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Consumers Union's Comments on Docket No. 96N-0135,
Substances Prohibited for Use in Animal Food or Feed;
Animal Proteins Prohibited in Ruminant Feed, Draft Rule
April 28, 1997
Summary
Consumers Union commends the U.S. Food & Drug Administration (FDA) for considering steps to prevent the possible occurrence and spread of transmissible spongiform encephalopathies (TSEs) in ruminants. However, the draft rule is not adequate to protect public health, because it would continue to leave the door open for a porcine TSE to contaminate pork and other meat.
In January, the FDA proposed banning the use of protein derived from ruminant and mink tissues in ruminant feeds. The present draft rule states that protein derived from any mammalian tissues would be prohibited in ruminant feed. Although this sounds like a significant extension of the original proposal, it really is not, primarily because pigs are excluded from the definition of "any mammalian tissue."
Further, we think that this draft rule sends a particularly dangerous message. The draft rule suggests, that of all mammals, pigs are the safest and/or least likely to be infected with a TSE. We think this message is incorrect. Evidence from a number of sources suggests that pigs may already be infected with a TSE or TSE-like disease. The evidence comes from a 1979 USDA study of pigs and from two epidemiological studies that link consumption of pork to a human TSE-Creutzfeldt Jakob Disease (CJD).
The FDA should ban the use of all mammalian protein, including porcine protein, blood and gelatin, from all feed intended for food animals (not just ruminant feed), as has been done in the United Kingdom. Anything less than this leaves open the possibility that a TSE could, in fact, spread among food animals in the United States.
USDA 1979 study
The evidence for a TSE disease in pigs comes from a 1979 USDA study of pigs with Central Nervous System (CNS) symptoms at a packing plant in upstate New York. The study was discussed in some detail in a letter we sent to the FDA on March 27, 1997. That letter is appended to these comments and we request that it be included in the docket.
In brief, the 1979 study involved 106 pigs that exhibited similar clinical behaviors consistent with CNS symptoms. The study consisted of both clinical and pathological work. Known infectious diseases were ruled out. Thirteen of the affected pigs were filmed to document the subtle CNS symptoms. A pathological examination of the brains of these animals revealed no consistent patterns. The brain of one pig (#2709), however, had evidence suggestive of a TSE (vacuolation of neurons, astrocytosis). The Pathologist-in-Charge at USDA's Eastern Pathology lab, who examined the brain, stated that the pathologic evidence was similar to that seen in scrapie and transmissible mink encephalopathy and diagnosed the case as "Encephalopathy and diffuse gliosis [astrocytosis] of undetermined etiology" (Langheinrich, 1979).
Since BSE had not emerged in 1979, nothing came of the USDA work. However, the USDA inspector who did the 1979 study noticed that the symptoms displayed by cows with BSE were remarkably similar to the behaviors seen in the pigs in 1979. Indeed, virtually all the behaviors mentioned as characteristic of BSE in a USDA training video containing footage from BSE-affected cattle in the UK are also seen in the pigs from the 1979 study in the film of the 13 affected pigs (Doi, pers. com., April 14, 1997).
In November, 1996, the USDA sent a single slide from pig brain #2709 to Dr. William Hadlow, a retired USDA researcher and one of the foremost veterinary pathology experts on TSEs in the world. He found evidence suggestive of a TSE, but felt that it would be useful to see sections from other portions of the brain.
In late March, 1997, the USDA sent Dr. Hadlow slides from seven other parts of the brain of pig #2709 and he has examined them. A copy of his report is attached. The staining of the slides made interpretation difficult: "All sections of nervous tissue are small and faintly stained (pale pink) with H&E making it difficult to identify and evaluate specific structures. . . . Because of the extremely pale staining, neither spongiform change nor neuronal degeneration/loss is identified with certainty" (Hadlow, 1997). However, he continues to find the evidence suggestive of a TSE. Dr. Hadlow found diffuse astrocytosis, another characteristic of TSEs, in all the slides. He speculates that a TSE in pigs could be expressed morphologically mainly by astrocytosis, without other symptoms (e.g. spongiform change and neuronal degeneration/loss) characteristic of TSEs: "Should neurologic disease occur in swine exposed to that agent, conceivably it could be expressed microscopically mainly by astrocytosis, as is scrapie in some sheep and as is the encephalopathy in cattle experimentally infected with the scrapie agent from American sheep" (Hadlow, 1997: 2).
