations, you would find a considerably

16   lower reference exposure level.  And so you clearly made a

17   decision to base yours on human evidence, and I would

18   generally support that, but this particular dog study seems

19   to indicate that you can have cardiovascular effects at a

20   somewhat lower level than your -- and you're ending up with

21   24 parts per million as your reference level, and this study

22   shows arrhythmias and decreased cardiac input at essentially

23   the same value.

24             DR. ALEXEEFF:  Okay.

25             CHAIRMAN FROINES:  That makes -- you're assuming



 1   then that that's not relevant and that's not a good

 2   assumption, I think.

 3             DR. ALEXEEFF:  Okay.  I think you have a good

 4   point then.

 5             DR. MARTY:  I think from looking back at the paper

 6   what -- the adverse effects were first noted after 90

 7   minutes of exposure and they continued the exposures and

 8   kept measuring.  So I'm thinking that the reason we called

 9   that a low observed effect level was the difference because

10   we're looking for a one-hour exposure.

11             DR. BLANC:  But you have a way of back

12   extrapolating from 90 minutes to one hour, if that's the

13   exercise you wanted to do.

14             DR. ALEXEEFF:  That's what we did.

15             DR. MARTY:  That's right.  That's what we did.  We

16   use C squared in the Haber's Law.

17             DR. FRIEDMAN:  Another concern I had on this, the

18   bottom of that page, the last sentence in that last

19   paragraph, you talk about exposure aggravating angina and

20   then you say since angina is considered a severe adverse

21   effect, this later concentration should be considered and

22   the derivation of the severe adverse effect level, and then

23   you immediately say after that, under level protective

24   against severe adverse effects, no recommendation is made

25   due to the limitations of the database.



 1             It seems inconsistent.

 2             CHAIRMAN FROINES:  Let's go ahead, let's mark

 3   those questions and we'll go ahead.

 4             DR. FRIEDMAN:  Well, then I have five -- I think I

 5   would like to, if it's agreeable, then I'll just deal with

 6   the staff on -- or do you want to hear them all?  Do you

 7   want to hear all my concerns about other chemicals too?  If

 8   everybody does this, you're going to be here all day.

 9             DR. GLANTZ:  No, go ahead.

10             CHAIRMAN FROINES:  You can see that good questions

11   have been raised about these chemicals.

12             DR. GLANTZ:  Why don't you keep going.

13             DR. FUCALORO:  Can I just add a generic --

14             DR. GLANTZ:  It will be shorter later.  I have all

15   the same questions.

16             DR. FUCALORO:  Can I add a little generic comment

17   here, and Paul started talking about the difficulty with

18   physical and chemical properties.

19             I think OEHHA has got to stop using just a

20   template because sometimes they're actually doing specific

21   gravity, and sometimes they're actually doing density.

22             For example, if you look under carbon monoxide,

23   what you really have there is a density, 1.25 grams per

24   liter at zero degrees Centigrade, that clearly is the gas.

25   That's what it was.



 1             Now, if you look at the methylene chloride under

 2   the same thing, specific gravity, it says 1.32 at 20 degrees

 3   Centigrade.  Now the question is is that a liquid or a gas.

 4   It could be a vapor or something like that.

 5             It's actually the liquid and it's related and it's

 6   1.32 times and it has no units there, because of specific

 7   gravity.  1.32 times the density of water, and that's how

 8   specific gravity is ratioed against.

 9             So putting units in, I think it's important to --

10   I think for the purpose just to avoid confusion, try to be

11   consistent, and look at what a density is and what a

12   specific gravity is.  Don't be unduly forced into some of

13   these things by the template that you have.  I mean, it's a

14   good one principally.

15             CHAIRMAN FROINES:  Go ahead, Gary.

16             DR. FRIEDMAN:  Hydrochloric acid.

17             DR. BLANC:  Try to put in if it's heavier than

18   air.

19             DR. ATKINSON:  Actually you can tell from the

20   molecular weight.  If the molecular weight's greater than

21   somewhere between 28 and 30, it's heavier than air.

22             DR. BLANC:  Thank you for that clarification.

23             DR. FUCALORO:  Density is the molecular weight

24   over RT.

25             DR. BLANC:  For those of us who are nonphysical



 1   chemists.

 2             DR. GLANTZ:  They had to say something.

 3             DR. FRIEDMAN:  Hydrochloric acid, under Roman

 4   numeral IV, on my page 142, there's on the fourth line, it

 5   says reactive airways dysfunction syndrome, RADS.  I've

 6   never heard of that and I don't know what that is, and I'm a

 7   physician, so I think maybe it needs some explanation.

 8             DR. ALEXEEFF:  Okay.

 9             DR. WITSCHI:  That's recognized.

10             DR. FRIEDMAN:  That's fine.  I'm sure it is.  It

11   was capitalized here and everything, but I don't know what

12   it is.  I mean, it's such a vague term.  What is it, like

13   asthma or something or bronchoconstriction?

14             DR. ALEXEEFF:  We can put in there a definition of

15   that in the glossary, but basically it's chemically induced

16   asthma, simplist way.

17             DR. BLANC:  Acute irritant induced asthma.

18             DR. FRIEDMAN:  Fine.  I think that should be

19   explained.

20             Then on the next paragraph or the second to the

21   next paragraph under acute toxicity, the laboratory animal's

22   right lung lobe, you say in the right lung lobe, I think the

23   right lung must have more than one lobe, so that was a

24   little bit vague there.

25             Let's see.  The RD 50, I guess that's when the



 1   respiratory rate is decreased by 50 percent; is that

 2   correct?

 3             DR. ALEXEEFF:  Correct.

 4             DR. FRIEDMAN:  That's under level protective

 5   against severe adverse effects.  Why is decrease in -- why

 6   is the decrease in respiratory rate by 50 percent important,

 7   in what way is that a severe effect?  Not clear to me.

 8             DR. ALEXEEFF:  Okay.

 9             DR. FRIEDMAN:  And right above that it says the

10   lack of effects on the pulmonary functions measured is not

11   surprising because of the extreme water solubility of HCL.

12   The high water solubility supports upper airway effects as

13   the most sensitive target endpoint.

14             I think what you're trying to say there is that

15   the hydrochloric acid gets dissolved in the upper airway

16   before it can make it to the lower, but I think you could

17   word that a little more clearly.  I found that hard to

18   understand.  I had to keep going over it until I figured out

19   what you were trying to say.

20             And then under level protective against severe

21   adverse effects, the last paragraph, let's see, however

22   since the development of the SPEGL, Stevens et al, human

23   studies became available in addition to a number of

24   additional animal studies.  For this reason we recommend the

25   EEGL as the level protective against severe adverse effects.



 1   Levels should be reevaluated when more data become

 2   available.

 3             I found, I wrote down here, I'm not clear in my

 4   mind, I said non sequitur, since EEGL is based on rats.

 5             Oh, you're recommending the EEGL even though it's

 6   based on rats, but you have the SPEGL based on humans, so I

 7   didn't understand why you didn't use the SPEGL.

 8             DR. ALEXEEFF:  Okay.  The SPEGL is based upon the

 9   mouse study.  Okay.

10             Both the EEGL -- both the EEGL and the SPEGL are

11   based upon the mouse study.  Okay.

12             So when NRD -- when NRC had evaluated this, that's

13   the evidence that was available to them, was this RD 50 data

14   set.  So they based both of those two levels on that.

15             And to get to the SPEGL, they added an additional

16   uncertainty factor at that time from the EEGL to the SPEGL.

17             But since that time, this was in 1987, that the

18   NRC made that determination, there's been another study that

19   came out by Stevens, which is described here, which shows

20   that the human effects are not occurring in such a low

21   level.  In other words, there would be -- if we agree on the

22   reference level of being 1.4, you know, for the -- if you

23   look higher up in the -- under section 7, if we agree that

24   the Stevens is the correct level to calculate the REL of

25   1.4, then you can't have a severe level that's below the



 1   level that's not -- that's mild.

 2             And so we're trying to clarify in this statement,

 3   maybe we should add a little more information here, that

 4   because of the results of the Stevens study, which wasn't

 5   available previously, we've rejected the SPEGL calculation

 6   here and are now using the EEGL value.

 7             But in other cases if there was less data -- and

 8   specifically what NRC looked at, they said the reason we're

 9   adding this additional uncertainty factor is because of the

10   absence of human data.

11             So since that time, new human data came in, so we

12   took it out.  That's what we were trying to explain in that

13   one.

14             DR. FRIEDMAN:  I think it might need a little more

15   explanation.

16             DR. ALEXEEFF:  Okay.  Sounds like it.

17             DR. FRIEDMAN:  See, what's my next one.

18             DR. BLANC:  Can I just ask a quick question on

19   ozone.  I think your sources with exposure should explicitly

20   say that certain welding operations can generate it.

21             And I don't know whether you feel compelled to say

22   that other equipment that involves strong light sources and

23   electric --

24             DR. FRIEDMAN:  Since you brought up ozone, since

25   that's one of mine, maybe we should just go to that one.



 1             DR. BLANC:  Wasn't that what you were just -- I'm

 2   sorry.  I thought you were doing those.

 3             DR. ALEXEEFF:  We were still on HCL.

 4             DR. BLANC:  Never mind.  Sorry to be out of order.

 5             DR. FRIEDMAN:  I couldn't -- let's see, under

 6   ozone, inhalation reference exposure, the very first thing,

 7   180 micrograms per meter cubed, and then you say odor

 8   threshold, 0.0076 to 0.0036 part per million.

 9             I just can't -- I couldn't relate those two.  I

10   just felt that it would be nice to have them in the same

11   units, so one could get some idea of how the --

12             DR. ALEXEEFF:  We can add the other units.

13             DR. FRIEDMAN:  I also felt that you might want to

14   say something about ozone being normally present in the air.

15   I think that's what I've heard long ago that when you

16   sometimes get this fresh air smell after a rainstorm or

17   something, it's due to the ozone in the air.  So I wonder if

18   that isn't worth mentioning, that's a normal constituent.

19             DR. BYUS:  We have that in Riverside all the time.

20             DR. FRIEDMAN:  Because the air is so fresh there?

21             DR. FUCALORO:  Just look at the paint peeling off

22   the houses.

23             DR. FRIEDMAN:  Then there was a sentence that I

24   thought was ambiguous, under level protective against severe

25   adverse effects, the last sentence in that paragraph says



 1   the significant harm level is unacceptable for exposure of

 2   the general public due to the lack of formal protocol for

 3   its derivation.

 4             I wasn't sure whether you meant that the choice of

 5   that level was unacceptable or the exposure was

 6   unacceptable.

 7             DR. ALEXEEFF:  Oh, I see.  We can clarify that.

 8   It's the choice.

 9             The reason we have no recommendation is because we

10   didn't know how the -- they never explained how it was

11   derived.

12             DR. FRIEDMAN:  Then going backwards, I had

13   hydrogen fluoride, we're moving along here.  Under Roman

14   numeral VII, derivation of acute --

15             DR. ALEXEEFF:  Which substance are we on now?

16             DR. FRIEDMAN:  Back to hydrogen fluoride.

17             I remember that's one thing they wouldn't let us

18   have in high school chemistry, because it's so toxic.

19             This is the paragraph under Roman numeral VII says

20   self-reported upper airway and eye irritation occurred after

21   one hour of exposure to HF at such and such a concentration,

22   with four out of six subjects reporting low symptoms.

23   However, symptoms were not increased following exposure at

24   the next concentration range.  That next concentration

25   range, .7 to 2.4 milligrams per meter cubed was considered



 1   to be a NOEL, and the range of 2.5 to 5.2 is deemed to be a

 2   LOEL.  Since three out of seven subjects in the latter group

 3   reported upper airway symptoms scores, as well as 0/7 in the

 4   former group reported high upper airway symptoms.

 5             What I don't understand is if there were some

 6   symptoms at the lower concentrations of 0.7 to 2.4, in fact

 7   it was even at four out of six subjects reported symptoms

 8   scores at 0.2 to 0.6, why that wasn't the NOEL, rather than

 9   using the higher level.

10             DR. ALEXEEFF:  Well, I think maybe we should

11   clarify this sentence.  I think it's symptoms were not

12   increased compared to controls, compared to unexposed.

13             See, so what we have is that the lowest level, .2

14   to .6, there was some increase in upper respiratory effects

15   in comparison to nonexposure, but at the next level there

16   wasn't.

17             DR. MARTY:  It points to an inconsistency in the

18   data, but that is what they observed.

19             DR. FRIEDMAN:  I see.  So you chose to use that

20   second level?

21             DR. MARTY:  As a no observed adverse effect.

22             DR. FRIEDMAN:  I think it would have been more

23   safe and conservative to use the lower level, since there

24   was a difference between -- but, you know, again, I'm

25   feeling rushed and this is open -- I would be happy to



 1   discuss that with you further.

 2             DR. MARTY:  I can go back to the paper too and see

 3   if that was statistically significant or not.  And see what

 4   the author said, because when we reviewed the papers, we

 5   weighted what the author's interpretations were.  We can do

 6   that.

 7             DR. ALEXEEFF:  We can get the paper out and talk

 8   about it.

