McDonald's and USA BSE aka mad cow disease

McDonald's AND Seriologicals USA NOT PROTECTED FROM MAD COW

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

December 19, 2005

Division of Dockets Management (HFA-305)

Food and Drug Administration

5630 Fishers Lane

Room 1061 Rockville, MD 20852

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

Substances Prohibited From Use in Animal Food and Feed

Dear Sir or Madame:

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

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

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

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

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

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

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

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

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

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

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

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

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

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

· Alternative uses for animal byproducts which would maintain some value

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

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

Respectfully,

Dick Crawford

Corporate Vice President, Government Relations

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dick.crawford@mcd.com

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December 20, 2005

Division of Dockets Management (HFA-305)

Food and Drug Administration

5630 Fishers Lane

Room 1061 Rockville, MD 20852

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

Substances Prohibited From Use in Animal Food and Feed

Dear Sir or Madame:

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

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

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

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

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

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

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

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

3. Cross contamination of ruminant and non-ruminant feed

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

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

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

Source of the agent: SRMs (Specified Risk Materials)

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

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

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

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

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

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

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

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

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

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

“Peripheral Nerves

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

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

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

Source of the agent: Deadstock

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

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

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

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

Inflammation and TSEs

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

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

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

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

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

Exposure: Industry Practices or Exemptions which may pose a risk

Poultry Litter

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

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

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

Ruminant Blood

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

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

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

Unfiltered Tallow

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

Plate Waste

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

Exposure: Cross Feeding and Cross Contamination

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

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

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

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

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

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

Exposure: Susceptibility of other Species

Felines

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

Other species

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

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

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

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

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

Recommendations of the World Health Organization (WHO)

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

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

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

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

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

Office of International Epizooties (OIE)

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

BSE Code Article 2.3.13.18

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

Conclusion

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

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

Signatories:

Paul W. Brown, M.D.

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

Consultant, TSE Risk Management

xxxxxxxxxxxx

xxxxxxxxxxxxx

xxxxxxxxxx

Email: paulwbrown@comcast.net

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

xxxxxxxxxxxxxxxxx

e-mail: neil.cashman@utoronto.ca

Linda A. Detwiler, DVM Consultant, TSE Risk Management

xxxxxxxxxxxxxxxxxxxxxxx

xxxxxxxxxxxxxxxxxxxx

xxxxxxxxxxxxxxxxxx

Email: LAVet22@aol.com

Laura Manuelidis, MD

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

xxxxxxxxxxxxxxxxxxxx email: laura.manuelidis@yale.edu xxxxxxxxxxxxxxxxxxxxxxxx

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

xxxxxxxxxxxxxxxxxxxx

jbartz@creighton.edu

Robert B. Petersen, Ph.D.

Associate Professor of Pathology and Neuroscience

Case Western Reserve University

5-123 Wolstein Building

2103 Cornell Road

Cleveland, OH 44106-2622

xxxxxxxxxxxxxxxxxxxxxxx

xxxxxxxxxxxxxxxxxxx

Email rbp@cwru.edu

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

email: rrohwer@umaryland.edu

REFERENCES

Andreoletti O, Simon S, Lacroux C, Morel N, Tabouret G, Chabert A, Lugan S, Corbiere F, Ferre P, Foucras G, Laude H, Eychenne F, Grassi J, Schelcher F. PrPSc accumulation in myocytes from sheep incubating natural scrapie. Nat Med. 2004 Jun;10(6):591-3. Epub 2004 May 23.

Anil,M.H.; Love,S.; Helps,C.R.; McKinstry,J.L.; Brown,S.N.; Philips,A.; Williams,S.; Shand,A.; Bakirel,T.; Harbour,D.A. - Jugular venous emboli of brain tissue induced in sheep by the use of captive bolt guns - Veterinary Record 2001 May 19; 148: 619-20

Anil,M.H.; Harbour,D.A. - Current stunning and slaughter methods in cattle and sheep. Potential for carcass contamination with central nervous tissue and microorganisms - Fleischwirtschaft 2001; 11: 123

Anil,M.H.; Love,S.; Helps,C.R.; Harbour,D. - Potential for carcass contamination with brain tissue following stunning and slaughter in cattle and sheep - Food Control 2002; 13: 431-6

Bartz JC, Kincaid AE, Bessen RA. Retrograde transport of transmissible mink encephalopathy within descending motor tracts. J Virol. 2002 Jun;76(11):5759-68.

