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McDonald's AND Seriologicals USA NOT PROTECTED FROM MAD COW

McDonald's AND Seriologicals USA NOT PROTECTED FROM MAD COW

Subject: Re: McDonald's Corp. seven scientists and experts and a
pharmaceutical supplier Seriologicals Corp. U.S. NOT PROTECTED AGAINST MAD
COW DISEASE
Date: January 11, 2006 at 9:27 am PST

December 19, 2005

Division of Dockets Management (HFA-305)

Food and Drug Administration

5630 Fishers Lane

Room 1061
Rockville, MD 20852

Re: Docket No: 2002N-0273 (formerly Docket No. 02N-0273)

Substances Prohibited From Use in Animal Food and Feed

Dear Sir or Madame:

The McDonalds Corporation buys more beef than any other restaurant in the
United States. It is essential for our customers and our company that the
beef has the highest level of safety. Concerning BSE, the most effective way
to insure this is to create a system that processes cattle that are not
exposed to the disease. As a company we take numerous precautions via our
strict specifications to help and assure this, however we feel that the
force of federal regulation is important to ensure that the risk of exposure
in the entire production system is reduced to as close to zero as possible.
The exemptions in the current ban as well as in the newly proposed rule make
this difficult if not impossible, as there are still legal avenues for
ruminants to consume potentially contaminated ruminant protein. In addition,
the USDA still has not implemented a system of identification and
traceability. It is our opinion that the government can take further action
to reduce this risk and appreciate the opportunity to submit comments to
this very important proposed rule.

After the identification of bovine spongiform encephalopathy (BSE) in
indigenous North American cattle, the U.S. Department of Agriculture (USDA)
responded rapidly to implement measures to protect public health in regard
to food. Our company recognizes and supports the importance of the current
feed ban which went into effect in August 1997. However, given what is known
about the epidemiology and characteristically long incubation period of BSE,
we urge the FDA to act without further delay and implement additional
measures which will reduce the risk of BSE recycling in the US cattle herd.
We caution against using the 18 month enhanced surveillance as a
justification to relax or impede further actions. While this surveillance
indicates an epidemic is not underway, it does not clear the US cattle herd
from infection. The positive cases indicate probable exposure prior to the
1997 feed ban, a time when BSE appears to have been circulating in animal
feed. BSE cases are most likely clustered in time and location, so while
enhanced surveillance provides an 18 month snapshot, it does not negate the
fact that US and Canadian cattle were exposed to BSE and that the current
feed controls contain “leaks”.

We feel that for the FDA to provide a more comprehensive and protective feed
ban, specified risk materials (SRMs) and deadstock must be removed from all
animal feed and that legal exemptions which allow ruminant protein to be fed
back to ruminants (with the exception of milk) should be discontinued.

SRMs, as defined by the USDA, are tissues which, in a BSE infected animal,
are known to either harbor BSE infectivity or to be closely associated with
infectivity. If SRMs are not removed, they may introduce BSE infectivity and
continue to provide a source of animal feed contamination. Rendering will
reduce infectivity but it will not totally eliminate it. This is
significant, as research in the United Kingdom has shown that a calf may be
infected with BSE by the ingestion of as little as .001 gram of untreated
brain.

The current proposed rule falls short of this and would still leave a
potential source of infectivity in the system. In fact by the FDA’s own
statement the exempted tissues which are known to have infectivity (such as
distal ileum, DRGs, etc) would cumulatively amount to approximately 10% of
the infectivity in an infected animal. Leaving approximately 10% of the
infectious tissues in the system is not good enough. The proposed rule still
allows the possibility for cattle to be exposed to BSE through:

Feeding of materials currently subject to legal exemptions from the ban
(e.g., poultry litter, plate waste)
Cross feeding (the feeding of non-ruminant rations to ruminants) on farms;
and
Cross contamination of ruminant and non-ruminant feed

We are most concerned that the FDA has chosen to include a provision that
would allow tissues from deadstock into the feed chain. We do not support
the provision to allow the removal of brain and spinal cord from down and
deadstock over 30 months of age for several reasons. These are the animals
with the highest level of infectivity in tissues which include more than
brain and spinal cord. Firstly, there are two issues regarding the complex
logistics of this option. We do not feel that it is possible to have
adequate removal especially during the warmer months. In addition, we do not
feel that there are adequate means to enforce complete removal. Unlike
slaughterhouses, there are no government inspectors at rendering plants or
deadstock collection points.

Most importantly, there is emerging information that at end stage disease (a
natural BSE case); infectivity may also be included in additional tissues
such as peripheral nerves (Buschmann and Groschup, 2005 – see attached).
This published work supports publicly reported studies in Japan where by
western blot testing, prions have been found in the peripheral nerves of a
naturally infected 94-month-old cow. If this is the case, the amount of
infectivity left in the system from an infected bovine would surpass 10% and
the full extent is still unknown.

McDonalds has convened it own International Scientific Advisory Committee
(ISAC) as well as co-sponsored a symposium of TSE scientists on the issue of
tissue distribution. The consensus of both groups was that the pathogenesis
of BSE might not be entirely different from TSEs in other species at the
point where the animal is showing signs of the disease. These scientists
feel that the studies as reported above have merit. The current studies not
only re-enforce the risk of down and deadstock but also appear to provide
additional information that these animals may be a potential source of
greater levels of infectivity into the feed system. Hence, we suggest that
the FDA consult with TSE scientists as well.

Leaving the tissues from the highest risk category of cattle in the animal
feed chain will effectively nullify the intent of this regulation. This
point is illustrated by the 2001 Harvard risk assessment model that
demonstrated that eliminating dead and downer, 4D cattle, from the feed
stream was a disproportionately effective means of reducing the risk of
re-infection.

“The disposition of cattle that die on the farm would also have a
substantial influence on the spread of BSE if the disease were introduced.”
The base case scenario showed that the mean total number of ID50s (i.e.,
dosage sufficient to infect 50 percent of exposed cattle) from healthy
animals at slaughter presented to the food/feed system was 1500. The mean
total number of ID50s from adult cattle deadstock presented to the feed
system was 37,000. This illustrates the risk of “4D cattle” (i.e.,
deadstock).

From the Harvard Risk Assessment, 2001, Appendix 3A Base Case and Harvard
Risk Assessment, 2001 Executive Summary

McDonalds also urges agencies of the US government to work with academia and
industry on research in the following areas:

· Methods to inactivate TSEs agents which then may allow a product to be
used and even fed to animals without risk

· Alternative uses for animal byproducts which would maintain some value

In July 2004, McDonalds in cooperation with others sponsored a meeting at
Penn State. The purpose of the meeting was to review work conducted by Dr.
Bruce Miller looking at the feasibility of using carcasses and animal
byproducts as renewable alternatives to fossil fuels in large energy
generating boilers. A number of government representatives were also invited
to this meeting. We are aware that Dr. Miller continues this work which
shows great promise. We suggest that the FDA explore the possibility of this
alternative use that may also have a positive impact on the environment.

The McDonalds Corporation will continue to work with the FDA and other
government agencies to implement a strong BSE risk control program. We would
like to reiterate our opinion that for the FDA to provide a more
comprehensive and protective feed ban, specified risk materials (SRMs) and
deadstock must be removed from all animal feed and that legal exemptions
which allow ruminant protein to be fed back to ruminants (with the exception
of milk) should be discontinued. Thank you for the opportunity to submit
these comments to the public record.

Respectfully,

Dick Crawford

Corporate Vice President, Government Relations

xxxxxxxxxxxxxxxxxxxxxxxxxxxxx

xxxxxxxxxxxxxxxxxxxxxxxxxxx

xxxxxxxxxxxxxxxxxxxxxxxx

dick.crawford@mcd.com

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December 20, 2005

Division of Dockets Management (HFA-305)

Food and Drug Administration

5630 Fishers Lane

Room 1061
Rockville, MD 20852

Re: Docket No: 2002N-0273 (formerly Docket No. 02N-0273)

Substances Prohibited From Use in Animal Food and Feed

Dear Sir or Madame:

As scientists and recognized experts who have worked in the field of TSEs
for decades, we are deeply concerned by the recent discoveries of indigenous
BSE infected cattle in North America and appreciate the opportunity to
submit comments to this very important proposed rule We strongly supported
the measures that USDA and FDA implemented to protect public health after
the discovery of the case of bovine spongiform encephalopathy (BSE) found in
Washington State in 2003. We know of no event or discovery since then that
could justify relaxing the existing specified risk material (SRM) and
non-ambulatory bans and surveillance that were implemented at that time.
Further, we strongly supported the codification of those changes, as well as
additional measures to strengthen the entire feed and food system. The
discovery of additional cases of indigenous BSE in North America since that
time has validated our position and strengthened our convictions.

We caution against using the 18 month enhanced surveillance as a
justification to relax or impede further actions. While this surveillance
has not uncovered an epidemic, it does not clear the US cattle herd from
infection. While it is highly likely that US and Canadian cattle were
exposed to BSE prior to the 1997 feed ban, we do not know how many cattle
were infected or how widely the infection was dispersed. BSE cases are most
likely clustered in time and location, so while enhanced surveillance
provides an 18 month snapshot, it does not negate the fact that US and
Canadian cattle were exposed to BSE. We also do not know in any quantitative
or controlled way how effective the feed ban has been, especially at the
farm level. At this point we cannot even make a thorough assessment of the
USDA surveillance as details such as age, risk category and regional
distribution have not been released.

A number of countries initially attempted to take partial steps in regard to
feed controls only to face repeated disappointments in predicted downturns
of the epidemic course. We in North America could do this experiment all
over again, waiting for each new warning before adding more stringency to
our control measures, or we can benefit from the experience of others and
take decisive measures now to arrest any further development of underlying
cases that is implicit in those already discovered to date.

The discovery of 5 indigenous North American cases, including one born after
the implementation of the current feed ban, should provide the necessary
incentive to implement, monitor and enforce a comprehensive and protective
feed ban that is more congruent with the measures that have been proven to
be effective throughout the world. In particular, we urge the FDA to act
without further delay to strengthen the animal feed regulations by
implementing the program proposed by the Canadian Food Inspection Agency
(CFIA) in the December 11, 2004 Gazette. This includes removing all
specified risk materials (SRMs) and deadstock from all animal feed. We also
urge that the FDA discontinues the legal exemptions which allow ruminant
protein to be fed back to ruminants (with the exception of milk). Many of
these exemptions do not exist in other countries.

Bovine products and byproducts are used for both food and pharmaceuticals.
These human uses require the highest level of safety. Because of the hardy
nature of the BSE agent and its high potential for cross contamination, the
most effective way to protect bovine products and bovine derived materials
from contamination by BSE is to ensure that infected animals or carcasses
never enter processing plants. The goal would be to discover and remove
infected animals from production as early as possible in the infection and
long before they would be sent to slaughter. Until we have diagnostic tools
powerful enough to allow us to discover the disease early in its prolonged
pre-clinical incubation, we have to rely on the next best strategy which is
to prevent any exposure through feed. The exemptions in the current ban as
well as in the newly proposed rule make this difficult if not impossible, as
they still provide legal avenues for ruminants to consume potentially
contaminated ruminant protein.

It is our opinion that the proposed rule falls woefully short in effective
measures to minimize the potential for further transmissions of the disease.
By the FDA’s own analysis, exempted tissues (such as distal ileum, DRGs,
etc) contain approximately 10% of the infectivity in affected animals. Thus
the proposed rule still allows the possibility for cattle to be exposed to
BSE through:

1. Feeding of materials currently subject to legal exemptions from the ban
(e.g., poultry litter, plate waste)

2. Cross feeding (the feeding of non-ruminant rations to ruminants) on
farms; and

3. Cross contamination of ruminant and non-ruminant feed

We are most concerned that the FDA has chosen to include a provision that
would allow tissues from deadstock into the feed chain. We do not believe
that down or dead stock should be allowed into the food or feed chain
whatever the age of the animal and whether or not the CNS tissues are
removed. We do not support the provision to allow removal of brain and
spinal cord from deadstock over 30 months for a number of reasons. [RR1]
This category of animals contains the highest level of infectivity and that
infectivity is in other tissues besides just brain and spinal cord. Recent
improvements in the BSE bioassay, have now made it possible to detect BSE
infectivity 1000 time more efficiently than before. This assay has revealed
the presence of BSE infectivity in some but not all peripheral nerves and in
one muscle. (Buschmann and Groschup, 2005) This published and peer reviewed
work is consistent with other publicly reported studies in Japan where, by
western blot testing, prions were found in the peripheral nerves of a
naturally infected 94-month-old cow. We feel that the studies as reported
above have merit. The current studies not only re-enforce the risk of down
and deadstock but also appear to provide additional information that these
animals may be a potential source of greater levels of infectivity into the
feed system. We also doubt that brain and spinal cord can be completely
removed especially during warmer weather. Given the biological composition
of these tissues, they are predisposed to rapid autolysis.

As world wide surveillance for BSE increases, several atypical cases of
bovine TSE have been discovered. These cases either show no clinical signs,
or present as ‘downers’, and have an atypical neuropathology with respect to
lesion morphology and distribution, causing problems in both clinical and
post-mortem diagnosis. The origin of the cases are unclear but they suggest
that even should typical BSE be eliminated, there may be other TSE diseases
of cattle that could result by “mutation” and selection. Refeeding of
contaminated protein could potentially perpetuate transmission much like
typical BSE. An effective feed ban could prevent the expansion of such
strains. We also note that there are other species which are susceptible to
BSE and the current regulations allow for SRMs to be included in feed for
these animals.

For BSE to be perpetuated, the animal production system must have a source
of agent and a means by which cattle or other susceptible species are
exposed to this agent. We feel that in North America, the source and routes
of exposure still exist, hence allowing for the continued recycling of BSE.
We have detailed the scientific justifications for our position below.

Source of the agent: SRMs (Specified Risk Materials)

SRMs, as defined by the USDA, are tissues which, in a BSE infected animal,
are known to either harbor BSE infectivity or to be closely associated with
infectivity. If SRMs are not removed, they may introduce BSE infectivity and
continue to provide a source of animal feed contamination. For example, the
skull and vertebral column which encase the brain and spinal cord,
respectively, can be assumed to have gross contamination. Rendering will
reduce infectivity but it will not totally eliminate it. This is significant
as research in the United Kingdom has shown that a calf may be infected with
BSE by the ingestion of as little as .001 gram of untreated brain.

The tissue distribution of infectivity in BSE infected cattle has primarily
been determined by 3 studies conducted in the United Kingdom all of which
had limitations.