 9             DR. FRIEDMAN:  Then the level protective against

10   severe adverse effects, the last little short paragraph

11   after that, in comparison with the severe adverse effect

12   level for HF, an alternative analysis yielded a level of two

13   parts per million that is protective against severe effects

14   from a single one-hour exposure to HF.

15             I just -- gives you a reference to your paper,

16   George -- and I just didn't understand.  I found that

17   unclear.

18             DR. ALEXEEFF:  Okay.

19             DR. FRIEDMAN:  And I found the next paragraph

20   unclear.  And below that you talk about based on comparison

21   with the available literature.  I thought you might want to

22   site and summarize that literature, rather than just saying

23   it.  And that paragraph I found unclear also.

24             DR. ALEXEEFF:  Which is the one you felt we should

25   just say it and summarize it, which paragraph are you



 1   referring to?

 2             DR. FRIEDMAN:  It says based on a comparison of

 3   available literature.

 4             DR. ALEXEEFF:  Okay.

 5             DR. FRIEDMAN:  But, you know, those I think we'd

 6   have to spend a lot of time getting into these paragraphs,

 7   but if you could just read them for clarity.

 8             DR. ALEXEEFF:  Right.

 9             DR. FRIEDMAN:  See, what's next here.  Someone

10   have the list?

11             DR. BLANC:  Sulfur dioxide and vinyl chloride.

12             CHAIRMAN FROINES:  An alternative way to do

13   this --

14             DR. FRIEDMAN:  I will be done in a second.

15             CHAIRMAN FROINES:  No, no, go ahead while you're

16   looking.  I'm just talking while you're looking -- would be

17   to have each person submit comments in writing.  At this

18   pace we're going to be here until midnight.

19             DR. GLANTZ:  I don't think that's going to be the

20   case.

21             DR. FRIEDMAN:  Sulfur dioxide I had nothing, so we

22   can move on to vinyl chloride.

23             DR. FUCALORO:  We can make a profit out of it.

24             DR. GLANTZ:  Another reason we should get a raise.

25             DR. FRIEDMAN:  I guess I had nothing on those



 1   either.  I guess I got tired.

 2             CHAIRMAN FROINES:  That's what it took one of us

 3   to do, and we're now going to go to Dr. Kennedy, who is on

 4   the phone.

 5             But you wanted to make a comment.

 6             DR. FUCALORO:  Just one minute.  Dr. Atkinson and

 7   I have been looking, as we were wont to do, at the physical

 8   and chemical properties, and there were some real mistakes

 9   there.

10             And with your permission, Mr. Chairman, he and I,

11   since we have no chemicals assigned to us, would be happy to

12   go through all of these and then present something in

13   writing, so that they can be corrected.  There's not much

14   controversy, it's just a matter of correcting things.

15             For example, you put down for the flashpoint for

16   hydrochloric acid as not known.  I know what the flashpoint

17   is, it's about 15 million degrees when you can start the

18   fusion reaction with the hydrogen.  There's no flashpoint.

19   Not applicable, is the correct answer.

20             So with that, if that meets your approval.

21             CHAIRMAN FROINES:  Well, let me ask the question

22   that I was going -- yes, for sure.

23             You weren't complaining, were you, that we didn't

24   give you any chemicals, because we certainly could have.

25             DR. FUCALORO:  Not complaining, but of course we



 1   like to have our share of the load.

 2             CHAIRMAN FROINES:  Absolutely.  And we -- and the

 3   next time we have 51 chemicals, we'll be happy to include

 4   you in them.

 5             But seriously, Craig and Paul and myself and Peter

 6   and Stan, do you want to make --

 7             DR. BLANC:  No.  Let's just keep going.  I think

 8   it's very useful for me to hear what other people are

 9   picking up on because I think it's useful for you to hear,

10   will inform other discussions --

11             DR. GLANTZ:  I think some of the issues that are

12   being raised are sort of generic, so I think the discussion

13   will tend to speed up.

14             CHAIRMAN FROINES:  That's fine.  I think that's

15   much better, because we'll actually bring it to closure

16   better then.  So but I didn't know whether people were

17   thinking --

18             DR. GLANTZ:  Poor Dr. Kennedy's ear is probably

19   getting tired of being on the phone.

20             DR. KENNEDY:  I'm watching The Brighter Day while

21   I listen.

22             DR. GLANTZ:  What did he say?

23             DR. KENNEDY:  I said I'm watching The Brighter Day

24   while I listen.

25             CHAIRMAN FROINES:  Jerry Springer is over?



 1             Go ahead, Peter.

 2             DR. KENNEDY:  Okay.  My comments are in a generic

 3   sense slightly different.  I have less concern about the

 4   syntactic issues than I'm sort of amazed at the conclusions

 5   that we're forced to draw, based on often limited data.

 6             The compounds that I had to review, and I'll go

 7   through them individually briefly, are largely organic

 8   solvents, they're irritants, they have some reproductive

 9   toxicities as a class, but in terms of the final definitions

10   of REL and the assignation of NOEL and LOEL, that there is

11   sort of a motley collection of available information that

12   the folks at OEHHA had to use, and I have to applaud them

13   for their efforts, but I think some of the inconsistencies

14   and inadequacies need to be pointed out.

15             The first one is epichlorohydrin.  This is a

16   compound that's used in the manufacture of epoxy and phenoxy

17   resins, and it has uses as an insect fumigant.  It's also

18   part of your eyeglass lenses, I guess.

19             It was of interest to me that it has a

20   characteristic odor in the physical chemical property

21   section.

22             The basis for the calculation of the REL is based

23   upon a paper in 1971 which apparently is no longer extent.

24   It is cited in a publication in 1976, but as I understand it

25   the original data are not available.  And that was basically



 1   description of the case reports of exposure in the

 2   workplace.  And, again, it's an irritant primarily of the

 3   eye and nose.  It is a dermal sensitizer which can have

 4   effects that last for several months after brief exposure.

 5             This represented the human studies population used

 6   for calculation of the REL.

 7             The uncertainty factor was 60, which is sort of

 8   modest for this group of compounds as a whole, but it

 9   strikes me as being a little bit unsettling.

10             This is, all of these compounds have significant

11   reproductive effects.  It's hard to define, because they're

12   both maternal effects, as well as fetal problems.

13             And that because of its irritant effect, it's

14   suggested that patients with asthma might have an increased

15   sensitivity.

16             The second compound, going through the list in

17   order in the manual here, is ethylene glycol monobutyl

18   ether.  This is again a solvent that's used as a coupling

19   agent in developing metal cleaners.  It's also used in spray

20   lacquers, enamels and varnish removers.

21             One of its interesting components is that it has

22   significant hemolytic properties not in itself, but through

23   one of its metabolites, butoxyacetic acid, which we don't

24   generate very well, but animals, rats and mice, do, so that

25   the major toxicity in animals is quite different from



 1   toxicity in man.

 2             In establishing the REL, there were some very

 3   limited studies using a total of, I think, nine volunteers,

 4   and from this again irritation of nose and eyes is a primary

 5   critical effect for REL, using a cumulative uncertainty

 6   factor of only ten in this case, an REL of 2.8 ppm was

 7   described.

 8             Again, my concern is that we're putting this out

 9   for all the world based on what may have been good

10   observations, but extremely limited in terms of their

11   quantity of information available to us.

12             Of interest in this compound is that they did

13   demonstrate a NOEL based on the subjective failure of these

14   people under observation to notice any irritative effect.

15             The third one is ethylene glycol monoethyl ether.

16   This is a compound used again in varnish removers and such.

17   It's also important in the dying and printing of textiles,

18   so it's fairly ubiquitous compound.  It is in chronic

19   exposure it has perhaps an important impact on bone marrow

20   with increased incidence of anemia and granulocytopenia in

21   shipyard painters who had been exposed to low levels for

22   long periods of time.  This was, of course, not utilized in

23   the calculation of the REL.

24             That calculation was made in the pregnant rat as a

25   primary, and general defects were obvious.



 1             And this is one of the compounds in which the

 2   experimental data used a longer exposure time of six hours

 3   for several days, and the calculation of the one-hour REL

 4   had to be extrapolated.  The cumulative uncertainty factor

 5   here is getting a little bit bigger to a hundred.  There is

 6   a fairly extensive analysis of the level protective against

 7   life threatening and severe effects.

 8             George, would you comment a little bit on that, to

 9   help me understand?

10             CHAIRMAN FROINES:  Peter, which one are we on?

11             DR. KENNEDY:  I'm on page 117, ethylene glycol

12   monoethyl ether.

13             And my question is related to Roman numeral VII,

14   the level protective against life-threatening effects.

15             There is calculations at several different dose

16   levels, which I think is good.  We don't get to see this

17   very often.

18             And then they printed information on benchmark

19   concentrations at the one in five percent level, and I just

20   wanted George's comments on that information, if he can give

21   it to me.

22             DR. ALEXEEFF:  Yeah.  This is an example where we

23   did have dose response data, and so we wanted to go through

24   the calculations because we know that over time hopefully we

25   will be putting together more data sets or finding data sets



 1   for which we can incorporate the dose response and the

 2   calculation.

 3             So in this example we've done that benchmark

 4   calculation, so we have the doses that we used, and then we

 5   calculated for our purposes the benchmark at a five percent

 6   response rate.

 7             We also calculated the one percent response rate

 8   just so one can get a sense as to how much difference those

 9   levels are in looking at both the maximum likely estimate,

10   which would be the actual dose response line, and then the

11   lower confidence bound.  So that gives you a sense as to --

12   looking at those two give you a sense of the tightness of

13   the data, how much variability are in that data.

14             And so in this case the variability is not that --

15   not that large.

16             CHAIRMAN FROINES:  George, I have a question for

17   you.

18             And it's a -- Peter, excuse me, for just a second.

19             DR. KENNEDY:  Go ahead.

20             CHAIRMAN FROINES:  It's a fundamental question.

21             I'm very uncomfortable with all these

22   determinations with the glycol ethers and with others where

23   in essence you're taking exposures that last six hours a day

24   over a period of six to 15 days of gestation and then we're

25   calculating an acute value.



 1             I don't think it's appropriate to use Haber's Law

 2   and to make an estimate for a very brief exposure and assume

 3   it has relevance to an exposure that went on for nine days,

 4   six hours a day.  That's not an acute study.

 5             And so it seems to me that there's -- it's

 6   fundamentally wrong to essentially develop an REL based on

 7   that kind of data.

 8             It seems to me you should develop an REL based

 9   on -- that should almost be included as either a chronic or

10   subchronic risk assessment and not as an acute value,

11   because this is not an acute event at the levels you're

12   talking about.

13             So I fundamentally don't agree with this approach

14   and I don't see quite how you can justify it.

15             DR. KENNEDY:  That was basically my summary

16   comment was that I question with data that are as spread

17   over here and gone as these are, do we want some sort of

18   consistent sense to come out of these REL calculations,

19   because pretty clearly your comments about this experiment,

20   which in fact, as was pointed out by the group, may not even

21   be entirely appropriate because of the timing of the

22   exposure and uterine implantation.  You can't separate the

23   maternal effects from the fetal effects, and, you know, how

24   does that relate to any sort of reasonable assumption we can

25   make about an acute exposure in man?



 1             CHAIRMAN FROINES:  Start out with 50 -- a LOEL of

 2   50 parts per million, then you extrapolate to a one-hour

 3   concentration, which is 24 parts per million, and then you

 4   add hundred-fold safety factor and you're at .24 parts per

 5   million, do you really believe that you're going to see

 6   birth defects at .24 parts per million over one hour?

 7             I don't.  I think it's -- I just don't think that

 8   that's the way the science works.

 9             DR. MARTY:  Can I address the reason that we did

10   that?

11             If you are going to take into account reproductive

12   and developmental toxicity studies, you are stuck with this

13   protocol.  Nobody logistically would look at each hour of

14   gestation to figure out where in that gestational period

15   that effect occurs.

16             So we made the assumption, since we're looking at

17   exposures of the general population, including pregnant

18   women, we don't know where in gestation they are when they

19   were exposed.

20             So we have decided to use the repro studies in

21   order to account for possible reproductive adverse outcome

22   in people who are exposed.

23             So we think -- we realize that it's a repeated

24   dose study, but it may not -- the dose may not matter after

25   the important gestational window has occurred.



 1             DR. KENNEDY:  Can I comment on that?

 2             CHAIRMAN FROINES:  Sure.

 3             DR. KENNEDY:  We were discussing this this

 4   morning, and my daughter, who is a distinctly childbearing

 5   age, was commenting on the fact that while looking for a

 6   varnish remover she was gratified to see that there were

 7   warning signs put on various products.

 8             I've got no problem with that, but I think in

 9   keeping with the comments that Gary made, that you need to

10   make it clear that this concern is there, that these

11   constraints are necessary, and for purposes of public

12   concern we're making this jump or taking this side path.

13             I can understand you need to do it, but it would

14   be very helpful to us if you offered more elaborate

15   explanation of what you were doing.

16             CHAIRMAN FROINES:  Well, I think that you can't

17   take a nine-day study over a six-hour day and call that an

18   one-hour acute study.  I simply don't think it's correct as

19   a matter of science.

20             Now, it's the greatest public health protection in

21   the history of humankind at some level.