Bosque PJ, Ryou C, Telling G, Peretz D, Legname G, DeArmond SJ, Prusiner SB. Prions in skeletal muscle. Proc Natl Acad Sci U S A. 2002 Mar 19;99(6):3812-7.

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

Dawson,M.; Wells,G.A.H.; Parker,B.N.; Scott,A.C. - Primary parenteral transmission of bovine spongiform encephalopathy to the pig - Veterinary Record 1990 Sep 29; 127(13): 338

Doherr,M.G.; Hett,A.R.; Rufenacht,J.; Zurbriggen,A.; Heim,D. - Geographical clustering of cases of bovine spongiform encephalopathy (BSE) born in Switzerland after the feed ban - Veterinary Record 2002 Oct 19; 151(16): 467-72

Glatzel M, Abela E, Maissen M, Aguzzi A. Extraneural pathologic prion protein in sporadic Creutzfeldt-Jakob disease. N Engl J Med. 2003 Nov 6;349(19):1812-20.

Hadlow W. J., Kennedy R. C. & Race R. E. (1982) Natural infection of Suffolk sheep with Scrapie virus. J. Infect. Dis., 146, 657-664

Hoinville,L.J. - Decline in the incidence of BSE in cattle born after the introduction of the 'feed ban' - Veterinary Record 1994 Mar 12; 134(11): 274-5

Hoinville,L.J.; Wilesmith,J.W.; Richards,M.S. - An investigation of risk factors for cases of bovine spongiform encephalopathy born after the introduction of the 'feed ban' - Veterinary Record 1995 Apr 1; 136(13): 312-8

Houston,E.F.; Foster,J.D.; Chong,A.; Hunter,N.; Bostock,C.J. – Transmission of BSE by blood transfusion in sheep – Lancet 2000 Sep 16; 356(9234); 999-1000

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.; Anil,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(1-2): 53-8

Mulcahy ER, Bartz JC, Kincaid AE, Bessen RA. Prion infection of skeletal muscle cells and papillae in the tongue. J Virol. 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 prion's perplexing persistence. - Nature. 1998 Apr 23;392(6678):763-4

Race,R.E.; Raines,A.; Raymond,G.J.; Caughey,B.W.; Chesebro,B. - Long-term 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 Virology 2001 Nov; 75(21): 10106-12

Race,R.E.; Meade-White,K.; Raines,A.; Raymond,G.J.; Caughey,B.W.; Chesebro,B. - Subclinical Scrapie Infection in a Resistant Species: Persistence, Replication, and Adaptation of Infectivity during Four Passages. - Journal of Infectious Diseases 2002 Dec 1; 186 Suppl 2: S166-70

Schreuder, B.E.C., Geertsma, R.E., van Keulen, L.J.M., van Asten, J.A.A.M., Enthoven, P., Oberthür, R.C., de Koeijer, A.A., Osterhaus, A.D.M.E., 1998. Studies on the efficacy of hyperbaric rendering procedures in inactivating bovine spongiform encephalopathy (BSE) and scrapie agents. Veterinary Record 142, 474-480

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

Taylor, D.M., Woodgate, S.L., Atkinson, M.J., 1995. Inactivation of the bovine spongiform encephalopathy agent by rendering procedures. Veterinary Record, Vol.137: pp.605-610.

Taylor, D.M., Woodgate, S.L., Fleetwood, A.J., Cawthorne, R.J.G., 1997. The effect of rendering procedures on scrapie agent. Veterinary Record, Vol.141, pp 643-649.

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

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

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

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

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

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

Wyatt. J. M. et al. 1991. Naturally occurring scrapie-like spongiform encephalopathy in five domestic cats. Veterinary Record. 129. 233.

---------------------------------------------------------------------------- ----

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

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

EC 203 McDonald's Restaurants Corporation Vol #: 34

EC 205 McDonald's Restaurants Corp Vol #: 34

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


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

EMC 134 McDonald's Corporation Vol #: 14

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


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

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

C 435 Government of Japan Vol #: 36

snip...

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

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

snip...

