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From: Terry S. Singeltary Sr. (216-119-134-158.ipset14.wt.net)
Subject: TSE ADVISORY COMMITTEE Friday, January 19, 2001
Date: September 29, 2004 at 6:33 pm PST

-------- Original Message --------
Subject: TSE ADVISORY COMMITTEE Friday, January 19, 2001
Date: Wed, 29 Sep 2004 16:56:33 -0500
From: "Terry S. Singeltary Sr."
Reply-To: Bovine Spongiform Encephalopathy
To: BSE-L@UNI-KARLSRUHE.DE


##################### Bovine Spongiform Encephalopathy #####################

DEPARTMENT OF HEALTH AND HUMAN SERVICES
FOOD AND DRUG ADMINISTRATION
CENTER FOR BIOLOGICS EVALUATION AND RESEARCH
*****
TRANSMISSIBLE SPONGIFORM ENCEPHALOPATHIES
ADVISORY COMMITTEE
*****
This transcript has not been edrlted or corrected, but
appears as received from the commerical transcribing
service. Accordingly the Food and Drug Administration
makes no representation as to its accuracy.
Friday, January 19, 2001
8:30 a.m.
Holiday Inn Bethesda
Versailles I and II
8120 Wisconsin Avenue
Bethesda, Maryland

snip...

22 We held off all of the discussion and the voting

Topic 2
Committee Discussion (Continued)
DR. BROWN: Good morning. If we really get
cracking, only half the committee is here, we can probably
Jet through several of the votes. We are, in fact,
beginning today with the conclusion of yesterday's
deliberations on Topic 2 which concerns tissues and cells
and cell products.
until today. I think, actually, quite seriously, we can
vote on question 1 because there is no way that we can vote
in any other way than yes. But, I will read the question

MILLER REPORTING COMPANY, INC.
735 C Street, S.E.
Washington, D.C. 20003-2802
(202) 546-6666

and you will see why; compared to the risk of transmission
of variant CJD by blood transfusion, is there a significant
risk of transmission of vCJD from human cells, tissues and
cellular and tissue-based products that are transplanted,
implanted, infused or transferred?
The answer has to be yes because the cornea is
demonstrably infectious. So I suggest we vote on that and
get to the important question which is what are the relative
risks for different cells and tissues.
Is there discussion before we do this? Ray?
DR. ROOS: Now, this is variant CJD.
DR. BROWN: That's right; this is variant.
DR. ROOS: Do you know that the cornea--
DR. BROWN: NO; we don't.
DR. ROOS: Oh.
DR. BROWN: But we know that the cornea alone,
among tissues with standard CJD, has been infectious and
there is no reason to suppose that, in this one tissue,
variant would be less rather than more infectious than
standard CJD.
DR. ROOS: I think we probably have--
DR. BROWN: Relative to blood, bear in mind, which
is not--
DR. ROOS: I think we have no data, Paul, on
natural variant CJD in humans as far as tissue distribution.
MILLER REPORTING COMPANY, INC.
735 C Street, S.E.
Washington, D.C. 20003-2802
(202) 546-6666

Maybe I am wrong.
DR. BROWN: We have PrP data.
DR. ROOS: PrP data.
DR. BROWN: In all the tissues that have been
looked at, the amount of protein in variant CJD exceeds
that. In fact, there is not any demonstrable in classical...

snip...


http://www.fda.gov/ohrms/dockets/ac/01/transcripts/3681t2_01.pdf

> DR. BROWN: In all the tissues that have been
> looked at, the amount of protein in variant CJD exceeds
> that. In fact, there is not any demonstrable in classical.

CONSIDERING that sporadic CJD consists of many strains
of CJD, with further strains very likely, would this assessment
above by Paul Brown be incorrect (especially with the current
data from Aguzzi and Prusiner on muscle tissue infectivity in
victims of sporadic CJD, where the thought of infectivity there
was nil, until these more sensitive TSE testing came about)? ...TSS


It was a paper that was focussed on normal protein
and in platelets. They also studied about twenty-odd CJD
patients--it was almost a throwaway line in the paper--none
of whom had any PrP that was proteinase-resistant. So the
conclusion was there was no pathologic protein, whereas
there was plenty of normal protein.
The other fact is that we do know that bone marrow
was positive, presumably in a single BSE cow. It is not
much, but it is all we have and it would be plausible to
suppose that the origin of cells, in blood, which we have
already decided pose a possible potential threat, would be
present at their birth as well as their maturity.
DR. EWENSTEIN: I was just going to make the same
point about the lymphoid tissue. I think, as we take a look
at the list in the absence of apparently rigorous dissection
of all of these tissues that have been available here so
far, the only other ones that I would worry about would be
some of the fluids.
I don't know, for example, in semen, whether the
white cells in that fluid might not have--
DR. BROWN: These have been looked at in other
forms of CJD and no infectivity has ever been documented.
DR. EWENSTEIN: In other forms, I know. But when
we think about the difference between CJD and variant, I
think the lymphocyte distribution is the difference that I
am concentrating on here. So I just bring it up because I
think the risk here is of a different nature as well because
we are talking about elective procedures and we are talking
about the possible infection of a would-be embryo.
So I think that one would have to put, I think, a
question mark on that until we had some real data.
DR. BURKE: The other factor that plays in here
that is a bit different than the blood is the requirement
for close matching in some of these, particularly the bone
marrow. As I understand it, there may be a significant
number of people that would not match if--
DR. BROWN: This is correct, Don. But I do want
to stick to question 1. This is really under question 2;
that is, all of the benefit aspects will be discussed after
we make a vote on question 1. Question 1 really is a
scientific question.
DR. BURKE: Fair enough. I will hold it:
DR. BROWN: This is not, actually, a yes/no vote.
I don't think, actually, we have to vote on it because this
is a kind of a discussion. So we are going to escape a
vote.
DR. DETWILER: Just one other scientific thing.
You said about bone marrow, but in scrapie, in sheep, on
occasion, there had been evidence of infectivity also in
bone marrow. I think that is maybe why the FDA had asked
Dr. Priola to come and to show the differences in the
diseases and that variant CJD, at least with the peripheral,
may be closer to scrapie than BSE. But that is just to add
that.
DR. BROWN: That is a good point. Scrapie has
been one of the diseases that marrow has occasionally been
positive in....

snip...


DR. BROWN: Steve, we will hear from you and then,
Sue, would you like to chime in on this.
DR. LEITMAN: In the case of marrow and stem
cells, if, at the time that an identical six out of six
antigen match is identified and what is called IDM,
infectious disease markers, are measured, at that point, if
a marker is positive, short of HIV, if it is hepatitis C,
hepatitis B, various other surrogate markers, anti-core,
that information is conveyed to the transplanting physician
who conveys it to their patient and it is discussed, the
relative risk/benefit of using the only potential product,
transplantable product, matched problem, is weighed against
the risk of possible infection transmission.
SO there is lots of precedence for biohazard
labeling and in-depth discussion of the transplanting
physician with the patient of the risk/benefit
considerations. So that could be applied here as it is
already being applied in different situations.
DR. DeARMOND: Steve DeArmond, UCSF. I want to
actually address a question to the. committee and maybe Stan
could help a lot on this because of his knowledge of it, but
in assessing the risk/benefit and trying to decrease the
risk, especially for things like hematopoietic stem cells
where you are taking them from living patients and you are
already testing them in great detail for a variety of
markers, wouldn't it be possible to further test the patient
for homozygosity at 129 because; first of all, all of the
new variants occur right now in methionine-methionine.
We may see a methionine-valine some time in the
future, but that doesn't seem to be the case. 90 percent of
CJD, whether it is sporadic or acquired by infection, occurs
in people who are homozygous. It seems if that piece of
information were known from a donor that you would at least
increase the population, or retrieve a population, that
could be a donor...

> Preclinical vCJD after blood transfusion in a PRNP codon 129
> heterozygous patient
>
> Alexander H Peden, Mark W Head, Diane L Ritchie, Jeanne E Bell, James W
> Ironside
> We report a case of preclinical variant Creutzfeldt-Jakob disease (vCJD)
> in a patient who died from a nonneurological
> disorder 5 years after receiving a blood transfusion from a donor who
> subsequently developed vCJD.
> Protease-resistant prion protein (PrPres) was detected by western blot,
> paraffin-embedded tissue blot, and
> immunohistochemistry in the spleen, but not in the brain.
> Immunohistochemistry for prion protein was also
> positive in a cervical lymph node. The patient was a heterozygote at
> codon 129 of PRNP, suggesting that
> susceptibility to vCJD infection is not confined to the methionine
> homozygous PRNP genotype. These findings
> have major implications for future estimates and surveillance of vCJD in
> the UK...

> http://www.thelancet.com/...TSS

snip...


DR. BROWN: The question we are asking is focused
on donor deferral. If there is no more discussion, we will
take a vote on it. The question is, the committee has
previously assessed the risk of transmission of variant CJD
by blood and has made recommendations accordingly. Based
upon the committee's assessment of the risk of transmission
of variant CJD by human cells and tissue and considering the
potential impact on supply, should the FDA recommend donor
deferral criteria for possible exposure to the BSE agent?
Stan, you are first.
DR. PRUSINER: I say yes.
DR. WILLIAMS: Yes.
DR. LURIE: Yes.
DR. CLIVER: Yes.
DR. BELAY: No.
DR. BROWN: No.
DR. BOLTON: No.
DR. NELSON: No.
DR. GAYLOR: Yes.
DR. PICCARDO: Yes.
DR. McCURDY: No.
DR. BURKE: No.

DR. EWENSTEIN: Yes.
DR. DETWILER: Yes.
DR. ROOS: Yes.
DR. FREAS: To verify the no votes, the no votes
were Drs. Burke, McCurdy, Nelson, Bolton I Brown and Belay.
That is six no votes, nine yes votes, no abstentions.

snip...

DR. BROWN: I think we can vote on A. We have
just been relieved of the responsibility of having to vote
on B. The committee always wants additional data so why
don't we vote on A. and send a signal to the FDA that we
need more data, if they haven't already got it.
DR. BOLTON: A. only comes into play if we voted
no. Since we voted yes--I mean, the yes carried. I didn't
vote yes.
DR. BROWN: I can't have it both ways.
DR. BOLTON: That's right.
DR. BROWN: I had hoped no one would notice that.
DR. BOLTON: I should have been quiet.

snip...

DR. BOLTON: Since we can't settle 2B about a
deferral policy, I think it seems pointless to argue and
discuss much about 3.
DR. BROWN: I am happy with that.

snip...

CHRONIC WASTING DISEASE CWD

15 even in the captive.
DR. MILLER: Not that I am aware of and certainly
not that have been reported.
DR. BURKE: Is there any reasonable surveillance
or any efforts to identify that anywhere else in the world?
DR. MILLER: I know that the folks in New Zealand
have done considerable surveillance in their red-deer
industry. As far as other free-ranging populations,
truly not sure.
I am
DR. DETWILER: I can address that just a
bit. I think that is a valid assessment, that there
has not been much surveillance done. New Zealand is
really
doing
captive. I know Argentina is doing some captive but, to my
knowledge, none in the free-ranging and very, very limited

DR. MILLER:. As far as the artificial feed, Glen
could probably address that. It is banned. Certainly, in
practice, in our research facility, we have had chronic
wasting disease for decades and we don't use, and to my
knowledge never have used, meat and bonemeal. Certainly, in
free-ranging animals, meat and bonemeal is not being
used and certainly does not seem to part of what is
perpetuating the problem...