22             DR. MARTY:  But how do you know at which hour of

23   exposure this gestational window occurred?  See, that's the

24   argument.  You can't -- there are -- I don't know of any

25   studies where they actually took each hour of gestation, did



 1   the exposure then, and then looked at the result.

 2             CHAIRMAN FROINES:  It doesn't necessarily --

 3             DR. MARTY:  It's a shotgun approach.

 4             CHAIRMAN FROINES:  -- occur in an hour.  It's a

 5   process that occurs over time.

 6             DR. MARTY:  But the actual event may occur in a

 7   very short time frame.

 8             CHAIRMAN FROINES:  At a certain dose that's not .2

 9   parts per million.

10             DR. MARTY:  I mean, look at thalidomide.  There

11   were people who took it for a day or two and then had

12   thalidomide babies.

13             Unless you're going to ignore the reproductive and

14   development toxicity in the acute reference exposure level

15   development, you are really stuck with using this kind of

16   data.

17             We did get that comment, incidentally, from

18   outside commenters, that we shouldn't be using repeated dose

19   studies, and that was our response to that comment.

20             DR. ALEXEEFF:  This is one that we've -- this type

21   of issue is one that we've struggled with throughout, and

22   that's why we identified it up-front as an issue.

23             And so we've looked at it and we've also spoken

24   within our department to our experts in this field.  And

25   their concern is that not looking at the uncertainty factor



 1   aspect of it, but looking at the timing of the doses, that

 2   it is -- there is a critical period that where the exposure

 3   has to occur, and you can't discern from these studies if

 4   it's due to a exposure over the whole period or due to the

 5   exposure from a one-day period.

 6             And that the advice that their guidelines, the

 7   reproductive guidelines, were to look at it as a short time

 8   frame like this.

 9             Now, if the panel doesn't think it's

10   scientifically appropriate, then, you know, we can go back

11   and try and figure out -- I'm not sure.  There's a couple

12   choices one has.

13             One is we could not consider reproductive effects.

14   We've tried to -- there were a lot of reproductive effects

15   that we ended up not considering, because the nature of the

16   effects were not as clear as these are, but this one is

17   already it's clearly listed as a reproductive hazard, so the

18   basis that it does cause reproductive problem is fairly well

19   laid out.

20             And in this case, you know, the effect is fairly

21   specific.

22             DR. BLANC:  Is this point of clarification, is

23   this the only chemical in this whole volume for which the

24   hazard target index is reproductive outcome?

25             DR. KENNEDY:  I have another one in my group.



 1             DR. BLANC:  How many are there, roughly?

 2             DR. ALEXEEFF:  If you look at page A-2, we've

 3   listed them.  So you can see this would be for -- I presume

 4   they're going to be calculated roughly the same way for

 5   arsenic, benzene, carbon disulfide.  There's quite a few

 6   here.

 7             DR. KENNEDY:  It seems to me that --

 8             DR. BLANC:  Where are you?

 9             DR. MARTY:  Page A-2, Table A-1 describes the

10   toxicological endpoint.

11             DR. ALEXEEFF:  I guess there really are only

12   eight, but really one of them doesn't make a difference if

13   you look at the reproductive -- for chloroform it's roughly

14   the same level, and actually we just note the reproductive

15   calculation for chloroform, but it's really not the driver,

16   it's the irritation that's driving it in chloroform.  It's

17   really only seven, seven RELs, that are affected by this

18   particular methodology.

19             DR. BLANC:  And for how many of those is the acute

20   extrapolation based on an exposure which is the seven days

21   or longer?

22             DR. MARTY:  I think they all are, because the

23   typical is day 6 to 15 of the gestation in the mouse and

24   rat.

25             DR. BLANC:  Well, that's only seven days, isn't



 1   it?

 2             DR. MARTY:  Yeah.

 3             DR. BLANC:  So it's seven days.

 4             DR. MARTY:  6 through 15, so it's actually nine

 5   days.  There may be some that are a little shorter than

 6   that, but that's sort of standard protocol.

 7             DR. GLANTZ:  This came up at one of the earlier

 8   meetings and maybe in some conversations I had with OEHHA,

 9   and it was raised in the comments, but I think I kind of

10   agree with what Melanie says.  I think you're kind of stuck

11   on this, because you don't know exactly when the compound is

12   acting.

13             And I think there's two issues here.

14             One of them, I think that the document should

15   reflect this discussion at the very least, recognize this as

16   a limitation that you have to take into account.  I don't

17   think we should ignore the data.

18             The other thing is to say, I mean raise the issues

19   in recognizing that the effects that you're looking at are

20   probably only occurring for a short time out of the seven-

21   or eight-day exposure, does that mean that the safety

22   factors that you're using, or I forget what we call them,

23   you know, the multipliers, maybe there should be some

24   different numbers used there to adjust for the fact that

25   just doing a straight time extrapolation is probably not the



 1   right thing to do for the reasons that John brought up.

 2             But I think we should -- I think we should take --

 3   I think that the information needs to stay in the report.  I

 4   think at a very minimum we need this -- we need to reflect

 5   the discussion, but the other question is should the

 6   modifying factor be adjusted to account for the fact of the

 7   problems that John raises, which I think are legitimate

 8   issues.

 9             CHAIRMAN FROINES:  Yeah.  George, I want to -- I

10   picked ethylene glycol monoethyl ether to make this point

11   particularly, because since the mid '80s there's no question

12   that these two glycol ethers are extremely powerful

13   teratogens, and that they're so powerful that the

14   teratogenicity occurred at the levels that they were

15   regulated at in the '70s and still are, in fact.

16             So that I'm not for a second suggesting that this

17   isn't one of the -- two of the most dangerous chemicals that

18   have ever been used in the workplace.

19             And I think that they have -- a terrible job has

20   been done regulating them.  I think they should have been

21   regulated as reproductive toxins or, rather, developmental

22   toxins 25 years ago, and that we are way behind on this one.

23             Secondly, in fact they are so toxic most

24   industries have eliminated their use.  They're almost not

25   used anymore.  They've just gotten rid of them because



 1   they're so dangerous.  The semiconductor industry got rid of

 2   these two in the '80s.

 3             So, I don't for a moment quarrel with you as a

 4   matter of the health effects of the two chemicals, but I'm

 5   worried about the policy, which is to assume a nine-day

 6   study, six hours a day, can be used for a one-hour acute

 7   toxicity determination.  And that's the thing that bothers

 8   me, because it's not just a question that there is a

 9   microsecond in which .24 parts per million will operate.

10   The effects will probably occur over a period of time.  It's

11   not a one-hour phenomenon.

12             Now, we may need some people who are mechanistic

13   teratologists to advise us on this, and there are a number

14   around.

15             But I don't think it's so simple to say at .24

16   parts per million over a one-hour period you're going to

17   start seeing birth defects.  I don't believe it, frankly.

18             And I think we need to go back and consider how as

19   a methodologic issue we should deal with this, and maybe

20   take these out and say we're not sure, and then figure out

21   how we want to do it and bring it back in again.

22             But I think that -- I don't know what you've done

23   about looking at toxicokinetics of these compounds and what

24   happens at .24 parts per million over one hour and how much

25   actually becomes toxicologically important.



 1             DR. KENNEDY:  John, can I add one thing?

 2             CHAIRMAN FROINES:  Sure.

 3             DR. KENNEDY:  In the next compound, and it's sort

 4   of the same story, although ethylene glycol monoethyl ether

 5   has already been identified, has long been identified as a

 6   teratogen, the uncertainty factor in calculating the REL

 7   there is a thousand, and it just -- it seems that we're

 8   trying to squeeze two issues into one formula.  And maybe

 9   they're best dealt -- maybe these compounds are best dealt

10   with their own warning and their own characterization and it

11   may not be appropriate or it may be more appropriate to

12   simply describe that we, at this moment, cannot define the

13   appropriateness of an REL for this toxic property.

14             CHAIRMAN FROINES:  I think this is an important

15   issue, because there are lot of glycol ethers that are used

16   in cleaning solvents, so there's considerable exposure to

17   glycol ethers.  So we want to be right on it because there

18   are people out there right now being exposed to them.

19             DR. MARTY:  It seems to me that the biggest issue,

20   aside from having to use large uncertainty factors because

21   the studies are in animals and sometimes you don't see a

22   NOEL, is the time extrapolation issue.  It may make the most

23   sense to take them out of the acute REL arena, and either

24   put them in a subacute category of itself or even in the

25   chronic document, although they're not really chronic



 1   exposures.  They're subacute exposures.

 2             DR. BYUS:  I've got benzene and chloroform, and

 3   they both fall in this category.  To answer your question,

 4   there are some toxic kinetic variables for benzene that may

 5   not accumulate some of the things within an hour, and for

 6   chloroform it's less clear.

 7             I think I sort of, when I read it first, it didn't

 8   strike me, but I, because I sort of realized it, then I

 9   thought this is really being health conservative, I really

10   don't know what the answer is.  I think we should just

11   define it in the front of the document as that we're going

12   to use either, that there is this time variable and that you

13   really don't know what's happening, or either call it

14   something else, define it differently, make it clear that

15   what it is we're doing.

16             I know thalidomide, you can get one pill at one

17   time, one day, one exposure, up and down kinetics of the

18   drug, it is sufficient in that situation to cause the birth

19   defects.

20             CHAIRMAN FROINES:  Well, I know that.  But that

21   pill contains how much thalidomide?  Was it .24 parts per

22   million?  I'll bet it was in the milligram range.

23             So let's call a spade a spade.  I mean, there is a

24   dose phenomenon, particularly because we think of these

25   things as having thresholds, so that for the most part we



 1   would assume that teratogens have thresholds.  Now, that may

 2   not be true.

 3             DR. BYUS:  I think they do.

 4             CHAIRMAN FROINES:  So the trouble when we act very

 5   conservatively, we may put ourselves in a position where

 6   we --

 7             DR. GLANTZ:  Would it make sense, I mean, this is

 8   something where I'm not terribly expert, but would it make

 9   sense to not do the time extrapolation at all?  If you're

10   arguing that there's some window that, you know, the drug --

11   or not the drug, if the compound is there during some

12   crucial period, it's going to have an effect and if it's not

13   there -- if it's there at other times, it's not going to

14   have an effect, and all you're doing by giving it for eight

15   days is making sure it will be there when this brief window

16   opens, maybe you shouldn't be doing the time adjustment.

17             DR. BLANC:  Doesn't the time adjustment only make

18   the dose go up?

19             DR. ALEXEEFF:  Yeah.

20             DR. BLANC:  If you didn't do the time adjustment,

21   you'd have an even lower number.

22             DR. GLANTZ:  No.  The time adjustment -- no.

23   Well, the time adjustment, if you don't do the time

24   adjustment, the REL would go up.  You would -- the higher

25   exposure would be considered.



 1             CHAIRMAN FROINES:  But this isn't theology we're

 2   talking about.

 3             DR. MARTY:  That's backwards, Stan, I'm sorry.

 4             CHAIRMAN FROINES:  His point is wrong.  His point

 5   is wrong.

 6             It's like that if you have any amount of the

 7   chemical at the right time, it will produce the teratogenic

 8   effect.  I don't think that's right.

 9             DR. GLANTZ:  No, I'm not saying any amount.

10             What I'm saying is they have these studies that

11   show that if they have a certain amount of exposure over an

12   eight-day period, over a eight-day period that they get an

13   effect, and what they're doing is they're saying, okay, if

14   we adjust that and assume the effect occurred over an hour,

15   then you adjust the dose that you would allow.

16             What I'm saying is what if you didn't adjust for

17   the fact that there's an eight-day exposure.  Just say

18   there's a certain level of exposure present and, you know,

19   if that's present at the wrong time, you have the effect,

20   and it doesn't matter that you expose the rats, or whatever

21   they were, for eight days.  If you could have exposed them

22   to the level that they used for one hour for the right hour,

23   you would have gotten the effect.

24             DR. ATKINSON:  That's a factor of 2.4 in this

25   case.



 1             DR. GLANTZ:  Does that make sense what I'm saying?

 2             DR. KENNEDY:  Dr. Froines, I think you made a

 3   comment that seems to me the most appropriate.  We're all

 4   talking around an issue that none of us fully understand.

 5   There have got to be people who understand it better.

 6             And I would propose that these compounds, rather

 7   than trying to fit their toxic characteristics into a shoe

 8   box that may not be the right shoe box, let's get some more

 9   information.

10             DR. ALEXEEFF:  Just speaking of it right now and

11   based upon what Melanie was saying earlier, it might make

12   more sense -- this depends upon where the concerns are of

13   the panel.

14             If the concern is with regards to use of the

15   uncertainty factors, that's one issue.

16             But if the concerns is with regard to the exposure

17   time regimen, okay, our intention in creating this document

18   was to try to come up with an acute exposure for the air

19   districts to use, and they would do one-hour modeling and so

20   then we would fit everything to one hour.

21             So but it may be in this case where we have a

22   situation of a reproductive concern that if -- and it's

23   based upon this kind of number, maybe we simply should say,

24   well, if you want to evaluate the impact of the substance,

25   you're going to have to do an average time of equivalent to



 1   several days and instead of a one-hour averaging time, and

 2   to look at -- and then calculate the exposure without

 3   adjusting for that, to one hour, but looking at it more over

 4   a short-term period of several days of exposure.

