August 13, 2004

Division of Dockets Management (HFA-305)

Food and Drug Administration

5630 Fishers Lane

# Room 1061

Rockville, MD 20852

Re: Docket No: 2004N-0081

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 Advance Notice of
Proposed Rulemaking (ANPRM). 69 Fed. Reg. 42288 (July 14, 2004).

We hope that the discovery of these indigenous cases will at last
provide the necessary impetus 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 the United Kingdom.
The currently implemented ban in the UK evolved in response to repeated
disappointments in predicted downturns in the epidemic course. The feed
ban was implemented in 1988 followed by a specified bovine offals (SBO)
ban two years later. The epidemic peaked two years after that but
lingered much longer than anticipated. To bring it fully under control
required increasingly inclusive bans and much more stringent
enforcement. Inspired and justified by the appearance of the first human
cases and the looming threat of a vCJD epidemic, beginning in 1996 there
was an extension of the SBO ban to "specified risk materials", SRMs;
implementation of the OTM scheme in which cattle over thirty months of
age are placed in a higher risk category; and gradual extensions of the
feed ban to all mammals and then all vertebrates and finally all feed
uses. The change in enforcement in 1996 is readily evident in the
epidemic record giving rise to the term BARBs, "Born After the Real Ban"
in UK scientific circles. 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 British
experience and take decisive measures now to arrest any further
development of the underlying epidemic that is implicit in the two BSE
cases discovered to date.

Hopefully, the cases that have currently come to light in North America
represent the peak of whatever epidemic was incubating at the time that
our own feed bans were implemented in 1998. If the bans (US and Canada)
were effective, and the epidemic progressed similarly to that in the UK,
we would expect a peak in 2004. However, if the bans have not been
effective, either due to its exclusions, limited scope, or inadequate
enforcement, the epidemic could still be growing.

There is no way to distinguish these two possibilities from the
currently available data. The only way to obtain this data is through a
much more comprehensive testing program than that proposed by the USDA,
one designed specifically to establish the current prevalence of
infected animals. (We recognize that a comprehensive program of this
sort would also have ancillary benefits as a screening test for food.)
Since we hope that the prevalence rates are low and stay low, we do not
see how this can be accomplished credibly without universal testing.
Without sound data on the actual prevalence of the infection it will not
be possible to track the effectiveness of any control measures that are
implemented. If the control measures are not effective it will
eventually become apparent in the appearance of increasing numbers of
new cases. However, the UK epidemic has taught us that by the time a BSE
epidemic becomes readily apparent there are already a large cohort of
infected individuals, large numbers of humans have already been put at
risk, and it becomes increasingly difficult to control.

To guarantee our safety, it is essential that the North American bans
provide absolute controls for specified risk materials (SRMs) by
eliminating existing exemptions; by eliminating dead ruminant livestock
as a source of animal feed; and by providing for greater control over
cross contamination of ruminant feed by ruminant protein.

With SRM exemptions providing a source of infectivity to the animal feed
system, the current US feed ban, still allows the possibility for cattle
to be exposed to BSE through:

1.  Feeding of ruminant protein back to ruminants per legal exemptions
    (*e.g*., poultry litter, plate waste)

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

3.  Cross contamination of ruminant and non-ruminant feed

In addition, there are other species which are susceptible to BSE and
the regulations allow for SRMs to still be included in feed for these
animals.

Hence we believe that FDA must assure that all possible sources of
contaminated materials are fully removed from all animal feeds and that
legal exemptions which allow ruminant protein to be fed back to
ruminants (with the exception of milk) should be discontinued.[^1]

**SRMs**

Because infectivity studies are logistically challenging and expensive
not every tissue on the SRM list has been bioassayed. The SRMs included
in the USDA regulation, are tissues known to contain infectivity or to
be closely associated with tissues known to contain infectivity. For
example, the skull and vertebral column which encase the brain and
spinal cord, respectively, can be assumed to have gross contamination.
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 serious limitations.

In two of the studies bioassays were done in mice which are at least
1000 fold less sensitive to BSE than cattle themselves. Only the high
titers of infectivity can be detected by this method. These
investigations found infectivity in the brain and central nervous system
as expected but also in the distal ileum of experimentally infected
calves beginning only six months after challenge and continuing
throughout life. (Wells et. al., 1994; 1998). Positive immunostaining
for PrP^res^ was identified along the length of the intestine providing
evidence that the entire intestine should be considered as SRM
consistent with EU regulations (personal communication Danny Matthews,
UK, VLA). We also note that the International Advisory Committee
appointed by Secretary Veneman also recommended that the SRM ban in the
US be amended to include the entire intestine from duodenum to rectum.
Studies bioassayed in calves where sensitivity of the assay should be
high has produced similar results and in addition found infectivity in
tonsil and bone marrow and the lymphoid tissue of third eyelid (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 (four to six years for high titer inoculum,
and \>10 to 12 years for low titer inoculations) 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. For example, while muscle produced no infections, only
0.5g of muscle was bioassayed from a total of 1500 kg (Gerald Wells, UK
DEFRA personal communication). In contrast, three recent reports have
found either TSE infectivity or PrP amyloid in the muscles of sheep and
rodents. In contrast with humans, sheep, monkeys, mice and hamsters, no
infectivity was found in the blood of BSE infected cattle. We consider
it very 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 a measure of the lack of sensitivity of the experimental methods
of measurement. If blood is infected then all vascularized tissues can
be expected to contain some infectivity in proportion to the content of
residual blood. Certainly, blood and blood proteins should not be used
as feed without conclusive evidence that they are safe.

