##################### Bovine Spongiform Encephalopathy #####################
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
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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
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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:
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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.
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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
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: [email protected].
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: [email protected]
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Bushmann, A., and Groschup, M.; Highly Bovine Spongiform Encephalopathy-Sensitive
Transgenic Mice Confilm the Essential Restriction of Infectivity to the Nervous System
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of cases of bovine spongiform encephalopathy (BSE) born in Switzerland after the feed
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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.
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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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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-vol40.pdf
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
http://www.fsis.usda.gov/OPPDE/Comments/03-025IFA/03-025IFA-2.pdf
Docket No, 04-047-l Regulatory Identification No. (RIN) 091O-AF46 NEW BSE SAFEGUARDS (comment submission)
https://web01.aphis.usda.gov/regpublic.nsf/0/eff9eff1f7c5cf2b87256ecf000df08d?OpenDocument
Docket No. 03-080-1 -- USDA ISSUES PROPOSED RULE TO ALLOW LIVE ANIMAL
IMPORTS FROM CANADA
https://web01.aphis.usda.gov/BSEcom.nsf/0/b78ba677e2b0c12185256dd300649f9d?OpenDocument&AutoFramed
Docket No. 2003N-0312 Animal Feed Safety System [TSS SUBMISSION]
http://www.fda.gov/ohrms/dockets/dockets/03n0312/03N-0312_emc-000001.txt
TSS
Link: SEE CONSUMER UNION SUBMISSION
http://www.fda.gov/ohrms/dockets/dockets/02n0273/02n-0273-c000486-01-vol40.pdf
#################### https://lists.aegee.org/bse-l.html ####################
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
the disease recycling. This is especially true in countries likethe 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: [email protected].
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: [email protected]
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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-vol40.pdf
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
http://www.fsis.usda.gov/OPPDE/Comments/03-025IFA/03-025IFA-2.pdf
Docket No, 04-047-l Regulatory Identification No. (RIN) 091O-AF46 NEW BSE SAFEGUARDS (comment submission)
https://web01.aphis.usda.gov/regpublic.nsf/0/eff9eff1f7c5cf2b87256ecf000df08d?OpenDocument
Docket No. 03-080-1 -- USDA ISSUES PROPOSED RULE TO ALLOW LIVE ANIMAL
IMPORTS FROM CANADA
https://web01.aphis.usda.gov/BSEcom.nsf/0/b78ba677e2b0c12185256dd300649f9d?OpenDocument&AutoFramed
Docket No. 2003N-0312 Animal Feed Safety System [TSS SUBMISSION]
http://www.fda.gov/ohrms/dockets/dockets/03n0312/03N-0312_emc-000001.txt
TSS
Link: SEE CONSUMER UNION SUBMISSION
http://www.fda.gov/ohrms/dockets/dockets/02n0273/02n-0273-c000486-01-vol40.pdf
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