> Subject: MAD DEER/ELK DISEASE AND POTENTIAL SOURCES
> Date: Sat, 25 May 2002 18:41:46 -0700
> From: "Terry S. Singeltary Sr."
> Reply-To: BSE-L
> To: BSE-L
>
> 8420-20.5% Antler Developer
> For Deer and Game in the wild
> Guaranteed Analysis Ingredients / Products Feeding Directions
>
> snip...
>
> _animal protein_
>
> http://www.surefed.com/deer.htm
>
> BODE'S GAME FEED SUPPLEMENT #400
> A RATION FOR DEER
> NET WEIGHT 50 POUNDS
> 22.6 KG.
>
> snip...
>
> _animal protein_
>
> http://www.bodefeed.com/prod7.htm
>
> Ingredients
>
> Grain Products, Plant Protein Products, Processed Grain By-Products,
> Forage Products, Roughage Products 15%, Molasses Products,
> __Animal Protein Products__,
> Monocalcium Phosphate, Dicalcium Pyosphate, Salt,
> Calcium Carbonate, Vitamin A Acetate with D-activated Animal Sterol
> (source of Vitamin D3), Vitamin E Supplement, Vitamin B12 Supplement,
> Riboflavin Supplement, Niacin Supplement, Calcium Panothenate, Choline
> Chloride, Folic Acid, Menadione Soduim Bisulfite Complex, Pyridoxine
> Hydorchloride, Thiamine Mononitrate, d-Biotin, Manganous Oxide, Zinc
> Oxide, Ferrous Carbonate, Calcium Iodate, Cobalt Carbonate, Dried
> Sacchoromyces Berevisiae Fermentation Solubles, Cellulose gum,
> Artificial Flavors added.
>
> http://www.bodefeed.com/prod6.htm
> ===================================
>
> MORE ANIMAL PROTEIN PRODUCTS FOR DEER
>
> Bode's #1 Game Pellets
> A RATION FOR DEER
> F3153
>
> GUARANTEED ANALYSIS
> Crude Protein (Min) 16%
> Crude Fat (Min) 2.0%
> Crude Fiber (Max) 19%
> Calcium (Ca) (Min) 1.25%
> Calcium (Ca) (Max) 1.75%
> Phosphorus (P) (Min) 1.0%
> Salt (Min) .30%
> Salt (Max) .70%
>
>
> Ingredients
>
> Grain Products, Plant Protein Products, Processed Grain By-Products,
> Forage Products, Roughage Products, 15% Molasses Products,
> __Animal Protein Products__,
> Monocalcium Phosphate, Dicalcium Phosphate, Salt,
> Calcium Carbonate, Vitamin A Acetate with D-activated Animal Sterol
> (source of Vitamin D3) Vitamin E Supplement, Vitamin B12 Supplement,
> Roboflavin Supplement, Niacin Supplement, Calcium Pantothenate, Choline
> Chloride, Folic Acid, Menadione Sodium Bisulfite Complex, Pyridoxine
> Hydrochloride, Thiamine Mononitrate, e - Biotin, Manganous Oxide, Zinc
> Oxide, Ferrous Carbonate, Calcium Iodate, Cobalt Carbonate, Dried
> Saccharyomyces Cerevisiae Fermentation Solubles, Cellulose gum,
> Artificial Flavors added.
>
> FEEDING DIRECTIONS
> Feed as Creep Feed with Normal Diet
>
> http://www.bodefeed.com/prod8.htm
>
> INGREDIENTS
>
> Grain Products, Roughage Products (not more than 35%), Processed Grain
> By-Products, Plant Protein Products, Forage Products,
> __Animal Protein Products__,
> L-Lysine, Calcium Carbonate, Salt, Monocalcium/Dicalcium
> Phosphate, Yeast Culture, Magnesium Oxide, Cobalt Carbonate, Basic
> Copper Chloride, Manganese Sulfate, Manganous Oxide, Sodium Selenite,
> Zinc Sulfate, Zinc Oxide, Sodium Selenite, Potassium Iodide,
> Ethylenediamine Dihydriodide, Vitamin E Supplement, Vitamin A
> Supplement, Vitamin D3 Supplement, Mineral Oil, Mold Inhibitor, Calcium
> Lignin Sulfonate, Vitamin B12 Supplement, Menadione Sodium Bisulfite
> Complex, Calcium Pantothenate, Riboflavin, Niacin, Biotin, Folic Acid,
> Pyridoxine Hydrochloride, Mineral Oil, Chromium Tripicolinate
>
> DIRECTIONS FOR USE
>
> Deer Builder Pellets is designed to be fed to deer under range
> conditions or deer that require higher levels of protein. Feed to deer
> during gestation, fawning, lactation, antler growth and pre-rut, all
> phases which require a higher level of nutrition. Provide adequate
> amounts of good quality roughage and fresh water at all times.
>
> http://www.profilenutrition.com/Products/Specialty/deer_builder_pellets.html
>
> ===================================================
>
> DEPARTMENT OF HEALTH & HUMAN SERVICES
> PUBLIC HEALTH SERVICE
> FOOD AND DRUG ADMINISTRATION
>
> April 9, 2001 WARNING LETTER
>
> 01-PHI-12
> CERTIFIED MAIL
> RETURN RECEIPT REQUESTED
>
> Brian J. Raymond, Owner
> Sandy Lake Mills
> 26 Mill Street
> P.O. Box 117
> Sandy Lake, PA 16145
> PHILADELPHIA DISTRICT
>
> Tel: 215-597-4390
>
> Dear Mr. Raymond:
>
> Food and Drug Administration Investigator Gregory E. Beichner conducted
> an inspection of your animal feed manufacturing operation, located in
> Sandy Lake, Pennsylvania, on March 23,
> 2001, and determined that your firm manufactures animal feeds including
> feeds containing prohibited materials. The inspection found significant
> deviations from the requirements set forth in
> Title 21, code of Federal Regulations, part 589.2000 - Animal Proteins
> Prohibited in Ruminant Feed. The regulation is intended to prevent the
> establishment and amplification of Bovine Spongiform Encephalopathy
> (BSE) . Such deviations cause products being manufactured at this
> facility to be misbranded within the meaning of Section 403(f), of the
> Federal Food, Drug, and Cosmetic
> Act (the Act).
>
> Our investigation found failure to label your
> swine feed with the required cautionary statement "Do Not Feed to cattle
> or other Ruminants" The FDA suggests that the statement be
> distinguished
> by different type-size or color or other means of highlighting the
> statement so that it is easily noticed by a purchaser.
>
> In addition, we note that you are using approximately 140 pounds of
> cracked corn to flush your mixer used in the manufacture of animal
> feeds containing prohibited material. This
> flushed material is fed to wild game including deer, a ruminant animal.
> Feed material which may potentially contain prohibited material should
> not be fed to ruminant animals which may become part of the food chain.
>
> The above is not intended to be an all-inclusive list of deviations from
> the regulations. As a manufacturer of materials intended for animal
> feed use, you are responsible for assuring that your overall operation
> and the products you manufacture and distribute are in compliance with
> the law. We have enclosed a copy of FDA's Small Entity Compliance Guide
> to assist you with complying with the regulation... blah, blah, blah...
>
> http://www.fda.gov/foi/warning_letters/g1115d.pdf
>
>
> snip...END
>
> http://www.fda.gov/ohrms/dockets/dailys/03/Jun03/060903/060903.htm#2003d0186
>
> The killer among us
>
> December 31, 2002 Milwaukee Magazine by Mary Van de Kamp Nohl
>
> snip...
>
> The most troubling explanation for CWD's appearance came from neither
> state agency but from veteran agricultural and environmental writer
> Mike Irwin, freelancing in Madison's Capital Times. Irwin's
> groundbreaking reporting linked CWD to a group of landowners in
> western Dane County who, in 1990, began a concentrated effort at deer
> management in order to raise "super" bucks. The landowners, who
> controlled 12 abutting square-mile sections in the northwestern part
> of the town of Vermont, agreed to give young bucks six years to grow
> so they'd develop the imposing antlers and muscular bodies that would
> get them into the record books. Then they began long-term feeding of
> nutritional supplements to wild deer. Their effort succeeded: Between
> 1990 and 2000, Dane County recorded the third-highest number of trophy
> bucks in North America.
>
> Up until August 1997, when the FDA, reacting to Britain's mad cow
> epidemic, banned all ruminant-to-ruminant feeding (sheep, cattle,
> goats, elk, deer, antelope and buffalo) in the United States,
> Midwestern rendering plants routinely processed Wisconsin deer
> carcasses into meat and bone meal that went into feed mill products
> fed back to ruminants, including deer. (Cows, sheep and deer can still
> legally be processed into bone and blood meal feed for pigs, pets and
> chickens; then they can be rendered and fed back to cows, deer and
> other ruminants.)
>
> snip...
>
> http://www.organicconsumers.org/madcow/killer123103.cfm
>
>
> 2003D-0186
>
>
> Guidance for Industry: Use of Material From Deer and Elk In Animal Feed
>
> 2003D-0186
> Guidance for Industry: Use of Material From Deer and Elk In Animal Feed
>
>
>
>
> EMC 1
> Terry S. Singeltary Sr.
> Vol #:
> 1
>
> http://www.fda.gov/ohrms/dockets/dailys/03/Jun03/060903/060903.htm#2003d0186

continued;

DR. BROWN: Actually, the more interesting
question is the converse; do they ever wind up as meat and
bonemeal?
DR. PRUSINER: This number of 10 percent'
revalence in this slaughter sample, where is this
published? In all of the materials we have, I can't find
it. I ask people this and when I quote this figure,
everyone is absolutely astounded. I would like to see the
published data.
DR. MILLER: I will hand you a reprint when we get
lone.
DR. PRUSINER: Okay.
DR. MILLER: It is in the journal Wildlife
diseases, October of this last year.
DR. PRUSINER: Great. Thank you.
DR. DAVEY: Dr. Miller, could you just enlighten
us a little bit in terms of venison and gelatin, what other
products, byproducts, meat products, from these animals get
into the human food chain?
DR. MILLER: Again, I am thinking Glen is probably
going to hit on some of this stuff later on. With respect
to the free-ranging animals we harvested, virtually none.
Those were essentially animals that are taken in to private
possession and processed for meat, muscle tissue.
As far as rendering and things, I would think--the
industry is so small right now, and there are so few animals
that go to slaughter, it is mostly custom slaughter, is it
not--Glen, very little, if any, of that, would be going into
rendered product or into those other products.
DR. DeARMOND: What happens to road kill, when a
deer is run down in the road?
DR. MILLER: It depends on where it gets hit. In
some places, the coyotes and the magpies and the other
scavengers clean it up. In other places, it is allowed for
people to pick those road kills up as long as they get the
proper permits.
DR. MILLER: In California, I think you have to
report it and I think they take it and they grind it up and
make it into feed for other animals; is that not right?
DR. MILLER: We don't do that; no.
DR. MANUELIDIS: You mentioned something very
interesting. You said that this was not like scrapie in
Europe. Maybe you could sort of expand and update us a
Little bit on what the sort of experimental models of this
are currently going on and if it is related, you think, to
scrapie in the United States that began not to be under
surveillance?

