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From: TSS ()
Marie A. Vodicka, PhD Assistant Vice President Biologics & Blotechnology Scientlflc & Regulatory Affairs SCIENCE & REG AFFAIRS Division of Dockets Management (HFA-305) Food and Drug Administration 5630 Fishers Lane, rrn . 1061 Rackville, MD 20862 No. 2002N-0273 February 14, 2006 Dear Sir or Madam : The Pharmaceutical Research and Manufacturers of America (PhRMA) is providing comment to the proposed rules issued. by the Food and Drug Administration (FDA) Center for Veterinary Medicine (CVM) entitled Substances Prohibited From Use in Animal Food or Feed ; Proposed Rule, 21 CFR Part 589; 70 Federal Register 58570 (October 6, 2005). PhRMA applauds the FDA's continued actions to protect the cattle population of the United States from BSE (bovine spongiform encephalopat.hy) and, as discussed further below, strongly supports additional safeguards in addition to those proposed in amended 21 CFR Part 589_ PhRMA represents the country's leading research-based pharmaceutical and biotechnology companies, which are devoted to inventing medicines that allow patients to lead longer, healthier and more productive lives. Investing more than $30 billion annually in discovering and developing new medicines, PhRMA companies are leading the way in the search for cures . Animal-derived materials are ubiquitous in our lives and have many important uses . They are often used in pharmaceutical manufacturing and are sourced according to Pharmaceutical Research and Manufacturers of America Page 2of7 guidelines issued by regulatory authorities and the specifications outlined by the quality systems of the pharmaceutical company. The BSE status of the country where the animal lived and an assessment of the controls in place to prevent the spread of the disease, if it should occur, are important considerations in sourcing bovine-derived materials . While a country may have animals diagnosed with BSE, evaluation of the measures put in place to halt the spread of the disease is as crucial as identification of the disease itself. PhRMA continues to support an internationally harmonized, sciencebased approach to determining appropriate safeguards against BSE. PhRMA believes that FDA efforts to communicate these science-based concepts to our trading partners worldwide are critical. It is just as important to institute sound science-based policies in order to stop the spread of disease. Consideration of the safeguards enacted in the various countries where ruminant derived raw materials are sourced provides the underpinning for regulatory guidance. The cattle population of the United States must continue to be an acceptable source of bovine-derived raw materials for human food and pharmaceutical manufacturing. As such, continual re-evaluation of existing safeguards against BSE must occur based on new information and advances in science . Due to confirmation that BSE is indeed present in North America, rapid implementation of enhanced safeguards for cattle and animal feed is required . We continue to be concerned about the amount of time it has taken the Center for veterinary Medicine (CVM) to institute any changes to the 1997 feed ban; a lot has happened since 1997, not the least of which is the identification of a BSE cow native to the United States (June 2004). As we have urged for many years, the 1997 feed ban must be enhanced based on new information, including the experimental results that Page 3 of 7 show as little as 0.001 gram of infected tissue fed orally to cattle may result in BSE infection of cattle1. PhRMA supports actions of the Food and Drug Administration Center for Veterinary Medicine (FDA CVM ) to extend certain provisions in the 1997 Ruminant to Ruminant feed ban to all animal feed . As noted in the 1997 ruminant feed final rule (§ 589.2000) and described in the October 6, 2005 Federal Register notice,2 the use of mammalian derived proteins is currently prohibited in ruminant feed, with the exception of certain proteins believed not to pose a risk of BSE transmission . These exceptions to the definition of "protein derived from mammalian tissues" include: blood and blood products; gelatin; inspected meat products which have been cooked and offered for human food and further heat processed for feed (such as plate waste and used cellulosic food casings), referred to herein as "plate waste" ; milk products (milk and milk protein) ; and any product whose only mammalian protein consists entirely of porcine or equine protein. The 1997 ruminant feed final rule does not prohibit ruminant animals from being fed processed animal proteins derived from non-mammalian species (e .g ., avian or aquatic animals). The 1997 ruminant feed final rule permits the manufacture of non-ruminant feed containing prohibited mammalian protein and ruminant feed on the same premises, provided that separate equipment is used in the production of ruminant feed or that documented adequate clean-out procedures are used between production batches . PhRMA has commented numerous times on the inadequacy of the 1997 feed ban (our latest comments were provided to Federal Register Docket 2004N-0264 and dated August 12, 2004). We stated that the current exemptions in the feed ban must be Page 4 of 7 critically examined in light of the identification of BSE positive animals in Canada, Washington, and subsequently in Texas. Over the last few years, PhRMA has urged that serious consideration be given to prohibiting all specified risk material (SRM) in rendered product used for non-ruminant feed due to the potential for "on farm" cross contamination with feed designated for ruminants . We have strongly recommended implementation of measures to ensure that SRM is excluded from all animal feed . In addition, PhRMA urged the complete removal of the exception for ruminant blood and the exemptions for plate waste and poultry litter from the ruminant feed ban. As such, we strongly support the current FDA position to eliminate SRM from all animal feed and urge its immediate implementation. This safeguard must be implemented rapidly. Regrettably, FDA proposes to eliminate only the brain and spinal cord from cattle 30 months of age or older, not the complete list of SRMs currently designated for human food . Given the absence of a species barrier when non-ruminant feed is fed (inadvertently or deliberately) to ruminants, we urge the FDA to reconsider its position and eliminate the complete list of SRM from all animal feed. We are steadfast in our position urging the removal of the exemption for plate waste and poultry litter . This position is based on the lack of species barrier and the inclusion of tissues with potentially high levels of infectivity present in plate waste and poultry litter . Allowing the exception for plate waste provides a direct route for feeding ruminants to ruminants because plate waste may contain uneaten food items such as T-bone steak waste, including bone innervated with dorsal root ganglia (DRG). The absence of a species barrier when feeding ruminants to ruminants would facilitate the transmission of infectivity by the demonstrated high titer DRG, if infectivity were present . We have evaluated the rationale provide by FDA CVM for not banning plate waste (in summary: SRMs are prohibited in human food therefore plate waste will not contain SRMs and can be fed back to cattle). This rationale does not take into account the lack of a species barrier when feeding cattle plate waste containing beef. The lack Page 5 of 7 of a species barrier, coupled with the definition of SRMs limited to cows over 30 months of age, combined with the knowledge that there is circulating BSE agent (albeit at exceedingly low levels) in North America, are strong reasons to completely ban the feeding of plate waste to bovines . In addition, the FDA states in the proposed rules that they do not have an estimate of the amount of plate waste added to bovine feed, but the