ATDEPARTMENT OF HEALTH AND HUMAN SERVICES

> FOOD AND DRUG ADMINISTRATION
>
> CENTER FOR FOOD SAFETY AND APPLIED NUTRITION
>
> **FOOD ADVISORY COMMITTEE**
>
> **METHYLMERCURY**
>
> Tuesday, July 23, 2002
>
> 8:30 a.m.
>
> Sheraton College Park Hotel
>
> 4095 Powder Mill Road
>
> Beltsville, Maryland 20705
>
> PARTICIPANTS
>
> Sanford A. Miller, Ph.D., Chair
>
> Catherine DeRoever, Executive Secretary
>
> MEMBERS
>
> Alex D.W. Acholonu, Ph.D.
>
> Francis Fredrick Busta, Ph.D.
>
> Annette Dickinson, Ph.D.
>
> Johanna Dwyer, Ph.D.
>
> Lawrence J. Fischer, Ph.D.
>
> Marion H. Fuller, D.V.M.
>
> Joseph H. Hotchkiss, Ph.D.
>
> Lawrence N. Kuzminski, Ph.D.
>
> Ken Lee, Ph.D.
>
> Thomas J. Montville, Ph.D.
>
> Robert M. Russell, M.D.
>
> Mr. Brandon Scholz
>
> Michael W. Shannon, M.D.
>
> TEMPORARY VOTING MEMBERS
>
> H. Vas Aposhian, Ph.D.
>
> Sarah L. Friedman, M.D.
>
> Ms. Jean M. Halloran, Consumer Representative
>
> Margaret McBride, M.D.
>
> Richard E. Nordgren, M.D.
>
> Clifford Scherer, Ph.D.
>
> GUEST SPEAKERS
>
> Mr. Harvey Clewell
>
> Dr. Christopher DeRosa
>
> Ms. Caroline Smith DeWaal
>
> Dr. Philippe Grandjean
>
> Dr. James Heimbach
>
> Dr. Joseph Jacobson
>
> Dr. Penny Kris-Etherton
>
> Dr. Gary Myers
>
> Dr. Susan Schober
>
> FDA
>
> Ms. Linda Hayden
>
> [C O N T E N T S]{.underline}
>
> Welcome
>
> Dr. Sanford Miller 5
>
> Conflict of Interest Statement
>
> Catherine DeRoever 7
>
> Opening Remarks
>
> Joseph A. Levitt 9
>
> Introductions 19
>
> National Academy of Sciences Report on
>
> the Toxicological Effects of Methylmercury
>
> Dr. Joseph Jacobson 22
>
> Questions of Clarification 46
>
> Faroe Island Study
>
> Dr. Philippe Grandjean 51
>
> Questions of Clarification 72
>
> Seychelles Study
>
> Dr. Gary Myers 87
>
> Questions of Clarification 105
>
> Agency for Toxic Substances and
>
> Disease Registry
>
> Dr. Christopher DeRosa 117
>
> Questions of Clarification 135
>
> Consumer Messages
>
> Dr. Penny Kris-Etherton 139
>
> Questions of Clarification 152
>
> National Health and Nutrition Examination Survey
>
> Dr. Susan Schober 159
>
> Questions of Clarification 172
>
> Risk Management Strategies for Methylmercury
>
> in Seafood - A Consumer Perspective
>
> Ms. Caroline Smith DeWaal 183
>
> Questions of Clarification 198
>
> [C O N T E N T S]{.underline}(Continued)
>
> Fish Consumption Data and Risk Assessment Calculations
>
> Dr. James Heimbach 215
>
> Questions of Clarification 241
>
> Mr. Harvey Clewell 244
>
> Questions of Clarification 259
>
> Public Comment
>
> Dr. Rhona Applebaum, NFPA 273
>
> Dr. J.H. Lee, NCPR 277
>
> Dr. Richard Fisher 283
>
> [P]{.underline} [R]{.underline} [O]{.underline} [C]{.underline}
> [E]{.underline} [E]{.underline} [D]{.underline} [I]{.underline}
> [N]{.underline} [G]{.underline} [S]{.underline}
>
> **Welcome and Introductions**
>
> DR. MILLER: Good morning. I am Sandy Miller and I am serving as the
> Chairman of the Food Advisory Committee for the Center for Food Safety
> and Applied Nutrition. I would like to welcome you all to this
> meeting, which was called in order to help the Center develop a policy
> for methylmercury in food.
>
> The Center has developed a number of questions which they want the
> committee to consider, and these will be discussed in just a few
> moments.
>
> Let me just go into the agenda. Let me just see if I can get some
> ground rules in place. This is a very tightly packed agenda. If we are
> going to be done anytime within the next month or two, we are going to
> have to stick to the exact times that have been assigned by the
> secretary. These generally have been determined by the speakers
> themselves, but in some cases, in order to finish the agenda, the
> times have slightly changed.
>
> Nevertheless, the important thing is that exactly on time, I will ask
> you to step down. I will try five minutes before the end of your time
> to remind you that there is five minutes to go, but it is really
> important that we stick to the time.
>
> I know this is an issue of some concern and a great deal of passion to
> a lot of people, and it is of vital importance to us, but we want to
> be fair to everybody, the times must really be kept.
>
> Secondly, just to indicate the basis for which the committee is
> operating, it is the function of this committee to look at these
> questions which we will be asked on the basis of the science. Our
> recommendations are individual recommendations to the Center to be
> based entirely on that issue.
>
> Policy determinations are complex and they involve things that are
> equally important to the science, but are different. This committee is
> not designed to deal with those issues, so I am asking you all to try
> to focus your attention on the issues concerned with the science and
> the science only.
>
> Let me introduce to you Cathy DeRoever, who is the Executive Secretary
> of the Food Advisory Committee, who will talk about some housekeeping
> issues.
>
> MS. DeROEVER: Thank you, Dr. Miller.
>
> Good morning. I would like to welcome all of our members and our
> temporary voting members. Thank you very much for being here today.
> Before I do actually the administrative announcement, for the record,
> I want to announce that we have appointed several temporary voting
> members.
>
> **Conflict of Interest Statement**
>
> The authority to appoint such members is granted to the Center
> Director, and I have letters for the temporary voting members that
> state: By the authority granted under the Food Advisory Committee
> Charter, I appoint Dr. Aposhian, Dr. Friedman, Ms. Halloran, Dr.
> McBride, Dr. Nordgren, and Dr. Scherer as temporary voting members of
> the Food Advisory Committee for the July 23rd through 25th, 2002
> meeting on methylmercury
>
> The letter is signed by the Center Director, Center for Food Safety
> and Applied Nutrition, U.S. Food and Drug Administration, Mr. Joseph
> Levitt.
>
> Second, also for the record, all members and temporary voting members
> have been screened for financial conflicts of interest. Upon review of
> the FDA Form 3410, which is the financial disclosure report for
> special government employees, we have determined that no financial
> conflicts exist.
>
> Similarly, we have asked all our guest speakers to complete a
> financial interest and professional relationship certificate for
> guests and guest speakers to identify any potential conflicts.
>
> We have not received all of those forms, but for the record, there are
> two that I would like to mention. Dr. Heimbach has had a relationship
> with the seafood industry, and Dr. Kris-Etherton, who will be speaking
> I believe it\'s tomorrow, has a relationship also with the seafood
> industry.
>
> Moving on to the administrative matter, for the people at the table,
> in your notebook is a menu that we are going to ask you if you would
> like to have lunch, we have tried to overcome some past problems we
> have had with respect to timing, so if you would take a moment and
> complete it, the staff will collect it and your lunch will be ready,
> hopefully, when we break. If this works well, we will try it again for
> Wednesday and Thursday, but I will appreciate your feedback on that.
>
> With that, I turn it back to Dr. Miller.
>
> DR. MILLER: Thank you, Cathy.
>
> To open this session of the Food Advisory Committee, Mr. Joseph
> Levitt, who is Director of the Center for Food Safety and Applied
> Nutrition, has some opening remarks.
>
> **Opening Remarks**
>
> **Joseph A. Levitt**
>
> MR. LEVITT: Good morning. Again, my name is Joe Levitt. I am Director
> of the Center for Food Safety and Applied Nutrition. I am pleased to
> welcome all of you here for a meeting of the Food Advisory Committee.
>
> This is my first visit with the committee since you were
> reconstituted. I was on vacation when there was a meeting earlier this
> spring. I welcome Dr. Miller, who is chair of our committee. Simply no
> one has more experience in the broad issues facing our Center than Dr.
> Miller given his past experience at the Agency and his work on many
> National Academy of Sciences committees.
>
> I also will look forward to working with the committee as a whole and
> its many subcommittees over the coming months and years, and in the
> fall, I will look forward to providing you on a day when we have a
> less intense agenda with an overview of our Center\'s activities and
> on engaging your advice on a number of important scientific and public
> health issues, which brings me to this week\'s meeting on FDA\'s
> Consumer Advisory regarding methylmercury and seafood consumption.
>
> We consider this issue to be a very important public health issue.
> Indeed, I can\'t think of anything more important than ensuring the
> health of pregnant women and their unborn children.
>
> That is why we went to great lengths to assemble such a distinguished
> committee. For those not familiar with our committee structure, we
> have included here members of our standing Food Advisory Committee,
> members of our new Subcommittee on Food Contaminants, and additional
> scientific experts in specialties needed for the methylmercury issue
> that we did not already have.
>
> This includes medical experts in pediatrics and neurology, as well as
> additional experts in developmental psychology and risk communication.
>
> Finally, I want to thank Jean Halloran of Consumers Union for serving
> as our consumer rep given that our standing consumer rep was not here.
> I am not sure I see her yet, but we will thank her in advance of her
> arrival.
>
> Again, I want to thank everybody for taking the time from your very
> busy schedules to address this subject.
>
> This issue methylmercury in fish has a long history dating back to the
> 1970s. This includes industrial poisonings in Japan and Iraq, major
> studies being conducted in geographical areas of heavy fish
> consumption, steps being initiated by both the FDA and the
> Environmental Protection Agency, as well as a number of risk analyses
> and data gathering exercises.
>
> You will hear about all of this and more over the next three days I
> can assure you. The critical point of departure for this week\'s
> discussion is a report issued by the National Academy of Sciences on
> July 11th, 2000. The report was actually directed to EPA under the
> rubric of reducing environmental pollution by this relevant to FDA
> regarding commercial seafood consumption was readily apparent.
>
> Therefore, after the National Academy of Sciences\' report, we, at
> FDA, undertook a very extensive process to examine the risks of
> methylmercury in commercial seafood and to determine what advice to
> give consumers at the national level.
>
> We consulted with many of the same people and organizations that you
> will hear at this meeting. We conducted a series of focus groups with
> consumers to examine communication style and format that any new
> advisory would have, and we consulted with EPA, which issues
> advisories to states for recreationally caught fish.
>
> I personally led this outreach effort and I participated in every or
> nearly every meeting with outside groups. I also met regularly with
> our internal staff on a regular basis. The culmination of this effort
> was an updated consumer advisory that FDA issued in January 2001 with
> a small revision in March a couple months later.
>
> Let me now summarize the advisory itself. The consumer advisory was
> addressed to pregnant women and women of childbearing age who may
> become pregnant. In short, the advisory has two main parts. The first
> part says to avoid eating four kinds of fish with the highest levels
> of mercury, namely, shark, swordfish, king mackerel, and tilefish,
> avoid these completely if you are in that category.
>
> No. 2. Eat 12 ounces per week of a variety of other fish including
> shellfish, canned fish, smaller ocean fish or farm-raised fish. Just
> be sure to pick a variety of different species.
>
> I tend to summarize this advisory to say avoid the top four fish and
> eat the rest in moderation.
>
> Now, in issuing this advisory, FDA also put on our web site our
> written rationale for the advisory and data tables showing levels of
> methylmercury in different species of commercial fish, so the public
> could see how we reached the conclusion we did.
>
> We followed the issuance of the advisory with an extensive outreach
> campaign and were able to get our message into a number of newspapers,
> magazine, and other information outlets.
>
> When we issued this advisory in early 2001, it was our genuine belief
> that if women conscientiously followed this advisory, based on
> knowledge of methylmercury levels in fish and consumers\' fish
> consumption levels, that these women would be protecting their unborn
> children from harm due to methylmercury. That was our goal.
>
> But I can tell you, a year and a half later, the subject remains
> controversial and I will tell you quite candidly that a number of
> persons and organizations still feel that we fell somewhat short of
> the mark. That is why we are here.
>
> We want American women to have the best advice possible and for that
> advice to be arrived at in an open and transparent way. At the time
> that we constructed our advisory a year and a half ago, CFSAN did not
> have at the time the benefit of our Food Advisory Committee. We were
> in the process of recharging and restructuring it, and so forth.
>
> So, we assembled the advisory ourselves using the best information we
> had and the process that I described, but now that we have
> reconstituted this advisory committee and it is fully functioning, we
> wanted to bring the issue to you. We look forward to a full airing of
> the issues, ultimately focusing on whether, after everything is
> considered, the advisory is as strong as it needs to be to protect
> public health.
>
> Now, over the next three days, you will hear a wide range of views on
> this subject. Your job is first to listen critically to the whole
> story that will be presented to you over the next three days. You will
> hear, starting with the representative from the Academy that issued
> the report. You will hear directly from a number of researchers who
> have conducted the key studies.
>
> You will hear from state and federal officials, from physicians, from
> consumer groups, from industry representatives. Finally, you will hear
> from experts in our center who will try to explain how we arrived at
> the conclusions that we did.
>
> Then, we will stop and you will have your discussion. We want your
> best thinking and advice on our advisory on whether it is adequate in
> its present form or whether any adjustments need to be made.
>
> Now, let me go through the specific charge.
>
> This will be circulated and everybody will have copies of this if they
> don\'t already. It will be coming around shortly.
>
> \[Slide.\]
>
> The charge to the committee, I have kind of a long version and a short
> version. The long version says:
>
> The committee is being asked to evaluate, in light of all the relevant
> information about potential consumption, exposures, population body
> burden, hazard and consumer messages, whether the Agency\'s Consumer
> Public Health Advisory on Methylmercury is adequate to protect the
> health of those who follow that advice.
>
> When I read that, I said that covers everything, but let\'s say it a
> little more simply.
>
> \[Slide.\]
>
> To put it more simply, does the FDA advisory provide adequate
> protection for pregnant women and women of childbearing age who may
> become pregnant? That\'s the bottom line question. If not, what
> changes are needed and why? If yes, are there nevertheless
> enhancements to the advisory that would make it easier and more
> effective for women to follow it?
>
> Now, to help answer this general charge, we have framed it in five
> questions.
>
> The first question says: Has the Agency adequately addressed and
> appropriately considered all the relevant factors and information that
> bear upon the elaboration of a consumer advisory on fish consumption?
> Are any factors not relevant? Are there additional factors that should
> be relevant? In other words, have we considered the landscape.
>
> No. 2. Focusing on the first part of the advisory, should the advisory
> have specifically advised pregnant women to avoid any other species
> not specifically mentioned, and if so, what would be the scientific
> rationale?
>
> I will tell you as you will hear, that the species most commonly
> mentioned would be fresh tuna is the fish you will hear a lot about,
> whether it ought to be included here or not. So, we want that to be
> talked about.
>
> No. 3. In the second part of the advisory, should the Agency issue a
> fish listing as an adjunct to the advisory to clarify what is mean by
> \"variety of fish?\"
>
> As we have gone back and looked at the advisory with hindsight, we
> knew what we meant, but have we provided enough information on how to
> eat the appropriate variety of fish, so that women are adequately
> protected. We would like advice there.
>
> No. 4. You will hear a lot about FDA and EPA, so we ask the question:
> Should the Agency revised our advisory to make explicit that the 12
> ounces per week includes all sources of fish, both recreational and
> commercial, so there is a better nexus? There may be additional ways
> you consider how we and EPA can better be sure that we are connected,
> we have our web sites joined, and so forth, maybe there are additional
> ways.
>
> Finally, a subject of monitoring. Should the Agency increase its
> monitoring of methylmercury in commercial fish in order to keep this
> advice current? When you go through the data tables, you will see that
> some of the species have lots of samples, some have very few samples
> associated with them, and the question of monitoring and importance of
> that comes up, so we would like your advice on that.
>
> Let me conclude. Dr. Miller asked that I describe for you two things:
> Number one, why you are here, and, two, what FDA needs from you over
> the next three days. I hope I have done that.
>
> I also hope that I have conveyed that we are truly open and indeed
> want your best advice whether you agree with us or not. You will see I
> believe, as I did, that there is a wide range of strongly differing
> views about methylmercury in fish. It is an emotionally charged issue.
>
> There is also a long history of scientific debate about this issue
> that will not likely end with this meeting although it would be nice.
> Our collective challenge, therefore, during the next three days will
> be to rise above any such divisiveness. We need to do what is best for
> the American consumer, in this case, American women and their
> offspring. They certainly deserve no less.
>
> Thank you very much. I will try personally to stay for as much of the
> meeting as I can although I am sure a couple times I will get pulled
> out for different issues.
>
> Again, thank you for your time. You will have a fascinating three
> days, I can assure you, but most importantly, we hope that you will
> help us move and advance this issue in a way that will be best for
> American women and their children.
>
> Thank you again very, very much, and thank you, Dr. Miller, for
> chairing the meeting.
>
> DR. MILLER: Thank you, Joe.
>
> **Introductions**
>
> Before we proceed, let me take this opportunity of having the various
> members of the committee introduce themselves, at least for the
> record, so we know you are here.
>
> We will begin with Dr. Scherer.
>
> DR. SCHERER: Cliff Scherer, Cornell University, Department of
> Communications. My specialty is risk communication.
>
> DR. NORDGREN: Dick Nordgren. I am a pediatric neurologist from
> Dartmouth Medical School.
>
> DR. McBRIDE: Margaret McBride. I am a pediatric neurologist from
> Rochester, New York, and Akron, Ohio.
>
> DR. FRIEDMAN: Sarah Friedman from the National Institute of Child
> Health & Development, one of the NIH institutes. I am a developmental
> psychologist.
>
> DR. RUSSELL: Rob Russell. I am Director of the Human Nutrition
> Research Center at Tufts.
>
> DR. MONTVILLE: Tom Montville, Professor of Food Science from Rutgers,
> The State University of New Jersey.
>
> DR. FULLER: Marion Fuller. I am the Director of Food Safety for the
> Florida Department of Agriculture and Consumer Services.
>
> DR. FISCHER: I am Larry Fischer, Director of the Institute for
> Environmental Toxicology at Michigan State University.
>
> DR. HOTCHKISS: Joe Hotchkiss from the Department of Food Science at
> Cornell University.
>
> DR. LEE: Ken Lee, Ohio State University, Department of Food Science,
> Professor and Chair.
>
> DR. KUZMINSKI: I am Larry Kuzminski, a retired Vice President of
> Technology from Ocean Spray, had previous positions to Ocean Spray
> that included officer positions with the Kellogg Company and tenure
> professorship at University of Massachusetts.
>
> DR. MILLER: I am Sandy Miller and I am associated with the Center for
> Food Nutrition Policy at Virginia Tech University.
>
> MS. DeROEVER: Catherine DeRoever, FDA.
>
> DR. BUSTA: Frank Busta. I am a Professor Emeritus, Department of Food
> Science and Nutrition, at the University of Minnesota.
>
> DR. ACHOLONU: Alex Acholonu. I am from Alcorn State University in
> Mississippi. I am a Professor of Biology and my specialty is
> epidemiology of diseases.
>
> DR. DICKINSON: Annette Dickinson, Vice President for Scientific and
> Regulatory Affairs with the Council for Responsible Nutrition.
>
> DR. DWYER: Johanna Dwyer, Assistant Administrator for Human Nutrition,
> Agricultural Research Service, USDA.
>
> DR. SHANNON: I am Michael Shannon. I am a pediatrician and
> toxicologist at Children\'s Hospital and Harvard Medical School in
> Boston.
>
> DR. APOSHIAN: I an Vas Aposhian from the Department of Molecular &
> Cellular Biology and the Department of Pharmacology at the University
> of Arizona. My research interests have for many years been the
> toxicology of heavy metals including mercury and arsenic.
>
> DR. MILLER: Thank you all. There are still a couple of members of the
> committee that have not yet arrived. When they do, we will have them
> introduce themselves.
>
> Let me make a request, that when you speak, try to speak into the
> microphone since there is a record of this meeting being kept.
>
> Our first speaker is Dr. Joseph Jacobson, a member of the National
> Academy, Committee on Methylmercury. Dr. Jacobson is from Wayne State
> University.
>
> Dr. Jacobson.
>
> **National Academy of Sciences Report on**
>
> **the Toxicological Effects of Methylmercury**
>
> **Dr. Joseph Jacobson**
>
> DR. JACOBSON: First of all, I want to apologize. I am not quite sure
> how I got to the 20 minutes, but in reviewing this morning, I really
> am going to need 30. We are a little ahead, so hopefully, that won\'t
> be a problem for your schedule.
>
> DR. MILLER: Okay, as long as we stay within the schedule, the exact
> moment.
>
> DR. JACOBSON: I am a developmental psychologist and I am going to be
> giving you an overview of the history behind the constituting of the
> NAS panel, as well as some of the logic and thinking that went into
> the process of the conclusions that we reached in our report.
>
> Vas Aposhian was a member of the panel. He is here, so he can correct
> me if I get some of the details wrong.
>
> \[Slide.\]
>
> Obviously, everyone here I am sure is familiar with the fact that
> prenatal exposure to methylmercury can have very serious developmental
> consequences for the central nervous system was first established in
> the Minamata incident in Japan, that led to some of the more severe
> deficits that were seen at the very heavy levels of exposure in that
> population.
>
> \[Slide.\]
>
> And then, of course, the second famous mass poisoning was in Iraq in
> the early 1970s when seed grain that had been contaminated with the
> methylmercury fungicide was used to bake bread because there was
> drought and the infant who were born to mothers who ate the
> contaminated bread while they were pregnant showed very similar severe
> neurological problems.
>
> One important difference between the two episodes as that in Iraq, a
> group of researchers from the University of Rochester went in and did
> systematic assessments of a large number of the infants who were
> exposed, very systematic developmental assessments, and so we had, not
> just the qualitative descriptions, but also some reasonably
> semi-quantitative data that risk assessment could be based on.
>
> \[Slide.\]
>
> EPA, when it did, not the most recent risk assessment, but the one
> before that, used the Iraqi data as the basis for the risk assessment,
> and the developmental endpoints that they used were developmental
> milestones - age of walking, age of talking, which were affected by
> the very heavy exposure levels in this population.
>
> The EPA Iraqi risk assessment was the first to use a benchmark dose
> analysis for purposes of risk assessment. Prior to that, the method
> used was the NOAEL, the No Observed Adverse Effect Level method, which
> tended to be based on animal studies where different groups of animals
> would be exposed at different levels, and the lowest level at which no
> adverse effect was seen was the one that was used for the EPA
> reference dose, the reference dose being an estimate of the average
> daily intake at which you wouldn\'t find adverse effects.
>
> When EPA and other agencies began to move to human data, we got the
> increasing popularity of the benchmark dose statistical assessment,
> which doesn\'t look for discrete groups, and, of course, in human
> exposures, you don\'t get discrete groups, people tend to be exposed
> over a broad range of exposures, and the benchmark dose analysis uses
> the full range of exposures and the outcomes associated with those
> exposures to arrive at a statistically driven estimate of the level
> where you might not see an adverse effect.
>
> To do the benchmark dose analysis, you have to start out by taking a
> cutoff. Well, first of all, you have to start out by picking an
> endpoint, and I will talk later about the choice of endpoints that the
> NAS Panel considered based on the data that were before us, but you
> have to pick an endpoint.
>
> Once you have that endpoint, you have to pick a cutoff, and the cutoff
> represents the level at which you are saying the child is doing very
> poorly and we become very concerned. On an IQ test, we will often pick
> the level of 70, the borderline for mental retardation, and we will
> talk about 70 as the cutoff, that is, 70 as the level of poor
> performance that we are trying to prevent an increased incidence of.
>
> So, we take an endpoint that methylmercury increases the incidence in
> the population, an endpoint where methylmercury makes it more likely
> that we are going to get a bad effect, and we pick a cutoff, and we
> say we want to make sure that we do not appreciably increase the
> number of children who are performing at that level just by virtue of
> the fact that they were exposed to methylmercury.
>
> The benchmark response is our criterion for how much of an increase we
> are willing to tolerate. Let\'s say we are willing to tolerate a
> deficit of 70, an IQ deficit of 70, and we are willing to tolerate an
> increase of 1 percent or 2 percent.
>
> Typically, we don\'t want there to be enough methylmercury exposure in
> the population that the incidence of mental retardation is increased
> by 5 percent or 10 percent. So, the benchmark response is our
> decision.
>
> These are all policy driven, what level of performance is the cutoff,
> what level of performance are we really trying to prevent an increased
> incidence of, what benchmark response are we willing to tolerate how
> much of an increased incidence of poor performance are we willing to
> tolerate, and once we have made those decisions, we use the
> dose-response data from our studies to plot a dose-response line,
> usually, it is done as a straight line, and that dose- response data
> lets us determine the dose, the level of exposure at which we get that
> increased incidence that we are very, very eager to prevent.
>
> So, this is a statistically driven analysis. We use the full range of
> the dose-response data to derive a benchmark dose, and then we set 95
> percent confidence limits around that dose, and the lower 95th
> percentile is called the BMDL, the lower limit of the benchmark dose.
>
> That is the point of departure that EPA used in its Iraqi risk
> assessment, as well as in the more recent risk assessment to derive
> the RfD. What I am leaving out of this is once you get the BMDL, once
> you get the lowest level at which we expect to see a deficit in the
> normal population, then, you add the uncertainty factors that I am
> sure this group will be considering in more detail later on.
>
> \[Slide.\]
>
> As I said, the Iraqi data were used in the initial methylmercury
> assessment by EPA, but there were several problems with using the
> Iraqi data, and those included the fact that the developmental
> milestones, age of walking, age of talking, are fairly gross
> endpoints. They are not very sensitive, and they are not very
> predictive of how a child is going to do later on.
>
> They were used because they were the best that was available using
> human data. The alternative was to extrapolate from animal data, but
> humans and animals will often metabolize metals differently, and so
> the feeling is that if we go with human data, there are some
> advantages to that.
>
> The other major disadvantage with the Iraqi data was that the exposure
> was so high, that there were very few individuals in that sample who
> were exposed in the range at which we get exposure in the general
> population.
>
> So, we were plotting a dose-response curve and then extrapolating down
> to apply to our population in a range at which there were very few
> datapoints.
>
> So, although from some perspectives, the Iraqi risk assessment
> represented a real advance from a scientific point of view, there were
> really very serious problems in using it to make inferences for
> contemporary exposure, the other being, of course, that an acute
> exposure from seed grain is not necessarily going to have the same
> kind of damage as a chronic exposure from fish over a long period of
> time.
>
> As a result, NIEHS, the National Institute of Environmental Health
> Sciences, funded two very large and very well-designed, prospective
> longitudinal studies of prenatal methylmercury exposure that started
> during the early 1990s.
>
> One was in the Seychelles Island in the Indian Ocean, the other in the
> Faroe Islands in the North Sea. Those locations were chosen because
> they had populations where there were people who ate a lot of fish,
> and so you could get\--and it is always optimal in these kinds of
> samples\--to take a population where there is a broad range of
> exposures, in other words, you are going to get the clearest picture
> if you can see the full dose-response curve.
>
> There still was good overlap with the exposures that we get in the
> U.S. population, but there was a broader range, and so that made those
> two populations optimal.
>
> \[Slide.\]
>
> The Seychelles Islands was the first to report effects, and the first
> effect that they reported came from a pilot study. It\'s actually
> rather large by my standards for a pilot study, and this was 217
> children who were assessed at age 5, and they actually, mainly had
> very low exposed children and heavily exposed children.
>
> They assessed 9 developmental endpoints, and I am showing them 3 of
> them here, but actually, they found statistically significant
> associations between prenatal methylmercury exposure and adverse
> outcome on 4 of their developmental endpoints.
>
> One was the General Cognitive Index, which is like an IQ score for
> pre-schoolchildren from the McCarthy scales of children\'s abilities,
> which is an IQ-type test for pre-schoolchildren. Another was on the
> Perceptual Performance subtest of the McCarthy, visual-spatial
> function, preschool language, and Auditory Comprehension was the
> fourth one that is not shown.
>
> What was unusual about this report was that the investigators
> themselves, after reporting the data, tended to discount it, and they
> discounted it on two grounds - one, that there were 4 outliers, which
> when they were dropped from the analysis, the results were no longer
> statistically significant, and the other was that they had not
> measured a full range of potential confounding variables, particularly
> social class, and had not controlled for them.
>
> The Panel reviewing these data raised questions about whether they
> should have been discounted. Dropping outliers, not all statisticians
> agree that is the best way to handle outliers. A lot of statisticians
> feel they should be recoded. The social class, we did not think was
> necessarily such a serious problem here, because methylmercury tends
> to be more concentrated in more expensive fish, and, if anything, it
> is likely that the more middle class children got the heavy exposures.
>
> But again, this is a pilot study, and these are tentative data, and no
> one would do a risk assessment based on these data, but they were the
> first indication from this more recent series of studies of adverse
> effects.
>
> \[Slide.\]
>
> However, when the Seychelles group, which is the University of
> Rochester group, assessed the main study, the full cohort several
> years later, at the same age, that is, at age 5 1/2, they found no
> evidence of adverse effect.
>
> \[Slide.\]
>
> I have a slide here to demonstrate there just was no relationship
> between exposure and outcome. I mean, you know, you can look and look
> and look, but there is nothing going on in these data of this second
> main cohort.
>
> \[Slide.\]
>
> The endpoints they assessed tended to be relatively global endpoints,
> that is, again the McCarthy General Cognitive Index, preschool
> language tests, tests of academic achievement as opposed to what we
> call narrow band, domain-specific tests where a test might look in
> great detail at one aspect of cognitive function, such as sustained
> attention or vocabulary or visual-spatial reasoning, and so forth.
>
> Here, the Seychelles group tended to use more global tests and saw no
> adverse effect.
>
> \[Slide.\]
>
> They also used maternal hair as their measure of prenatal exposure.
> Mercury is excreted in the hair, and so if the mother has long hair,
> which most of the women in this population do, and you get a sample of
> her hair after she delivers\--and hair we know grows at a rate of
> about 1.1 cm per month\--you can take the hair, you can estimate when
> during pregnancy the mercury was excreted into the hair, and get a
> very accurate retrospective picture of the mercury intake during
> pregnancy.
>
> \[Slide.\]
>
> So, as I said, Seychelles, age 5 1/2, main study, no evidence of
> adverse effect, not even a hint or a suggestion in the data.
>
> By contrast, we had the Faroe study at age 7, which did not use global
> tests, they used more narrow band, domain-specific tests, and they
> reported I think it\'s out of 20 outcomes, they found adverse effects
> on 8 of them, and these were actually in many domains.
>
> Even though they were domain-specific tests, adverse effects were
> found across the full range of cognitive and neuromotor functioning
> including fine motor function, finger tapping, sustained attention,
> short-term memory as assessed in the digit span test, vocabulary as
> assessed in the Boston Naming test, and verbal learning and memory as
> assessed in the California Verbal Learning test.
>
> The publication of these two studies, as I said, both well designed,
> both very large samples, exposure levels, very similar, presented
> quite a quandary both to scientists and regulators - how is it
> possible that you can conduct two large-scale comprehensive,
> state-of-the-art studies and come up with such absolutely
> contradictory findings.
>
> One of the first responses to the appearance of these two sets of
> contradictory data was that NIEHS and EPA, and other agencies, ATSDR,
> Chris DeRosa was involved in this who is here today, convened a
> workshop in Raleigh, North Carolina in 1998, where there were 50
> scientists assembled. Larry Fischer was one of the scientists on that
> panel. We spent 2 1/2 days intensively scrutinizing these two studies,
> and we brought in the investigators, and, boy, I would not have liked
> to have been in their shoes for the close questioning, detail by
> detail, that these people underwent.
>
> But we learned a lot. We learned a lot about the studies at that time,
> and the question, as I said, from a scientific point of view, is how
> can you have two large-scale studies come up with absolutely
> contradictory findings.
>
> \[Slide.\]
>
> At the end of the 2 1/2 days, having considered the data, the panel
> concluded that there were several differences in exposure and design
> that could explain how one study concluded there were adverse effects
> and the other study concluded no adverse effects.
>
> One had to do with biomarker of exposure. As I mentioned, the
> Seychelles study used maternal hair mercury. I didn\'t mention the
> Faroe study, in their initial reports, used cord blood mercury. Now,
> cord blood mercury reflects intake during pregnancy during the last, I
> think it is 12 weeks or the latter part of pregnancy, and that is the
> period when we get a lot of neuronal proliferation differentiation and
> brain development that might well be involved in the kind of endpoints
> that were being assessed in these studies.