DR. BROWN: Dr. Miller, any questions that you get
which you know are going to be covered subsequently by other
people, you can defer.
DR. MILLER: I am not sure on that one. Dr. Bruce
and her colleagues over in Edinburgh have actually put
wasting disease into their mouse pathogenesis profile. I
don't believe those data have been published yet. .
DR. WILLIAMS: Only mentioned in Dr. Bruce's
Nature article in 1997. So it was a mention, not really a
documentation of that transmission.
DR. MILLER: In terms of other studies, Linda, did
she have a comment about--in terms of looking at the
relationships between wasting disease and scrapie, there is
obviously a lot of fertile ground there. I think the folks
at Ames, at ARS, have done some work putting scrapie into
elk. There are other cross-species transmission studies
underway. But scrapie into deer; I don't know whether
anybody has started that one yet.
DR. DETWILER: That has been talked about but I
don't know. There are a lot of things that are ongoing.
Since you referred to me, I just want to go back and, lest
we go down the path of the sampling of live animals through
tonsil, I will just really reiterate what Mike said. You
heard the human community saying about doing the testing on
cadavers , that that is logistically a nightmare...

snip...

http://www.fda.gov/ohrms/dockets/ac/01/transcripts/3681t2_01.pdf

PART 2

In conclusion, although the occurrence of three
unusually young CJD patients who were reported to have
regularly consumed deer and elk meat suggested a possible
relationship of their illness with CWD, our follow-up
investigation found no strong evidence for a causal link
between CWD and CJD in the three patients.
However, our conclusions are limited to the three
patients and continued surveillance remains very critical to
continue to monitor the possible transmission of chronic
wasting disease to humans.
Thank you.
[Applause. 1
DR. BROWN: I have one question for you, Ermias.
By analogy to the BSE situation in variant CJD, are there
any characteristic or distinctive glygotyping patterns in
deer or elk that might also have been seen in any of the
patients glycotyped? That seems to me to be, by analogy,
probably the single most important phenomenon that might
totally blow away the straw man that you have constructed.
DR. BELAY: We have considered that possibility.
Dr. Pierluigi Gambetti has been involved in studying the
glycoform ratios of PrP obtained from chronic-wastingdisease-
infected animals. I will give Dr. Gambetti a chance
to comment on that.
DR. GAMBETTI: These studies are very preliminary
ut, in our hands, the protein, the scrapie prion protein
rom the chronic wasting disease is what we call type 1. It
s the unglycosylated isoform migrates at 21 kilodalton.
the ratio of the glycoforms, as I said, we haven't examined
sufficient number of cases, but, so far, it looks like it
is not remarkable. It looks certainly not like one of the
few variants.
so, in terms of proteins, scrapie prion protein,
the chronic wasting disease does not seem to offer very much
help in being very typical and, therefore, from this area,
we cannot draw any conclusions.
DR. BELAY: Can I add some comments?
DR. BROWN: Sure.
DR. BELAY: I think what is also relevant is what
Beth mentioned in terms of the strain typing that was
performed by Dr. Moore. Although it was limited to just one
animal, that investigation actually suggested that the PrP
scrapie or PrP-res in CWD-infected animals is actually
different from any other PrP-res that we are aware of.
DR. BROWN: Right; but to make sense of that, you
would need--
DR. BELAY: With the limitations of the study.
DR. BROWN: That's fine, even one. But to make
any interpretation of that, you would need to do one of the
cases similarly. In other words, you want to see some

104
lrrelation between the human ,and the elk. I gather that
as not possible.
DR. BELAY: We have not done any strain typing in
he patients and also in the chronic-wasting-diseasenfected
animals...

snip...


DR. BELAY: As you can imagine, a case-control
study in this group of diseases is extremely difficult
because, by the time the patients die, you would be
eliciting information that took place pretty much for a
lifetime period. So you would asking questions like, "Did
you ever eat venison?" and that information would have to be
obtained from family members.
The bottom line is case-control studies would be
complicated. But I agree that case-control studies have
some value at the same time. In addition to the limitation
of getting the information from the family members, casecontrol
studies are also limited by their ability to detect
a low level of transmission.
In other words, if there was a low level of
transmission, you may not see any difference between the
cases and the controls that you would be investigating. But
such a case-control study is underway in Canada that I am
aware of. They have included questions like consumption of
venison and we are awaiting that study to see if that would
warrant a larger-scale case-control study in the United
States...

snip...

3 congratulated because this could have been like the
4 anecdotal stories about squirrel meat that just hang in the

19 DR. GAMBETTI: In case 2, several areas. The
20 diagnosis was initially established from a biopsy and, when
21 the autopsy tissue was obtained, it was confirmed, the
22 result was confirmed with samples from different areas.
23 Case no. 3, I don't remember specifically whether it was

107
DR. BROWN: Don, the short answer is no. The CDC
and Dr. Belay and Dr. Gambetti really are to be
breeze without anybody ever really looking into it.
I give them all the credit in the world for
actually driving these as far as they can. But they are
still anecdotal.
DR. PICCARDO: Case no. 1, there is no immunoblood
analysis. In case 2 and 3, there are immunoblood analyses.
Extensive immunoblood analyses from different areas was done
or from a single area?
DR. BELAY: Do you want to comment on that, Dr.
Gambetti?
DR. GAMBETTI: could you say the question again?
DR. PICCARDO: On cases 2 and 3, the immunoblood
was from a single area or were multiple areas analyzed by
Western blot?
several areas, but, generally, that is our rule. We perform
a Western blot on multiple samples.

108
DR. PICCARDO: In all cases, you saw type 1, you
never saw a mixture of type 1 and 2, or a weird pattern in
any of the--
DR. GAMBETTI: Case 1, we did not receive frozen
tissue.
DR. PICCARDO: No, no; from cases 2 and 3, all the
Western blots show a type 1 PrP.
DR. GAMBETTI: Exactly. Correct.
DR. BROWN: Just in closing this presentation, the
other interesting interface that one of these patients had
for this group was that he was a professional blood donor
and had donated multiple, multiple, multiple units of blood
even into his early clinical phase.
Now, on to the next presentation, diagnostics by
Dr. Kathy O'Rourke.
Diagnosis of Elk-Associated and Deer-Associated
Chronic Wasting Disease

snip...

Five, each batch of velvet antler we produce is
thoroughly tested in an independently licensed laboratory
not only for compositional conformity to our standards but,
also, for food-borne pathogens and other contaminants such
as heavy metals. When a live animal test for CWD is
validated, we will require that test as well...

snip...


DR. WILLIAMS: There is a situation with some of
3ur experimental herds within the endemic research
facilities where we do have cases where animals have been
removed from particular paddocks and then animals from CWDnegative
herds reintroduced into those facilities. Under

153
those circumstances, with environmental contamination and
potentially fence-line contamination, we have had prevalence
in those herds up to 50 or 60 percent.
DR. BROWN: So this is an extraordinarily
contagious disease, relative to something like scrapie which
is 1 to 2 percent, BSE which maybe' doesn't get horizontally
transmitted at all. But, certainly, by comparison .with
scrapie, in terms of the data such as it is, this is
explosive.
DR. WILLIAMS: Linda, do you want to comment on
the occurrence or the prevalence of scrapie within endemic
flocks?

snip...


DR. PICCARDO: You are absolutely right, Paul.
But, then, I have another question maybe for Beth or Linda.
For the ones that tested negative on immunohistochemistry in
humans--in humans where it is supposed to be more ideal
conditions, if you wait long enough, or the material is
fixed long enough, sometimes you might have a negative by
immunohistochemistry due to the long fixation or the notideal
condition of the material.
How ideal is the material that you test?
DR. WILLIAMS: It is variable. But, in general,
especially the plants that have been used to doing this, we
get good samples from them. We get the right part. And
they are typically only fixed for a short period of time
because the carcasses are hanging and, obviously, they don't
want to leave them hanging for very long if they are going
to move on into the food chain.
So they do send us pretty good samples. I will
say that we have a little bit of information in terms of
experimentally infected elk looking at the time at which we
can detect PrP in the brain. This would be for elk. It is
a little bit different than deer, as has been mentioned. By
six months, post oral inoculation, we 24
25
we can detect it at the
obex.
In those two cases, the staining was relatively
strong suggesting that it could have been picked up even
prior to six months. But, again, experimental or
inoculation.
DR. BELAY: Dr. Brown, it was my understanding
that there is actually a proposal to change what we are
discussing interms of whether or not a test-negative animal
from an infected herd should be allowed to go into‘the human
food chain. My understanding was there is a proposal to
change that. Is that true? I am asking this question to
Lynn. Dr. Creekmore?

snip...

DR. CREEKMORE: My name is Lynn Creekmore. I am
with USDA APHIS Veterinary Services, the National Animal
Health Program staff, and I am the staff veterinarian
working on the chronic wasting disease proposed program.
Right now, the proposed program isn't dealing with that
issue of whether or not test-negative animals from a
positive or exposed herd should or should not enter the food
chain.

snip...


DR. BROWN: Because there is no reason--in spite
of what you heard this morning, or you might have taken away
from this morning, a priori, there is no reason to equate a
syndrome due to CWD in a primate with the syndrome of
variant CJD. It might look like blue-bottle fever. We have
no idea. But it is not likely and, from what you say, it is
very unlikely that it would turn up as a very unusual
unrecognizable syndrome in humans.
SO if it looks like a TSE--and I won't go through
the rest of it...

snip...

Has CWD been put into any primate?
DR. WILLIAMS: It has been put into squirrel
monkeys and it was positive in one case.
DR. BROWN: out of--
DR. WILLIAMS: I don't even know how many--Dick
Marsh did the work and I don't know how many squirrel
monkeys he inoculated.
DR. BROWN: It was intracerebral inoculation?
DR. WILLIAMS: Intracerebral inoculation; yes.
DR. BROWN: It looked rather like TSE?
DR. WILLIAMS: Yes; it was a spongiform
encephalopathy.
DR. BROW-N: Because there is no reason--in spite
of what you heard this morning, or you might have taken away
from this morning, a priori, there is no reason to equate a
syndrome due to CWD in a primate with the syndrome of
variant CJD. It might look like blue-bottle fever. We have
no idea. But it is not likely and, from what you say, it is
very unlikely that it would turn up as a very unusual
unrecognizable syndrome in humans.
SO if it looks like a TSE--and I won't go through
the rest of it.
DR. ROOS: I wanted to note that the pathology is
very different. I wondered whether there was data about the

167
subhuman primate transmission and its pathology.
DR. BROWN: That is a good point, also, about the
primate neuropathology.
DR. WILLIAMS: Unfortunately, that was not well
examined and the slides are gone. I have not been able to
retrieve those slides. I, personally, haven't looked at
them so I can't comment on how the spongiform encephalopathy
in that squirrel monkey might compare with other
intracerebral inoculations of other TSEs. I can't comment
on that. I know it was a spongiform encephalopathy but that
is not based on my personal examination and the slides
spear, and the blocks appear, to be gone...

snip...