However, because astrocytosis can be caused by a number of injuries to nervous tissue, Dr. Hadlow believes that finding alone is not enough to conclusively state that the pig had a TSE. To be sure of a TSE diagnosis would require a detailed microscopic examination of the brain and/or immunostaining for PrP-res: "A thorough microscopic examination of the brain, which included key structures affected in TSE of animals, would have to be made to evaluate fully the morphologic basis of the neurologic disease in this pig. This can not be done with the several small poorly-stained sections I examined" (Hadlow, 1997: 1). Dr. Hadlow concludes his letter by suggesting that (if any preserved brain tissue still exists and can be located) immunostaining for PrP-res could help resolve the question of whether this pig had a TSE: "the results of immunostaining for PrP-res would help resolve the uncertainty about the nature of the neurologic disease in this pig. The presence of PrP-res in the central nervous system is now generally accepted as conclusive evidence of TSE in both man and animals. The technique is especially useful in determining whether a neurologic disease is TSE when that can not be done histologically because the findings are insufficient or equivocal, as in this pig" italics added (Hadlow, 1997: 2).
In sum, although Dr. Hadlow can't conclusively say that pig #2709 had a TSE, he thinks the evidence is suggestive: "Thus, although pig #2709 could have suffered from a scrapie-like disease, I can not conclude that . . . I do not think concluding otherwise at this time is justified by the limited microscopic findings, however suggestive of a TSE they may be" italics added (Hadlow, 1997).
Epidemiological Studies Linking CJD to Pork Consumption
As for the human epidemiological evidence, we are aware of two epidemiological studies in the scientific literature that address whether there are any dietary risk factors for CJD. Both studies found links to pork. The first study was published in 1973 and involved 38 CJD patients (Bobowick et al., 1973); the controls consisted of the nearest relative (n=35), usually a spouse; and/or a friend of the patient of the same sex and age of the patient (n=33). The study asked only three questions about food items (eating of brains, raw meat or raw seafood) and found that over one-third of the CJD patients ate brains (14 of 38, or 36.8%). Clearly, far fewer than one-third of the general population consumes brains, so there is an overabundance of brain eaters among the CJD patients. Sources at USDA tell us that approximately 1 million animal brains are removed for human consumption every year. If each brain eater only consumed one brain a year, this would mean that less than 1% of the population consumes brains.
In the study, 28.6% (10 of 35) of the nearest relatives and 36.4% (12 of 33) of the friends also ate brains, so that there were no statistically significant differences between patients and controls. The overabundance of brain eaters in the control groups is probably due to the phenomenon of over matching of the controls. As the authors note, "by controlling with a relative and close friend, we run the risk of over matching, and while detectable differences are more impressive, factors which could be important etiologically would not be apparent because they are shared by the controls" (Bobowick et al., 1973: 391). Food items would be one such factor; spouses and friends are arguably likely to eat the same unusual foods as patients.
In spite of the problem of overmatching, the authors noted that compared to controls, "the practice [of eating brains] was more frequent among patients and the patients had a greater preference for hog brains" (Bobowick et al., 1973: 381). Among the CJD patients, 71% (10 of 14) consumed hog brains compared to 60% (6 of 10) for relatives and 25% (3 of 12) for friends. The others who ate brains did so rarely and didn't know what kind of brain it was. Ten of the 14 CJD patients had also eaten brains within the past 5 years.
The second study, published twelve years later in 1985, involved 26 CJD patients; the controls consisted of the nearest relative (n=18), usually a sibling (14 of 18), and a hospital control (n=22) (Davanipour et al., 1985). Hospital controls consisted of an inpatient (of the same sex and age) admitted to the same hospital at about the same time as each CJD case. This study included questions about 45 separate food items and how frequently--never, ever, low [less than once a month], and high [greater than once a month]-- they were eaten.