>
> So, it was plausible to say maybe the Faroe\'s group was measuring
> mercury at the right time to see the problem. However, subsequently,
> the Faroe\'s group, they also had the hair samples, they just hadn\'t
> analyzed them yet, analyzed the maternal hair and looked at it in
> relation to these developmental endpoints, and found the same adverse
> effects as they had found with cord blood, so the first theory which
> seemed to explain the differences kind of fell by the wayside.
>
> The second was that global tests were used in the Seychelles,
> domain-specific tests in the Faroes. In retrospect, that doesn\'t seem
> all that convincing to me, because the Faroes group used the
> domain-specific tests, but found adverse effects across a broad range
> of domains, so the global tests, in my view, should have picked up.
> The narrow band tests are important if the deficit is only in one or
> two narrow domains, but it is clear from the Faroe\'s data that it
> isn\'t.
>
> So, in retrospect, that one, I think we should have not put as much
> stock in as we did at the time. The age point, 5 1/2 years, is not a
> good time to do developmental testing because it is a period of rapid
> brain growth, rapid cognitive reorganization, and relatively subtle
> neurotoxic effects are not likely to show up.
>
> The Faroe\'s group, I think picked a better age point, 7. Once
> children have gotten past that developmental period, they usually
> perform in ways that are more stable and reliable over time.
>
> Then, a fourth difference was the source of exposure. Both populations
> ate a lot of fish, but in the Faroe\'s, they also get a lot of
> methylmercury exposure from whale meat, and the difference in the
> fish, it is a low level chronic exposure, the woman is eating a little
> bit every day.
>
> The whale meat, the methylmercury is much more concentrated, and they
> will beach the whale, there will be a big party, there will be
> splurging on whale meat, so to speak, and you could get some very
> heavy doses that perhaps could explain why you might see the adverse
> effects in the Seychelles, and not in the Faroes.
>
> The fifth difference, that is not up there, is that the Faroes were
> heavily exposed to PCBs, which is a ubiquitous environmental
> contaminant, and there are two concerns about PCBs that you have to
> understand.
>
> One is that it is possible, since you get PCBs from fish and
> methylmercury from fish, it is possible that we have confounding. It
> is possible that the same children who get heavy methylmercury
> exposures, also get heavy PCB exposures, and that where you think you
> are measuring methylmercury, you are really measuring PCBs. That is
> one possible problem with the PCB exposure.
>
> A second possible problem is that there may be synergism between the
> PCB and methylmercury exposure, that is, being exposed to
> methylmercury when you are also at the same time being exposed to PCBs
> may make the methylmercury more toxic. There is no good mechanism that
> has been hypothesized as to why the synergism would exist, but it
> certainly is possible in theory.
>
> So, basically, these differences between the two cohorts allowed the
> 50 scientists in the Raleigh meeting to come up with an intellectually
> very satisfying understanding about why one well-designed study would
> lead to one set of results and another two, a very different set of
> results, but it presented no relief to the regulators who these are
> the data they have, and they have to one way or another make sense of
> them and come up with some criteria and recommendations.
>
> Around this time, EPA was eager to set up some new rules to regulate
> emissions from coal-fired utility plants in the Midwest, and
> methylmercury is a major pollutant from that source.
>
> They tried to issue the regulations and were blocked by congressmen
> from West Virginia and Ohio, and then the resulting battle in Congress
> led to a directive to NAS to convene an expert panel to try to look
> more carefully at the data and from a regulator\'s point of view, do a
> better job than the Raleigh group and come up with something that
> could be useful from a regulatory point of view.
>
> \[Slide.\]
>
> That is how the NAS panel was convened with representatives from a
> broad range of relevant disciplines, epidemiology, developmental
> psychology, statistics, methylmercury chemistry, and so forth.
>
> \[Slide.\]
>
> One key difference in our deliberations, in the deliberations of the
> NAS panel, over what had come before in the Raleigh panel, was that in
> the NAS panel, we considered the results from an earlier study, from a
> study that was conducted in the late 1980s in New Zealand, which the
> Raleigh panel was instructed not to pay attention to because it
> wasn\'t published.
>
> Well, after the Raleigh panel meeting, some of it became published,
> and we considered it in the NAS panel. Although it is not as large a
> sample, I think there were about 230 children, not as well designed in
> terms of controlling for confounders. There was some control, but not
> as comprehensive. It is actually quite a good epidemiological study as
> these studies go.
>
> What is interesting about it is that in terms of the sources of
> exposure and the design of the study, it is very similar to the
> Seychelles study, that is, the methylmercury was measured in the
> mother\'s hair, the children were assessed at about the same age, it
> was age 6 rather than age 5 1/2, the developmental endpoints were very
> many of the same global IQ and achievement tests, and so forth.
>
> The difference was that the New Zealand study found adverse effects
> using the same exposure measures, the same research design,
> essentially the same research design as the Seychelles, they saw
> adverse effects.
>
> In epidemiological studies, oftentimes what you have to do is go with
> the weight of the evidence.
>
> Actually, let me put that off, because that point will be a little bit
> easier to make toward the end.
>
> \[Slide.\]
>
> So, basically, when we included the Seychelles pilot data and the New
> Zealand data, these differences that we thought had explained why we
> are seeing effects in one study, and not in the other, fell by the
> wayside.
>
> We are seeing adverse effects with cord blood, mercury, and maternal
> hair mercury in multiple studies. We are seeing them on global tests,
> not just on narrow band tests. We are seeing them at age 5 1/2 and 6,
> and we are seeing them in populations where the exposure is just from
> fish.
>
> PCBs, we don\'t know what the PCB exposures are in New Zealand, but
> there is no reason to expect there to be particularly high levels of
> exposure in New Zealand.
>
> DR. MILLER: Dr. Jacobson, we have about five more minutes.
>
> DR. JACOBSON: I will just try to say very briefly what the other slide
> was going to show, which has to do with the confounding of PCBs and
> methylmercury in the Faroe study. There were four endpoints which we
> shown on the slide where methylmercury affected the endpoint and PCBs
> did not. There were four where both methylmercury and PCBs affected
> the endpoint, and it was very difficult to tease apart that
> difference, and if people have more questions about it, I will try to
> explain that in greater detail.
>
> Basically, once we see that these factors do not explain the
> differences between the two studies, you are left with the question,
> who could explain the difference between the two studies.
>
> Well, one conclusion that we came up with on the panel was that we
> think that there is an issue of power. Now, when you have samples of
> 700 and 900 children, it is kind of funny to talk about power, because
> that would seem to be an adequate sample size to detect anything.
>
> \[Slide.\]
>
> There are two factors. First of all, much of the effect is going to be
> seen above 15 parts per million in maternal hair. We have got lots of
> cases at the lower end, but when you think about power, power is going
> to be weakened in these studies\--this is the Seychelles data\--even
> in a study of 700 children when you have a limited number of children
> whose exposure is in the upper end of the distribution where most of
> the effect is going to be seen, so there may have been a power problem
> from that point of view.
>
> \[Slide.\]
>
> Then, we took the raw regression coefficients that had been reported
> in the studies and transformed the standardized regression
> coefficients to try to get a sense for the magnitude of the effects,
> and what we find is that the magnitude of a lot of these effects is
> very, very small, so even very large samples may find it difficult to
> detect some of these very small effects.
>
> \[Slide.\]
>
> The other issue in an epidemiological study is there are many
> uncontrolled factors, there are many possible unmeasured confounders.
> We find this in the lead literature, the PCB literature, these other
> exposures where many studies have been done. You can have a
> well-designed study that fails to detect an effect that is seen in
> study after study.
>
> The reasons are probably that in many populations or in any given
> sample, there may well be unmeasured factors that you are unable to
> control for because it doesn\'t occur to you that there could be
> confounders, and that is basically why you have to go with the weight
> of the evidence.
>
> The basic conclusion in the NAS panel was even though one very
> well-designed study clearly failed to find effects, one very
> well-designed study did, one quite well-designed study did, and even
> the Seychelles pilot gave some indication, so the weight of the
> evidence seemed to be pretty clearly in the direction of adverse
> effect.
>
> \[Slide.\]
>
> When you do the benchmark analysis, you have to figure out, the way
> the methodology works is you have to choose a developmental endpoint
> that is going to be your guide, that is going to be the one that you
> do your statistic analyses based on.
>
> Some people argue it should be the most sensitive endpoint, that is,
> the endpoint at which you see an effect at the lowest level of
> exposure. If we had recommended the most sensitive endpoint to EPA, we
> would have gone with the New Zealand data because effects were seen at
> the lowest levels in the New Zealand study.
>
> We felt that since it was not a well-designed study, it had not had as
> extensive peer review, it was not as large a sample, that we would do
> better going with the Faroe study, which did show adverse effects at
> somewhat higher levels of exposure.
>
> Based on methylmercury maternal hair, the endpoint at which we saw
> effects at the lowest doses was the Boston Naming Test, it\'s a
> vocabulary test, so that was the endpoint that we decided to go with
> in terms of recommendation for EPA for its risk assessment benchmark
> dose computation.
>
> Thank you.
>
> DR. MILLER: Thank you very much.
>
> Comments, questions from the committee? Yes, Dr. Russell.
>
> **Questions of Clarification**
>
> DR. RUSSELL: I was wondering, is another possible explanation for the
> differences that the diets eaten in these various areas differ in
> other components that could affect the absorption or the
> bioavailability, if you will, of the methylmercury? In other words, if
> the rest of the diet that was eaten with fish is vastly different from
> place to place, could that affect the amount that is absorbed?
>
> DR. JACOBSON: In principle, yes. I am not sure and I don\'t think
> there is any really good theory sketching out what components of the
> diet that would be.
>
> There has been research on selenium. I am pretty sure\--well,
> actually, I am not sure about the Faroes\--how is the selenium levels
> in the Faroes, are they fairly high? I am pretty sure they are fairly
> high in the Seychelles. Maybe we will that off until Philippe has his
> talk.
>
> It is certainly plausible. Then, of course, you have to ask yourself
> would those particular nutrients be particularly high in the U.S.
> diet, but, yes, that is something that obviously should be considered
> and something that we don\'t have good comprehensive data on.
>
> DR. MILLER: Dr. Fischer.
>
> DR. FISCHER: Joe, when you chose the Boston Naming Test as the test
> that was most sensitive to the effects, and calculated a benchmark
> dose using that, why did you pick a single test instead of picking a
> score of a group of tests, either those tests that showed an effect or
> maybe even the whole neurological analysis, a score?
>
> In other words, it seems to me what you are doing there is picking
> data from a single test and using it to regulate, when, in fact, you
> had a whole lot of data that you just seemed to not use.
>
> DR. JACOBSON: It is traditional in risk assessment to go with the most
> sensitive endpoint because from my understanding, the philosophy is we
> want to protect, so we want to err in the direction of caution, we
> want to pick the most sensitive endpoint.
>
> I was particularly comfortable with taking the Boston Naming Test
> because vocabulary is actually a very, very good surrogate for overall
> IQ, and if you had to pick a specific test that would be likely to be
> predictive of how the child would do later on, you would do best with
> the Boston Naming Test.
>
> When we looked at the cord blood measure in the Faroe study, there was
> another test that was actually more sensitive, which was the Sustained
> Attention Test. I wasn\'t comfortable going with that one, first of
> all, because data had been collected only on half the cohort.
> Secondly, it doesn\'t have very good predictive validity to a broad
> range of other aspects of function, the way the vocabulary did.
>
> I would philosophically see nothing wrong with developing a composite
> measure, and we considered it, but we went in this direction to follow
> what is traditionally done in the field, that is, to err in the
> direction of caution.
>
> DR. FISCHER: So, scientifically, you would have picked a group of
> scores, right?
>
> DR. JACOBSON: Normally, but I can\'t make a strong scientific argument
> that a group of scores would have been any better than vocabulary,
> because vocabulary is such a robust predictor of a broad range of
> effects.
>
> DR. FISCHER: Then, why do the other tests?
>
> DR. JACOBSON: Scientists do the other tests because they want to get a
> comprehensive understanding of what is going on. A risk assessor may
> or may not take all of that information. You know, formulas are
> developed, procedures and approaches are developed for various
> reasons, and as I said, I think the rationale here is to try to get
> maximal protection.
>
> DR. MILLER: Dr. Dwyer.
>
> DR. DWYER: Are there any other confounders that come to your mind?
>
> DR. JACOBSON: My sense was that these groups did an excellent job of
> controlling for confounders, and we actually looked at that in great
> detail in the Raleigh meeting, and were very impressed with it.
>
> We put the Faroes people, we raked them over the coals, we made them
> construct an urban/rural variable, and they seemed to pass all the
> tests. It seemed no matter what you controlled for, the effects were
> still there. Sometimes the effects looked a little weaker, sometimes a
> little stronger, but my sense is all the things I can think of were
> controlled for.
>
> DR. MILLER: Other questions?
>
> DR. KUZMINSKI: Please correct me if I am wrong, but the question is
> along the same line as Dr. Fischer\'s, and that in your presentation
> here today, you have outlined the three studies and the differences
> and the parameters, but from what I have read in the pre-read
> material\--again, correct me if I am wrong\--the Academy committee did
> not consider the results of the Seychelles study in the deliberation
> towards recommendations to the EPA on the RfD.
>
> Am I interpreting that correctly?
>
> DR. JACOBSON: Well, we actually did two exercises. We did one exercise
> where we took the data from the three studies and integrated them.
> This was a statistical exercise, which is kind of averaging along the
> lines that Dr. Fischer was recommending, and that analysis would have
> led to a set of recommendations that were surprisingly similar to
> those that we finally did make.
>
> But again, we felt that it was appropriate to follow some of the
> protocols of the way risk assessment has traditionally been done, and
> typically, what is done is a single study is selected, the best study
> is selected, the one that appears to be most valid, most sound, most
> solid, and then within that study, the most sensitive endpoint is
> selected.
>
> So, in our final recommendations, we went with what we considered to
> be the traditional risk assessment approach. However, as I said, the
> other exercise did lead us to a surprisingly similar conclusion.
>
> DR. MILLER: Thank you very much.
>
> There are two speakers now dealing with the two principal studies. The
> first, Dr. Philippe Grandjean from Odense University to talk about the
> Faroe Islands study.
>
> Dr. Grandjean.
>
> **Faroe Islands Study**
>
> DR. GRANDJEAN: Thank you. I am very pleased to be here. I have
> previously worked with colleagues in the U.S. EPA at the ATSDR, at the
> European Commission. I am very pleased to be here with FDA now to tell
> you about our experience in the Faroe Islands.
>
> \[Slide.\]
>
> What I am going to do today is try to look at that research and see
> what can we learn from that experience if we go beyond the results as
> such.
>
> \[Slide.\]
>
> Let me just give you a brief overview of why we chose doing research
> in the Faroe Islands. It is a rainy place in the North Atlantic
> between Iceland and Norway. It\'s rather cool in summer, but the
> winters are mild. The reason it is interesting to us environmental
> epidemiologists is that people in the Faroes have this tradition of
> eating pilot whale.
>
> They chase pods into shallow bays, pods that come near the coast, and
> for hundreds and hundreds of years, the tradition has been that they
> kill of pods of these small whales that are nonendangered, it\'s a
> sustainable use of the species, so they get this extra supply of
> proteins and fatty acids, essential fatty acids and vitamins, but
> unfortunately, it has turned out that the meat and the blubber are
> contaminated with methylmercury and PCBs respectively.
>
> \[Slide.\]
>
> The reason for doing the research in the Faroes is that it is almost
> like a natural experiment because the pods do not come in regularly,
> and when they come in, when they come near the coast, you can\'t be
> sure if they will be near one island or another island, therefore, the
> communities are exposed to methylmercury or PCBs on an irregular
> basis. You can\'t choose it, so it depends on availability of the
> whale meat.
>
> At the same time, these people eat a lot of fish, they eat fish for
> dinner three times a week on the average. They eat lots of cod,
> halibut, salmon, the types of fish that you would normally eat when
> you are in the North Atlantic.
>
> It is a homogeneous population. It is a wealthy, developed,
> industrialized country with scandinavian background, with what you
> would call socialized medicine, equal access to social support and
> health care. In studies we have conducted there, we have had a high
> participation rate.
>
> \[Slide.\]
>
> Now, this study has been in international collaboration between Faroes
> and Danish researchers, researchers from the U.S., Sweden, Japan
> primarily. So far we have looked at three cohorts, and here, I am
> going to talk about, first of all, Cohort 1, I will talk a little bit
> about Cohort 2, and we have some preliminary findings on Cohort 3.
>
> \[Slide.\]
>
> First of all, the conclusions so far from these studies have been that
> we see neurobehavioral adverse effects associated with developmental
> methylmercury exposure. We see that that exposure is also associated
> with increased blood pressure, poorer heart rate control, and also
> decreased growth of all physical growth postnatally, and we see that
> the prenatal exposure is much more closely associated with these
> adverse effects than the postnatal.
>
> The preliminary results from the follow-up at age 14 of Cohort 1 are
> in agreement with the results that we saw at age 7. This is not
> published, so I can only give you the preliminary results.
>
> \[Slide.\]
>
> When you do research on this area, there are a couple of very crucial
> issues. One issue that Dr. Jacobson touched upon was the validity of
> the exposure estimate. If you do a regression analysis to assess the
> effects of an exposure with regard to some effects, your basic
> assumption is that the exposure is measured without error, it is a
> precise measure, but there is no such thing as a precise exposure
> measurement because what you would like to know is how much
> methylmercury is there at the target, let\'s say, of some particular
> part of the brain.
>
> We will never know that, so anything else that we are using is a
> proxy. That means we are going to have an underestimation of the true
> effects of methylmercury. Now, these are the exposure biomarkers that
> we have used, and I will talk a little bit about those.
>
> \[Slide.\]
>
> First of all, you have to have as precise a result as possible from
> the layout, and I will show you briefly on the next slide what I mean
> when I say that. The other issue here is that the timing of the sample
> has to relate to the toxicokinetics of behavior of methylmercury in
> the body, and you also have to consider the characteristics of the
> specimen, and particularly that is a problem with hair.
>
> Hair varies a lot between people, and hair structure or hair treatment
> even varies a lot, and that causes uncertainty. Finally, the bottom
> line is obviously the predictive validity, which one correlates the
> best with the outcomes that you are looking at.
>
> \[Slide.\]
>
> So, here are the issues in regard to the laboratory validity. I think
> we have done as well as we can possibly do with modern atomic
> absorption techniques and supporting methods. The chemists told me
> that the imprecision of the microanalysis, it should be better than 5
> percent.
>
> So, being confident environmental epidemiologists, we thought, oh,
> wonderful, we have an exposure estimate which has an imprecision of
> about 5 percent, that is great, we are in a fabulous position here.
>
> Well, I will tell you a little bit down the road that this was a naive
> assumption. These exposure biomarkers are not all that precise.
>
> \[Slide.\]
>
> Here is one issue, though, you have to consider, and that is a
> variability of exposure. Now, the colleagues in Rochester looked at
> hair from the Faroes that they chopped into segments, and we followed
> up on that issue, and we have a total of 21 long hair samples where
> the average was above 10 ppm that we had chopped into these segments,
> and these are the three that showed the greatest variability with a
> coefficient of variation of about 25 percent.
>
> Actually, you can see there is only one of them where there is a
> definite clinal tendency. It is only 1 out of 21 samples, but anyway,
> this kind of temporal variability will mean that you will have an
> imprecision associated with just about any exposure biomarkers that
> you choose, simply because there is variability during pregnancy.
>
> Now, we have chopped this into segments of 1.5 or 1.1 cm simply
> because the mercury half-life is about 45 days, so each segment
> corresponds to a half-life. That is the reason for doing this. We have
> also looked at profiles with colleagues in New York, trying to see if
> there were shorter term variabilities.
>
> We compared hairs from the Seychelles and the Faroes. I have
> reservations about the technique that they use, because the results,
> in my view, were not all that reliable, but the conclusion from that
> study was that the profiles were indistinguishable between the Faroe
> and the Seychelles.
>
> \[Slide.\]
>
> The first biomarker we looked at in this regard was the long hair
> sample of 8 or 9 cm from the women, that the hair was taken at
> parturition, at the time of childbirth, and this graph essentially
> shows you the contribution of mercury exposure during pregnancy and
> before actually to the hair mercury concentration in that particular
> sample we obtained at childbirth, which is here indicated as Week 40.
>
> There is a lag time because some of the most recently observed
> methylmercury will still be in the hair root, so it will not have made
> it into the maternal hair at the point where we sampled the hair, but
> then you can see that this type of a sample will overestimate the
> importance of the first and second trimesters of pregnancy.
>
> We then, for about 600 of these kids, we were able to obtain from the
> remaining hair sample, if there was any hair sample or remaining after
> the first analysis, we were able to cut off the proximal 2 cm hair
> sample, the one closest to the root, and you can see from this
> representation that that would better reflect the end of the second
> and the early part of the third trimester methylmercury exposure.
>
> \[Slide.\]
>
> When we compare them as predictors of the outcomes that Dr. Jacobson
> also focused on, the finger tapping, the attention, the
> Bender/Gestalt, the Boston Naming, and the California Verbal Learning
> Test, you can see that there is perhaps a slight tendency that the
> proximal hair sample is better than the long hair sample, but these
> small differences are by no means significant, also because we are
> losing power as we get from the 900 to the 600.
>
> \[Slide.\]
>
> This slide shows you the correlation between the two hair mercury
> concentration measures. I have indicated the ones with open circles
> where the coefficient of variation is more than 25 percent. This is
> about 10 percent of the samples where the coefficient of variation
> based on those two measurements only was large.
>
> So those must have been the individuals where the mother had a
> variable methylmercury exposure during pregnancy. Now, the interesting
> thing is then going to be what happens if we remove the 10 percent of
> the kids who had a variable methylmercury exposure during pregnancy.
>
> \[Slide.\]
>
> This is what we did. We used the third exposure biomarker, namely, the
> cord blood measure as the independent judge. Is there any difference
> between stable and variable or mercury exposure, and indeed the bottom
> line is that if you remove the ones with variable methylmercury
> exposure, you get an increased power. It is easier to see the mercury
> exposure simply because you eliminate one source of imprecision.
>
> So, on the other hand, this also indicates to us that variable
> exposure or peak exposure cannot be the reason for our seeing that
> there is an association with the cord blood measure.
>
> \[Slide.\]
>
> We also did a separate analysis, let\'s say, a neutral statistical
> analysis to see what are the uncertainties involved here if we have
> absolutely no other assumptions other than the three exposure measures
> must be in some way a measure of some sort of true mercury exposure
> that we don\'t know.
>
> Each of them has to be a reflection associated with some error
> indicated by the epsilon on the right of this equation. In order to
> solve this equation, you have to have three sets of equations, and
> then you can do a factor analysis.
>
> So, we used the cord blood measure, the long hair mercury measure, and
> there is a third independent variable, the dietary questionnaire
> information, namely, how often have you eaten pilot whale for dinner
> during the pregnancy. So, when we fed that into the computer and
> calculated the overall epsilon for each of those three biomarkers,
> then, this is what we find.
>
> \[Slide.\]
>
> We set the loading factor for the cord blood to 1. You can see that
> the two other parameters are less good indicators of the true mercury
> exposure defined as the best, let\'s say, background that can be
> calculated from this imprecise information that we have here.
>
> But the important thing is that the coefficient of variation is,
> number one, 30 percent for the cord blood mercury. This is much more
> than what the chemists told us, much more than the 5 percent. The
> other important information is here that hair mercury is much more
> imprecise than the cord blood is.
>
> This is not based on any toxicokinetic information. It is simply based
> on the concrete numbers for each child with regard to these three
> exposure variables only, nothing else.
>
> \[Slide.\]
>
> So how come a hair measure is more imprecise than a blood measure?
> Well, there are some issues involved here like I referred to before,
> that hair is not just hair, it varies between people, and there are
> several issues that you might want to consider, and it was actually
> done in the NAS report. They looked at this very carefully.
>
> \[Slide.\]
>
> I am showing you again this hair curve because I wanted to compare
> with the cord blood. The cord blood is, of course, obtained at the
> only time you can obtain it, at the time of parturition.
>
> \[Slide.\]
>
> Here, you actually have a representation of the last trimester. If we
> want to consider cord blood in regard to the predictive validity, you
> have to think of the windows of vulnerability here - is it important
> to have a representation of the last trimester?
>
> People who work in developmental psychology, like Dr. Jacobson, would
> say the third trimester is certainly very important with regard to the
> programming of the brain.
>
> \[Slide.\]
>
> These are the results that we published in 1997, but what I have done
> here is to compute the regression coefficients as percent of the
> standard deviation for each outcome variable associated with a
> doubling of the mercury exposure.
>
> The doubling is obviously you take the regression coefficient for the
> log transformation and multiply by 0.301, and then you divide by the
> standard deviation that is present in percent. You can do it yourself
> from the regression coefficients, but this way you can actually
> compare the results from the different domains, and you can see that
> it is really attention and language that appear to be the most
> sensitive.
>
> Here, we are in a way going beyond the psychometric properties of each
> of these tests. It looks like attention and language are the
> modalities that are affected the most.
>
> The important thing is here, blood is a much better risk indicator
> than is hair.
>
> \[Slide.\]
>
> Conclusions on these issues is that the cord blood is the best risk
> predictor, but it is still imprecise. We still have to consider this
> 30 percent imprecision, and I will get back to that. The more
> imprecision we have, the more we underestimate the true extent of the
> effect. There is nothing new in this, this is in perfect accordance
> with everything we have learned in the past from lead and many other
> situations.
>
> \[Slide.\]
>
> Now, if we go back to the regression coefficients for blood, we can
> actually do a sensitivity analysis and adjust for the 30 percent
> imprecision, and this is what I have done here. I am giving you the
> regression coefficients before, adjusted, and then you can see the
> increase.
>
> Overall, it looks like for each doubling of the mercury exposure, you
> lose something that corresponds to about 10 percent of the standard
> deviation, perhaps a little more for attention and language, about 10
> percent for these sensitive modalities.
>
> \[Slide.\]
>
> Now, I am going to talk a little bit about the outcome variables,
> because that is a second issue that you have to consider.
>
> In regression analysis, you do take into account that they are
> imprecise, but there are psychometric issues that are important
> because some tests are very useful and some tests have a lot of noise
> involved like they may depend on the child\'s motivation or the
> testing situation or the testing situation, the training of the
> tester, or whatever. Many variables may play a role here, so you have
> to consider these tests very carefully and also the age of testing.
>
> \[Slide.
>
> These are the criteria that we use for the selection of clinical
> tests. Unfortunately, the Faroes is a scandinavian society, so what we
> did was to apply tests that are also applied in Denmark and Norway and
> other countries like that, also the United States, but we did use
> internal age standardization and we piloted the tests, we translated
> them, of course, and made sure that they functioned in that society
> before we went ahead.
>
> \[Slide.
>
> Now, let me just point out a couple of concerns that we have about
> outcomes like this. The first issue I wanted to bring out is that it
> is important that a test has as many possible outcomes as possible
> meaning that if you do the clinical tests of catching a ball, it is
> something that pediatric neurologists do, they throw a ball in the
> clinic and then the child has to catch it a distance of 10 feet, and
> the ball has to have a particular size. Either the child catches the
> ball or the child fumbles or the child doesn\'t catch the ball, so you
> have only three outcomes.
>
> This is a very simple test, and it shows an association with mercury
> in the right direction, but the p-value doesn\'t prove anything, but
> if you use tests that reflect attention and which have an increased
> number of possible outcomes, then, the digits bend forward score is
> better and the computer assisted reaction time is even better than
> that simply because it is better to dissociate within the patterns of
> gray, because we are looking for some subtle, we are not looking for
> sick kids, we are looking for something subtle.
>
> \[Slide.
>
> The second issue here is that some of these tests are I would say they
> are complicated to do the same way every time. They have to be done in
> an extremely standardized way, and you sometimes run into trouble if
> you have technicians or nurses do the test, and we have emphasized
> that we wanted the highest possible expertise, board-certified staff
> to administer the tests, and we saw a clear example when the
> similarities tests simply could not fit into the neuropsychologist\'s
> time allotment.
>
> We had to move the test to another examination station where a
> technician did it, and when we looked at the kids that the
> neuropsychologist had examined, there was a mercury effect, but the
> result that we published in 1997 was the bottom line where we used the
> results from both stations and adjusted for the examiner and then you
> don\'t see a mercury effect.
>
> The question is if it is not more reliable to look at, even if it is a
> smaller number, than to look at the kids that were examined by the
> neuropsychologist.
>
> \[Slide.
>
> Let me just say a few words about the outcomes at age 14. These
> results have not even been submitted for publication yet. We are still
> grinding confounder adjustments through the computer, but let me give
> you one which is reasonably simple to explain and one of the tests
> that Dr. Jacobson also mentioned, the reaction time measure using the
> NES continuous performance test.
>
> We actually used a revised version with animal silhouettes because at
> age 7 we were not sure that all the kids all knew the letters\--and
> that is a standard version for adults\--equally well, but we were
> quite sure that they all knew animal silhouettes. So, instead of the
> letters, we used five different animals, and the kids had to react to
> the. You see this cat on the screen here.
>
> So, the only difference between 7 and 14 years is that at 14 years,
> the test was extended to last for 10 minutes rather than 4, which was
> the time we used at 7 years. Now, this was administered by the
> neuropsychologist.
>
> \[Slide.
>
> These are the results. These are the correlation coefficients that are
> not adjusted for confounders, but what you see here is that cord blood
> is still a significant predictor of the outcome 14 years later, and it
> is actually better than maternal hair and also better than the
> postnatal measures.
>
> At age 14, it turns out that the kids\' exposure at that time actually
> correlates pretty well with what the mother had 14 years before,
> possibly an indication that dietary habits are quite stable within
> families at particular locations.
>
> So, when we do a multiple regression analysis, we try to leave in as
> many predictors of mercury exposure as possible. It turns out that the
> cord blood microconcentration is the only one that remains.
>
> \[Slide.
>
> The important thing with this slide is that the beta for age is almost
> the same as the beta for mercury, which means that if you increase the
> mercury exposure by a factor of 10, then, the child has a result which
> would have been similar to the situation had the child been one year
> younger.
>
> In other words, if you increase the mercury exposure by 10-fold, then,
> the effect is similar to losing one year of development.
>
> \[Slide.
>
> Now, let me just say a few words the Cohort 2.
>
> DR. MILLER: Dr. Grandjean, you have five more minutes.
>
> DR. GRANDJEAN: Okay. I will run through this quickly.
>
> Cohort 2. These results were published in the Journal of Pediatrics.
> These are the results for age 2 weeks.
>
> \[Slide.
>
> This is PCB. Dr. Jacobson talked about this. We have looked into PCB.
>
> \[Slide.
>
> And we have validated the cord tissue PCB and even if we assume that
> there is a large imprecision in the PCB measure, PCB is not a
> significant determinant of the outcome in this study.
>
> \[Slide.
>
> These are the results from the paper published last year that shows
> that PCB has an effect in this population, but only in the kids who
> have a high mercury exposure at the same time.
>
> \[Slide.
>
> These are results of brain stem auditory-evoked potentials from two
> locations, the Faroes and Madeira, and we see that the evoked
> potentials increase in latency, and the increase is similar in the
> Faroes and in Madeira.
>
> \[Slide.
>
> The results of brain stem auditory-evoked potentials used for
> calculation of benchmark doses are very parallel to the results that
> the National Academy came up with. You can see that the results for
> Madeira and the Faroes are quite similar to the neuropsychological
> benchmark doses published by the National Academy.
>
> \[Slide.
>
> These are the blood pressure results. You have the publication, so I
> won\'t dwell into that. I will just say that this is an effect which
> is seen below the current reference dose that the EPA has decided
> upon. We don\'t know the implications yet, but I am just saying this
> is an effect which is seen in very low exposure levels.
>
> \[Slide.
>
> These are unpublished data on Cohort 2 where we show the weight at age
> 18 months adjusted for confounders. We see that kids with the highest
> mercury exposure actually weigh about 1 kilogram less than kids with
> the lowest exposure.
>
> \[Slide.
>
> The bottom line of all of this is how do we translate this to public
> health. I have already said that you can compare this to the age, the
> effect of age on development, and the result that we see is that for
> every time you double the mercury exposure, the child loses some
> months in its development.
>
> Ten percent of the standard deviation had this been an IQ, it would
> have been 1.5 points of IQ, so our results would translate to a loss
> of about 1.5 IQ points every time you double the exposure.
>
> Thank you very much.
>
> DR. MILLER: Thank you.
>
> Questions from the committee? Dr. Dwyer.
>
> **Questions of Clarification**
>
> DR. DWYER: I was wondering if there would be any effect of alcohol on
> absorption of methylmercury.
>
> DR. GRANDJEAN: The Faroes is a very traditional society where men
> drink, but women don\'t, and it is a very small percentage of women
> who have at all touched alcohol during pregnancy. The Faroes have the
> lowest alcohol use in I think all of European countries simply because
> it is more traditional.