available anecdotal information states that the amount is not significant. If there is only a limited amount of plate waste being processed to bovine feed, given the lack of species barrier, it appears logical to prohibit the use of plate waste completely. PhRMA does not agree that eliminating all plate waste from bovine feed is an 'unnecessary measure' and we strongly urge CVM to reevaluate its position. Both specified risk materials (SRM) and plate waste are currently allowed in poultry feed. We recommend that both SRM and plate waste be removed from poultry feed so that poultry litter can be used as a bovine nitrogen source. If these materials are not removed from poultry feed, then we recommend that poultry litter be banned from the diet of cattle. The proposed rule contains a provision to utilize certain dead cattle in animal feed. Allowing deadstock (dead, down, disabled, diseased) into the animal food chain if the brain and spinal cords have been removed does not take into account that these animals are the most likely to harbor infectivity as symptoms of BSE disease confound the segregation of these animals. The total amount of infectivity does not reside in the brain and spinal cord and removal of these tissues does not make the remainder of the carcass acceptable to process into animal feed . According to risk assessment models, adult cattle deadstock are the population harboring the majority of the potential Page 6 of 7 infectivity if BSE were! circulating in a population 3. Elimination of the deadstock from the animal food chain is critical to prevent the spread of disease. The other exemptions in the 1997 feed ban such as blood and milk/milk products are less problematic as Iong as milk and blood are sourced to prevent cross-contamination with high infiectivity tissues. We agree with the FDA's approach to these two tissues if the potential for cross-contamination is minimized . In summary, we recognize the tremendous efforts CVM has expended on defining a strategy for enhanced feed controls in the United States to help stop the spread of BSE. The thoughtful evaluation of all comments as a result of the publication of the Advance Notice of Public Rule Making (July 14, 2004) reflects an Agency attempting to balance the risks of continuing current feeding practices with the practical considerations of various industries . We appreciate a risk based approach but have misgivings about the level of safeguards contained in the proposed rule. To reiterate, our main concerns center on the following three issues - the narrow definition of the SRM to be excluded from non-ruminant feed, instead of a complete ban as for ruminant feed; the continued allowance of plate waste and poultry litter in ruminant feed and finally, the provision to allow certain deadstock cattle into the animal food chain . PhRMA appreciates the opportunity to comment on the proposed changes to the ruminant feed ban and the implementation of controls on non-ruminant feed_ PhRMA member companies manufacture human medicines using a wide variety of materials . We continue to source animal derived raw materials according to regulations of FDA Page 7 of 7 and the quality systems of the company. The United States must continue to be recognized as an acceptable source of these animal derived raw materials both domestically and by our international trading partners . Using sound science to influence regulatory approaches to animal husbandry is the key to preventing the spread of BSE in the United States. FDA and USDA have already done a lot to protect the United States but more must be done as reflected in our comments herein . Please contact me if you have any questions or would like to arrange a meeting to discuss our comments. Sincerely, Marie A. Vodicka, PhD http://www.fda.gov/ohrms/dockets/dockets/02n0273/02n-0273-c000534-01-vol45.pdf December 20,2005 Division of Dockets Management (HFA-305) Food and Drug Administration 5630 Fishers Lane Room 1061 Rockville, MD 20852 Re: Docket No: 2002N-0273 (formerly Docket No. 02N-0273) Substances Prohibited From Use in Animal Food and Feed Dear Sir or Madame: As scientists and Irecognized experts who have worked in the field of TSEs for decades, we are deeply concerned by the recent discoveries of indigenous BSE infected cattle in North America and appreciate the opportunity to submit comments to this very important proposed rule We strongly supported the measures that USDA and FDA implemented to protect public health after the discovery of the case of bovine spongiform encephalopathy (BSE) found in Washington State in 2003. We know of no event or discovery since then that could justify relaxing the existing specified risk material (SRM) and non-ambulatory bans and surveillance that were implemented at that time. Further, we strongly supported the codification of those changes, as well as additional measures to strengthen the entire feed and food system. The discovery of additional cases of indigenous BSE in North America since that time has validated our position and strengthened OUT convictions. We caution against using the 18 month enhanced surveillance as a justification to relax or impede further actions. While this surveillance has not uncovered an epidemic, it does not clear the US cattle herd from infection. While it is highly likely that US and Canadian cattle were exposed to BSE prior to the 1997 feed ban, we do not know how many cattle were infected or how widely the infection was dispersed. BSE cases are most likely clustered in time and location, so while enhanced surveillance provides an 18 month snapshot, it does uot negate the fact that US and Canadian cattle were exposed to BSE. We also do not know in any quantitative or controlled way how effective the feed ban has been, especially at the farm level. At this point we cannot even make a thorough assessment of the USDA surveillance as details such as age, risk category and regional distribution have not been released. A number of countries initially attempted to take partial steps in regard to feed controls only to face repeated disappointments in predicted downturns of the epidemic course. We in North America could do this experiment all over again, waiting for each new warning before adding more stringency to our control measures, or we can benefit from the experience of others and take decisive measures now to arrest any further development of underlying cases that is implicit in those already discovered to date. The discovery of 5 indigenous North American cases, including one born after the implementation of the current feed ban, should provide the necessary incentive to implement, monitor and enforce a comprehensive and protective feed ban that is more congruent with the measures that have been proven to be effective throughout the world. In particular, we urge the FDA to act without f&ther delay to strengthen the animal feed regulations by implementing the program proposed by the Canadian Food Inspection Agency (CFIA) in the December 11, 2004 Gazette. This includes removing all specified risk materials (SRMs) and deadstock from all animal feed. We also urge that the FDA discontinues the legal exemptions which allow ruminant protein to be fed back to ruminants (with the excelption of milk). Many of these exemptions do not exist in other countries. Bovine products and byproducts are used for both food and pharmaceuticals. These human uses require the highest level of safety. Because of the hardy nature of the BSE agent and its high potential for cross contamination, the most effective way to protect bovine products and bovine derived materials from contamination by BSE is to ensure that infected animals or carcasses never enter processing plants. The goal would be to discover and remove infected animals fi-om production as early as possible in the infection and long before they wouid be sent to slaughter. Until we have diagnostic tools powerful enough to allow us to discover the disease early