 5             Would that make more sense?  In other words,

 6   make -- instead of adjusting the study to fit the exposure

 7   need, adjust the modeling to fit the repro studies, is what

 8   I'm saying, and then we wouldn't be --

 9             DR. GLANTZ:  I think that makes a lot more sense,

10   because then you're basing it on the data that you have.

11             DR. ALEXEEFF:  Because that seems to be the

12   concern in large part is that we're assuming that this very

13   brief one-hour exposure could result in this, as opposed to

14   more prolonged.

15             DR. GLANTZ:  I think --

16             DR. BYUS:  You don't need it for six days, though.

17             DR. ALEXEEFF:  The next question would be, what

18   would be the exposure time?  Would we adjust it to exposure

19   time in the animal studies or would we adjust it to nine

20   months with the gestation period --

21             DR. BYUS:  I don't know the answer to that.

22   Clearly I don't think you need six days.  What you need is,

23   it would be hard to determine from the animal studies

24   exactly.

25             But you're assuming, I agree with you, Melanie,



 1   most of those studies, the ones I have seen, they do this

 2   standard 6- to 15-day exposure and then establish it as a

 3   reproductive or developmental toxin, rather than going back

 4   and exposing it for so many hours at each stage of

 5   development.

 6             FROM THE AUDIENCE:  Those studies were done

 7   earlier.  The long studies is catching everything, because

 8   they know certain substances work in a two-day period, the

 9   next two-day period.

10             DR. BYUS:  My feeling is to assume that it only

11   would take a minimum exposure of a half a day or a day to

12   anything if it was done at the worst possible -- take the

13   worst case scenario, that that would be sufficient to cause

14   the toxicity, to cause the developmental failure.  I would

15   take the shortest possible time it would take in the human

16   situation, if you don't have the data, which is somewhere

17   around a day, or is it around a day?

18             DR. MARTY:  I don't know.

19             DR. BYUS:  I don't know either.

20             DR. BLANC:  Would the following work, to sort of

21   saving you to making a third whole document, because I think

22   that might be counterproductive, perhaps.

23             But for the compounds for which the reproductive

24   outcome is what's driving the extrapolation, that you've

25   actually gotten a lower number than you've gotten with the



 1   others, that you recalculate that for a 24-hour exposure and

 2   that you state at the outset of that section that the

 3   following -- for reproductive outcomes this is not one-hour

 4   modeling, this is 24-hour modeling.  The REL for the next

 5   most sensitive end organ effect on a one-hour exposure basis

 6   would yield X value, so that for any air control district

 7   they do have the one-hour exposure REL, but that you have a

 8   separate section for those places where the -- where

 9   reproductive would otherwise be driving it, and then you do

10   the calculation for a -- on a 24-hour basis, because I think

11   the leap from six days to one day is, you know, 24 times

12   less of a leap than from six days to one hour, or whatever.

13             DR. MARTY:  I guess the issue would be do you take

14   the entire dose that is received over the nine days and

15   extrapolate that back to one day?  I think that gets in a

16   really really --

17             DR. GLANTZ:  I think --

18             DR. BLANC:  I think Haber's Law is conservative,

19   because you're going to come out with a lower number if

20   you --

21             DR. MARTY:  It would almost be the identical

22   extrapolation, because we've only taken the six-hour

23   exposure from a single day and extrapolated that back to one

24   hour.

25             DR. BYUS:  It takes four times the half-life to



 1   reach the steady state, so that some of these kinetic

 2   variables for these metabolites can also get factored in

 3   here, could actually take you -- one of the metabolites, I

 4   think, were benzene or chloroform, I forget, which is 17

 5   hours, so it may take a long time, days, to reach -- you

 6   might not reach a study.  It's complicated.  I don't know.

 7   I really don't know the answer.

 8             DR. MARTY:  Maybe we should just set them aside

 9   for now, and base a one-hour REL on the next most sensitive

10   endpoint.

11             DR. BLANC:  I think you should, but I think it

12   would be advisable -- everybody is saying don't ignore

13   completely the reproductive data, especially for the things

14   which we know are primarily reproductive toxins, but to put

15   in some calculation which is not a one-hour exposure and

16   that people know that the modeling -- and people still have

17   the one-hour REL for the non-repro effects, but for repro

18   effects there's no point to making a one-hour REL.  For

19   those where there is a significant repro effect, which

20   you've already determined which eight chemicals that is,

21   that you provide an estimate for 24 hour, or one day

22   exposure or something.

23             DR. GLANTZ:  I mean if the study is for six hours

24   a day exposure, why not just use that?  Say --

25             DR. MARTY:  You actually come out with a lower



 1   number if you do that, because you have ten ppm, no time

 2   extrapolation and you would divide it by the cumulative

 3   uncertainty factor of a hundred and end up with a tenth ppm.

 4             DR. BLANC:  You understand that?

 5             DR. GLANTZ:  No.

 6             DR. BLANC:  The way the algebra works is if you

 7   extrapolate back from six hours to one hour then it would

 8   have had to have been at a higher exposure for one hour to

 9   have the same effect as a lower exposure because it's

10   cumulative dose.

11             DR. GLANTZ:  Okay.

12             DR. BLANC:  Simple way of saying it.

13             DR. BYUS:  I think this is a very important point.

14             DR. ALEXEEFF:  We struggled with this many many

15   weeks, and we rewrote this section many times before we --

16             DR. BYUS:  You should have given us a little hint

17   on this then and we could have thought about it a little

18   more.

19             DR. ALEXEEFF:  We dropped hints.

20             DR. BYUS:  Drop them on top of us, would you?

21             DR. GLANTZ:  I don't remember where, but I know

22   I've discussed this.  I don't know if it was at one of these

23   meetings or if it was with them, and it was raised in the

24   comments and responded to.

25             CHAIRMAN FROINES:  This is an issue --



 1             DR. GLANTZ:  But I kind of agree with Paul.  I

 2   don't want to -- I think while it's difficult, I feel bad if

 3   we were to just pull it out of the document.  I think we

 4   need to come up with a reasonable way to handle it, given

 5   the current state of affairs, and then if people -- as

 6   knowledge -- I think we've got the best information in front

 7   of us, and I think that, you know, we can leave it open and

 8   invite OEHHA to come back or bring more experts back, but I

 9   guess I would be against pulling it out.

10             DR. BLANC:  I suggest you do come back to us and

11   that the general thrust of your proposal to us be that there

12   not be one-hour RELs for reproductive, but there be an REL

13   for reproductive outcomes where those are critical endpoints

14   and that those RELs be based upon something like, you know,

15   well one-day exposure and the technical way in which you

16   make the extrapolation.  You should come back to us and give

17   us -- what, after consulting with your experts, what you

18   think is the most reasonable way of doing it.

19             DR. GLANTZ:  They have spent a lot of time

20   consulting.

21             DR. BLANC:  They weren't dealing with this

22   approach particularly.

23             CHAIRMAN FROINES:  They've been through it.

24             But I agree with Paul hundred percent.  I think

25   that that's the best way to handle it for the -- at this



 1   point, and that we will have to develop a longer term

 2   policy, if you will, to address this, and you can come back

 3   with an interim solution that the districts can use.

 4             I would say, George, that if there's anybody in

 5   the district in this room, if I were you, I would recommend

 6   that EGBMD and EGEE be banned.  They should not be being

 7   used, period.  They're much too toxic to the reproductive

 8   system in terms of being able to be used.

 9             So that we're trying to come up with a

10   reproductive policy for how to handle more than the acute

11   exposures, but it doesn't in any way suggest that people

12   should be using those chemicals.  They shouldn't be being

13   used at this point.  We should be using pollution

14   prevention.

15             I mean it's -- it's not as though they are

16   essential.  They were used primarily in photo resist in the

17   semiconductor industry and there's not a semiconductor plant

18   in plant in California that uses them right now, because of

19   this.

20             DR. BYUS:  But the benzene and the chloroform are

21   pretty -- they're also reproductively toxic, and if I were

22   pregnant, I wouldn't want to work around them at all.

23   Basically you shouldn't be -- you shouldn't be working

24   around benzene and chloroform.

25             CHAIRMAN FROINES:  This is one of the things that



 1   this whole process I want to ask you about when we get past

 2   this, because this whole process has particular relevance

 3   for occupational exposures, but that's really not what we're

 4   supposed to be doing in here.  I mean, sodium hydroxide

 5   there's not a lot in the ambient environment out there.

 6             DR. KENNEDY:  So we're going to hear an interim

 7   report?

 8             CHAIRMAN FROINES:  We're waiting to hear from

 9   George and Melanie.

10             DR. ALEXEEFF:  Just to mention this, if we did

11   this calculation -- we have done this calculation, but if we

12   did this using the procedures that we have in our document

13   as to when we'll go about doing this, we would come up with

14   a 24-hour level of 0.024 parts per million, so it actually

15   would drop down tenfold, but it would be a 24-hour exposure

16   concentration as opposed to a one-hour exposure

17   concentration.

18             So if you figured it -- so like -- so the actual

19   cumulative dose is a little bit more.  If you -- but that's

20   because of the way the extrapolation procedure works.

21             I just mention that, just because if that doesn't

22   make sense, it was like no point in us doing it.

23             CHAIRMAN FROINES:  Why don't you assume for the

24   sake of argument that's the way we're going to go, and go

25   back and review it and then let us know if in the next day



 1   or two you come up with any major --

 2             DR. BYUS:  Most of the inhalation studies were six

 3   hours.  See, it goes up and then it drops down, then it goes

 4   up and drops down.

 5             DR. GLANTZ:  It seems to me that at least

 6   extrapolation to do here, the least extrapolation to do

 7   would be to present six-hour, you know, six-hour level.

 8   That's what was done in the studies.  And that just based

 9   REL on the reproductive toxic on six hours, because that's

10   what they did and that has no time extrapolation at all.

11             DR. MARTY:  That would be one-tenth of a ppm.

12             DR. GLANTZ:  Well, then fine.

13             DR. BYUS:  You're going to assume it takes one

14   day.

15             DR. ALEXEEFF:  That would be the assumption that

16   we're making is that it's a one-day as opposed to --

17             DR. BYUS:  Of the six hours.

18             DR. MARTY:  Six-hour exposure could produce the

19   same effect in a person.

20             DR. GLANTZ:  I think that's --

21             DR. BYUS:  That's reasonable.

22             DR. GLANTZ:  I think that's what they ought to do.

23   I think there needs to be a very clear reflection of this

24   discussion in the document itself explaining why it's being

25   done that way, and the associated uncertainty.  And that way



 1   you're not having to do a time extrapolation at all, which I

 2   think sidesteps a lot of the problems, and it also addresses

 3   the issues that one of the commenters brought up when they

 4   raised the same point.

 5             Are you happy with that, John?  Okay.

 6             John has, for the record, John sighed and nodded

 7   his head yes.

 8             CHAIRMAN FROINES:  I don't think it's easy.  I

 9   don't think we should let it go by.  It's too serious.

10             DR. GLANTZ:  But I think this is a lot more

11   defendable the way it's being done right now.

12             CHAIRMAN FROINES:  Peter, you really thought you

13   were going to go through quickly, and that certainly didn't

14   prove to be the case.

15             DR. KENNEDY:  No.

16             DR. GLANTZ:  He is missing another soap opera too.

17             DR. KENNEDY:  Wait and see what it looks like, but

18   it was obviously an important issue.

19             The last compound, and I'll be gone, is

20   triethylamine, and it's very simple and straightforward, and

21   I don't think it -- again is based on information developed

22   on two volunteers, but it's a whole lot easier than any of

23   the ethylene glycol compounds.

24             So thank you for your attention.  And I'll see you

25   on the slopes.



 1             CHAIRMAN FROINES:  Great.

 2             I have a question on triethylamine for George.

 3             I'm still assuming that we are operating as a

 4   panel as dealing with air issues, and that we are a panel

 5   that is not dealing with occupational issues.  We all agree

 6   to that?

 7             DR. BYUS:  No.  I think my comment to you is that

 8   I think these RELs are used for more than one purpose.

 9   Clearly, the pesticide stuff will be.  Maybe even here they

10   will be as well.

11             CHAIRMAN FROINES:  No.  But that's precisely the

12   question I'm asking, because these -- here's the problem.  I

13   understand that.  That's why I asked it.

14             The question, George, is these RELs in some cases

15   will only have relevance to occupational situations.  There

16   isn't any ambient exposures, for the most part.

17             Now, you can show me exceptions, I'm sure, but a

18   lot of these there won't be anything but occupational

19   exposures, and I suspect triethylamine -- the concern, it's

20   not that somebody is using it in a factory and there won't

21   be a little bit going out into the air, but the amount going

22   into the air is going to be vanishingly small.

23             DR. ATKINSON:  It comes out of cattle feedlot.

24             CHAIRMAN FROINES:  What?

25             DR. ATKINSON:  Cattle feedlots.



 1             CHAIRMAN FROINES:  I stand corrected.

 2             But sodium hydroxide, I would argue that there's

 3   probably only occupational exposure.