>
> DR. RUSSELL: I wonder if you would clarify one thing for me. Is the
> level in codfish caught in the Faroe Islands likely to be the same as
> caught in Cape Cod, for example, or another geographical location?
>
> DR. GRANDJEAN: I don\'t know what the level is here, but in the
> Faroes, the mercury content of cod is about 0.1 ppm. Does that make
> sense?
>
> DR. RUSSELL: I guess what I am getting at is whether there is large
> geographical distribution, wide variation in mercury levels in a
> particular species of fish depending on the geography of where it is
> caught in the Atlantic or the Pacific.
>
> DR. GRANDJEAN: I am not an expert. All I can say is that the main
> source of exposure is pilot whale, which overlaps with swordfish and
> tilefish, et cetera, but the average is higher. It is about 2 ppm. The
> Faroese eat it both as chunks, as steaks, and they also eat it like
> pemmican, like little slices, and that exposure is sort of diluted
> because they eat a lot of fish at the same time, so they may have some
> peak exposures now and then, but then they also have a background from
> the pemmican and the fish.
>
> DR. LEE: I was wondering if you can give me a feel for how much the
> mercury in the hair comes from dietary versus environmental exposure.
>
> DR. GRANDJEAN: What do you mean when you say environmental?
>
> DR. LEE: Well, for example, polluted water or smoke. I mean if I am
> being exposed to mercury via polluted water, will it get into my hair?
> What kind of exposure can I expect from that?
>
> DR. GRANDJEAN: It is possible that the hair and also the blood may
> contain some inorganic. In the speciation that we have done, more than
> 90 percent is methylmercury, and not inorganic mercury.
>
> Methylmercury would, as far as I know, come from marine food or
> freshwater fish only. I am not aware of any other important sources
> except perhaps if there is some internal methylation of inorganic
> mercury, but I think it would be an extremely small contribution.
>
> DR. LEE: So, you are saying all the mercury that I would find in my
> hair would be from food sources?
>
> DR. GRANDJEAN: I would think so, but there is a possibility which has
> been seen in various instances that hair might absorb inorganic in
> particular mercury from outside sources.
>
> DR. FISCHER: Dr. Grandjean, tell me or tell us, knowing the exposure
> to PCBs of this population that we have studied, would you expect that
> the levels of PCBs would allow a contribution of those substances to
> the effects that you are attributing to methylmercury?
>
> DR. GRANDJEAN: It is a very good question and perhaps Dr. Jacobson
> might also contribute to this. The difference between the evidence
> that we have on PCB and the evidence we have on methylmercury is that
> the PCB studies that have been carried out in North Carolina, with the
> Great Lakes, and in the Netherlands, have not been adjusted for
> methylmercury, so we don\'t really know what the methylmercury
> contribution to the PCB associated or attributive effects might have
> been.
>
> In the Faroes at least, we have measured the PCB both in Cohort 1 and
> Cohort 2, and we have been able to adjust for PCB, and it is very hard
> to see what the PCB contribution is in these cohorts because the
> mercury effect is so strong, so we were not able to discern any clear
> PCB effect.
>
> It doesn\'t mean that PCB is not neurotoxic in the Faroes. It simply
> means that it is less neurotoxic than methylmercury at the levels that
> we have in that population.
>
> DR. FISCHER: And the method you use to adjust for the PCBs, would you
> explain that to us?
>
> DR. GRANDJEAN: We did regression analysis that have been published. We
> also have a paper in press where we used structural equation analysis,
> and the structural equation analysis indicates that even if we assume
> that our PCB measure is vastly imprecise, it never reaches a level of
> statistical significance of 0.05. It simply doesn\'t become
> significant, but mercury is.
>
> DR. DWYER: Have you ever looked at meconium in the fetus?
>
> DR. GRANDJEAN: No.
>
> DR. MILLER: Dr. Friedman.
>
> DR. FRIEDMAN: Is there a reason why you looked only at cognitive
> outcomes, cognitive/achievement outcomes, and not at social/emotional
> outcomes?
>
> DR. GRANDJEAN: We looked at the Child Behavior Checklist, but we had
> difficulty translating it into Faroese.
>
> DR. FRIEDMAN: What was that measure that was mentioned?
>
> DR. JACOBSON: Child Behavior Checklist.
>
> DR. FRIEDMAN: CGCL, okay.
>
> DR. GRANDJEAN: Which is the standard measure, and it is only currently
> being standardized into the language of Danish, and we tried to
> translate it and pilot it in Faroese, and the mothers simply had great
> difficulty answering these questions perhaps because of linguistic
> problems and perhaps because of cultural problems.
>
> This is a test that has been I think developed in New Hampshire?
>
> DR. JACOBSON: In Vermont, but it has been standardized in the
> Netherlands and many European countries.
>
> DR. GRANDJEAN: Anyway, we could not apply it. We tried and we failed,
> and it was, in our hands, a very unreliable instrument and therefore
> we did not dare to go ahead with this. I think you are right, that it
> is an aspect that should be looked into, but I think that one should
> not look at that aspect in the Faroes population without having
> something that is standardized, and we don\'t.
>
> DR. APOSHIAN: Dr. Grandjean, would you say something about the amount
> of selenium in the diet in the Faroe Islands, Seychelles Islands in
> New Zealand, please?
>
> DR. GRANDJEAN: We measured selenium in cord blood and the average
> concentration is I think about 30 or 40 percent higher than in the
> Danish population, clearly because the Faroes depend so heavily on
> seafood.
>
> We also looked at the mercury-selenium ratio as a predictor of these
> outcomes because both mercury and selenium were measured in cord
> blood, and the mercury-selenium ratio was not a better predictor than
> the mercury concentration as such.
>
> So, it looks like selenium deficiency does not explain the effects,
> nor does high intakes of selenium protect against mercury toxicity. We
> have done the same exercise in Cohort 2 with essential fatty acids
> especially docosa-hexaenoic acid, and DHA prolongs pregnancy and
> mercury has no effect on birth weight.
>
> It could be that the DHA intake protects against effects on birth
> weight by methylmercury, because we have been unable to see any
> effects. Likewise, we have not seen effects on visual-evoked
> potentials in the Faroes, perhaps because DHA protects the visual part
> of the brain.
>
> These are research issues. I can\'t make any conclusions, but it is
> speculation that some of these essential nutrients in seafood are
> perhaps modifying, however, only slightly the mercury toxicity that we
> see.
>
> DR. RUSSELL: I think in the Faroe Islands, the dietary fiber levels
> are fairly low because of a lack of a large amount of fruit and
> vegetables.
>
> Is there any evidence at all that dietary fiber alters the
> bioavailability? It does for other metals. I have no idea about
> mercury.
>
> DR. GRANDJEAN: I think the difference between methylmercury and other
> metals is that methylmercury is almost completely absorbed in the gut,
> and any interference due to dietary fibers would have a very small
> impact simply because of the lipophilic character of the methylmercury
> species. Whether it might affect the bacterial environment, so that it
> might affect the methylation or demethylation in the gut, I can\'t
> say, but I am not able to make any judgment. I would think, if
> anything, it would only have a minor effect.
>
> DR. KUZMINSKI: Dr. Grandjean, is there, in your data, any way of
> backing out the effects of the whale consumption and isolating only
> the fish consumption, because in the comparison of the Faroese
> consumption of fish and whale compared to U.S. consumption, that seems
> to come out as the one big difference?
>
> DR. GRANDJEAN: I think had the Faroese have exposure through drinking
> water, you would pose the same question. We look at methylmercury as
> the toxic species, and it doesn\'t matter from where it comes. I may
> be wrong, but sometimes a methylmercury concentration in the whale
> meat is like 0.5 or 0.8 ppm, which you would not consider high.
> Sometimes it is as much as 3 ppm, and people who eat the whale meat
> don\'t know. It is only after the methylmercury has been absorbed from
> fish or whole or shellfish, wherever it comes from, that we can detect
> it, and then we measure the blood or the hair or whatever.
>
> I would have sincere disagreements with you if you felt the
> methylmercury from whale meat would have any different effects from
> methylmercury from fish. It is the same species.
>
> DR. KUZMINSKI: Where I was headed, this is intuitively, was trying to
> ascertain an effect just due to fish consumption and not whale
> consumption. It is not the whale mercury being different from fish
> mercury, no.
>
> DR. GRANDJEAN: I don\'t think we can do it. I also don\'t think that I
> understand what the scientific basis would be, but even if one would
> do it, I don\'t think it is possible to do simply because people who
> eat a lot of whale meat also eat a lot of fish, so it is very
> difficult to sort out where it comes from.
>
> DR. RUSSELL: I have one final question on the diet. Can you give us
> some feel for the percentage of calories coming in as fat in the Faroe
> Islanders? In other words, is it more or less comparative to American
> fat intake or is it higher because of the blubber and the lack of
> fruit and vegetables?
>
> DR. GRANDJEAN: I think fat intake may be more relevant because of the
> lipophilic character of the methylmercury. People who would eat a lot
> of blubber might have a higher relative fat intake than people who eat
> less.
>
> The overall average in the Faroes has not been calculated. I would
> assume it is similar to scandinavian levels, which are similar to U.S.
>
> DR. McBRIDE: Do you have any information on birth weight? Fatter
> babies might store mercury and have an exposure after birth. Do you
> have any information on birth weight effects and their variables?
>
> DR. GRANDJEAN: Number one, the Faroese have one of the highest birth
> weights in the world, and our interpretation is that they have such a
> high intake of essential fatty acids from seafood, especially DHA, and
> we have also been able to show that the high the DHA intake, the
> longer the duration of pregnancy.
>
> I mean most of these women have a pregnancy duration of 40 weeks, some
> of them even 41, so it is an effect of prolonged gestation. When we
> tried to figure out if there is a mercury or a PCB effect, because
> this has been seen in some studies that these toxicants might affect
> birth weight, we don\'t see anything, but when we look at postnatal
> growth, we see that the prenatal mercury exposure affects the
> postnatal weight gain.
>
> DR. McBRIDE: But does birth weight affect the outcome on your
> psychological tests?
>
> DR. GRANDJEAN: It would have been if we had used kids who were also
> pre-term. All of these kids were normal full term.
>
> DR. McBRIDE: But I am not thinking of pre-term effects, I am really
> thinking of birth weight.
>
> DR. GRANDJEAN: No, birth weight does not have an effect. I mean all of
> these birth weights are above 2,500 grams, and we looked at it. It
> doesn\'t affect anything.
>
> DR. McBRIDE: So, I mean you looked at birth weight compared to
> outcome.
>
> DR. GRANDJEAN: Yes, birth weight was included with other risk factors
> like previous history of skull trauma, history of meningitis, neonatal
> jaundice. We looked at all these factors, and we didn\'t find an
> effect.
>
> DR. FRIEDMAN: There is no way in your study, which is a kind of a
> natural history study, to disassociate the prenatal effects from later
> effects, right? That is, the children continued to have high
> consumption of the same foods that their mothers had.
>
> Is there a way to know whether this could be reversible if the mothers
> had high consumption and then, after birth, it stopped, would the
> children look the same later on? This is all hypothetical, but I guess
> we are talking a lot here about prenatal effects, and I am not sure if
> those are really just prenatal effects of cumulative effects over
> time.
>
> DR. GRANDJEAN: There are two things here. After the child gets born,
> the mercury content in the child would drop way down, because the
> supply from the mother would cease except for those kids who get
> breast fed.
>
> We see at age 12 months that there is a very clear association between
> the hair mercury concentration of the child and the duration of breast
> feeding, so those who have been breast fed for a long time have more
> methylmercury in the hair because the mother continues to contribute.
>
> However, the hair mercury concentration at 12 months is only about 20
> percent of the average of the hair mercury concentration of the
> mother, so there is less mercury coming through human milk. We can
> still see it, but it\'s less.
>
> Now, after weaning, it is going to take some time before a child start
> eating whale meat. Usually, they will get other kinds of food before
> the mother will introduce fish or whale meat. At age 7, I don\'t
> remember the percentage of children who had started eating whale meat,
> but it was not a majority.
>
> So, it is only when you get up to age 14 that they are closer to
> eating the adult diet. We have two issues involved here, namely, one,
> we have a scale of mercury, potential mercury exposures, and then we
> also have a scale of susceptibility that we have to take into account.
>
> It is going to be very difficult to figure out how these two different
> factors play a role. The only thing we can do is to do multiple
> regression analysis and also structural equation analysis, and the
> cord blood measure is way, way, way strongest predictor of these
> outcomes.
>
> DR. MILLER: One more question and then we have got to move on.
>
> DR. APOSHIAN: Did the Faroe Island studies separate the effects of
> breast feeding and no breast feeding as far as the domain results were
> concerned? As a confounding factor, in other words.
>
> DR. GRANDJEAN: We did two things here. We looked at milestone
> achievement during the first year of life, and it is very clear that
> there is an advantage to being breast fed that overrides the possible
> adverse effects of getting methylmercury from breast milk.
>
> We have also looked at the outcomes at age 7, and there is an
> advantage associated with having been breast fed for a long time.
> There were very few mothers who didn\'t breast feed at all, so I can
> say is there is an association with the duration of breast feeding,
> and the duration of breast feeding is not associated at all with the
> exposure level, neither mercury nor PCB, there is no association here,
> so it is not really a confounder, but there is a small advantage that
> we can see.
>
> This is a paper which is going to be submitted very shortly, and I
> don\'t quite remember if there was a difference in the domains.
>
> DR. APOSHIAN: Along those same lines, and this may not be a fair
> question, maybe I should wait for Dr. Myers, is there a difference in
> the length of breast feeding of a child in the Seychelles Islands
> versus the Faroe Islands, do you know?
>
> DR. GRANDJEAN: All I can say is that kids in the Faroes are being
> breast fed much longer than kids in scandinavia. They do not live up
> to the World Health Organization recommendation, as nobody does, so
> breast feeding is the rule in the Faroes, and we see an advantage
> associated with it, and the duration is not associated with the
> exposure level.
>
> DR. MILLER: Thank you very much.
>
> I will take this opportunity, another member of the committee has
> shown up, Ms. Halloran from Consumers Union. Welcome.
>
> The next speaker is Dr. Gary Myers of the University of Rochester to
> talk about the Seychelles study.
>
> **Seychelles Study**
>
> **Dr. Gary Myers**
>
> DR. MYERS: Thank you very much for inviting us here to present our
> study.
>
> I would like to go through the Seychelles study with you and then
> answer whatever questions I can.
>
> \[Slide.
>
> This is the hypothesis that we have been addressing in the Seychelles
> study - whether or not prenatal exposure to methylmercury from
> maternal fish consumption during pregnancy can adversely affect
> children\'s developmental outcomes.
>
> \[Slide.
>
> This hypothesis actually came out of work that we did in Iraq, which
> was mentioned earlier. This is just one of the graphs from a
> publication that Dr. Cox was the first author in back in 1989, and
> this one looks at the frequency of retarded walking, and as was
> mentioned earlier, the endpoints in Iraq were somewhat less
> sophisticated that they were in our Seychelles study and as they have
> been in other studies since that time.
>
> Retarded walking was simply defined as walking before or after 18
> months of age. When one plots the abnormals versus the normals and
> does this hockey stick plot, if you will look at the top of the graph,
> there are all these little pluses, those are individual cases where
> the child had an abnormality of walking. Along the bottom, the pluses
> are all individual cases of where the child was normal in walking.
>
> As you can see, there are a couple of things that come out of the
> graph. The first is that if you project this lying downward, it looks
> like you might have effects down around 10 to 20 parts per million.
> These are concentrations in maternal hair, which is, in fact, the
> biomarker which has been used by every other study, studying this
> issue, and for reasons which I will try to address briefly in a
> moment.
>
> So, that is one thing. You see that down around 10 to 20 parts per
> million, one might expect to have some effects. The other thing that
> you see is that when you look at the top, there isn\'t any data or
> very little or very few points of data below about 50 parts per
> million.
>
> \[Slide.
>
> Following that, we actually proposed this hypothesis that these lower
> levels in fish might actually have some sort of adverse effect, and we
> looked at the literature and we came to some interesting conclusions.
>
> First, it seemed pretty clear that the fetal brain was much more
> sensitive than the postnatal brain to the effects of mercury.
>
> The second was that it looked like from the neuropathological studies
> and all of the other clinical things that had been done previously,
> and which have, in fact, been done since, that the effect really
> should be global. We couldn\'t see a reason why it would be domain
> specific from our review of the literature.
>
> We decided that if there were going to be any effects from the
> consumption of fish at these low exposures, they would probably be
> subtle effects. We wouldn\'t expect any of the major things that were
> seen at Minamata.
>
> Just an aside about Minamata, one of the interesting things about
> Minamata is there were either serious affected children or they were
> non-affected children. Nobody really described this spectrum of
> decreasing morbidity. Whether that was because it wasn\'t studied or
> because it didn\'t occur has never been clear, but it still hasn\'t
> been described from the Japanese experience.
>
> The other thing is that we thought that peer analysis was really an
> excellent way of looking at exposure and, in fact, we have
> subsequently looked at neuropathology in relationship to hair mercury
> concentrations, and they correlate better than fetal blood in our
> pathological specimens, and there is some evidence\--and Dr. Clarkson
> will be down in a day or two and perhaps speak more eloquently to
> this\--that the transport mechanism into hair for methylmercury is
> much more akin to what happens in mercury getting into the brain. Of
> course, the brain is the target organ that we are all worried about.
>
> The last thing is that actually, you ought to be able to detect these
> effects early on. After all, the Iraq study, the average age of the
> children studied in Iraq was 30 months, so waiting five or six years
> didn\'t really make sense to us.
>
> When Dr. Marsh talked me into going out to Seychelles and starting
> this study, he told me, he said if you don\'t find anything in six
> months, you probably won\'t find anything. It turned out that wasn\'t
> necessarily true.
>
> \[Slide.
>
> Anyway, we looked for a population that had large consumption of fish.
> We actually started several studies before we ended up in Seychelles,
> and there were a variety of reasons why the other studies didn\'t work
> out, but it is very difficult to set up these studies. Dr. Grandjean
> is fortunate to have the Faroes, and we are fortunate to have the
> Seychelles. There are many places in the world where these sorts of
> detailed studies simply can\'t be done.
>
> For those of you who are not familiar with the Seychelles, it is where
> the three red lines come together there.
>
> \[Slide.
>
> These are some of the characteristics of Seychelles, and I will be
> glad to elaborate on them later if anybody wants to ask, but they have
> a high fish consumption. Dr. Grandjean presented some evidence earlier
> that in Faroes, they have three fish meals a week.
>
> Well, when I started the study there to gather the main cohort, we
> asked a question how many fish meals do you eat a week, and they told
> us 12 was the average, so between 10 and 12 fish meals a week is the
> average in Seychelles.
>
> It has been a socialistic state for quite some time, for the last 30
> years. They have free universal health care. The infant mortality is
> lower than in the U.S. They have a 98 percent immunization rate, which
> is better than the U.S. You wouldn\'t want to get sick there, but
> actually, the preventive care is excellent. Free universal education.
> All the child start in the educational system at age 3 1/2, and it
> goes on from there up into the teenage years.
>
> They have really very limited poverty. There is a social structure,
> but it\'s very compressed. There is literally no malnutrition on the
> island, and they quite low levels of other sorts of contaminants.
>
> \[Slide.
>
> This is downtown Victoria, which is really the only major city on the
> island.
>
> \[Slide.
>
> This is just the fish market. People go the market every day and buy
> fish or they buy it on the roadsides or the beaches, but the people
> eat large quantities of quite fresh fish.
>
> \[Slide.
>
> We have looked at PCBs in Seychelles, and they are really below
> detectable limits. We have looked at lead, and lead levels are quite
> low. We haven\'t actually measured PCBs, but we are told that the
> levels of pesticide exposure are substantially below the FAO Codex
> Alimentarius reference levels for a problem.
>
> \[Slide.
>
> So, as best we can tell, the other sorts of exposures that one might
> be exposed to are very low levels.
>
> Let\'s go back to that slide a second.
>
> We measured prenatal exposure in maternal hair. This gives you really
> a very excellent index of exposure for the whole pregnancy as opposed
> to just the final trimester. We have not measured cord blood in
> Seychelles. The exposure averaged about 7 parts per million and ranged
> from below 1 part per million up to about 27 parts per million.
>
> \[Slide.
>
> This gives you some idea. We adopted a longitudinal design to the
> study which I will show you in a moment, but this gives you some idea
> of the numbers of children that have been seen at each one of these
> ages, so we have actually examined these children on five occasions
> now.
>
> We have been able to maintain quite a substantial number of the
> cohort. It is a small island, there is not a great deal of the
> population that emigrates, and it is easy to find them.
>
> We have excluded individuals for various reasons. Among the 39, the
> major reason for exclusion was that we really couldn\'t recapitulate
> their mercury exposure. When we looked at the hair samples that we
> had, we simply couldn\'t recapitulate their exposure, but we have also
> removed from the cohort, a few individuals who had perinatal seizures,
> intraventricular hemorrhage, substantial head trauma, and other things
> that are known to be highly correlated with abnormal children\'s
> development.
>
> \[Slide.
>
> We looked at a variety of covariates in our population. We have looked
> at socioeconomic status, IQ. We have been to every one of the homes in
> Seychelles and assessed their home environment with the Caldwell
> Bradley assessment of the home.
>
> We have looked at maternal smoking and alcohol. They are extremely low
> in Seychelles. We have looked at the medical history of the mothers,
> and we have also looked carefully at the language spoken in the home.
> About 98 percent of the people there speak Creole, so the vast
> majority of them actually have Creole.
>
> \[Slide.
>
> This is simply one of our testing rooms and one of our testers
> administering the KBIT for maternal intelligence.
>
> \[Slide.
>
> This is a typical home in Seychelles. The two women on the left are
> the nurses who were in the home doing the home environment, the HOME
> Scale.
>
> \[Slide.
>
> We have looked at a number of covariates that affect the children. We
> have looked at gender obviously, because that is a significant thing.
> We have looked at hearing in the children. We have looked at their
> health history, their birth weight, gestational age, birth order,
> length of breast feeding, and a variety of other things.
>
> \[Slide.
>
> This is the design of the study. We started the main cohort. We did
> have a pilot cohort, as Dr. Jacobson mentioned earlier. The pilot
> cohort was done originally by myself before we started the main
> cohort, and then I went to Seychelles and lived there for a year to
> enroll the children at the six-month evaluation, so I did all of the
> Denvers and Fagans and neurological examinations at that point in
> time.
>
> Subsequently, we have used a battery of Seychelles professionals who
> have done the testing for us. We have now examined the children, over
> 700 children at each one of these five points, and the list of test is
> shown there.
>
> I did put down in the corner there, there has been a double-blind
> study just to remind myself to mention to you that from the beginning,
> we have never shared mercury levels with anyone in Seychelles, nor
> with any of the investigators who are clinically looking at the data.
> So, it has been double-blind from day one, which goes back to about
> 1987. The Seychelles have been very cooperative with that.
>
> They have reviewed all of the data that we have published and made
> their own decisions about their choices in terms of regulation.
>
> \[Slide.
>
> We have felt that the most important thing is not so much the tester,
> although we have used professionals, but doing reliability on the
> testers to be sure that, in fact, they are reliable. So, we have used
> two types of reliability.
>
> First, we have used what we call the gold standard. The gold standard
> is one of our psychologists from Rochester, a Ph.D. psychologist, who
> goes to Seychelles, sits down with the tester, and actually scores the
> test while the tester is administering the test.
>
> Then, we have used interscore reliability, which is each week we have
> two of our testers score the same child independently, and we have
> compared them. We have looked carefully at those statistics, and they
> have had very high correlation.
>
> \[Slide.
>
> This is Dr. Davidson here on the right, one of our nurses, is simply
> doing a gold standard.
>
> \[Slide.
>
> When we looked at our results during infancy, this is what we found.
> We did find the expected effects of covariates - maternal
> intelligence, birth weight, and other things. We had most r-squareds
> for our study. This is consistent with what has been found in most
> developmental studies.
>
> We did not find any adverse associations between the prenatal exposure
> and any of our endpoints at 6, 19, and 29 months. We did one
> association between an item from the infant behavior record and
> methylmercury, and at 29 months, on the infant behavior record, there
> was a decrease in the examiner\'s scoring of the activity level, and
> it was present only in boys.
>
> We have been confused as to how to interpret that. It is a very
> subjective endpoint, the infant behavior record, and we are not sure
> whether it is better for boys to be less active or more active.
>
> \[Slide.
>
> We like data. We like to see the points and share them with people,
> and let them know what, in fact, the data looks like. This is the
> visual recognition memory on the top and the visual attention on the
> bottom. This is data from the Fagan test, which is I am told by
> psychologists felt to be one of the premier tests for intelligence at
> these early ages.
>
> This is at the 6-month examination, and there was no association with
> mercury within the range we have been studying.
>
> \[Slide.
>
> This is data from the 29-month examination. This is the metal
> developmental index from the Bailey, at 19 months on the top and at 29
> months on the bottom, and that is on the left. On the right is this
> infant behavior record. You can see that in girls, the slope is flat,
> and in boys, it tails off as one goes to higher mercury levels. That
> is the association that we are not sure whether it is a beneficial or
> adverse association.
>
> \[Slide.
>
> When we get up into early childhood, again, we find the effects that
> we would expect from a variety of different covariates. Again, most
> r-squareds. Again, no association between exposure and the endpoint.
> We did find one beneficial association
>
> \[Slide.
>
> This is the McCarthy GCI adjusted for covariates, and these are
> partial residual plots. Again, we like data. This is the 66th month
> examination all plotted against prenatal methylmercury exposure, and
> there is no significance there.
>
> \[Slide.
>
> This is the PLS language score adjusted for covariates at 66 months.
> There is an association, but it seems to be a positive association
> here, we are not sure what to make of that, but no adverse
> association.
>
> \[Slide.
>
> This is the Woodcock-Johnson applied problems, which is the
> mathematical part of it. Again, no association at 66 months.
>
> \[Slide.
>
> This is the Bender. What you see here is that this is the errors on
> the Bender test. What you see is that males are flat and in females,
> there is a slight downward slope meaning fewer errors. This is one of
> the ones where when it goes down, there are fewer errors, so that is a
> beneficial effect.
>
> \[Slide.
>
> At 107 months, we examined the children again. This is the nine year
> evaluation, which we are in the process of publishing. Again, we
> looked at socioeconomic status, maternal IQ, age, family status,
> health history, and the home environment.
>
> \[Slide.
>
> For the child, we did use postnatal methylmercury, age of testing,
> gender, hearing level, and examiner. We have included examiner in
> these analyses, as well.
>
> \[Slide.
>
> This is just one of the tests. I just have a couple pictures of the
> tests. This is finger tapping. It is how many taps you do in a certain
> period of time.
>
> \[Slide.
>
> This is a grooved pegboard using either preferred or non-preferred,
> and these are little pegs that have a little notch in them, and you
> have to fit them into holes. It is how quickly one can do the test.
>
> \[Slide.
>
> This is a picture completion. It is just a series of pictures, and you
> have to put them together in a story from the WISC.
>
> \[Slide.
>
> This is from the Woodcock-Johnson test.
>
> DR. MILLER: Dr. Myers, you have five more minutes.
>
> DR. MYERS: Okay.
>
> \[Slide.
>
> When we looked at the results from the 107th month evaluation, again,
> we found the expected associations with covariates. Again, modest
> R-squareds. Out of the 21 endpoints that we examined, we found 1
> adverse association and 1 beneficial association.
>
> \[Slide.
>
> This is the Connors Teacher Rating Scale, the hyperactivity index from
> it. We had every teacher of all of our main cohort children evaluate
> the children on this scale, and the line goes down, which is a
> beneficial effect.
>
> \[Slide.
>
> This is our adverse effect here. This is the grooved pegboard, and it
> is of the children using their non-preferred hand, and what you see is
> that in females, the slope is essentially negative, it is not
> significant, or flat and nonsignificant.
>
> In males, one sees that there is a slight upward slope here, and that
> means that it takes them longer to do the grooved pegboard, so that
> would be an adverse effect.
>
> So, out of 21 endpoints, there is 1 adverse effect we found at 9 years
> of age.
>
> \[Slide.
>
> This is just a graph to show you the effect of covariates on the
> various tests here. We found a lot of associations with covariates, so
> we have every confidence that the tests are working there. They are
> picking up other things that we know affect child development.
>
> \[Slide.
>
> So, our outcome so far is that we found a lot of associations between
> predictors and between covariates of the endpoints at every age. We
> have not found an association with mercury exposure from the fish
> consumption.
>
> I didn\'t mention, but the people in Seychelles do not eat whales at
> all, they don\'t eat sea mammals, it is purely fish consumption. All
> of these associations were in the direction that one expects. We have
> only found one adverse association in our five evaluations.
>
> That raises the question of how do you interpret it. Well, it is good
> to remember that we were the group that originally raised the issue
> from Iraq and proposed the hypothesis, so we like to think that, you
> know, our studies have become more sophisticated since that time
> rather than that we have lost our ability scientifically.
>
> So, we look at other interpretations. One interpretation may be that
> the exposure level is simply below the toxic threshold. Another
> possibility, though, that we are currently exploring in Seychelles is
> that there is neurotoxicity, but somehow it is modified at these
> levels. Either there is something beneficial about fish that overcomes
> whatever the toxic effect is, or maybe there is something else in fish
> that is mitigating that, either fatty acids or selenium or something
> else.
>
> We are looking currently at a new cohort that is being studied very
> carefully from the time the women are first pregnant, looking at these
> nutritional factors. The other possibility is that perhaps there is
> toxicity, but it simply doesn\'t occur until much later in life.
>
> \[Slide.
>
> We like to think that the Seychelles is a bit of a sentinel population
> for the U.S. One reason is that the source of exposure is about the
> same as what we have here in the U.S. It is really open ocean fish.
>
> The second reason is that we have looked carefully at the mercury
> content of the fish in Seychelles, and it is very similar to what is
> on the market here in the U.S., but, in fact, the women\'s hair levels
> are between 10 and 20 times those of the U.S. levels.
>
> So, we like to think that perhaps Seychelles could serve as a sentinel
> population for the U.S.
>
> I would be happy to answer questions.
>
> DR. MILLER: Thank you.
>
> Comments, questions from the committee? Dr. Friedman.
>
> **Questions of Clarification**
>
> DR. FRIEDMAN: Dr. Myers, I was wondering whether\--I am sure you
> looked, but only didn\'t present\--at interactions. Do children of
> poor quality home environments show different outcomes relative to the
> effects of\--
>
> DR. MYERS: We have included socioeconomic status in all of our
> analyses.
>
> DR. FRIEDMAN: You controlled for everything.
>
> DR. MYERS: Yes.
>
> DR. FRIEDMAN: But I am asking whether if you took out the control of
> the HOME, for example, and then looked at the children who are high on
> the HOME versus low on the HOME, would you find the same relationship
> holding in the two extreme groups.
>
> DR. MYERS: We have looked at social effects, and there are some. I am
> not very good at this. Dr. Cox, who is in the audience, may recall the
> social effects better than I.
>
> Chris, the question has to do with the social effects on the outcomes.
>
> DR. FRIEDMAN: The interaction.
>
> DR. COX: I will do my best. As I heard it, the term was interaction,
> so the way I would interpret that is to ask whether the effects of
> mercury are modified by levels of other variables, for example,
> socioeconomic status.
>
> Is that the question?
>
> DR. FRIEDMAN: I guess so. Let me try to phrase it. I realize there are
> many things that operate to produce the outcomes that we see on
> psychological testing, and what we are trying to do with statistical
> analysis is to clean out the effects of variables that we are not
> interested in and ask if this was an experimental design, would
> mercury have an effect, but as I said before, we realize different
> things work together, and it may be that a high-quality family
> environment and high-quality out of home environment actually work
> against the ill effects of mercury.
>
> DR. COX: That is modify the effect.
>
> DR. FRIEDMAN: Right.
>
> DR. COX: So, we are both saying the same thing. Do levels of whatever
> factor you might want to look at change or modify the association
> between mercury and outcome, right?
>
> That is I think what is usually meant by the term \"interaction.\"
> Because of results in a study done in Canada, we felt there was some
> evidence for an interaction between gender and mercury, and that
> interaction was included in all the models that we looked at, and you
> saw an example of that here.
>
> Dr. Davidson, who unfortunately couldn\'t be here today, was also
> interested in interactions between mercury and other variables -
> socioeconomic factors, maternal age, what have you. One problem was
> looking at such interactions, there is a very long list, and one can
> look at a great many interactions, and it is difficult. You have to be
> careful, we all have to keep our hats on.
>
> I am a statistician, I am not a toxicologist, I am not a developmental
> psychologist, but my sense is that it is difficult to know what
> interactions one ought to look at.
>
> We have, however, done, to get to the answer to your question, we have
> done and published some analyses looking at interaction effects. I can
> give you a reference to a paper if you are interested.
>
> I didn\'t know that that question would come up, so I can\'t summarize
> the results very well for you, but my own view is we didn\'t find
> anything that was very consistent, but we did find some evidence for
> differential effects. It is hard for me to know what it means.