## Specific Exemptions to the feed ban that should be eliminated

[Poultry Litter]{.underline}

There are two 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. Poultry traditionally
consumed a large proportion of the MBM produced in the US. Given that
ruminant protein can no longer be fed to ruminants in the US and that
most if not all countries will no longer import our ruminant MBM, an
even larger part of poultry diets is now ruminant MBM. Spillage provides
a direct link to back to cattle.

There is also no reason to expect that TSE infectivity would be
inactivated by passage through the poultry gut, and only a dim
possibility that it would be inactivated by composting. Thus the 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
(Dickinson et al) 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.**

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.

[Plate Waste]{.underline}

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
bovine sources of infectivity but 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.

[Ruminant Blood]{.underline}

As discussed above, we consider likely that the blood of BSE infected
cattle contains low levels of infectivity similar to those found in
humans, monkeys, sheep, mice and hamsters including sheep and mice
infected with BSE. However, there is another, perhaps even more
dangerous source of blood-borne infectivity in slaughtered cattle
carrying the infection. This is because stunning releases micro emboli
of brain tissue into the circulatory system where they become widely
distributed in the few moments before the exsanguination and
death. (Anil et al, 1999; Anil, et al, 2001a & b; Anil et al, 2002;
Love, et al, 2000; Mackey and Derrick, 1979) The risks from this source
of infection extend really to all tissues in the body including those
that end up as food and plate waste and as a consequence this issue has
profound implications for public health as well as bovine health. It
also impacts the significance and rational for SRM and clearly needs to
be understood far better than it is at present to be fully accounted for
in a science based policy. This may be a special problem where sprayed
dried blood is being used as a milk replacer for calves.  The infection
might never be seen in veal calves where this practice is most common,
but could nevertheless amplify the spread the disease through other loop
holes in the ban like plate waste. It is thought that young animals are
especially susceptible to infection.

[Unfiltered Tallow]{.underline}

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 FDA 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.  However, it is not clear that this
is adequate to remove the risk of transmission and there is no
requirement to meet even this standard.

**Risk from Deadstock**

The levels of total infectivity in a TSE infected animal increase as the
animal approaches and progresses to clinical disease and infected
individuals only exhibit recognizable clinical symptoms 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. An animal which dies of BSE would be at the peak of
infectivity, that is they would carry the greatest amount of agent at
this point in the disease.

In the 2001 Harvard risk assessment model it was shown that eliminating
dead and downer, 4D cattle, from the feed stream was a
disproportionately effective means of reducing the risk of reinfection.
We endorse this approach and strongly recommend provisions to eliminate
this source of exposure from ruminant feed. (Harvard Risk Assessment,
2001 Executive Summary)

**Exposure: Cross Feeding and Cross Contmaination**

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 has found
that .1 gr of brain transmitted BSE to 3 cows out of 15 thus far, and
.01 and .001gr of brain has 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 does not take much infectivity to contaminate feed
and keep the disease recycling. This is especially true in the US and
other countries 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 inadvertent practice of
feeding meal for poultry or pigs (which has a likelihood of being
ruminant MBM) to cattle on the same farm. This is usually due to simple
human error. (Hoinville, 1994; Hoinville et al, 1995; Doherr et al,
2002a; Stevenson et al, 2000)

FDA, CVM reports that compliance with the feed ban is over 90%. 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 have cattle, pigs, chickens etc. The
sheer numbers of farms make it very difficult to assure compliance on
farm and to adequately cover all farms by inspection. The rendering
industry and feed industry can maintain 100% compliance at there
facilities but if a producer inadvertently feeds chicken feed to cattle
the compliance rate higher in the chain is negated.