In two of the studies, bioassays were done in mice which are at least 1000
fold less sensitive to BSE infection than cattle themselves. Only higher
titers of infectivity can be detected by this method. These investigations
found infectivity in the brain, spinal cord, retina, trigeminal ganglia,
dorsal root ganglia, distal ileum and bone marrow (the bone marrow finding
was from one animal). Infectivity was found in distal ileum of
experimentally infected calves beginning six months after challenge and
continuing at other intervals throughout life. (Wells et. al., 1994; 1998).
The bioassay study in calves has produced similar results and in addition
infectivity has been found in tonsil. The study is still in progress.
Another project has found infectivity in the lymphoid tissue of third eyelid
from naturally infected animals. (Dr. Danny Matthews, UK DEFRA, personal
communication).

While bioassay in cattle is far preferable to mice in terms of sensitivity,
cattle nevertheless present their own limitations in terms of the long
incubation time and the limited number of animals that can be used for assay
compared to rodents. As a consequence the significance of the negative
finding for many tissues is questionable. In fact, by the end of 2004 there
was increasing evidence in species other than cattle that peripheral nerves
and muscle have infectivity. (Bosque et al., 2002; Glatzel et al.,
2003;Bartz et al., 2002; Androletti et al., 2004; Mulcahy et al., 2004;
Thomzig et al., 2003; Thomzig et al., 2004)

In some of these species, studies indicate that the agent migrates to the
brain and spinal cord, replicates to high levels in the CNS and then spreads
centrifugally from the spinal cord back down through the spinal neurons to
the junction of the nerves and muscle into the muscle cells themselves. A
recent German study (Buschmann and Groschup, 2005) examined nerves and
muscle from a cow naturally infected with BSE and found that infectivity was
present in several peripheral nerves and one muscle. The method of detection
was bioassay in bovinized transgenic mice that show the same or greater
sensitivity to transmission of BSE as cattle. This research concurs with
findings by Japanese scientists that BSE infectivity is present in
peripheral nerves at least in the clinical stage of disease.

It is our opinion that there is increasing evidence that the pathogenesis of
BSE might not be entirely different from TSEs in other species at the point
of clinical disease in that there is peripheral involvement. We feel that
the studies as reported above have merit. The current studies not only
re-enforce the risk of down and deadstock but also appear to provide
additional information that these animals may be a potential source of
greater levels of infectivity into the feed system.

In the event that FDA may confer with USDA about the risks associated with
peripheral nerves we want to point out one issue. In the recent publication
of the final rule on the importation of whole cuts of boneless beef from
Japan, 9 CFR Part 94 [Docket No. 05-004-2] RIN 0579-AB93, we disagree with
the interpretation provided by USDA, APHIS.

APHIS seems to discount the studies conducted by Groschup et al. 2005. on
the basis that the transgenic mouse bioassay that they used may be too
sensitive. In taking this position they have failed to realize that the
point of an assay is to reveal in which tissues the infectivity resides and
its relative concentration to brain or spinal cord. For this purpose, no
assay can be too sensitive. Of course, the probability of an actual
infection will be affected by the efficiency of infection which will be a
function of dose, route of exposure and any host barrier effects that are
present.

We would also like to point out a factual error in the conclusion. APHIS
states, “Given these factors, APHIS has determined that the finding of BSE
infectivity in facial and sciatic nerves of the transgenic mice is not
directly applicable to cattle naturally infected with BSE. Therefore, we do
not consider it necessary to make any adjustments to the risk analysis for
this rulemaking or to extend the comment period to solicit additional public
comment on this issue.” It is incorrect that the infectivity was found in
the peripheral nerves of transgenic mice. The peripheral nerves were
harvested from a cow naturally infected with BSE. Transgenic mice were used
as a bioassay model.

From [Docket No. 05-004-2] RIN 0579-AB93[RR2] :

“Peripheral Nerves

Issue: Two commenters stated that the underlying assumption of the proposed
rule, that whole cuts of boneless beef from Japan will not contain tissues
that may carry the BSE agent, is no longer valid because researchers have
found peripheral nervous system tissues, including facial and sciatic
nerves, that contain BSE infectivity.\2\ One of these commenters requested
APHIS to explain whether and what additional mitigation measures are needed
to reduce the risks that
these tissues may be present in Japanese beef. This commenter further
requested an additional comment period to obtain public comments to treat
this new scientific finding.
---------------------------------------------------------------------------

\2\ Bushmann, A., and Groschup, M.; Highly Bovine Spongiform
Encephalopathy-Sensitive Transgenic Mice Confirm the Essential
Restriction of Infectivity to the Nervous System in Clinically
Diseased Cattle. The Journal of Infectious Diseases, 192: 934-42,
September 1, 2005.
---------------------------------------------------------------------------

Response: APHIS is familiar with the results of the study mentioned by the
commenters in which mice, genetically engineered to be highly susceptible to
BSE and to overexpress the bovine prion protein, were inoculated with
tissues from a BSE-infected cow. This study demonstrated low levels of
infectivity in the mouse assay in the facial and sciatic nerves of the
peripheral nervous system. APHIS has evaluated these findings in the context
of the potential occurrence of
infectivity in the peripheral nerves of cattle and the corresponding risks
of the presence of infectivity in such tissues resulting in cattle or human
exposure to the BSE agent. The results from these experiments in genetically
engineered mice should be interpreted with caution, as the findings may be
influenced by the overexpression of prion proteins and may not accurately
predict the natural distribution of BSE infectivity in cattle. Further, the
overexpression of prion
proteins in transgenic mice may not accurately mimic the natural disease
process because the transgenic overexpressing mice have been shown to
develop spontaneous lethal neurological disease involving spongiform changes
in the brain and muscle degeneration.\3\ In addition, the route of
administration to the mice was both intraperitoneal and intracerebral, which
are two very efficient routes of infection as compared to oral consumption.
Given these factors, APHIS has determined that the finding of BSE
infectivity in facial and sciatic nerves of the transgenic mice is not
directly applicable to cattle naturally infected with BSE. Therefore, we do
not consider it
necessary to make any adjustments to the risk analysis for this rulemaking
or to extend the comment period to solicit additional public comment on this
issue.”

Source of the agent: Deadstock

The total amount of TSE infectivity in a TSE infected animal increases
steadily throughout the infection and exponentially once the infectivity
reaches the brain. Infected individuals only exhibit recognizable clinical
signs once infectivity titers have reached high levels in the brain.
Surveillance data collected throughout Europe indicates there is a much
greater likelihood for BSE to be detected in dead or down cattle than from
healthy normal animals. This has so far also been borne out by the
experience in North America. Animals that die of BSE harbor the greatest
amount of agent that can be produced by the disease. Leaving the tissues
from the highest risk category of cattle in the animal feed chain will
effectively nullify the purported intent of this regulation. This point is
supported by the 2001 Harvard risk assessment model that demonstrated that
eliminating dead and downer, 4D cattle, from the feed stream was a
disproportionately effective means of reducing the risk of re-infection.

“The disposition of cattle that die on the farm would also have a
substantial influence on the spread of BSE if the disease were introduced.”
The base case scenario showed that the mean total number of ID50s (i.e.,
dosage sufficient to infect 50 percent of exposed cattle) from healthy
animals at slaughter presented to the food/feed system was 1500. The mean
total number of ID50s from adult cattle deadstock presented to the feed
system was 37,000. This illustrates the risk of “4D cattle” (i.e.,
deadstock).

From the Harvard Risk Assessment, 2001, Appendix 3A Base Case and Harvard
Risk Assessment, 2001 Executive Summary

It is likely that these numbers would have to be adjusted upwards, if the UK
attack rate and Groschup data were considered.

Inflammation and TSEs

There have been 3 recent peer reviewed publications which indicate that
chronic inflammatory conditions in a host with a TSE may induce prion
replication in, or distribution to organs previously thought to be low or no
risk. They are as follows:

Chronic Lymphocytic Inflammation Specifies the Organ Tropism of Prions
(Heikenwalder et. al. 2005 http://www.sciencexpress.org/20 January 2005/ Page 1/
10.1126/science.1106460)

2. Coincident Scrapie Infection and Nephritis Lead to Urinary Prion
Excretion (Seeger et al., Science 14 October 2005:Vol. 310. no. 5746, pp.
324 – 326 DOI: 10.1126/science.1118829)

3. PrPsc in mammary glands of sheep affected by scrapie and mastitis (Ligios
C., et al. Nature Medicine, 11. 1137 – 1138, 2005)

These studies from the Aguzzi laboratory warn that concurrent chronic
inflammatory disease could dramatically alter the distribution of BSE
infectivity in infected cattle. Down and dead stock are at higher risk for
both BSE and other systemic conditions. If the results reported above are
also applicable to cattle, the carcasses of dead and down stock affected by
BSE might contain even higher levels of infectivity, or contribute
infectivity via tissues that are not ordinarily at risk in normal animals.

Exposure: Industry Practices or Exemptions which may pose a risk

Poultry Litter

In the United States poultry litter can be fed to cattle. There are two
potential sources of risk from poultry litter. Poultry litter not only
consists of digested feed but also of feed which spills from the cages. As a
consequence, the practice of feeding litter back to cattle is by its nature
non-compliant with the current feed ban if the poultry themselves are being
fed ruminant protein. Given that ruminant protein can no longer be fed to
ruminants in the United States and that most, if not all, countries will no
longer import North American ruminant MBM, an even larger part of poultry
diets is now ruminant MBM. Spillage provides a direct link to back to cattle
but feces are also likely to contain infectivity.

There is no reason to expect that TSE infectivity would be inactivated by
passage through the poultry gut, and only a slim possibility that composting
would reduce infectivity at all. Thus poultry feces are another potential
route of transmission back to cattle. Evidence for this comes from rodent
experiments where infectivity was demonstrated in the feces after being fed:
“Laboratory experiments show that mice orally challenged with scrapie have
detectable infectivity that passes through the gut. Gut contents and fecal
matter may therefore contain infectivity, and it is noted that in
experimental oral challenges in cattle conducted in the UK, feces must be
treated as medical waste for one month following the challenge. It is
concluded that digestive contents and fecal material from livestock or
poultry currently being fed with MBM potentially contaminated with BSE
should not be used as a feed ingredient for animal feed.” [Proceedings:
Joint WHO/FAO/OIE/ Technical Consultation on BSE: public health, animal
health and trade. Paris, 10-14 June 2001; and Alan Dickinson, personal
communication].

It may be possible to remove the risk from poultry litter by sterilization.
However, unless or until a method can be developed and validated, poultry
litter should be banned from ruminant feed.

Ruminant Blood

In contrast with humans, sheep, monkeys, mice and hamsters, including sheep
and mice infected with BSE and humans infected with vCJD considered
identical to BSE, no infectivity has so far been demonstrated in the blood
of BSE infected cattle. However, we consider it unlikely that cattle are the
sole outlier to what has been a consistent finding in all other TSE diseases
where the measurement has been made with sufficient sensitivity to detect
the low levels of infectivity that are present in blood. Rather, this
failure is more likely the result of the very small volumes of blood that
were used for the inoculations (less than 1 ml), whereas whole transfusions
were administered to assay animals in the published sheep scrapie/BSE
experiments. If blood is infected then all vascularized tissues can be
expected to contain some infectivity in proportion to the content of
residual blood.

Micro emboli are a possible source of blood-borne agent that could be at
much higher titer than blood itself, in slaughtered cattle carrying BSE
infection. Stunning can release micro emboli of brain tissue into the
circulatory system from where they can be distributed to other tissues in
the few moments before the exsanguination and death. (Anil, et al, 2001a &
b; Anil et al, 2002; Love, et al, 2000). This source of infection could
extend a higher infectivity risk to tissues that would otherwise be at low
risk, thereby allowing exposure of cattle through any of the legal
exemptions and potentially producing a feed and food risk. Blood-borne
contamination may be a special problem where spray-dried blood is being used
as a milk replacer for calves, as it is thought that young animals are
especially susceptible to infection.

Certainly, blood and blood proteins should not be used as feed without
conclusive evidence that they are safe.

Unfiltered Tallow

Ruminant tallow is exempted from the current feed ban. Tallow contains
protein impurities (i.e. MBM) that could be a source of TSE infectivity.
There are no impurity level requirements for this tallow. It has been
reported that it is standard practice to produce tallow which has an
impurity level of .15% or below, but it is not clear that this is fully
adequate to remove the risk of transmission and there is no requirement to
meet even this standard. We urge that protein contaminants be excluded from
tallow and that SRMs also be removed.

Plate Waste

Plate waste is not limited to meat (muscle tissue). For example, cuts that
include a portion of the spinal cord or that are contaminated by cord or
ganglia during preparation could contain high levels of infectivity if
derived from a TSE infected animal late in the preclinical stage of
infection. At best this material would only be exposed to normal cooking
temperatures. USDA, APHIS experience with the Swine Health Protection Act
has revealed that plate waste also includes uncooked trimmings and bones.
Although the current FDA regulation requires the plate waste be treated
again, there are no specifications which would render a TSE agent inactive.
Of greatest risk would be any bovine source of infectivity but also sheep
scrapie, although not known to be a risk for human consumption, is one of
the possible origins of BSE. The sheep scrapie agent is known to be widely
dispersed including relatively high titers in lymphoid as well as nervous
tissue. We support the USDA’s opposition to the exemption of “plate waste”
as stated in written comments since 1997.

Exposure: Cross Feeding and Cross Contamination

The UK epidemiology has clearly shown that BSE contaminated feed is the
primary if not sole vehicle for the transmission of BSE between cattle.
Moreover, results from the United Kingdom’s attack rate study indicate that
it does not take much exposure to transmit BSE to cattle. Recent results
from the attack rate study which is still in progress have found that .1 g
of brain transmitted BSE by the oral route to 3 cows out of 15 thus far, and
.01 and .001gr of brain have transmitted BSE (1 cow out of 15). (Danny
Matthews, DEFRA presentation at TAFS meeting, Washington, DC April 2004).

Rendering may reduce infectivity but it does not eliminate it. (Taylor et
al, 1995; Taylor et al, 1997; Schreuder et al, 1998). Given that BSE can be
transmitted to cattle via an oral route with just .001 gram of infected
tissue, it may not take much infectivity to contaminate feed and keep the
disease recycling. This is especially true in countries like the US and
Canada which do not have dedicated lines and equipment to manufacture and
process feed for ruminants and non-ruminants.