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

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

Animal Food or Feed; Animal Proteins Prohibited in Ruminant Feed

Comment Number: EC -10

Accepted - Volume 2

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


PART 2

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


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

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

Page 1 of 17

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

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

To: fsis.regulationscomments@fsis.usda.gov

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

for the Disposition of Non-Ambulatory Disabled Cattle

Greetings FSIS,

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

Requirements for the Disposition of Non-Ambulatory Disabled C

Top Login or register to post comments 1 point Tags: Politics Fri, 2006-01-13 12:22 #1 flounder Offline Joined: 01/01/2006 Posts: 123 Points: 0 McDonald's AND Seriologicals USA NOT PROTECTED FROM MAD COW [Docket No. 03-025IFA] FSIS Prohibition of the Use of Specified Risk Materials for Human Food and Requirement for the Disposition of Non-Ambulatory Disabled Cattle

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

Page 1 of 17

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

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

To: fsis.regulationscomments@fsis.usda.gov

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

for the Disposition of Non-Ambulatory Disabled Cattle

Greetings FSIS,

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

Requirements for the Disposition of Non-Ambulatory Disabled Cattle

THE BSE/TSE SUB CLINICAL Non-Ambulatory Disabled Cattle

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

snip...FULL TEXT ;

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


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

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

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

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

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

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

OLD TSS SUBMISSIONS;

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

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

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

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

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

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


TSS

McDonald's AND Seriologicals USA NOT PROTECTED FROM MAD COW SEROLOGICALS CORPORATION James J. Kramer, Ph.D. Vice President, Corporate Operations

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

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

C 435 Government of Japan Vol #: 36

snip...

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

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

snip...

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

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

PAUL BROWN

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

December 20,2005

Division of Dockets Management (HFA-305)

Food and Drug Administration

5630 Fishers Lane

Room 1061

Rockville, MD 20852

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

Substances Prohibited From Use in Animal Food and Feed

Dear Sir or Madame:

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

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

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

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

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

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

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

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

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

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

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

strengthened OUT convictions.

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

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

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

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

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

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

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

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

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

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

distribution have not been released.

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

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

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

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

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

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

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

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

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

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

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

regulations by implementing the program proposed by the Canadian Food Inspection

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

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

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

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

countries.

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

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

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

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

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

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

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

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

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

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

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

consume potentially contaminated ruminant protein.

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

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

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

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

for cattle to be exposed to BSE through:

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

poultry litter, plate waste)

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

3. Cross contamination of ruminant and non-ruminant feed

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

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

E-d

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

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

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

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

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

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

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

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

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

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

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

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

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

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

completely removed especially during warmer weather. Given the biological

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

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

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

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

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

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

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

contaminated protein could potentially perpetuate transmission much like typical BSE.

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

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

SRMs to be included in feed for these animals.

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

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

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

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

position below.

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

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

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

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

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

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

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

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

ingestion of as little as AI01 gram of untreated brain.

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

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

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

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

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

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

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

experimentally infected calves beginning six months after challenge and continuing at

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

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

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

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

personal communication).

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

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

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

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

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

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

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

2003; Thomzig et al., 2004)

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

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

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

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

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

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

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

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

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

clinical stage of disease.

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

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

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

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

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

levels of infectivity into the feed system.

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

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

SSOI-Z6L.-ZEL

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

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

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

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

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

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

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

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

and any host barrier effects that are present.

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

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

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

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

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

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

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

used as a bioassay model.

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

“Peripheral Nerves

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

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

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

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

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

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

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

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

Encephalopathy-Sensitive Transgenic Mice Confirm the Essential

Restriction of Infectivity to the Nervous System in Clinically

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

September 1, 2005.

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

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

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

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

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

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

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

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

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

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

s-d

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

transgenic overexpressing mice have been shown to develop spontaneous lethal neurological

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

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

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

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

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

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

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

Source of the agent: Deaalstock

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

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

Infected individuals only exhibit recognizable clinical signs once infectivity titers have

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

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

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

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

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

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

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

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

effective means of reducing the risk of re-infection.

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

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

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

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

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

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

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

Assessment, 200 1 Executive Summary

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

and Groschup data were considered.

Inflammation and TSErr

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

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

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

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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.

6-d

Plate Waste

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

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

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

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

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

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

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

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

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

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

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

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

stated in written comments since 1997.

Exposure: Cross Feeding and Cross Contamination

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

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

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

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

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

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

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

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

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

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

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

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

process feed for ruminants and non-ruminants.

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

farms were completely depopulated.

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

enforcement is problematical when confronted with the extreme logistical challenges of

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

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

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

contribute to the recycling of BSE.