in its prolonged pre-clinical incubation, we have to rely on the next best strategy which is to prevent any exposure through feed. The exemptions in the current ban as well as in the newly proposed rule make this difficult if not impossible, as they still provide legal avenues for ruminants to consume potentially contaminated ruminant protein. It is our opinion that the Iproposed rule falls woetilly short in effective measures to minimize the potential for further transmissions of the disease. By the FDA’s own analysis, exempted tissues (such as distal ileum, DRGs, etc) contain approximately 10% of the infectivity in affected animals. Thus the proposed rule still allows the possibility for cattle to be exposed to BSE through: 1. Feeding of materials currently subject to legal exemptions from the ban (e.g., poultry litter, plate waste) 2. Cross feeding (the feeding of non-ruminant rations to runiinants) on farms; and 3. Cross contamination of ruminant and non-ruminant feed We are most concerned that the FDA has chosen to include a provision that would allow tissues from deadstock into the feed chain. We do not believe that down or dead stock E-d should be allowed into the food or feed chain whatever the age of the animal and whether or not the CNS tissues are removed. We do not support the provision to allow removal of brain and spinal cord from deadstock over 30 months for a number of reasons. This category of animals contains the highest level of infectivity and that infectivity is in other tissues besides just brain and spinal cord. Recent improvements in the BSE bioassay, have now made it possible to detect BSE infectivity 1000 time more efficiently than before. This assay has revealed the presence of BSE infectivity in some but not all peripheral nerves and in one muscle. (Buschmann and Groschup, 2005) This published and peer reviewed work is consistent with other publicly reported studies in Japan where, by western blot testing, ,prions were found in the peripheral nerves of a naturally infected 94-month-old cow. We feel that the studies as reported above have merit. The current studies not only re-etiorce the risk of down and deadstock but also appear to provide additional information that these animals may be a potential source of greater levels of infectivity into the feed .system. We also doubt that brain and spinal cord can be completely removed especially during warmer weather. Given the biological composition of these tissues, they are predisposed to rapid autolysis. As world wide surveillance for BSE increases, several atypical cases of bovine TSE have been discovered. These cases either show no clinical signs, or present as ‘downers’, and have an atypical neuropathology with respect to lesion morphology and distribution, causing problems in both clinical and post-mortem diagnosis. The origin of the cases are unclear but they suggest that even should typical BSE be eliminated, there may be other TSE diseases of cattle that could result by “mutation” and selection. Refeeding of contaminated protein could potentially perpetuate transmission much like typical BSE. An effective feed ban could prevent the expansion of such strains. We also note that there are other species which are susceptible to BSE and the current regulations allow for SRMs to be included in feed for these animals. For BSE to be perpetuated, the animal production system must have a source of agent and a means by which cattle or other susceptible species are exposed to this agent. We feel that in North America, the source and routes of exposure still exist, hence allowing for the continued recycling of BSE. We have detailed the scientific justifications for our position below. Source of the agent: SRMs (Specified Risk Materials) r SRMs, as defined by the USDA, are tissues which, in a BSE infected animal, are known to either harbor BSE i&:ctivity or to be closely associated with infectivity. If SRMs are not removed, they may introduce BSE infectivity and continue tq provide a source of animal feed contamination. For example, the skull and vertebral column which encase the brain and spinal cord, respectively, can be assumed to have gross contamination. Rendering will reduce infectivity but it will not totally eliminate it. This is significant as research in the United Kilngdom has shown that a calf may be infected with BSE by the ingestion of as little as AI01 gram of untreated brain. The tissue distribution of infectivity in BSE infected cattle has primarily been determined by 3 studies conducted in the United Kingdom all of which had limitations. In two of the studies, bioassays were done in mice which are at least 1000 fold less sensitive to BSE infection than cattle themselves. Only higher titers of infectivity can be detected by this method. These investigations found infectivity in the brain, spinal cord, retina, trigeminal ganglia, dorsal root ganglia, distal ileum and bone marrow (the bone marrow finding was from one animal). Infectivity was found in distal ileum of experimentally infected calves beginning six months after challenge and continuing at other intervals throughout life. (Wells et. al., 1994; 1998). The bioassay study in calves has produced similar results and in addition infectivity has been found in tonsil. The study is still in progress. Another project has found infectivity in the lymphoid tissue of third eyelid from naturally infected animals. (Dr. Danny Matthews, UK DEFRA, personal communication). While bioassay in cattle is far preferable to mice in terms of sensitivity, cattle nevertheless present their own limitations in terms of the long incubation time and the limited number of anim& that can be used for assay compared to rodents. As a consequence the significance of the negative finding for many tissues is questionable. In fact, by the end of 2004 there was increasing evidence in species other than cattle that peripheral nerves and muscle have infectivity. (Bosque et al., 2002; Glatzel et al., 2003;Bartz et al., 2002; Androletti et al., 2004; Mulcahy et al., 2004; Thomzig et al., 2003; Thomzig et al., 2004) In some of these species, studies indicate that the agent migrates to the brain and spinal cord, replicates to high levels in the CNS and then spreads centrifugally from the spinal cord back down through the spinal neurons to the junction of the nerves and muscle into the muscle cells themselves. A recent German study (Buschmann and Groschup, 2005) examined nerves and muscle from a cow naturally infected with BSE and found tbat infectivity was present in several peripheral nerves and one muscle. The method of detection was bioassay in bovinized transgenic mice that show the same or greater sensitivity to transmission of BSE as cattle. This research concurs with findings by Japanese scientists that BSE infectivity is present in peripheral nerves at least in the clinical stage of disease. It is our opinion that there is increasing evidence that the pathogenesis of BSE might not be entirely different from TSEs in other species at the point of clinical disease in that there is peripheral involvement. We feel that the studies as reported above have merit. The current studies not only re-enforce the risk of down and deadstock but also appear to provide additional information that these animals may be a potential source of greater levels of infectivity into the feed system. In the event that FDA may confer with USDA about the risks associated with peripheral nerves we want to point out one issue. In the recent publication of the final rule on the SSOI-Z6L.