In addition, epidemiological investigations in European countries have shown
that cross feeding and cross contamination on farm can be a significant
vehicle for continued BSE transmission even after feed bans are well
established. Cross feeding is the practice of feeding meal for poultry or
pigs or pet food (which can legally contain ruminant MBM) to cattle on the
same farm. This is usually due to simple human error or negligence.
(Hoinville, 1994; Hoinville et al, 1995; Doherr et al, 2002a; Stevenson et
al, 2000)

FDA, CVM reports that compliance with the existing feed ban is high. For the
most part this does not include the compliance level on the farm. There are
hundreds of thousands of farms in the US. Many of these have multiple
species. That is, they raise cattle, pigs, chickens etc., on the same
premises. The sheer numbers of farms make it very difficult to assure
compliance on farm and to adequately cover all farms by inspection. Even if
the rendering industry and feed industry can maintain 100% compliance at
their facilities, if a producer inadvertently feeds chicken feed containing
bovine MBM to their cattle, they negate a perfect compliance rate higher in
the chain. Recent data from the Harvard BSE risk assessment suggest that the
level of misfeeding on farms plays a significant role in the ability of the
agent to recycle. In fact George Gray, principal investigator for the study,
stated that if, in the United States, misfeeding were to occur at a level of
15%, the R0 would be over 1, indicating that the BSE level would not be
declining. (George Gray presentation at the Meeting on BSE Prevention in
North America: An Analysis of the Science and Risk; January 27, 2005,
Washington, DC.)

The May 2003 Canadian BSE case illustrates the difficulty of on farm
enforcement and its serious ramifications. The BSE positive cow was rendered
and the MBM distributed to various locations. Two of these locations were
poultry farms which mixed their own feed. The farms also had cattle. The
subsequent investigation could not eliminate the possibility that the cattle
had been fed the same feed as the poultry. The cattle on these farms were
completely depopulated.

Human error is extremely difficult to prevent, and managing the risk through
enforcement is problematical when confronted with the extreme logistical
challenges of on farm monitoring. By eliminating the highest risk materials
(SRMs and deadstock) which could introduce infectivity into the feed stream,
the MBM resulting from processing becomes inherently safer. If mistakes are
then made on farm, they no longer contribute to the recycling of BSE.

Exposure: Susceptibility of other Species

Felines

A transmissible spongiform encephalopathy has been diagnosed in eight
species of captive wild ruminants as well as exotic felines (cheetahs,
pumas, a tiger and an ocelot) and domestic cats (Wyatt 1991). There have
been over 80 domestic cat cases of Feline Spongiform Encephalopathy (FSE) in
Great Britain, and cats in Norway, Northern Ireland, Lichtenstein and
Switzerland. The agent isolated from several of these cases is
indistinguishable from BSE in cattle using strain typing in mice, suggesting
that FSE is actually BSE in exotic and domestic cats. Epidemiological
evidence suggests BSE contaminated feed to be the probable source of
infection in these species. (MAFF Progress Report, June 1997), thus
providing additional supporting evidence for the dangers of BSE contaminated
feed and reinforcing the necessity of removing all sources of potential
contamination from the feed stream.

Other species

Studies conducted at the National Institutes of Health Rocky Mountain
Laboratory caution against assuming that animals which do not become
clinically ill are not infected. It is unknown if certain animals may become
carriers, i.e., become infected, shed agent but do not progress to clinical
disease. Infection of certain rodent species with different TSE strains
suggests the possibility of a carrier state (Race and Chesebro, 1998; Race
et. al, 2001, Race et al., 2002). In the more recent studies, mice were
inoculated with 263K hamster scrapie. There was a prolonged period
(approximately one year) where there was no evidence of replication of
infectivity. Furthermore, there was no evidence of PrPres during this phase
of inactive persistence, which was followed by a period of active
replication of infectivity and agent adaptation. In most cases, PrPres was
not detected in the active phase as well. It is important to determine if
this persistence and adaptation occurs in other species exposed to TSEs as
it may have significance in feeding programs which continually expose other
species to BSE infectivity. For example, if BSE infected brain and spinal
cord are continually fed to certain species, it may be possible for the
agent to persist and adapt in these new species. Over time, the ‘resistant’
species may become a source of agent. The results of Race and colleagues,
warns that an inactive persistent phase might not produce detectable PrPres,
yet there would be infectivity (Race et. al., 2001).

Pigs displayed evidence of TSE infection after exposure to BSE by 3 distinct
parenteral routes. Evidence of infectivity was found in the CNS, stomach,
intestine and pancreas (Dawson et. al., 1990). Oral transmission has also
been attempted in swine, but after an observation period of 84 months there
was neither clinical nor pathological evidence of infection (Dawson et. al.,
1990). Parenteral and oral transmission has also been attempted in chickens
with no evidence of disease. Tissues from the BSE-challenged pigs and
chickens were inoculated into susceptible mice to look for residual
infectivity, but to date none has been found. In both instances the
detection sensitivity was limited by the use of mice for bioassay instead of
same species transmissions into cattle (or pigs and chickens).

If any of these scenarios played out and inapparent infections became
established in commercial species, those species could become reservoirs for
reinfection of cattle and perpetuation or reintroduction of the epidemic. We
also do not know if atypical cases of BSE are more pathogenic for other
species and if chronic inflammation may influence the susceptibility of
other species. We offer these possibilities to reinforce the need to
eliminate all possible sources of infectivity from the feed stream.

In January 2005, the European Union announced that BSE had been confirmed in
a goat in France illustrating that the disease can be naturally transmitted
to one of the small ruminants. The potential ramifications of this and the
logistical challenges associated with controlling BSE in sheep or goats also
provides a justification for removing SRMs from all animal feed. Although
these species are covered under the current regulations the cross
contamination and cross feeding aspects stated for cattle are applicable.

The need to remove high risk material from all animal feed is also supported
by other bodies with expertise in the field of TSEs:

Recommendations of the World Health Organization (WHO)

The World Health Organization (WHO) has issued the following recommendations
for countries with BSE or those where a known exposure exists:

· No part or product of any animal which has shown signs of a TSE should
enter any food chain (human or animal). In particular:

o All countries must ensure the killing and safe disposal of all parts or
products of such animals so that TSE infectivity cannot enter any food
chain.

o Countries should not permit tissues that are likely to contain the BSE
agent to enter any food chain (human or animal).

From the report of a WHO Consultation on Public Health Issues related to
Human and Animal Transmissible Spongiform Encephalopathies WHO/EMC/DIS
96.147, Geneva, 2-3 April 1996.

Office of International Epizooties (OIE)

The OIE is recommending that a list of SRMs which include brain, spinal
cord, eyes, skull and vertebral column be removed from preparations used for
food, feed, fertilizer, etc. If these tissues should not be traded we feel
that they should not be used in domestic products either.

BSE Code Article 2.3.13.18

“From cattle, originating from a country or zone with a minimal BSE risk,
that were at the time of slaughter over 30 months of age, the following
commodities, and any commodity contaminated by them, should not be traded
for the preparation of food, feed, fertilizers, cosmetics, pharmaceuticals
including biologicals, or medical devices: brains, eyes and spinal cord,
skull, vertebral column and derived protein products. Food, feed,
fertilizers, cosmetics, pharmaceuticals or medical devices prepared using
these commodities should also not be traded.”

Conclusion

In conclusion we urge the FDA to implement, monitor and enforce a
comprehensive and protective feed ban that is more congruent with the
measures that have been proven to be effective in other countries that have
experienced BSE. We do not feel that we can overstate the dangers from the
insidious threat from these diseases and the need to control and arrest them
to prevent any possibility of spread.

We also wish to emphasize that as scientists who have dedicated substantive
portions of our careers to defining the risks from TSEs as well as
developing strategies for managing those risks, we are confident that
technical solutions will be found for many of the challenges posed by these
diseases. Thus, we urge the FDA to frame its regulations in terms that allow
for the future use of any banned material if it can be proven safe for a
given application.

Signatories:

Paul W. Brown, M.D.

Medical Director, USPHS, and Senior Investigator, NIH (retired)

Consultant, TSE Risk Management

xxxxxxxxxxxx

xxxxxxxxxxxxx

xxxxxxxxxx

Email: paulwbrown@comcast.net

Neil R. Cashman MD
Professor, Department of Medicine (Neurology)
Diener Chair of Neurodegenerative Diseases
Centre for Research in Neurodegenerative Diseases
6 Queen's Park Crescent West
Toronto Ontario M5S3H2
xxxxxxxxxxxxxxxxxx

xxxxxxxxxxxxxxxxx

e-mail: neil.cashman@utoronto.ca

Linda A. Detwiler, DVM
Consultant, TSE Risk Management

xxxxxxxxxxxxxxxxxxxxxxx

xxxxxxxxxxxxxxxxxxxx

xxxxxxxxxxxxxxxxxx

Email: LAVet22@aol.com

Laura Manuelidis, MD

Professor and Head of Neuropathology,
Department of Surgery and Faculty of Neurosciences
Yale Medical School

xxxxxxxxxxxxxxxxxxxx
email: laura.manuelidis@yale.edu
xxxxxxxxxxxxxxxxxxxxxxxx

Jason C. Bartz, Ph.D.
Assistant Professor
Department of Medical Microbiology and Immunology
Creighton University
2500 California Plaza
Omaha, NE 68178
xxxxxxxxxxxxxxxxxxxxx

xxxxxxxxxxxxxxxxxxxx

jbartz@creighton.edu

Robert B. Petersen, Ph.D.

Associate Professor of Pathology and Neuroscience

Case Western Reserve University

5-123 Wolstein Building

2103 Cornell Road

Cleveland, OH 44106-2622

xxxxxxxxxxxxxxxxxxxxxxx

xxxxxxxxxxxxxxxxxxx

Email rbp@cwru.edu

Robert G. Rohwer, Ph.D.
Director, Molecular Neurovirology Laboratory
Veterans Affairs Medical Center
Medical Research Service 151
Assoc. Professor of Neurology
School of Medicine
University of Maryland at Baltimore
10 N. Greene St.
Baltimore, MD 21201
xxxxxxxxxxxxxxxxx
xxxxxxxxxxxxxxx

email: rrohwer@umaryland.edu

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Hoinville,L.J.; Wilesmith,J.W.; Richards,M.S. - An investigation of risk
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Houston,E.F.; Foster,J.D.; Chong,A.; Hunter,N.; Bostock,C.J. – Transmission
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Hunter,N.; Foster,J; Chong,A.; McCutcheon,S.; Parnham,D.; Eaton,S.;
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Love,S.; Helps,C.R.; Williams,S.; Shand,A.; McKinstry,J.L.; Brown,S.N.;
Harbour,D.A.; Anil,M.H. - Methods for detection of haematogenous
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Mulcahy ER, Bartz JC, Kincaid AE, Bessen RA. Prion infection of skeletal
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Race, R.; Chesebro, B. – Scrapie infectivity found in resistant species.
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Aguzzi,A.; Weissmann,C. - Spongiform encephalopathies. The prion's
perplexing persistence. - Nature. 1998 Apr 23;392(6678):763-4

Race,R.E.; Raines,A.; Raymond,G.J.; Caughey,B.W.; Chesebro,B. - Long-term
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resistant species: analogies to bovine spongiform encephalopathy and variant
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Race,R.E.; Meade-White,K.; Raines,A.; Raymond,G.J.; Caughey,B.W.;
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Enthoven, P., Oberthür, R.C., de Koeijer, A.A., Osterhaus, A.D.M.E., 1998.
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142, 474-480

Stevenson, M. A., Wilesmith, J. W., Ryan, J. B. M., Morris, R.S., Lockhart,
J. W., Lin, D. & Jackson, R. (2000) Temporal aspects of bovine spongiform
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Stevenson, M. A., Wilesmith, J. W., Ryan, J. B. M., Morris, R. S., Lawson,
A.B., Pfeiffer, D. U. & Lin, D. (2000) Descriptive spatial analysis of the
epidemic of bovine spongiform encephalopathy in Great Britain to June 1997.
Vet. Rec. 147, 379-384.

Taylor, D.M., Woodgate, S.L., Atkinson, M.J., 1995. Inactivation of the
bovine spongiform encephalopathy agent by rendering procedures. Veterinary
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Taylor, D.M., Woodgate, S.L., Fleetwood, A.J., Cawthorne, R.J.G., 1997. The
effect of rendering procedures on scrapie agent. Veterinary Record, Vol.141,
pp 643-649.

Thomzig A, Schulz-Schaeffer W, Kratzel C, Mai J, Beekes M. Preclinical
deposition of pathological prion protein PrPSc in muscles of hamsters orally
exposed to scrapie.
J Clin Invest. 2004 May;113(10):1465-72.

Thomzig A, Kratzel C, Lenz G, Kruger D, Beekes M. Widespread PrPSc
accumulation in muscles of hamsters orally infected with scrapie. EMBO Rep.
2003 May;4(5):530-3.

Wilesmith, J.W., Ryan, J. B. M., Hueston, W. D., & Hoinville, L. J. (1992)
Bovine spongiform encephalopathy: epidemiological features 1985 to 1990.
Vet. Rec., 130, 90-94.

Wilesmith, J. W., Wells, G. A. H., Ryan, J. B. M., Gavier-Widen, D., &
Simmons, M. M. (1997) A cohort study to examine maternally associated risk
factors for bovine spongiform encephalopathy. Vet. Rec., 141, 239-243.

Wells G.A.H., Dawson M., Hawkins, S.A.C., Green R. B., Dexter I., Francis M.
E., Simmons M. M., Austin A. R., & Horigan M. W. (1994) Infectivity in the
ileum of cattle challenged orally with bovine spongiform encephalopathy.
Vet. Rec., 135, 40-41.

Wells G.A.H., Hawkins, S.A.C., Green R. B., Austin A. R., Dexter I.,
Spencer, Y. I., Chaplin, M. J., Stack, M. J., & Dawson, M. (1998)
Preliminary observations on the pathogenesis of experimental bovine
spongiform encephalopathy (BSE): an update. Vet. Rec., 142, 103-106.

Wyatt. J. M. et al. 1991. Naturally occurring scrapie-like spongiform
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----------------------------------------------------------------------------
----

[RR1] I am not sure of the point here. If they are going to use dead stock
then certainly they should at a minimum remove the CNS tissue but rather I
would think the point should be that we don’t want them using dead stock
with or without the CNS included.

[RR2]I am not sure that the actual text of the CFR is still required to make
the point. However, I am glad I had it to verify the original argument.