>
> I think that kind of question is very difficult. There has been some
> work done in the lead literature, as well, looking for interaction
> effects. It is tough. So, I don\'t think, besides gender, I don\'t
> think we have any very consistent evidence for modification of mercury
> effects by other variables that would be from the Seychelles study.
>
> DR. FRIEDMAN: Thank you.
>
> DR. MILLER: Dr. Nordgren.
>
> DR. NORDGREN: This may be unrelated, but a recent area of controversy
> is the subject of autism, and I was going to ask also Dr. Grandjean,
> did you find any increased level of autism on the Seychelles or in
> your cohorts?
>
> DR. MYERS: Well, the answer is no, but I qualify it by saying we have
> not done tests for autism. In fact, we are in the process now of
> putting together a proposal to do that very study with detailed tests
> looking for autism in Seychelles to see if there is an increased
> incidence.
>
> Just from our casual experience, we have not recognized it, if there
> is, but that doesn\'t mean that it is not there.
>
> MS. HALLORAN: Do you have information on the types of fish that were
> commonly eaten and what the mercury levels were, the range commonly
> seen in those species, and whether there is any season variation? I am
> trying to get at whether there might have been peak exposures or it\'s
> a very constant exposure.
>
> DR. MYERS: We have looked at hair analyses longitudinally, and there
> are season variations, but they are not like what we saw in Iraq. They
> are down in the low range, and if they go up 30 percent, they go from
> 6 to 7 or 8 or 9, so it is within a very narrow range basically even
> though there are seasonal differences that we have seen.
>
> We have quite a bit of information about the mercury content of fish
> in Seychelles. The majority of the fish eaten, probably the commonest
> species is the species called Karong, and the mercury concentrations
> in it are below a half part per million, down around 0.3.
>
> They eat a lot of reef fish, and the reef fish, some of those are some
> of the lowest concentrations that we have ever recorded in fish.
>
> DR. MILLER: Can we let Dr. Dwyer ask a question?
>
> DR. DWYER: Thank you. Just two perhaps silly ones. One is do you have
> any information on fetal wastage, and secondly, were there other
> prespecified interactions that you looked at.
>
> DR. MYERS: As far as fetal wastage, we don\'t really have any
> information on fetal wastage, so I can\'t really provide anything on
> that. We have thought about looking at it, but we have not done it
> yet.
>
> As far as other interactions, the only interaction that we have
> consistently had in our analyses is that for gender. I think that is
> correct, isn\'t it, Chris?
>
> DR. COX: Yes.
>
> DR. APOSHIAN: Dr. Myers, as I remember from the Raleigh White House
> Conference and from the NIEHS, the recommendation was made that both
> groups standardize the neurobehavior tests or neuropsychological tests
> being used.
>
> The 107-month study that you say is in press or is about to be
> written, either one, does that have the same tests that were done in
> the Faroe Islands? I wasn\'t quite certain about your abbreviations.
> For example, the Boston Naming Test, was that done?
>
> DR. MYERS: Actually, the tests are almost identical. The Faroes were
> good enough to share their test battery with us, and we looked at the
> tests and decided what to do, and there is a great deal of overlap in
> the testing.
>
> DR. APOSHIAN: The second question I wanted to ask was everyone, of
> course, is concerned about the difference between the Faroe Islands
> and Seychelles Islands. Nowhere have I seen anything take into
> consideration racial, genetic makeups. For example, for
> N-acetyltransferase, as I am certain you know, but let me just say for
> the others, that the American population is quite different from the
> Chinese mainland population, which is also different from the Egyptian
> population.
>
> Has any attempt been made to do genetic markings or genetic marker
> tests to see whether the differences between the Faroe Islands and the
> Seychelles Islands studies on methylmercury are due to difference in
> genetic makeup?
>
> DR. MYERS: I don\'t know whether that has been done in the Faroes. We
> have not done it in Seychelles. As part of our current study, studying
> the nutritional components, we are measuring some DNA things, but not
> a wide range of them.
>
> I think there are a lot of differences between the Faroes and the
> Seychelles. One is in cold water, one is in warm water, one is
> predominantly scandinavian, one is predominantly African in origin.
> Their diets are vastly different really. The exposure is different.
> There are a whole series of things that differentiate the two
> populations in my mind.
>
> DR. MILLER: Dr. Lee.
>
> DR. LEE: Dr. Myers, your last slide indicated that we are eating some
> of the same seafoods here in the United States, yet, the maternal hair
> there is about 10 to 20 times the mercury than U.S. samples.
>
> Do you attribute all of that 10- to 20-fold difference to diet?
>
> DR. MYERS: As far as we can tell, it is dietary, yes. They literally
> eat fish twice a day in Seychelles. Even given a choice, they love
> fish.
>
> DR. LEE: So, that is corroborated by your direct measurements of the
> mercury in the diet?
>
> DR. MYERS: No, that is not corroborated by mercury measurements in the
> diet. We are currently doing that in a new cohort. The main cohort
> that I have just been talking about, this was examined longitudinally
> five times over nine years. That cohort was enrolled at six months of
> age, so we did not do things prospectively in that cohort.
>
> We had prenatal exposure because we had been collecting hair at
> antenatal clinics for a long time, so we had quite a bit of prenatal
> exposure data on all of these women, but we didn\'t have other things.
> We didn\'t measure nutritional factors during pregnancy, which we are
> doing with this cohort.
>
> DR. MILLER: Dr. Fischer.
>
> DR. FISCHER: Looking for differences between the two studies, have you
> looked at the differences in preparation of the fish in each case? I
> have no idea how the whale meat is eaten, for example. Anyway, the
> possibility exists that there could be something there.
>
> DR. MYERS: My only experience with whale was when I attended a
> conference there, and they eat it, like Dr. Grandjean said, as
> pemmican, you know, just a chunk of blubber and you put it in your
> mouth, and I think it is an acquired taste myself.
>
> \[Laughter.\]
>
> DR. MYERS: As far as food preparation in Seychelles, you know, they
> are eating fish twice a day, they are eating a great variety of fish,
> and really it is prepared in multiple different ways, and we are
> actually looking at preparation and other things for fish at the
> current time, but in the main cohort, we did not do that.
>
> DR. MILLER: Just the one question. Hopefully, as the Chair, maybe I
> could ask the last question before getting on.
>
> Why don\'t you ask your question and then I will hopefully get to my
> naive one.
>
> DR. ACHOLONU: The last speaker, Dr. Grandjean, made reference to the
> fact that the concentration of methylmercury drops after a child is
> born, and you have said that the toxicity of methylmercury may show
> later in life.
>
> What I would like to know is, is the concentration cumulative in the
> person, the concentration of methylmercury, is it cumulative in the
> person?
>
> DR. MYERS: Well, there is a half-life to it, and there is excretion,
> but it is slow excretion. We, as in the Faroes, have measured hair
> levels in the children, and they are generally fairly low until the
> children get older.
>
> It is excreted some in breast milk. Chris, do you want to answer that?
>
> DR. COX: Well, I think Dr. Clarkson will be here, you could ask him,
> but I believe the half-time is 50 days.
>
> DR. MYERS: That was mentioned earlier, that is correct, 45 to 50 days.
>
> DR. MILLER: Just one question that kind of puzzles me. Given actually
> in both populations, but given in the Seychelles that you have a
> population that is compressed socially, I think you said, that this is
> a relatively isolated community, at least in terms of its dietary
> sources, what explains the 27 times variation that you found I think
> in your hair?
>
> DR. MYERS: That\'s a good question. I am not sure we have an answer.
> We have assumed that it is dietary and related to the species of fish
> that is being eaten and favorite. People have different favorites, and
> there are fish that have higher concentrations. Mackerel and bekin,
> which is\--I have forgotten the name\--barracuda, barracuda, shark do
> have higher concentrations.
>
> So, if you eat enough of the higher concentration fish, that could
> explain everything, but we have not studied it specifically.
>
> DR. MILLER: Thank you very much.
>
> We are going to call a break now, 10 minutes, please, and be back
> about 10:15.
>
> \[Break.\]
>
> DR. MILLER: The next speaker is Dr. Christopher DeRosa from Centers
> for Disease Control to talk about the recommendations from the Agency
> for Toxic Substances and Disease Registry.
>
> **Agency for Toxic Substances and Disease Registry**
>
> **Dr. Christopher DeRosa**
>
> DR. DeROSA: I would like to thank FDA for the opportunity to share
> with you some of our Agency\'s perspectives regarding the Agency\'s
> views on mercury and related compounds. I would also like to
> acknowledge my colleagues John Risher and Dennis Jones, who assisted
> me in preparing some of the materials for today\'s meeting.
>
> Today, what I would like to do is provide you a brief background of
> our agency. We are affiliated with the Centers for Disease Control,
> but we are actually one of eight independent agencies of the U.S.
> Public Health Service within the Department of Health and Human
> Services, and we are the primary health agency or the primary federal
> agency dealing with the implementation of the health mandates of
> Superfund.
>
> It is not totally incorrect to affiliate me with CDC because our
> administrator is also the director of CDC, as was currently announced,
> Dr. Julie Gerberding.
>
> I would also like to provide a chronology of some of our key
> activities over the years, talk about the rationale for the position
> we took in our toxicological profile, a document that we published in
> 1999, an update of two previous toxicological profiles, and then some
> insight as to our future activities and some current ongoing
> activities that may have a bearing as this dialogue at this meeting
> will have as we go forward with a reassessment of methylmercury, as
> well as other forms of mercury.
>
> \[Slide.
>
> Among the health mandates that we have under the Superfund or CERCLA
> legislation are to prepare toxicological profiles. These are documents
> that appear and publicly reviewed, articulating what we know in the
> broad areas of exposure, toxicity, and epidemiology.
>
> They attempt to provide health guidance for methylmercury, as well as
> other compounds that identify what the adverse effects are that we
> need to be concerned about and at what level those effects might be a
> concern.
>
> These are based on a list of priority pollutants that we prepare in
> conjunction with our colleagues at EPA on a biannual basis. It lists
> in priority order the 275 substances most frequently encountered at
> waste sites, on controlled hazardous waste sites, based on the
> probability of human exposure, toxicity, and frequency of occurrence
> at those sites.
>
> So, we have prepared 250 profiles addressing some 1,000 chemicals, and
> they are inclusive of mercury, which is No. 3 on our priority list of
> 275 chemicals.
>
> We also are mandated to initiate a research program, an applied
> research program to address what we don\'t know. I think it is
> important that the profiles, in addition to setting forth what we do
> know, also address what we don\'t know, which is sometimes a
> challenging effort in terms of identifying mechanisms to fill those
> data gaps, but we have identified 200 priority data needs, and they
> are currently addressing those in cooperation with our colleagues at
> EPA, NIEHS, and through some grants mechanisms, as well.
>
> Once a site becomes listed on what is referred to by EPA as an NPL or
> National Priorities List site, we are required by law to prepare a
> public health assessment on the health hazards associated with that
> site.
>
> This is based on four general avenues of information - health outcome
> data that the community might provide, what the community concerns
> are, environmental monitoring data provided by EPA, as well as the
> information contained in our toxicological profiles prepared on those
> substances that might be encountered at a given site.
>
> Finally, we are required to update those profiles at intervals not to
> exceed three years. Our first profile on mercury was released in 1989,
> and we have had subsequent updates on two occasions since then.
>
> \[Slide.
>
> This slide is really some of what we knew and when we knew it in terms
> of the documentation regarding mercury. I mentioned the first profile
> in 1989. In 1993, we updated that profile using the Iraqi study to
> develop the chronic MRL of 1 microgram per kilogram per day, similar
> to EPA\'s current value.
>
> We had convened an expert panel to discuss a benchmark dose approach
> for methylmercury, but we are advised that the Iraqi study at that
> time had been somewhat overextended and overinterpreted and that it
> would be better that we wait for the outcome of the information coming
> out of the Seychelles.
>
> We convened a second expert panel in \'95 to address the issue of
> bioavailability. This is working intermittently, which is worse than
> not at all, and then we began consideration of the update of our
> profile from \'93 based on the publication in 1995 of some of the data
> coming out of the Seychelles.
>
> So, we initiated the update in \'97, and the next slide is a
> continuation of that.
>
> \[Slide.
>
> We involved in that process an extensive peer review process including
> an expert panel review of the post-public comments that we had on the
> draft that was released for public comment. We had representatives of
> EPA and other federal agencies, but importantly, from the Faroes and
> the Seychelles there to further vet some of the data that they had
> developed to date.
>
> I am sure there is an activation point on this one, too, but I can\'t
> quite see it, but at any rate, the point being that one of the things
> that we were strongly reliant on was this workshop that was
> referenced. It was a workshop initiated by the President\'s Office of
> Science and Technology Policy.
>
> It was one which brought together four expert panels in some broad
> disciplinary areas to really dig into the critical data sets, not only
> in the Seychelles and Faroes, but some of the work that Donna Mergler
> \[ph\] in Canada had done, as well as others.
>
> So, we followed that very closely and we used that as a key basis for
> some of the decisions we made in releasing the mercury profile to the
> public. I would like to just mention for a second that our mandate is
> one of getting information in the hands of citizens, so that they can
> make informed decisions about their health.
>
> In addition to methylmercury, elemental mercury is an issue from the
> standpoint of emergency response, which we also have responsibility
> for under the National Contingency Plan. It is the number one agent
> that is involved in emergency responses at our agency.
>
> We also have concerns about the salts of mercury, also
> dimethylmercury, which was responsible for the unfortunate death of a
> researcher at Dartmouth because it is used as a calibrating agent in
> some instrumentation.
>
> More recently, since the publication of the profile, the question of
> the safety of vaccines has come into play based on the use of
> thimerosol ethylmercury as a preservative in batch vaccines, and then
> finally, more recently, we have become very concerned about the use
> and misuse of chelation therapy by a number of individuals who are
> profiting at the expense of both physiologically and financially of
> the people they are treating in some instances.
>
> The next slide really talks a little bit about what you have already
> heard, and I am not going to spend a lot of time on this because it
> has already been discussed at length.
>
> \[Slide.
>
> I would say that two key issues with respect to the Seychelles that
> have been cited is this issue of lack of an effect although we now
> have seen that there are effects. The reason that lack of an effect
> may be of concern to some is that it may suggest that your protocol
> was not vigorous enough to detect what you were looking for, there may
> be some other issue that you need to be concerned about, but they
> have, in fact, demonstrated some enhanced performance on some of the
> tests and, as we just saw, one report of an adverse effect in addition
> to the one at 29 months in the boys.
>
> Then, the missing domain-specific endpoints that had not yet been
> assessed at 66 months was something that we took into consideration in
> our treatment of uncertainty, and we relied in part on the Faroes data
> to help us deal with that.
>
> In terms of the Faroe Island, another excellent study, we have the
> benefit of two very fine epidemiologic studies. There is the issue of
> the type of and duration of exposure. By that, I mean the whale
> blubber being consumed perhaps once to twice a month at relatively
> high levels, 3 parts per million as opposed to 0.3 parts per million,
> which is characteristic of fish sold commercially in this country.
>
> Then, the concurrent exposure to PCBs and other persistent organic
> pollutants. PCBs are at levels 10 times higher than in the U.S.
> population in the Faroes, and at three times the level of FDA\'s
> tolerable daily intake.
>
> Other persistent organic pollutants are also a concern because PCBs
> are generally considered to be a marker for other POPs. For example,
> DDT is present at a level, in terms of exposure, five times our health
> guidance value for that compound.
>
> This has already been referenced in terms of the work of Todd Kelstrom
> \[ph\] and his colleagues done in New Zealand, and the sensitivity to
> outliers. The initial report, the initial analysis was not significant
> until one of the most highly exposed individuals, who showed no
> adverse effects or associations, was deleted, and then we did see the
> association in some areas become positive. So, that is just the issue
> of the sensitivity to one outlier, and the question is, is the outlier
> relevant statistically, is it relevant biologically, and I think as
> geneticist Dijanski \[ph\] said many years ago, \"Treasure your
> outliers or your exceptions.\" That is a significant issue.
>
> \[Slide.
>
> Now, going ahead to the workshop held in \'98 in North Carolina, you
> can see a very distinguished panel dealing with the confounders and
> variables issue including Dr. Jacobson, who is here with us today.
>
> I would like to share with you just some of the findings that we have
> really centered on as we went forward in trying to bring our document
> to closure, because I think it illustrates some of the deliberative
> process and some of the key concerns that we had as we attempted to
> deal with this issue.
>
> \[Slide.
>
> This is the first of one of the findings dealing with PCBs. When PCBs
> and mercury are included together in the model that was used to
> analyze the outcomes, one of the outcomes is specifically related to
> mercury exposure, one of the four that had been reported as positive.
> For the other three, which included the Boston Naming Test, both PCB
> and mercury effects fall show of conventional levels of statistical
> significance. So, I think that that is a key finding that we focused
> on.
>
> \[Slide.
>
> Again dealing with this issue of PCBs is that it is likely that both
> of these contaminants adversely affect these three outcomes, but the
> relative contributions cannot be determined given their co-occurrence
> in the population.
>
> \[Slide.
>
> Finally, regarding the concurrent PCB exposure, the Statistics and
> Design Expert Panel determined that the best method to deal with this
> would be to study a population where exposure to PCBs is not an issue.
>
> \[Slide.
>
> This is simply a listing of those individuals who served on that, and
> these people have published extensively in this field and are
> recognized obviously as experts in the field.
>
> \[Slide.
>
> Turning now to a little bit about the health guidance value, well, let
> me just back up and talk about why we use the Seychelles cohort as the
> primary study, but we also relied heavily on the Faroes study, as
> well.
>
> With the exception of two things, these issues, these attributes are
> all linked to both the Faroes study, as well as the Seychelles study.
> The two that I would like to bring out, that I think relate
> specifically to the Seychelles, is the issue of the pattern of
> exposure and the levels of exposure over time.
>
> Obviously, there are 10 to 20 times higher levels in the Seychelles,
> but it is not because the fish is more contaminated, it is because
> they eat more fish. They have the highest per capita consumption of
> fish in the world.
>
> Then, the issue of confounding factors, we felt that there were fewer
> personal and lifestyle confounding factors, that it is a relatively
> pristine environment, and those levels of some of the other
> contaminants of concern were shared by Dr. Myers. As he also pointed
> out, there is basic health and education infrastructure that is really
> quite remarkable in my mind, having had the opportunity to visit and
> observe some of the activities of the researchers there, and then
> again this issue of confounding for a number of other factors.
>
> \[Slide.
>
> Turning to the issue of health guidance, there are a number of
> different terms used for health guidance factors. They are very much
> analogous in the way that these different terms are derived. Our
> agency uses the term \"minimal risk level,\" which is analogous to the
> reference dose, the tolerable daily intake, and previously referred to
> as the \"acceptable daily intake.\"
>
> So, it is an estimate of exposure that is thought to be without
> significant risk of an adverse health outcome over a given route and
> duration of exposure in addition to deriving chronic oral exposures,
> chronic inhalation exposure guidance values, we also deal with acute,
> defined as less than 14 days, and intermediate, 15 days to a year in
> our documents.
>
> \[Slide.
>
> This is the generic formula that we used to derive a minimal risk
> level. If it is not visible, it is probably because there is a rule
> that you have to have at least one slide that no one can see when you
> present. This probably is not the only one, but at any rate, the MRL
> is simply derived operationally in a very straightforward way,
> analogous to the reference dose.
>
> You identify a toxicity benchmark, a no observed adverse effect level,
> or a low observed adverse effect level, or a benchmark dose, as was
> mentioned earlier, divided by an uncertainty factor whose magnitude is
> inversely related to our confidence in the database. The larger the
> uncertainty factor, the less our confidence in the database.
>
> DR. MILLER: Dr. DeRosa, you have 5 minutes more.
>
> DR. DeROSA: Thanks.
>
> \[Slide.
>
> In the derivation of the MRL, the issue is that you have mercury
> ingested by the mothers, the offspring of the group of concern. Hair
> mercury levels are measured in the mothers, and you have to have
> hair-to-blood ratio in order to calculate a daily intake based on the
> blood concentration.
>
> Fortunately, we have some very good human data to provide this ratio.
> The point of central tendencies of about 14 studies is about 250 to 1.
>
> \[Slide.
>
> This just shows you some of the calculus that goes into identifying
> what the dietary intake is. It is related to this issue of the
> fraction of the daily intake that is actually taken up by the blood,
> which is defined by what is absorbed, and then what portion of what is
> absorbed actually makes its way into the bloodstream. It also is
> related to the blood volume, which is about 7 percent. That is about
> standard, about the second trimester of pregnancy.
>
> This is what we have the concentration in the blood is based on what
> we see in the hair and the ratio that I just mentioned.
>
> \[Slide.
>
> This just lays out the mathematics of this and the concentration in
> the blood that equates to dietary intake in milligrams per kilogram
> per day was divided by an uncertainty factor of 4.5, providing us with
> an MRL of 3 micrograms or 0.003 milligram per kilogram per day.
>
> \[Slide.
>
> Some people say that I posed for this, but I did not pose for this
> slide. How certain are we about what we know?
>
> \[Slide.
>
> This attempts to lay out\--this may be one of those other illegible
> slides\--the standard factors of 10 that are typically used in
> deriving an MRL, 1 to 10 for human variability, 1 to 10 for animal to
> human extrapolation, 1 to 10 for extrapolation from an NOAEL to a
> LOAEL, a modifying factor to adjust for scientific quality of the
> database lack missing datasets perhaps, and 1 to extrapolate across
> duration.
>
> Some have said that we do this because we have 10 fingers, but these
> are biologically distributed phenomena that we are looking at,
> generally speaking, so dividing by 10, you encompass 95 percent of the
> variability. So, it does have some basis in biological science.
>
> \[Slide.
>
> This slide simply sorts out our treatment of uncertainty. Because we
> have human subjects being assessed, there is no species-to-species
> extrapolation factor other than 1, because we used the NOAEL
> identified in the Seychelles study. We used a 1 because of the issue
> of lifetime or long-term study over multiple generations or exposure
> over multiple generations we use 1.
>
> In terms of human variability, we used a factor of 3. This is a factor
> of 1.5 for pharmacokinetics, which we had determined through some
> modeling that I believe Harvey Clewell or Kenny Krump \[ph\] did for
> us, and then we have the World Health Organization Steering Committee
> on Risk Assessment pointed out, and I participated as a member of the
> Steering Committee, that these are equally determined by
> pharmacodynamics and pharmacokinetics. Kinetics is how it gets there,
> dynamics is what does it do once it gets to the target.
>
> So, we added these two components of this, and it sometimes has been
> said that we multiplied uncertainty factors. We did not do that. We
> added these two components of this uncertainty factor and then
> multiplied it by a modifying factor of 1.5 to account for our concern
> regarding domain-specific effects out of the Seychelles.
>
> \[Slide.
>
> In summary, we have MRLs for multiple forms of mercury. The critical
> study was based upon some of the things that I have just mentioned and
> that have been touched upon elsewhere.
>
> \[Slide.
>
> Some ongoing activities. We are just again following the science,
> where it leads in terms of the data coming out of the Seychelles and
> the Faroes. We have developed an interaction profile on the
> contaminants typically found in contaminated fish in this country in
> cooperation with EPA\'s Office of Research and Development.
>
> We are engaged in a study in the Czech and Slovak Republics to look at
> perinatal exposures to persistent organic pollutants. We are looking
> at thimerosol in some rodent studies to identify the comparative
> kinetics of thimerosol and methylmercury , and it turns out that while
> methylmercury has a half-life of from 45 to 50 days, thimerosol
> ethylmercury has a half-life about one-fifth of that.
>
> We are planning a chelation workshop to come around this issue of
> chelation. The mercury document also served as the basis for WHO\'s
> International Assessment document recently released. John Risher, who
> is here today, is the author of that document. We are participating in
> the OSTP-CNR Working group.
>
> I think there is one more slide and I will be finished here.
>
> \[Slide.
>
> Obviously, there is a lot of work going on, not only on methylmercury,
> but other forms of mercury. We are committed to a continuing
> evaluation and understanding insofar as we can reduce uncertainty and
> provide some improved guidance to the public.
>
> We will be looking carefully at the deliberations of bodies, such as
> this, as we go forward with the update of our tox profile later this
> year.
>
> Thank you.
>
> DR. MILLER: Thank you.
>
> Questions, comments?
>
> **Questions of Clarification**
>
> DR. HOTCHKISS: I just wanted to make sure that I understood. You went
> through your MRL pretty quickly. Your kind of bottom line number was
> 0.3 mcg/kg/day?
>
> DR. DeROSA: It was 0.3 mcg/kg/day, and it was 0.0003 mg/kg/day.
>
> DR. HOTCHKISS: Then, I got that number, and that is based on a number
> of factors, but, in essence, on one or more studies during the outcome
> of exposure during pregnancy, is that correct?
>
> DR. DeROSA: Yes, the two studies that were pivotal there were the
> Seychelles, we used the mean hair level and the highest quartile
> studied in the Seychelles of I think it was 15.3 ppm in maternal hair,
> converted that to a blood level, then used that blood level to
> back-calculate a daily intake, and that daily intake was then divided
> by the uncertainty factor of 4.5.
>
> DR. HOTCHKISS: And the 0.3 mcg/kg/day, can you tell me when your
> agency publicly released that amount and what the response to that has
> been? Is it published in the scientific literature?
>
> DR. DeROSA: The 0.3?
>
> DR. HOTCHKISS: Yes, and the rationale for it.
>
> DR. DeROSA: Yes, the rationale and the overall evaluation of the
> database is in the toxicological profile on mercury. That is about a
> 750-page document. It went through some extensive peer review, as well
> as public comment period.
>
> We have had a range of different comments on that. There is a wide
> spectrum of opinion about what the health guidance value for mercury
> should be, but I think that more important than what the divergence of
> what that opinion is, is that there is no disagreement that
> methylmercury is a neurotoxicant of the first degree, the one that we
> have to be concerned about minimizing exposures to, and that while we
> continue to espouse the benefit of fish as a component of the diet,
> that because mercury is bad, if you had consumed fish with highly
> contaminated levels of mercury, there may be implications for your
> health depending on the time of your exposure.
>
> DR. HOTCHKISS: Thank you.
>
> DR. MILLER: Dr. Nordgren.
>
> DR. NORDGREN: I was wondering, would it be possible for you to make
> copies of the last few slides on how you determined this?
>
> DR. DeROSA: Yes, we can make those available to you.
>
> DR. NORDGREN: I think that is kind of crucial to what we are trying to
> do here.
>
> DR. DeROSA: Right.
>
> DR. MILLER: Other questions or comments?
>
> If not, we thank you very much. It looks like we are right on
> schedule.
>
> We will now break for lunch. Please be back here at 1 o\'clock. We
> will begin at 1 o\'clock precisely whether it\'s just me or anybody
> else.
>
> \[Whereupon, at 11:50 a.m., the proceedings were recessed, to be
> resumed at 1:00 p.m.\]
>
> AFTERNOON PROCEEDINGS
>
> \[1:00 p.m.\]
>
> DR. MILLER: I call the committee to order.
>
> Our first speaker this afternoon is Dr. Penny Kris-Etherton of Penn
> State University, who will be talking about consumer messages.
>
> Dr. Kris-Etherton.
>
> **Consumer Messages**
>
> **Dr. Penny Kris-Etherton**
>
> DR. KRIS-ETHERTON: The topics I am going to cover are shown on this
> slide. I will talk about fish recommendations from professional
> organizations and government agencies, such as FDA.
>
> I am going to just give a real brief truncated version of a talk that
> I give communicating fish recommendations from both American Heart
> Association, other professional groups, and FDA, and then we will talk
> a little bit about effective risk communication principles.
>
> Then, I am going to present a consumer research model developed by the
> International Food Information Council for communicating food and
> nutrition messages effectively. Then, we will sum it up.
>
> \[Slide.
>
> A number of professional groups have made recommendations for fish
> consumption. American Dietetic Association recommends eating two to
> three fish meals per week to decrease risk of cardiovascular disease.
> In the late 1990s, ADA published a position paper on women\'s health
> and nutrition, and this recommended consuming fish two to three times
> a week.
>
> \[Slide.
>
> In the year 2000, the American Heart Association released their
> revised dietary guidelines, and I had the distinct privilege of
> serving on the Nutrition Committee that developed these food-based
> dietary recommendations. They differed from other dietary
> recommendations that were nutrient based in terms of specific percent
> recommendations.
>
> So, American Heart Association recommends two servings of fish per
> week to confer cardioprotective effects.
>
> Then, USDA, Department of Health and Human Services, in their dietary
> guidelines as presented in the Food Guide Pyramid, encourages two to
> three servings of fish weekly.
>
> \[Slide.
>
> In terms of the fish recommendations made by American Heart
> Association, as I noted, in the 2000 dietary guidelines, a fish
> recommendation was made, and that was published in 2000. There was a
> science advisory published in 1996 entitled, \"Fish Consumption, Fish
> Oil, Lipids, and Risk of Coronary Heart Disease.\" Well, a lot has
> happened since 1996 with respect to fish and health benefits in terms
> of heart disease, so there is another science advisory in the
> pipeline, and I am not at liberty to tell you what it says except to
> say that at least it is in the pipeline, it is going to be published
> pretty soon, and the American Heart Association took the position of
> looking at health benefits with respect to heart disease and safety
> issues with respect to environmental contamination.
>
> So, they balanced a consumer message on the basis of health and risk.
> That will be coming out somewhat soon.
>
> \[Slide.
>
> As I said, I am going to give just a truncated version of a little
> talk that I give on fish and cardioprotective effects of omega-3 fatty
> acids. I have given this talk many times and, as a cardiovascular
> nutritionist, I am deeply committed to the health benefits of omega-3
> fatty acids.
>
> You are going to hear a detailed discussion on nutrition issues
> tomorrow from Dr. Bill Connor, and this is just sort of the tip of the
> iceberg of what I present.
>
> \[Slide.
>
> The exact quote from the HA Dietary Guidelines is shown on this slide.
> \"Because of increased evidence for the cardiovascular benefits of
> fish, particularly fatty fish, consumption of at least two fish
> servings per week is now recommended.\"
>
> What is the science evidence that led to this recommendation?
>
> \[Slide.
>
> Well, this particular slide just shows the many, the multiple
> cardioprotective effects of omega-3 fatty acids in fish, and in
> particular, I will show you some evidence that shows decreased
> incidence of sudden death, reduced arrhythmias, antiplatelet effects
> which protects against thrombosis, marked triglyceride lowering such
> that omega-3\'s are used by some physicians in hypertriglyceridemic
> patients, reduced coronary disease, morbidity and mortality, and what
> we know is that both alpha-linolenic acid, the plant derived source of
> omega-3 fatty acids, and marine-based omega-3 fatty acids, EPA and
> DHA, have cardioprotective effects, higher intakes, about 900 mg/day
> of EPA and DHA given as a fish oil supplement may benefit patients
> with coronary disease.
>
> Tomorrow, you are going to hear about striking neurological benefits
> in terms of the brain, the vasculature, eyes, for fetuses, infants,
> and young children. So, again, many, many health benefits of omega-3
> fatty acids.
>
> \[Slide.
>
> Here are some of the epidemiologic evidence that we have looked at
> that we took into account when we made the recommendation for two
> servings of fish per week. This is from the Physicians Health Study
> Follow-up from the Harvard Group. It was published in 1998.
>
> What you see here is that with one to two servings of fish per week
> and more, risk of sudden death is cut in half.
>
> \[Slide.
>
> In a very well-known study, the DART study, which stands for Diet and
> Reinfarction Trial, a secondary intervention study, it was shown that
> men with heart disease who were given fish advice to consume between 6
> and 12 ounces of fish per week had a much greater survival rate, as
> you can see, than men who got no fish advice.
>
> In fact, for people who didn\'t want to eat fish, they were given a
> fish oil supplement of about 1 gram per day, and those individuals
> have the same greater survival rate as did individuals who ate fish,
> showing that the cardioprotective effects are due to omega-3 fatty
> acids.
>
> \[Slide.
>
> So, given all this, and given the FDA advice, I think that we have to
> put recommendations for fish consumption in perspective, in the proper
> context, so that people realize benefits and risks associated with
> fish consumption.
>
> This is a slide that Bill Harris put together, and this is what we
> tell people. For pregnant women and women who may became pregnant, the
> risk for CVD is very low, the risk for methylmercury toxicity is very
> high, and so the recommendations for fish consumption are to avoid
> shark, king mackerel, tilefish, swordfish, consume no more than 12
> ounces per week of fish low in methylmercury, and select a variety of
> fish low in mercury and PCBs.
>
> \[Slide.
>
> To deal with other population groups, men under 45 and premenopausal
> women, they have a moderate risk of heart disease, risk of
> methylmercury is pretty low, and the fish message for them is consume
> at least two servings of fish, preferably fatty fish, per week,
> consume a variety of fish, follow state and federal advisories, and
> for men greater than 45 years of age and postmenopausal women, who
> have a high risk of CVD and low risk of methylmercury toxicity, we
> give them the same recommendations as we do for the younger cohorts -
> consume at least two servings of fish, eat a variety of fish, and
> follow state and federal advisories.