Exposure: Susceptibility of other Species

Felines

A transmissible spongifoim encephalopathy has been diagnosed in eight species of

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

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

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

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

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

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

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

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

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

of potential contamination from the feed stream

Other species

Studies conducted at the National lnstitutes of Health Rocky Mountain Laboratory

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

et. al., 2001).

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

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

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

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

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

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

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

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

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

and chickens).

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

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

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

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

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

eliminate all possible sources of infectivity from the feed stream.

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

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

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

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

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

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

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

bodies with expertise in the field of TSEs:

Recommendations of the World Health Organization (WHO)

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

countries with BSE or those where a known exposure exists:

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

food chain (human or animal). In particular:

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

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

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

enter any food chain (human or animal).

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

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

2-3 April 1996.

Office of International El-

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

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

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

products either.

BSE Code Article 2.3.13.18

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

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

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

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

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

commodities should also not be traded.”

Conclusion

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

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

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

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

and arrest them to prevent any possibility of spread.

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

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

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

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

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

given application.

El-d

Signatories:

Paul W. Brown, M.D.

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

Consultant, TSE Risk Management

78 15 Exeter Rd.

Bethesda, MD 208 14

Fax 301-652-43 12

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

Neil R Cashman MD

Professor, Department 0-C Medicine (Neurology)

Diener Chair of Neurode:generaGve Diseases

Centre for Research in Neurodegenerative Diseases

6 Queen’s Park Crescent West

Toronto Ontario M5S3H2

Ph: 416-978-1875

Fax: 4 16-978- 1878

e-mail: neil.cashman@utoronto.ca

Linda A. Detwiler, DVM

Consultant, TSE Risk Management

225 Hwy 35

Red Bank, NJ 07701

Ph 732-74 l-2290

Fax 732-741-775 1

Email: l.~\Vc~92’rr’ac,l.c0111.

Laura Manuelidis, MD

Professor and Head of Neuropathology,

Department of Surgery and Faculty of Neurosciences

Yale Medical School

333 Cedar St.

New Haven, CT 065 10

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

Tel: 203-785-4442

Jason C. Bar-k, Ph.D.

Assistant Professor

Department of Medical Microbiology and Immunology

Creighton University

2500 California Plaza

Omaha, NE 68178

(402) 280- 18 11 voice

(402) 280-l 875 fax

jbartz@creighton .edu

Robert B. Petersen, Ph.D.

Associate Professor of Pathology and Neuroscience

Case Western Reserve University

5- 123 Wolstein 13~1ilding

2 103 Cornell Road

Cleveland, OH 44 106-26122

Phone 216-368-6709

FAX 360-838-9226

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

Robert G. Rohwer, Ph.D.

Director, Molecular Neurovirology Laboratory

Veterans Affairs Medicall Center

Medical Research Service 151

Assoc. Professor of Neurology

School of Medicine

University of Maryland ;at Baltimore

10 N. Greene St.

Baltimore, MD 21201

ph. 4 1 O-605-7000 x6462

Fax 4 1 o-605-7959

email: rrohwer@maryland.edu

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F, Ferre P, Fouc,ras G, Laude H, Eychenne F, Grassi J, Schelcher F. PrPSc accumulation

in myocytes from sheep incubating natural scrapie. Nat Med. 2004 Jun;10(6):591-3.

Epub 2004 May 23.

Ani1,M.H.; Love,S.; Hr:lps,C.R.; McKinstry.J.L.; Brown,S.N.; Philips,A.; Williams,S.;

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

sheep by the use of captive bolt guns - Veterinary Record 2001 May 19; 148: 619-20

Ani1,M.H.; Harbour,D.A. - Current stunnin g and slaughter methods in cattle and sheep.

Potential for carcass contamination with central nervous tissue and microorganisms -

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Ani1,M.H.; Love& He:lps,C.R.; Harbour,D. - Potential for carcass contamination with

brain tissue following stunning and slaughter in cattle and sheep - Food Control 2002; 13:

431-6

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

encephalopathy within (descending motor tracts. J Virol. 2002 Jun;76(11):5759-68.

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

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

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

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

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

1,2005.