EC 203 McDonald's Restaurants Corporation Vol #: 34

EC 205 McDonald's Restaurants Corp Vol #: 34

http://www.fda.gov/ohrms/dockets/dailys/05/Dec05/122205/122205.htm

also, i see another (or the same) poster here also;

EMC 134 McDonald's Corporation Vol #: 14

http://www.fda.gov/ohrms/dockets/dailys/06/jan06/011006/011006.htm

9 December 2005
Division of Dockets Management (RFA-305)
Food and Drug Administration
5630 Fishers Lane
Room 1061
Rockville, MD 20852
Re: Docket No: 2002N-0273 (formerly Docket No. 02N-0273)
Substances Prohibited From Use in Animal Food and Feed
Dear Sir or Madame:
Serologicals Corporation is a global provider of biological products to life
science companies.
The Company’s products are essential for the research, development and
manufacturing of
biologically based diagnostic, pharmaceutical and biological products.
customers include
many of the leading research institutions, diagnostic and pharmaceutical
companies throughout
the world. The Company’s products and technologies are used in a wide
variety of applications
within the areas of neurobiology, cell signaling, oncology, angiogenesis,
apoptosis,
developmental biology, cellular physiology, hematology, immunology,
cardiology, infectious
diseases and molecular biology.
A number of our products are derived from bovine blood or other bovine
tissues sourced in the
United States, hence the overall health of the national herd is extremely
important to our
company as well as to our customers and their patients. Some of our bovine
based products are
used in the manufacture of vaccines and drugs for humans, hence it is
critical that all measures
are taken to assure these are safe and free from disease especially Bovine
Spongiform
Encephalopathy (BSE). The most effective way to insure this is to create a
system which
processes cattle that are BSE free. As a company there are a number of
precautions that we can
take by our strict specifications but many of the needed precautions require
the force of federal
regulation, hence we appreciate the opportunity to submit comments to this
very important
proposed rule.
After the identification of bovine spongiform encephalopathy (BSE) in
indigenous North
American cattle, the U.S. Department of Agriculture (USDA) responded rapidly
to implement
measures to protect public health in regard to food. Our company recognizes
and supports the
importance of the current feed ban which went into effect in August 1997.
However, given what
is known about the epidemiology and characteristically long incubation
period of BSE, we urge
5655 Spalding Drive * Norcross, GA 30092
678-728-2000 * 800-842-9099 * Facsimile 678-728-2299
http://www.serologicais.com
Division of Dockets Management (HFA-305)
Page 2
9 December 2005
the FDA to act without further delay and implement additional measures which
will reduce the
risk of BSE recycling in the US cattle herd.
We feel that for the FDA to provide a more comprehensive and protective feed
ban, specified
risk materials (SRMs) and deadstock must be removed from all animal feed and
that legal
exemptions which allow ruminant protein to be fed back to ruminants (with
the exception of
milk) should be discontinued.
SRMs, as defined by the USDA, are tissues which, in a BSE infected animal,
are known to either
harbor BSE infectivity or to be closely associated with infectivity. If SRMs
are not removed,
they may introduce BSE infectivity and continue to provide a source of
animal feed
contamination. Rendering will reduce infectivity but it will not totally
eliminate it. This is
significant as research in the United Kingdom has shown that a calf may be
infected with BSE
by the ingestion of as little as .OOl gram of untreated brain.
The current proposed rule falls short of this and would still leave a
potential source of infectivity
in the system. In fact by the FDA’s own statement the exempted tissues which
are known to
have infectivity (such as distal ileum, DRGs, etc) would cumulatively amount
to 10% of the
infectivity in an infected animal, This proposed rule would still allow for
the possibility that
cattle could be exposed to BSE through:
1. Feeding of materials currently subject to legal exemptions from the ban
(e.g., poultry
litter, plate waste)
2. Cross feeding (the feeding of non-ruminant rations to ruminants) on
farms; and
3. Cross contamination of ruminant and non-ruminant feed
We are most concerned that the FDA has chosen to include a provision which
would allow
tissues from deadstock into the feed chain. We do not support the provision
to allow the removal
of brain and spinal cord from down and deadstock over 30 months of age for
several reasons.
These are the animals with the highest level of infectivity in tissues which
include more than
brain and spinal cord. We do not feel that there can be adequate removal and
enforcement of this
regulation especially during warmer weather. In addition there is emerging
information that at
end stage disease, infectivity may also be included in additionai tissues
such as peripheral nerves
(Buschmann and Groschup, 2005).
Leaving the tissues from these cattle in the animal feed chain will
effectively nullify the intent of
this regulation. This point is illustrated by the 2001 Harvard risk
assessment model which
demonstrated that eliminating dead and downer, 4D cattle, from the feed
stream was a
disproportionately effective means of reducing the risk of re-infection “The
disposition of c&e
that die on the farm would also have a substantial influence on the spread
of BSE if the disease
were in traduced. ” The base case scenario showed that the mean total number
ofID.50~ (i.e.,
dosage sufficient to infect SO percent of exposed cattte) from healthy
animals at slaughter
presented to the food/feed system was 1500, The mean total number of ID.50.s
from adult cattle
Division of Dockets Management (HFA-305)
Page 3
9 December 2005
deadstockpresented to the feed system was 3 7,000.
deadstock).
This illustrates the risk of “40 cattle” (i.e.,
From the Harvard Risk Assessment, 2001, Appendix 3A Base Case and Harvard
Risk
Assessment, 200 1 Executive Summary
Serologicals and companies like ours which supply components of drugs and
biologicals have a
responsibility to the manufacturers of these products, the medical community
and their patients
as well as regulatory agencies throughout the world to provide the safest
products as possible.
Since there is no test for BSE in live cattle or for product, the regulatory
agencies throughout the
world expect us to reduce or eliminate risk via suurcing criteria, These
parameters may include
but not be limited to country of origin, herd of origin, age of the animal,
etc. The United States
is no longer a country with negligible risk, hence individual animal
criteria has become more
important. In fact other Centers of the FDA have stated that more attention
should be given to
sourcing from herds likely to be a source of BSE free animals. The
exemptions in the current
ban as well as in the newly proposed rule make this difficult if not
impossible as there are still
legal avenues for ruminants to consume potentially contaminated ruminant
protein. In addition,
the USDA still has not implemented a system of identification and
traceability.
Serologicals urges agencies of the US government to work with academia and
industry on
research in the following areas:
e Methods to inactivate TSEs agents which then may allow a product to be
used and even
fed to animals without risk
l Alternative uses for animal byproducts which would maintain value
Serologicals will continue to work with the FDA and other government
agencies to implement a
strong BSE risk control program, Serologicals would like to reiterate our
opinion that for the
FDA to provide a more comprehensive and protective feed ban, specified risk
materials (SRMs)
and deadstock must be removed from all animal feed and that legal exemptions
which allow
ruminant protein to be fed back to ruminants (with the exception of milk)
should be
discontinued. Thank you for the opportunity to submit these comments to the
public record.
Respectfully,
SEROLOGICALS CORPORATION
James J. Kramer, Ph.D.
Vice President, Corporate Operations

http://www.fda.gov/ohrms/dockets/dockets/02n0273/02n-0273-c000383-01-vol...
df

C 435 Government of Japan Vol #: 36

snip...

The Food safety risk assessment related to the import of beef and beef offal
from the U.S.A. and Canada by the Food Safety Commission of Japan (FSC) was
completed on December 8, 2005. REGARDING the feed ban, the following was
noted as an ADDENDUM TO THE CONCLUSION ON THE RISK ASSESSMENT REPORT OF FSC:

"To prevent BSE exposure and amplification in U.S.A. and Canada, the use of
SRM must be prohibited COMPLETELY. The ban must be applied not only to
cattle feed but ALSO TO ALL OTHER ANIMAL FOOD/FEED that may cause
cross-contamination."

snip...

http://www.fda.gov/ohrms/dockets/dockets/02n0273/02n-0273-c000435-01-vol...

Docket Management Docket: 02N-0273 - Substances Prohibited From Use in

Animal Food or Feed; Animal Proteins Prohibited in Ruminant Feed

Comment Number: EC -10

Accepted - Volume 2

http://www.fda.gov/ohrms/dockets/dailys/03/Jan03/012403/8004be07.html

PART 2

http://www.fda.gov/ohrms/dockets/dailys/03/Jan03/012403/8004be09.html

[Docket No. 03-025IFA] FSIS Prohibition of the Use of Specified Risk Materials for Human Food and Requirement for the Disposition of Non-Ambulatory Disabled Cattle

03-025IFA
03-025IFA-2
Terry S. Singeltary

Page 1 of 17

From: Terry S. Singeltary Sr. [flounder9@verizon.net]

Sent: Thursday, September 08, 2005 6:17 PM

To: fsis.regulationscomments@fsis.usda.gov

Subject: [Docket No. 03-025IFA] FSIS Prohibition of the Use of Specified Risk Materials for Human Food and Requirements

for the Disposition of Non-Ambulatory Disabled Cattle

Greetings FSIS,

I would kindly like to submit the following to [Docket No. 03-025IFA] FSIS Prohibition of the Use of Specified Risk Materials for Human Food and

Requirements for the Disposition of Non-Ambulatory Disabled C

Offline
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Posts: 230
McDonald's AND Seriologicals USA NOT PROTECTED FROM MAD COW

[Docket No. 03-025IFA] FSIS Prohibition of the Use of Specified Risk Materials for Human Food and Requirement for the Disposition of Non-Ambulatory Disabled Cattle

03-025IFA
03-025IFA-2
Terry S. Singeltary

Page 1 of 17

From: Terry S. Singeltary Sr. [flounder9@verizon.net]

Sent: Thursday, September 08, 2005 6:17 PM

To: fsis.regulationscomments@fsis.usda.gov

Subject: [Docket No. 03-025IFA] FSIS Prohibition of the Use of Specified Risk Materials for Human Food and Requirements

for the Disposition of Non-Ambulatory Disabled Cattle

Greetings FSIS,

I would kindly like to submit the following to [Docket No. 03-025IFA] FSIS Prohibition of the Use of Specified Risk Materials for Human Food and

Requirements for the Disposition of Non-Ambulatory Disabled Cattle

THE BSE/TSE SUB CLINICAL Non-Ambulatory Disabled Cattle

Broken bones and such may be the first signs of a sub clinical BSE/TSE Non-Ambulatory Disabled Cattle ;

snip...FULL TEXT ;

http://www.fsis.usda.gov/OPPDE/Comments/03-025IFA/03-025IFA-2.pdf

Importation of Whole Cuts of Boneless Beef from Japan [Docket No. 05-004-1] RIN 0579-AB93 TSS SUBMISSION

http://docket.epa.gov/edkfed/do/EDKStaffItemDetailView?objectId=090007d4...

http://docket.epa.gov/edkfed/do/EDKStaffAttachDownloadPDF?objectId=09000...

http://docket.epa.gov/edkfed/do/EDKStaffCollectionDetailView?objectId=0b...

========================================================

========================================================

OLD TSS SUBMISSIONS;

Docket No, 04-047-l Regulatory Identification No. (RIN) 091O-AF46 NEW BSE SAFEGUARDS (comment submission)

https://web01.aphis.usda.gov/regpublic.nsf/0/eff9eff1f7c5cf2b87256ecf000...

Docket No. 03-080-1 -- USDA ISSUES PROPOSED RULE TO ALLOW LIVE ANIMAL
IMPORTS FROM CANADA

https://web01.aphis.usda.gov/BSEcom.nsf/0/b78ba677e2b0c12185256dd300649f...

Docket No. 2003N-0312 Animal Feed Safety System [TSS SUBMISSION]

http://www.fda.gov/ohrms/dockets/dockets/03n0312/03N-0312_emc-000001.txt

TSS

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Joined: 01/01/2006
Posts: 230
McDonald's AND Seriologicals USA NOT PROTECTED FROM MAD COW

SEROLOGICALS CORPORATION
James J. Kramer, Ph.D.
Vice President, Corporate Operations

9 December 2005
Division of Dockets Management (RFA-305)
Food and Drug Administration
5630 Fishers Lane
Room 1061
Rockville, MD 20852
Re: Docket No: 2002N-0273 (formerly Docket No. 02N-0273)
Substances Prohibited From Use in Animal Food and Feed
Dear Sir or Madame:
Serologicals Corporation is a global provider of biological products to life
science companies.
The Company’s products are essential for the research, development and
manufacturing of
biologically based diagnostic, pharmaceutical and biological products.
customers include
many of the leading research institutions, diagnostic and pharmaceutical
companies throughout
the world. The Company’s products and technologies are used in a wide
variety of applications
within the areas of neurobiology, cell signaling, oncology, angiogenesis,
apoptosis,
developmental biology, cellular physiology, hematology, immunology,
cardiology, infectious
diseases and molecular biology.
A number of our products are derived from bovine blood or other bovine
tissues sourced in the
United States, hence the overall health of the national herd is extremely
important to our
company as well as to our customers and their patients. Some of our bovine
based products are
used in the manufacture of vaccines and drugs for humans, hence it is
critical that all measures
are taken to assure these are safe and free from disease especially Bovine
Spongiform
Encephalopathy (BSE). The most effective way to insure this is to create a
system which
processes cattle that are BSE free. As a company there are a number of
precautions that we can
take by our strict specifications but many of the needed precautions require
the force of federal
regulation, hence we appreciate the opportunity to submit comments to this
very important
proposed rule.
After the identification of bovine spongiform encephalopathy (BSE) in
indigenous North
American cattle, the U.S. Department of Agriculture (USDA) responded rapidly
to implement
measures to protect public health in regard to food. Our company recognizes
and supports the
importance of the current feed ban which went into effect in August 1997.
However, given what
is known about the epidemiology and characteristically long incubation
period of BSE, we urge
5655 Spalding Drive * Norcross, GA 30092
678-728-2000 * 800-842-9099 * Facsimile 678-728-2299
http://www.serologicais.com
Division of Dockets Management (HFA-305)
Page 2
9 December 2005
the FDA to act without further delay and implement additional measures which
will reduce the
risk of BSE recycling in the US cattle herd.
We feel that for the FDA to provide a more comprehensive and protective feed
ban, specified
risk materials (SRMs) and deadstock must be removed from all animal feed and
that legal
exemptions which allow ruminant protein to be fed back to ruminants (with
the exception of
milk) should be discontinued.
SRMs, as defined by the USDA, are tissues which, in a BSE infected animal,
are known to either
harbor BSE infectivity or to be closely associated with infectivity. If SRMs
are not removed,
they may introduce BSE infectivity and continue to provide a source of
animal feed
contamination. Rendering will reduce infectivity but it will not totally
eliminate it. This is
significant as research in the United Kingdom has shown that a calf may be
infected with BSE
by the ingestion of as little as .OOl gram of untreated brain.
The current proposed rule falls short of this and would still leave a
potential source of infectivity
in the system. In fact by the FDA’s own statement the exempted tissues which
are known to
have infectivity (such as distal ileum, DRGs, etc) would cumulatively amount
to 10% of the
infectivity in an infected animal, This proposed rule would still allow for
the possibility that
cattle could be exposed to BSE through:
1. Feeding of materials currently subject to legal exemptions from the ban
(e.g., poultry
litter, plate waste)
2. Cross feeding (the feeding of non-ruminant rations to ruminants) on
farms; and
3. Cross contamination of ruminant and non-ruminant feed
We are most concerned that the FDA has chosen to include a provision which
would allow
tissues from deadstock into the feed chain. We do not support the provision
to allow the removal
of brain and spinal cord from down and deadstock over 30 months of age for
several reasons.
These are the animals with the highest level of infectivity in tissues which
include more than
brain and spinal cord. We do not feel that there can be adequate removal and
enforcement of this
regulation especially during warmer weather. In addition there is emerging
information that at
end stage disease, infectivity may also be included in additionai tissues
such as peripheral nerves
(Buschmann and Groschup, 2005).
Leaving the tissues from these cattle in the animal feed chain will
effectively nullify the intent of
this regulation. This point is illustrated by the 2001 Harvard risk
assessment model which
demonstrated that eliminating dead and downer, 4D cattle, from the feed
stream was a
disproportionately effective means of reducing the risk of re-infection “The
disposition of c&e
that die on the farm would also have a substantial influence on the spread
of BSE if the disease
were in traduced. ” The base case scenario showed that the mean total number
ofID.50~ (i.e.,
dosage sufficient to infect SO percent of exposed cattte) from healthy
animals at slaughter
presented to the food/feed system was 1500, The mean total number of ID.50.s
from adult cattle
Division of Dockets Management (HFA-305)
Page 3
9 December 2005
deadstockpresented to the feed system was 3 7,000.
deadstock).
This illustrates the risk of “40 cattle” (i.e.,
From the Harvard Risk Assessment, 2001, Appendix 3A Base Case and Harvard
Risk
Assessment, 200 1 Executive Summary
Serologicals and companies like ours which supply components of drugs and
biologicals have a
responsibility to the manufacturers of these products, the medical community
and their patients
as well as regulatory agencies throughout the world to provide the safest
products as possible.
Since there is no test for BSE in live cattle or for product, the regulatory
agencies throughout the
world expect us to reduce or eliminate risk via suurcing criteria, These
parameters may include
but not be limited to country of origin, herd of origin, age of the animal,
etc. The United States
is no longer a country with negligible risk, hence individual animal
criteria has become more
important. In fact other Centers of the FDA have stated that more attention
should be given to
sourcing from herds likely to be a source of BSE free animals. The
exemptions in the current
ban as well as in the newly proposed rule make this difficult if not
impossible as there are still
legal avenues for ruminants to consume potentially contaminated ruminant
protein. In addition,
the USDA still has not implemented a system of identification and
traceability.
Serologicals urges agencies of the US government to work with academia and
industry on
research in the following areas:
e Methods to inactivate TSEs agents which then may allow a product to be
used and even
fed to animals without risk
l Alternative uses for animal byproducts which would maintain value
Serologicals will continue to work with the FDA and other government
agencies to implement a
strong BSE risk control program, Serologicals would like to reiterate our
opinion that for the
FDA to provide a more comprehensive and protective feed ban, specified risk
materials (SRMs)
and deadstock must be removed from all animal feed and that legal exemptions
which allow
ruminant protein to be fed back to ruminants (with the exception of milk)
should be
discontinued. Thank you for the opportunity to submit these comments to the
public record.
Respectfully,
SEROLOGICALS CORPORATION
James J. Kramer, Ph.D.
Vice President, Corporate Operations