DR. ROOS I don't think that the CJD surveillance
program is well advertised in the general neurology
community. Maybe I am mistaken about that, but in journals
and at meetings, at least up until this point. Ermias,
maybe you have some idea about how many cases do you think
you are missing in your registry?. What percent of general
neurologists know about your registry?
DR. BELAY: Which registry are you talking about?
We have several mechanisms for CJD surveillance. The one
you are referring to is probably the national center that
Dr. Gambetti is the head of. Dr. Gambetti will probably
speak for himself that just recently have gave a talk in the
American Association of Neurology.
I will let Dr. Gambetti speak for that. He went
to a major neurology association meeting trying to advertise
the system and encourage them to utilize this national
center for diagnostic and surveillance purposes.
Dr. Gambetti?
DR. GAMBETTI: I agree 100 percent with the
statement that our national surveillance center, that the
National Prion Pathology Surveillance Center, is not really
seeing a representative number of cases. So I agree with
the statement that it is not really fulfilling his job. Why
we are not seeing in a year a sufficient number of cases.
I give you some numbers. In the Year 2000, we

171
have examined or received already examined--for example,
from Dr. Prusiner and DRM Laboratories, a total of 109
cases. Now, these represent the prevalence of CDJ in the
United States as the same as in Western Europe, just 35 to
40 percent of the cases suspected.
Those cases are very thoroughly examined.
However, as I said, they represent only 35 to 40 percent of
the cases. We try very hard to increase this number. It
looks like there are at least three problems and all, of
course, are related to the fact that our resources are, at
the time, limited.
One of the problems is exactly as Dr. Roos
indicated. We have been unable, and maybe Dr. Belay can
explain better--
DR. BROWN: I think we don't need or want a long
explanation. It is a little off focus.
DR. GAMBETTI: But that was the question.
DR. BROWN: No, no; the question was would--I
don't mean to be rude, Pierluigi, but we are off the focus.
The question was is there an adequate surveillance, a
systematic adequate surveillance. The answer is no.
DR. GAMBETTI: The answer is no.
DR. BROWN: It is not your fault.
DR. GAMBETTI: But you have to give me a chance to
explain why. Yes; you have, because otherwise we are left

172
with the idea that the surveillance is doing nothing and it
is not true.
The reason why we cannot see many more cases is
one, we have been unable, for a question of regulation, to
contact the neurologists at the national level. We have
been able to contact several times neuropathologists and
pathologists. I am planning to present, to give a‘
presentation, at the American Academy of Neurology, the
'lenary session. So we try to inform all the neurologists.
Second, and perhaps the major reason, autopsies.
The autopsy rate in the United States is about 20 to
30 percent, no exception for CJD. So autopsies are not
performed. If we had more resources, we would reimburse the
institution for performing autopsies. I am sure that the
autopsy rate will go up.
Third, we have to have a system like the European
surveillance center in which the family of the patient and
the caring physicians are contacted when the patient is
alive and right away a rapport, a relationship is
established, and the patient is followed and, if he expires,
an autopsy is performed regularly.
So these are the thing I am trying very hard to
pursue. Unfortunately, so far, the resources have not been
sufficient to do all this.
DR. BROWN: Thank you.

snip...

DR. BROWN: I think the FDA simply wanted us to
record the fact that there is likely to be infectivity in
various organs, tissues and cells of disease-affected elk
and deer. We have no basis, really, to predict how that
distribution is going to shake out, but it wouldn't be
shocking if spleens and a heart and sinus and maybe
something else in a bioassay that was sensitive turned out
to have infectivity. It would be very surprising if they
didn't.
So the potential is there. That is about all we
can say.
DR. NELSON: It seems like, from what we were told
today, that the highest human tissue exposure may be to
velvet antlers. However, we were told that they were not
coming from infected animals but whether or not, in other
producers, or- -they could be.
DR. BROWN: And it is all going to South Korea
anyway; right?
DR. NELSON: I can assure you it is in Thailand as
well...

snip...

DR. BROWN: Any other discussion on this aspect?
Question 5 was, if there is a potential for
transmission of a TSE from infected or exposed animals or
animal parts to human, what is the likelihood of
transmission. If there is no objection, we will go on to
topic 4.
DR. DETWILER: Should we vote on no. 2?
DR. BROWN: Would you like to? We can vote on
anything that you--if the committee would like to register
votes on any of those questions it is perfectly okay.
DR. DETWILER: I think the vote would go on
record; right? I think that is important for the industry,
for the FDA. I don't know how the FDA feels. I shouldn't
speak for them.

DR. BROWN: Why don't we very quickly, then,
again, for the record, vote on 1, 2 and 3. We can run
through these very quickly. 1 was the transmission animal
to animal, elk to elk, deer to deer. Can I have just a show
of hands? The hands are up for yes.
[Show of hands.]
DR. FREAS: Thirteen hands are raised.
DR. BROWN: Anybody on the committee believe that
there is no scientific data to support transmission of CWD
from animal to animal.
[One hand raised.]
DR. BROWN: One negative.
The second question, are there scientific data or
other scientific evidence for transmission of a TSE to
people consuming or using products made from deer or elk
with chronic wasting disease. Show of hands on this one as
well? The hands, again, will be for yes, there is such
evidence.
[Show of hands.]
DR. BROWN: Since there are none, we will just
make it concrete, a show of hands for no.
[No response.]
DR. FREAS: Fourteen no votes.
DR. BROWN: 3 just extends that. Do you want to
vote on 3? Do you think 3 is important, Linda? We have no
idea about exposed to.
183
DR. DETWILER: I throw that back to FDA.
DR. BROWN: In this case, instead of saying
consuming or using products, we are saying consuming and
using products made from deer or elk exposed to, not even
necessarily infected, just exposed to the disease. Show of
hands for yes, there is such scientific evidence. .
[No response.]
DR. BROWN: Show of hands for no, there does not
exist such scientific evidence.
[Show of hands. 1
DR. FREAS: Fourteen.
DR. BROWN: I guess we can continue on. Why not?
This is a piece of cake...

snip...

Under those circumstances, we have heard this is
certainly lots of PrP depending on the species and
circumstances in the third eyelid and tonsil of infected
animals. So there is definitely evidence of potential

186
infectivity apart from the central nervous system but no
evidence of real infectivity apart from the central nervous
system. Curious phrase.
So I read question 4 as being a yes answer under
those circumstances. But the committee should now vote on
that, or we have decided we will. So, on this one, why
don't we just go around because it is conceivable that there
may be differences of opinion on that. Ray?
DR. ROOS: Yes.
DR. DETWILER: Yes.
DR. BURKE: I vote yes and would like to emphasize
that my concern that, since velvet antlers is so widely used
by so many people, that would be one that should have
special attention paid to it.
DR. McCURDY: Yes.
DR. PICCARDO: Yes.
DR. GAYLOR: Abstain.
DR. NELSON: Yes.
DR. BOLTON: Yes.
DR. BROWN: Yes.
DR. BELAY: Yes.
DR. CLIVER: Yes.
DR. LURIE: Yes.
DR. WILLIAMS: Yes.
DR. PRUSINER: Yes.

187
DR. FREAS: One person abstained. Thirteen people
voted yes with one abstention.

snip...

DR. BROWN: All one would need to get a lot of
money, more money than you ever imagined possible, would be
to mix up the diagnosis on two brains and report out an elk
in place of a cow and find daisy plaques in a cow in
Montana, say That would be very bad news.
DR. BELAY: I agree that this situation is
different from the scrapie situation. It goes back to what
Peter said earlier and that is that government, actually, is
required in this area. One of the government actions,
potentially, would be a surveillance for chronic wasting
disease and the elimination program that we heard about.

snip...

DR. BELAY: I agree that this situation is
different from the scrapie situation. It goes back to what
Peter said earlier and that is that government, actually, is
required in this area. One of the government actions,
potentially, would be a surveillance for chronic wasting
disease and the elimination program that we heard about.
Effective surveillance, I believe, would require

192
ruminant proteins to other ruminants.
[Slide. 1
We are going to address now the suitability of
blood, plasma and tissue donors exposed to various TSE
agents of animals. The accidental infection of blood,
plasma and tissue donors with animal TSE agents would be of
special concern because, theoretically, at least, such
infections might, then, be passed to recipients with greater
efficiency than the initial infection due to loss of the
species barrier, in jargon, a dead-end host would become an
amplifying host.
In 1996, new-variant CJD was first described in
the medical literature and was clearly linked to exposure to
the BSE agent. That link increased the concern of
regulators about the possibility that the BSE agent might
accidentally make its way into products containing or made
with ruminant components.
Our concern regarding BSE and vaccines were
discussed by a joint meeting of this committee and the
vaccine and related biological products committee in July of
last year and the theoretical risks associated with blood
products and tissues were discussed yesterday and earlier
today. Other products will be considered briefly this
afternoon.
The BSE/variant-CJD connection also increased our

193
concern about human exposures to other animal TSE agents
that will be considered in this session. Three animal TSE
agents have been recognized in the USA; chronic wasting
disease, which has just been discussed and will be
considered again, briefly, in a short time ; transmissible
mink encephalopathy, which has not been seen in this country
since 1985. Opportunities for human exposure to mink
tissues appear to be limited and I won't mention mink
encephalopathy any further; and, finally, scrapie of sheep
and goats.
[Slide. 1
Implications of the scrapie agent for biologics
and devices were considered nineteen months ago when the
committee reviewed safe sourcing of materials derived from
sheep and goats for the manufacture of FDA-regulated
injectable and implantable products.
Human exposures to scrapie of sheep and goats
historically have not been of concern. There is a long and
uneventful history of human exposures extending to infected
animals and their products extending back for probably more
than two-hundred years. There is no convincing anecdotal or
epidemiological evidence of any transmission to humans.
CJD prevalences are similar in countries with
scrapie and those without scrapie and attempts to transmit
scrapie experimentally to chimpanzees have failed.

However, even for scrapie of sheep and goats,
there were some uncertainties. Multiple strains of scrapie
agent have different biological properties and there is at
least a suspicion that the BSE agent may have originated as
a strain of scrapie agent. Attempts to transmit scrapie to
chimpanzees were very limited and scrapie was transmitted to
several species of monkeys so that there cannot be an
absolute species barrier between scrapie of sheep and
primates.

The committee advised the FDA to continue to avoid
using sheep and goats with scrapie as sources of material to
manufacturer FDA-regulated injectable and implantable
products. However, no concern was expressed about human
exposures to scrapie agent in food. We have had a long
experience with that.
[Slide.]
The FDA has received inquiries expressing some
concerns about the potential transmissibility to humans of
various TSEs of animals. You have heard typical discussions
during the previous hour. Except for new-variant CJD, of
course, no human TSE has been attributed to infection with
an animal TSE agent and BSE agent, the presumable cause of
new-variant CJD, has never been found in U.S. cattle.
194...

NOT...TSS


DR. BROWN: Thank you, Dave.
The first presentation, then, will be from Linda
Detwiler from the USDA and she will tell us about the flap
in Vermont.

197
Undifferentiated TSE in Flocks of Sheet in Vermont
DR. DETWILER: That is probably an understatement.
[Slide.]
I just wanted to at least give a slight overview
of BSE in sheep just to bring everybody--I have just three
slides here to bring everyone up--'1 think we have talked
enough about scrapie, not only today but in the past, on the
committee that people understand at least what is known
about scrapie pathogenesis because, in this case, in these
sheep in Vermont, the disease actually could be scrapie or
BSE.
Just quickly, BSE in sheep, Foster, et al., 1993
and 1996, put BSE orally into sheep. They had this negative
and positive line sheep. They are just genetics. The
negative line are sheep that they normally don't see the
natural scrapie in. The positive line are genetically the
type of sheep that they normally do see natural scrapie in.
In the negative line of six animals inoculated
with half a gram of brain tissue, one did--one came down
with clinical disease and then, in Bruce's strain typing, it
was identified to be the same strain as BSE. So BSE-in and
BSE-out identified.
In the positive line, there were five animals
total. Two came down with clinical disease. However, when
strain typed, they came down with a more atypical, or

198
something that did not look like BSE in the strain typing or
other known strains of scrapie. So they called it atypical
on the research paper.
[Slide.]
So far, research of BSE in sheep, distribution of
infectivity, brain, spinal cord and spleen, and that is
actual infectivity by mouse inoculation. In the intestine,
most likely the Peyer's patches associated with the
intestine, it is PrP-res or the abnormal form of the prion
protein.
Yesterday, we heard of the one report of the blood
transfusion, 400 mls from a sheep that was fed BSE in the
incubation stage and a transfusion to another sheep that
developed disease. This is ongoing research so there will
be new information. So that is BSE in sheep.
Right now, it looks like it will be very similar
to scrapie in sheep versus BSE in cattle, in oral
experiment.
[Slide.]
So where is Europe on the situation with sheep.
This is all experimental data. The European Union, in 1998,
issued an opinion paper which stated that it was highly
likely that there was exposure of their sheep and goat
populations to feed contaminated with BSE. So meat and bone
meal with BSE agent.