Dawson,M.; Wells,G.A.H.; Parker,B.N.; Scott,A.C. - Primary parenteral transmission of

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

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Doherr,M.G.; Hett,A.R.; Rufenacht,J.; Zurbriggen,A.; Heim,D. - Geographical clustering

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

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

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

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

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

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

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

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

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

of bovine spongiform encephalopathy born after the introduction of the ‘feed ban’ -

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

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

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

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

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

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

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

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

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

99( l-2): 53-8

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

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

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

23;392(6678):770.

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

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

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

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

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

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

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

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

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

1; 186 Suppl2: S166-70

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

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

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

scrapie agents. Veterinary Record I42,474-480

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

94.

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

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

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

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

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

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

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

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

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

Rec., 142, 103-106.

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

five domestic cats. Veterinary Record. 129. 233.

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

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

(would not copy good...tss)

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





maybe the good senator from nebraska ben nelson should ask first, why these countries don't want usda certified beef ?



Even McDonald’s, an international business symbolic of American culture, advertises that it uses only “pure Australian beef” in South Korea. Burger King announced that it only uses beef from Australia and New Zealand. Why? Even famous brands like McDonald’s cannot survive if they are perceived as using unsafe ingredients. They know that Koreans still do not trust the safety of American beef and must distance their brands from American beef.

Kwon Seung-woo, a professor at Korea University Business School

see full article here ;

[Letters] Made in the the USA versus raised in the USA

November 09, 2010




Kwon Seung-woo, a professor at Korea University Business School



http://joongangdaily.joins.com/article/view.asp?aid=2928098




Tuesday, November 02, 2010


BSE - ATYPICAL LESION DISTRIBUTION (RBSE 92-21367) statutory (obex only) diagnostic criteria CVL 1992


THIS seems to be another lesson on 'how not to find BSE' via the 'statutory (obex only) diagnostic criteria'. However, this was some 10 years before Dr. Detwiler was warning of this very practice, and how they would be 'MISSING' cases of BSE if USED, which the USDA et al seemed to use as the 'GOLD STANDARD'. NOW we see the UK used it. This seems to put a different light on the true numbers of BSE mad cow cases that were documented, or, better yet, how many were NOT documented $$$ IN THE USA AND ABROAD ???

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

ATYPICAL LESION DISTRIBUTION (RBSE 92/21367)

A 6 year old, home bred (HB), Friesian x Holstein cow in a dairy herd in Aberdeenshirer submitted as a suspect BSE case in the negative study (SE0203), has been diagnosed as BSE negative on standard, statutory (obex only), diagnostic criteria at CVL.

Further examination by Dr Jeffrey at Lasswade, as required by the project design, has revealed vacuolar change in the septal nucleus and putamen which co-localised with PrP immunoreactivity. No significant lesions were found in any other part of the brain, neither was PrP found in the medulla.

It is important to note that examination of four brain blocks used earlier in the epidemic would not have detected the lesion but a 16 block study (as used in the very days of BSE) would.

FURTHER INFORMATION

The herd of origin has had 15, HB, suspect cases of BSE since July 1989 and a further case is still alive.

2. Of the 15, eight have been confirmed by standard histopathology and seven diagnosed negative (including the above case).

3. Fixed brain tissue from the negative cases exists at Lasswade (because they always collect whole brain in Scotland) but has not so far been examined further. No frozen tissue was collected so neither SAF nor PrP detection (by immunoblotting) has been attempted.

4. Mr Wells agrees with Dr Jeffrey's and Dr Simmons' findings.

FURTHER ACTION IN PROGRESS

1. The brain tissue from the negative cases will be examined in detail by conventional histopathology and ICC.

2. Kevin Taylor and his veterinary colleagues have been alerted to the situation.

OTHER RECOMMENDED ACTIONS

1. TRANSMISSION Attempt transmission from the 'case' to standard mice strains. (Note: In regard to strain typing, formalin may have modified strain phenotype - we need to discuss with NPU). Further transmission studies (eg in cattle) might be suggested if primary transmission in mice fails. These proposals have funding implications.

CODE 18-77

93/2.17/1.1

2. PrP GENOTYPING - Although only fixed brain tissue is available we are considering genotyping from parents/offspring/fixed brain. As a first step we are attempting to extract DNA from the fixed brain and to amplify the PrP gene by PCR.

3. John Wilesmith has interrogated the data base for the herd history. Other than the high proportion of negative cases nothing significant is apparent.

4. Familial relationships between suspect (including positive and negative) cases in this herd could be examined and tracings of breeding animals initiated.