 4             Here's my question.

 5             These numbers may get used by agencies other than

 6   AQMDs for example.  There may be -- you know, WSPA showed,

 7   made a comparison between HCGIH values, their views, and

 8   WSPA argues about using the TLVs.  So one of the things we

 9   need to be aware of is that in fact these numbers are going

10   to be used by people in an occupational setting, and they

11   could form the basis for whatever.  I don't know.  But

12   they're not free of having implications in the workplace.

13             DR. GLANTZ:  I think that's true.  But I don't

14   think that's a problem.

15             And I think that the -- that these numbers are

16   developed -- I mean the science behind these numbers would

17   basically be the same and I think the limitations, with the

18   exception of the things that we've been talking about, are

19   pretty well laid out in the document.

20             CHAIRMAN FROINES:  But it's important to recognize

21   that if OSHA were to set a standard for triethylamine, they

22   would not use this methodology to do so.  They would use a

23   different methodology.

24             And so to the degree that they get used in

25   occupational settings, they run counter to the legal



 1   framework that's established in the OSHA act.  So we have to

 2   be aware.

 3             DR. BYUS:  Is that true?

 4             CHAIRMAN FROINES:  Absolutely true.

 5             DR. BYUS:  How would they do it?

 6             CHAIRMAN FROINES:  The first thing is that they

 7   have certain requirements that they have to meet.  They have

 8   to demonstrate that the standard that they develop has to be

 9   feasible, so if they picked a number here for triethylamine,

10   they would have to show that .68 parts per million in a

11   workplace is feasible.

12             DR. GLANTZ:  That's risk management.

13             CHAIRMAN FROINES:  No, it's not.  It's the

14   definition of a standard.

15             DR. GLANTZ:  But that's --

16             CHAIRMAN FROINES:  OSHA does not separate risk

17   assessment and risk management, it's all part of the same

18   process.

19             DR. GLANTZ:  I understand.

20             CHAIRMAN FROINES:  All I'm saying is we need to be

21   aware of that.

22             DR. ALEXEEFF:  My only comment is it's not our

23   intention that these are to be used at all in an

24   occupational environment, and under the situation that you

25   described, the way we would see it, if there is no ambient



 1   exposure from that substance, then that particular REL won't

 2   be used.  I mean, that's from our vantage point.

 3             And so at the same time, as we have discussed

 4   earlier, our intention was to try to derive RELs that do

 5   have emissions, as far as we know.

 6             Now, whether or not the actual off-site emissions

 7   actually go really off the site is a separate modeling kind

 8   of question, and not the question we're trying to address

 9   here.

10             But our only interest is in the public and not in

11   the occupational environment.

12             CHAIRMAN FROINES:  You probably should say that in

13   your document.

14             DR. WITSCHI:  I have a question.  Maybe I'm

15   unclear on the concept.

16             But some of those values differ from TLVs by a

17   factor of ten, sometime more, 50, 100, 300.

18             Now, if somebody exposed occupationally, what if

19   he makes a point, well, I'm like the average Joe on the road

20   on the street, why shouldn't I have the same protection just

21   because I have a job in industry?

22             DR. BLANC:  I think I'll address that.

23             In fact, TLVs from the ACGIH, as well as

24   permissible exposure limits from OSHA, or whatever they're

25   called, do not in fact -- are not -- intentionally not



 1   designed to protect sensitive individuals.

 2             So any TLVs should be, if you were looking at an

 3   eight-hour exposure, at least ten times higher than anything

 4   that they have here, because they always have a factor of

 5   ten for sensitive individuals.

 6             CHAIRMAN FROINES:  Peter, in OSHA risk assessment

 7   policy, the acceptable risk is one cancer in a thousand.  As

 8   what -- Bill Jordan said today the acceptable risk at EPA is

 9   one cancer in a million, so it's a factor of a thousand

10   difference.

11             DR. MARTY:  We do have on page 12 under

12   populations of concern, section 1-5, a discussion that we're

13   targeting the general population, including sensitive

14   individuals.

15             CHAIRMAN FROINES:  Why don't we move ahead.

16             And since Peter is all by himself over there, why

17   don't we go to him.

18             DR. WITSCHI:  I have hydrogen cyanide, which I

19   think Dr. Blanc should look at that one too, because the

20   work and your paper is prominently quoted.

21             The thing that struck me, George, are there no

22   human data?  Because you developed your REL from monkeys.

23   You know, if you know about hydrogen cyanide, there were no

24   human data you can use?

25             DR. ALEXEEFF:  Yeah.  We were unable to find any



 1   human data, quantitative human data.  I mean there are case

 2   reports.

 3             So also this is one of those situations where the

 4   lethal effects are fairly close to severe effects, in terms

 5   of a severity dose response curve.  The actual doses are not

 6   that far apart.

 7             So that you can see when you look at some of these

 8   studies where in one species they may test it and they're

 9   showing neurological effects and in other species there may

10   be a lethality, or the lethality is just twofold higher in

11   one species or threefold in another.

12             So to get the quantitative data in humans would be

13   very very difficult.

14             DR. WITSCHI:  Okay.  The other question I had is

15   hydrogen sulfide, we really have this big difference to the

16   TLV of a factor of 300, which is actually quite a lot.  Is

17   this because of the smell, because you can smell it?

18             DR. ALEXEEFF:  Hydrogen sulfide, yes.

19             DR. MARTY:  Yes.  That's based on -- we're back to

20   the ambient air quality standard on that one, incidentally,

21   and that is based on physiological response to odor, so

22   headache, nausea.  As opposed to a classical toxicological

23   effect.

24             DR. WITSCHI:  Do we have in California any paper

25   mills?  I know up in Oregon there are quite a few and you



 1   can smell it.

 2             DR. MARTY:  Yes.  There are paper mills who have

 3   to monitor their reduced sulfur.

 4             CHAIRMAN FROINES:  There's a lot of petroleum

 5   refiners.

 6             DR. WITSCHI:  So anyway.

 7             Another one I had some problems with was really

 8   the mercury.  Because you throw about everything in that

 9   remotely has mercury in it, and yet I think mercury toxicity

10   is not mercury toxicity, is not mercury toxicity.  The

11   vapors are different from the organo compounds from the

12   chlorides.

13             So I think in general basis as it happens with a

14   few other metals too, this is not very satisfactory to me on

15   a general principle.  You know, you cannot discuss and

16   develop RELs by going through mercury chlorides, nitrates,

17   sulfide and all those kind of things.  They just don't

18   belong together.

19             DR. MARTY:  I think that the way we've had to

20   approach that is that in the air toxics hot spots program,

21   which these are destined to be used in, the emissions are

22   reported as just the metal, not the sulfur, the metal or the

23   metal compound.

24             So we have decided to use data that reflects more

25   sensitive endpoint and more toxic compound of that group of



 1   compounds to set the reference exposure level.

 2             So I agree that it is not the best solution, but

 3   until facility X can say it's mercuric chloride and not

 4   mercuric other stuff, we're sort of stuck in that situation

 5   right now.

 6             In other words, we don't have the exposure

 7   information or the emissions information on which mercury

 8   compounds are coming out of the stack.  It's going to vary

 9   for combustion source -- you will get some elemental

10   mercury.  You'll also probably get mercuric oxide and

11   possibly mercuric chloride.

12             DR. WITSCHI:  Yes.  As I said, these are different

13   levels of concern, these are different toxicities.

14             DR. MARTY:  I think we purposely, I hope we did

15   this, we didn't include like methyl mercury or --

16             DR. FUCALORO:  Which of course is deadly.

17             DR. MARTY:  Right.  Because it is so different

18   from the other mercury compounds.

19             DR. WITSCHI:  No.  Actually, not quite.  You know

20   mercury has many similarities in its toxicity with mercury

21   vapor.  I mean, they're not so much different from each

22   other.  The one that's totally different is the mercuric

23   chloride and mercuric salts.

24             So of course they are differences between the

25   mercury vapors and the methyl mercury.



 1             CHAIRMAN FROINES:  I guess the key question is do

 2   you have a basis for differentiating between mercury salts

 3   in terms of toxicity?

 4             DR. WITSCHI:  How do you mean, the basis?

 5             CHAIRMAN FROINES:  I'm saying is there an

 6   evidentiary basis to develop different RELs for different

 7   compounds?

 8             DR. WITSCHI:  First of all, I don't think under

 9   what circumstances mercuric chloride is an inhalation

10   hazard.  I don't know.

11             DR. BLANC:  Very rarely, I would say.

12             DR. WITSCHI:  Yeah.  But mercury vapor definitely

13   is.

14             DR. BLANC:  The one I think would also be would be

15   is, what was it called, corrosive sublimate, mercuric

16   dichloride, is that right?  Do I have that right?  That

17   would be the other one that is sort of airborne.  Corrosive

18   sublimate.

19             DR. WITSCHI:  Yes.

20             Just the REL is based on a study, inhalation

21   study, mercury vapor.  That's okay.  That one I didn't have

22   any problems with that one, because that was even a

23   one-hour-a-day study.

24             DR. BLANC:  Can we go back to the cyanide for a

25   second.



 1             DR. WITSCHI:  Yes.

 2             DR. BLANC:  I notice in your literature you don't

 3   cite the ACGIH threshold limit value documentation book.

 4   You know what I'm talking about?

 5             DR. ALEXEEFF:  We're back to hydrogen sulfide?

 6             DR. BLANC:  The ACGIH documentation threshold

 7   limit value book, which a lot of times does have, you know,

 8   plausi-published information from I would think in

 9   particular from the plating industry.  Because isn't the

10   short-term exposure limit the OSHA short-term or NIOSH

11   recommended short-term exposure limit something like five

12   parts per million for cyanide?

13             John, do you know what the STEL is for cyanide?

14             If it was five parts per million -- let me say it

15   a different way.  If it was eight parts per million, you

16   would -- or if it was six parts per million, I guess is a

17   better way of saying it, you would come out with the same

18   number that you come out with, I guess.

19             Oh, no, you wouldn't.  It would be up higher

20   because it would be for an hour.  I think you should just

21   double check and make sure that you're in the same ballpark

22   that you're getting to anyway, with the monkey falling over

23   endpoint.

24             DR. WITSCHI:  I think I would check that one.  The

25   monkey number is lower than the TLV is.  I looked up the



 1   TLV.  The monkey number is lower.

 2             DR. BLANC:  Just to make sure.

 3             DR. MARTY:  You're talking about the 15 minutes

 4   STELs.

 5             DR. BLANC:  Yeah.  Just how they got to that.

 6             It seems to me that there must be human data

 7   related to plating facility, airborne levels in plating

 8   facility.  I just can't believe that there's no industrial

 9   hygiene data with endpoints like what number of the workers

10   have headache or nausea, if you get up to certain level.

11             CHAIRMAN FROINES:  Are you talking about hydrogen

12   cyanide?

13             DR. BLANC:  Yeah.

14             CHAIRMAN FROINES:  There's also, Paul, a very

15   extensive literature on neurotoxicity -- oh, that's chronic.

16   Never mind.

17             DR. MARTY:  I think that when we've looked at the

18   human information, part of our problem is that we're coming

19   from a perspective of well is there a dose response curve

20   demonstrated in this data and I know you know that it's

21   extremely rare to have that.  So we're always running

22   against, well, ten percent of the people had headaches and

23   the concentration is measured where X to Y --

24             DR. BLANC:  Yeah.  But for cyanide, this is a good

25   example of something where the people having daily headaches



 1   when they're working with cyanide, this is not a chronic

 2   cumulative issue.  This is a series of acute responses.

 3             So if, you know, if you -- if the data show that

 4   when you have levels of two parts per million airborne

 5   levels, and you don't have skin exposure to cyanide salts in

 6   solution, people don't have headaches and nausea, and when

 7   you have five parts per million you start getting people

 8   with having these acute symptoms, then that's an acute

 9   symptom, even if it's been measured on a chronic basis.

10   Because that's how cyanide works.

11             Really, the only chronic health outcomes that are

12   theoretically a problem with cyanide are these B12 depletion

13   issues and certain other neuroeffects that may have to do

14   with a chronic series of insults or the sequelae subacute

15   anoxia, or the literature on thyroid exposure.  Those will

16   be the things that you will be dealing with in your chronic

17   document.

18             But in terms of, you know, having syncope,

19   certainly, but headaches, nausea, all of that stuff, those

20   are all acute effects, even if they're happening day after

21   day.

22             CHAIRMAN FROINES:  We've got to move on.

23             DR. ALEXEEFF:  We'll take a look --

24             DR. FUCALORO:  I just need to make a quick

25   statement.



 1             Just on the table you had, normally, I mean,

 2   mercury one is dimeric, so I believe it's HG2, N03 twice, is

 3   what you have on that.

 4             I think you ought to check the synonym mercury

 5   bisulfate.  That may be HGHSO4.  Might be.  That's the

 6   normal prefix bias when there's a hydrogen as one of the

 7   cations.

 8             Down in the melting point, incorrect formula, you

 9   didn't put down mercury nitrate, whether it was mercury one

10   or mercury two.  You put down mercury nitric acid, HNO3.