The study found that 9 individual food items were statistically linked to increased risk of CJD (the study actually calculated odds ratios for the various food items). Of these 9 food items, 6 came from pigs: "An increased consumption among [CJD] patients was found for roast pork, ham, hot dogs (p < .05), roast lamb, pork chops, smoked pork, and scrapple (p < .10)" (Davanipour et al., 1985: 443). An excess consumption of liver and raw oysters/clams was also reported among the patients. Furthermore, there was evidence of dosage dependency with the pork products, i.e. the more you ate the greater the risk of contracting CJD: "The data also suggest a dose-response relationship for most of the process meats examined. A positive association for smoked pork, deli ham/canned ham, hot dogs and scrapple was found" (Davanipour et al., 1985: 446). The authors state that the results suggest that a TSE agent could already be present in pigs: "The present study indicated that consumption of pork as well as its processed products (e.g., ham, scrapple) may be considered as risk factors in the development of Creutzfeldt-Jakob disease. While scrapie has not been reported in pigs, a subclinical form of the disease or a pig reservoir for the scrapie agent might conceivably exist" italics added (Davanipour et al., 1985: 448).
Given the relatively small number of CJD patients in the study, the authors called for more focused research involving larger numbers of patients: "If Creutzfeldt-Jakob disease is acquired through ingestion of foods containing the agent, then the food items identified may be among those which need to be evaluated more intensively. Larger case-control studies with more focused dietary questions are warranted" (Davanipour et al., 1985: 443). To our knowledge, such a larger case-controlled study, which clearly needs to be done, has not been undertaken.
In sum, there is some suggestive, but not definitive, evidence from the 1979 pig study in upstate New York for the existence of a previously unrecognized pig TSE. The epidemiological evidence further suggests a connection between consumption of pork products and increased risk of CJD, a human TSE. The epidemiological study implies both that a TSE may be present in pigs and further that the pig TSE is infectious to humans. The fact that evidence from a pig study and human studies both point to a unrecognized TSE in pigs is very disturbing.
Related Data on CJD Incidence
It is frequently argued that TSEs are not in the food supply and do not pose a potential threat to human health because the incidence of CJD has not risen over the years and is remarkably stable at about 1 in a million. However, a number of studies suggest that CJD may be misdiagnosed as Alzheimer's disease or other senile dementia and that a small percentage of the Alzheimer's cases are actually CJD. A study at the University of Pittsburgh, in which autopsies were done on 54 demented patients diagnosed as having probable or possible Alzheimer's or some other dementia (but not CJD), found 3 cases (or 5.5%) of CJD among the 54 studied (Boller et al., 1989). A Yale study found that of 46 patients diagnosed with Alzheimer's , 6 (or 13%) were CJD at autopsy (Manuelidis and Manuelidis, 1989). Since there are over two million cases of Alzheimer's disease currently in the United States, if even a small percentage of them turned out to be CJD, there could be a hidden CJD epidemic.
Until more definitive evidence can be gathered on the potential for a TSE in pigs, on the connection between consumption of pig products and CJD, and on the extent of CJD, CU feels that FDA must expand their feed ban to include hogs. By this we mean that FDA should expand the feed ban so that no mammalian protein including pork is fed back to any animal destined for human consumption. If FDA does not expand the feed ban, this could potentially lead to a spreading of a TSE in pigs, cattle and sheep, and possible deaths from CJD.
Exemptions for Blood Products and Gelatin
In the draft rule, there are five exceptions to the definition of mammalian protein, i.e. five different classes of mammalian protein that would be exempt from the rule. We disagree with three of the five exceptions.
First, as noted above, porcine protein should not be exempt from the definition of mammalian protein.
Second, FDA should not allow any exemption for blood and blood products. There is evidence that suggests that blood products may contain the infectious agent. A paper published in 1985 demonstrated that blood products from CJD victims (the "buffy coat" fraction) induced a TSE in guinea pigs (Manuelidis et al., 1985); this is not surprising as the prion protein is found on the surface of white blood cells (the "buffy coat" fraction). In 1996, the United Kingdom's Spongiform Encephalopathy Advisory Committee recommended that blood meal not be used as either a feed ingredient or a fertilizer (SEAC, 1996).