http://www.fda.gov/ohrms/dockets/dockets/02n0273/02n-0273-c000383-01-vol...

C 435 Government of Japan Vol #: 36

snip...

The Food safety risk assessment related to the import of beef and beef offal
from the U.S.A. and Canada by the Food Safety Commission of Japan (FSC) was
completed on December 8, 2005. REGARDING the feed ban, the following was
noted as an ADDENDUM TO THE CONCLUSION ON THE RISK ASSESSMENT REPORT OF FSC:

"To prevent BSE exposure and amplification in U.S.A. and Canada, the use of
SRM must be prohibited COMPLETELY. The ban must be applied not only to
cattle feed but ALSO TO ALL OTHER ANIMAL FOOD/FEED that may cause
cross-contamination."

snip...

http://www.fda.gov/ohrms/dockets/dockets/02n0273/02n-0273-c000435-01-vol...

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

PAUL BROWN

Subject: Docket No: 2002N-0273 (formerly Docket No. 02N-0273) Substances Prohibited From Use in Animal Food and Feed PAUL BROWN
Date: January 20, 2006 at 9:31 am PST

December 20,2005

Division of Dockets Management (HFA-305)

Food and Drug Administration

5630 Fishers Lane

Room 1061

Rockville, MD 20852

Re: Docket No: 2002N-0273 (formerly Docket No. 02N-0273)

Substances Prohibited From Use in Animal Food and Feed

Dear Sir or Madame:

As scientists and Irecognized experts who have worked in the field of TSEs for

decades, we are deeply concerned by the recent discoveries of indigenous BSE infected

cattle in North America and appreciate the opportunity to submit comments to this very

important proposed rule We strongly supported the measures that USDA and FDA

implemented to protect public health after the discovery of the case of bovine spongiform

encephalopathy (BSE) found in Washington State in 2003. We know of no event or

discovery since then that could justify relaxing the existing specified risk material

(SRM) and non-ambulatory bans and surveillance that were implemented at that time.

Further, we strongly supported the codification of those changes, as well as additional

measures to strengthen the entire feed and food system. The discovery of additional

cases of indigenous BSE in North America since that time has validated our position and

strengthened OUT convictions.

We caution against using the 18 month enhanced surveillance as a justification to relax or

impede further actions. While this surveillance has not uncovered an epidemic, it does

not clear the US cattle herd from infection. While it is highly likely that US and

Canadian cattle were exposed to BSE prior to the 1997 feed ban, we do not know how

many cattle were infected or how widely the infection was dispersed. BSE cases are

most likely clustered in time and location, so while enhanced surveillance provides an 18

month snapshot, it does uot negate the fact that US and Canadian cattle were exposed to

BSE. We also do not know in any quantitative or controlled way how effective the feed

ban has been, especially at the farm level. At this point we cannot even make a thorough

assessment of the USDA surveillance as details such as age, risk category and regional

distribution have not been released.

A number of countries initially attempted to take partial steps in regard to feed controls

only to face repeated disappointments in predicted downturns of the epidemic course.

We in North America could do this experiment all over again, waiting for each new

warning before adding more stringency to our control measures, or we can benefit from

the experience of others and take decisive measures now to arrest any further

development of underlying cases that is implicit in those already discovered to date.

The discovery of 5 indigenous North American cases, including one born after the

implementation of the current feed ban, should provide the necessary incentive to

implement, monitor and enforce a comprehensive and protective feed ban that is more

congruent with the measures that have been proven to be effective throughout the world.

In particular, we urge the FDA to act without f&ther delay to strengthen the animal feed

regulations by implementing the program proposed by the Canadian Food Inspection

Agency (CFIA) in the December 11, 2004 Gazette. This includes removing all specified

risk materials (SRMs) and deadstock from all animal feed. We also urge that the FDA

discontinues the legal exemptions which allow ruminant protein to be fed back to

ruminants (with the excelption of milk). Many of these exemptions do not exist in other

countries.

Bovine products and byproducts are used for both food and pharmaceuticals. These

human uses require the highest level of safety. Because of the hardy nature of the BSE

agent and its high potential for cross contamination, the most effective way to protect

bovine products and bovine derived materials from contamination by BSE is to ensure

that infected animals or carcasses never enter processing plants. The goal would be to

discover and remove infected animals fi-om production as early as possible in the

infection and long before they wouid be sent to slaughter. Until we have diagnostic tools

powerful enough to allow us to discover the disease early in its prolonged pre-clinical

incubation, we have to rely on the next best strategy which is to prevent any exposure

through feed. The exemptions in the current ban as well as in the newly proposed rule

make this difficult if not impossible, as they still provide legal avenues for ruminants to

consume potentially contaminated ruminant protein.

It is our opinion that the Iproposed rule falls woetilly short in effective measures to

minimize the potential for further transmissions of the disease. By the FDA’s own

analysis, exempted tissues (such as distal ileum, DRGs, etc) contain approximately 10%

of the infectivity in affected animals. Thus the proposed rule still allows the possibility

for cattle to be exposed to BSE through:

1. Feeding of materials currently subject to legal exemptions from the ban (e.g.,

poultry litter, plate waste)

2. Cross feeding (the feeding of non-ruminant rations to runiinants) on farms; and

3. Cross contamination of ruminant and non-ruminant feed

We are most concerned that the FDA has chosen to include a provision that would allow

tissues from deadstock into the feed chain. We do not believe that down or dead stock

E-d

should be allowed into the food or feed chain whatever the age of the animal and whether

or not the CNS tissues are removed. We do not support the provision to allow removal of

brain and spinal cord from deadstock over 30 months for a number of reasons. This

category of animals contains the highest level of infectivity and that infectivity is in other

tissues besides just brain and spinal cord. Recent improvements in the BSE bioassay,

have now made it possible to detect BSE infectivity 1000 time more efficiently than

before. This assay has revealed the presence of BSE infectivity in some but not all

peripheral nerves and in one muscle. (Buschmann and Groschup, 2005) This published

and peer reviewed work is consistent with other publicly reported studies in Japan where,

by western blot testing, ,prions were found in the peripheral nerves of a naturally infected

94-month-old cow. We feel that the studies as reported above have merit. The current

studies not only re-etiorce the risk of down and deadstock but also appear to provide

additional information that these animals may be a potential source of greater levels of

infectivity into the feed .system. We also doubt that brain and spinal cord can be

completely removed especially during warmer weather. Given the biological

composition of these tissues, they are predisposed to rapid autolysis.

As world wide surveillance for BSE increases, several atypical cases of bovine TSE have

been discovered. These cases either show no clinical signs, or present as ‘downers’, and

have an atypical neuropathology with respect to lesion morphology and distribution,

causing problems in both clinical and post-mortem diagnosis. The origin of the cases are

unclear but they suggest that even should typical BSE be eliminated, there may be other

TSE diseases of cattle that could result by “mutation” and selection. Refeeding of

contaminated protein could potentially perpetuate transmission much like typical BSE.

An effective feed ban could prevent the expansion of such strains. We also note that

there are other species which are susceptible to BSE and the current regulations allow for

SRMs to be included in feed for these animals.

For BSE to be perpetuated, the animal production system must have a source of agent and

a means by which cattle or other susceptible species are exposed to this agent. We feel

that in North America, the source and routes of exposure still exist, hence allowing for

the continued recycling of BSE. We have detailed the scientific justifications for our

position below.

Source of the agent: SRMs (Specified Risk Materials) r

SRMs, as defined by the USDA, are tissues which, in a BSE infected animal, are known

to either harbor BSE i&:ctivity or to be closely associated with infectivity. If SRMs are

not removed, they may introduce BSE infectivity and continue tq provide a source of

animal feed contamination. For example, the skull and vertebral column which encase

the brain and spinal cord, respectively, can be assumed to have gross contamination.

Rendering will reduce infectivity but it will not totally eliminate it. This is significant as

research in the United Kilngdom has shown that a calf may be infected with BSE by the

ingestion of as little as AI01 gram of untreated brain.

The tissue distribution of infectivity in BSE infected cattle has primarily been determined

by 3 studies conducted in the United Kingdom all of which had limitations.

In two of the studies, bioassays were done in mice which are at least 1000 fold less

sensitive to BSE infection than cattle themselves. Only higher titers of infectivity can be

detected by this method. These investigations found infectivity in the brain, spinal cord,

retina, trigeminal ganglia, dorsal root ganglia, distal ileum and bone marrow (the bone

marrow finding was from one animal). Infectivity was found in distal ileum of

experimentally infected calves beginning six months after challenge and continuing at

other intervals throughout life. (Wells et. al., 1994; 1998). The bioassay study in calves

has produced similar results and in addition infectivity has been found in tonsil. The

study is still in progress. Another project has found infectivity in the lymphoid tissue of

third eyelid from naturally infected animals. (Dr. Danny Matthews, UK DEFRA,

personal communication).

While bioassay in cattle is far preferable to mice in terms of sensitivity, cattle

nevertheless present their own limitations in terms of the long incubation time and the

limited number of anim& that can be used for assay compared to rodents. As a

consequence the significance of the negative finding for many tissues is questionable. In

fact, by the end of 2004 there was increasing evidence in species other than cattle that

peripheral nerves and muscle have infectivity. (Bosque et al., 2002; Glatzel et al.,

2003;Bartz et al., 2002; Androletti et al., 2004; Mulcahy et al., 2004; Thomzig et al.,

2003; Thomzig et al., 2004)

In some of these species, studies indicate that the agent migrates to the brain and spinal

cord, replicates to high levels in the CNS and then spreads centrifugally from the spinal

cord back down through the spinal neurons to the junction of the nerves and muscle into

the muscle cells themselves. A recent German study (Buschmann and Groschup, 2005)

examined nerves and muscle from a cow naturally infected with BSE and found tbat

infectivity was present in several peripheral nerves and one muscle. The method of

detection was bioassay in bovinized transgenic mice that show the same or greater

sensitivity to transmission of BSE as cattle. This research concurs with findings by

Japanese scientists that BSE infectivity is present in peripheral nerves at least in the

clinical stage of disease.

It is our opinion that there is increasing evidence that the pathogenesis of BSE might not

be entirely different from TSEs in other species at the point of clinical disease in that

there is peripheral involvement. We feel that the studies as reported above have merit.

The current studies not only re-enforce the risk of down and deadstock but also appear to

provide additional information that these animals may be a potential source of greater

levels of infectivity into the feed system.

In the event that FDA may confer with USDA about the risks associated with peripheral

nerves we want to point out one issue. In the recent publication of the final rule on the

SSOI-Z6L.-ZEL

importation of whole cuts OF boneless beef from Japan, 9 CFR Part 94 [Docket No. 05-

004-21 RIN 0579-AB93, we disagree with the interpretation provided by USDA, APHIS.

APHIS seems to discount the studies conducted by Groschup et al. 2005. on the basis that

the transgenic mouse bioassay that they used may be too sensitive. In taking this position

they have failed to realize that the point oFan assay is to reveal in which tissues the

infectivity resides and its relative concentration to brain or spinal cord. For this purpose,

no assay can be too sensitive. Of course, the probability of an actual infection will he

affected by the efficiency of infection which will be a function of dose, route of exposure

and any host barrier effects that are present.