>
> So, this is one way I think of balancing the health message with a
> risk message, and that is, telling people health benefits and what FDA
> is recommending.
>
> \[Slide.
>
> Let\'s talk a little bit about effective communication strategies for
> consumers. I just want to say two things real quickly on the side.
>
> I have given the talk that I just showed you in more depth to a number
> of groups to date, and I talked to dieticians and nurses and students,
> many of whom are non-nutrition majors, and they are very interested in
> the fish data, and I also talk about FDA recommendations.
>
> I mention those four fish that should be avoided by certain population
> groups, and they are intensely interested in this, they haven\'t heard
> this message before, and I see them writing furiously when I give that
> message. Many of them come up to me afterwards and want more
> information about it.
>
> So, I am feeling that the message is getting out, health benefits, but
> there are these risks because these people now are conduits to
> consumers. Hopefully, they are getting the message to balance health
> issues with risk concerns.
>
> Then, one other thing that I do want to say is that because of new
> processing techniques and plant breeding techniques, consumption of
> alpha-linolenic acid in the United States is decreasing. Soybean oil
> and canola oil are rich sources of alpha-linolenic acid, the
> plant-derived source of omega-3 fatty acids, and a lot of food
> processors are trying to decrease alpha-linolenic acid in these oils
> to make these oils more stable and increase their shelf life.
>
> We have actually had an increase in alpha-linolenic acid since the
> 1970s. We used to eat corn oil and safflower oil, and now that we eat
> soybean oil and canola oil, the intake of alpha-linolenic acid has
> increased markedly.
>
> Now, it is going to decrease with these new plant breeding techniques
> and food processing techniques, and so that door is closing, and
> consumers need a source of omega-3 fatty acids, and that can be fish
> eaten in the proper context.
>
> So, let\'s look at effective consumer messages. I want to talk a
> little bit about challenges and barriers in communicating risk-benefit
> messages. You have to keep in mind that people are different. Some
> understand and want a lot of technical information, and others do not.
>
> So, the current advisory that FDA has, has an 888 number, so consumers
> have easy access to additional information, somewhat extensive
> personal control over potential risks and others prefer not to be
> bothered. They say, okay, FDA is taking care of this, I don\'t need to
> worry about it.
>
> Here is where I think there is sort of a double-edged sword here in
> that often messages are precise and accurate, and they are too complex
> for most to understand, and yet, on the other hand, simpler messages
> may be accused of being inaccurate, incomplete, or manipulative, and
> so somehow we have got to come up with a balance here and communicate
> effectively with consumers, giving them a message that they can
> understand quite simply, but then giving them access to additional
> information.
>
> I think FDA does a wonderful job with that.
>
> \[Slide.
>
> What are some factors that interfere with messages being heard? Well,
> at the top of the list is credibility of the source, and here is where
> FDA has no problem with credibility. They are seen by consumers as
> being a safety net for the public. They are not an advocacy group,
> they are not a self-serving group.
>
> One other problem that consumers are faced with is inconsistent and
> contradictory messages across credible sources. This happens all the
> time. It happens with professional organizations, and I think we all
> know about conflicting agency messages, as well.
>
> These are all problems that I think can be dealt with.
>
> \[Slide.
>
> So, how can we overcome barriers? That is with credibility and trust.
> It is really important to know and target an audience, respect their
> concerns. I think FDA does a real good job with that in terms of
> printed guidance with pregnant women. We need to use plain, clear
> language. Keep messages short, but refer to other references, and
> there are some people who really do want a lot of additional
> information, and that can be done using an 800 number or a web site.
>
> DR. MILLER: Dr. Kris-Etherton, you have five more minutes.
>
> DR. KRIS-ETHERTON: Okay.
>
> \[Slide.
>
> I just want to say that it is really important that messages be placed
> in the proper context.
>
> \[Slide.
>
> We have very good examples where this isn\'t done. Here is a headline
> that came out in the local news - \"Transfusion fat is unsafe to
> eat,\" and this is in response to a National Academy of Science
> recommendation saying that there should be no upper limit for trans
> fat and that the recommended level then is at zero.
>
> Well, we know that it is impossible to eat a healthy diet, for the
> most part, with a trans fat intake of less than zero, but here is an
> example where I think a well-intended message got misconstrued, so
> that with fish, then, it is really important that consumers understand
> the context of the health message and the risk message.
>
> So, for example, one way that this could go awry is if we say to
> pregnant women eliminate these fish, well, should pregnant women
> eliminate all fish, that is one thing that could happen, and then
> finally it could be misconstrued that everybody should eliminate all
> fish.
>
> So, we have got to be real careful to get our messages out carefully.
>
> \[Slide.
>
> Just real quickly. Here is an IFIC model for effective communication
> in health messages.
>
> \[Slide.
>
> Consumers want messages that are positive, short and simple,
> individualized, specific and manageable, provide a payoff, and they
> want things to be fun. Life needs to be a lot of fun.
>
> \[Slide.
>
> Here are some examples, real quickly. Be positive. I am going to use
> an example from the Consumer Advisory from FDA. Seafood can be an
> important part of a balanced diet for pregnant women. It is a good
> source of high-quality protein and other nutrients, and is low in fat.
> A very positive message.
>
> \[Slide.
>
> Crafting tips with consumer appeal. Keep it short and simple. Try a
> different fish recipe each week. Try many different species of fish.
>
> \[Slide.
>
> Individualize the message. If you love deep-fried fish, try pan-fried
> fish with just a little vegetable oil.
>
> \[Slide.
>
> Crafting tips with consumer appeal. Here is one that I think is very
> relevant to the topic at hand. Make it specific and manageable. If you
> are pregnant or planning to become pregnant, avoid shark, tilefish,
> king mackerel, and swordfish.
>
> \[Slide.
>
> And then provide the payoff. Follow EPA, FDA, ADA, AHA, USDA
> guidelines for fish consumption. You will be safe and healthy.
>
> \[Slide.
>
> Finally, make it fun.
>
> \[Slide.
>
> My last slide is a summary. I have shown you significant health
> benefits of fish consumption, and because of this, the scientific
> community has made a specific dietary recommendation, however,
> consumers have to be aware of recommendations of FDA for fish
> consumption, and they need to know how to balance benefits and risks
> in implementing these recommendations.
>
> Thank you very much.
>
> DR. MILLER: Thank you.
>
> Questions? Ms. Halloran.
>
> **Questions of Clarification**
>
> MS. HALLORAN: In your presentation, you mentioned that when you
> indicated these species of fish, that shouldn\'t be eaten by pregnant
> women, everyone takes avid notes.
>
> DR. KRIS-ETHERTON: Yes.
>
> MS. HALLORAN: It was also my experience in preparing for this meeting
> and mentioning to people what it was about, that it was very much the
> same, nobody knew that pregnant women weren\'t supposed to eat
> swordfish.
>
> DR. KRIS-ETHERTON: Yes.
>
> MS. HALLORAN: I wonder if you know\--to me, this is more of negative
> message than a positive one, that this message is not getting out and
> that somehow this is not an effective public health tool, at least as
> it is being done presently\--I wonder if you are aware of or if
> anybody is aware of information or surveys or research indicating how
> much of the American public of child-bearing age who is female
> actually knows about this advice.
>
> DR. KRIS-ETHERTON: I don\'t know that information, but your point is
> very well taken because, frankly, with every talk that I have given,
> at least 10 and probably more than that, it is clear to me that this
> is news to everybody, virtually everybody.
>
> DR. MILLER: Dr. Dwyer.
>
> DR. DWYER: I have a Boston Naming problem I guess. I don\'t know what
> tilefish is. Is there another name for tilefish, does it go by another
> name?
>
> I guess I know what mackerel is because I am Irish, but what about
> tilefish, is there a name that people recognize when you give these
> talks?
>
> DR. KRIS-ETHERTON: Actually, when I say tilefish, nobody knows what it
> is. It is a fish that is not commonly consumed. I have never seen it
> in restaurants, I have never seen it in the supermarket.
>
> PARTICIPANT: Golden or white mackerel it is called.
>
> DR. KRIS-ETHERTON: No wonder I have never seen it. Thank you.
>
> DR. RUSSELL: Another question with regard to naming. King mackerel, is
> there other types of mackerel and does someone have to go in and say
> is this king mackerel?
>
> DR. KRIS-ETHERTON: I have seen mackerel in the supermarket as
> mackerel.
>
> DR. RUSSELL: Yes. I have never seen it otherwise differentiated.
> Johanna, you being Irish, are there several types of mackerel?
>
> PARTICIPANT: There are a lot of types of mackerel.
>
> DR. RUSSELL: Is that the type that would be most commonly in the fish
> store? I just don\'t know.
>
> PARTICIPANT: You see Spanish mackerel a lot in the sushi restaurants,
> that is the one with shiny skin on the outside with the yellow spots.
>
> DR. MILLER: Could you identify yourself for the record?
>
> DR. RAINES: Yes, sir, Ben Raines \[ph\]. \[Off mike.\]
>
> DR. BUSTA: Penny, I am assuming that these studies that show increased
> fish consumption being beneficial take into consideration that this
> reduces the eating of other kinds of food.
>
> DR. KRIS-ETHERTON: That is a very good point, and that is another
> benefit of eating fish is that oftentimes it is a substitute for fatty
> meat, and so it is a real good way to decrease calories, total fat,
> and saturated fat.
>
> DR. BUSTA: Is that possibly the main reason it works rather than the
> fish itself, if you just didn\'t eat 12 ounces of meat?
>
> DR. KRIS-ETHERTON: That is a very good question, and, in fact, there
> are a couple of supplement studies out. One is a very famous one,
> Jissie \[ph\] study, and it\'s a long Italian name. It was a very
> large secondary prevention study where people who had a heart attack
> got a fish oil supplement every day compared with those that didn\'t,
> and with the fish oil supplement, there was a marked reduction in all
> secondary events.
>
> DR. MILLER: Dr. Fischer.
>
> DR. FISCHER: In the recommendations, it is indicated that if the woman
> is pregnant or considering becoming pregnant, they should not eat the
> list of fish.
>
> This tells me that we think that the damage done to development by
> methylmercury can occur very early, during the first trimester anyway,
> right? Now, is there scientific data to back that up, that you know
> of?
>
> DR. KRIS-ETHERTON: The data that I know of is what happened in World
> War II, when women were exposed to enormous doses of methylmercury in
> the early trimester. There were effects at that point, but these were
> really huge, enormous doses of methylmercury.
>
> So, early on in pregnancy, it can have an effect is my understanding,
> but it has got to be real large doses.
>
> DR. FISCHER: We heard some reference that the effects were more toward
> the end of pregnancy, during brain development, that was the critical
> time, so I am just asking whether these recommendations were based
> upon firm scientific data.
>
> DR. KRIS-ETHERTON: I guess what I know is, you know, from what
> happened in World War II, that some women, even in their first
> trimester of pregnancy, had adverse pregnancy outcome, that\'s all.
>
> DR. APOSHIAN: Is Dr. Myers still here, because in his review article,
> I think he\--is he here or has he left\--in a recent review article,
> he points that methylmercury has an effect on brain growth during the
> late period of pregnancy and during the first few years of the
> person\'s life.
>
> DR. MILLER: Well, I think in listening to Dr. Kris-Etherton, she is
> talking about pregnancy outcome, so the influence of mercury was on
> the pregnancy rather than on the fetus. Isn\'t that what you were
> saying, Penny?
>
> DR. KRIS-ETHERTON: Yes.
>
> DR. APOSHIAN: Then, the American Heart Association has not taken a
> stand on the vulnerability of the fetus to methylmercury in fish?
>
> DR. KRIS-ETHERTON: They really haven\'t considered that.
>
> DR. DWYER: Is there, in fact, firm evidence that the only effects of
> methylmercury are on the third trimester of pregnancy?
>
> DR. KRIS-ETHERTON: I don\'t think so, Johanna, based on what I know
> about what happened in World War II, but that is my only knowledge of
> that, I don\'t know.
>
> DR. FISCHER: I must say I don\'t know this World War II data.
>
> DR. APOSHIAN: Is that published in the scientific literature, the
> World War II data?
>
> DR. KRIS-ETHERTON: Let me delve into this a little bit further.
>
> DR. MILLER: Other comments?
>
> If not, thank you.
>
> DR. MILLER: Just to explain to those of you who thought you would see
> Dr. Schober, Dr. Kris-Etherton has to make a plane, and Dr. Schober
> agreed to move down one slot.
>
> Our next speaker is Dr. Susan Schober to talk about the NHANES study.
>
> **National Health and Nutrition Examination Survey**
>
> **Dr. Susan Schober**
>
> DR. SCHOBER: Good afternoon.
>
> \[Slide.
>
> This afternoon, I will describe the current National Health and
> Nutrition Examination Survey or the NHANES and present data from the
> just released 1999-2000 NHANES on blood mercury levels in children and
> in women of child-bearing years.
>
> \[Slide.
>
> First, I would like to acknowledge that the NHANES mercury component
> is the result of collaboration with several agencies. In addition to
> the CDC, my center, the National Center for Health Statistics and the
> National Center for Environmental Health that did the laboratory work,
> the collaborators in this component are the Food and Drug
> Administration, EPA, the Department of Energy, NIH, and the National
> Oceanic and Atmospheric Administration.
>
> \[Slide.
>
> The primary objective of the NHANES program is to assess the health
> and nutritional status of adults and children in the United States.
>
> \[Slide.
>
> The analytic and research goals for NHANES are listed in this slide
> and the next one. These goals are driven by what is unique about this
> survey, and that is the ability to address public health issues that
> can best be addressed through physical examinations of the U.S.
> population.
>
> The goals are to estimate the prevalence of health conditions and
> related risk factors in the U.S., to describe awareness, treatment,
> and control of selected diseases, to monitor trends in health and risk
> behaviors and environmental exposures over time.
>
> \[Slide.
>
> To study the relationship of diet, nutrition, and health, to explore
> emerging public health issues, and to establish a national probability
> sample of genetic material.
>
> \[Slide.
>
> The survey is comprised to two parts. There is a household interview
> and an examination component. The household interview covers a wide
> range of topics including sociodemographic information, questions on
> medical history, health care coverage and need, health behaviors,
> nutrition, and there are some questions on environmental occupational
> exposures.
>
> The examination component of the survey is conducted in specially
> outfitted mobile exam centers. There is an example of one shown in
> this slide. The topics, the major health topics that we cover in the
> examination component include cardiovascular disease, osteoporosis,
> oral health, vision, hearing, balance, fitness and strength,
> nutrition, anthropometry - there is a whole list, mental health risk
> behaviors, and environmental exposures and infectious diseases.
>
> As part of the examination, blood is obtained by venipuncture from all
> participants who are one year and older.
>
> \[Slide.
>
> The NHANES uses a complex sampling strategy to obtain a sample that is
> nationally representative of the civilian non-institutionalized
> household population. Persons of all ages and from all states and the
> District of Columbia are eligible to be included in this survey.
>
> The first stage of sample selection is the selection of counties or
> primary sampling units, and then within those counties, household
> segments are selected, and finally, sample persons from the selected
> households.
>
> It is important to note that within each geographic location where we
> conduct the study, people are not selected to be representative of
> that location.
>
> \[Slide.
>
> Beginning in 1999, NHANES became a continuous survey with annual
> samples representative of the U.S. population. The continuous survey
> will be released as public use data in two-year groupings or cycles in
> order to provide adequate sample size for subgroup analyses.
>
> Typically, we go to 15 primary sampling units each year, are selected
> each year, and the annual sample size is approximately 5,000.
>
> \[Slide.
>
> The NHANES sample design includes oversampling of minority populations
> and other groups in order to provide reliable estimates for these
> subgroups. In the current survey, we are oversampling adolescents,
> older persons, pregnant women, blacks, Mexican-Americans, and
> beginning in 2000, we also oversampled low-income whites.
>
> \[Slide.
>
> This slide shows the response rate and sample size information for the
> 1999-2000 NHANES that was just released. We went to 26 locations
> throughout the United States; 12,160 people were selected to
> participate in the study, and, of those, almost 9,300 participated in
> both the interview and the examination, which gave us a response rate
> to the examination component of 76 percent.
>
> \[Slide.
>
> The NHANES mercury component was conducted for two subgroups for whom
> mercury exposure is of particular concern - women in child-bearing
> years, and in our study, we define that as women 16 to 49 years old,
> and in children 1 to 5 years old.
>
> As we know from this meeting, the mercury exposure among women of
> child-bearing age is of particular concern because the developing
> nervous system of the fetus is most sensitive to the adverse effects
> of mercury exposure.
>
> Mercury exposure in young children is also of interest because of
> continuing neurobehavioral growth and development in this period of
> life.
>
> \[Slide.
>
> Today, I will be presenting information on total mercury
> concentrations in blood. In the future, there will also be information
> on hair mercury levels in the women and children, and also on urine
> mercury levels in just the women.
>
> \[Slide.
>
> The sample size for the children 1 to 5 years old is 705, and the
> sample size is 1,709 for the women.
>
> \[Slide.
>
> The blood specimens were analyzed for total mercury and inorganic
> mercury in the Trace Elements Laboratory of the National Center for
> Environmental Health at CDC in Atlanta. The laboratory used an
> automated cold vapor atomic absorption spectrophotometry to conduct
> these measurements. The detection limit was 0.14 mcg/liter or ppb for
> total mercury, and 0.4 for inorganic mercury.
>
> The inorganic mercury was non-detectable in 98 percent of the sample,
> and I will only be presenting information for total mercury.
>
> \[Slide.
>
> The distribution of blood mercury levels in children and women for
> this presentation are described through the calculation of percentiles
> in geometric means. Sample weights were used to account for the
> complex survey design, the oversampling, and for non-response.
>
> Standard errors are calculated with a statistical package of programs
> called SUDAAN, which accounts for the complex survey design.
>
> \[Slide.
>
> The mercury component also includes questions about fish and shellfish
> consumption. Survey participants or its proxy respondents for the
> children were asked about fish and shellfish consumption during the
> past 30 days. They answered questions about fish and shellfish
> separately.
>
> The basic question is: \"During the past 30 days, did you eat any
> types of fish listed on this card? Include any foods that had fish or
> shellfish in them, such as sandwiches, soups, or salads.\"
>
> The list of fish and then also the list of shellfish included other
> and unknown categories, as well as specific species.
>
> These questions were asked after respondents had completed a 24-hour
> dietary recall that is conducted in the mobile exam center, so there
> is also information from the 24-hour recall about fish consumption.
>
> \[Slide.
>
> The geometric mean concentration of total mercury in blood was 0.3
> mcg/liter for the children 1 to 5 years old, and approximately 1
> mcg/liter in the U.S. women 16 to 49 years old. We can see from this
> that the blood mercury levels were approximately 3-fold higher in the
> women compared to the children.
>
> \[Slide.
>
> This slide shows the cumulative distribution of blood mercury levels
> in the children and women, so it is showing the percentiles on the X
> axis, and the blood mercury levels in mcg/liter in the Y axis.
>
> One can see from the graph that the difference between levels of women
> and children is greater at the upper percentiles.
>
> \[Slide.
>
> I actually show the numbers for the upper percentiles, the 90 at the
> 95th for women and children. The confidence intervals around those
> estimates are in parentheses and I see that in the 95th percentile, it
> goes over to the left.
>
> \[Slide.
>
> Blood mercury levels were positively associated with fish consumption
> in the past 30 days. This graph again shows the cumulative
> distribution of blood mercury levels, and this is for women for three
> categories of fish consumption - those who ate no fish in the last
> month, those who ate one or two servings, and those who ate three or
> more servings.
>
> Blood mercury levels increased with the fish meals consumed. The
> pattern was observed throughout the distribution from the lowest to
> the highest percentiles.
>
> I don\'t have a slide for this, but the geometric mean mercury levels
> were almost 4-fold higher in the women who ate three or more servings
> of fish in the past month compared to women who ate no fish in that
> time period
>
> \[Slide.
>
> Here, I show the cumulative distribution for fish and shellfish
> consumption together to sort of examine how we need to look at this. I
> understand that there can be some exposure to mercury from shellfish,
> but what we see in this slide is that women who ate both fish and
> shellfish had the highest mercury concentrations compared to women who
> ate only fish or shellfish.
>
> This could be related to the fact that women who eat both just eat
> more, and the women who ate only shellfish had slightly higher levels
> than women who ate neither fish or shellfish during the past 30 days.
>
> \[Slide.
>
> Among women 16 to 49 years, I have already shown that the 90th and
> 95th percentiles for blood mercury concentrations were 4 and 7
> mcg/liter respectively.
>
> In 2000, we have already heard discussion of the National Academy of
> Sciences committee report. They recommended a lower limit benchmark
> dose or BMDL modeled from the Faroe Island study of the developmental
> effects of in utero exposure.
>
> The BMDL that was recommended was 58 mcg/liter. I am comparing the
> NHANES results to just the NAS recommendations, not to other effects
> or risk levels that have been identified by other groups.
>
> In order to account for the uncertainties of exposure measures and the
> variability in individual response to toxic effects of mercury, the
> National Academy of Sciences committee further recommended using an
> uncertainty factor of 10 to calculate the reference dose.
>
> This corresponds to a concentration of 5.8 mcg/liter of mercury in
> cord blood.
>
> \[Slide.
>
> In the NHANES, 1999-2000, there were no women who had blood mercury
> concentrations at or above the BMDL of 58 mcg/liter. The highest blood
> mercury concentration that we measured in this sample of women was 39
> mcg/liter.
>
> But if you look at the proportion of women whose mercury levels were
> at the value of 5.8 or higher, that proportion is 7.8 percent. The
> confidence intervals around that estimate are from 5 percent to 10
> percent.
>
> \[Slide.
>
> On this slide, I have listed a couple of limitations of the NHANES
> with regard to providing information on mercury exposure in the U.S.
>
> First, the NHANES samples was not designed to oversample subgroups
> within the U.S. population, who are frequent consumers of fish or who
> might be frequent consumers of fish, so it was just sports fishermen
> or certain American Indian or Alaskan Native groups, or population
> groups who may have higher mercury exposure because of geographic
> location.
>
> Related to this point, it is not possible to examine geographic
> variation in mercury exposure in this study, and this is partly
> because we didn\'t oversample based on geographic location, and also
> we do not provide geographic information in the public release data
> because of statistical disclosure issues.
>
> Finally, even the sample sizes might seem quite adequate, they are
> still quite small for subgroup analyses that people might be
> interested in.
>
> DR. MILLER: Dr. Schober, you have five minutes.
>
> DR. SCHOBER: Thank you.
>
> \[Slide.
>
> The major strength, of course, of the NHANES is that the survey
> provides estimates that are representative of the general U.S.
> population. In the case of the mercury measures, we just did it in
> these two age groups, so these are representative of young children
> and women of child-bearing age.
>
> These estimates may be used as a reference for studies conducted in
> other communities or groups who might have potentially higher
> exposures.
>
> As we continue to measure blood mercury levels in future years of this
> study, these data will allow examination of secular trends to evaluate
> continuing efforts to reduce mercury exposure in the United States.
>
> This survey also provides sociodemographic information, as well as
> fish and shellfish consumption information that may be examined in
> relation to the blood mercury levels.
>
> In conclusion, the NHANES measures of mercury exposure in women and
> children are well below the levels considered hazardous from the
> epidemiologic studies, however, almost 8 percent of women had blood
> mercury levels at or above the cord blood concentration that
> corresponds to the reference dose recommended by the NAS committee.
>
> This is a level that takes into account uncertainties in measurements
> in the epidemiologic studies and variation in individual response to
> the adverse effects of mercury.
>
> I hope that these NHANES data will be useful to the FDA, the Food
> Advisory Committee, as well as other groups in developing the best
> advice for pregnant women and women of child-bearing age about the
> inclusion of fish in their diet.
>
> Fish is a nutritious food. We have heard that from the last speaker,
> and we don\'t want to tell women not to eat any fish at all.
>
> \[Slide.
>
> My last slide shows the web site for NHANES where one can go for more
> information about the study, the survey, as well as to find the link
> to download the data that we just released from the 1999-2000 survey.
>
> Thank you.
>
> DR. MILLER: Thank you.
>
> Comments or questions from the committee?
>
> **Questions of Clarification**
>
> DR. HOTCHKISS: I just wanted to make sure I understood. The NHANES
> population that you are talking about, particularly the women in here,
> you would consider representative of the U.S. female population in
> large, but not representative of any subpopulation of that group, am I
> correct in that assumption?
>
> DR. SCHOBER: It is representative of the U.S. population in total, but
> we cannot say anything about within the U.S. population smaller
> groups. We couldn\'t make separate estimates for groups that might
> have a higher level of exposure because of more frequent fish
> consumption. That is beyond what is the average in the U.S.
> population.
>
> DR. HOTCHKISS: Then, the assumption that 8 percent of the female U.S.
> population would have a blood level above 5.8, which thumbnail I
> calculate out about 11 million women in the U.S. probably have a blood
> level above that level, is that correct?
>
> DR. SCHOBER: I didn\'t actually look at the number of women, but it
> would be\--
>
> DR. HOTCHKISS: If you consider there are 280 million residents and
> roughly half of them are women, I think probably it is a little more
> than half.
>
> DR. SCHOBER: We can actually get that figure exactly from our
> analysis.
>
> DR. HOTCHKISS: So, it would roughly be 11 million give or take a few
> probably.
>
> DR. BUSTA: This is the first time I have heard shellfish mentioned. I
> know we have been talking about fish, and I am not sure that we have
> included shellfish in this activity.
>
> Did you do much differentiation about shellfish and fish, the way it
> is prepared, what types, any kind of other specifics?
>
> DR. SCHOBER: We didn\'t. In this analysis, is it just looking at any
> shellfish at all in the past 30 days.
>
> DR. BUSTA: And any fish in the past.
>
> DR. SCHOBER: And any fish except for that first slide where I had the
> three levels of fish consumption, but that was in the past 30 days.
>
> DR. MILLER: Dr. Shannon.
>
> DR. SHANNON: I have actually more than one question, so you will have
> to tell me when my time is up.
>
> My first question is I wonder why the mercury isn\'t speciated. We are
> here to discuss methylmercury, but only total is being measured, and,
> for example, I think about either measuring mercury in children during
> a time when they are getting so many immunizations, and you can\'t
> tell us if the mercury you are measuring is methyl or from the
> thimerosol or what the source is.
>
> I am sure your lab has the ability to do that speciation, so why
> wouldn\'t it?
>
> DR. SCHOBER: As I understand, the lab has, at least during the time
> period for these two years, had the ability to do the speciation to
> measure inorganic mercury. Inorganic mercury is best measured in urine
> rather than in blood, so the inorganic mercury levels were below the
> limit of detection for the majority of the women and children in the
> sample, so we feel that the total mercury is a good indicator of
> methylmercury.
>
> DR. SHANNON: But it wouldn\'t be in a child, right?
>
> DR. SCHOBER: I am not sure about that part of it.
>
> DR. SHANNON: And if you look at children between 1 and 5, and you are
> measuring mercury, you don\'t really\--I think it is more likely to be
> from ethylmercury and thimerosol than it is from methylmercury and
> eating fish in a 1 to 5-year old.
>
> DR. SCHOBER: I don\'t know what the laboratory plans are for further
> speciation particularly in the children.
>
> DR. SHANNON: Am I able to ask another question?
>
> DR. MILLER: Go right ahead.
>
> DR. SHANNON: One of the advantages of the old NHANES methodologies was
> that even though it took longer, there was large enough sampling that
> you could produce more accurate estimates of prevalence.
>
> So, for example, the data that we still hear about, the prevalence of
> childhood lead poisoning is based on the 1991-94 data, and in doing
> annual surveys with such a smaller sample size, the best we can do is
> what you have given us here, are some 95 percent confidence intervals.
>
> So, I am wondering if there is any type of plan to take advantage of
> what the old NHANES offered in terms of giving us prevalence data that
> we can feel comfortable with.
>
> DR. SCHOBER: The survey is now continuous, so we will be putting data
> out into your groupings. The next data release will be data for 2001
> and 2002, and then the two, two-year releases can be combined for four
> years of information, which would provide larger samples sizes for
> some of these smaller groups in the lower prevalence, estimates that
> are of interest.
>
> DR. SHANNON: Just finally, a comment more than a question. I wonder
> and worry about the value in looking at the blood mercury in women and
> extrapolating it to a cord blood mercury. Do we really know enough
> about the kinetics of methylmercury to feel that what you have in
> terms of blood mercury really is going to accurately reflect what the
> cord blood would have been?
>
> DR. SCHOBER: I am not an expert in that at all, but I do believe from
> the literature that there are different estimates of the
> correspondence between what would be measured in cord blood versus
> maternal blood.
>
> In some cases, I have heard there is a 1 to 1 ratio, in other cases I
> have heard\--and I hope I get the direction correct\--that it is a 1
> to 2 for maternal to cord blood\--or 20 percent higher, actually, not
> 1 to 2, but 20 percent higher.
>
> MR. CLEWELL: Anywhere from the same to 2 times higher in the cord
> blood.
>
> DR. MILLER: Dr. Dwyer.
>
> DR. DWYER: Thank you. I was interested in the probe after you ask have
> you had fish in the last 30 days or shellfish, and then you show them
> a card with all of these different names of fish on it.
>
> DR. SCHOBER: Yes.
>
> DR. DWYER: Do you have the names of the fish that you asked for, or
> could you make it available to us?
>
> DR. SCHOBER: Yes, I could do that.
>
> DR. DWYER: Thank you.
>
> DR. MILLER: Dr. Nordgren.
>
> DR. NORDGREN: The slide with the three different groups of
> consumption, could you repeat those?
>
> DR. SCHOBER: The lowest was no fish consumption at all in the past 30
> days. Then, it was one to two fish servings in the past 30 days. Then,
> three or more fish servings in the past 30 days.
>
> DR. NORDGREN: So, this is 30 days versus the recommendation that we
> have for twice a week.
>
> DR. SCHOBER: Right.
>
> DR. NORDGREN: Two servings per week.
>
> DR. SCHOBER: The reason I showed the data the way I did, I was
> interested in showing the cumulative distribution, the upper
> percentiles.
>
> The sample size for women who ate fish twice a week or eight times in
> the past 30 days or more is 99, and that is getting to be a pretty
> small sample size to be looking at these distributions.
>
> DR. MILLER: Dr. Friedman.
>
> DR. FRIEDMAN: I am interested if you have in the dataset in general,
> not the part that you presented today, demographic information about
> the women and the developmental data about the children.
>
> DR. SCHOBER: We have some demographic information about the women, but
> not developmental information about the children. It\'s a
> cross-sectional study. You mean the children\--
>
> DR. FRIEDMAN: Assessment. It could be cross-sectional.
>
> DR. SCHOBER: You mean the children 1 to 5.
>
> DR. FRIEDMAN: Yes.
>
> DR. SCHOBER: I don\'t think we do this time, no, we don\'t. We have
> done the WISC rat in the previous survey, but we are not doing that
> currently.
>
> DR. FRIEDMAN: Thank you.
>
> DR. ACHOLONU: You showed that in your studies you used blood level of
> mercury. Some people have done some work and have shown that the two
> major target organs for long-time exposure to mercury is the nervous
> system and the kidney, which means that we should be testing urine.
>
> Why is your work limited to blood, why have you not checked urine? And
> if you have not, why have you not done the urine samples?
>
> DR. SCHOBER: I didn\'t speak comprehensively about everything that we
> do in the survey. We do a very large number of laboratory assessments.
> We do collect urine samples. I know that there is a couple of tests
> that we do in the urine, samples that might speak to kidney
> dysfunction. I can\'t say exactly what those might be.
>
> We could look at that. One would have to keep in mind that this is a
> cross-sectional study and we are looking at current exposure, and it
> would a current assessment of kidney dysfunction. We wouldn\'t be able
> to say anything about the exposure over the lifetime of the person.
>
> DR. NORDGREN: Can I respond to that question?
>
> DR. MILLER: Yes, sure.
>
> DR. NORDGREN: It would be very hard to do urine because mercury levels
> in urine would be pretty meaningless unless it was a 24-hour urine
> because the urine is so diluted and concentrated, so if you are
> measuring mercury at levels in a spot urine check, it would be pretty
> meaningless versus doing a 24-hour urine.
>
> DR. SCHOBER: Excuse me. I misunderstood the question. I was thinking
> that you were referring to tests that would be reflective of kidney
> dysfunction in the urine. We are measuring mercury levels in urine,
> but I wouldn\'t think that that would be an indication of known effect
> on the kidney, and it is a spot urine.
>
> DR. APOSHIAN: I think, going back to mercury in the urine, that that
> is still one of the classical ways of detecting mercury toxicity by
> doing a creatinine that goes along with it. So, spot urines are
> perfectly acceptable in the toxicology community.
>
> DR. SCHOBER: We do do creatinine correction for our urine assessments.