11   You mean HGNO3 taken twice, and so on.

12             And again on the next page where it says most HG

13   plus forms of water soluble, that's in fact true, but it's

14   usually, again, you see it in the literature, people see

15   this, because it's HG2, 2 plus, is the mercury one and a

16   cation.

17             CHAIRMAN FROINES:  To try and finish off mercury

18   and deal with Peter's comments, it seems to me that the

19   concern I would have, I don't know, say, what the South

20   Coast Air Quality Management District will do if they think

21   that they need to be concerned about airborne releases of

22   mercuric nitrate, for example, and they go out and they put

23   some sort of regulatory controls on someplace and it's a

24   bronze foundery, for example, to avoid mercuric nitrate.

25             So part of the problem with when you link



 1   everything together, is you're linking apples and oranges a

 2   little bit, but it may have regulatory consequences in terms

 3   of permitting, and that's what worries me, I think.

 4             And that is that it seems to me that the REL

 5   you've got here is for mercury.  It's for mercury vapor that

 6   people inhale.  It is not really for mercury nitrate,

 7   mercuric nitrate, nor is there going to be a heck of a lot

 8   of mercuric nitrate going out of anybody's stack.  I suspect

 9   there won't be any, unless there's some way in the

10   industrial process that it were to be aerosolized through

11   water, steam or something.

12             So it seems to me that we should put a sentence or

13   two in there that says this REL was derived basically from

14   mercury vapor, it is -- there would be probably less concern

15   where you have mercury salts because they would tend to

16   be -- have no significant vapor pressure at atmospheric, and

17   the only concern would be if there's a fire or water

18   vaporization, aerosolization or something, something like

19   that, that makes it appear that we know what we're talking

20   about in terms of the properties of these different

21   chemicals.

22             DR. FUCALORO:  They are dangerous if you ingest

23   them, but we're dealing with the air.

24             CHAIRMAN FROINES:  That make sense?

25             DR. MARTY:  It does make sense.  I would hazard a



 1   guess that most of the emissions they're dealing with are

 2   elemental anyway.  But it makes sense to put that in here

 3   that that's what we're --

 4             CHAIRMAN FROINES:  But I had a student once who I

 5   said let's do some studies of vinyl chloride, and he went

 6   out and bought a bottle as a gas chromatographic standard of

 7   polyvinyl chloride dust.  And I said I don't think you're

 8   ever going to get this through your gas chromatograph.

 9             So people who aren't technically trained,

10   sometimes make big mistakes.  So you don't want somebody who

11   is in someplace who says, oh, my God, we've got to worry

12   about Joe Smith down the street who's got this mercuric

13   chloride.

14             DR. FUCALORO:  Because mistakes like that also in

15   some way in people's minds with this credit of the document,

16   I think people tend to see errors in there and that's one of

17   the reasons I always suggest to try to get it polished well,

18   because it just looks like a professional job.  I know it's

19   a professional job and mistakes are made.  These things are

20   a huge amount of work here, so I'm happy to help on some of

21   those typos and things like that.

22             CHAIRMAN FROINES:  Peter.

23             DR. WITSCHI:  That's all I have.

24             CHAIRMAN FROINES:  Paul.

25             DR. BLANC:  Okay.  Carbon disulfide is first,



 1   right?

 2             I think you got the generic comments before about

 3   physical properties.  I think that that's great that they're

 4   going to go through that.

 5             And you should be careful in the document when

 6   you're talking about vapor versus gas for the same reasons

 7   that were just said.  So in section 4 you say, however,

 8   experimental exposure to the pure gas has not resulted in

 9   this effect.  I guess you mean the pure vapor, technically.

10   But I don't know what you mean.

11             I was surprised that in this section there were no

12   citations to the group from Belgium and their studies.  Is

13   that because they're all chronic carbon disulfide?  You

14   know, Louruss and that group.  They've really been the

15   research group.

16             DR. ALEXEEFF:  I would think so.

17             DR. BLANC:  Just double check that you didn't miss

18   it.

19             I do think that although it's going to be the main

20   part of your chronic document, you need to say that it has

21   cardiovascular effects, since I think most of the neurologic

22   stuff is chronic also.  It's an imbalance here.

23             And on the next page, I have no idea what slow

24   vital capacity is.  That must be taken out of a paper, but I

25   don't know whether that means flow at low volumes or



 1   terminal flow, but it's not a term that --

 2             DR. ALEXEEFF:  Okay.

 3             DR. BLANC:  I think that you need to talk about

 4   another medical risk group would be anybody who takes

 5   disulfiram or antabuse, since it is metabolized to carbon

 6   disulfide in the body.  And here are two abstracts which may

 7   be helpful in that regard.

 8             And I'll leave it that my comments of carbon

 9   disulfide at that.

10             The next one is chlorine.

11             And, again, chlorine in the physical properties

12   it's the gas, not the vapor, for this one.  You have the

13   specific gravity and then you're talking about it being 2.1

14   times heavier than air.

15             I think you need to say in terms of sources, the

16   major sources, the mixture of hypochloride solution with any

17   acid.  That's the most common source.

18             Let me make a comment here that I think is generic

19   to many places in the document.  You have this template of

20   predisposing conditions.  For many of these under medical,

21   you've apparently taken the predisposing conditions from

22   Poisontext or some version of Poisontext.  I mean Reprotext

23   is Micromedex.

24             First of all, you used a 1994 version, because

25   that's when you started this process, but that is, you know,



 1   already we're in 1999, so that's a bit out of date.

 2             But rather than force yourself to have a

 3   reference, I would take the following template approach.

 4             For things which are irritants, you should say

 5   that a medical at-risk group would be people who have

 6   underlying cardiopulmonary disease.

 7             For things which are neurologic, say that if you

 8   have underlying neurologic disease.

 9             And if there are reasons for which you think that

10   reproductive outcomes are particularly germane, obviously

11   anyone who is pregnant, because there's a lot of

12   inconsistency in your document.  Sometimes you're using

13   Reprotext.

14             On one of my other ones it says people who have

15   congestive heart failure are going to be more at risk for

16   phosgene or something, because they're going to be -- I

17   mean, that's from the World War I literature.  Anybody with

18   underlying cardiopulmonary disease would be more at risk of

19   the effects of phosgene or chlorine or chloropicrin.  I

20   would just be generic in that regard.

21             And I thought this was also a good example

22   where -- let me bring up one other thing.  I think that for

23   chlorine and phosgene, chloropicrin, I was surprised to see

24   given that you very diligently went back to some of the

25   World War I or post-World War I poison gas literature that



 1   Winternitz, the pathology of war gas poison in 1920, was not

 2   cited, because it has a lot of animal data for all three of

 3   these things and it must be most relevant, I think, to

 4   chloropicrin as one of the few documents that has a lot of

 5   chloropicrin stuff in it.  So I would just double check

 6   that.

 7             You've got Underhill here from Yale University,

 8   1920, but there's a simple book by Winternitz, and I would

 9   pull that and just double check all three things.

10             The next one is chloropicrin and since

11   chloropicrin is used as an agricultural chemical, I was

12   wondering, given what we've heard earlier today about FIFRA

13   and recertification, if there aren't any acute rat

14   inhalation studies somewhere.

15             DR. ALEXEEFF:  There aren't.  We checked.

16             DR. BLANC:  When was the last time you checked?

17             DR. ALEXEEFF:  Today.

18             DR. BLANC:  Why is that?

19             DR. ALEXEEFF:  We asked basically it has to do --

20   anyway, they are currently under design.  They're going to

21   be submitted or developed over the next year or so.

22             DR. BLANC:  There are some animal data in

23   Winternitz, so go look at that.

24             And then I thought this was also a good generic

25   example, if you look at your reference page for



 1   chloropicrin, there are a series of references, book

 2   references, where there weren't page citations, so just try

 3   to be rigorous and go back and when you cite a book, this is

 4   not the only place where I found it, but this was one of the

 5   more glaring examples, that some of the books have the

 6   pages, some of the books don't have the pages, and it makes

 7   me suspicious that sometimes when you're citing a book, you

 8   have not really pulled the book, but the book was cited by

 9   somebody else, and I think that's a bad idea because in my

10   experience people miscite things.  So what they said it says

11   may not be what it said.

12             I think that of all the substances where we might

13   possibly be missing the boat, because I think for so much

14   data on the war gas agents and so forth that you're not

15   going to be off, my general take was that your levels were

16   conservative, was dioxene, because the data seems so spotty.

17             I just -- I just worry about this one.  This is

18   more sort of an intuitive unease.  I know that's not very

19   helpful.

20             But this is one where you might want to go the

21   extra mile.

22             Now, for example, I pulled for you a citation of a

23   review that was done for ATSDR and published in Toxicology

24   and Industrial Health.  It wasn't cited in your reference

25   list.  I would pull that, just make double sure that there's



 1   nothing in there that you missed.

 2             And the other thing is that dioxene there's an

 3   offhand comment here, which I was glad to see, but I think

 4   needs to be expanded on, in major uses or source you say

 5   1,4-dioxene is used as a solvent for oils, resins, waxes,

 6   adhesives, bla-bla, it is also used as a stabilizer in

 7   chlorinated solvents.  That's quite correct and that is

 8   probably the major exposure to people.  It is very important

 9   in things like 1,1,1-trichloroethane, and that's where

10   people get exposed and they don't even know it.

11             And I think that needs to be expanded on, and like

12   to say what percentage it is by volume and most -- in these

13   common solvents, because I'm sure that's the major source of

14   release.  Ubiquitous may be too strong a word.

15             What's the next one?  Nickel.  In terms of nickel,

16   I think you've got to do some research on this question.  I

17   wasn't able to get to the bottom of it.  I did pull some

18   references that may have part of the answer for you.

19             Sensitivity to nickel in the population is really

20   common, but that sensitive to delayed skin sensitivity,

21   right, it's about 10 to 20 percent of the population, so

22   it's really really common.

23             What is unclear to me is whether or not that is a

24   risk factor for having a bronchospastic response, which is

25   to inhalation of nickel, but that has to drive your risk



 1   assessment in terms of the sensitive subpopulation and the

 2   endpoint that you want to look at, because the amount of

 3   nickel that will induce a bronchospasm in somebody who has

 4   been presensitized is going to be very very much lower.

 5             It will correct the factor of ten, because you're

 6   already dealing with the sensitive population, but I think

 7   you'll -- if you have evidence to believe that sensitized

 8   people -- you're going to have to use that number, it may be

 9   what you're already doing, but it needs to be stated more

10   explicitly.

11             DR. ALEXEEFF:  Okay.

12             DR. BLANC:  So here are some references.  One is

13   small case series and one is a report, two are case reports,

14   but they may, either within them or in their references,

15   give you some hint as to that.

16             DR. WITSCHI:  Can I ask something about what just

17   you mentioned.  Where do you have nickel carbonyl?  I mean,

18   that's the one I'd be really worried about when it comes to

19   nickel.

20             DR. ALEXEEFF:  Why don't we have it?

21             DR. FUCALORO:  The same with the mercury, zero

22   mercury, these are dangerous --

23             DR. WITSCHI:  Nickel --

24             DR. ALEXEEFF:  We separated nickel carbonyl from

25   the other nickel compounds because we felt that the toxicity



 1   was different.  We just haven't done that analysis.

 2             DR. WITSCHI:  You haven't done it?

 3             DR. ALEXEEFF:  Okay.

 4             DR. FUCALORO:  I'm looking at this for the first

 5   time.  Just maybe it's here and I'm missing it.  You have

 6   odor description.  What is that for?

 7             DR. MARTY:  Which compound is it for?

 8             DR. FUCALORO:  Nickel.  It says nickel, nickel.

 9   And then you say its vapor pressure is not applicable.  Now,

10   vapor pressure may be small, but it could be applicable.  I

11   mean, certainly small for mercury and certainly important to

12   know it, so I'm not exactly sure about this, what the heck

13   we're talking about.

14             None of the -- maybe I'm missing it.  None of

15   these compounds listed here have appreciable vapor

16   pressures, as near as I can tell.  I've never seen nickel

17   subsulfide.  I've never seen that compound, but my guess is

18   that's pretty low vapor pressure.  So, I'm not exactly sure

19   what we're dealing with here.

20             CHAIRMAN FROINES:  What page are you on?

21             DR. FUCALORO:  Could be I'm missing it all.

22             DR. MARTY:  It's an interesting point, because

23   there are a lot of nickel emissions into the ambient air.

24   For example, from nickel plating shops.

25             DR. FUCALORO:  Sure.  Maybe it's -- if it is in



 1   fact to particulate matter that's very small, very small

 2   particles -- I don't know the answer to that.

 3             Do you know, Hanspeter?

 4             Yeah, I just don't know.

 5             DR. MARTY:  It could be aerosolized or very small

 6   particles.

 7             DR. FUCALORO:  It has some oxidation to it, if

 8   it's that small, I would guess.

 9             DR. BLANC:  I don't know.  Given, though, the

10   number of species you're dealing with, I do think you need

11   to say explicitly the nickel carbonyls are specifically not

12   being dealt with here, just to make sure.

13             DR. FUCALORO:  But, Paul, do you know what

14   specifically gets into the air in this particular thing?