We would also like to point out a factual error in the conclusion. APHIS states, “Given

these factors, APHIS has determined that the finding of l3SE infectivity in facial and sciatic nerves

of the transgenic mice is nalt directly applicable to cattle naturally infected with BSE. Therefore,

we do not consider it necessary to make any adjustments to the risk analysis for this rulemaking

or to extend the comment Fleriod to solicit additional public comment on this issue.” It is incorrect

that the infectivity was found in the peripheral nerves of transgenic mice. The peripheral

nerves were harvested from a cow naturally infected with BSE. Transgenic mice were

used as a bioassay model.

From [Docket No. 05-004-21 RIN 0579-AB93:

“Peripheral Nerves

Issue: Two commenters stalted that the underlying assumption of the proposed rule. that whole

cuts of boneless beef from #Japan will not contain tissues that may carry the BSE agent, is no

longer valid because researchers have found peripheral nervous system tissues, including facial

and sciatic nerves, that contain BSE infectivity.U One of these commenters requested API-W to

explain whether and what additional mitigation measures are needed to reduce the risks that

these tissues may be present in Japanese beef. This commenter further requested an additional

comment period to obtain public comments to treat this new scientiic finding.

\2\ Bushmann, A., and Groschup, M.; Highly Bovine Spongiform

Encephalopathy-Sensitive Transgenic Mice Confirm the Essential

Restriction of Infectivity to the Nervous System in Clinically

Diseased Cattle. The Journal of Infectious Diseases, 192: 93442,

September 1, 2005.

Response: APHIS is familiar with the results of the study mentloned by the commenters in which

mice, genetically engineered to be highly susceptible to BSE and to overexpress the bovine prion

protein, were inoculated with tissues from a BSE-infected cow. This study demonstrated low

levels of infectivity in the mouse assay in the facial and sciatic nerves of the peripheral nervous

system. APHIS has evaluated these findings in the context of the potential occurrence of

infectivity in the peripheral nerves of cattle and the corresponding risks of the presence of

infectivity in such tissues resulting in cattle or human exposure to the BSE agent. The results

from these experiments in genetically engineered mice should be interpreted with caution, as the

findings may be influenced by the overexpression of prion proteins and may not accurately

predict the natural distribution of BSE infectivity in cattle. Further, the overexpression of priori

s-d

proteins in transgenic mice may not accurately mimic the natural disease process because the

transgenic overexpressing mice have been shown to develop spontaneous lethal neurological

disease involving spongifolrm changes in the brain and muscle degeneration.\3\ In addition, the

route of administration to the mice was both intraperitoneal and intracerebral, which are two very

efficient routes of infection as compared to oral consumption. Given these factors, APHIS has

determined that the finding of BSE infectivity in facial and sciatic nerves of the transgenic mice is

not directly applicable to cattle naturally infected with BSE. Therefore, we do not consider it

necessary to make any adjustments to the risk analysis for this rulemaking or to extend the

comment period to solicit additional public comment on this issue.”

Source of the agent: Deaalstock

The total amount of TSE infectivity in a TSE infected animal increases steadily

throughout the infection and exponentially once the infectivity reaches the brain.

Infected individuals only exhibit recognizable clinical signs once infectivity titers have

reached high levels in the brain. Surveillance data collected throughout Europe indicates

there is a much greater likelihood for BSE to be detected in dead or down cattle than

from healthy normal animals. This has so far also been borne out by the experience in

North America. Animals that die of BSE harbor the greatest amount of agent that can be

produced by the disease. Leaving the tissues from the highest risk category of cattle in

the animal feed chain will effectively nullify the purported intent of this regulation. This

point is supported by the 2001 Harvard risk assessment model that demonstrated that

eliminating dead and downer, 4D cattle, from the feed stream was a disproportionately

effective means of reducing the risk of re-infection.

“The disposition of cattle thot die on the farm would also huve a substantial influence on

the spread of BSE if the disease were introduced ” The base case scenario showed that

the mean rota? number oj’IDS0.s (i.e., dosage suficient to infecf 50percent of exposed

cattle) f;om healthy animals at slaughter presented to the foodfeed system was 1500.

The mean total number yf IDSOsfiom adult cuttle deadstockpresented fo the feed system

was 3 7,000. This illustrates the risk of “40 cattle ” (i.e.. deadstock).

From the Harvard Risk Assessment, 200 1, Appendix 3A Base Case and Harvard Risk

Assessment, 200 1 Executive Summary

It is likely that these numbers would have to be adjusted upwards, if the UK attack rate

and Groschup data were considered.

Inflammation and TSErr

There have been 3 recent peer reviewed publications which indicate that chronic

ir&unmatory conditions in a host with a TSE may induce priori replication in, or

distribution to organs previously thought to be low or no risk. They are as follows:

s-d

1 _ Chronic Lymphocytic Inflammation Specifies the Organ Tropism of Prions

(Heikenwalder et. al. 2005 >~xx .sci~:n~c\rpl-css.~~r~/~O .lunuarv 2005/ Parrc l/

&).I 1zois~icllcc.l lOh4hO)

2. Coincident Scrapie Infection and Nephritis Lead to Urinary Priori Excretion

(Seeger et al., Science 14 October 2005:Vol. 310. no. 5746, pp. 324 - 326

DOI: lO.l126/science. 1118829)

3. PrPS” in mammary glands of sheep affected by scrapie and mastitis (Ligios C., et

al. Nature Medicine, 11. 3 137 - 1138, 2005)

These studies from the Aguzzi laboratory warn that concurrent chronic inflammatory

disease could dramatically alter the distribution of BSE infectivity in infected cattle.

Down and dead stock are at higher risk for both BSE and other systemic conditions. If

the results reported above are also applicable to cattle, the carcasses of dead and down

stock affected by BSE might contain even higher levels of infectivity, or contribute

infectivity via tissues thai. are not ordinarily at risk in normal animals.

Exposure: tndustry Practices or Exemptions which may pose a risk

Poultry Litter

In the United States poultry litter can be fed to cattle. There are two potential sources of

risk from poultry litter. Poultry litter not only consists of digested feed but also of feed

which spills from the cages. As a consequence, the practice of feeding litter back to

cattle is by its nature non--compliant with the current feed ban if the poultry themselves

are being fed ruminant protein. Given that ruminant protein can no longer be fed to

ruminants in the United States and that most. if not all. countries will no longer import

North American ruminant MBM, an even larger part of poultry diets is now ruminant

MBM. Spillage provides a direct link to back to cattle but feces are also likely to contain

infectivity.

There is no reason to expect that TSE infectivity would be inactivated by passage through

the poultry gut, and only a slim possibility that composting would reduce infectivity at

all. Thus poultry feces are another potential route of transmission back to cattle.

Evidence for this comes from rodent experiments where infectivity was demonstrated in

the feces after being fed: “Laboratory experiments show that mice orally challenged with

scrapie have detectable infectivity that passes through the gut. Gut contents and fecal

matter may therefore contain infectivity, and it is noted that in experimental oral

challenges in cattle conducted in the UK, feces must be treated asamedical waste for one

month following the challenge. It is concluded that digestive contents and fecal material

from livestock or poultry currently being fed with MBM potentially contaminated with

BSE should not be used a.s a feed ingredient for animal feed.” [Proceedings: Joint

WHO/FAO/OIE/ Technical Consultation on BSE: public health, animal health and

trade. Paris, lo-14 June 2001; and Alan Dickinson, personal communication].

It may be possible to remove the risk from poultry litter by sterilization. However, unless

or until a method can be developed and validated, poultry litter should be banned from

ruminant feed.

Ruminant Blood

In contrast with humans, sheep, monkeys, mice and hamsters, including sheep and mice

infected with BSE and humans infected with vCJD considered identical to BSE, no

infectivity has so far been demonstrated in the blood of BSE infected cattle. However,

we consider it unlikely that cattle are the sole outlier to what has been a consistent finding

in all other TSE diseases where the measurement has been made with sufficient

sensitivity to detect the low levels of infectivity that are present in blood. Rather, this

failure is more likely the result of the very small volumes of blood that were used for the

inoculations (less than 1 ml), whereas whole transfusions were administered to assay

animals in the published .sheep scrapie/BSE experiments. If blood is infected then all

vascularized tissues can bc expected to contain some infectivity in proportion to the

content of residual blood..

Micro emboli are a possible source of blood-borne agent that could be at much higher

titer than blood itself, in slaughtered cattle carrying BSE infection. Stunning can release

micro emboli of brain tissue into the circulatory system from where they can be

distributed to other tissues in the few moments before the exsanguination and

death. (Anil, et al, 2001a & b; Anil et al, 2002; Love, et al, 2000). This source of

infection couid extend a higher infectivity risk to tissues that would otherwise be at low

risk, thereby allowing exposure of cattle through any of the legal exemptions and

potentially producing a feed and food risk. Blood-borne contamination may be a special

problem where spray-dried blood is being used as a milk replacer for calves, as it is

thought that young animals are especially susceptible to infection.

Certainly, blood and bloald proteins should not be used as feed without conclusive

evidence that they are saf’e.

Unfiltered Tallow

Ruminant tallow is exempted from the current feed ban. Tallow contains protein

impurities (i.e. MBM) that could be a source of TSE infectivity. There are no impurity

level requirements for this tallow. It has been reported that it is standard practice to

produce tallow which has an impurity level of _ 15% or below, but it is not clear that this

is fully adequate to remove the risk of transmission and there is no requirement to meet

even this standard. We urge that protein contaminants be excluded from tallow and that

SRMs also be removed.

6-d

Plate Waste

Plate waste is not limiteld to meat (muscle tissue). For example, cuts that include a

portion of the spinal cor’d or that are contaminated by cord or ganglia during preparation

could contain high levels of infectivity if derived from a TSE infected animal late in the

preclinical stage of infection. At best this material would only be exposed to normal

cooking temperatures. USDA, APHIS experience with the Swine Health Protection Act

has revealed that plate waste also includes uncooked trimmings and bones. Although the

current FDA regulation requires the plate waste be treated again, there are no

specifications which would render a TSE agent inactive. Of greatest risk would be any

bovine source of infectivity but also sheep scrapie, although not known to be a risk for

human consumption, is one of the possible origins of BSE. The sheep scrapie agent is

known to be widely dispersed including relatively high titers in lymphoid as well as

nervous tissue. We support the USDA’s opposition to the exemption of “plate waste” as

stated in written comments since 1997.

Exposure: Cross Feeding and Cross Contamination

The UK epidemiology has clearly shown that BSE contaminated feed is the primary if

not sole vehicle for the transmission of BSE between cattle. Moreover, results from the

United Kingdom’s attack: rate study indicate that it does not take much exposure to

transmit BSE to cattle. FLecent results from the attack rate study which is still in progress

have found that _ 1 g of brain transmitted BSE by the oral route to 3 cows out of 15 thus

far, and .Ol and .OOl gr of brain have transmitted BSE (1 cow out of 15). (Danny

Matthews, DEFRA presentation at TAFS meeting, Washington, DC April 2004).

Rendering may reduce infectivity but it does not eliminate it. (Taylor et al, 1995; Taylor

et al, 1997; Schreuder et al, 1998). Given that BSE can be transmitted to cattle via an

oral route with just .OO 1 gram of infected tissue, it may not take much infectivity to

contaminate feed and kee:p the disease recycling. This is especially true in countries like

the US and Canada which do not have dedicated lines and equipment to manufacture and

process feed for ruminants and non-ruminants.

In addition, epidemiological investigations in European countries have shown that cross

feeding and cross contamination on farm can be a significant vehicle for continued BSE

transmission even after feed bans are well established. Cross feeding is the practice of

feeding meal for poultry or pigs or pet food (which can legally contain ruminant MBM)

to cattle on the same farm. This is usually due to simple human error or negligence.

(Hoinville, 1994; Hoinville et al, 1995; Doherr et al, 2002% Stevenson et al, 2000)

FDA, CVM reports that compliance with the existing feed ban is high. For the most part

this does not include the compliance level on the farm. There are hundreds of thousands

of farms in the US. Many of these have multiple species- That is, they raise cattle, pigs,

chickens etc., on the same premises. The sheer numbers of farms make it very difficult to

assure compliance on farm and to adequately cover all farms by inspection- Even if the

rendering industry and feed industry can maintain 100% compliance at their facilities, if a

producer inadvertently feeds chicken feed containing bovine MBM to their cattle, they

negate a perfect compliance rate higher in the chain. Recent data from the Harvard BSE

risk assessment suggest that the level of misfeeding on farms plays a significant role in

the ability of the agent to recycle. In fact George Gray, principal investigator for the

study, stated that if, in the United States, misfeeding were to occur at a level of 15%, the

RO would be over 1, indicating that the BSE level would not be declining. (George Gray

presentation at the Meeting on BSE Prevention in North America: An Analysis of the

Science and Risk; January 27,2005, Washington, DC.)

The May 2003 Canadian BSE case illustrates the difficulty of on farm enforcement and

its serious ramifications. The BSE positive cow was rendered and the MBM distributed

to various locations. Two of these locations were poultry farms which mixed their own

feed. The farms also had cattle. The subsequent investigation could not eliminate the

possibility that the cattle had been fed the same feed as the poultry. The cattle on these

farms were completely depopulated.

Human error is extremel:y difftcult to prevent, and managing the risk through

enforcement is problematical when confronted with the extreme logistical challenges of

on farm monitoring. By eliminating the highest risk materials (SRMs and deadstock)

which could introduce infectivity into the feed stream, the MBM resulting from

processing becomes inherently safer. If mistakes are then made on farm, they no longer

contribute to the recycling of BSE.

Exposure: Susceptibility of other Species

Felines

A transmissible spongifoim encephalopathy has been diagnosed in eight species of

captive wild ruminants as well as exotic felines (cheetahs, pumas, a tiger and an ocelot)

and domestic cats (Wyatt 1991). There have been over 80 domestic cat cases of Feline

Spongiform Encephalopathy (FSE) in Great Britain, and cats in Norway, Northern

Ireland, Lichtenstein and Switzerland. The agent isolated from several of these cases is

indistinguishable from BSE in cattle using strain typing in mice, duggesting that FSE is

actually BSE in exotic and domestic cats. Epidemiological evidence suggests BSE

contaminated feed to be the probable source of infection in these species. (MAFF

Progress Report, June 1997), thus providing additional supporting evidence for the

dangers of BSE contaminated feed and reinforcing the necessity of removing all sources

of potential contamination from the feed stream

Other species

Studies conducted at the National lnstitutes of Health Rocky Mountain Laboratory

caution against assuming that animals which do not become clinically ill are not infected.