>
> DR. APOSHIAN: But urine mercuries are usually considered to be
> indicative of long-term exposure, whereas, as you said, blood
> mercuries are indicative of short-term or recent exposure.
>
> DR. NORDGREN: I thought he asked mercury levels in the urine. I
> thought that was the question.
>
> DR. APOSHIAN: Mercury levels can be done relatively routinely,
> automatically now. Most labs can get down to 2 mcg/liter without any
> trouble whatsoever. I see mass spec and other techniques, and even
> with the cold vapor method of determining mercury, you can get down to
> about 2 mcg/liter if it is a good laboratory.
>
> DR. NORDGREN: But that is on a one sample. If you are measuring\--the
> concentration in the urine depends how dilute the urine is. So, if you
> drank a gallon of water just before you gave your sample\--
>
> DR. APOSHIAN: But that is why the creatinine is done.
>
> DR. NORDGREN: Right.
>
> DR. APOSHIAN: So, if you base your data on the creatinine
> concentration, it does away with the dilution factor.
>
> DR. SHANNON: Isn\'t the primary issue, though, that methylmercury is
> not excreted in urine, the primary route of excretion for
> methylmercury is bile, so we wouldn\'t be that interested in measuring
> mercury in urine anyway if we were interested in the extent of
> methylmercury exposure.
>
> DR. MILLER: Any other comments or questions?
>
> If not, thank you.
>
> The next speaker is Ms. Caroline Smith DeWaal from CSPI to talk about
> Risk Management Strategies for Methylmercury in Seafood - A Consumer
> Perspective.
>
> **Risk Management Strategies for Methylmercury in**
>
> **Seafood - A Consumer Perspective**
>
> **Ms. Caroline Smith DeWaal**
>
> MS. SMITH DeWAAL: Good afternoon. I want to thank FDA for inviting me.
> I also want to apologize. We had a major outbreak and recall last
> Friday, which has kept me fully occupied, and I do not have a
> PowerPoint presentation, so I apologize.
>
> Leora Begosin, however, is going to hand out a petition and also
> consumer advisory that we have prepared that is part of my
> presentation, and, in addition, probably tomorrow or the next day, we
> will get you copies of the actual presentation.
>
> CSPI is supported by 800,000 consumers in both the U.S. and Canada,
> and we are totally independent. We don\'t accept government, industry,
> or even union contributions. We are really supported by consumers.
>
> Methylmercury in seafood is not a new issue to the Food and Drug
> Administration, but luckily for the public, it is one that is getting
> increased attention. I apologize in advance if my talk seems somewhat
> like a history lesson, but this is a topic that I have been working on
> since the early 1990s, and there is a lot of history that I don\'t
> think this committee has gotten yet.
>
> The Food Advisory Committee is being asked to evaluate whether FDA\'s
> Consumer Advisory on Methylmercury is adequate to protect the health
> of those who follow the advice.
>
> To answer this question, I believe that the committee must first be
> satisfied that the FDA\'s standard or action level is sufficient to
> protect vulnerable consumers. This is the same standard that the
> National Academy of Sciences harshly criticizes in 1991 with the
> publication of a report called Seafood Safety, which I don\'t believe
> has been discussed yet at this meeting.
>
> Second, the committee should evaluate the appropriateness of placing
> the entire burden for preventing the adverse consequences of
> methylmercury in seafood on the consuming public. This committee
> should explore the issue whether FDA should be more proactive in
> preventing the most highly contaminated seafood from reaching the
> marketplace especially given the current status of the at-risk
> population and the failure of FDA\'s past seafood safety policies in
> addressing methylmercury.
>
> In 1999, we got the first glimpse of the current levels of consumer
> exposure to methylmercury in the NHANES study, the data which has just
> been presented.
>
> This study showed that 1 in 10 women of child-bearing age in the U.S.
> are at risk of having babies with learning disabilities or other
> developmental defects because of in-utero mercury exposure, primarily
> through fish consumption.
>
> This data shows, gives real-time measurement of the effectiveness of
> current risk management strategies in protecting women of
> child-bearing age from accumulating levels of methylmercury that may
> have adverse effects.
>
> Unfortunately, the structure of the federal food safety regulatory
> system is fragmented and it is ill equipped to meet this challenge.
>
> Two federal agencies, the Food and Drug Administration and the EPA,
> both have regulatory authority over this issue, and a third federal
> agency has an additional standard which we have heard about today, the
> Agency for Toxic Substances and Disease Registry, the ATSDR.
>
> All three agencies have established standards for human exposure of
> methylmercury from fish and shellfish, but none of the standards agree
> on what level of methylmercury represents a threat to consumers.
>
> The FDA has primary authority for regulating seafood that is in the
> marketplace, that is commercially sold, and it is most of the seafood
> that is being consumed by the U.S. public.
>
> Using its public health mandate, the FDA established an action level
> of 1 part per million for mercury-contaminated commercial seafood. For
> recreationally caught freshwater fish, however, that standard doesn\'t
> apply, and EPA has issued its own methylmercury guideline under water
> pollution laws.
>
> The EPA\'s water quality criterion is based on the Agency\'s reference
> dose for mercury, which is 0.1 mcg/kilogram/body weight/day. I think
> we have heard this already, this is the daily exposure of the human
> population including sensitive subgroups that is likely to be without
> appreciable risk of deleterious effects during a lifetime.
>
> In simpler terms, a reference dose represents the daily dose of a
> substance that would be acceptably safe even to sensitive subgroups.
> So, in the case of mercury, EPA\'s reference dose is designed to
> account for effects on the developing fetus.
>
> In addition, we have already heard about the ASTDR standard, which has
> its own standard of 0.3 mcg/kilogram/day. Ironically, the most
> protective public health standard is the one put forward by the
> Environmental Protection Agency, and not the one put forward by FDA.
>
> FDA\'s action level of 1 part per million for mercury in fish was
> calculated only to protect adults. It was not developed with the
> consequences to the fetus in mind, and I will go into that later in my
> paper.
>
> In terms of human exposure, and it is difficult to make all these
> numbers fit, but the FDA\'s action level translates to 4 mcg/kg/body
> weight/day. So, EPA is at 0.1, ASTDR is at 0.3, and FDA is at 0.4
> mcg/kg/body weight/day, which is four times higher than EPA\'s
> reference dose.
>
> Unfortunately, for pregnant women and their children, the seafood sold
> in supermarkets and restaurants is regulated under FDA\'s weaker
> standard. Moreover, the FDA\'s action level is only an informal
> enforcement policy, and it is not legally binding either on the Agency
> or on the seafood companies.
>
> More importantly, it does absolutely nothing to prevent heavily
> contaminated fish from being sold to consumers. FDA\'s action level on
> methylmercury is truly a toothless tiger.
>
> What FDA has done in response to the mounting evidence about the
> inadequacy of its standard is to issue a consumer advisory, placing
> the burden firmly on consumers to protect themselves from the risks
> that this toxic agent in seafood poses.
>
> In January of 2001, FDA issued a press release telling women who are
> or may become pregnant not to eat shark, swordfish, king mackerel, and
> tilefish due to likely contamination. These women were told that it
> was safe to eat up to 12 ounces per week of other types of cooked
> fish, no warning. The warning was silent on tuna.
>
> The FDA advisory also states that it would be prudent for nursing
> mothers and young children to follow the same recommendations as women
> who may or are pregnant, may become or are pregnant.
>
> FDA\'s decision to regulate by press release has been highly
> ineffective and here are a few reasons. First, there was major rollout
> of the new advisory. There weren\'t public meetings, there wasn\'t a
> press conference. There is also no labeling or retail display programs
> as part of this program.
>
> Second, many consumers who need to hear the advisory are very likely
> to actually hear it. Media outlets frequently don\'t reach people who
> don\'t speak English as a primary language. Moreover, half of all
> pregnancies are unplanned, so to reach the appropriate audience, the
> message really needs to be directed to all women of child-bearing age.
>
> FDA\'s advice is so incomplete that several other consumer and public
> health groups have developed competing advice in order to fill this
> void. CSPI issued its own advice in the Nutrition Action Health
> Letter, which goes to our 800,000 members back in September of last
> year, and we have very specific recommendations for young children
> about tuna consumption, an area where FDA has been notably silent.
>
> In addition, Consumer Reports magazine has issued their own consumer
> advice including young children, and Environmental Working Group has
> another piece of advice and has listed many more types of fish. I know
> you will be hearing from Richard Wiles tomorrow.
>
> At the same time that FDA came out with its new consumer advisory, EPA
> issued a national consumer advisory on recreationally caught
> freshwater fish, and EPA recommended that women who are or may become
> pregnant or nursing mothers should eat no more than 6 ounces of cooked
> freshwater fish per week, and young children should eat no more than 2
> ounces of cooked freshwater fish.
>
> Although EPA\'s guidance covers different fish species, for most
> consumers, they were hearing a conflicting message - should I be
> eating 12 ounces of fish, 6 ounces of fish. It is very difficult to
> communicate clearly when we have all these competing messages coming
> out of the government.
>
> Fundamentally, one of the problems that exists is the advisories for
> recreationally caught fish are put out by the states and local
> governments. They get to pick and choose which standard they use. So,
> you can have one state using the FDA standard, you can have another
> using the EPA standard, even some states using more protective
> standards, some using the Canadian standard, which is more protective
> than FDA.
>
> So, again, consumers are getting messages that are competing and are
> not clear because of these problems with the federal standard for
> methylmercury.
>
> What is the response to all these conflicting messages coming from the
> government? I think consumers learn to mistrust the government
> messages and also there is huge confusion. People really don\'t know
> what advice to follow.
>
> The result is a loss of confidence that the messages that are coming
> out of the government are really truthful. We think one of the
> responses to this, and a critical response, is to have an actual
> enforceable standard for methylmercury and seafood that FDA enforces.
>
> The current action level was first issued as an administrative
> guideline for fish in 1969 in response to the Minamata outbreak. At
> that time, the Agency set the permissible level of mercury at 5 parts
> per million\--0.5, 0.5 parts per million.
>
> FDA converted this standard to an action level in 1974, recognizing
> that chronic exposure to fish and shellfish containing methylmercury
> poses a greater potential for danger to women of child-bearing age
> than to the general population.
>
> So, in 1974, they recognized that pregnant women were an important
> subgroup to consider, but in later action, FDA ignored this critical
> public health consideration. Following litigation challenging its
> mercury action level, in 1979, FDA relaxed the mercury standard to 1
> part per million because of new information on consumption and
> socioeconomic impacts presented by the National Marine Fisheries
> Service.
>
> According to FDA, NMFS, National Marine Fisheries Service, concluded
> that\--and I am quoting here\--\"The higher level would provide a
> significant economic benefit to those industries most seriously
> affected by regulatory actions under the 0.5 part per million
> guideline.\"
>
> In 1984, FDA revised the 1 part per million mercury action level
> again, so that it applied only to methylmercury. In doing so, FDA
> acknowledged that the revision of the action level might result in
> increased consumer exposure to methylmercury, but concluded that this
> increase in exposure will not be a public health concern.
>
> Despite the recognition by FDA in 1974 that exposure to methylmercury
> might harm fetuses, no allowance was made in setting the action level
> and in revising this action level to provide protection for pregnant
> women and children.
>
> Later decisions in 1979 and 1984 that increased exposure to mercury
> never revisited the issue of fetal effects. It should not be
> surprising then that when the National Academy of Sciences issued its
> seafood safety reports in 1991, it extensively criticized FDA\'s
> methylmercury action level for not adequately protecting pregnant
> women and children.
>
> Most notably, the NAS criticized FDA for basing its standard on the
> lowest blood level of mercury reported to produce effects, the LOAEL,
> not the NOAEL, rather than its typical approach of using the no
> observable effects level.
>
> Additionally, NAS pointed out that the FDA standard failed to account
> for two critical variables, the well-documented differences among
> individual rates of mercury elimination and among the fetal response
> to mercury exposure.
>
> The NAS concluded\--and I am quoting\--\"Although the 10-fold safety
> factor as applied appears to offer a reasonable degree of protection
> for adult effects, projections of the fetal dose-response data suggest
> the possibility of appreciable risk from methylmercury exposure even
> at levels to which many people are exposed via their diet.\"
>
> FDA did nothing to respond to this damning report. Based on the
> mounting evidence of flaws in FDA\'s mercury action level, in 1992, I
> petitioned FDA on behalf of a consumer organization to establish a
> regulatory limit for methylmercury in seafood that would protect
> pregnant women and children.
>
> There were two significant components to this petition. First, we
> sought more stringent standards that would account for the fetal
> effects, but equally important, it asked FDA to set a regulatory limit
> rather than just an action level.
>
> An action level identifies the level of contamination above which FDA
> may bring enforcement action. At best, an action level is a yellow
> light for the industry signaling when FDA may consider a food to be
> adulterated, but each time FDA brings a case to remove seafood on the
> basis of that action level, it must prove the threat to public health
> caused by the seafood in question. You have to bring the same case
> over and over again.
>
> A regulatory limit, by contrast, is a red light. It signals to the
> industry that it cannot sell seafood that exceeds that limit. It is a
> legally enforceable standard that is binding both on the Agency and on
> the industry.
>
> It eliminates the need for FDA to justify and rejustify its action
> level in every separate case. Unfortunately, FDA never responded to
> this petition.
>
> During the 1990s, much of the public debate over mercury centered on
> EPA\'s efforts to clamp down on mercury emissions from fossil
> fuel-burning power plants. The issue of mercury-tainted fish was never
> far from the spotlight, however, since Congress had asked EPA for a
> report on the health effects of such emissions.
>
> DR. MILLER: Caroline, five minutes.
>
> MS. SMITH DeWAAL: Five minutes? Thank you.
>
> In its mercury study report to Congress in 1997, EPA estimated that
> between 1 and 3 percent of women of child-bearing age eats sufficient
> amounts of fish to be at risk for methylmercury exposure. We now know
> that to be an underestimate.
>
> EPA also reaffirmed its 1 mcg/kg standard as protective of brain
> development in young children. EPA\'s report was not well received,
> however, and so Congress instructed EPA to commission another NAS
> study on the appropriate reference dose for methylmercury.
>
> The new NAS report was released in July 2000 and garnered significant
> media attention. The 2000 NAS committee endorsed EPA\'s mercury
> standard of 1 mcg/kg/body weight/day.
>
> NAS said EPA\'s reference dose is \"scientifically justifiable for the
> protection of public health.\" Of particular note, the NAS estimated
> that over 60,000 U.S. children are born each year at risk or
> neurological problems due to in-utero exposure to methylmercury.
>
> What got little attention in the report was the committee\'s call for
> harmonization of the mercury standard among the different agencies,
> and as the earlier NAS report found, several of the panel\'s
> recommendations, when applied to FDA\'s action level for
> methylmercury, revealed fatal flaws in FDA\'s standard-setting
> process.
>
> Specifically, the 2000 NAS panel found the following: There is a
> strong database of human and animal studies showing neurotoxic
> effects, but that these are not included in the basis for FDA\'s
> current action level.
>
> Second, the NAS said that the developmental neurotoxicity should be
> the endpoint in calculating the appropriate regulatory level for
> methylmercury, but FDA has used overt neurological symptoms in adults
> as the endpoint, therefore, its action level is set to protect adult
> men weighing 154 pounds and over.
>
> Third, the NAS recommended a benchmark limit of 58 parts per billion
> in the cord blood, which corresponds to approximately 12 parts per
> million in hair, but FDA\'s standard is approximately four times
> higher than this.
>
> This report added to the large body of science showing the adverse
> effects of low level methylmercury exposure on the developing fetus,
> and since then, CSPI has resubmitted our petition asking again for FDA
> to take action.
>
> More than a decade has passed since the first National Academy of
> Sciences\' report criticized FDA\'s standard for failing to offer
> adequate protection especially for the unborn. A full decade has
> passed since consumer groups first petitioned FDA to address this
> flaw.
>
> Consumers should not have to continue to wait. We have waited through
> the publication of two National Academy of Sciences\' reports, which
> essentially reached the same conclusion, for the FDA to take action to
> protect our health and our children.
>
> We have a mountain of evidence today supporting our call for a more
> protective standard for methylmercury in seafood, and we hope that
> this committee will help move the Agency in the direction of setting
> an enforceable standard.
>
> Thank you.
>
> DR. MILLER: Thank you, Caroline.
>
> Comments, questions?
>
> **Questions of Clarification**
>
> DR. APOSHIAN: If there are no questions, I would like to make a
> comment and a request. From the reading that I have done, especially
> on Sunday, there is a report put out by the General Accounting
> Office\--is that what it is called, GAO of the U.S. Government.
>
> It is dated January 31st, 2001. It is a critique of the FDA\'s Seafood
> Safety Program. It is GAO-01204. Could the members of the committee
> get an executive summary, a copy of the executive summary of that
> report? Is that possible, because I think it would be valuable for us
> especially in light of what was just said in criticism of the FDA to
> see what the General Accounting Office\'s comments were. Thank you.
>
> DR. DICKINSON: Caroline, I saw your petition on the web materials that
> were provided for us here. I believe you asked for an actual action
> level or limit or regulatory limit of 0.1?
>
> MS. SMITH DeWAAL: No, 1 part per million is the current standard. We
> considered asking for\--actually, no, you are right, the cover letter
> to the petition this time asked them to use the EPA reference dose as
> their new action level while they set a formal regulatory limit.
>
> DR. DICKINSON: And that would be 0.1.
>
> MS. SMITH DeWAAL: Yes.
>
> DR. DICKINSON: Micrograms per what?
>
> MS. SMITH DeWAAL: Micrograms per kilogram.
>
> DR. DICKINSON: Per kilogram of?
>
> MS. SMITH DeWAAL: Body weight. The problem is they have got to
> transfer that back to allowable level in fish.
>
> DR. DICKINSON: And what, in your view, would be that level?
>
> MS. SMITH DeWAAL: It would probably be 0.25.
>
> DR. DICKINSON: And we have been given a number of tables.
>
> MS. SMITH DeWAAL: That is 0.25 part per million.
>
> DR. DICKINSON: Parts per million, right. We have been given 0.25 parts
> per million, right?
>
> MS. SMITH DeWAAL: 0.25.
>
> DR. DICKINSON: We have been given a number of tables on mercury levels
> in fish, and a substantial number of the samples do appear to exceed
> that level.
>
> MS. SMITH DeWAAL: Yes.
>
> DR. DICKINSON: What would be your comment on the impact of that?
>
> MS. SMITH DeWAAL: Well, I think, number one, it would allow them to
> make consumer advice that is more consistent and more health
> protective than the advice they have today, but in addition, the data
> that you have on the amount of mercury in fish is quite flawed. It is
> based on some data that was collected, some of it 20 years ago, 30
> years ago.
>
> There has been ongoing investigation of this by a newspaper down in
> Alabama, the Alabama Register, and they found significant amount of
> methylmercury in a number of species that aren\'t even listed by FDA.
>
> They also note that the U.S. Commerce Department has admitted that the
> data that FDA is using today to analyze methylmercury concentrations
> in seafood is seriously flawed, and I believe they are doing a new
> study, a new seafood fish study to determine what are appropriate
> levels.
>
> DR. DICKINSON: Without regard to exactly how old this data is, because
> I think we do have some newer data here, what is your comment if the
> result of that is to basically put out of bounds a large fraction of
> the current seafood supply?
>
> MS. SMITH DeWAAL: Well, first of all, I think the first question this
> committee needs to look at is regarding the consumer advisory and
> whether the basis, the 1 part per million standard should be the basis
> for that consumer advisory.
>
> I think you need to have a more protective standard in order to
> evaluate the fish that are taken in as part of that consumer advisory.
>
> Secondly, there are some species of fish which will never come within
> the legal limit. I believe that some species of shark and there are
> probably some species of swordfish which are regularly exceeding that
> limit.
>
> I think they need significant warnings. You know, we are basing these
> advice on the average consumer, but realistically, people who eat
> swordfish, eat it over and over again. People who eat shark, eat it
> over and over again, and most of us never eat it.
>
> So, I think we need to be realistic about who the consumers are, and
> there may be some species of fish which shouldn\'t be sold
> commercially. They could still be recreationally caught perhaps, but
> they shouldn\'t be sold commercially if they can\'t meet government
> limits.
>
> DR. SHANNON: I have for you, Dr. Miller, a question of process. You
> gave us five specific charges and questions we are here to address,
> and the issue that has come up here is both the maximum daily intake
> that the FDA uses of 0.4, should that be revised, and the issue of
> whether the FDA should be thinking about a regulatory action.
>
> Neither of those are part of the five questions. Should we, as the
> committee, therefore assume that we are not going to touch that?
>
> DR. MILLER: No, I think there are issues. We want to concentrate on
> the five questions, because that is the questions the Agency asked us
> to respond to, but the question of the dose level, I think is one of
> the questions, it is included in one of the questions.
>
> All of these issues have to be determined if you are going to try and
> answer the questions.
>
> DR. RUSSELL: You didn\'t speak too much about the ATSDR advisory,
> which I think their conclusion was that the level should be set at 0.3
> mcg/kg/day.
>
> As I look at that study, looked at the way they did it, they used the
> Seychelles study as the lead study or the critical study, whereas, the
> National Academy, as I look at their summary, I don\'t have the whole
> report, but as I look at the summary, is the Faroes study is the
> critical study.
>
> So, it is judging the science, I guess\--see if I have got this
> right\--it is two different committees, each feeling, one feeling that
> the science that should be emphasized in one analysis was different
> from the other analysis, so it is sort of a scientific disagreement, I
> gather. Is that correct?
>
> MS. SMITH DeWAAL: Yes, and I think there are two points I would make
> on this question. The first is that there are actually two studies
> that show adverse effects. One is the Faroe Islands, but the other is
> the New Zealand data.
>
> So, I think you have to look also at the New Zealand study because
> that should be weighted into this decision of which study to use. But
> the other thing is the Faroe Island study\--and I attended the meeting
> down in Raleigh, North Carolina, where all the scientists from both
> studies, and actually, it was about four studies, got together to
> compare their studies\--and clearly, there is a confounder in the
> Faroe Island study because of the presence of PCBs in that study, that
> is probably not in the fish in the Seychelles Islands.
>
> But a key consideration is in the U.S. population, we probably have
> similar consumption of PCBs in the seafood, so if there is a
> synergistic effect because of those two chemicals in the diet or in
> the fish at the same time, that may also be happening in the U.S.
> population.
>
> So, again, this is difficult because they are both well-designed
> studies, they are both by very excellent researchers and groups of
> researchers, but I think you need to figure out what best applies to
> the U.S. population.
>
> I will note that under the Food Quality Protection Act, which isn\'t
> applicable here, but it will tell you where Congress is going with
> that, they have told EPA to consider the synergistic effect of
> different chemicals in our diet.
>
> So, that is something that is currently going on at EPA in terms of
> their analysis of pesticides, and I think chemical residues in seafood
> is an extension of that analysis.
>
> DR. HOTCHKISS: We have heard and I think most would agree that there
> is good evidence for positive health benefits from consuming seafood
> products, and I think it is reasonable to expect that any restriction
> in the standard for methylmercury or mercury compounds in fish will
> either drive up the cost or reduce the availability of seafood
> products.
>
> Are you concerned that this may, in fact, have a negative health
> benefit for the U.S. population rather than a positive?
>
> MS. SMITH DeWAAL: Well, I think we are talking about different types
> of fish. I mean there are over 300 species of fish for sale in the
> U.S. There is a huge variety of fish. Some of them have methylmercury,
> a lot of them don\'t. The ones that have methylmercury tend to be
> predatory fish, they tend to be at the top of the food chain.
>
> You know, consumers could reduce their consumption of swordfish and
> shark and even fresh tuna steaks, and probably fill in with other
> species of fish that don\'t raise this problem. So, I don\'t see it as
> an either/or issue.
>
> DR. MILLER: Dr. McBride.
>
> DR. McBRIDE: I sense your concern about this issue, and perhaps we are
> not here to address the question of a regulation, but does your
> organization take a stand on the availability of cigarettes for the
> pregnant woman?
>
> MS. SMITH DeWAAL: The availability of cigarettes?
>
> DR. McBRIDE: Should they not be sold because they are toxic to
> pregnant women?
>
> MS. SMITH DeWAAL: We haven\'t worked on that issue. I don\'t know what
> our formal position would be. I mean there are specific warning labels
> on cigarettes that deal with pregnancy and on alcoholic beverages that
> deal with pregnancy.
>
> I don\'t see specific warning labels on seafood products for pregnant
> women.
>
> DR. McBRIDE: Might that not be an alternative to regulation?
>
> MS. SMITH DeWAAL: As long as the science is good and the data is good
> about which species of fish are actually the ones that are most at
> risk of causing harm including recommendations on tuna and other
> things, yes, warning labels might be a risk management strategy.
>
> DR. MILLER: Dr. Montville.
>
> DR. MONTVILLE: Dr. Miller mentioned this morning when we started that
> science is an important component of policy, but not all of it, and
> while we discussed the numbers, whether they should 0.1 or 0.4, I am
> really struck by Dr. Hotchkiss\' comment and yours that 1 in 10 women
> are over the current standards, so we have 11 million women over the
> current standard, and I don\'t think whether we lower it to 0.1 or
> 0.01, will have much effect on that.
>
> As a consumer activist, how can we get that word out and make it more
> effectively received, so that we have the end product we want, which
> is fewer women going over the limit?
>
> MS. SMITH DeWAAL: I have struggled with that question because this is,
> as I said when I started, this is something I have been working on for
> about 10 years with very little success.
>
> But one concept is the fish we are talking about tend to be pricey,
> they tend to be top end. Now, there is a whole issue about
> recreationally caught fish and subsistence, people who are fishing to
> actually provide protein for their families, but for the FDA model, we
> are really dealing with fish that are top-end fish.
>
> You know, perhaps there is a way to get the message out to those
> consumers who tend to be\--you know, I mean women who are anticipating
> becoming pregnant tend to be information seekers.
>
> We are trying to get consumer messages out to him on listeria already,
> I mean so there might be a way to do this, but the NHANES data clearly
> shows that the risk management strategies in use today are not working
> adequately to protect this population, and so we need, you know, and
> one idea is to just let\'s take the worst fish off the market to get
> the largest\--because it\'s not all tuna, it\'s probably not all
> shark, it\'s the large ones, it\'s the ones that are really that are
> older that have lived a long time. They are probably also the
> breeders.
>
> So, you need to figure out how you are going to manage this, and one
> way to manage it is the size of the fish that is allowed for
> commercial consumption, and if you had smaller versions of that\--I
> would urge people on this committee to go back and look at the
> original 1991 NAS study, because they actually went through and
> analyzed if you reduced the size of the fish available for commercial
> consumption, what kind of impact that might have.
>
> DR. MILLER: Other questions?
>
> MR. SCHOLZ: Could you maybe just spend a minute, that you had
> mentioned in passing, a little bit on labels and signage at retail,
> what would your expectations be considering what you just said about
> which fish should be made available based on size, what if we have
> acceptable levels, and because we are targeting a certain part of the
> population at retail, what would the expectation be to try and address
> it with either warning label or signage?
>
> MS. SMITH DeWAAL: Well, I think the most effective tool is to use a
> label that actually affixes to the package, and the reason being that
> sometimes the person who is doing the shopping is not, in fact, the
> at-risk person.
>
> So, if you have it actually affixed to the package as it goes to the
> home, I think that is preferable to in-store signage, but it still
> doesn\'t deal with how to deal with the problem in restaurants. A lot
> of this fish is sold through restaurants.
>
> You know, it is a very popular menu item, and I suggested actually to
> the National Fisheries Institute that they run a campaign talking
> about how it\'s okay to have swordfish for your 50th, your golden
> anniversary, but it\'s not okay to celebrate the birth of your
> grandchild.
>
> You know, they are trying to put a message out there that people
> within a certain age group, women within a certain age group should
> not be eating these species of fish and trying to get that message out
> because a lot of it, even packaged stuff, label affixed to the package
> won\'t address the complete problem.
>
> Consumer education also is limited. I mean we have a lot of messages
> we need to get out to consumers. Right now I am working on like cook
> your hamburgers, which after years and years, 10 years of major
> problems, we are still having to get that message out, and we are
> still having a limited effectiveness.
>
> So, I just want to tell you from someone who really works hard to get
> good consumer messages out to the public, and with a readership of
> 800,000, this is tough to get messages out and have them listened to.
>
> DR. APOSHIAN: I have learned more about fish during the last three
> weeks than I thought I would ever know in my whole life, but I am a
> skeptic and I went looking for data, and it is my understanding that
> the FDA does not have enough money to assay fish for mercury.
>
> So, I took that on myself. I didn\'t do it in my own lab. I bought 11
> cans of tuna fish. I went to the store and I was quite shocked. My
> wife doesn\'t let me into grocery stores because she knows I am going
> to buy cakes and jelly doughnuts all the time, but I was surprised to
> find there are 21 different kinds of end brands of canned tuna fish,
> 6-ounce cans. I am not talking about the big one.
>
> I wonder about some uneducated person walking in. But anyway, we took
> 1 of 11. We bought 11 different cans for I think it was about \$12.00.
>
> I called the Clarkson Laboratory. I didn\'t want to bias this with my
> own laboratory doing the work. The Clarkson Lab at the University of
> Rochester is considered to be the best analytical laboratory for
> mercury in the world. Some people might argue that, but I think the
> majority of people would say that, and they were very gracious.
>
> They agreed to analyze the tuna fish. Now, the action level of the FDA
> is 1 part per million, as I understand it, so I was curious to see how
> many of these samples were anywhere near 1 part per million.
>
> I also was surprised to find in my reading that something like 27
> percent of the seafood consumed in the United States is canned tuna. I
> think there is a figure something like that, that you can verify by
> going to some FDA data.
>
> To make a long story short, one of the samples, I won\'t say the brand
> name, but it was a sample of low sodium, so if your wife is pregnant,
> has high blood pressure, I am not a clinician, but I assume someone
> might say if you are going to eat canned tuna fish, take the low
> sodium one.
>
> That sample had 1.24 parts per million. It has 207.6 micrograms of
> methylmercury we are talking about in the six-ounce can. The mean of
> all these 11 was on the order of 0.233 parts per million.
>
> I am sort of surprised that our government doesn\'t give the FDA
> enough money to do this kind of survey. We just did 11 cans, but
> certainly I would not, and my wife still could become pregnant, that
> is, I certainly would not want her to be eating tuna fish with a 1.24
> parts per million of methylmercury, and I think something has to be
> done about protecting pregnant women and, more important for the
> future of the country, the children that are going to be born to these
> women from methylmercury, and if we don\'t advise them by putting it
> on a can, then, I think we are sort of wasting our time if it is
> canned.
>
> Certainly, when I go to a store now, or even when I buy a candy bar, I
> read how many calories are on the candy bar, and what else is in
> there, and I should think that the labeling of the amount of
> methylmercury, I know it is difficult in fresh fish bought in the
> market or in the restaurant, but in the can, the labeling of
> methylmercury in a can of fish ought to be a relatively easy thing to
> do.
>
> Thank you.
>
> DR. MILLER: That is an issue. Rather than get into a debate on
> solutions before we are ready for that debate, that issue will come up
> when we meet on Wednesday.
>
> Are there other comments?
>
> If not, thank you. You can run off to your chopped meat now.
>
> It is time for a break. Please be back and we will start exactly at
> 3:10.
>
> \[Break.\]
>
> Before Dr. Heimbach makes his presentation, Ms. DeRoever has a comment
> to make.
>
> MS. DeROEVER: This morning I believe I mentioned that we have asked
> our guest speakers to fill out a form related to possible financial
> associations with the seafood industry. I believe I this morning I
> mentioned that one of the gentlemen did, but at this time, the other
> form has come back and, for the record, I do want to announce that
> both Dr. Heimbach and Mr. Clewell do have a financial relationship
> with the seafood industry.
>
> DR. MILLER: The next speakers are Dr. James Heimbach and Mr. Harvey
> Clewell from the Environ Corporation talking about Fish Consumption
> Data and Risk Assessment Calculations.
>
> **Fish Consumption Data and Risk Assessment Calculations**
>
> **Dr. James Heimbach**
>
> DR. HEIMBACH: Thank you very much, Dr. Miller.
>
> My name is Jim Heimbach. I was asked to just real quickly fill in who
> is Jim Heimbach. I worked for the Food and Drug Administration for 10
> years, from 1978 to 1988, which is a period just about concurrent with
> Dr. Miller\'s tenure as the director of the Center for Food Safety and
> Applied Nutrition.
>
> After that, I spent four years in the Department of Agriculture as
> Associate Administrator of the Human Nutrition Information Service,
> Acting Administrator for two years. That is the part of USDA that does
> the food consumption surveys, so I had a fairly heavy hand in
> redesigning the continuing survey of food intakes for individuals to
> the form that it has taken and the data that we are going to be
> looking at today.