-ZEL importation of whole cuts OF boneless beef from Japan, 9 CFR Part 94 [Docket No. 05- 004-21 RIN 0579-AB93, we disagree with the interpretation provided by USDA, APHIS. APHIS seems to discount the studies conducted by Groschup et al. 2005. on the basis that the transgenic mouse bioassay that they used may be too sensitive. In taking this position they have failed to realize that the point oFan assay is to reveal in which tissues the infectivity resides and its relative concentration to brain or spinal cord. For this purpose, no assay can be too sensitive. Of course, the probability of an actual infection will he affected by the efficiency of infection which will be a function of dose, route of exposure and any host barrier effects that are present. We would also like to point out a factual error in the conclusion. APHIS states, “Given these factors, APHIS has determined that the finding of l3SE infectivity in facial and sciatic nerves of the transgenic mice is nalt directly applicable to cattle naturally infected with BSE. Therefore, we do not consider it necessary to make any adjustments to the risk analysis for this rulemaking or to extend the comment Fleriod to solicit additional public comment on this issue.” It is incorrect that the infectivity was found in the peripheral nerves of transgenic mice. The peripheral nerves were harvested from a cow naturally infected with BSE. Transgenic mice were used as a bioassay model. From [Docket No. 05-004-21 RIN 0579-AB93: “Peripheral Nerves Issue: Two commenters stalted that the underlying assumption of the proposed rule. that whole cuts of boneless beef from #Japan will not contain tissues that may carry the BSE agent, is no longer valid because researchers have found peripheral nervous system tissues, including facial and sciatic nerves, that contain BSE infectivity.U One of these commenters requested API-W to explain whether and what additional mitigation measures are needed to reduce the risks that these tissues may be present in Japanese beef. This commenter further requested an additional comment period to obtain public comments to treat this new scientiic finding. \2\ Bushmann, A., and Groschup, M.; Highly Bovine Spongiform Encephalopathy-Sensitive Transgenic Mice Confirm the Essential Restriction of Infectivity to the Nervous System in Clinically Diseased Cattle. The Journal of Infectious Diseases, 192: 93442, September 1, 2005. Response: APHIS is familiar with the results of the study mentloned by the commenters in which mice, genetically engineered to be highly susceptible to BSE and to overexpress the bovine prion protein, were inoculated with tissues from a BSE-infected cow. This study demonstrated low levels of infectivity in the mouse assay in the facial and sciatic nerves of the peripheral nervous system. APHIS has evaluated these findings in the context of the potential occurrence of infectivity in the peripheral nerves of cattle and the corresponding risks of the presence of infectivity in such tissues resulting in cattle or human exposure to the BSE agent. The results from these experiments in genetically engineered mice should be interpreted with caution, as the findings may be influenced by the overexpression of prion proteins and may not accurately predict the natural distribution of BSE infectivity in cattle. Further, the overexpression of priori s-d proteins in transgenic mice may not accurately mimic the natural disease process because the transgenic overexpressing mice have been shown to develop spontaneous lethal neurological disease involving spongifolrm changes in the brain and muscle degeneration.\3\ In addition, the route of administration to the mice was both intraperitoneal and intracerebral, which are two very efficient routes of infection as compared to oral consumption. Given these factors, APHIS has determined that the finding of BSE infectivity in facial and sciatic nerves of the transgenic mice is not directly applicable to cattle naturally infected with BSE. Therefore, we do not consider it necessary to make any adjustments to the risk analysis for this rulemaking or to extend the comment period to solicit additional public comment on this issue.” Source of the agent: Deaalstock The total amount of TSE infectivity in a TSE infected animal increases steadily throughout the infection and exponentially once the infectivity reaches the brain. Infected individuals only exhibit recognizable clinical signs once infectivity titers have reached high levels in the brain. Surveillance data collected throughout Europe indicates there is a much greater likelihood for BSE to be detected in dead or down cattle than from healthy normal animals. This has so far also been borne out by the experience in North America. Animals that die of BSE harbor the greatest amount of agent that can be produced by the disease. Leaving the tissues from the highest risk category of cattle in the animal feed chain will effectively nullify the purported intent of this regulation. This point is supported by the 2001 Harvard risk assessment model that demonstrated that eliminating dead and downer, 4D cattle, from the feed stream was a disproportionately effective means of reducing the risk of re-infection. “The disposition of cattle thot die on the farm would also huve a substantial influence on the spread of BSE if the disease were introduced ” The base case scenario showed that the mean rota? number oj’IDS0.s (i.e., dosage suficient to infecf 50percent of exposed cattle) f;om healthy animals at slaughter presented to the foodfeed system was 1500. The mean total number yf IDSOsfiom adult cuttle deadstockpresented fo the feed system was 3 7,000. This illustrates the risk of “40 cattle ” (i.e.. deadstock). From the Harvard Risk Assessment, 200 1, Appendix 3A Base Case and Harvard Risk Assessment, 200 1 Executive Summary It is likely that these numbers would have to be adjusted upwards, if the UK attack rate and Groschup data were considered. Inflammation and TSErr There have been 3 recent peer reviewed publications which indicate that chronic ir&unmatory conditions in a host with a TSE may induce priori replication in, or distribution to organs previously thought to be low or no risk. They are as follows: s-d 1 _ Chronic Lymphocytic Inflammation Specifies the Organ Tropism of Prions (Heikenwalder et. al. 2005 >~xx .sci~:n~c\rpl-css.~~r~/~O .lunuarv 2005/ Parrc l/ &).I 1zois~icllcc.l lOh4hO) 2. Coincident Scrapie Infection and Nephritis Lead to Urinary Priori Excretion (Seeger et al., Science 14 October 2005:Vol. 310. no. 5746, pp. 324 - 326 DOI: lO.l126/science. 1118829) 3. PrPS” in mammary glands of sheep affected by scrapie and mastitis (Ligios C., et al. Nature Medicine, 11. 3 137 - 1138, 2005) These studies from the Aguzzi laboratory warn that concurrent chronic inflammatory disease could dramatically alter the distribution of BSE infectivity in infected cattle. Down and dead stock are at higher risk for both BSE and other systemic conditions. If the results reported above are also applicable to cattle, the carcasses of dead and down stock affected by BSE might contain even higher levels of infectivity, or contribute infectivity via tissues thai. are not ordinarily at risk in normal animals. Exposure: tndustry Practices or Exemptions which may pose a risk Poultry Litter In the United States poultry litter can be fed to cattle. There are two potential sources of risk from poultry litter. Poultry litter not only consists of digested feed but also of feed which spills from the cages. As a consequence, the practice of feeding litter back to cattle is by its nature non--compliant with the current feed ban if the poultry themselves are being fed ruminant protein. Given that ruminant protein can no longer be fed to ruminants in the United States and that most. if not all. countries will no longer import North American ruminant MBM, an even larger part of poultry diets is now ruminant MBM. Spillage provides a direct link to back to cattle but feces are also likely to contain infectivity. There is no reason to expect that TSE infectivity would be inactivated by passage through the poultry gut, and only a slim possibility that composting would reduce infectivity at all. Thus poultry feces are another potential route of transmission back to cattle. Evidence for this comes from rodent experiments where infectivity was demonstrated