It is unknown if certain animals may become carriers, i.e., become infected, shed agent

but do not progress to clinical disease. Infection of certain rodent species with different

TSE strains suggests the possibility of a carrier state (Race and Chesebro, 1998; Race et.

al, 2001, Race et al., 2002). In the more recent studies, mice were inoculated with 263K

hamster scrapie. There was a prolonged period (approximately one year) where there was

no evidence of replication of infectivity. Furthermore, there was no evidence of PrPres

during this phase of inactive persistence, which was followed by a period of active

replication of infectivity and agent adaptation. In most cases, PrPres was not detected in

the active phase as well. It is important to determine if this persistence and adaptation

occurs in other species exposed to TSEs as it may have significance in feeding programs

which continually expose other species to BSE infectivity. For example, if BSE infected

brain and spinal cord are continually fed to certain species, it may be possible for the

agent to persist and adapt in these new species. Over time, the ‘resistant’ species may

become a source of agenl. The results of Race and colleagues, warns that an inactive

persistent phase might not produce detectable PrPres, yet there would be infectivity (Race

et. al., 2001).

Pigs displayed evidence of TSE infection after exposure to BSE by 3 distinct parer&ml

routes. Evidence of infectivity was found in the CNS, stomach, intestine and pancreas

(Dawson et. al., 1990). CIral transmission has also been attempted in swine, but after an

observation period of 84 months there was neither clinical nor pathological evidence of

infection (Dawson et. al., 1990). Parenteral and oral transmission has also been

attempted in chickens with no evidence of disease. Tissues from the BSE-challenged

pigs and chickens were inoculated into susceptible mice to look for residual infectivity,

but to date none has been found. In both instances the detection sensitivity was limited

by the use of mice for bioassay instead of same species transmissions into cattle (or pigs

and chickens).

If any of these scenarios played out and inapparent infections became established in

commercial species, those species could become reservoirs for reinfection of cattle and

perpetuation or reintroduction of the epidemic. We also do not know if atypical cases of

BSE are more pathogenic for other species and if chronic inflammation may influence the

susceptibility of other species. We offer these possibilities to reitiorce the need to

eliminate all possible sources of infectivity from the feed stream.

In January 2005, the European Union announced that BSE had been confirmed in a goat

in France illustrating that the disease can be naturally transmitted to one of the small

ruminants. The potential ramifications of this and the logistical chaIlenges associated

with controlling BSE in sheep or goats also provides a justification for removing SRMs

from all animal feed. Although these species are covered under the current regulations

the cross contamination and cross feeding aspects stated for cattle are applicable.

The need to remove high risk material from all animal feed is also supported by other

bodies with expertise in the field of TSEs:

Recommendations of the World Health Organization (WHO)

The World Health Organization (WHO) has issued the following recommendations for

countries with BSE or those where a known exposure exists:

l No part or product of any animal which has shown signs of a TSE should enter any

food chain (human or animal). In particular:

o All countries must ensure the killing and safe disposal of all parts or products

of such animals so that TSE infectivity cannot enter any food chain.

o Countries sholuld not permit tissues that are likely to contain the BSE agent to

enter any food chain (human or animal).

From the report of a WHO Consultation on Public Health Issues related to Human and

Animal Transmissible Spongiform Encephalopathies WHO/EMC/DIS 96.147, Geneva,

2-3 April 1996.

Office of International El-

The OIE is recommendinlg that a list of SRMs which include brain, spinal cord, eyes,

skull and vertebral column be removed from preparations used for food, feed, fertilizer,

etc. If these tissues sholtld not be traded we feel that they should not be used in domestic

products either.

BSE Code Article 2.3.13.18

“From cattle, originating from a country or zone with a minimal BSE risk, that were at the time of

slaughter over 30 months of age, the following commodities, and any commodity contaminated by them,

should not be traded for the preparation of Food, feed, fertilizers, cosmetics, pharmaceuticals including

biologicals, or medical device:s: brains, eyes and spinal cord, skull, vertebral column and derived protein

products. Food, feed, fertilizers, cosmetics, pharmaceuticals or medical devices prepared using these

commodities should also not be traded.”

Conclusion

In conclusion we urge the: FDA to implement, monitor and enforce a comprehensive and

protective feed ban that is more congruent with the measures that have been proven to be

effective in other countries that have experienced BSE. We do not feel that we can

overstate the dangers from the insidious threat from these diseases and the need to control

and arrest them to prevent any possibility of spread.

We also wish to emphasize that as scientists who have dedicated substantive portions of

our careers to defining the risks from TSEs as well as developing strategies for managing

those risks, we are confident that technical solutions will be found for many of the

challenges posed by these diseases. Thus, we urge the FDA to frame its regulations in

terms that allow for the future use of any banned material if it can be proven safe for a

given application.

El-d

Signatories:

Paul W. Brown, M.D.

Medical Director, USPH[S, and Senior Investigator, NIH (retired)

Consultant, TSE Risk Management

78 15 Exeter Rd.

Bethesda, MD 208 14

Fax 301-652-43 12

Email: paLII\\ hr-c~~~rl~~/‘~c)m~as~.rlct -----

Neil R Cashman MD

Professor, Department 0-C Medicine (Neurology)

Diener Chair of Neurode:generaGve Diseases

Centre for Research in Neurodegenerative Diseases

6 Queen’s Park Crescent West

Toronto Ontario M5S3H2

Ph: 416-978-1875

Fax: 4 16-978- 1878

e-mail: neil.cashman@utoronto.ca

Linda A. Detwiler, DVM

Consultant, TSE Risk Management

225 Hwy 35

Red Bank, NJ 07701

Ph 732-74 l-2290

Fax 732-741-775 1

Email: l.~\Vc~92’rr’ac,l.c0111.

Laura Manuelidis, MD

Professor and Head of Neuropathology,

Department of Surgery and Faculty of Neurosciences

Yale Medical School

333 Cedar St.

New Haven, CT 065 10

email: I~IL~ra.~~~ar~clclirli~~~~~~alc.cdi~

Tel: 203-785-4442

Jason C. Bar-k, Ph.D.

Assistant Professor

Department of Medical Microbiology and Immunology

Creighton University

2500 California Plaza

Omaha, NE 68178

(402) 280- 18 11 voice

(402) 280-l 875 fax

jbartz@creighton .edu

Robert B. Petersen, Ph.D.

Associate Professor of Pathology and Neuroscience

Case Western Reserve University

5- 123 Wolstein 13~1ilding

2 103 Cornell Road

Cleveland, OH 44 106-26122

Phone 216-368-6709

FAX 360-838-9226

Email rhp~,-c\\~~.c~!t~

Robert G. Rohwer, Ph.D.

Director, Molecular Neurovirology Laboratory

Veterans Affairs Medicall Center

Medical Research Service 151

Assoc. Professor of Neurology

School of Medicine

University of Maryland ;at Baltimore

10 N. Greene St.

Baltimore, MD 21201

ph. 4 1 O-605-7000 x6462

Fax 4 1 o-605-7959

email: rrohwer@maryland.edu

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Shand,A.; Baki.rel,T.; Harbour,D.A. - Jugular venous emboli of brain tissue induced in

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Bartz JC, Kincaid AE, IBessen RA. Retrograde transport of transmissible mink

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Bosque PJ, Ryou C, Telling G, Peretz D, Legname G, DeArmond SJ, Prusiner SB.

Prions in skeletal muscle. Proc Nat1 Acad Sci U S A. 2002 Mar 19;99(6):3812-7.

Bushmann, A., and Groschup, M.; Highly Bovine Spongiform Encephalopathy-Sensitive

Transgenic Mice Confilm the Essential Restriction of Infectivity to the Nervous System

in Clinically Diseased Cattle. The Journal of Infectious Diseases, 192: 934-42, September

1,2005.

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bovine spongiform encephalopathy to the pig - Veterinary Record 1990 Sep 29; 127( 13):

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of cases of bovine spongiform encephalopathy (BSE) born in Switzerland after the feed

ban - Veterinary Record 2002 Ott 19; 15 1(16): 467-72

Glatzel M, Abela E, Ma.issen M, Aguzzi A. Extraneural pathologic prion protein in

sporadic Creutzfeldt-Jakob disease. N Engl J Med. 2003 Nov 6;349(19): 1812-20.

Hadlow W. J., Kennedy R. C. & Race R. E. (1982) Natural infection of Suffolk sheep

with Scrapie virus. J. hfect. Dis., 146, 657-664

Hoinville,L.J. - Decline in the incidence of BSE in cattle born after the introduction of the

‘feed ban’ - Veterinary IRecord 1994 Mar 12; 134( 11): 274-5

Hoinville,L.J.; Wi1esmithJ.W.; Richards,M.S. - An investigation of risk factors for cases

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Veterinary Record 199.5 Apr 1; 136( 13): 3 12-8

Houston,E.F.; Foster,J.D.; Chong,A.; Hunter,N.; Bostock,C.J. - Transmission of BSE by

blood transfusion in sheep - Lancet 2000 Sep 16; 356(9234); 999-l 000

Hunter,N.; Foster,J; Chong,A.; McCutcheon,S.; Parnham,D.; Eaton,S.; MacKenzie,C.;

Houston,E.F. - Transmission of prion diseases by blood transfusion - Journal of General

Virology 2002 ‘Nov, 83(Pt 11); 2897-905.

Love,S.; Helps,C.R.; Williams,S.; Shand,A.; McKinstry,J.L.; Brown,S,N.; Harbour,D.A.;

Ani1,M.H. - Methods for detection of haematogenous dissemination of brain tissue after

stunning of cattle with captive bolt guns - Journal of Neuroscience Methods 2000 Jun 30;

99( l-2): 53-8

Mukahy ER, Bar-& JC, Kincaid AE, Bessen RA. Priori infection of skeletal muscle cells

and papillae in the tongue. .J Viral. 2004 Jul;78(13):6792-8.

Race, R.; Chesebro, B. - Scrapie infectivity found in resistant species. Nature -1998 Apr

23;392(6678):770.

Aguzzi,A.; Weissmann,C. - Spongiform encephalopathies. The priori’s perplexing

persistence. - Nature. 1998 Apr 23;392(6678):763-4

Race,R.E.; Raines,A.; Raymond,G.J.; Caughey,B. W.; Chesebro,B. - Long-term

subclinical carrier state precedes scrapie replication and adaptation in a resistant species:

analogies to bovine spongiform encephalopathy and variant Creutzfeldt-Jakob disease in

humans. - Journal of V:irology 2001 Nov; 75(2 1): 10106-l 2

Race,R.E.; Meade-White&; Raines,A.; Raymond,G.J.; Caughey,B.W.; Chesebro,B. -

Subclinical Scrapie Infkction in a Resistant Species: Persistence, Replication, and

Adaptation of Infectivity during Four Passages. - Journal of Infectious Diseases 2002 Dee

1; 186 Suppl2: S166-70

Schreuder, B.E.C., Geertsma, R.E., van Keulen, L.J.M., van Asten, J.A.A.M., Enthoven, P.,

Oberthiir, R.C., de Koeijer, A.A., Osterhaus, A.D.M.E., 1998. Studies on the effkacy of

hyperbaric rendering procedures in inactivating bovine spongiform encephalopathy (BSE) and

scrapie agents. Veterinary Record I42,474-480

Stevenson, M. A., Wilesmith, J. W., Ryan, J. B. M., Morris, R.S., Lockhart, J. W., Lin,

D. & Jackson, R. (2000) Temporal aspects of bovine spongiform encepalopathy in Great

Britain: individual animal-associated risk factors for the disease. Vet. Rec. 147, 349-354.

Stevenson, M. A., Wilesmith, J. W., Ryan, J. B. M., Morris, R. S., Lawson, A.B.,

Pfeiffer, D. U. & Lin, D. (2000) Descriptive spatial analysis of the epidemic of bovine

spongiform encephalopalthy in Great Britain to June 1997. Vet. Rec. 147,379-384.

Taylor, D.M., Woodgate, !S.L., Atkinson, M.J., 1995. Inactivation of the bovine spongiform

encephalopathy agent by rendering procedures. Veterinary Record, Vol.1 37: pp.605-610.

Taylor, D.M., Woodgate, S-L., Fleetwood, A.J., Cawthome, R.J.G., 1997. The effect of rendering

procedures on scrapie agent. Veterinary Record, Vol. 141, pp 643-649.

Thornzig A, Schulz-Schaeffer W, KratzeI C, Mai J, Beekes M. Preclinical deposition of

pathological prion protein PrPSc in muscles of hamsters orally exposed to scrapie.

J Clin Invest. 2004 May; 113( 10): 1465-72.

Thomzig A, Kratzel C, Lenz G, Kruger D, Beekes M. Widespread PrPSc accumulation

in muscles of hamsters orally infected with scrapie. EMBO Rep. 2003 IUay;4(5):530-3.

Wilesmitb, J.W., Ryan, J. B. M., Hueston, W. D., & Hoinville, L. J. (1992) Bovine

spongifozm encephalopathy: epidemiological features 1985 to 1990. Vet. Rec., 130,90-

94.

Wilesmith, J. W., Wells, G. A. H., Ryan, J. B. M., Gavier-Widen, D., & Simmons, M. M.

(1997) A cohort study to examine maternally associated risk factors for bovine

spongiform encephalopathy. vet. Rec., 141,239-243.

Wells G.A.H., Dawson h/Z., Hawkins, S-A-C., Green R. B., Dexter I., Francis M. E.,

Simmons M. M., Austin A. R., & Horigan M. W. (1994) Infectivity in the ileum of

cattle challenged orally with bovine spongiform encephalopathy. Vet. Rec., 135,40-41.

Wells G.A.H., Hawkins, S.A.C., Green R. B., Austin A. R., Dexter I., Spencer, Y. I-,

Chaplin, M. J., Stack, M. J., & Dawson, M. (1998) Preliminary observations on tbe

pathogenesis of experimental bovine spongiform encephalopathy (BSE): an update. Vet.

Rec., 142, 103-106.

Wyatt. J. M. et al. 1991. INaturally occurring scrap&like spongiform encephalopathy in

five domestic cats. Veterinary Record. 129. 233.

http://www.fda.gov/ohrms/dockets/dockets/02n0273/02n-0273-c000490-vol40.pdf

FDA Docket No. 2002N-0273: CONSUMER UNION COMMENTS

(would not copy good...tss)

http://www.fda.gov/ohrms/dockets/dockets/02n0273/02n-0273-c000486-01-vol...

TSS

Offline
Location: Colorado
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Posts: 166
McDonald's AND Seriologicals USA NOT PROTECTED FROM MAD COW

You don't actually expect anyone to read all of that, do you?

rambo's picture
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Location: Winnipeg,MB
Joined: 10/16/2005
Posts: 102
McDonald's AND Seriologicals USA NOT PROTECTED FROM MAD COW

honestly, i started reading that then i said "i dont have time to read all this s*#@ and now im posting this.

cowgal's picture
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Posts: 1787
McDonald's AND Seriologicals USA NOT PROTECTED FROM MAD COW

Yeah, I'm sure this is important and serious stuff, but I'm not going to plow through this either...