15             CHAIRMAN FROINES:  You mean from what?

16             DR. BLANC:  When you speciate all nickel in the

17   air, in ambient air pollution, what forms of nickel --

18             DR. FUCALORO:  You say fumes and dust.

19             DR. ATKINSON:  It's on the next page, page C 223,

20   first couple of lines.

21             DR. FUCALORO:  Maybe that's it.

22             DR. BLANC:  Should I move on to phosgene?

23             CHAIRMAN FROINES:  There's an interesting point

24   about nickel.  I got asked to testify on Friday about nickel

25   before the South Coast Air Quality Management District, who



 1   have had serious questions raised about their nickel

 2   document.  Does anybody remember who was the lead person on

 3   nickel?

 4             DR. MARTY:  Dr. Witschi.

 5             DR. GLANTZ:  I thought it was me.

 6             It was him.

 7             CHAIRMAN FROINES:  Dr. Witschi's name as the lead

 8   on the nickel.  And they can contact him.  They want

 9   somebody to testify on nickel.

10             DR. MARTY:  I think it's Stan.

11             CHAIRMAN FROINES:  From the panel.

12             And unless somebody volunteers -- they asked, the

13   chair, is that who it's called, the chair of AQMD asked to

14   have a representative from the SRP testify on nickel.

15             DR. MARTY:  That's this Friday?  That's the day

16   after tomorrow.

17             DR. GLANTZ:  The day after tomorrow?

18             DR. MARTY:  The issue is carcinogenicity of

19   soluble versus insoluble.

20             DR. GLANTZ:  Oh, God.  How many years ago did we

21   do that report?

22             DR. MARTY:  Eight.

23             DR. WITSCHI:  Well --

24             DR. GLANTZ:  You sure you don't want to do it?

25             CHAIRMAN FROINES:  Can't.  I don't want to have to



 1   learn the subject before.

 2             DR. GLANTZ:  I've already forgotten it all.

 3             DR. BYUS:  It's pretty complicated.  One of my old

 4   colleagues works on nickel carcinogenicity.  It can be kind

 5   of complicated.

 6             DR. WITSCHI:  The one --

 7             DR. GLANTZ:  Maybe Byus should do it, since he

 8   lives in Southern California.

 9             I don't even have the report.

10             DR. WITSCHI:  The potency, according to a study

11   that was done on nickel subsulfide, which is kind of a

12   miserable study, which had been done in 1976, and I think

13   that's even installation stuff, because there was no good

14   study available on inhalation of nickel oxide or whatever it

15   was.

16             The other one in nickel carcinogenesis, and I

17   never could put my finger on what it was, human

18   carcinogenesis came from some old studies in refineries and

19   the people from the nickel industry, particular Stuart

20   Werner, I think they emphasized in the '40s or '50s the

21   nickel industry somewhat changed its process, and since they

22   changed the process on how they refine nickel ores, there

23   was no cancer risk anymore.

24             DR. BYUS:  This friend of mine, former guy in my

25   lab, I used to work in the same lab, he's worked out a



 1   mechanism that has to do with methylation.  He worked it out

 2   about three or four years ago.  Very well-funded lab.  It

 3   must be right.

 4             CHAIRMAN FROINES:  Why don't you give us his name.

 5             DR. BYUS:  He'd be the person I'd -- because it's

 6   clearly worked out very very nice mechanism.

 7             CHAIRMAN FROINES:  Let's go ahead.

 8             DR. ALEXEEFF:  The basis of our document is on the

 9   epidemiology, so that's what ours is based on, the one that

10   was reviewed by the panel.

11             CHAIRMAN FROINES:  Paul is finished?

12             DR. BLANC:  Phosgene.  Parallel with what you're

13   going to say about chloropicrin I think you have to say a

14   source of phosgene can be the breakdown of chloropicrin.  I

15   need to see your parallel in your sources.

16             There was a line, this is a small thing, but I

17   don't know whether this kind of happens elsewhere in the

18   document, this is the only place where I saw it, there's a

19   line at the last line in section 4 where you say the former

20   causes increased irritation to mucosal surfaces.  When you

21   use the word cause, I tend to use the word may account for,

22   or something like that.  I'm not sure -- I mean, it's

23   hypothyreosis that it breaks down, and that that may be part

24   of it, but I don't think it's really very well known.  It's

25   actually not established even with chlorine what the final



 1   active moity that's causing the damage.

 2             DR. ALEXEEFF:  Okay.

 3             DR. BLANC:  And one of the comments that I made

 4   about Internet supply here.

 5             And the last one is vanadium, which is a real

 6   challenge, I know, because the data are so lousy for

 7   vanadium.  But in fact what you base the REL on is a study

 8   by Zenz and Berg, which you nowhere discuss in the body of

 9   the text, and then Zenz and Berg you say cite in NAS, which

10   makes me wonder whether you pulled it or not.  That might be

11   some oversight or something.

12             And then the other thing that I would say is that

13   I don't think, since you don't have the study described in

14   detail, unless I couldn't find it, I don't think that mucous

15   hypersecretion with vanadium is a mild adverse effect that

16   would make you use a LOEL as equivalent to a NOEL, because

17   the whole effect of the vanadium is mucous hypersecretion of

18   chronic bronchitis.  So it's clearly a marker of the effect

19   that you care about, which is not a trivial effect.

20             So I actually think if you -- assuming that

21   everything else is right about the study, then you have to

22   use .1 as -- you have to go back and either use one-tenth of

23   .1 or somehow think about it.

24             DR. ALEXEEFF:  I see.

25             DR. MARTY:  Need to --



 1             DR. ALEXEEFF:  It would be --

 2             DR. BLANC:  Maybe there is a NOEL.

 3             DR. ALEXEEFF:  Factor of six in this case.

 4             DR. MARTY:  I don't --

 5             DR. ALEXEEFF:  Okay.

 6             DR. BLANC:  I think there's one other thing I

 7   forgot about.

 8             I think in carbon disulfide, if we can go back to

 9   that for a second.

10             DR. ALEXEEFF:  We back to carbon disulfide?

11             DR. BLANC:  Yes.  I hate to jump back and forth,

12   but I think it's something I forgot to mention.

13             Forget it.  If I find my question -- it was a

14   study which I think it was maybe not carbon disulfide.  It

15   was a reproductive study where you didn't cite the dose

16   response, just mentioned the study.  When I pulled the

17   abstract, the abstract didn't have the dose response.  Made

18   me wonder if somebody only looked at the abstract and not

19   the study.

20             DR. ALEXEEFF:  Okay.

21             DR. BLANC:  That's it.

22             CHAIRMAN FROINES:  We need a take a break.  Very

23   short time.

24             We have Dr. Glantz, Dr. Byus and me left.

25             We probably aren't going to finish by 2:00.



 1             The question for --

 2             DR. GLANTZ:  Which time zone?

 3             CHAIRMAN FROINES:  Do you have a lot?

 4             DR. BYUS:  No.  Quick.

 5             DR. GLANTZ:  Quick?  He can't be quick.

 6             DR. BYUS:  You've been coming up with --

 7             DR. GLANTZ:  He refers to the chair.

 8             CHAIRMAN FROINES:  I will be happy, on things that

 9   become difficult, I'll defer, and we'll do them in writing

10   so we can try and move it to a close.

11             Let's take a break.

12             (Thereupon a short recess was taken.)

13             CHAIRMAN FROINES:  Since Stan is not here, let's

14   go directly to Dr. Byus, and he has a bunch of easy ones.

15             DR. BYUS:  Thank you.

16             Generally I did read them all over and I was

17   amazed at how you could distill down such a large amount of

18   literature into several pages.

19             But generally I thought it was good for all of

20   them, except for this issue of reproductive toxicity, which

21   I didn't catch until John brought it up.

22             I do have one question, though, about why is it

23   that there are certain sections are underlined all

24   throughout the document?

25             DR. MARTY:  Is this the yellow covered one?



 1             DR. BYUS:  Okay.  I looked through the appendix, I

 2   tried to find it.

 3             That, and the other thing was the units on the

 4   molecular weight were sometimes you have them and sometimes

 5   you don't.

 6             The same with specific gravity.

 7             And other than that, I have no other comment.

 8             And I did read them all.

 9             CHAIRMAN FROINES:  We had no doubt.

10             DR. BLANC:  John, you're next.

11             DR. WITSCHI:  Where is Stan?

12             CHAIRMAN FROINES:  He ducked out.  John is next.

13             Well --

14             DR. BYUS:  I will say, I think you did weigh, for

15   example, benzene, the various kinds of toxicity, you went

16   through and weighed everything correctly and gave it the

17   correct emphasis.

18             And the other thing was the pharmokinetics, I know

19   something about that.  I reviewed that and you did put that

20   in where appropriate and had it in there.  I think it's as

21   good as can be.

22             CHAIRMAN FROINES:  Arsenic.  I'll only say one

23   thing, which is that arsenic has the same problem that we've

24   got to resolve, which is four hours per day for nine to 12

25   days of gestation, and so that represents the issue of



 1   concern.  And however we end up dealing with that, I think

 2   will be appropriate.

 3             I read the Western States Petroleum Association

 4   comments, and they were objecting to the use of using a

 5   reproductive study for arsenic, and I don't have it here.

 6             We recommend that OEHHA consider developing

 7   one-hour RELs for different forms of the organic, inorganic

 8   and metallic arsenic compounds.

 9             I think that if you think that the phenotoxic

10   effects are appropriate, and we can work out the timing

11   issue, I think that would be okay.

12             I'm assuming that your document does not include

13   the methylate organic derivatives, and so we're just dealing

14   with basically arsenic 3, essentially.

15             Arsenic 3 when taken in, ends up being oxidized

16   often to arsenic 5, and then it gets by and goes back with

17   arsenic 3.  So I don't think you have to worry about it.

18             Arsenic 3 and arsenic 5 are different, but I don't

19   think we really need to worry about that in here.

20             DR. FUCALORO:  Unless the molecular form of the

21   compound, I'm not so familiar with, applies in arsenic 2,

22   which I think is probably the same.

23             CHAIRMAN FROINES:  Okay.  So that's that.

24             Now, let me go over here to my next one, which

25   is -- formaldehyde I'm not going to do.  I gave Melanie the



 1   information and we can talk about it separate from this.

 2             Perchloroethylene.  I think there's a typo.  You

 3   say over here on page 255 in the green book that the

 4   exposure duration is three hours, but as I read the Romberg,

 5   the reference, Stewart et al 1970, it says studies were

 6   exposed seven hours per day for five days.

 7             DR. ALEXEEFF:  Right.  I think as I recall that

 8   one, the effects began to occur after three hours.

 9             CHAIRMAN FROINES:  Why don't you go back and look

10   it over.

11             Phenol, I didn't have any comments on.

12             Propylene oxide, let me see if I did.

13             Again, the reproductive and developmental issue

14   is -- here's one of the things I was thinking of.

15             DR. ALEXEEFF:  Which substance are we on now?

16             CHAIRMAN FROINES:  Propylene oxide.

17             I want to make a generic comment.

18             One of the things that you do is to find the most

19   sensitive endpoint, so you end up with the lowest REL, and

20   so you have RELs for nasal and throat irritation, for

21   example.

22             Well, there may be other endpoints which are much

23   more serious, and you say levels protection against severe

24   adverse effects, but it seems to me there may be

25   reproductive endpoints is the best example I can think of,



 1   that I think you ought to develop an REL for, even if it's

 2   higher than your lowest value.  Because the public needs to

 3   know that, say, it's a teratogen, or reduce -- or causes low

 4   birth weight or some either toxicity or lethality associated

 5   with it, then it seems to me that it would be useful for the

 6   public to know an exposure, an REL for something that is

 7   actually more serious but higher than your lowest effect,

 8   which may be much less serious.

 9             And so think about that, because it seems to me

10   that it may be that if something is a teratogen at ten times

11   over what your lowest like irritant endpoint is, that that

12   would still be useful to know.

13             DR. ALEXEEFF:  Right.  No.  We agreed.  We've

14   tried to do that, but we can look at a couple of these that

15   we didn't do it at and see if there's data in there.

16             CHAIRMAN FROINES:  Okay.  George, and then the

17   next thing on selenium, my problem with selenium is that it

18   appears to me that you've made a calculation of -- that you

19   call for selenium, but you're actually making the

20   calculation based on studies of hydrogen selenium.

21             And I think hydrogen selenium and selenium are two

22   different compounds and you should do them separately.

23             DR. MARTY:  We had trouble with that ourselves.

24             DR. BLANC:  John's point is completely well taken.

25   It's like looking at an irritant versus a non-irritant.



 1             For the same rationale that you did not include

 2   nickel carbonyl in your nickel assessment, you can't include

 3   this selenium, because it is an irritant.

 4             CHAIRMAN FROINES:  It's also true that according

 5   to your document there is no hydrogen selenium that's used

 6   for the most part.

 7             DR. BLANC:  It can be created in certain -- it's a

 8   byproduct of certain combustion situations.

 9             CHAIRMAN FROINES:  So there's a potential.

10             DR. BLANC:  There's a potential for exposure.

11             I don't know if it's what the exact form is, but

12   it's the hydrogen selenium.  There was a case report of

13   exposure in India that you could find if you look.

14             DR. ALEXEEFF:  It indicates in the document that

15   it's created mostly as a byproduct in mixtures with acidic

16   mixtures.

