1 MEETING
2 OF THE
3 SCIENTIFIC REVIEW PANEL ON TOXIC AIR CONTAMINANTS
4 CALIFORNIA AIR RESOURCES BOARD
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6
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10 SOUTH SAN FRANCISCO CONFERENCE CENTER
11 255 SOUTH AIRPORT BOULEVARD
12 SOUTH SAN FRANCISCO, CALIFORNIA
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WEDNESDAY, FEBRUARY 10, 1999
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9:30 A.M.
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24 Janet H. Nicol
Certified Shorthand Reporter
25 License Number 9764
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1 APPEARANCES
2 MEMBERS PRESENT:
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
8
REPRESENTING THE CALIFORNIA AIR RESOURCES BOARD:
9
Mr. Bill Lockett, Deputy Ombudsman, Northern California
10 Mr. Peter Mathews, Office of the Ombudsman
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REPRESENTING THE OFFICE OF ENVIRONMENTAL HEALTH HAZARD
12 ASSESSMENT:
13 Dr. George Alexeeff, Deputy Director for Scientific Affairs
Dr. Melanie Marty, Senior Toxicologist
14
15 REPRESENTING THE DEPARTMENT OF PESTICIDE REGULATION:
16 Paul Goesslin, Assistant Director
17 REPRESENTING UNITED STATES ENVIRONMENTAL PROTECTION AGENCY:
18 Bill Jordan
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1 INDEX
2 PAGE
AGENDA ITEMS:
3
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)
7
3 Discussion of margin of exposure and reference
8 exposure level (REL) approaches. Department of
Pesticide Regulation and OEHHA
9
Adjournment 180
10
Certificate of Reporter 181
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12
13
14
15
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17
18
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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
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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
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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
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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
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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
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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
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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
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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
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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
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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
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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
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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
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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.
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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.
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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
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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.
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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
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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
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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
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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
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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
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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
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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
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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
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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
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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
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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.
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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.
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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.
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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
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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.
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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.
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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
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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
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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
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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.
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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
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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
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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
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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
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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.
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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
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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,
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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
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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
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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.
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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
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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.
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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
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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.
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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
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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?
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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
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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
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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,
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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?
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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
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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
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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.
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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.
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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
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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
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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
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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.
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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.
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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.
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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
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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.
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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.
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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.
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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
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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
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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.
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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?
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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.
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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
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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
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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.
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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.
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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.
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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.
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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
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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
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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
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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
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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?
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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
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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
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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
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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,
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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
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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.
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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.
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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
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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
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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.
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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
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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.
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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
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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
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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
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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
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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
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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
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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?
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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
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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
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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.
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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
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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.
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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?
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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.
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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
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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
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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.
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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
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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
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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
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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.
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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
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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
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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.
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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.
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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
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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,
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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
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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
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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
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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 --
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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
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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
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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
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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
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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.
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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.
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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
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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
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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
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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
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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
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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
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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.
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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.
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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
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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
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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.
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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
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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
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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,
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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
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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,
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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
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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
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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
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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
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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
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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
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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
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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
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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
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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
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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 --
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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.
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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?
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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
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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
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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,
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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.
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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.
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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
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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
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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
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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
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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
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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.
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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.
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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
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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
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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
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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.)
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1 CERTIFICATE OF SHORTHAND REPORTER
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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.
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Janet H. Nicol
17 Certified Shorthand Reporter
License Number 9764
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