in the feces after being fed: “Laboratory experiments show that mice orally challenged with scrapie have detectable infectivity that passes through the gut. Gut contents and fecal matter may therefore contain infectivity, and it is noted that in experimental oral challenges in cattle conducted in the UK, feces must be treated asamedical waste for one month following the challenge. It is concluded that digestive contents and fecal material from livestock or poultry currently being fed with MBM potentially contaminated with BSE should not be used a.s a feed ingredient for animal feed.” [Proceedings: Joint WHO/FAO/OIE/ Technical Consultation on BSE: public health, animal health and trade. Paris, lo-14 June 2001; and Alan Dickinson, personal communication]. It may be possible to remove the risk from poultry litter by sterilization. However, unless or until a method can be developed and validated, poultry litter should be banned from ruminant feed. Ruminant Blood In contrast with humans, sheep, monkeys, mice and hamsters, including sheep and mice infected with BSE and humans infected with vCJD considered identical to BSE, no infectivity has so far been demonstrated in the blood of BSE infected cattle. However, we consider it unlikely that cattle are the sole outlier to what has been a consistent finding in all other TSE diseases where the measurement has been made with sufficient sensitivity to detect the low levels of infectivity that are present in blood. Rather, this failure is more likely the result of the very small volumes of blood that were used for the inoculations (less than 1 ml), whereas whole transfusions were administered to assay animals in the published .sheep scrapie/BSE experiments. If blood is infected then all vascularized tissues can bc expected to contain some infectivity in proportion to the content of residual blood.. Micro emboli are a possible source of blood-borne agent that could be at much higher titer than blood itself, in slaughtered cattle carrying BSE infection. Stunning can release micro emboli of brain tissue into the circulatory system from where they can be distributed to other tissues in the few moments before the exsanguination and death. (Anil, et al, 2001a & b; Anil et al, 2002; Love, et al, 2000). This source of infection couid extend a higher infectivity risk to tissues that would otherwise be at low risk, thereby allowing exposure of cattle through any of the legal exemptions and potentially producing a feed and food risk. Blood-borne contamination may be a special problem where spray-dried blood is being used as a milk replacer for calves, as it is thought that young animals are especially susceptible to infection. Certainly, blood and bloald proteins should not be used as feed without conclusive evidence that they are saf’e. Unfiltered Tallow Ruminant tallow is exempted from the current feed ban. Tallow contains protein impurities (i.e. MBM) that could be a source of TSE infectivity. There are no impurity level requirements for this tallow. It has been reported that it is standard practice to produce tallow which has an impurity level of _ 15% or below, but it is not clear that this is fully adequate to remove the risk of transmission and there is no requirement to meet even this standard. We urge that protein contaminants be excluded from tallow and that SRMs also be removed. 6-d Plate Waste Plate waste is not limiteld to meat (muscle tissue). For example, cuts that include a portion of the spinal cor’d or that are contaminated by cord or ganglia during preparation could contain high levels of infectivity if derived from a TSE infected animal late in the preclinical stage of infection. At best this material would only be exposed to normal cooking temperatures. USDA, APHIS experience with the Swine Health Protection Act has revealed that plate waste also includes uncooked trimmings and bones. Although the current FDA regulation requires the plate waste be treated again, there are no specifications which would render a TSE agent inactive. Of greatest risk would be any bovine source of infectivity but also sheep scrapie, although not known to be a risk for human consumption, is one of the possible origins of BSE. The sheep scrapie agent is known to be widely dispersed including relatively high titers in lymphoid as well as nervous tissue. We support the USDA’s opposition to the exemption of “plate waste” as stated in written comments since 1997. Exposure: Cross Feeding and Cross Contamination The UK epidemiology has clearly shown that BSE contaminated feed is the primary if not sole vehicle for the transmission of BSE between cattle. Moreover, results from the United Kingdom’s attack: rate study indicate that it does not take much exposure to transmit BSE to cattle. FLecent results from the attack rate study which is still in progress have found that _ 1 g of brain transmitted BSE by the oral route to 3 cows out of 15 thus far, and .Ol and .OOl gr of brain have transmitted BSE (1 cow out of 15). (Danny Matthews, DEFRA presentation at TAFS meeting, Washington, DC April 2004). Rendering may reduce infectivity but it does not eliminate it. (Taylor et al, 1995; Taylor et al, 1997; Schreuder et al, 1998). Given that BSE can be transmitted to cattle via an oral route with just .OO 1 gram of infected tissue, it may not take much infectivity to contaminate feed and kee:p the disease recycling. This is especially true in countries like the US and Canada which do not have dedicated lines and equipment to manufacture and process feed for ruminants and non-ruminants. In addition, epidemiological investigations in European countries have shown that cross feeding and cross contamination on farm can be a significant vehicle for continued BSE transmission even after feed bans are well established. Cross feeding is the practice of feeding meal for poultry or pigs or pet food (which can legally contain ruminant MBM) to cattle on the same farm. This is usually due to simple human error or negligence. (Hoinville, 1994; Hoinville et al, 1995; Doherr et al, 2002% Stevenson et al, 2000) FDA, CVM reports that compliance with the existing feed ban is high. For the most part this does not include the compliance level on the farm. There are hundreds of thousands of farms in the US. Many of these have multiple species- That is, they raise cattle, pigs, chickens etc., on the same premises. The sheer numbers of farms make it very difficult to assure compliance on farm and to adequately cover all farms by inspection- Even if the rendering industry and feed industry can maintain 100% compliance at their facilities, if a producer inadvertently feeds chicken feed containing bovine MBM to their cattle, they negate a perfect compliance rate higher in the chain. Recent data from the Harvard BSE risk assessment suggest that the level of misfeeding on farms plays a significant role in the ability of the agent to recycle. In fact George Gray, principal investigator for the study, stated that if, in the United States, misfeeding were to occur at a level of 15%, the RO would be over 1, indicating that the BSE level would not be declining. (George Gray presentation at the Meeting on BSE Prevention in North America: An Analysis of the Science and Risk; January 27,2005, Washington, DC.) The May 2003 Canadian BSE case illustrates the difficulty of on farm enforcement and its serious ramifications. The BSE positive cow was rendered and the MBM distributed to various locations. Two of these locations were poultry farms which mixed their own feed. The farms also had cattle. The subsequent investigation could not eliminate the possibility that the cattle had been fed the same feed as the poultry. The cattle on these farms were completely depopulated. Human error is extremel:y difftcult to prevent, and managing the risk through enforcement is problematical when confronted with the extreme logistical challenges of on farm monitoring. By eliminating the highest risk materials (SRMs