>
> In 1992, I left and went into consulting, and was most recently with
> Environ, which is how I am listed in the program, although in point of
> fact, about three weeks ago, I took early retirement and am now a
> private consultant. So, I should announce that most of the work that I
> am going to be reporting here was done while I was at Environ even
> though I am now presenting this as a private consultant.
>
> \[Slide.
>
> From where I am standing, I can\'t see this, so I am going to pull
> this out just to make sure I don\'t lose my place. You do have a
> handout version of my presentation. The handout version includes an
> abstract, which I am not putting on the screen for obvious reasons. It
> has lots of little words and you wouldn\'t be able to read it on the
> screen.
>
> Does exposure matter? Why am I talking about exposure? The EWG
> brochure suggested that the amount of fish that women eat should not
> have no impact on whether they receive sound advice about safe
> consumption levels.
>
> What I am simply pointing out is that the beginning of safety
> evaluation is looking at exposure, and while I am not going to presume
> to advise either the Food and Drug Administration or this committee on
> how you should approach your risk management responsibilities, I am
> going to suggest that an understanding of what the actual exposure
> situation looks like is an important starting point in determining how
> you want to move ahead.
>
> \[Slide.
>
> I so want to start with a very frequently misquoted line from
> Hippocrates, \"Make a habit of two things - to help, or at least do no
> harm.\"
>
> Can we move quickly through these slides.
>
> \[Slide.
>
> This is simply a reminder to everyone that fish is not simply a
> carrier for methylmercury or a carrier for dioxin or a carrier for
> PCBs or whatever we may be concerned about at the moment.
>
> It is a food. It is a food that is a very important part of the
> healthy diet.
>
> \[Slide.
>
> It has various benefits.
>
> \[Slide.
>
> Other speakers are going to be talking in far more detail as was
> already mentioned by Penny Kris-Etherton earlier. Both the American
> Heart Association and the American Dietetic Association, representing
> also the dieticians of Canada, have been recommending actually
> increasing consumption of fish in this country.
>
> \[Slide.
>
> That being said, let\'s take a look at what is the real information
> about fish consumption in the United States and exposure to
> methylmercury from this consumption.
>
> \[Slide.
>
> For some of you, this is going to be taking you back to kindergarten,
> but for those of you who do not make a career of dietary assessment, I
> just want to explain that the standard model that is used by virtually
> everyone who does dietary assessment as a portion of a risk analysis
> is that exposure is a function for each source of the food, what is
> the concentration of the contaminant of concern, and how much of that
> food do people eat.
>
> You multiply those two together, sum it over all of the different
> foods, and that gives you the total exposure.
>
> \[Slide.
>
> The information that we are using here or that we are going to be
> talking about here to estimate exposure are two sets of food
> consumption surveys. There is the Continuing Survey of Food Intakes by
> Individuals, known in typical governmentalese as the CSFII, 1989 to
> 1991, which was a three-day survey with one day of 24-hour recall
> followed by two days of food records kept by the respondents. That
> reports all foods consumed either at home or away from home, and
> includes estimates of the portion sizes of the food.
>
> In that survey, among the women age 15 to 44, 30.5 percent reported
> consuming fish at least one time over the three-day period.
>
> A more recent survey is the CSFII, 1994 and 96. This is also a
> national sample. This has two non-consecutive days of 24-hour recalls.
> That was part of the redesign that I was responsible for back when I
> was the Acting Administrator.
>
> Again, though, it reports all foods consumed both at home and away
> from home, and includes estimates of portion sizes.
>
> In that survey, 25.4 percent of the women age 15 to 44, who provided
> two days of data, reported consuming fish on at least one of those
> days.
>
> \[Slide.
>
> Now, here is basically the way we estimate exposure. Suppose we are
> interested in looking at exposure to caffeine. We might for a fairly
> typical woman that on day 1, she reports 180 grams of coffee and 240
> grams of tea, and I provided here some representative values for what
> the caffeine concentration might be in the coffee and the tea, which
> would lead to estimates of 90 milligrams of caffeine and 72 milligrams
> of caffeine from the coffee and tea respectively.
>
> On day 2, this woman might have had the same amount of coffee, and on
> that day she didn\'t have tea, but she had 360 grams of a soft drink
> with a caffeine content.
>
> So, what we would simply do is add up the caffeine intake across the 2
> days and get 288 milligrams. Since that represents caffeine intake
> over 2 days, we divide by 2 to get an intake estimate of 144
> milligrams of caffeine per day.
>
> Now, for a frequently consumed food or nutrient or contaminant, that
> is one, that has a non-zero exposure almost every day, this can be up
> to a point regarded as an estimate of the usual intake.
>
> In other words, it would not be unrealistic to say that this woman,
> this fictitious woman, usual intake is 144 milligrams of caffeine a
> day. You might legitimately estimate that her consumption over a week
> is about 7 times that, and over a month, is about 30 times that.
>
> \[Slide.
>
> However, if you are dealing with an infrequently consumed food, you
> can\'t use exactly that model, and my favorite example of an
> infrequently consumed food is liver. In the 1994 and 96 survey, about
> 1 percent of the respondents reported consuming liver.
>
> The 2-day average mean daily intake is 38 grams for these people who
> consumed liver. That would work out to a little over 30 pounds of
> liver a year. It would be really not very valid to assume that this 38
> grams a day represents a usual intake, that liver consumers consume 38
> grams of liver day-in, day-out, over a year.
>
> The 95th percentile would be over 100 pounds of liver in a year. So,
> we cannot for an infrequently consumed food, just take the information
> from a 2- or 3-day survey and directly regard it as the usual intake.
>
> \[Slide.
>
> Now, that may sound like something that no one would do, but in point
> of fact, it does happen, and here is a case where it did happen. This
> 60,000 newborns annually at risk has become sort of an urban legend.
> As a matter of fact, we just heard it in the previous presentation.
>
> This was given in the NAS report, the Toxicological Effects of
> Methylmercury. In the report itself, there was no explanation provided
> of where that number came from, and consequently, Joseph Levitt, the
> Director of CFSAN, wrote a letter to Dr. Robert Goyer, the chair of
> the committee, asking if he could provide more information about the
> basis for that number.
>
> \[Slide.
>
> From the letter that Dr. Goyer wrote back on December 6, 2000, this
> information was provided both in the body of the letter and in an
> attachment of a table from EPA, that the U.S. population of women of
> that age is 60 million, 30.5 percent are fish consumption, gives you
> 18 million. The highest 5 percent consuming 100 grams of fish per day
> gives you 918,000. Then you apply the birth rate, and you get 60,000
> newborns at risk.
>
> \[Slide.
>
> I want to focus on two of these numbers, the percent reporting fish
> consumption, 30.5 percent, and the highest 5 percent exposed consume
> 100 grams of fish per day.
>
> \[Slide.
>
> At the top, it just repeats those numbers. The bottom shows where
> those numbers come from. They were both buried in the EPA Mercury
> Study Report to Congress from 1997, which reported in the text, it
> actually wasn\'t in any tables, that 30.5 percent of women aged 15 to
> 44 report fish consumption during the 3-day survey period.
>
> This is not the percentage of women who consumed fish, which is more
> like 80-some percent. This is how many women consumed food during that
> 3-day period.
>
> Similarly, the 95th percentile fish consumption of women age\--it said
> 15 to 45, I don\'t know if they changed the base or just wrote the
> number down wrong\--is 113 grams based on the average of 3, 24-hour
> dietary recalls. Now, it is actually one dietary recall and 2-day
> records, but the point is that is a 3-day average. That is not for an
> infrequently consumed food, such as fish, a legitimate estimator of
> the usual intake.
>
> \[Slide.
>
> In conclusion, the figure on fish consumption is 3-day average. It
> represents only the distribution of fish consumption over those 3 days
> by the women who reported fish consumption during that period.
>
> It overestimates the usual intake of fish even for those women who
> were going to be obviously over-representing frequent fish consumers,
> and it clearly overestimates the usual intake of fish for the women
> population aged 15 to 44 in the U.S. The actual best estimator is more
> on the range of 45 grams, as we will see later.
>
> So, this shows the importance to my mind of doing your exposure
> estimations correctly.
>
> \[Slide.
>
> When we are looking at an infrequently consumed food, then, we have to
> have a different way of approaching what constitutes the consumption,
> and the way that is universally used by FDA, by EPA, by JCFA, part of
> WHO, pretty universally around the world is to redefine the
> consumption as being the amount consumed per eating occasion or the
> portion for short, times the frequency of eating occasions.
>
> So, now, our exposure estimator is what is the concentration of
> contaminant X in the food, what is the portion size chosen of that
> food, and what is the frequency with which that food is eaten. You
> multiply those three together and sum it over all of the sources, and
> that is your estimator of usual exposure.
>
> \[Slide.
>
> Now, in a dream world, we would have all this information on the same
> people. The only way we could have that is to have many days of intake
> data, have data for a month, say, or possibly to have intake data and
> a food frequency questionnaire administered to the same population,
> which is now what has been instituted with NHANES, but had not been
> done before the 1999-2000 survey.
>
> Even there, there are some questions about the validity of food
> frequency questionnaires.
>
> If you do not have information from the same people, then, what you do
> is you use probabilistic methods to put these distributions together.
> So, we will select from a frequency distribution that has a
> distribution of how frequently women of age 15 to 44 consume fish.
>
> We will select for each eating occasion from what amounts of fish they
> consume on each of their eating occasions, and we will select from
> distribution depending on what species of fish we have here from the
> mercury concentration distribution for that species of fish, and bring
> these all together with Monte Carlo.
>
> \[Slide.
>
> So, we need information on the concentrations, the distribution of
> concentrations of methylmercury in all species of fish for which
> consumption is reported in the surveys. We need to know the fish
> dishes and the portion sizes that are selected by women age 15 to 44,
> and the frequency of fish eating occasions.
>
> \[Slide.
>
> First, methylmercury concentrations. There are lots of datasets. This
> has been alluded to with methylmercury concentration. We specifically
> and very deliberately use the mean methylmercury concentrations that
> EPA used in its 1997 Report to Congress.
>
> The reason for this is simply that with different estimation methods,
> you end up with slightly different numbers. It is nice to have at
> least some things in common, so that you can understand what is the
> effect of your methods versus what is the effect of different
> databases that you used, so we deliberately start with the same data.
>
> We use that same information in a report that we provided to FDA in
> 2000 and in a paper that we presented at the Society for Risk Analysis
> in Seattle in December of 2001. Those were only point estimates.
>
> The distribution data came from the National Marine Fisheries Service
> 1975 Interim Report. The complete dataset that relates to those means
> has been lost, and despite a lot of efforts by FDA and the National
> Marine Fisheries and us and the National Fisheries Institute, and who
> else defined it, we never could, so we found this interim report, and
> we used that as the basis to use regressions to derive log-linear
> models of the methylmercury distribution for fish.
>
> I should mention, by the way, that when you use a mathematical model,
> you realize they are unbounded, whereas, biological distributions
> usually are bounded, so we actually produced some mathematical
> estimators of mercury concentration in fish that probably would never
> be met with in real life, even higher than even numbers that have ever
> appeared in analytical testing. We used them anyway.
>
> Finally, when you apply these methylmercury concentrations that were
> measured on raw fish to fish as consumed, you have to take into
> account the fact that when fish is prepared, usually with heating
> methods of one sort or another, it drives off moisture, and since the
> methylmercury is not driven off, the fish, as consumed, has a higher
> concentration of methylmercury than the raw fish did. So, that needs
> to be taken into account when you are estimating exposure also.
>
> \[Slide.
>
> For portion sizes, we used data from the CSFII 94-96, where the foods
> are reported \"as consumed.\" Now that means that somebody says I had
> a tuna casserole or I had fish sticks. They don\'t say I had 13.6
> grams of salmon, for example. To go from the food as consumed to how
> much fish people consumed, we used these two translation files, first,
> the EPA translation file followed by the recipe files from USDA.
>
> \[Slide.
>
> Here is an example. Here actually are two examples, I am just going to
> mention the top one, Food Code 28355260 is lobster gumbo. That is a
> moist heat processing meaning that whatever is the concentration that
> we draw in the Monte Carlo for the mercury concentration of the
> lobster, we will multiply that by 1.14 to estimate what the mercury
> concentration is going to be in the lobster as consumed in this.
>
> This recipe file shows the lobster constitutes 11.06 percent of this
> dish, so for every 100 grams of lobster gumbo somebody consumes, the
> assumption is they got 11.06 grams of lobster.
>
> The second one there is simply to point out that some foods actually
> contain more than one type of fish, and if so, we need to sum the
> mercury concentration from all of the fish to estimate what the person
> is getting from that eating occasion.
>
> \[Slide.
>
> In the CSFII, 593 women reported a total of 717 fish-eating occasions,
> representing 34 species of fish. Now, this 34 species, there are
> actually more forms than that because we have fresh tuna, for example,
> separately from canned tuna. We have fresh lobster separately from
> canned lobster, and like that. We have farm trout separately from
> caught trout.
>
> This, you are going to see the significance of in a minute. For the
> women who reported more than a single fish-eating occasion, the same
> species was reported 30 percent of the time. This refers back to
> something that a couple of previous speakers have alluded to, that
> there is a certain degree of species loyalty, if you will. Women who
> eat canned tuna tend to re-eat canned tuna. Women who eat salmon tend
> to re-eat salmon, men, too, I suppose, but we are looking at women
> here, so you will see what we did with that in a moment.
>
> Also, you will see what you did with this in a moment, 64 percent of
> the reported fish-eating occasions at home, 36 percent away from home.
>
> \[Slide.
>
> Now, to estimate frequency, first, we used a single food frequency
> question from NHANES III that asked the number of times fish was eaten
> per day, per week, or per month. The problem with that data set is it
> provides very weak information at the higher frequencies of
> distribution.
>
> One of the things that you have in your packet of materials is an
> analysis that we provided to FDA back in 2000 on consumption of canned
> tuna. There, we did a little convergent validity study looking at
> three different ways of estimating frequency.
>
> One was just using the NHANES question alone. The second brought in
> the NET survey, which I will describe in a moment. Using the NET
> survey, actually, it gave us the highest estimates of frequency of
> consumption, so it is a very conservative way to go, but it does give
> us a better estimator, and that is our goal, was to get the best
> estimate we can.
>
> The National Eating Trends Survey is a diary of foods eaten over 14
> days. It is a demographically balanced sample, but it is a national
> probability sample. They do not report portion size data, they merely
> report the fact of eating.
>
> We put together four years of data to get a reasonable sample size,
> and we had a sample size of 3,881 women age 18 to 44 was the closest
> we could get to our 15 to 44 group that we were using, of whom just
> over half reported eating fish consumption at least once over the 14
> days. Of those, just over half reported eating it exactly once.
>
> However, that is only fish eaten at home. So, first, we multiplied by
> 30/14ths to estimate times per month and then we estimated total
> consumption by multiplying by 100/64, remember that 64 percent of fish
> was eaten at home, to get include meals away from home.
>
> Now, that does mean that the minimum that could be reported, if a
> woman reported eating one fish meal in that 14-day survey, it would be
> estimate of three fish meals a month would result from that estimate.
>
> So, then we used the NHANES data to estimate the proportion of people
> eating fish once or two times a month, and for the analysis we did, of
> course, we simply did not include at all women who did not report
> eating fish ever.
>
> \[Slide.
>
> Now, the first study we did with using this approach was done
> following exactly that methodology except we did not get into the
> mercury concentrations, we simply used the point estimate from the EPA
> Report to Congress, and this is what we used for the report that we
> provided to FDA in November of 2000 and presented at the Society for
> Risk Analysis.
>
> \[Slide.
>
> According to that analysis, the data on the consumption of fish\--and
> the reason I am going back here is because on the current analysis, we
> focused only on mercury, and actually, we didn\'t estimate fish, the
> Monte Carlo took us right through fish to mercury\--estimated that the
> mean, and I am going to go straight to the mean intake of fish per
> eating occasion, so that is the average portion size is 32.4 grams.
>
> I want to interrupt to point out that is 2.6 ounces, and there seems
> to be a tendency to take FDA\'s advisory of not go over about 12
> ounces a week to two, 6-ounce servings. Very few women eat a serving
> of fish anywhere near 6 ounces.
>
> It is no accident that the reference amount commonly consumed for the
> purpose of labeling set by FDA was 55 grams for canned fish and 85
> grams for fish steaks and fish fillets, and so forth, and those
> numbers are actually based on information from the 1989 to 1991 CSFII,
> about what portion sizes are most commonly chosen.
>
> So, this 72.4 grams that we have represents an average of the roughly
> 30-odd percent that was canned fish combined with the others. So, the
> women actually only average 2.6 ounces per eating occasion of fish.
>
> The average frequency of eating fish is about 4.6 times a month, a
> little over once per week, and consequently, the usual intake is about
> 11.3 grams a day, which is the equivalent of about 2.8 ounces of fish
> per week. So, that is the mean fish intake of women age 15 to 44 in
> the United States.
>
> The 95th percentile intake, taking us up near the top of the
> distribution, comes out to about 11.3 ounces per week. Now,
> interestingly enough, FDA also estimated usual intake at relatively
> high levels of intake using a somewhat different methodology and
> estimated that the 96th percentile is the 12 ounces of week that is
> the limit of their recommended intake, so there is very high
> correspondence between our estimate of the 95th percentile is 11.3
> ounces, and FDA\'s estimate that the 96th percentile is 12 ounces.
>
> \[Slide.
>
> So, for the current analysis, we did a 100,000 iterations. The basic
> approach is first you do draw from the frequency distribution. You
> might draw this woman, has 3 fish-eating occasions per month.
>
> Then, you go into the CSFII dish/portion distribution, randomly select
> one of the 717 eating occasions, say this is what that woman ate, and
> then for that portion, depending on what species, how it is prepared,
> you draw from the methylmercury concentration distribution for that
> species, adjust for the cooking factor to increase the methylmercury
> content, and then you go back to the basically draw the second
> occasion.
>
> \[Slide.
>
> Now, let\'s see what we did with the repeat meal probability. For the
> repeat meal probability, based on the fact that women have a
> preference here to go back to the same foods, what we did was
> establish a 0.3 probability that when we go back for the second draw
> for the same woman, for the one that we have drawn, let\'s say she is
> going to have fish 3 times in the month.
>
> If our first draw was, let\'s say, 85 grams of salmon, for the second
> draw, instead of drawing randomly, if that 0.3 probability comes up,
> we give her 85 grams of salmon again. Now, we redraw from the
> methylmercury distribution because it is going to be a new source of
> salmon, but she has a 0.3 probability of getting exactly the same
> species and the same portion size again.
>
> This tends to increase for this brand loyalty. Some who was first
> selected as having canned tuna, is more likely on the next draw to get
> canned tuna again than somebody who had a different species, and so
> forth.
>
> What this does tend to do, it tends to draw out your extremes. It
> increases the 95th, 99th, and so forth, percentiles. It doesn\'t
> change the mean, but it puts the percentiles further out because the
> women who have a preference for relatively high
> methylmercury-containing fish, will get up higher by repeating that
> fish for them over and over than if we were randomly selecting the
> fish each time.
>
> \[Slide.
>
> Here is where we come out. The mean intake of methylmercury is about
> 1.4 mcg/day. Now, in comparing that with the EPA RfD, which is 0.1
> mcg/kg, our intake of course is per person, not per kilogram. For a
> 60-kg woman, that works out to 6 mcg a day. That is a little
> conservative. More often you use 65 kg, which would give you 6.5 mcg a
> day, but looking at what would be protective for even a somewhat
> smaller than average woman.
>
> All the way down at the 95th percentile of intake, we are still
> looking at an intake of about 4.7 mcg/person/day or, for a 60-gram
> woman, 0.08 mcg/kg/body weight. It is not until we get up well beyond
> the 95th percentile that we pass the RfD.
>
> At the 99th percentile of intake, we are looking at 8.9 mcg/day. Keep
> in mind what I told you, though, that this is an unbounded
> distribution. As we get up high enough, we begin to see more and more
> the effects of us not drawing a limit on biological plausibility for
> how much mercury one sample of fish might be assumed to have.
>
> \[Slide.
>
> We compared the intake distribution with three endpoints that have
> been discussed - the EPA RfD of 0.1 mcg/kg, the ATSDR minimal risk
> level of 0.3 mcg/kg/body weight/day, and EPA\'s BMDL of 1.0
> mcg/kg/day.
>
> Now, I am not a toxicologist, I am not going to attempt to discuss
> what the biological significance of exceeding those numbers is. I am
> simply using those as markers.
>
> What we get is that about 2.9 percent of women, assuming 60 kg women,
> are above the RfD, 0.2 percent above the MRL, and something on the
> order of 0.0001 percent above the benchmark dose.
>
> \[Slide.
>
> Now, you may remember that FDA\'s advisory had put some emphasis on
> variety. I highlighted it a couple of places here by putting it in
> red. As long as you select a variety of other kinds of fish, you can
> safely enjoy eating them. Just pick a variety of different species.
>
> Now, we can look at the effect of increasing the variety of fish by
> taking out that repeat meal probability. Remember, we basically made a
> woman who selected one type of fish for her first meal, to have a 0.3
> probability of getting that same fish assigned to her willy-nilly.
> Just by taking that down to zero, so that each meal is assumed to
> select according to marker probability, now, canned tuna still has
> about a 29 percent chance of being selected and porgy has a very small
> chance of being selected, but we are not enforcing it.
>
> \[Slide.
>
> The effect of dropping that repeat meal probability from 0.3 to zero
> is to reduce the number of exposures over the RfD by about 10 percent,
> from 2.9 to 2.6 percent, drop exposures over the MRL by about 50
> percent, from 0.2 percent to about 0.1 percent, and exposures over the
> BMDL were essentially at zero anyway, and they add another couple of
> decimal points before the first figure when you increase the variety.
>
> \[Slide.
>
> So, what do we conclude? First, at current levels of fish consumption,
> women age 15 to 44 are very rarely exposed to methylmercury from
> commercial fish, and I do want to emphasize we are only looking at
> commercial fish here. We are not taking into account recreational or
> subsistence fisher information, which are not fish that are regulated
> by FDA, and it is not directly influenced by FDA advisory.
>
> They simply are not exposed to levels of methylmercury that would
> place the newborn children at risk.
>
> Second, FDA\'s current advisory, assuming it is adequately publicized,
> is adequately protective of pregnant women, not just average women,
> but also women who are fairly heavy consumers of fish.
>
> Finally, further, FDA\'s advice to choose a variety of fish is
> appropriate advice, it is well-conceived advice, it is certainly very
> sound nutritional advice, and also is advice that will result, to the
> extent that it is followed, in reducing methylmercury intake for the
> same level of consumption of fish.
>
> \[Slide.
>
> Additional conclusions. The exposure data do not suggest a need to
> revise the current FDA advisory. They do not suggest a need to advise
> women to avoid or limit consumptions of species of fish other than
> those listed.
>
> As I said, the modeling indicates that increasing the variety may
> reduce exposure to methylmercury, and suggests that perhaps that part
> of the advisory might be strengthened.
>
> Thank you very much for your attention.
>
> DR. MILLER: Thank you.
>
> Comments or questions?
>
> **Questions of Clarification**
>
> DR. NORDGREN: How many people eat porgy? That\'s the worst tasting
> stuff.
>
> DR. HEIMBACH: I suspect very few. That is actually why I selected it
> as an example of one that is infrequently reported. To tell you the
> truth, I don\'t know if we even had a single eating occasion of it
> reported.
>
> I should mention, by the way, that we are writing up these data now
> for publication, believing fairly strongly that something is not
> really a scientifically justifiable piece of material until it has
> been peer reviewed and published.
>
> DR. SHANNON: If I have been following the afternoon, your data are
> very different from the data from NHANES, which suggested that some
> significant percentage of women have excess amounts of mercury in
> their blood from a source that seems to be fish, and that there is a
> fairly good correlation between their fish consumption and their blood
> mercury.
>
> Can you kind of help me reconcile what you just told us with what she
> said? They are different, aren\'t they?
>
> DR. HEIMBACH: Only to a point can I help you reconcile, and actually
> Harvey is going to address that more. I have no expertise whatsoever
> in the pharmacokinetics of mercury transport and the linkage between
> what fish goes in and what ends up in your blood or in your hair is
> not where I have expertise.
>
> I would simply point out that although for most people, my
> understanding is fish is the major, not to say the predominant, source
> of methylmercury in the diet, it is certainly not the only source of
> either methylmercury or mercury in general.
>
> As a matter of fact, although I have not looked at the raw data, I am
> given to understand that the woman that was mentioned as having the
> highest blood level that they got in the survey, 29\--was it
> micrograms per liter\--is actually somebody who had reported no fish
> consumption, so there are other possible sources of mercury in the
> diet.
>
> So, I would not necessarily expect to find an exact\--I would expect
> to find a correlation certainly, but not necessarily an exact
> one-to-one correspondence between fish consumption or even
> methylmercury consumption and blood methylmercury level.
>
> DR. SHANNON: But I am looking at a result based on someone\'s real
> data on real American women, and really what seems to be a lot of
> probability really and more theory on your part, and I see
> differences, and actually what you just said doesn\'t help me in terms
> of understanding why you can say that you don\'t think there is excess
> exposure, no reason to change anything when we have real live data
> measurements in blood to suggest that there is a problem.
>
> DR. HEIMBACH: As I said, I am going to let Harvey address most of
> this. I don\'t see that what you see as a difference is that great. I
> will point out I mean we are talking real live people in the exposure
> estimate, too, but we are talking about dietary intake, not blood
> mercury levels.
>
> According to the dietary intake data, we would have approximately 2.9
> percent of women ingesting methylmercury from fish above the RfD, and
> I believe the NHANES had an estimate of 7.8 percent above the RfD
> based on blood levels.
>
> I would be perfectly happy to suggest that as estimates of this kind
> of thing go with the unanswered question, those are actually not
> tremendously divergent numbers.
>
> DR. MILLER: Before we go ahead, I hadn\'t realized that Mr. Clewell
> was going to speak also on the subject. Why don\'t we let him provide
> his information. That may help clarify some of these issues.
>
> **Mr. Harvey Clewell**
>
> MR. CLEWELL: I am going to continue on from where Jim left off.
>
> \[Slide.
>
> He was predicting intakes. We use very similar methods in terms of the
> Monte Carlo analysis, selecting fish meals, to what he described, but
> we used a pharmacokinetic model to predict blood levels as opposed to
> just predicting intakes.
>
> \[Slide.
>
> First of all, I was asked to look at the Environmental Working Group
> pamphlet that is called \"Brain Food,\" that talked about analysis of
> maternal blood levels, and see if we could reproduce their
> calculations and what we would say about those calculations.
>
> I will tell you a little about that, and then I will talk about one of
> the kind of implicit assumptions in many of the analyses that have
> been done and talked about, which is the appropriateness of using the
> reference dose as a bright line for evaluation of safety.
>
> Then, I will give you our analysis, which is the end-gestation blood
> levels associated with current fish ingestion patterns in U.S. women
> of child-bearing age.
>
> Finally, I will compare that with the NHANES analysis in terms of a
> reality check for the calculations.
>
> \[Slide.
>
> The initial scenarios that we ran were based on, as I mentioned,
> analyses performed by the Environmental Working Group. One was a
> maximal ingestion of a variety of fish, two, 6-ounce meals each and
> every week through pregnancy, and then the second was the repeated
> ingestion of just a single type of fish through pregnancy.
>
> We tried as best as we could to reproduce the assumptions of the
> Environmental Working Group analysis in terms of the scenario for the
> exposure, and what we were really doing was using our published
> physiologically-based pharmacokinetic model of methylmercury kinetics
> during pregnancy instead of the one compartment model of Allen Stern
> that was used by the Environmental Working Group.
>
> The model that I am going to show you on the next couple of slides is
> the same model that Dr. DeRosa mentioned this morning. I did some
> calculations that were used by ATSDR in the development of their
> minimal risk level, and that analysis has been published in that
> Clewell, et al. 1999 risk analysis.
>
> \[Slide.
>
> This is the model, and there is a lot of compartments, and actually,
> years ago when I started working on methylmercury, I thought it was
> kind of funny to suggest using more than one compartment for
> methylmercury kinetics, but I found when you are doing Monte Carlo
> analysis, you actually need all those compartments, and in particular,
> if you are trying to model gestation, pregnancy and gestation, they
> are absolutely critical to look at the changes in tissues during
> gestation, changes in fluids.
>
> The mother\'s tissues, of course, change relative volume at the same
> time that the fetus is growing, and so all of these many compartments
> are actually required in order to track the behavior of methylmercury
> during pregnancy and gestation as opposed to just in a non-pregnant
> adult.
>
> So, the model actually has time-dependent values for all of the
> parameters for the various tissues, blood flows, and so on, in both
> the mother and the fetus.
>
> \[Slide.
>
> You see here just an example of using the model. We actually developed
> the model originally in monkey data and then we extrapolated to the
> human and validated it with the human data. This is a study by
> Gunderson, which shows the time course. The actual bars there are the
> best estimates and error bars for the data that was collected by
> Gunderson for a 50 mcg/kg/day methylmercury exposure in the diet of
> monkeys, and the dotted line represents conception.
>
> You can see a fairly complex time course of methylmercury even though
> the daily dose is constant, and this is because, of course, the change
> in the tissues in both the fetus and the mother through pregnancy and
> also the mother\'s tendency to change her dietary ingestion rate, the
> number of kilograms she ingests per day of food.
>
> So, the solid lines then, they are thick because actually, the model
> is dosing each day with whatever the dietary intake is, and so there
> is a little bit of increase at the time of the meal, but those are the
> predictions of the model for this monkey study, the lower points and
> line being the mother, and the upper one being the blood of the infant
> at birth.
>
> I want to mention while this reminds me regarding sensitive window. If
> you have high enough mercury levels, you can actually kill the fetus.
> See the fetal toxic levels, that will occur in the first trimester,
> they won\'t make it past the first trimester.
>
> Lower levels, still very high, Minamata type levels, you actually will
> survive and be born, however, there will be severe malformations. Choi
> \[ph\] has shown that those primarily occur. The major malformations,
> primarily the effects occur in the second trimester.
>
> For the subtle neurological effects that we are talking about now, the
> group at Rochester has argued, and I agree, that the effects are
> primarily third trimester and probably continue on postnatally if
> there were exposure. Typically, mercury exposures reduce at birth
> because you don\'t immediately begin eating fish, and there is not
> very much lactational transfer.
>
> So, the susceptible window for what we are worrying about here is the
> third trimester.
>
> \[Slide.
>
> This is an example one of the validation datasets. This is a
> mother-infant pair from the Iraqi poisoning. Amin-Zaki recorded the
> blood levels and hair levels of this individual. She was admitted
> because of toxicity to the hospital after she had already been
> pregnant for some time.
>
> They were able to reconstruct her exposure using hair segments, and so
> you can see the circles and the solid line are the observed and
> predicted maternal hair levels during the period of pregnancy as shown
> by the solid bar near the bottom there, that goes from about 200 days
> to 460 days.
>
> Then, once she was admitted, they began to measure her blood, and
> those are the triangles. You can see the model predictions for the
> blood. It shows the concentrations during pregnancy were actually much
> higher than they were during early pregnancy, were actually much
> higher than they were at the time she was admitted to the hospital,
> which was during the third trimester.
>
> Finally, when the infant was born, then, they measured its blood
> levels. Those are shown as the diamonds, and you can see that the
> model also predicts the blood levels at birth. So, this is the model
> that we used in this analysis.
>
> \[Slide.
>
> Unfortunately, we were unable to reproduce the Environmental Working
> Group\'s results for their first scenario. The 12 ounces per week, we
> were able to generate a lot of different numbers, but none that were
> anywhere near the ones that they had reported in their figure, so we
> finally gave up.
>
> We were, however, able to reproduce the second scenario, which is
> using a single type of fish. It was a simpler analysis, and it was
> easier for us to figure out what they had done.
>
> So, when we used the same pharmacokinetic model they used, the Stern
> model, then, we were able to reproduce their data, but as I will show
> you on the next slide, if we used the model I just showed you, we
> actually get lower blood level estimates.
>
> I actually anticipated this would be true because in some earlier work
> I did, I found that Allen Stern\'s model overestimates blood
> concentrations resulting from dietary methylmercury exposures. He was
> doing a Monte Carlo analysis, and wasn\'t actually validating the
> model against the exposure data that was available, so it just
> happened that the model parameters give you high estimates.
>
> That is documented in a publication, which is an entire of issue of
> Toxicology and Industrial Health, Shipp et al\--I am one of the
> al\'s\--that came out recently.
>
> \[Slide.
>
> On the left is the actual figure from the Brain Food pamphlet. We have
> made all of the curves black except for the ones that we reproduced or
> attempted to reproduce. We just selected some in order to test whether
> our understanding of the methodology was correct.
>
> If you compare the green and purple and yellow and orange lines, you
> will see we got fairly good reproductions given the fact that we were
> using a very different pharmacokinetic model. The only one we weren\'t
> able to really reproduce was sea bass, which is the highest value up
> there, but so we felt reasonably good that we probably understood what
> the Environmental Working Group was doing.