5. Consideration might be given to collecting frozen spinal cord from new cases in this herd or in dispersals from it for (SAF/PrP examination).

CONCLUSIONS

1. At present it is unclear whether or not this is a singleton incident or whether the other negative cases in this herd show a similar lesion.

2. The discovery might indicate the existence of a different strain of BSE from that present in the general epidemic or an unusual response by an individual host.

3. If further atypical lesion distribution cases are revealed in this herd then implications of misdiagnosis of 'negative' cases in other herds may not be insignificant.

4. If this is a new strain all the implications need to be considered including whether or not to proceed with the further investigation of future cases negative for BSE on obex examination alone and from which whole brains are available (as in Scotland) or collected in the future. Also perhaps investigation of the tissue distribution of infectivity in these animals might be considered.

5. Animal and public health controls in place should be sufficient since all tissues (other than brain for diagnosis) are incinerated.

We observe that Dr Tyrrell would wish to be informed of this at an early opportunity and that the SEAC would wish to discuss it at their meeting in April.

R BRADLEY

M DAWSON

17 February 1993

CVO - for information and comment on further action please

cc Mr K C Taylor

Dr B J Shreeve

93/2.17/1.2

This minute is re-issued with a wider distribution.

The information contained herein should not be disseminated further except on the basis of "NEED TO KNOW".

Mr Scudamore

Mr R C Lowson

Dr D Matthews

Mr I Robertson

Dr K MacOwan

Mr C Randall

Mr J W Wilesmith

Mr G A H Wells

Dr M Jeffrey

Dr M Simmons

93/2.17/1.3

http://tna.europarchive.org/20080609145105/http://www.bseinquiry.gov.uk/files/yb/1993/02/17001001.pdf




IN CONFIDENCE

BSE - ATYPICAL LESION DISTRIBUTION (RBSE 92-21367)

http://tna.europarchive.org/20080609145105/http://www.bseinquiry.gov.uk/files/yb/1993/03/14001001.pdf




1992

NEW BRAIN DISORDER

3. WHAT ABOUT REPORTS OF NEW FORM OF BSE ?

THE VETERINARY RECORD HAS PUBLISHED AN ARTICLE ON A NEW BRAIN DISORDER OF CATTLE DISCOVERED THROUGH OUR CONTROL MEASURES FOR BSE. ALTHOUGH IT PRESENTS SIMILAR CLINICAL SIGNS TO BSE THERE ARE MAJOR DIFFERENCES IN HISTOPATHOLOGY AND INCUBATION PERIODS BETWEEN THE TWO. MUST EMPHASISE THAT THIS IS _NOT_ BSE.

4. IS THIS NEW BRAIN DISORDER A THREAT ?

WE DO NOT EVEN KNOW WHETHER THE AGENT OF THIS DISEASE IS TRANSMISSIBLE. IN ANY CASE, CASES SO FAR IDENTIFIED HAD SHOWN SIMILAR SYMPTOMS TO THOSE OF BSE, AND THEREFORE HAVE BEEN SLAUGHTERED AND INCINERATED, SO THAT IF A TRANSMISSIBLE AGENT WERE INVOLVED IT WOULD HAVE BEEN ELIMINATED. ...

http://collections.europarchive.org/tna/20090114131343/http://www.bseinquiry.gov.uk/files/yb/1992/10/26001001.pdf




Tuesday, November 17, 2009

SEAC NEW RESULTS ON IDIOPATHIC BRAINSTEM NEURONAL CHROMATOLYSIS (IBNC) FROM THE VETERINARY LABORATORIES AGENCY (VLA) SEAC 103/1

http://bse-atypical.blogspot.com/2009/11/seac-new-results-on-idiopathic.html




NEW RESULTS ON IDIOPATHIC BRAINSTEM NEURONAL CHROMATOLYSIS "All of the 15 cattle tested showed that the brains had abnormally accumulated PrP" 2009

http://bse-atypical.blogspot.com/2009/02/new-results-on-idiopathic-brainstem.html




========

NOW, what about the 'obex only' mode of testing used by the USDA et al for TSE, prions $$$ works for them too, a sure fire way NOT TO FIND MAD COW DISEASE $$$

NOW, read the following please, and then ask yourself, WHY the USDA et al were ONLY TESTING THE OBEX PART OF THE BRAIN in USA cattle for BSE $$$

BECAUSE they knew that would be the least likely way to find BSE/TSE in USA cattle $$$...TSS

=========


Discussion

In the five cats in this study with a spongiform encephalopathy, fibrils were observed by electron microscopy and their major protein, Prpsc, was identified by SDS-PAGE and Western blot. The fibrils were similar to those described in sheep with scrapie (Rubenstein and others 1987, Gibson and others 1987, Scott and others 1987, Dawson and others 1987), cattle with bovine spongiform encephalopathy (Wells and others 1987, Hope and others 1988, Scott and others 1990) and humans with Creutzfeldt-Jakob disease (Merz and others 1984).