199
However, in the diseases, clinically,
histologically, the tests for PrP to date, and they are
working on some new tests, that they don't differentiate
between the two diseases, scrapie and BSE. Most
differentiate scrapie from the mouse bioassay system, and
that can take up to two to three years. That is Bruce's
system.
So, right now, what they are having to do is take
what they are reported as natural cases of scrapie that
might be high risk or suspect for potential for BSE, put
those in the mouse bioassay systems and wait this long time
to determine what disease it is.
So far, there have been no natural cases of BSE in
sheep detected to date. However, the numbers assessed are
small, less than 100, that have been completed. But, in
regards to their public-health protection in the European
Union, they have specified risk material, so the high-risk
tissues from sheep and goat tissues of animals going to
slaughter waiting for other data to come out.
[Slide.]
Where are we in this whole situation? 1947 was
our first case of scrapie. In 1952, we put a control
program in place. We then closed the door pretty much, the
imports of sheep and goats, other than from a few countries;
Australia, New Zealand, that are considered free of scrapie,

200
and then Canada with a similar program.
We didn't want to introduce any new strains of
scrapie into the United States. However, the sheep
industry, goat industry, asked us for new genetics and if
there was a way to bring those in under a monitoring to
introduce some new genetics into the country.
so, in April of 1996, the regulations were changed
to allow sheep and goats to come in and be monitored under
the Scrapie Certification Program for five years. Under
this provision, these two shipments were imported.
Originally, we thought they were from Belgium and we later
found out they were actually from Belgium and The
Netherlands.
They were imported in both August and November in
two different groups. There were 65 head, total. The
distribution was 52 went to one of the Vermont farms.
Eleven went to the other Vermont farm. And then two rams
went to a New York farm.
[Slide. 1
They have been monitored since entry. That was
part of the requirement to come in. They have been under
actual quarantine since October of .'98. That was right
after the opinion paper came out to give the legality or
basis for an actual full quarantine.
They were allowed to sell, from premise, progeny.

PART 2

MILLER REPORTING COMPANY, INC.
735 C Street, S.E.
Washington, D.C. 20003-2802
(202) 546-6666


http://www.fda.gov/ohrms/dockets/ac/01/transcripts/3681t2_02.pdf

PART 3

201
They had to be sold into other scrapie-monitored flocks.
that was the thing. They could not sell any of the original
imports. They could sell progeny into other scrapiecertification
flocks. So there were nine sold.
Of these nine animals sold, there were seven ram
Lambs. We did go out and contact the owners and purchase
all those and destroyed all those animals, took samples.
There were two ewe lambs and another ram lamb sold to
another premise. Because there were ewe lambs that lambed
in this flock, we asked the owner and purchased this entire
Elock as well, again with the transmission of scrapie.
These samples have been tested from this flock and
there was no evidence of disease. But there were three
actual progeny into this third flock.
[Slide.]
Other product, cheese, was sold throughout the
United States. These were predominantly East Frisian milk
sheep. They were manufacturing cheese, especially the
larger farm, and selling throughout the United States.
Then, prior to the quarantine, there were 45 carcasses that
went for human consumption. I will talk more about those.
[Slide.]
This is just to show you the breakdown. They came
in in 1996 but didn't start lambing until '97 because they
were young when they came in. This is a breakdown of how '

202
many lambs, when they went and the poundage. The poundage I
put on here just to give you an idea of the age. So they
would be six months or less.
The last two shipments that went for slaughter, we
were able to bring the carcasses back after the European
Union opinion and then we destroyed those, or the last two
shipments.
So where did they go? Where did these go? They
were sold at two local stores, like mom-and-pop outlets.
They were sold off-farm. None were sold through the
internet. 10 percent of the sales off the farm went to
friends, acquaintances and tourists, and the family and
their attorney consumed the product. They are in court with
us, now, too.
[Slide. 1
What happened after the quarantine? We bought
all, then, the culled, sick, picked up the deads. In these
situations, in order to milk sheep, I just want to explain,
you have to keep breeding them. So they produce young and
then they produce the milk. So we did get a lot of
offspring in the meantime from when they went under
quarantine; in fact, over 300.
But what the USDA did with those is we purchased
them like we were the slaughter outlet because you cannot
have a quarantine--that, by the way, was applied by the

10 histology. Most of the sheep had one of the lesions, two of
11 the lesions. One had three, but none had all four. So
12 there was no regulatory basis that we could act upon these

21 back blood-positive. We took brains, then, from those sheep
22 that were positive by the CE and tested those under our
23 regime of testing, and four of those tested positive by the
24 Western blot analysis. That was done by Dr. Richard
25 Rubenstein, with whom we have a cooperative agreement, at
203
State of Vermont--unless you give an outlet. So we
purchased them like a slaughter outlet and incinerated the
carcasses. So we have been doing that ever since. Anything
that was older, that was culled, sick or died, we sampled it
and then incinerated the carcasses.
The results? On histology, we found in some of
these vacuolated neurons, astrocytosis and neuronaldegeneration.
By regulation, in the USDA, we have to have,
for TSE, scrapie diagnosis, four confirmed lesions for
sheep.
There was capillary electrophoresis, again, I just
want to emphasize. But this has been talked about publicly
and, also, in court. There were blood-positives on some of
these sheep and that was done, even though the test is under
development, at the request of one of the owners who said,
"Test my sheep because I think it will clear them."
Lo and behold, we did have six sheep that came
21 back blood-positive. We took brains, then, from those sheep
22 that were positive by the CE and tested those under our
23 regime of testing, and four of those tested positive by the
24 Western blot analysis. That was done by Dr. Richard
25 Rubenstein, with whom we have a cooperative agreement, at

204
the Institute for Basic Research in Staten Island, New York.
The Western blot done by actually had a little
hearing of its own. Would you like to see the Western blot,
the committee? You have to click in the middle. I couldn't
figure out how to cut and paste this on.
Why don't we go on. Then I will come back and try
and get it up there for you to take a look at.
[Slide.]
So what happened? This happened in July of this
past summer, the Year 2000. We approached the owners--at
chat time, there were the three flocks in existence, the one
with the ewe lambs and these other two--to ask them to
voluntarily depopulate the flock.
By the way, the entire time from when they started
to be under quarantine and even prior to that, we had asked
them if they wanted to sell the flocks to us and that we
would pay for the flocks, just to remove the risk. They
chose, at that time, not to do that. So, even up to before
this, they were asked if they would depopulate those flocks.
Then, after the positive diagnosis with the
Western blot, because that is, for us, a legally binding
test, the owners were asked one more time to voluntarily
depopulate. The small flock, the one with the progeny, did
agree, so those sheep were removed, as I told you earlier.
Then, on July 14, the Secretary of Agriculture

205
declared an extraordinary emergency. That is what we need,
in the USDA, in order to seize property. So an emergency
order had to be declared for us to obtain money. Orders
were then issued by the Department to seize the flocks, the
two flocks.
[Slide.]
One of the things here, now, I will talk'to about
is what it is we found. The tests that we have run, so the
histology, the immunohistochemistry and the Western blot,
they don't differentiate between different strains or
variants of scrapie from BSE. So these tissues would, too,
then have to go in mouse bioassay. So we don't really know
what disease we are dealing with here.
It was named this atypical, because of the
histology. We had Gerald Wells from the U.K. look at the
histology and that is one of the ways he described it; "TSE
of foreign origin." The foreign origin came into play
because these sheep came in as groups and there was no
exposure to U.S. animals or U.S. product.
[Slide. 1
What happened next is really history because it
really played in the media. The two owners went to court
for a temporary restraining order. The judge denied the
temporary restraining order, as I said. There was even a
hearing on the Western blot test. He did not grant the

206
temporary restraining order.
However, he asked them to voluntarily comply.
They did not. So then we had to go back to court and ask
for a motion for an order to comply and for the judge to
rule on the merits. So we filed final briefs at the end of
December and we are waiting on a court decision.
By the way, they have been maintained, again under
quarantine and under surveillance, with the same protocols
in place, that anything that dies, anything is removed, we
get and sample.
How about if I try and bring that Western blot up?
That is all I have.
[Applause.]
DR. BROWN: Thank you, Linda. We will look for
the Western. One question, Linda, and that is in the
history, had there ever been a prior case of scrapie on
those farms, ever, before the imported sheep came?
DR. DETWILER: I should have probably talked about
the history of the flocks. They came out of about ten
different flocks in Belgium and the Netherlands.
DR. BROWN: No; I am more interested, actually, in
the U.S.
DR. DETWILER: oh. NO , no. They were brought in
for different premises where we had no reports of ever
having sheep there, nor were they commingled with anything

207
here. They were brought in as separate groups for this
purpose.
DR. BROWN: So, essentially, it is virgin pasture.
DR. DETWILER: Correct; at least to the best of
our knowledge.
DR. BURKE: What is the reluctance on the part of
owners to voluntarily depopulate?
DR. DETWILER: They do not believe, and I am just
paraphrasing so--they do not believe that there is a problem
in these flocks. I will give you a history--I think that
might help, too--on the situation in Europe. We did go back
and try and get a lot of information. We haven't been that
successful of getting information from the government. We
have requested it, but they have said they have got their
hands full with other things right now.
One of the things that we did find from just
getting other data from sources like the veterinarian that
signed the health certificates, that they were fed
concentrate. So we do know that, that they were fed
concentrate made in local mills that did produce both
ruminant and non-ruminant feed, although we have
certifications that said they didn't include ruminant meat
and bonemeal in the feeds at least since certain amounts of
times when the feed bans went into place.
SO we have those, but there is a likelihood, in

208
Europe, of cross-contamination. They did come in with
scrapie certification statements, that they had been
monitored. But even now, since that time, we have found
that some of them have not been monitored as long as they
nay have seemed to have been. So there is some question,
even on exposure to scrapie.
[Slide.]
This is the Western blot. I couldn't get the
other block. He had that on a separate one, the fourth
sample, on a different one. I'm sorry. I got one to go but
I couldn't get the other one, to bring it with me.
DR. RRUSINER: Could you explain--
DR. DETWILER: I can only explain the three
positives because this is Rich's stuff. These, I think, are
two sheep from there that he did call no--these three, he
caused positive. And then, over to the side, are some of
the controls.
So these three, at least what Rich explained in
court, were the three that he called positive. These two
were also sheep, as I recall, from the flocks. You know
what? I don't know much about Western blot. Bob Roher, he
helped with the thing and the Western, so he probably could
answer more, or you can talk to--
These, I believe, are controls.
any other questions?

209
DR. ROOS: Two questions. First, how many other
flocks were imported during this window.
DR. DETWILER: That's it.
DR. ROOS: Oh; this is it?
DR. DETWILER: This is it.
DR. ROOS: The second is. how did these come to
your attention? Were there sick animals or you pursued them
because you know them came in?
DR. DETWILER: When things change, one of our jobs
is to monitor what is changing in science and what is
changing in the world. One of the things we noticed, as the
science changed in '96--oh, by the way. That is a good
point you bring up. At the end of '96, when the publication
of Foster's paper that showed that it was not only in brain
and spinal cord, when it was in spleen, then we thought,
"Oh, oh; it might be--" and the paper suggests that maybe,
if BSE became natural in sheep, that it could spread like
scrapie and then feed bans wouldn't control it.
So we, again, shut the door at the end of '96 to
all sheep and goat imports with the exception of going back
to the same countries, Canada, Australia and New Zealand.

snip...