>
> We were using the Stern model there, I am sorry, but so we were able
> to roughly reproduce what they had done.
>
> \[Slide.
>
> Now, this slide shows the difference between using the Stern
> pharmacokinetic one-compartment model and using our model on the
> right. You can see that the sea bass now is the purple line in the
> center of the diagram on the right. All of the predicted
> concentrations come down.
>
> I don\'t actually know how to describe what these plots are. I presume
> you will hear that from the Environmental Working Group. The Y axis is
> kind of astounding. Percent increase in the number of women whose
> blood mercury level would exceed 5.8 parts per billion for more than a
> month of pregnancy. I have never actually seen a risk metric described
> that way.
>
> At any rate, it is sort of a measure of blood levels, and I believe
> that the EWG\'s are overestimates.
>
> \[Slide.
>
> This has been described in three different talks this morning, but I
> just want to remind you that the basis of the reference dose, the RfD
> was the neurological effects in fishing, the populations that were
> exposed for generations.
>
> The dose-response was used to predict a benchmark dose. I am a
> benchmark dose modeler and a BMR of 5 percent is quite conservative.
> Actually, in studies where they have compared it with the NOAEL, it is
> more conservative than a No Effect Level, so this is a very
> conservative estimate of an effect level. This is not an estimate that
> should be comparable to a lowest observed adverse effect level. It is
> actually more conservative than a no observed adverse effect level.
>
> The Boston Naming Test, BMDL of 5 was used with an uncertainty factor
> of 10 to drive the RfD.
>
> \[Slide.
>
> As has been mentioned a number of times, the Faroe Islands study was a
> large study, but it was compromised in terms of implications of fish
> ingestion by the consumption of whale meat, as well, which is not only
> higher in methylmercury and the blubber contains PCBs, but also it\'s
> a seasonal thing, so that there is more spiking in terms of large
> presentation of mercury to the fetus.
>
> As a result, there is a continuing controversy which will not be
> resolved regarding co-exposure to PCBs and other potentially
> confounding factors, such as the Torshaven effect. Some people with
> low mercury mostly lived in Torshaven, whereas, the people with high
> mercury typically live out on the Islands. It is very difficult to
> work out that kind of an issue.
>
> One quick comment on the PCB co-exposure. I am the only one here who
> can probably tell you this, because Kenny Crump is not here, he\'s in
> China teaching Chinese how to speak English, but he was the one who,
> at that meeting that Chris DeRosa mentioned, pointed out that if you
> have co-exposure to two contaminants, and the uncertainty in the
> measurements of one of those contaminants is greater than the other,
> then, the statistical analysis will always tend to suggest that the
> primary factor in the effect was the more precisely defined
> co-exposure chemical.
>
> So, this is a statistical outcome, and I can\'t get into the details
> of it, but that was the basis for that decision by that particular
> group in North Carolina that it would really be nice if you could have
> an exposure without PCBs because it is probably not going to be
> possible to de-convolute the impact of PCBs, the fact that on a
> particular test, it was not significant for PCB doesn\'t mean that it
> doesn\'t have an effect on the benchmark for mercury, and the extent
> to which it has an effect is not determinable.
>
> DR. MILLER: Five more minutes, please.
>
> MR. CLEWELL: Okay, good.
>
> \[Slide.
>
> So, it\'s a highly conservative estimate for continuous exposure
> throughout pregnancy. The measure that was actually used in the Faroe
> Islands was the end pregnancy blood level, cord blood level. The blood
> levels could fluctuate higher or lower than that value for durations
> during pregnancy, that was not the maximum value achieved during
> pregnancy and trying to compare it with a maximum value achieved would
> be inappropriate.
>
> To compare with the RfD blood level, one needs to calculate the end
> pregnancy blood level to be able to compare apples with apples.
>
> \[Slide.
>
> The Presbyterian Book of Order says that despite the fact that there
> is but one truth, there will always be matters upon which men of
> goodwill will nonetheless disagree, and here are some men of goodwill,
> various organizations, who disagree about the proper limit for
> methylmercury exposure. At the low end, as they always are, is the
> USEPA, and they work up from there through ATSDR, FDA, WHO, and TERA
> has a risk assessment, the Toxicology Excellence for Risk Assessment,
> Mike Darson\'s group, has one on their web site, International
> Toxicology Estimates of Risk 0.35, so you can see there is a range of
> estimates.
>
> \[Slide.
>
> So, what I did in order to try to characterize for our analysis the
> results, I used not only the RfD blood concentration, but also the MRL
> blood concentration, and also the BMDL, which was actually the \"No
> Effect level\" in the Faroe Islands study.
>
> You can see this is the distribution, this is our main results. We
> have determined that 2.3 percent of the women at the end of pregnancy
> would be at or above the RfD blood concentration of 5.8 mcg/liter and
> that about 0.4 percent would be above the MRL.
>
> So, this actually compares reasonably closely with Jim\'s analysis on
> the basis of intakes. I think he was 2.9.
>
> As a reality check, the question that came up is exactly the question
> I had, so how does this relate to the data that has been collected?
>
> \[Slide.
>
> We have a NHANES analysis, and you can see that the results of the
> NHANES analysis, as was mentioned earlier today, I might be off by 0.1
> percent there. I can\'t remember whether she said 7.8 or 7.9, but 7.8
> percent of women at or above the RfD blood concentration, and as it
> turns out, 0.4 percent above the MRL.
>
> So, although there are a small proportion of women that are above the
> RfD blood concentration at the end of pregnancy using\--well,
> no\--well, the drawback of this is this is not women at the end of
> their pregnancy. This is women. Some of them were pregnant when these
> NHANES measurements were made, most of them were not.
>
> So, this is women in general, age 14 to 45. So, it is not exactly the
> same thing that I just showed you, it is not. So, you can\'t really
> say, well, this is ground truth and the other thing is just a
> prediction.
>
> The other thing is predicting what we want to know, which is what you
> could relate to the RfD blood level. This is something that is similar
> to that, but different, but it does, in my mind, just as Jim said,
> that\'s good agreement to me.
>
> When I say it\'s about 3 percent, and this says it\'s 7.8 percent,
> that is still a small fraction of the population being above the RfD,
> and complete agreement about the MRL, 0.3 mcg/kg/day level, that only
> less than 0.4 percent of the women would exceed that. Also, it agrees
> that none of the women are above the BMDL, the No Effect Level of 58
> mcg/liter.
>
> \[Slide.
>
> This is the summary. Maternal blood concentrations may indeed
> sometimes exceed the RfD blood concentration for worst-case or
> high-end exposure scenarios.
>
> The use of the RfD as a bright line for evaluation of safety, though,
> is not appropriate. That is not the only information one should use in
> order to process the question of is there a potential for health
> effects.
>
> As Dr. Grandjean said, they were looking for subtle effects, these are
> not sick kids. So, the kinds of things that you have to bring into
> play are all of the various factors that determines the word
> \"safety.\"
>
> The realistic exposure scenarios result in maximum blood levels that
> are within a factor of three of the RfD and are well below the effect
> levels in the Faroe Islands.
>
> Thank you.
>
> DR. MILLER: I just want to remind the committee that the Environmental
> Working Group will have an opportunity tomorrow to present their data.
> I want to make sure that we understand that.
>
> **Questions of Clarification**
>
> DR. APOSHIAN: Can we go back to Dr. Heimbach for a minute? I am a
> little disturbed about one comment that you made, namely, that there
> are other sources of methylmercury than fish or seafood.
>
> To my understanding\--and you can correct me\--
>
> DR. HEIMBACH: What I meant to say, if I didn\'t say, is there are
> other sources of mercury, I don\'t know if they are methyl or not.
>
> DR. APOSHIAN: That is not what you said. You said other sources of
> methylmercury.
>
> DR. HEIMBACH: I apologize. In the blood mercury, there could be other
> sources of that.
>
> DR. APOSHIAN: But since you brought up again other sources of mercury,
> I think the committee ought to realize that there are other sources of
> mercury, not methylmercury, but other sources of mercury that can also
> do similar damage to a child and to a pregnant woman, and that is
> mercury from dental amalgams.
>
> I am not trying to tell you that mercury from dental amalgams is safe
> or not safe. I am not getting into that argument. All I am saying is
> it is well established, the World Health Organization has published
> such data, it is in the peer-reviewed literature that the major source
> of the American population to mercury is from dental amalgams, whether
> it is toxic or not, I don\'t want to get into it.
>
> But the other point I want to make about methylmercury is there is
> increasing data that methylmercury in the brain is slowly converted to
> mercuric mercury, as is elemental mercury that gets from dental
> amalgams to the brain is slowly converted to mercuric mercury.
>
> So, in the real world, you have got to consider more than one kind of
> mercury in any kind of risk assessments, and I think Harvey knows
> that. I am a great admirer of Harvey\'s, by the way, we have known
> each other for a long time, but it seems to me that just to make a
> risk assessment on methylmercury and ignoring the potential of amalgam
> mercury or elemental mercury affecting the brain is dangerous.
>
> Again, I will say one more thing and then I will shut up I think for
> the day because I am getting tired, I don\'t know about the rest of
> you, but there is a classical example in this country of a family in
> New Mexico who ate a pig, a swine, that was contaminated with
> methylmercury, a large amount of methylmercury.
>
> One child was born\--the woman was pregnant, and two other young
> children\--anyway, one of those children lived to 21 years of age, and
> the Rochester group was involved in these analyses also. At 21 years
> of age, that person who died and had been exposed to methylmercury had
> a level of inorganic mercury in her brain 100 times the level that is
> normally seen.
>
> So, I think in the real world, toxicity usually is not due to one
> compound or one agent. In the real world, you have got to consider the
> other sources of mercury, but i did want to clarify the methylmercury.
>
> MR. CLEWELL: I will go ahead and take that as a question, so I can
> answer something, but I agree with you certainly in terms of risk
> management particularly, since I have a risk management, we need to
> consider all the sources. We were just asked to look at the
> contribution from fish ingestion, and it would be obviously
> problematic to do an estimate of the contribution from amalgams,
> because it is very poor data in that area.
>
> Another area that I had learned from ATSDR, to my shock, that
> contributes to high end exposures is religious practices and putting
> mercury in candles. So, as Jim mentioned, the highest blood level in
> this was for someone who said they don\'t eat fish, so there is
> something else going on with that woman.
>
> So, this analysis is indeed\--and then I wouldn\'t say that that is
> all the difference, but that is one of the reasons for the difference
> between the results of our fish ingestion analysis and the NHANES
> survey, which the NHANES is looking at total mercury in the blood, so
> it is amalgams, burning mercury, everything.
>
> DR. MILLER: But surely, you would not disagree with any attempt to
> reduce any one of the sources.
>
> DR. APOSHIAN: I would be delighted if every one of the sources were
> reduced.
>
> DR. MILLER: I am glad to get it on the record.
>
> DR. DWYER: I don\'t know which of you to ask, but if you could go back
> to the 60,000 estimate again and just give us what your estimate would
> be.
>
> DR. HEIMBACH: I will answer first. I don\'t have an estimate, I
> seriously don\'t.
>
> MR. CLEWELL: Why did you want to go first?
>
> DR. HEIMBACH: There are a lot of issues that go into a question of,
> quote, how many newborns are at risk from anything, and I don\'t know
> the answer for anything.
>
> All I know is that the basis that was provided to explain where the
> NAS Methylmercury Committee derived that 60,000 number was not a valid
> basis for establishing a number of newborns at risk. That is all I
> know. I do not have an estimator of my own.
>
> MR. CLEWELL: I also don\'t have a number, but I can tell you a reason
> for a substantial overestimate, which is because the analysis requires
> assuming that the uncertainty factor of 10 actually doesn\'t lower the
> risk. If the entire population remains at the risk associated with the
> benchmark analysis of the Faroes population in spite of a reduction of
> 10-fold, and so if I had to hazard a guess, I would say it is probably
> 10-fold too high, because if the high end exposures are in the
> vicinity of the RfD, which is 10-fold below where there is the MDL
> 0.5, then, statistically speaking, even if you assume a linear model
> for the risk, which is the kind of worst-case typically, then you
> would say that the risks were actually down about 10-fold on a
> population basis, so much lower is about all I can really say.
>
> DR. RUSSELL: Perhaps, Dr. Heimbach, you can answer this. I was very
> impressed with Dr. Aposhian\'s tuna fish data showing the huge
> variability of levels can to can, and I am wondering, is that known
> for other fish species, what kind of variability it is?
>
> He was showing over 12 times variability for the same type of canned,
> chunk, white tuna in water, for example, just a huge variability, and
> I was wondering what is the variability in other fish species.
>
> I was wondering also, a question I asked before, does it vary by
> geography of where the fish is caught.
>
> DR. HEIMBACH: I don\'t have answers to all of that. The answer to the
> first part is that generally speaking, the methylmercury concentration
> in fish does seem to be quite highly variable. It certainly has to do
> with the maturity of the fish, size of the fish.
>
> I would be somewhat surprised if it doesn\'t have some geographical
> variability, but I don\'t know for certain that it does.
>
> I was surprised at his numbers simply because that\--I am not
> surprised at the average he found, the 0.22, that\'s probably in about
> the right range. FDA\'s estimate based on several hundred cans
> analyzed in the early 1990s was 0.17, which is again, as we said, for
> these kinds of estimates, when you are within 20 percent of so of each
> other, that constitutes agreement to my mind. The 1.24 is kind of a
> shock. Certainly, FDA never came up with anything anywhere near that
> high in its hundreds of analyses.
>
> If there isn\'t some sort of error in the analysis of this can, I
> suspect something odd sort of happened that caused a contamination of
> the fish, I don\'t know. The variability is not normally that
> variable, particularly for something like canned tuna, which tends to,
> by the nature of how the fish is processed, have less variability can
> to can than you would have fish to fish for raw fish, but it does tend
> to be fairly highly variable concentration.
>
> DR. MILLER: Dr. Hotchkiss.
>
> DR. HOTCHKISS: I am just trying to get a picture I understand of some
> of these numbers. When you are talking about 2.3 percent above the
> reference dose, you are considering EPA\'s reference dose. Earlier,
> there was a number of 2.9 percent, I don\'t think that is a lot
> different, but am I understanding that correctly?
>
> MR. CLEWELL: 2.3 percent was based on blood level calculations at end
> of pregnancy, and 2.9 percent was based on just tissue changes.
>
> DR. HOTCHKISS: Diet. So, we are faced with a number that was about 7.8
> percent based on the HANES data for which you are saying that
> basically, at least in a dietary sense, some important considerations
> were not accounted for, particularly for a food that is eaten
> infrequently, is that right?
>
> DR. HEIMBACH: No, no, I am not saying that. I am saying my estimate
> based on fish intake alone was about 2.9 percent above the RfD.
> Harvey\'s estimate, based on both fish ingestion and pharmacokinetics,
> is that we would expect about 2.3 percent blood levels above. Now, I
> was strictly talking ingestion. Then, the HANES number that we are
> talking about, the 7.8 percent, is the total mercury concentrations in
> blood that are above, and what we are suggesting is that some of that
> total mercury in blood for some individuals may be due to sources
> other than fish consumption, and that might explain why the 7.8
> percent, there is a few more above the RfD in actual total mercury
> content that would be predicted based on fish ingestion alone.
>
> DR. HOTCHKISS: So, if we took that over the population, we just
> divided roughly that half of the population is female, which it is a
> number smaller than that\--
>
> MR. CLEWELL: Sixty million.
>
> DR. HOTCHKISS: So, if we multiply 2.3 percent times 60 million, we are
> still talking about roughly 3 million women who, on the lowest
> estimate, are above the reference, EPA\'s reference dose. At the high
> end, we are talking at something like 10 million.
>
> So, we are considering that whatever end of this data you believe, you
> believe the lowest end that we have heard so far, we are talking
> roughly 3 million women in that cohort or group, up to something like
> 10 million.
>
> MR. CLEWELL: I am not very comfortable with back-of-the-envelope
> calculations, particularly when you can get 7 percent of 60 million
> being 10 million. I don\'t think that works.
>
> It might be better if you actually let somebody calculate it. I would
> guess that it is actually less than that, but as I just got through
> mentioning, that is assuming that the risk at the reference dose is
> the same as the risk at the benchmark, which is 10-fold higher. In
> other words, that uncertainty factor didn\'t buy you anything in terms
> of protecting health.
>
> So, it is actually not a good calculation. You know, sometimes it is
> better off not doing a calculation that is meaningless than it is to
> do one and then people will believe it.
>
> DR. HOTCHKISS: Let me understand that then. The lowest we have heard
> is 2.3 percent, what you are suggesting is 2.3 percent receive above
> the RfD dose from fish, and you are saying that that population is 60
> million, but you are telling me I can\'t multiply\--
>
> MR. CLEWELL: So, that is 1.2 million people that are above the
> reference dose, that\'s right.
>
> DR. HOTCHKISS: So, the low end is 1.2 million, the high end of what we
> have heard, somewhere between\--
>
> DR. HEIMBACH: What I would like to say, and I said at the beginning I
> am not going to presume to advise either FDA or this committee how to
> do your risk management, but I do want to put this in the context,
> however, and I will let somebody from FDA or from EPA address this
> also, in estimating what are safe levels of intake of contaminants,
> pesticide residues, food additives, and so forth, there is never an
> expectation that you are going to have 100 percent of the population
> with expected exposures below level of safety.
>
> FDA standard rule, and there are other people here who can address
> this, for intake of food additives, color additives, GRAS ingredients,
> is look at the 90th percentile of intake, and assure that the 90th
> percentile of intake is within safe levels. EPA\'s approach to dealing
> with pesticide residues historically has been to look at the 95th
> percentile level of intake, and assure that the 95th percentile of
> intake is within safe limits.
>
> Now, all I am saying is that is the rubric that has most often been
> used. I am neither recommending it, nor disagreeing with it.
>
> DR. HOTCHKISS: Thank you. Let me follow that up. Thank you for that
> clarification. I, too, am a former FDA employee and understand what
> they are doing there. What I am trying to get is, okay, let\'s take
> whatever number you like. If you take the 90th percentile, how many
> actual individuals is that, and I think that is something we have to
> consider.
>
> DR. MILLER: Dr. Nordgren.
>
> DR. NORDGREN: You had a study from 1975 on levels of methylmercury in
> fish. You threw that up. My question is, are those levels different
> than what have in our book here from 1998?
>
> DR. HEIMBACH: I have not done a comparison of them. I used those data
> sources because those are the data source that EPA used for the 1997
> Report to Congress on mercury exposure.
>
> MR. CLEWELL: I might say that our analysis actually used all the data,
> not just the \'75 study, but used everything that is out there, and we
> ended up in roughly the same place. I don\'t think there is any
> evidence that the levels have changed.
>
> DR. MILLER: Dr. Shannon.
>
> DR. SHANNON: Would it be fair, then, I guess this question goes to
> both of you, to summarize your main findings as being the rate of
> exposure to excess mercury in women is much less than NHANES would
> suggest, the reference dose that is being used is useless, the mercury
> measured in NHANES may not be from fish at all, and we don\'t have
> anything to do here, because there is no reason to make any changes?
>
> MR. CLEWELL: It sound a bit argumentative to me. I might be being
> defensive, though. I thought we were actually just trying to project
> what we would expect the blood levels to be for methylmercury exposure
> from fish ingestion, and you can kind of take your own spin on it,
> which I am sure you will.
>
> I wasn\'t asked to give a risk management input, so I won\'t. You have
> the data in front of you. You can interpret NHANES any way you want
> to. We were just trying to\--I was actually pleased, really, that the
> prediction of the distribution of blood levels for women eating the
> reported fish ingestion is consistent with NHANES. I think it probably
> is actually to some extent you could argue that it is a better
> estimate of the contribution of fish ingestion, but as Vas has
> mentioned, from a risk management perspective, it is all important
> exposure to mercury.
>
> One of the things I find unfortunate is that the agencies don\'t do a
> very good job of translating their exposure limits into health and
> safety guidance, and that people will take a dose-response analysis in
> a study of an affected population, divide it by an uncertainty factor,
> and then talk as if the value they just derived is the borderline
> between safety and some sort of developmental deficit, which I think
> unfairly scares the population.
>
> DR. MILLER: We have reached I think the last part of our day\'s work.
> It is part of these hearings that at the end of the day, we provide
> some period of time for what is called Public Comment. Groups, and so
> on, who want to make short statements, are allowed to make them at
> that time if they have signed up with the Secretary.
>
> We have three requests for today. First, Dr. Rhona Applebaum of the
> NFPA.
>
> Rhona, you have five minutes. Remember, it is the end of the day.
>
> **Public Comment**
>
> DR. APPLEBAUM: Absolutely, Dr. Miller. Trust me, I won\'t go beyond my
> five minutes. Our written comments are at the desk, so I won\'t
> belabor the entire testimony before you today.
>
> Thank you for this opportunity and NFPA appreciates our time here to
> offer our comments on FDA\'s Consumer Advisory on Methylmercury and
> Fish Consumption. NFPA supports the use of sound scientific
> information in decisions affecting food safety and the food industry.
> Most importantly, we strongly advocate the use of sound science as the
> basis for any and all health advice given to consumers.
>
> There is every indication that FDA made its decision on how to frame
> the fish consumption advisory to consumers on the basis of the best
> science available to them.
>
> Advice to consumers on fish consumption, as with all health
> advice\--and we heard this, this morning, as well as this
> afternoon\--is a very complex issue that cannot and should not be
> addressed by looking at any one piece of information.
>
> We believe FDA met the challenge of integrating information from a
> wide variety of sources on the numerous factors that must be
> considered in providing sound, actionable advice to the public on
> safely consuming fish, which has repeatedly been recognized as
> contributing to a healthful diet.
>
> FDA, from our perspective, and that of recognized scientific experts
> and groups, looked at the totality of the evidence and the data before
> them, including quantities consumed and the benefits of fish
> consumption.
>
> As a public health agency, FDA then made a risk management decision
> and produced a risk communication message that provided the facts to
> consumers, as well as the necessary advice on methylmercury and fish
> consumption.
>
> Consequently, it is inconceivable that any public health agency,
> particularly FDA, would risk consumer health by doing anything other
> than looking at this issue from an objective scientific perspective.
>
> Health officials, the scientific community, and consumer advocates all
> meet regularly with the regulatory agencies. In fact, during the
> process of revising its seafood consumption advisory with respect to
> methylmercury, FDA actively sought input from, and met with, a number
> of different stakeholders to ensure that all sides of this issue were
> heard and valid scientific information considered. We believe this
> exchange of information is appropriate and necessary for bringing the
> best available science to bear on any action.
>
> NFPA itself regularly meets with regulatory agencies overseeing U.S.
> food production, and we provide them with information on industry
> programs and activities affecting safe food production, as well as
> with research findings that are intended to assist their science-based
> decisionmaking. In turn, the food industry regularly seeks information
> and input from the regulatory agencies on a variety of food science
> and food safety issues.
>
> NFPA does not always agree with the Agency\'s conclusions or decisions
> on all matters. In fact, Dr. Miller, that would take more than five
> minutes for me to identify all those areas. However, we firmly believe
> that FDA bases its decisions on what they believe the facts to be
> after careful and diligent efforts to identify, assess, consider, and
> interpret relevant, scientifically valid information. Their goal is
> always the health of the public, all subsets, all sectors.
>
> In closing, let me state again my Association\'s belief that FDA did
> an exemplary job in the development, focus, and wording of the
> Advisory with the information available to them at the time on the
> risks of methylmercury in fish and the documented benefits of fish
> consumption with focus on the targeted population, that being pregnant
> women and women of child-bearing age.
>
> Again, we thank you for this opportunity to provide our comments on
> this very important topic.
>
> Thank you.
>
> DR. MILLER: Thank you.
>
> The next speaker is Dr. Lee from the National Center for Policy
> Research. Five minutes, please.
>
> DR. LEE: Good afternoon. I am Dr. J. Huang Lee. I am a physician and
> the senior medical policy analyst at the National Center for Policy
> Research for Women and Families.
>
> I would like to thank the committee and the speakers today for a day
> of very interesting presentations.
>
> It appears that the Food and Drug Administration\'s current efforts at
> protecting the American public from the health risks of methylmercury
> are inadequate. First, the Agency is unable to provide consumers with
> truly up-to-date information since the Agency has failed to adequately
> monitor methylmercury levels in commercial fish supplies.
>
> Second, the FDA\'s rationale in performing its advisories is flawed
> and poorly suited to the chronic long-term nature of the health risks
> associated with methylmercury contamination.
>
> Third, the FDA has failed to effectively disseminate its findings and
> recommendations to the general public. Most consumers remain unaware
> of the health risks associated with methylmercury in fish, and even
> the most health conscious members of American society tend to be
> poorly informed of the dangers.
>
> During a Consumer Roundtable meeting with Director Joseph Levitt and
> other senior officials from the Center for Food Safety and Applied
> Nutrition here in College Park on June 20th of this year, I asked
> whether the Center was monitoring levels of methylmercury in
> commercial fish supplies. To my dismay, I was informed that the Center
> was not currently monitoring methylmercury levels and had no plans to
> initiate a surveillance program.
>
> We heard very briefly mention of possible budgetary reasons for this,
> but as a scientific explanation for the Center\'s disinterest in a
> surveillance program, I was informed by the Director of the Center\'s
> Office of Science that methylmercury levels in fish do not change
> significantly over time.
>
> I am puzzled as to how this can be known with any certainty if no one
> is monitoring methylmercury levels in the commercial fish supply.
> Historical data are no substitute for diligent surveillance.
>
> One can imagine how numerous factors including changing levels of
> environmental mercury contaminants from fossil fuel, utility plants
> can alter the level of methylmercury contamination if both freshwater
> and saltwater fish.
>
> In order to provide the American consumer with valid and up-to-date
> information, the Center should initiate routine surveillance of
> methylmercury levels in all commercially available fish species.
>
> In addition, commercially processed fish products should be monitored
> for methylmercury contamination in a manner analogous to the
> monitoring for bacterial contamination.
>
> I should note that with the previous discussion regarding
> methylmercury levels in canned tuna, the range in 248 samples of
> canned tuna ranged from non-detectable to 0.75 parts per million, so
> the range offered here today is not that surprising.
>
> To continue, even if we were to assume that reliable and valid
> information is available on methylmercury levels in fish, the FDA has
> not properly used these data in formulating its consumer advisories.
>
> Currently, only those fish species with the highest known levels of
> methylmercury are named in the FDA\'s consumer advisory. This approach
> may be suitable if the main concern were acute methylmercury toxicity,
> however, in the United States, the primary threat for methylmercury is
> chronic long-term exposure.
>
> It is therefore crucial to formulate advisories based on the overall
> public health impact of a particular fish species. The question is
> which fish species and fish preparations will contribute most to
> methylmercury exposure in vulnerable segments of the population.
>
> Answering this question requires one to consider the annual per capita
> consumption of a particular fish species in addition to the mean
> methylmercury levels, and this is seen in the Seychelles Island study.
>
> For example, canned tuna accounted for 75 percent of the canned fish
> consumed in the United States in 2000. In that year, more than 980
> million pounds of canned tuna were supplied to the American consumer.
>
> Although methylmercury levels in canned tuna are thought to be lower
> than in other fish species, and lower than that in fresh or frozen
> tuna, the sheer quantity consumed makes the public health impact of
> canned tuna far greater than that of any other species.
>
> It is more likely that women and children will be exposed to
> methylmercury through canned tuna consumption than through eating
> shark, swordfish, king mackerel, or tilefish.
>
> Therefore, canned tuna should specifically be named in any future
> advisory on methylmercury. Consumer advisories are a step in the right
> direction, but they are inadequate for disseminating information about
> the health risks associated with methylmercury contamination.
>
> It is fair to say that most Americans remain unaware of the current
> advisory for shark, swordfish, king mackerel, and tilefish. Even fewer
> are aware of the FDA\'s recommendation to limit fish consumption to an
> average of 12 ounces of cooked fish each week.
>
> The occasional advisory news story is simply not enough to properly
> inform the American consumer. So, what should be done?
>
> We can begin by placing the advisories where consumers are most likely
> to see them, on the packaging of fish. If the FDA believes pregnant
> women and young children should limit their consumption of cooked
> store-bought fish to an average of 12 ounces a week, why not say so on
> the package?
>
> DR. MILLER: Dr. Lee, can you consider summing up?
>
> DR. LEE: Yes, I am almost finished.
>
> If the FDA believes that canned tuna consumption should be limited to
> an average of 9 ounces per week, why not place such an advisory
> directly on the cans?
>
> In summary, clearly, the FDA must do better in collecting reliable and
> valid information regarding methylmercury contamination in fish. It is
> time for the Agency to adopt a more public health oriented approach to
> formulating its advisories.
>
> More importantly, the American consumer deserves better access to the
> information issued by the FDA. I urge the Advisory Committee to
> recommend significant changes in the way the Agency is managing this
> serious problem.
>
> Thank you.
>
> DR. MILLER: Thank you.
>
> The next and final speaker is Dr. Richard Fisher. Five minutes, Dr.
> Fisher.
>
> DR. FISHER: Thanks.
>
> I want to thank the panel for allowing me a few minutes of your time.
>
> My name is Rich Fisher. I am a dentist. I have practiced in suburban
> Washington for the last 30 years. The first 10 years of my practice I,
> like most of my colleagues, placed mercury-containing fillings into my
> patients\' mouths thinking I was doing them the best service that I
> knew how.
>
> In 1981, it was first published in the dental literature that the
> mercury from dental fillings escaped the fillings and was absorbed
> into the human body. We didn\'t know back then what we know now as far
> as how much was absorbed and to what levels they accumulated, but it
> seemed to me, as a health practitioner, whose first mission is to
> protect the health of my patients, that I would not use amalgam
> mercury fillings after that period of time, so in 1982, when I learned
> of this research, I stopped using mercury fillings, so for the last 20
> years I have been doing it right, so to speak.
>
> I am a member of the American Dental Association although I am not
> here as their official representative, as you might guess. Dental
> amalgam or mercury fillings contribute, as Dr. Aposhian mentioned
> earlier, more mercury to the human body burden than all other sources
> put together by far.
>
> The data that we have from World Health Organization, from Dr.
> Aposhian\'s study, as well as from the textbook published by Dr.
> Clarkson and Dr. Freiberg over 10 years ago, all show the same thing,
> and that about four times the amount of mercury that we absorb and
> retain from diet is coming in from our fillings, so we are getting
> four times that we are discussing here today.
>
> I am here to applaud your efforts on the dietary sources of mercury,
> but I do think we need to make some efforts to your colleagues within
> the FDA to address the even bigger aspect of this problem.
>
> To put it in another way, one average size dental mercury filling
> contains a half a gram of mercury. That, according to EPA standards
> for human exposure for adults, would exceed 100 years\' worth of
> exposure.
>
> From another perspective, if we were to disperse that half a gram of
> mercury into a 10-acre lake, you wouldn\'t be able to eat any of the
> fish coming out of that lake.
>
> There has been move afoot in this country to get rid of amalgam, to
> phase it out. There is a bill before Congress now to do that. I would
> love to see the FDA support that action. Other countries, such as
> Canada, Sweden, Norway, Denmark, United Kingdom, and France have
> already issued advisories in those countries to avoid using mercury
> fillings in pregnant women and young children, which again are the
> most vulnerable citizens.
>
> Looking at the data that we have from those studies, I have calculated
> for the nine-month gestation period, that dietary sources alone
> contribute about 620 micrograms into the pregnant woman during the
> nine-month gestation.
>
> About 10 percent of that goes into the fetus or about 62 micrograms
> enters the fetus from the mother\'s diet during that nine months.
> During that same nine months, the calculations for the mercury going
> into the mother from her fillings, on average, run 2,700 micrograms,
> and again, 10 percent of that, which is 270 micrograms, goes into the
> fetus, again, four times the amount that the dietary exposure
> generates.
>
> In addition, there is a secondary route of exposure coming from dental
> offices, which is largely overlooked. There have been several studies
> now, the last of which was funded by the American Dental Association,
> that shows that between 14 percent and 75 percent of the mercury
> coming out of municipal wastewaters is traced back to dental offices
> from the scrap amalgam, the stuff that is not put into the tooth, that
> is left over and disposed of.
>
> This, of course, gets bioconverted in the aquatic and marine
> environments. It is converted into methylmercury, which then gets into
> the food chain and the tuna, and so forth. So, I think this is another
> part that dentistry has to clean up its act.
>
> So, again, I am here for two reasons today, one, to applaud your
> efforts in what you are doing here, and I appreciate that very much,
> and to plead that you lobby your colleagues within the FDA to look at
> this other aspect of mercury poisoning, which is the dental amalgam
> issue.
>
> Thanks very much for your time.
>
> DR. MILLER: Thank you.
>
> This brings us to the end of this rather long day. We will adjourn for
> the moment until tomorrow morning at 8:30, when we will begin promptly
> on time I hope.
>
> \[Whereupon the proceedings were recessed at 4:30 p.m., to reconvene
> on Wednesday, July 24, 2002, at 8:30 a.m.\]

\- - -