Flounder, you need to post a shortened (much shorter!) and edited version of the above and in language that the the average person can read and understand. Maybe a scientist would find all the details interesting, but most folks simply want to know how it affects their every day lives.

I suggest you edit your post, in fact all your posts on this forum need to be edited. People simply will not read it in the manner that they are posted.

Offline
Joined: 01/01/2006
Posts: 230
McDonald's AND Seriologicals USA NOT PROTECTED FROM MAD COW

i can stop posting all together here.
i was ask this question.
i have wasted too much time here anyway..............

tss

rambo's picture
Offline
Location: Winnipeg,MB
Joined: 10/16/2005
Posts: 102
McDonald's AND Seriologicals USA NOT PROTECTED FROM MAD COW

No one said stop posting, we just said make it so people can understand it, and not like 25 pages long.

expatriate's picture
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Location: Arizona
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Posts: 3207
McDonald's AND Seriologicals USA NOT PROTECTED FROM MAD COW

I agree with rambo. Rather than post huge amounts of raw material, how about taking a position and expressing an opinion, and perhaps including a link to the raw data? You haven't stated where you stand on the issue, why you think it's important, or what point you're trying to make. Rather than throwing all that data out there hoping that people will read it and figure out what you're saying, why don't you just make your point and back it with the data? Throw us a bone and let us know what you think.

Offline
Joined: 01/01/2006
Posts: 230
McDonald's AND Seriologicals USA NOT PROTECTED FROM MAD COW

i posted this on jan 13 and it took until jan 25 to get upset about it.
that's a record. the submission from McDonalds was not available online,
this was a POLITICAL board, where you post political things i thought (McDonalds going against
The Presidents BSE MRR policy and SRM policy), so i posted it.

and since everyone is so worried about all the space i am taking up, i will make this as short as possible, and moove on.

> how about taking a position and expressing an opinion,

my opinion is meaningless, and my position is firm. i am trying to show you 'sound science' not bull sh!t rubber stamped from the USDA or your local state animal health department. i am not here to debate. like i said, i have wasted 8 years. the science is there. i chose this site to dump the data on because huntingpa.com/ banned me for posting about cwd after several years of posting there. i wanted PA to have the data, i went to another site, and i will move on from here. i have posted nothing offensive or broke any rules that i am aware of. just gave you 'sound science' on cwd. you dont want it, thats fine. again, i can state these facts all day long, they are meaningless coming from me, so i give the facts to you from the scientist themselves. you take them with how ever many grains of salt you wish. i have been on a thin thin thread this past two weeks because of the BSE in Japan, the SRMs sent to Japan, the Canadian BSE case, and trying to educate folks that don't want to be educated. i am about to short circut, well did the other day. but that is neither here nor there.

> You haven't stated where you stand on the issue, why you think it's important, or what point you're trying to make ;

http://ranchers.net/forum/viewtopic.php?t=7165

> why i do it ;

i have not figured that out myself. maybe someone can tell me.

someone else ask me that recently ;

skroll down to next posting after this to moms autopsy ;

r-kaiser wrote ;

Just think about what a waste of time your life will have been flounder, when the feed transmission thing turns out to be nothing but fear monguering and government employment.

All of that time reading and writing and proving and showing ---- for what, 5 or six cows in all of North America with no actual proof of infection, and not one human being other than a few suicides being actually affected.

Geez Terry, could you at least cut your posts down a bit. I am sure that most simply scroll down due to the shear length. I actually try to read most, but time is a factor for most here on ranchers.

+++++++++++++++++++++++++++++++++++++

i agree, it has been a waste of time, but i tried. rest assured, you will see less postings from me in the future. i have wasted 8 years of my life, and a great deal of it recently here. but i will leave you with one last thought, something i never forget, you only have to see it once ;

http://ranchers.net/forum/viewtopic.php?t=7129&start=45

> Throw us a bone and let us know what you think.

i have no bone tonight, sadly only muscle;

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

Subject: Prions in Skeletal Muscles of Deer with Chronic Wasting Disease [SCIENCE FULL TEXT]
Date: January 26, 2006 at 12:23 pm PST

Prions in Skeletal Muscles of Deer with Chronic Wasting Disease

Rachel C. Angers,1* Shawn R. Browning,1*† Tanya S. Seward,2 Christina J. Sigurdson,4‡ Michael W. Miller,5 Edward A. Hoover,4 Glenn C. Telling1,2,3§

1Department of Microbiology, Immunology and Molecular Genetics, 2Sanders Brown Center on Aging, 3Department of Neurology, University of Kentucky, Lexington, KY 40536, USA. 4Department of Microbiology, Immunology and Pathology, Colorado State University, Fort Collins, CO 80523, USA. 5Colorado Division of Wildlife, Wildlife Research Center, Fort Collins, CO 80526, USA.

*These authors contributed equally to this work.

†Present address: Department of Infectology, Scripps Research Institute, 5353 Parkside Drive, RF-2, Jupiter, Florida, 33458, USA.

‡Present address: Institute of Neuropathology, University of Zurich, Schmelzbergstrasse 12, 8091 Zurich, Switzerland.

§To whom correspondence should be addressed: E-mail: gtell2@uky.edu

Prions are transmissible proteinaceous agents of mammals that cause fatal neurodegenerative diseases of the central nervous system (CNS). The presence of infectivity in skeletal muscle of experimentally infected mice raised the possibility that dietary exposure to prions might occur through meat consumption (1). Chronic wasting disease (CWD), an enigmatic and contagious prion disease of North American cervids, is of particular concern. The emergence of CWD in an increasingly wide geographic area and the interspecies transmission of bovine spongiform encephalopathy (BSE) to humans as variant Creutzfeldt Jakob disease (vCJD) have raised concerns about zoonotic transmission of CWD.

To test whether skeletal muscle of diseased cervids contained prion infectivity, Tg(CerPrP)1536 mice (2) expressing cervid prion protein (CerPrP), were inoculated intracerebrally with extracts prepared from the semitendinosus/semimembranosus muscle group of CWD-affected mule deer or from CWD-negative deer. The availability of CNS materials also afforded direct comparisons of prion infectivity in skeletal muscle and brain. All skeletal muscle extracts from CWD-affected deer induced progressive neurological dysfunction in Tg(CerPrP)1536 mice with mean incubation times ranging between 360 and ~490 d, whereas the incubation times of prions from the CNS ranged from ~230 to 280 d (Table 1). For each inoculation group, the diagnosis of prion disease was confirmed by the presence of PrPSc in the brains of multiple infected Tg(CerPrP)1536 mice (see supporting online material for examples). In contrast, skeletal muscle and brain material from CWD-negative deer failed to induce disease in Tg(CerPrP)1536 mice (Table 1) and PrPSc was not detected in the brains of sacrificed asymptomatic mice as late as 523 d after inoculation (supporting online material).

Our results show that skeletal muscle as well as CNS tissue of deer with CWD contains infectious prions. Similar analyses of skeletal muscle BSE-affected cattle did not reveal high levels of prion infectivity (3). It will be important to assess the cellular location of PrPSc in muscle. Notably, while PrPSc has been detected in muscles of scrapie-affected sheep (4), previous studies failed to detect PrPSc by immunohistochemical analysis of skeletal muscle from deer with natural or experimental CWD (5, 6). Since the time of disease onset is inversely proportional to prion dose (7), the longer incubation times of prions from skeletal muscle extracts compared to matched brain samples indicated that prion titers were lower in muscle than in CNS where infectivity titers are known to reach high levels. Although possible effects of CWD strains or strain mixtures on these incubation times cannot be excluded, the variable 360 to ~490 d incubation times suggested a range of prion titers in skeletal muscles of CWD-affected deer. Muscle prion titers at the high end of the range produced the fastest incubation times that were ~30% longer than the incubation times of prions from the CNS of the same animal. Since all mice in each inoculation group developed disease, prion titers in muscle samples producing the longest incubation times were higher than the end point of the bioassay, defined as the infectious dose at which half the inoculated mice develop disease. Studies are in progress to accurately assess prion titers.

While the risk of exposure to CWD infectivity following consumption of prions in muscle is mitigated by relatively inefficient prion transmission via the oral route (8), these

results show that semitendinosus/semimembranosus muscle, which is likely to be consumed by humans, is a significant source of prion infectivity. Humans consuming or handling meat from CWD-infected deer are therefore at risk to prion exposure.

References and Notes

1. P. J. Bosque et al., Proc. Natl. Acad. Sci. U.S.A. 99, 3812 (2002).

2. S. R. Browning et al., J. Virol. 78, 13345 (2004).

3. A. Buschmann, M. H. Groschup, J. Infect. Dis. 192, 934 (2005).

4. O. Andreoletti et al., Nat. Med. 10, 591 (2004).

5. T. R. Spraker et al., Vet. Pathol. 39, 110 (2002).

6. A. N. Hamir, J. M. Miller, R. C. Cutlip, Vet. Pathol. 41, 78 (2004).

7. S. B. Prusiner et al., Biochemistry 21, 4883 (1980).

8. M. Prinz et al., Am. J. Pathol. 162, 1103 (2003).

9. This work was supported by grants from the U.S. Public Health Service 2RO1 NS040334-04 from the National Institute of Neurological Disorders and Stroke and N01-AI-25491 from the National Institute of Allergy and Infectious Diseases.

Supporting Online Material

http://www.sciencemag.org/

Materials and Methods

Fig. S1

21 November 2005; accepted 13 January 2006 Published online 26 January 2006; 10.1126/science.1122864 Include this information when citing this paper.

Table 1. Incubation times following inoculation of Tg(CerPrP)1536 mice with prions from skeletal muscle and brain samples of CWD-affected deer.

Inocula Incubation time, mean d ± SEM (n/n0)*

Skeletal muscle Brain

CWD-affected deer

H92 360 ± 2 d (6/6) 283 ± 7 d (6/6)

33968 367 ± 9 d (8/8) 278 ± 11 d (6/6)

5941 427 ± 18 d (7/7)

D10 483 ± 8 d (8/8) 231 ± 17 d (7/7)

D08 492 ± 4 d (7/7)

Averages 426 d 264 d

Non-diseased deer

FPS 6.98 >523 d (0/6)

FPS 9.98 >454 d (0/7) >454 d (0/6)

None >490 d (0/6)

PBS >589 d (0/5)

*The number of mice developing prion disease divided by the original number of inoculated mice is shown in parentheses. Mice dying of intercurrent illnesses were excluded.

http://www.sciencemag.org/

http://www.sciencemag.org/

Supporting Online Material for

Prions in Skeletal Muscles of Deer with Chronic Wasting Disease

Rachel C. Angers, Shawn R. Browning, Tanya S. Seward, Christina J. Sigurdson,

Michael W. Miller, Edward A. Hoover, Glenn C. Telling§

§To whom correspondence should be addressed: E-mail: gtell2@uky.edu

Published 26 January 2006 on Science Express

DOI: 10.1126/science.1122864

This PDF file includes:

Materials and Methods

Fig. S1

Supporting Online Materials

Materials and Methods

Homogenates of semitendinosus/semimembranosus muscle (10% w/v in phosphate

buffered saline) were prepared from five emaciated and somnolent mule deer, naturally

infected with CWD at the Colorado Division of Wildlife, Wildlife Research Center.

These deer were identified as D10, D08, 33968, H92, and 5941. CWD infection was

confirmed in all cases by the presence of histologic lesions in the brain including

spongiform degeneration of the perikaryon, the immunohistochemical detection of

disease-associated PrP in brain and tonsil, or by immunoblotting of protease-resistant,

disease associated PrP (CerPrPSc). Semitendinosus/semimembranosus muscle was also

obtained from two asymptomatic, mock inoculated deer, referred to as FPS 6.68 and 9.98,

that originated from a CWD non-endemic area and which were held indoors at Colorado

State University from ten days of age. These control deer were confirmed negative for

CWD by histopathological and immunohistochemical analysis of brain tissue at autopsy.

The utmost care was taken to avoid inclusion of obvious nervous tissue when muscle

biopsies were prepared and to ensure that contamination of skeletal muscle samples with

CNS tissue did not occur. Fresh, single-use instruments were used to collect each sample

biopsy and a central piece from each sample was prepared with fresh, disposable

instruments to further isolate muscle tissue for inoculum preparation. Brain samples for

transmission were prepared separately from muscle as additional insurance against cross

contamination.

1

Groups of anesthetized Tg(CerPrP)1536 mice were inoculated intracerebrally with 30 µl

of 1 % skeletal muscle or brain extracts prepared in phosphate buffered saline (PBS).

Inoculated Tg(CerPrP) mice were diagnosed with prion disease following the progressive

development of at least three neurologic symptoms including truncal ataxia, ‘plastic’ tail,

loss of extensor reflex, difficultly righting, and slowed movement. The time from

inoculation to the onset of clinical signs is referred to as the incubation time.

For PrP analysis in brain extracts of Tg(CerPrP)1536 mice, 10 % homogenates prepared

in PBS were either untreated (-) or treated (+) with 40 µg/ml proteinase K (PK) for one

hour at 37oC in the presence of 2% sarkosyl. Proteins were separated by sodium dodecyl

sulfate polyacrylamide gel electrophoresis, analyzed by immunoblotting using anti PrP

monoclonal antibody 6H4 (Prionics AG, Switzerland), incubated with appropriate

secondary antibody, developed using ECL-plus detection (Amersham), and analyzed

using a FLA-5000 scanner (Fuji).

2

Fig. S1

PrP in brain extracts from representative Tg(CerPrP)1536 mice receiving muscle or CNS

tissue inocula from CWD-affected or CWD-negative deer. Extracts were either treated

(+) or untreated (-) with proteinase K (PK) as indicated. The positions of protein

molecular weight markers at 21.3, 28.7, 33.5 kDa (from bottom to top) are shown to the

left of the immunoblot.

3

http://www.sciencemag.org/

hope that was short enough. sorry to have intruded on this board. ...

TSS

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Location: Colorado
Joined: 11/09/2005
Posts: 166
McDonald's AND Seriologicals USA NOT PROTECTED FROM MAD COW
flounder wrote:
my opinion is meaningless...

As long as you continue to refuse to express it, this will certainly remain true.

Any of us who wants to can take the time to look up all the long, tedious, background information on any subject we'd like. Simply reposting what we can find elsewhere does none of us any good. The benefit of a forum like this is the ability to exchange opinions with others.

Your time would be better spent summarizing your concerns and opinions for us, and then posting a link to the background data for those who want it. This is not intended as criticism of you, so don't take it personal. This is just some advice on how to more effectively communicate with the rest of us on this forum (or any similar forum, really).

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