17             CHAIRMAN FROINES:  Okay.  But I still think

18   selenium metal and hydrogen selenium should be dealt with

19   separately.

20             DR. BLANC:  The most common exposure in the air

21   is, I think, probably dust, entrained dust, because it's a

22   natural contaminant in certain areas, and that's probably

23   where you've detected it in the air, whereas this other

24   exposure scenario would be different.

25             CHAIRMAN FROINES:  Yeah.



 1             DR. MARTY:  Again, we did that because it's the

 2   most toxic selenium compound.  We're trying to cover the

 3   bases, but we had our own doubts about doing that.

 4             CHAIRMAN FROINES:  Okay.

 5             DR. BYUS:  It turns out to be markedly

 6   chemopreventive in some new epidemiology studies and

 7   nontoxic doses, but about 70 micrograms per day.

 8             DR. MARTY:  Selenium?

 9             DR. BYUS:  Selenium.  Virtually all cancers.

10             DR. FUCALORO:  I didn't catch that.

11             DR. BYUS:  It's chemopreventive.  It's one of the

12   compounds in the NCI study that studied its chemopreventive

13   measure.  You get it lot -- the normal dose you get from

14   plants, it takes it up out of the soil, depending on where

15   your plants are grown, you have different levels of it.

16             DR. WITSCHI:  I have to tell you, Stan, it's

17   probably going to be preventive against cigarette smoking.

18             DR. BYUS:  It's remarkably effective.  I mean, for

19   a chemopreventive.

20             DR. GLANTZ:  Add it into cigarettes.

21             DR. FUCALORO:  Trimethyl selenium cation.  The

22   metabolite.  Trimethyl selenium cation.  Check that out.

23             CHAIRMAN FROINES:  Presumably that sodium

24   hydroxide can actually end up being aerosolized wet mist in

25   some industrial processes.  I'll bet that doesn't get very



 1   far into the atmosphere.

 2             DR. GLANTZ:  I think that was an ironic comment,

 3   just for the record.

 4             DR. WITSCHI:  Softening up your lungs.

 5             CHAIRMAN FROINES:  The issue about the formation

 6   of the sodium hydroxide radicals in water, I thought, was an

 7   interesting comment, and therefore one needs not worry about

 8   sodium hydroxide in water because it forms these radicals

 9   that are no longer seeking moisture.

10             DR. MARTY:  You're talking about the public

11   comment?

12             DR. FUCALORO:  Hydroxide radicals, they're not

13   radicals.

14             CHAIRMAN FROINES:  Also my hydronic point.

15             And OEHHA, to its credit, suggested in fact it's

16   sodium ion and hydroxide ion rather than sodium radical and

17   hydroxide radical.

18             I don't know how much sodium hydroxide and water

19   ends up in the air, and Roger's comment about particle size

20   notwithstanding, it seems like not a major public health

21   issue, but what do I know.

22             DR. GLANTZ:  Dignified, dignified.

23             CHAIRMAN FROINES:  I'm sorry.  It's getting into

24   the day, getting a little less dignified.

25             So I've already -- I was worried about sodium



 1   hydroxide from the standpoint of being primarily an

 2   occupational rather than an ambient exposure, and I've

 3   already said that, so I won't say it again.

 4             And the last one I had was styrene.  Basically

 5   going over the data, there is a lot of data, as you know,

 6   and there was a reproductive endpoint, which I thought was

 7   important.  It's this Kishi study of 1995 looking at several

 8   neurobehavioral tests and they conclude exposure to 50 parts

 9   her million of styrene causes disturbance in the motor

10   coordination and delayed some motor and reflex developments,

11   and so at 50 parts per million you're seeing is a LOEL, in

12   an animal, which would get you down to .5 part per million

13   if you used that.  It's worth taking a look at that.

14             It's also worth looking at the Morgan study, I

15   think, which is the mouse study, and I went through the

16   numbers there, and I -- I'll just leave it for you to read

17   and look at again.

18             And that's it.

19             DR. ALEXEEFF:  We had a couple that we wanted to

20   talk to you about that we haven't touched on.

21             DR. GLANTZ:  We're not done yet.  Let Craig go

22   next.

23             CHAIRMAN FROINES:  He's gone.

24             DR. GLANTZ:  You were faster than I was.

25             CHAIRMAN FROINES:  Craig and I are running for the



 1   record.

 2             DR. GLANTZ:  I'll do even better.

 3             I only --

 4             DR. ALEXEEFF:  Should we do formaldehyde, since

 5   that one was yours?  We had a point on formaldehyde.

 6             CHAIRMAN FROINES:  I wanted to allow you to go

 7   back and read the formaldehyde papers that I gave the

 8   references on and then deal with it, you know.  There are a

 9   lot of references that I gave you that showed relatively low

10   effects, lower than you've been quoted in your document.  So

11   I figured you ought to go over those and then we should come

12   to a final determination.

13             I'm not trying to talk about it today, unless

14   Peter wants to weigh in on the issue.

15             DR. ALEXEEFF:  Okay.

16             DR. GLANTZ:  Well, did you find that one I was

17   telling you about, George?

18             DR. ALEXEEFF:  Yeah.  That was methyl ethyl

19   ketone.

20             DR. GLANTZ:  Okay.  In reading this thing through,

21   I only had one issue that I found, and, I mean, I've seen

22   just -- I was the lead person on this, so I looked at all

23   this before.

24             And the issue that -- the one issue that I had in

25   methyl ethyl ketone was that when you were setting the REL



 1   you were looking at responses to inhalation, and the study

 2   was done over two hours, and you just took that

 3   concentration and applied it for one hour, without doing

 4   your time adjustment.

 5             And I just like you to -- I didn't understand why.

 6             Could you just explain why you did it the way you

 7   did it there, rather than applying your Haber's Law like you

 8   did with everything else in your report.

 9             You had the 270 part per million, which was

10   exposed for two hours, but you said you extrapolated one

11   hour concentration was 270, but not extrapolated.  And I

12   just didn't follow the logic.

13             DR. ALEXEEFF:  I think that's because the symptoms

14   are reported during the two-hour exposure period, although

15   it didn't specify when.  So we felt that since the

16   symptoms -- in some of the studies we've looked at they say,

17   you know, the individuals answered the questions at the end

18   of the study.

19             But in this case we don't know exactly when the

20   exposure -- when the effects occurred, so that's why we --

21   it looked like it occurred during the study.

22             DR. GLANTZ:  Okay.

23             DR. ATKINSON:  Short paragraph right after the

24   table.

25             DR. ALEXEEFF:  It says lacrimation and sneezing



 1   also occurred during exposure.

 2             DR. GLANTZ:  Okay.  I'm sorry.

 3             DR. ALEXEEFF:  We don't know if it occurred half

 4   an hour or 90 minutes or but --

 5             DR. GLANTZ:  Okay.  Well, see, then that fits in

 6   with the discussion we had about the reproductive toxicity.

 7   It's the same basic point.

 8             Well, other than that, I was happy.

 9             And I just like to say, as the last -- as the

10   person who was the lead person on this, I think you guys

11   have done a really good job with this, except with the few

12   minor suggestions that were made today.  But, I mean, when I

13   think back, this has been in the mill for a couple years, I

14   think, and when we started this it was huge amorphous mass

15   of information that was very hard to get your arms around

16   it.

17             And, you know, I think, I mean, there are a lot of

18   limitations and problems which we've discussed, and which I

19   think are frankly addressed in the document, but I think you

20   really produced a remarkable document, especially when I

21   think back to just this morass of sort of undigested data

22   that we were confronted with when the whole thing started.

23             I think this is one of the nicer things that has

24   been produced in the whole time I've been on the panel,

25   actually.



 1             CHAIRMAN FROINES:  Would you be willing to make a

 2   motion about approval of the document?

 3             DR. GLANTZ:  Okay.  I move that we approve the

 4   document.

 5             DR. WITSCHI:  I second.

 6             DR. FUCALORO:  May I?

 7             DR. GLANTZ:  Subject to the few minor comments

 8   made at this meeting.

 9             DR. FUCALORO:  And some that may be forthcoming.

10             DR. GLANTZ:  And some that may be forthcoming.

11             That's what we want.  You wanted us to approve the

12   document, right?  That's what we need to do legally.

13             CHAIRMAN FROINES:  Now, just to make sure, ask the

14   question a bit rhetorically.  You're satisfied with methyl

15   bromide, because methyl bromide is an issue that's going to

16   haunt us.

17             DR. ALEXEEFF:  I wanted to bring up methyl bromide

18   before a decision was made, because at the last meeting,

19   see, we had --

20             DR. GLANTZ:  Oh, yeah.  There was --

21             DR. ALEXEEFF:  At the last meeting there was

22   methyl bromide at a level of four parts per million based

23   upon a different extrapolation calculation.

24             And then Dr. Blanc brought up the issue of the

25   waitress study.



 1             And we also went back and did a lit search of all

 2   the occupational studies to see if there was any other

 3   occupational study that might be of assistance in evaluating

 4   it.

 5             Well, our conclusion is that the waitress study is

 6   probably the best one of all the ones in terms of evaluating

 7   it.  There are some limitations because of the methods used

 8   and the age of the study.

 9             But if we were to assume -- we think a reasonable

10   assumption would be that effects were occurring as early as

11   two hours after exposure.  This was a very -- it was not a

12   chronic study here.  These were effects that were occurring

13   over a period of ten days or so.

14             But it was clear in the study that they were --

15   that there were acute effects.  The whole point of the study

16   was acute.

17             So if we looked at the waitress study, one could

18   come up, you assume two hours exposure, 35 parts per

19   million, which is what's reported in the document, then you

20   come up with a level of one part per million.

21             The effects that we're talking about in this case

22   are primarily headache and nausea, with some anorexia, but

23   it's not clear if the anorexia is an acute situation or a

24   prolonged effect.

25             So that's pretty much what we came up in terms if



 1   we were to use the waitress.  And, again, it's a weighing of

 2   well, now we have some human data.

 3             One could also say that, suggest that maybe the --

 4   well, there's one other point to look at.

 5             The level that we have, four parts per million, is

 6   severe effect in dogs, is convulsions and very severe

 7   toxicity, in contrast to the less severe effects in humans.

 8             So this could be considered, the one part per

 9   million, could be considered like a level one effect,

10   because there are more mild effects, headache and nausea.

11             I'm not sure about where anorexia comes in.

12             But so in that sense -- and I think it would be

13   consistent with the fact that you have not a large window of

14   concentration, but maybe a three or fourfold difference

15   between severe and some earlier effects like headache or

16   nausea.

17             DR. BLANC:  That's sounds reasonable.

18             DR. ALEXEEFF:  That sound reasonable?

19             That's what we came up with after looking at it

20   all.

21             And the other interesting thing to note, and I am

22   just noting it, because we're going to add it to the methyl

23   bromide, is in this literature search we found out that

24   there is a genetic polymorphism of glutathione transferace,

25   which affects the toxic response in people exposed, which



 1   actually was very interesting to note.  So we will put that

 2   in the document.

 3             DR. FUCALORO:  George, why in the document is

 4   acetone not listed?

 5             DR. ALEXEEFF:  Acetone was originally listed, but

 6   it was acetone was delisted because in the calculations that

 7   we did, you would not be able to generate a level that would

 8   reach the REL from an emission.  You couldn't generate an

 9   atmospheric concentration from emission.  That would be --

10             DR. FUCALORO:  The --

11             DR. ALEXEEFF:  -- taken off all the hazard lists.

12             CHAIRMAN FROINES:  Well, it's been a long day.

13             Thank you, George.

14             DR. BLANC:  I'm going to second Stan's motion, and

15   call the question.

16             FROM THE AUDIENCE:  It's been seconded.

17             DR. BLANC:  Call the question.

18             DR. FUCALORO:  He's thirding it.

19             CHAIRMAN FROINES:  We always understand his

20   motivations.

21             DR. BLANC:  Mr. Chair.

22             CHAIRMAN FROINES:  Yes, sir.

23             DR. BLANC:  Would you call the question.

24             CHAIRMAN FROINES:  I will ask for the vote then.

25             All in favor of Stan's motion, raise your right



 1   hand.

 2             (Members so signify.)

 3             CHAIRMAN FROINES:  Unanimous.

 4             DR. BLANC:  I move that we adjourn the meeting.

 5             CHAIRMAN FROINES:  Thank you, everybody.

 6             It was actually a very useful meeting.

 7             So the meeting is officially closed.

 8             (Thereupon the meeting was adjourned

 9             at 2:55 p.m.)





















 3             I, JANET H. NICOL, a Certified Shorthand Reporter

 4   of the State of California, do hereby certify that I am a

 5   disinterested person herein; that I reported the foregoing

 6   meeting in shorthand writing; that I thereafter caused my

 7   shorthand writing to be transcribed into typewriting.

 8             I further certify that I am not of counsel or

 9   attorney for any of the parties to said meeting, or in any

10   way interested in the outcome of said meeting.

11             IN WITNESS WHEREOF, I have hereunto set my hand

12   this 17th day of February 1999.




                                     Janet H. Nicol
17                                   Certified Shorthand Reporter
                                     License Number 9764