In sheep with scrapie, fibrils can be readily detected in several areas of the brain, including cerebral cortex (Stack and others 1991).

By contrast, the frequency with which fibrils were detected in cattle with BSE, DEPENDED ON THE REGION OF THE BRAIN SAMPLED; THE HIGHEST YIELD BEING OBTAINED FROM MEDULLA, MIDBRAIN, THALAMUS AND BASAL NUCLEI WHERE VACUOLA CHANGES ARE PRESENT (Scott and others 1990). This correlation between PrPsc accumulation and vacuolar pathology is also well established in laboratory animal models of scrapie (Bruce and others 1989). Because of the widespread distribution of changes in FSE (Whatt and others 1991) and the requirement, in the present study, not to compromise the histopathological examination of the brain, the frontal region of the cerebrum was therefore selected for fibril and PrPsc examinations. However, studies of the sensitivity of fibril detection in different parts of the brain in cats with FSE are required to determine whether detection can be made as readliy in other regions as in the frontal cerebral cortex.

IT IS OF INTEREST, that fibrils were detected in the brains of 3 cats (cases 9, 13, & 18) WITHOUT histopathological evidence of spongiform encephalopathy, and that in only one of them, (case 9), a Western blot for modified PrP was positive. There are precedents for the occurrence of abnormal PrP in the organs of animals incubation scrapie prior to clinical signs and/or spongiform encephalopathy...

snip...

(please see full text (and one might start downloading these documents for future use, as some disappear never to re-appear, as in some of the FDA's. ...TSS)

http://collections.europarchive.org/tna/20090113230941/http://www.bseinquiry.gov.uk/files/sc/seac12/tab04.pdf




PLEASE NOTE *

Over the next 8-10 weeks, approximately 40% of all the adult mink on the farm died from TME.

snip...

The rancher was a ''dead stock'' feeder using mostly (>95%) downer or dead dairy cattle...

http://web.archive.org/web/20030516051623/http://www.bseinquiry.gov.uk/files/mb/m09/tab05.pdf






AND THE USDA ET AL KNEW IT TOO, please see full text here ;





http://bse-atypical.blogspot.com/2010/11/bse-atypical-lesion-distribution-rbse.html



Saturday, November 6, 2010

TAFS1 Position Paper on Position Paper on Relaxation of the Feed Ban in the EU Berne, 2010

TAFS

INTERNATIONAL FORUM FOR TRANSMISSIBLE ANIMAL DISEASES AND FOOD SAFETY a non-profit Swiss Foundation


http://madcowfeed.blogspot.com/2010/11/tafs1-position-paper-on-position-paper.html





Sunday, October 24, 2010

Australia Mad cow assessments come to a standstill, USDA hasn't a clue $

"And then FSANZ received an incomplete application from the US, which says at this stage it doesn't have the resources to provide information."

http://www.abc.net.au/rural/news/content/201010/s3044237.htm




Sunday, October 24, 2010

Australia Mad cow assessments come to a standstill, USDA hasn't a clue $


http://usdameatexport.blogspot.com/2010/10/australia-mad-cow-assessments-come-to.html





Name: Terry S. Singeltary Sr. Date: Jan 26, 2007

Dear Terry S. Singeltary Sr.

My name in Seoungwon Lee and I work for National Assemblywoman (MP) Sang-Jeong Sim, in South Korea. Below is a message from Mr. Kwon. Please get back to us regarding the letter.

Thank you.


Seoungwon Lee Legislative Assistant National Assembly Republic of Korea


Dear Terry S. Singeltary Sr.

Greetings from Korea.

I have learned about what you and your family have been through a internet. Being the father of a small family, I can only imagine the sense of loss that you and your family still must feel regarding your mother.