Several weeks ago, at a World Health Organization meeting on BSE and CJD, Dr. Paul Brown announced that his lab had taken blood from mice infected with CJD, injected that blood into the brains of healthy mice, and the latter subsequently developed a TSE: "Paul Brown, a leading expert on both CJD and BSE based at the National Institute of Health in Bethesda, Maryland, said he injected blood from mice infected with the human form of mad cow disease into the brains of health mice, which became ill. He told a final news conference that the risk of blood plasma passing on CJD was small, but still existed" (Kaban, 1997). Dr. Brown's work conclusively demonstrates that blood and blood products do contain the TSE-causing agent. If this is true for CJD, we must assume that it would be true for BSE and other TSEs. Thus, on the basis of this new evidence, CU believes that FDA should include blood and blood products in their definition of mammalian protein.
The third problematic exemption from the definition of mammalian protein is gelatin, which comes primarily from the hide and hooves of cows and pigs. There is considerable concern that the infectious agent could be present in processed gelatin. The European Commission (EC) lifted an embargo on gelatin from the UK in June, 1996; however the decision was quite controversial. As pointed out in a report on BSE prepared for the European Parliament, "Between 11 and 15 April 1996, the Scientific Committee on Cosmetology, the Scientific Committee for Food and the European Medicine Evaluation Agency all expressed their opposition to ending the embargo on gelatin" (Ortega, 1996). Thus, the bulk of the scientific reports looked at by the EC recommended against lifting the gelatin embargo because definitive evidence that the infectious agent is not present in gelatin was not available.
In spite of the scientific uncertainty, the FDA so far has exempted gelatin from its regulations on BSE-derived materials. However, an FDA advisory committee just last week concluded that not enough scientific evidence exists to state that gelatin does not contain the TSE-causing agent and recommended 10-to-3 that FDA withdraw its exemption of gelatin from current regulations on BSE-derived materials: "A Food and Drug Administration advisory panel said Thursday that given scientific evidence to date, gelatin cannot be safely considered to be free of mad cow disease. The committee voted 10-to-three to recommend that FDA rescind the exemption gelatin currently has from the agency's regulations on bovine-derived materials" (Reuters, 1997). Since the FDA's own TSE Advisory Committee has concluded that gelatin may contain the TSE-causing agent, CU feels that gelatin should not be used in feed. Thus, CU urges FDA to include gelatin in the definition of mammalian protein.
Exemptions/renderers
The proposed draft rule requires renderers that manufacture products intended for animal feed that may contain mammalian protein to label the material ("Do not feed to cattle or other ruminants") and keep records to track the materials. We are particularly concerned about the three exemptions to the labeling and tracking requirements for renderers, even though at present all three exemptions are theoretical.
The first exemption is for renderers who use a manufacturing method that deactivates the agent that causes TSEs. We note that there is no manufacturing method that is known to completely deactivate the infectious agent (an abnormal prion protein). Part of the problem is the fact that no good test for the TSE agent exists either. Neither the mouse bioassay nor the immunohistochemical test used to detect the infectious agent (PrPres) are very sensitive; the agent may be present yet neither the bioassay nor the immunohistochemical test can detect PrPres. As Dr. Clarence Gibbs pointed out at the January 1997 Congressional hearings on BSE: "The assay for PrP [prions] is not sufficiently sensitive to detect it before infectious titers-that is, levels in the brain-reach many thousands of infectious doses per gram. In the mid-1960s, we demonstrated with our French and English collaborators that during the early incubation of the TSEs, when the virus titers in the brain was very low, there were already marked functional changes, even though no pathology was yet detectable . . . Thus, it is clear that early replication to only low level infectivity titer, far below that necessary to detect PrP biochemically or immunologically, can already lead to disease" italics added (Gibbs, 1997: 4). Thus, we would state that the first exemption should not be used unless the renderer can demonstrate complete deactivation of the mutant prion/infectious agent.