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

Human error is extremely difficult to prevent especially when
enforcement has extreme logistical challenges. By eliminating all
material (SRMs and deadstock) which may introduce infectivity into the
system before any processing, the resulting MBM becomes inherently
safer. If mistakes are then made on farm, they become much less relevant
in regards 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 (cheetahs, pumas, a
tiger and an ocelot) and domestic cats. 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. This also appears to be true for the
other ruminants. Epidemiological evidence suggests BSE contaminated feed
to be the primary source of infection in these species. (MAFF Progress
Report, June 1997), thus providing additional supporting evidence for
the dangers of BSE contaminated feed 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 develop clinical disease. Infection of certain rodent species with
different TSE strains suggests the possibility of a carrier state
(Collis and Kimberlin 1985; Race and Chesebro, 1998; Race et. al, 2001).
In the most recent study, 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 PrPSc during this phase of inactive persistence. This
study found that this phase was followed by a period of active
replication of infectivity and agent adaptation. In most cases, PrPSc
was not detected in the active phase as well (Race et. al., 2001). 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 certain 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. Considering the results of the study by Race
and colleagues, if there were an inactive persistence phase in certain
species, PrP Sc would not be detectable, yet there would be infectivity
(Race et. al., 2001).

Pigs displayed evidence of a TSE after exposure to BSE by 3 parenteral
routes(Dawson et. al., 1990). In this transmission there was evidence of
infectivity in the CNS, stomach, intestine and pancreas of the pigs.
Oral transmission has been attempted in swine. The inoculated swine were
euthanized after 84 months of age and had not exhibited any signs of a
TSE. 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, to date none has been found. The criticism of this
study is the use of mice instead of cattle as the assay model due to the
decrease of sensitivity.

If any of these scenarios became established in commercial species they
could become reservoirs for reinfection of cattle and perpetuation or
reintroduction of the epidemic. We offer these possibilities to
reinforce the need to eliminate all possible sources of contamination
from the feed stream.

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)]{.underline}

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:

    -   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.

    -   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.

[Recommendations of the Harvard/Tuskegee BSE Risk
Assessment]{.underline}

Executive Summary of the 2001 release:

"*Specific pathways or practices that would contribute the most to the
spread of BSE if it were introduced into the U.S. relate to compliance
with the FDA feed ban and include misfeeding on the farm and the
mislabeling of feed and feed products prohibited for consumption by
cattle. The disposition of cattle that die on the farm would also have a
substantial influence on the spread of BSE if this disease were
introduced into the U.S.*"

"*Our evaluation of potential risk mitigation actions highlights
potential measures to further reduce the already low likelihood that BSE
could spread to cattle or contaminate human food if it were to arise.
Prohibiting the rendering of animals that die on the farm, possibly of
BSE, removes a great deal of potential contamination in the animal feed
chain and reduces average predicted cases of BSE following introduction
of ten infected cattle by 77%. Implementation of a UK-style ban on
specified risk material (e.g., spinal cords, brains, vertebral columns)
from both human food and animal feed reduces the predicted number of BSE
cases in cattle by 80% and the potential human exposure by 95%.*"

*"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.

[Recommendations of the Subcommittee to the USDA's Foreign Animal and
Poultry Disease Advisory Committee]{.underline}

An international panel of transmissible spongiform encephalopathy (TSE)
experts appointed by Secretary of Agriculture Ann M. Veneman as a
subcommittee to the Foreign Animal and Poultry Disease Advisory
Committee issued a report in February 2004 which stated:

*"... given the epidemiological evidence indicating that BSE agent was
already circulating in ruminant feed prior to the feed ban in 1997, and
the integration of the North American cattle and feed industries, strong
consideration should be given to excluding all SRM from both the human
food and animal feed supplies."*

*"Considering the BSE situation in North America, the subcommittee
believes the partial (ruminant to ruminant) feed ban that is currently
in place is insufficient to prevent exposure of cattle to the BSE
agent."*

From the Secretary's Advisory Committee on Foreign Animal and Poultry
Diseases' Subcommittee on the United States' Response to the Detection
of a Case of Bovine Spongiform Encephalopathy, Report on Measures
Relating to Bovine Spongiform Encephalopathy (BSE) in the United States,
2 February 2004, p. 8.

### 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 the United Kingdom. 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 before the
spread widely.

However we also wish to emphasize that as scientists that 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 there will eventually be technical solutions to many of the
challenges that we currently confront from these diseases. Thus, we urge
the FDA to frame its regulations in terms that allow for the use of any
banned material if it can be proven safe for a given application.

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Doherr,M.G.; Hett,A.R.; Rufenacht,J.; Zurbriggen,A.; Heim,D. -
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Signatories:

### Linda Detwiler, DVM

Consultant, TSE Risk Management

**Robert G. Rohwer, Ph.D.**

Director, Molecular Neurovirology Laboratory

Veterans Affairs Medical Center

Medical Research Service 151

and

Assoc. Professor of Neurology

School of Medicine

University of Maryland at Baltimore

address:

10 N. Greene St.

Baltimore, MD 21201

ph. 410-605-7000 x6462

secretary x6466

Fax 410-605-7959

email: rrohwer@umaryland.edu

**Paul W. Brown, M.D**.

Consultant, TSE Risk Management

[^1]: Milk has not been a significant source of transmission of BSE in
    cattle.