The FDA's and the USDA's import alerts that we
just learned about prohibit the use of these organs in
foods, medicines and medical devices. But my reading of the
alert, 17-04, suggests that DSHEA does allow some loopholes
for these tissues to possible slip in.
I will just read from 17-04 that we heard. On the
first page, it says that, "This alert does not establish any
obligations on regulated entities." I love seeing
legislation that starts out with that caveat.
Then it says, further, "The USDA regulations do
not apply to bovine-derived materials intended for human
consumption as finished dietary supplements.11 We also learn
that the prohibition, or the import alert, is limited to
bulk lots of these tissues, completed tissues, from BSEderived
countries. It does not mention if it is not a bulk
import or.if it is raw materials rather than finished
materials.
Further, we know that it is strongly recommended
but not actually prohibited in the language here. So I have

233
not taken the assurances from that import alert that Dr.
Yoore was trying to convey to us.
so, in sum, dietary supplements sold in the United
States often contain ruminant tissues from undisclosed
sources. Personally, I am rather squeamish and I don't
think I would be eating prostate or testicle or pituitary,
out I am also a little bit wary of consuming products with
those glands, not just out of personal repugnance but simply
out of a health concern.
So my question to the advisory committee is this;
is my caution reasonable and, if it is, should we take
further efforts to inform, or even protect, the American
public from such exposure.
I was curious about Dr. Moore's remarks. I sensed
two messages. One was the initial reassurance that FDA has
the regulatory authority but then I also learned that it is
the manufacturer's responsibility to provide those
assurances, that the FDA doesn't actually inspect.

snip...


DR. McCURDY: Are there'data to indicate how many
grams, or whatever, of infected brain are likely to infect
an organism, either animal or man, when taken orally?
DR. BROWN: If I am not mistaken, and I can be
corrected, I think a half a gram is enough in a cow, orally;
in other words, one good dietary-supplement pill.
DR. McCURDY: What I am driving at is the question
we are asked is really not do we wish to regulate these
things coming in. I think the statements about difficulties
in regulating things in the future or near future for new
regulations were probably accurate.
But I think that we could exhibit some quite
reasonable concern about blood donors who are taking dietary
supplements that contain a certain amount of unspecifiedorigin
brain, brain-related, brain and pituitary material.
If they have done this for more than a sniff or something
like that, then, perhaps, they should be deferred as blood
donors.
That is probably worse than spending six months in
the U.K...

snip...

DR. NORTON: I am Scott Norton and I am a
physician in the Washington D.C. area. I am here speaking
as a private citizen today.
I first became concerned about the presence of

231
tissues from ruminant animals in dietary supplements about
six months ago and expressed my concern in a letter that was
published in New England Journal of Medicine in July of Year
2000...

(actually, I FIRST submitted my data to same journal, and they turned it
down, THEN, 6 months later, Dr. Nortons data appeared in
print, which was just about identical to mine, coincidence?
NO BIG DEAL, I to was gratefule somebody got the data published,
you see, i have no PhDs hanging on the wall, my fault :-(TSS).

later submitted this on the same topic of concern, again to FDA;

Docket Management Docket: 96N-0417 - Current Good Manufacturing Practice
in Manufacturing, Packing, or Holding Dietary Ingredients a
Comment Number: EC -2
Accepted - Volume 7

http://www.fda.gov/ohrms/dockets/dailys/03/Mar03/031403/96N-0417-EC-2.htm

snip...

continued;

DR. DETWILER: May I just, at least, correct one
thing, and then I will tell you how you can--Dr. Norton
nentioned about the USDA. There is no exemption for dietary
supplements. There is for cosmetics. There is for gelatin.
3ut there is no exemption for dietary supplements.
I will tell you one thing, though. In importation
and what happens with importation, USDA, if it is bulk
product, our regulations can keep out organs and tissues of
ruminant origin. That is a given. If it is labeled with
products of ruminant origin, we don't regulate end use. We

239
don't regulate end use.
Our regs is the material coming in. If it is
Labeled as ruminant-origin coming in, then our system can
pick it up and keep it out, with the exemptions of certain
tissues going for cosmetics, but then CFSAN has a system in
place there for cosmetics. Then gelatin, as this committee
has looked at the issue of gelatin, those are our two
exemptions.
The dietary supplements, since they are labeled
with certain tissues, we can keep them out. However, if the
Labeling is such where that is not apparent--that is what
happened in the vaccine issue--we don't know--there is no
way in our system, and maybe this is what you are alluding
to--there is no way in our system to pick that up. We have
no mechanism that says we know, the USDA knows, what is in
there.
But there is no exemption in the 9 CRR for dietary
supplements.
DR. NORTON: That's wonderful. I feel good to
hear that but I just know that what I can obtain from the
USDA's website it says, for example, since 1991, the USDA
has prohibited the importation in the U.S. of certain
tissues and organs from ruminants from countries where BSE
exists.
Then it goes on to that 9 CFR 94.18. But then, at

240
the end of the paragraph, it says, "The USDA regulations do
not apply to imports of bovine-derived materials intended
for human consumption as either finished dietary-supplement
products or for use as ingredients in dietary supplements.1'
DR. BROWN: The other point that could be made
here is that something which--
DR. DETWILER: This is not the USDA's; is it?
DR. NORTON: That is the FDA's import alert 17-04
that cites the USDA.
DR. DETWILER: I just want to correct--this is not
the USDA/s.
DR. BROWN: Let me say something here and that is
that it strikes me that if the FDA is depending on the USDA
to be the primary stop gap, then that is punting the ball.
If it is a question of the port authority stopping material
that might be a risk in terms of its presence in dietary
supplements, that is probably not the ideal solution.
It is nice that the USDA gets in on the act. It
is a little disquieting to think that the USDA has the
primary role in the act. I bring to the committee's
attention just a case that we published as part of our
iatrogenic disease paper a few months ago. I thought it
would be instructive.
It is an anecdote, but it was the case of a woman
in Massachusetts, several years ago, who died from CJD.

241
After the fact, it was discovered that she had been taking a
dietary supplement for a year or two or three before--more
than that, actually. She had been taking dietary
supplements for years.
That is probably not uncommon either. I think
probably it was, in fact, a case of sporadic CJD but it was
a little worrisome to learn the ingredients of what she was
taking. She was taking a half a gram of brain, of bovine
origin, which, on the label, said was "imported," as though
this was a merit.
It was not specified from what country it was
imported but it was specified that it had been specially
processed to retain all its natural purity and its potency.
Here is a lady who is taking half a gram of brain for years,
not knowing the origin of the brain, at a time when BSE was
rampant.
As I say, there is no indication that the two were
related. But it was a little troubling to realize that this
had occurred. Brain is a favorite substance in many dietary
supplements. And pituitary is a favorite substance in many
dietary supplements. God knows what they do, in terms of
improving human health. But I think there is a real
consideration that they might do the reverse.
That is one of the reasons why I hoped, and now
have gotten the opportunity, at least to bring into the

242
public domain certain concerns about these supplements.
MS. OLIVER: My name is Janice Oliver. I am from
FDA's Center for Food Safety. I would just like to comment
on a couple of things and a couple of comments that have
Deen made.
When Bob was commenting .on dietary-supplement
regulation in terms of BSE coming in from countries and how
we regulate it coming from other countries, he was not
commenting on DSHEA and its regulatory authority all the way
across the board. That would have taken much longer. He
had a very small presentation on it.
The import alerts that we have are guidances to
our field. The primary focus, because it is easier to do,
is looking at bovine ingredients that might be coming in
from BSE countries. That is in the bulk.
There are two ways for doing that. One is USDA,
and some of it is done through USDA. The other is that
companies, through Customs, have to notify FDA of any food
products or other products that are coming in, and so we get
notified. Our inspectors, then, are notified of those
things and automatically detain them. They are not allowed
into the country.
That is what the import alert does. It is
automatic for notifying the investigators and inspectors.
The products are also included in there that are dietary

243
supplements if they come from BSE-originated countries and
have bovine ingredients.
As you said, there are a number of products that
are on the market, and I think two were pointed out, that
don't have the source. They should have the source on them.
They are not required to have the country of origin for
bovine ingredients or for any ingredients on the list. It
is only when they come in that they know that or when we go
to the inspections of establishments to find out where do
they get their ingredients and what do they get.
I just wanted to clarify those things that you
were talking about before. That is an import alert which is
not a regulation. There are two parts to it. The first
part you read was very clear. I looked at it again this
morning and it is very clear dealing with the bulk
ingredients.
The second part is, basically, saying, if you get
dietary ingredients in, or a dietary supplement from, a
country that has BSE, then you are to call the Center for
Foods. There is a contact in there. It basically ends up
being an automatic detention. That is what happens. They
are detained.
DR. NELSON: But the number of countries that are
endemic for BSE are changing.
MS. OLIVER: Yes...


18 last week's meeting, or not?
19 DR. DETWILER: The one thing that I do--there are
20 loopholes. I am not going to say that--but I don't want

DR. NELSON: How quickly--I mean, you must always
be behind the risk, given the BSE situation?
MS. OLIVER: It originally said U.K. It has been
updated several times as it has been--I don't have the list
of countries. Bob has it. It includes all of Europe and it
includes a number of other countries, so it has been updated
since additional information has come in. That is‘what has
happened. It includes the new BSE countries as the
information comes from USDA.
DR. NELSON: Why is there no requirement that it
is on the label? That doesn't make sense--where it comes
from?
MS. OLIVER : There isn't any. I can't answer why,
but there is no requirement that it be on the label where
the specific ingredients come from.
DR. BROWN: Linda, would it be okay to share a
couple of--information about possible loopholes to this from
people to be misled. If it is brought to our attention, we
do have the regulatory authority to keep it out, other than
the exemptions that I said. So that is where I really
wanted to make it clear. I'm sorry. I get defensive about
that.

245
But there is nothing in our regs that exempts
dietary supplements per se, if it has those. But, again, we
have to know about it. See;. we have to know what is on
there in order to prevent that. I think that is where we
don't have--like, for animal vaccines; that is one thing
that comes under our jurisdiction: So we do require, just
like the FDA, for human vaccines, the list of things and
what is in there.

DR. BROW-N: Maybe I could just ask you what is the
way station for determining what, in fact, is in a package
or a bulk or anything. The first people that see it, when
it comes into this country, I think you said were the
Customs and Immigration people. They are responsible for
categorizing it according to what documentation they have.
DR. DETWILER: That's correct; yes.
DR. BROWN: One of the categories is
miscellaneous.
DR. DETWILER: This was something Bob probably
could address because that is something that he brought up
yesterday. I am not sure if that applied just to the
products. Maybe he could clarify that.
DR. BROWN: Even before he does, you remember the
wonderful story that was told about a bulk shipment of a
material that was labeled pesticide. I am just recounting
this to indicate what can happen. An alert Customs and

246
Immigration officer looked at the size of this thing and
said, "That is an awful big package for pesticide."
He opened it and it turned out to be meat and
bonemeal. It was meat and bonemeal because it was going to
be spread on ground to prevent grazing by deer who hate the
smell of meat and bonemeal. That is the kind of thing that
probably doesn't happen but very rarely, but it can happen.
If we are depending on sawy Customs and
Immigration officers as our first line of defense, it is a
very nice line of defense to have but it seems to me there
ought to be one or two closer to the FDA.
DR. DETWILER: That was a combination of Customs
and USDA. Just to give our guy credit.

snip...

