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
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(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 R
O C E E D I N G S
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.]
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