Through the internet, many people here in Korea have learnt about the story of your family and it has created a great deal of concern. Your experience had particular relevance for the citizens here, for the Korean government, in connection to the free trade agreement it is negotiating with the United States, is about to restart the sale of the unsafe American beef to the general public.

The Korean government has already imported the first load American beef and is currently going through the inspection period. There has been a great deal of controversy regarding the safety of these products, and a precipitous increase in public interest regarding the causes and symptoms of vCJD.

It is in this context that we are preparing a session together with National Assembly members and relevant NGOs to hear from those who have had direct experience with the human variant of BSE. We are very interested in hearing about the symptoms that your mother showed, your views on the response from the US government to the many deaths that resulted from this disease, the reaction from the general public, and any other area that you would wish to speak about. There would also be experts and academics in the area to speak at the session as well. We believe that it would greatly contribute to raising awareness about the issue, as well as help politicians and civic activists to consider the repercussions of the beef import issue.

We would like to request your help in this regard. We are planning for the session to be held in Seoul on the 23rd of this November. We would very much like to have you present in order to help prevent such tragic incidents from happening in Korea. We would, of course, pay for the trip and accommodations for the duration of your stay. If you were to participate, we could also meet with members from the agricultural committee of the National Assembly and from other related organizations to urge more interest to the issue.

Please do not hesitate to offer suggestions or ask us any questions that you might have. We look forward to a positive response and to meeting you in Seoul.

Thank you.

Sincerely, Sim Sang-Jeong

Head of the Democratic Labor Party Parliamentary Committee on the Korea-US FTA
Member of the National Assembly Republic of Korea


http://www.fpif.org/fpiftxt/3940




http://usdavskorea.blogspot.com/2008/05/concerned-americans-against-mad-cow.html





Monday, August 9, 2010

National Prion Disease Pathology Surveillance Center Cases Examined (July 31, 2010)

(please watch and listen to the video and the scientist speaking about atypical BSE and sporadic CJD and listen to Professor Aguzzi)

SEE where sporadic cjd in the USA went from 59 cases in 1997, to 216 cases in 2009. a steady increase since 1997. ...TSS

National Prion Disease Pathology Surveillance Center Cases Examined (July 31, 2010)

Year Total Referrals2 Prion Disease Sporadic Familial Iatrogenic vCJD

1997 114 68 59 9 0 0

to

2009 425 259 216 43 0 0

http://www.cjdsurveillance.com/pdf/case-table.pdf



see full text ;

http://prionunitusaupdate2008.blogspot.com/2010/08/national-prion-disease-pathology.html





2010


PLEASE NOTE REFERENCE LINES 5. AND 6. AT BOTTOM ;


Monday, August 9, 2010

National Prion Disease Pathology Surveillance Center Cases Examined (July
31, 2010) Year Total Referrals2 Prion Disease Sporadic Familial Iatrogenic
vCJD

1996 & earlier 51 33 28 5 0 0

1997 114 68 59 9 0 0

1998 88 52 44 7 1 0

1999 120 72 64 8 0 0

2000 146 103 89 14 0 0

2001 209 119 109 10 0 0

2002 248 149 125 22 2 0

2003 274 176 137 39 0 0

2004 325 186 164 21 0 1(3)

2005 344 194 157 36 1 0

2006 383 197 166 29 0 2(4)

2007 377 214 187 27 0 0

2008 394 231 204 25 0 0

2009 425 259 216 43 0 0

2010 204 124 85 20 0 0

TOTAL 3702(5) 2177(6) 1834 315 4 3

1 Listed based on the year of death or, if not available, on year of
referral;

2 Cases with suspected prion disease for which brain tissue and/or blood (in
familial cases) were submitted;

3 Disease acquired in the United Kingdom;

4 Disease was acquired in the United Kingdom in one case and in Saudi Arabia
in the other case;

5 Includes 16 cases in which the diagnosis is pending, and 18 inconclusive
cases;

6 Includes 21 (19 from 2010) cases with type determination pending in which
the diagnosis of vCJD has been excluded.

http://www.cjdsurveillance.com/pdf/case-table.pdf




TEST, TEST, TEST, with up to date TSE testing protocol, and the intent to find, forth with, and as true as honest abe, test, test, test, and they will come $$$



TSS

Terry S. Singeltary Sr. P.O. Box 42 Bacliff, Texas USA 77518