DR. BOLTON: What obligation is there of the
manufacturer to document and inform the FDA or the USDA of

261
the source of the raw materials in these products? Is there
any obligation?
DR. DETWILER: That is where I said before, those
things for human use, other than meat which comes under the
meat inspection, but for human use, those things don't come
under our authority to document what is in them.
DR. BOLTON: So if I am a manufacturer of a
supplement and I have a bottle on the shelf that does not
say where the raw materials come from, and I don't have to
document that and I don't have to inform anybody, how will
you find out?
MS. OLIVER: There are two things that we do. It
is not foolproof, but I can answer that question for how we
find out. One is on imported products that come in, if it
has a bovine ingredient, we will, from a BSE country--it is
coming from a BSE country--we will detain it and we will
require that they provide us the source of that information,
as long as we know about it.
If we go on inspections and it is one of the
things that Bob was saying, one of the things that we have
our inspectors do during inspections of dietary-supplement
manufacturers is, if a bovine ingredient is being used by
the firm, we ask that they find out the source of the bovine
ingredient and where it is coming from.
So they determine that. But the manufacturer does.

262
DR. BROWN: Would you run that by again, please,
one more time?
MS. OLIVER: Yes. The manufacturer--
DR. BROWN: The whole of that sentence.
MS. OLIVER: Okay. Going from the imports. On
the imported products, we have a directive, an import alert,
to our field that when the product comes in, and we have to
be notified of entry of dietary supplements, whether it be
in bulk or whether it be as a finished product. If we are
notified of it, and USDA is also one criteria for the bulk
ingredients- -if we are notified, we are to detain them which
is denying entry. We do not allow it entry from a BSE
country.
If it is an importer and it is from a BSE country
and it has multiple ingredients on it, some of which are
bovine origins, we will ask the importer to determine for us
where that has come from or we will deny it entry until
then.
If, during an inspection, and I say during an
inspection because we.do not require it of everybody, during
our inspections of dietary-supplement manufacturers, one of
the items that we have for the inspectors to check during
the inspections is if bovine ingredients are used in the
dietary supplements, to check the source. They are checking

263
to see if it has come from a BSE country. That is what they
are doing.
Now, we do not inspect every country regularly, if
you come back to ask what we do. But that is what we do
during the inspection.
DR. BROWN: What if Spain, or let's say what if a
manufacturer in this country using bovine brains, say, has
it processed in Spain. Perhaps it comes from Spain. And
then they send it to Canada. And then Canada runs it across
the country on a train?
MS. OLIVER: That was one of the things that Bob
Moore talked about earlier. He had a number of things that
he talked about in the slides and what we have found out in
inspecting dietary-supplement manufacturers is that some
products are shipped either from the United States, from
Canada, somewhere else to be further processed and that we
need to further look into what controls are needed and do
some additional work in that.
DR. BROWN: I agree, but--go ahead.
DR. BOLTON: So, for example, if a company was
using a bovine brain extract that was imported from Morocco,
say, there is no guarantee that that material might not have
actually originated in the United Kingdom, the brains being
sent to Morocco, ground into a paste, bottled and shipped
from Morocco. Here it would look like they came from

MS. OLIVER: The information we would have is the
source information that was either provided by the importer
or was provided by the processor.
264
Morocco...

snip...


DR. McCURDY: That was going to be my point. I
think we could probably bring this to closure by simply
making a recommendation or indicating that we are deeply
concerned about the likelihood that blood donors would be
taking orally sufficient brain-derived material to be of
potential risk for CJD.
DR. BROWN: One way to begin to bring it to
closure is to go ahead and vote on question 1, which we can
30, now, I think.
DR. DAVEY: Just one last comment, along with what
Paul has said, I think that I would agree with Dr. Roos that
we need to get data on the supplements. Whatever we can get

that makes sense at this point would be useful for
committee, I think.

We also need data on blood donors in terms of what
they are taking and how much of it before we can even begin
to address the problem because it is going to be a huge
percentage of donors. Before we move on to that, which we
are not, we have to have those data in hand.
DR. BROWN: Right. I want to remind the committee
and reread the question; should the FDA be sufficiently
concerned about the suitability of any blood donors
Fotentially exposed to TSE agents of animals to consider
recommending deferral. We are not voting on recommending
cieferral. We are voting on considering it.
DR. BELAY: Why don't we take out that last part
of the sentence?

DR. BROWN: Because I think it is an important
part of the sentence to leave in. That's why.
DR. BELAY: I agree with what Dr. Roos is saying.
This is because we don't know how many donors--
DR. BROWN: How much of the sentence do you want
to take out?

DR. BELAY: Just the last part.
DR. BROWN: That could be two-thirds, or two
words.
25 DR. BELAY: No, no; the part which starts with "to

consider recommending deferral."
DR. BROWN: Should the FDA be sufficiently
concerned about the suitability of any blood donors
potentially exposed to TSE agents of animals?
DR. BELAY: Yes.
DR. BROWN: Sufficiently concerned to do what?
consider recommending deferral.
DR. McCURDY: I think that is accurate.
9 DR. BROWN: I think we are going to vote on the
10 question as written.

DR. McCURDY: Yes.
DR. ROOS: It is not recommending deferral. It is
just considering it. So I think it is a little spongy.
DR. BROWN: Ray?
DR. ROOS: I will give it a yes.
DR. DETWILER: I just want this broad thing
because sheep scrapie is not known to--I don't know; would
that--I guess the FDA can sort that out; right? Because we
have already had that.
DR. FREAS: Is that a yes or a no?
DR. DETWILER: That is a yes.
DR. EWENSTEIN: Yes.
DR. BURKE: Yes, but it seems that the FDA is
already considering it.
DR. McCURDY: Yes.

8 DR. WILLIAMS: Yes, but with the same caveats
9 about U.S.-derived TSEs.
10 DR. PRUSINER: Yes.
11
12
13 question; if so, which animal TSE agents present or imported
14 into the USA, what types of product and intensity--has that
15 been crossed out of the final--should be or imported into.
16 Is that right, Dave? Is Dave still here? That didn't get
17 revised in time?
18 DR. ASHER: Give us a second here.
.lor here? No? DR. FREAS: Is Dr. Gay
DR. NELSPN: Yes.
DR. BOLTON: Yes.
DR. BROWN: Yes.
DR. BELAY: Yes.
DR. CLIVER: Yes.
DR. LURIE: Yes.

271
DR. FREAS: That was thirteen yes votes.
DR. BROWN: Thirteen to zero. The second

snip...


DR. BELAY: Dr. Brown, the only animal TSE that I
would be concerned about under question 2 would be BSE.
DR. BROWN: That is, obviously, the major concern.
DR. BELAY: I would say the only concern that I
would have.
DR. NELSON: But, actually, which countries are at
risk is changing and I am not sure how well even regulations
are keeping up with the change...

snip...

17 DR. BOLTON: 'Even if it was from the U.S. in a

24 The question specifically mentions whether or not we should

:crapie-free flock, I probably would not. I would be a
.ittle concerned about a dietary supplement that was made
Irom CNS tissue of sheep or bovines, even if they were
;ourced in the U.S.
DR. BELAY: But the question doesn't address
ahether or not we should consume--or consumption of brain.
consider deferring donors who have consumed this product...

snip...


DR. BROWN: That would be at the top of the list.
nd possibly brain, period, as a kind of unattractive
utrient.
DR. LURIE: Paul, maybe I am, again, confused
bout these questions, but I understood, when I looked at
hese questions, that 1 and 2 actually applied to these
hree specific products that were identified for us under
.ssue 4 which were products derived from deer and elk, the
'ermont sheep and the dietary supplements.
strictly
issue 3.
DR. BROWN: No, no; my reading is that this is a
independent issue. Issue 4 has nothing to do with
issue 4.
DR. LURIE: No, no, no; that was issue 4. That is
It says, "the following will be discussed."
DR. BROWN: Oh; the TSE agents. Right
DR. LURIE: Yes.

275
DR. BROWN: So we have the full basket of agents
;o think about but we don't have to make it global; that is,
de don't have to say, I'Yes; it has to be mink
ancephalopathy, BSE and scrapie." We can pick and choose.
DR. LURIE: My point is I thought we only had to
choose from these three. That is.the way I understood it.
DR. BROWN: It is animal TSE agents. That is
global, any animal TSE agent. But there are not many.
DR. NELSON: Three is ruminant-derived tissues.
So that would be the BSE.
DR. EWENSTEIN: I take the point that is being
nade. I think the FDA is directing us at a couple of very
specific points. I think it is fair to include, as our
chief concern, these dietary supplements which I find
astounding in terms of their risk given the fact that we
saw, even the data that Linda presented, if you want to give
a sheep BSE, you give them a half a gram. That is what you
were giving every day to that patient you took a look at.

DR. BROWN: No; I did not give that. No, no.
DR. EWENSTEIN: That is what "one" was giving to
that patient that you were asked to look at. But I think
there are specific questions. In other words, if someone is
heavily involved in this industry, if they eat deer or elk
meat, if they had cheese made from these Vermont sheep, I
think those are questions that we should address, even if

:he answer
;he FDA.
is we don't want to have an answer right now to
I think the FDA is asking us to address those
specific risks.
DR. ASHER: Yes; it would be helpful if you would
iddress exposures to chronic wasting disease, the Vermont
sheep and dietary supplements. You already know that we are
zoncerned about all exposures to BSE agent. The only
:oncern is whether there are ways in which it can enter the
Jnited States through these products.
You would be welcome to address scrapie but that
uas already addressed a year and a half ago at some length
ind no concern was expressed about dietary exposures, of
which we have a very long and reassuring experience.
DR. BROWN: Is the committee agreed that BSE is
:he prime villain as a potential danger?
DR. BOLTON: Can we include in that the
)ossibility that undifferentiated scrapie in sheep, at this
zime, may be BSE? It is going to take some time, I guess,
:o document whether that is, in fact, scrapie in those sheep
>r whether that is BSE in sheep.
At that time, does that become BSE in sheep or
does it become some other nomenclature?
DR. DETWILER: I think only time will tell. I
don't think we can predict that.
276

277
DR. BROWN : But, happily, there is no demonstrable
infectivity in any dairy product in any TSE. So that is a
good thing.
DR. DETWILER: That was the product--the broad
distribution was the cheese.
DR. EWENSTEIN: I think,' to try to come to
closure, on the Vermont flap, as you called it, I think that
Me can try to be reassuring in that the products that came
out probably are very low risk products even though we don't
Eully understand the nature of the infection, itself.
So I think the part that I am struggling with,
oecause I don't know enough about it, is the sort of deerand-
elk-meat exposure. Do we consider, at this point, that
is sufficient enough if somebody has consumed large amounts
3r is in that industry to worry about them being potential--
DR. BROWN:, It wouldn't be the meat. It would be
the velvet antlers because that is what would be in the
supplements. Just substitute "velvet antlers" for "meat.ll
DR. EWENSTEIN: Okay, but are we--
DR. BROWN: We are just talking about dietary
supplements. Therefore, deer and elk meat would not be at
issue.
DR. EWENSTEIN: Why are we just talking about
dietary supplements? Point 1 deals with all deer and elk
issues.