and deadstock) which could introduce infectivity into the feed stream, the MBM resulting from processing becomes inherently safer. If mistakes are then made on farm, they no longer contribute to the recycling of BSE. Exposure: Susceptibility of other Species Felines A transmissible spongifoim encephalopathy has been diagnosed in eight species of captive wild ruminants as well as exotic felines (cheetahs, pumas, a tiger and an ocelot) and domestic cats (Wyatt 1991). There have been over 80 domestic cat cases of Feline Spongiform Encephalopathy (FSE) in Great Britain, and cats in Norway, Northern Ireland, Lichtenstein and Switzerland. The agent isolated from several of these cases is indistinguishable from BSE in cattle using strain typing in mice, duggesting that FSE is actually BSE in exotic and domestic cats. Epidemiological evidence suggests BSE contaminated feed to be the probable source of infection in these species. (MAFF Progress Report, June 1997), thus providing additional supporting evidence for the dangers of BSE contaminated feed and reinforcing the necessity of removing all sources of potential contamination from the feed stream Other species Studies conducted at the National lnstitutes of Health Rocky Mountain Laboratory caution against assuming that animals which do not become clinically ill are not infected. It is unknown if certain animals may become carriers, i.e., become infected, shed agent but do not progress to clinical disease. Infection of certain rodent species with different TSE strains suggests the possibility of a carrier state (Race and Chesebro, 1998; Race et. al, 2001, Race et al., 2002). In the more recent studies, mice were inoculated with 263K hamster scrapie. There was a prolonged period (approximately one year) where there was no evidence of replication of infectivity. Furthermore, there was no evidence of PrPres during this phase of inactive persistence, which was followed by a period of active replication of infectivity and agent adaptation. In most cases, PrPres was not detected in the active phase as well. It is important to determine if this persistence and adaptation occurs in other species exposed to TSEs as it may have significance in feeding programs which continually expose other species to BSE infectivity. For example, if BSE infected brain and spinal cord are continually fed to certain species, it may be possible for the agent to persist and adapt in these new species. Over time, the ‘resistant’ species may become a source of agenl. The results of Race and colleagues, warns that an inactive persistent phase might not produce detectable PrPres, yet there would be infectivity (Race et. al., 2001). Pigs displayed evidence of TSE infection after exposure to BSE by 3 distinct parer&ml routes. Evidence of infectivity was found in the CNS, stomach, intestine and pancreas (Dawson et. al., 1990). CIral transmission has also been attempted in swine, but after an observation period of 84 months there was neither clinical nor pathological evidence of infection (Dawson et. al., 1990). Parenteral and oral transmission has also been attempted in chickens with no evidence of disease. Tissues from the BSE-challenged pigs and chickens were inoculated into susceptible mice to look for residual infectivity, but to date none has been found. In both instances the detection sensitivity was limited by the use of mice for bioassay instead of same species transmissions into cattle (or pigs and chickens). If any of these scenarios played out and inapparent infections became established in commercial species, those species could become reservoirs for reinfection of cattle and perpetuation or reintroduction of the epidemic. We also do not know if atypical cases of BSE are more pathogenic for other species and if chronic inflammation may influence the susceptibility of other species. We offer these possibilities to reitiorce the need to eliminate all possible sources of infectivity from the feed stream. In January 2005, the European Union announced that BSE had been confirmed in a goat in France illustrating that the disease can be naturally transmitted to one of the small ruminants. The potential ramifications of this and the logistical chaIlenges associated with controlling BSE in sheep or goats also provides a justification for removing SRMs from all animal feed. Although these species are covered under the current regulations the cross contamination and cross feeding aspects stated for cattle are applicable. The need to remove high risk material from all animal feed is also supported by other bodies with expertise in the field of TSEs: Recommendations of the World Health Organization (WHO) The World Health Organization (WHO) has issued the following recommendations for countries with BSE or those where a known exposure exists: l No part or product of any animal which has shown signs of a TSE should enter any food chain (human or animal). In particular: o All countries must ensure the killing and safe disposal of all parts or products of such animals so that TSE infectivity cannot enter any food chain. o Countries sholuld not permit tissues that are likely to contain the BSE agent to enter any food chain (human or animal). From the report of a WHO Consultation on Public Health Issues related to Human and Animal Transmissible Spongiform Encephalopathies WHO/EMC/DIS 96.147, Geneva, 2-3 April 1996. Office of International El- The OIE is recommendinlg that a list of SRMs which include brain, spinal cord, eyes, skull and vertebral column be removed from preparations used for food, feed, fertilizer, etc. If these tissues sholtld not be traded we feel that they should not be used in domestic products either. BSE Code Article 2.3.13.18 “From cattle, originating from a country or zone with a minimal BSE risk, that were at the time of slaughter over 30 months of age, the following commodities, and any commodity contaminated by them, should not be traded for the preparation of Food, feed, fertilizers, cosmetics, pharmaceuticals including biologicals, or medical device:s: brains, eyes and spinal cord, skull, vertebral column and derived protein products. Food, feed, fertilizers, cosmetics, pharmaceuticals or medical devices prepared using these commodities should also not be traded.” Conclusion In conclusion we urge the: FDA to implement, monitor and enforce a comprehensive and protective feed ban that is more congruent with the measures that have been proven to be effective in other countries that have experienced BSE. We do not feel that we can overstate the dangers from the insidious threat from these diseases and the need to control and arrest them to prevent any possibility of spread. We also wish to emphasize that as scientists who have dedicated substantive portions of our careers to defining the risks from TSEs as well as developing strategies for managing those risks, we are confident that technical solutions will be found for many of the challenges posed by these diseases. Thus, we urge the FDA to frame its regulations in terms that allow for the future use of any banned material if it can be proven safe for a given application. El-d Signatories: Paul W. Brown, M.D. Medical Director, USPH[S, and Senior Investigator, NIH (retired) Consultant, TSE Risk Management 78 15 Exeter Rd. Bethesda, MD 208 14 Fax 301-652-43 12 Email: paLII\\ hr-c~~~rl~~/‘~c)m~as~.rlct ----- Neil R Cashman MD Professor, Department 0-C Medicine (Neurology) Diener Chair of Neurode:generaGve Diseases Centre for Research in Neurodegenerative Diseases 6 Queen’s Park Crescent West Toronto Ontario M5S3H2 Ph: 416-978-1875 Fax: 4 16-978- 1878 e-mail: neil.cashman@utoronto.ca Linda A. Detwiler, DVM Consultant, TSE Risk Management 225 Hwy 35 Red Bank, NJ 07701 Ph 732-74 l-2290 Fax 732-741-775 1 Email: l.~\Vc~92’rr’ac,l.c0111. Laura Manuelidis, MD Professor and Head of Neuropathology, Department of Surgery and Faculty of Neurosciences Yale Medical School 333 Cedar St. New Haven, CT 065 10 email: I~IL~ra.