The second exemption concerns routine use of a method to detect the infectious agent. As noted above, no effective test method yet exists. However, if a renderer used a test method that could detect the infectious agent, FDA would only require that products that tested positive for the agent be labeled "Not for Use in Animal Feed." The product could still be used for other purposes such as a fertilizer or possibly in cosmetics. We find this completely unacceptable. This infectious agent causes a deadly disease. If another deadly disease agent, such as the smallpox virus or the anthrax virus or HIV, were found in a product destined for animal feed, would the FDA allow such a product to simply be labeled "Not for Use in Animal Feed"? Wouldn't FDA require the destruction of such products? We think it should.
It would be completely inappropriate to use a product containing a TSE-causing agent in fertilizer or cosmetics. We feel that use of materials contaminated with a TSE-causing agent for fertilizer could pose a potential hazard to human health due to exposure. Indeed, we note that the United Kingdom has banned the use of bone and blood meal as fertilizer due to the uncertainty about the safety of such products. Further, PrPres-containing products should not be used for cosmetics or any other purposes. FDA should require any products that test positive for the TSE-causing agent to be destroyed by incineration or some other effective method.
The third proposed exemption is for renderers that exclusively use "a method for controlling the manufacturing process that minimizes the risk of the TSE agent entering the product." We believe that the language in this exemption is unacceptably vague. We shouldn't be talking about "minimizing" the risk of a deadly disease-causing agent entering the feed; we should be talking about preventing it. Again, if the FDA found that the smallpox virus was getting into a product destined for animal feed, would the FDA settle for requiring renderers use a process that "minimized" the risk of the smallpox virus getting into the feed?
Finally, regarding paragraph (e)(1)(iii)(B)-"Use of clean-out procedures or other means adequate to prevent carry-over of protein derived from mammalian tissues into animal protein or feeds that may be used for ruminant," we know of no such procedures that would remove the infectious TSE agent and prevent it from cross-contaminating animal protein or feeds destined for ruminants. However, if such procedures were developed, the FDA should require that they be validated by the agency and that the design be made available to the public.
References
Bobowick, A.R., Brody, J.A., Matthews, M.R., Roos, R. and D.C. Gajdusek. 1973.
Creutzfeldt-Jakob disease: A case-control study. American Journal of Epidemiology
98: 381-394.
Boller, F., Lopez, O.L. and J. Moossy. 1989. Diagnosis of dementia: Clinicopathologic correlations. Neurology, 39: 76-79.
Davanipour, Z., Alter, M., Sobel, E., Asher, D.M. and D.C. Gajdusek. 1989. A case-control study of Creutzfeldt-Jakob disease: Dietary risk factors. American Journal of Epidemiology 122: 433-451.
Gibbs, C. 1997. Statement to the Committee on Government Reform and Oversight, Subcommittee on Human Resources and Intergovernmental Relations, U.S. House of Representatives. January 29, 1997.
Hadlow, W.J. 1997. Letter to Patrick McCaskey, USDA/FSIS/Eastern Lab, dated April 10, 1997.
Kaban, E. 1997. untitled news story. Reuters, March 27, 1997.
Manuelidis, E.F., Kim, J.H., Mericangas, J.R. and L. Manuelidis. 1985. Transmission of Creutzfeldt-Jakob Disease from human blood. The Lancet, 2: 896-897
---------------------- and L. Manuelidis. 1989. Suggested links between different types of dementias: Creutzfeldt-Jakob disease, Alzheimer disease, and rteroviral CNS infections. Alzheimer Disease and Associated Disorders, 2: 100-109.
Ortega, M.M. (rapporteur) 1996. Draft report of the Temporary Committee of Inquiry into BSE, submitted to the European Parliament. December, 1996.
Reuters, 1997. Gelatin not free of mad cow disease-US FDA panel. Reuters Financial Report, April 14, 2997.
Spongiform Encephalopathy Advisory Committee (SEAC). 1996. SEAC statement of March 24, 1996.