278
DR. BROWN: I may be wrong.
DR. ASHER: Please address all exposures to
chronic wasting disease, potential exposures.
DR. EWENSTEIN: Paul, point 3 was then focussing
on the dietary supplements, but I think the issue had to do
nrith the CDC's presentation on the young CJD exposures and
whether there was any possible connection. I think that is
:he point that the committee should address one way or the
Ither.
DR. BELAY: The BSE situation is different because
we have enough ample evidence that BSE is actually a human
pathogen whereas, in chronic wasting disease, we do not have
any evidence that chronic wasting disease is a human
pathogen.
It does not necessarily mean that there will never
oe a human pathogen, or it will never be transmitted to
numans, but we do not have enough evidence to start
Eormulating policies.
DR. BROWN: That brings us back to the original
idea that we don't have any indication that blood is
infectious either but we are deferring for six months. It
Jets back to the deferral, if you have stayed in Colorado
for six months. If you follow logical consistency long
enough, you get very illogical...

snip...


DR. DAVEY: I am not sure that is the right window
to be looking through right now.
DR. BROWN: But it is the only one we have.
DR. ASHER: It might be 'helpful if you attempted
to keep the discussion of the various exposures separate.
It would make it easier for us to intuit your opinions on
them. There is no reason why a conclusion has to be drawn.
I think that the agency now appreciates the level of concern
and also appreciates the level of uncertainty. That might
oe sufficient for our needs.
DR. BROWN: Do you want us to consider each of the
diseases now?
DR. ASHER: Yes.
DR. BROWN: Paul--was it Paul or Linda--there were
zwo expressions that chronic wasting disease, per se, was--
10; excuse me-- the Vermont sheep issue, that anything having
10 do with Vermont sheep was extremely low--well, low risk
and not to worry, no matter what the products. The products
that were widespread were cheese.
DR. BOLTON: What about the animals, themselves?
DR. DETWILER: I'm sorry?
DR. BOLTON: Eventually, the animals will either
die or be destroyed. Products derived from their eventual

282
demise, are we considering those as well?
DR. DETWILER: Oh; you mean the eventual demise?
DR. BOLTON: Yes.
DR. DETWILER: Oh; the eventual demise, they will
either go up some chimney or through a sodium-hydroxide
digester.
DR. EWENSTEIN: So if we are going to run through
three questions, then the first one, which seems the
easiest, is a decision that folks who have been exposed to
these Vermont products do not have to be deferred. That
seems to be the black-and-white question. That would be my
opinion.
DR. BROWN: While we are at that, does anyone
disagree with that? Are there any dissenting ideas? All
right; we have disposed to Vermont sheep
DR. LURIE: I want to add something to Vermont
sheep. I think that the scenario laid out by Linda is very
worrisome. I think as long as we have been using this
committee as a sort of the bully pulpit to make our concerns
clear, I think it would be helpful to have the committee on
record as fully supporting what the USDA has been trying to
do in this area.
DR. FREAS: If I could add to that, our charge and
mission, as this committee, is to make recommendations to
FDA on FDA policies. We really are stepping outside of our

16 Thus far, we have said that the BSE agent is the
17 )ne that we know has gone cross-species and, therefore, the
18 )ne that would be most closely related to that, meaning
sheep that might be infected with a BSE-like agent, would
Logically be the next most worrisome thing.
I am not saying that that is sufficient grounds
Eor deferral from donation, but just as a logical tree, that
xould make the most sense to me.
DR. BROWN: I think the point is well taken. I
think the only thing that really tempers it is the products

283 1
bounds of the mission of this committee. Advice is very
good. Even good advice is very welcome to the right place.
I honestly think, in light of the mission and the
large of this committee, for us to make recommendations
ther than to the Commissioner of FDA, we are stepping out
E our bounds.
DR. BROWN: The jury will disregard the last
eclaration. We have dispensed with the Vermont sheep and
ow we are on to--we haven't dispensed with the Vermont
sheep?
DR. BURKE: I am afraid we haven't. The rationale
ight be this way. The Vermont sheep are the closest thing
hat we have. If we were to make a hierarchy of all of the
ther agents available to us, the Vermont sheep appear to be
.s close, perhaps, to BSE as another agent.

284
that were distributed.
DR. ROOS: There were forty-five carcasses that
nrere sold for human consumption but, as I heard, some of it
Ment to the attorney.
DR. DETWILER: Just to put perspective, it was
muscle meat that was sold and it was of lambs.

hmm, muscle meat and scrapie???...TSS
EMBO reports AOP Published online: 11 April 2003 Widespread PrPSc
accumulation in muscles of hamsters orally infected with scrapie Achim
Thomzig, Christine Kratzel, Gudrun Lenz, Dominique Krüger & Michael
Beekes Robert Koch-Institut, P26, Nordufer 20, D-13353 Berlin, Germany

Received 13 February 2003; Accepted 13 March 2003; Published online 11
April 2003.

Abstract :

Scrapie, bovine spongiform encephalopathy and chronic wasting disease
are orally communicable, transmissible spongiform encephalopathies
(TSEs). As zoonotic transmissions of TSE agents may pose a risk to human
health, the identification of reservoirs for infectivity in animal
tissues and their exclusion from human consumption has become a matter
of great importance for consumer protection. In this study, a variety of
muscles from hamsters that were orally challenged with scrapie was
screened for the presence of a molecular marker for TSE infection, PrPSc
(the pathological isoform of the prion protein PrP). Sensitive western
blotting revealed consistent PrPSc accumulation in skeletal muscles from
forelimb and hindlimb, head, back and shoulder, and in tongue.
Previously, our animal model has provided substantial baseline
information about the peripheral routing of infection in naturally
occurring and orally acquired ruminant TSEs. Therefore, the findings
described here highlight further the necessity to investigate thoroughly
whether muscles of TSE-infected sheep, cattle, elk and deer contain
infectious agents.

http://www.emboreports.org/

Prions in skeletal muscle

Patrick J. Bosque*,dagger ,Dagger , Chongsuk Ryou*, Glenn Telling*,§,
David Peretz*,dagger , Giuseppe Legname*,dagger , Stephen J.
DeArmond*,dagger ,¶, and Stanley B. Prusiner*,dagger ,||,**

* Institute for Neurodegenerative Diseases and Departments of dagger
Neurology, ¶ Pathology, and || Biochemistry and Biophysics, University
of California, San Francisco, CA 94143

Contributed by Stanley B. Prusiner, December 28, 2001

Considerable evidence argues that consumption of beef products from
cattle infected with bovine spongiform encephalopathy (BSE) prions
causes new variant Creutzfeldt-Jakob disease. In an effort to prevent
new variant Creutzfeldt-Jakob disease, certain "specified offals,"
including neural and lymphatic tissues, thought to contain high titers
of prions have been excluded from foods destined for human consumption
[Phillips, N. A., Bridgeman, J. & Ferguson-Smith, M. (2000) in The BSE
Inquiry (Stationery Office, London), Vol. 6, pp. 413-451]. Here we
report that mouse skeletal muscle can propagate prions and accumulate
substantial titers of these pathogens. We found both high prion titers
and the disease-causing isoform of the prion protein (PrPSc) in the
skeletal muscle of wild-type mice inoculated with either the Me7 or
Rocky Mountain Laboratory strain of murine prions. Particular muscles
accumulated distinct levels of PrPSc, with the highest levels observed
in muscle from the hind limb. To determine whether prions are produced
or merely accumulate intramuscularly, we established transgenic mice
expressing either mouse or Syrian hamster PrP exclusively in muscle.
Inoculating these mice intramuscularly with prions resulted in the
formation of high titers of nascent prions in muscle. In contrast,
inoculating mice in which PrP expression was targeted to hepatocytes
resulted in low prion titers. Our data demonstrate that factors in
addition to the amount of PrP expressed determine the tropism of prions
for certain tissues. That some muscles are intrinsically capable of
accumulating substantial titers of prions is of particular concern.
Because significant dietary exposure to prions might occur through the
consumption of meat, even if it is largely free of neural and lymphatic
tissue, a comprehensive effort to map the distribution of prions in the
muscle of infected livestock is needed. Furthermore, muscle may provide
a readily biopsied tissue from which to diagnose prion disease in
asymptomatic animals and even humans. Dagger Present address: Department
of Medicine, Denver Health Medical Center, Denver, CO 80204.

§ Present address: Department of Microbiology and Immunology, University
of Kentucky, Lexington, KY 40536-0230.

** To whom reprint requests should be addressed. E-mail: vann@cgl.ucsf.edu.

www.pnas.org/cgi/doi/10.1073/pnas.052707499

http://www.pnas.org/


Extraneural Pathologic Prion Protein in Sporadic Creutzfeldtâ¬Jakob
Disease


Markus Glatzel, M.D., Eugenio Abela, Manuela Maissen, M.S., and Adriano
Aguzzi, M.D., Ph.D.


snip...


Conclusions Using sensitive techniques, we identified extraneural
deposition
of PrPSc in spleen and muscle samples from approximately one third of
patients
who died with sporadic Creutzfeldtâ¬Jakob disease. Extraneural PrPSc
appears
to correlate with a long duration of disease.

http://content.nejm.org/cgi/content/short/349/19/1812?query=TOC

continue;


DR. McCURDY: Paul, I think, again, trying to put
it in perspective, I wouldn't recommend anybody who had been
?ating brains from these sheep donate blood. I think they
should worry, but my information is that nobody has eaten
any brains.
DR. DETWILER: No brains.
DR. BROWN: That is what Linda said. It was
strictly meat. Not only strictly meat, it was young meat.
DR. McCURDY: Strictly meat and cheese. Young
meat and cheese. Those are low risk.
DR. BROWN: Right.
DR. EWENSTEIN: I understand, at best, these risk
assessments are semi-quantitative. They are probably just

285
qualitative, but I think if you look at what Dr. Belay was
saying, just taking everything together, the total amount of
exposure to any one donor in the U.S., the kind of product
that was consumed, et cetera, I think that this falls below,
and if we are using six months in the U.K. as some
threshold, and I know it is sort of an arbitrary threshold--
but, if we are using that, this seems to be falling below
that level, at least from what we know right now.
We have to make some sort of decision. Either we
are going to start tracking these people down who had some
of this cheese and say, you can't donate, or they can
donate. I think we have, probably by consensus, agreed that
they can. It seems like you can justify that on these sort
of qualitative grounds.
DR. DETWILER: One other issue on the cheese, just
because I know CDC, when they were requested for assistance
here on milk and cheese, is that milk and cheese, by WHO or
any milk and milk-products for known TSEs are not know to be
associated with infectivity. So this would open this whole
ball of wax on milk and cheese from Europe, actually, which
does freely move in and is consumed.
DR. BROWN: Dispense with Vermont.
DR. BURKE: With logical consistency; thank you.
DR. BROWN: The next issue, then, is chronic
wasting disease. I think everybody would agree that that is

286
in the middle of this triplet of hierarchies.
DR. WILLIAMS: I would just to say, and the
committee has already said, that there is no scientific
evidence that CWD is recognized as a human pathogen. Then,
10 make the jump, that, then, people will get it and then
transmit it via blood, I think, going a little bit too far.

snip...


DR. BROWN: Is there a sentiment to put chronic
Masting disease in the same low-risk category, then, as the
Jermont sheep? Are they similarly unrisky? You are you
zhink it probably is.
DR. McCURDY: Except for neural tissue.
DR. PRUSINER: I just think we know so little
about chronic wasting disease that we don't know how to
zhink about it. I think that is really what we ought to
say.
DR. BROWN: Except we could probably say it is not
a good idea to eat brain, I would imagine, from, say, an elk
zhat died with chronic wasting disease.
DR. PRUSINER: I wouldn't disagree.

snip...

END

MILLER REPORTING COMPANY, INC.
735 C Street, S.E.
Washington, D.C. 20003-2802
(202) 546-6666

http://www.fda.gov/ohrms/dockets/ac/01/transcripts/3681t2_03.pdf

thank you,
kind regards,

terry

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