~~~ar~clclirli~~~~~~alc.cdi~ Tel: 203-785-4442 Jason C. Bar-k, Ph.D. Assistant Professor Department of Medical Microbiology and Immunology Creighton University 2500 California Plaza Omaha, NE 68178 (402) 280- 18 11 voice (402) 280-l 875 fax jbartz@creighton .edu Robert B. Petersen, Ph.D. Associate Professor of Pathology and Neuroscience Case Western Reserve University 5- 123 Wolstein 13~1ilding 2 103 Cornell Road Cleveland, OH 44 106-26122 Phone 216-368-6709 FAX 360-838-9226 Email rhp~,-c\\~~.c~!t~ Robert G. Rohwer, Ph.D. Director, Molecular Neurovirology Laboratory Veterans Affairs Medicall Center Medical Research Service 151 Assoc. Professor of Neurology School of Medicine University of Maryland ;at Baltimore 10 N. Greene St. Baltimore, MD 21201 ph. 4 1 O-605-7000 x6462 Fax 4 1 o-605-7959 email: rrohwer@maryland.edu REFERENCES Andreoletti 0, Simon S, Lacroux C, Morel N, Tabouret G, Chabert A, Lugan S, Corbiere 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 - Fleischwirtschaft 200 1; 11: 123 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): 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 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. 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 McDonald’s 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: 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 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. McDonald’s 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 McDonald’s 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, McDonald’s 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 McDonald’s 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 630-623-6754 Direct 630-623-3057 Facsimile dick.crawford@mcd.com C:\Documents and Settings\mc07605\My Documents\MYDATA\BSE - US\FDA\Final McD's comments to FDA Rule 12-19-05.doc THE SEVEN SCIENTIST REPORT *** pharmaceutical supplier Seriologicals Corp. snip... The current proposed rule falls short of this and would still leave a snip... Respectfully, http://www.fda.gov/ohrms/dockets/dockets/02n0273/02n-0273-c000383-01-vol35.pdf Date: Tue, 10 Jan 2006 09:39:57 -0600 ##################### Bovine Spongiform Encephalopathy ##################### Subject: MAD COW FEED BAN WARNING LETTER December 21, 2005 Kansas City District CERTIFIED MAIL WARNING LETTER Ref. KAN 2006-08 Mr. Paul Rasmussen, President Dear Mr. Rasmussen: An investigator from our office conducted two inspections of your animal feed manufacturing operations at 415 N. Locust St., Goldfield, Iowa on August 23 and August 25 -26, 2005. During these inspections, a significant deviation from the requirements set forth in Title 21, Code of Federal Regulations (CFR), Part 589 .2000 [21 CFR 589 .2000] - Animal Proteins Prohibited in Ruminant Feed, was identified . The regulation is intended to prevent the establishment and amplification of Bovine Spongiform Encephalopathy (BSE). Our investigation found a failure to label one of your products, "ISLACT - IS LACTATION," a swine feed, with the statement "Do Not Feed to Cattle or Other Ruminants," as required by 21 CFR 589 .2000(d) . Although your swine feed is not formulated with protein derived from mammalian tissues as defined in 21 CFR 589 .2000(a)(1), which is prohibited in ruminant feed, your production practices may cause the finished product to contain such material. Our investigator found that your firm does not have a strategy for sequencing feeds and does not flush or otherwise clean shared production equipment between the manufacture of poultry feed formulated with protein derived from mammalian tissues and swine feed formulated without such material . As a result, swine feed may acquire protein derived from mammalian tissue from poultry feed residue remaining on the shared production equipment. Your failure to label your "ISLACT - IS LACTATION" swine feed with the statement "Do Not Feed to Cattle or Other Ruminants" causes it to be misbranded under section 403(a)(1) of the Act. The above is not intended to be an all-inclusive list of deficiencies at your facility. As a manufacturer of animal feed, you are responsible for ensuring that your overall operation and the products you manufacture and distribute comply with the law. You should take prompt action to correct this violation and establish a system whereby such violations do not recur. Failure to promptly correct this violation may result in regulatory action, such as seizure and/or injunction, without further notice. You should notify this office in writing of the steps you have taken to bring your firm into compliance with the law within fifteen (15) working days of receiving this letter. Your response should include an explanation of each step being taken to correct the violation and prevent its recurrence. If corrective action cannot be completed within fifteen (15) working days, state the reason for the delay and the date by which the corrections will be completed. Please include copies of any available documentation demonstrating that corrections have been made. Please send your reply to the Food and Drug Administration, Attention: Ralph Gray, Compliance Officer, 11630 West 80th Street, Lenexa, KS 66214-3340. Sincerely, C.R. Pendleton for John W. Thorsky #################### https://lists.aegee.org/bse-l.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 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 ; SUB CLINICAL PRION INFECTION MRC-43-00 Issued: Monday, 28 August 2000 NEW EVIDENCE OF SUB-CLINICAL PRION INFECTION: IMPORTANT RESEARCH FINDINGS RELEVANT TO CJD AND BSE P.O. Box 42 Bacliff, Texas USA 77518 9/13/2005 http://www.fsis.usda.gov/OPPDE/Comments/03-025IFA/03-025IFA-2.pdf Docket No, 04-047-l Regulatory Identification No. (RIN) 091O-AF46 NEW BSE SAFEGUARDS (comment submission) https://web01.aphis.usda.gov/regpublic.nsf/0/eff9eff1f7c5cf2b87256ecf000df08d?OpenDocument http://www.fda.gov/ohrms/dockets/dockets/03n0312/03N-0312_emc-000001.txt Animal Food or Feed; Animal Proteins Prohibited in Ruminant Feed Comment Number: EC -10 Accepted - Volume 2 Docket No. 2003N-0312 Animal Feed Safety System [TSS SUBMISSION http://www.fda.gov/ohrms/dockets/dockets/03n0312/03N-0312_emc-000001.txt PDF]Freas, William TSS SUBMISSION File Format: PDF/Adobe Acrobat - Page 1. J Freas, William From: Sent: To: Subject: Terry S. Singeltary Sr. [flounder@wt.net] Monday, January 08,200l 3:03 PM freas ... Asante/Collinge et al, that BSE transmission to the 129-methionine genotype can lead to an alternate phenotype that is indistinguishable from type 2 PrPSc, the commonest _sporadic_ CJD http://www.fda.gov/ohrms/dockets/ac/03/slides/3923s1_OPH.htm Docket: 02N-0276 - Bioterrorism Preparedness; Registration of Food Facilities, Section 305 snip... Greetings list members, i just cannot accept this; > 23 kg of meat in a suitcase (suitcase bomb...TSS) > The data do not provide a species of origin code for these > products, therefore they may not contain any ruminant product. what kind of statement is this? how stupid do they think we are? it could also very well mean that _all_ of it was ruminant based products ! snip... Greetings FDA and public, if you go to the below site, and search all BSE known countries and check out their air traffic illegal meat they have confiscated, and check out the low number checked, compared to actual passenger traffic, would not take too much for some nut to bring in FMD/TSEs into the USA as a 'suitcase bomb'. [[Under APHIS-PPQ's agricultural quarantine inspection monitoring, 284 air passengers from Israel were sampled for items of agricultural interest in fiscal year 2001. Seven of these passengers, or 2 percent, carried a total of 11 kg of meat items that could potentially harbor the pathogen that causes BSE. None of these passengers from whom meat items were confiscated reported plans to visit or work on a ranch or farm during their visit to the U.S.]] if they were to have questioned the terrorist that bombed the Twin Towers with jets, if they were to have questioned them at flight school in the USA, i am sure that they would have said they did not intend to visit the Twin Towers as a flying bomb either. what am i thinking, they probably did ask this? stupid me. [[In 1999 a small amount of non-species specific meat and offal was imported and a small amount of fetal bovine serum (FBS) was also imported. FBS is considered to have a relatively low risk of transmitting BSE.]] more of the USA infamous 'non-species coding system', wonder how many of these species are capable of carrying a TSE? snip... Greetings again List Members, let me kick a madcow around here a bit. on the imports from Poland and the infamous USA 'non-species' coding system. the USDA/APHIS states; > During the past four years (1998 - 2001), US imports from > Poland included non-species specific animal products > used in animal feeds and non-species specific sausage and offal > products (Table 3). Given US restrictions on ruminant product > imports, these US imports should not have contained ruminant > material. NOW, if you read Polands GBR risk assessment and opinion on BSE, especially _cross-contamination_, it states; ANNEX 1 Poland - Summary of the GBR-Assessment, February 2001 EXTERNAL CHALLENGE STABILITY INTERACTION OF EXTERNAL CHALLENGE AND STABILITY The very high to extremely high external challenge met a very unstable system and could have led to contamination of domestic cattle in Poland from 1987 onwards. This internal challenge again met the still very unstable system and increased over time. The continuing very high external challenge supported this development. Not OK MBM-ban since 1997, but no feed controls. Reasonably OK Heat treatment equivalent to 133°C / 20min / 3 bar standards, but no evidence provided on compliance. Not OK. No SRM-ban, SRM are rendered and included in cattle feed. BSE surveillance: Not sufficient before 2001. Cross-contamination: Lines for ruminant and non-ruminant feed in feed-mills only separated in time and no analytical controls carried out. Likely present since 1987 and growing. see full text and ANNEX 1 at; http://europa.eu.int/comm/food/fs/sc/ssc/out185_en.pdf so in my humble opinion, the statement by the USDA/APHIS that ''these US imports _should_ not have contained ruminant materials, is a joke. a sad joke indeed. * POLAND BSE GBR RISK ASSESSMENT http://europa.eu.int/comm/food/fs/sc/ssc/out185_en.pdf snip... full text; http://www.fda.gov/ohrms/dockets/dockets/02n0276/02N-0276-EC-254.htm 2006 POLAND BSE Subject: Poland Bse and animal nutrition & bse, scrapie testing Member States 01/2006 Poland Bse and animal nutrition 7693-2005 http://europa.eu.int/comm/food/fvo/act_getPDF.cfm?PDF_ID=4951 http://europa.eu.int/comm/food/fvo/act_getPDFannx.cfm?ANX_ID=4540 http://europa.eu.int/comm/food/fvo/act_getPDFannx.cfm?ANX_ID=4541 Subject: New case of mad cow disease in Poland AFX News Limited WARSAW (AFX) - A new case of bovine spongiform encephalopathy (BSE), or mad cow disease, has been detected in Poland, the country's veterinary service said. The head of the national veterinary service, Krzysztof Jazdzewski, said that the infected animal was found on a farm in the northwest of the country and had been put down. 'The disease was detected on a farm with a total of 18 animals. Eight of them have been identified as exposed to risk (of contamination) and have been killed,' he said. There have been more than 22 cases of mad cow disease in Poland since it began testing for BSE in 2001. newsdesk@afxnews.com afp/jsa Subject: BSE--U.S. 50 STATE CONFERENCE CALL Jan. 9, 2001 ######### Bovine Spongiform Encephalopathy Greetings List Members, I was lucky enough to sit in on this BSE conference I submitted a version of my notes to "They tell me it is a closed meeting and and i would have been doing just fine, (understand, these are taken from my notes for now. [host Richard Barns] [TSS] [no answer, you could hear in the back ground, [host Richard] [TSS] [not sure whom ask this] [TSS] [not sure who is speaking] [TSS] [not sure whom speaking] from this point, i was still connected, got to listen [unknown woman] [TSS] at this point the conference was turned back up, IF i were another Country, I would take heed to my RBARNS@ORA.FDA.GOV he would be glad to give you one ;-) Rockville Maryland, BSE issues in the U.S., The conference opened up with the explaining of although new cases in other countries were now Look at Germany whom said NO BSE and now have BSE. BSE increasing across Europe. Because of Temporary Ban on certain rendered product, A recent statement in Washington Post, said the BSE Risk is still low, minimal in U.S. with a greater HOWEVER, if BSE were to enter the U.S. (human health-they just threw that in cause i was listening. I will now 80% inspection of rendering *Problem-Complete coverage of rendering HAS NOT sizeable number of 1st time FAILED INITIAL INSPECTION, Compliance critical, Compliance poor in U.K. Gloria Dunason Rendering FDA license and NON FDA license system in place for home rendering & feed 279 inspectors Renderer at top of pyramid, significant failed to have caution statement render 56 FIRMS NEVER INSPECTED 1240 FDA license feed mills "close to 400 feed mills have not been inspected" 80% compliance for feed. 10% don't have system. NON-FDA licensed mills 40% do NOT have caution statement 'DO NOT FEED'. 74% Commingling compliance "This industry needs a lot of work and only half "700 Firms that were falitive, and need to be Quote to do BSE inspection in 19 states by end At this time, we will take questions. [I was about the third or fourth to ask question. someone asking about nutritional supplements and Some other Dr. Vet, whom were asking questions [Dennis Wilson] [Conference person] [Linda Singeltary ??? this was a another phone in (conference person) Dennis Blank, Ken Jackson (they really don't know how many non licensed Firms Linda Detwiler Warren-Maryland Dept. Agr. THE END TSS ############ http://mailhost.rz.uni-karlsruhe.de/warc/bse-l.html Subject: Re: BSE 50 STATE CONFERENCE CALL thread from BSE List and FDA Hi terry -- thanks for all your help. I know it made a difference with Many Makers of Feed Fail to Heed Rules on Mad Cow Disease Large numbers of companies involved in manufacturing animal feed are not The widespread failure of companies to follow the regulations, adopted But much more needs to be done to ensure that mad cow disease does not The regulations state that feed manufacturers and companies that render All products that contain rendered cattle or sheep must have a label Under the regulations, F.D.A. district offices and state veterinary Among 180 large companies that render cattle and another ruminant, Then there are some 6,000 to 8,000 feed mills so small they do not On the other hand, fewer than 10 percent of companies, big and small, The American Feed Industry Association in Arlington, Va., did not return http://www.nytimes.com/2001/01/11/science/11COW.html Subject: USDA/APHIS would like to provide clarification on the following point [Linda Detwiler asking everyone (me) not to use emergency BSE number, Dr. Detwiler was responding to an announcement made during the call to ############ http://mailhost.rz.uni-karlsruhe.de/warc/bse-l.html Subject: Hello Mr. Thomas, > What Mr. Singeltary failed to do was provide would you and the USDA/APHIS be so kind as to supply > The system has been in place for over 10 years. that seems to be a very long time for a system to be in Why does the U.S. insist on not doing massive testing Please tell me why my question was not answered? > U.S. cattle, what kind of guarantee can you It was a very simple question, a very important If all these years, we have been hearing that Before i was ask to be 'disconnected', could you please be so kind, as to answer these thank you, P.S. if you will also notice, i did not post that BUT, they should be reported, some are infected with TSE. 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