May 5, 1997
Thomas Billy, Administrator
Food Safety Inspection Service
United States Department of Agriculture
Room 331E, Whitten Building
1400 Jefferson Drive
Washington D.C. 20150
Dear Mr. Billy,
We would like to discuss the steps USDA is taking to prevent mad cow disease and related transmissible spongiform encephalopathies (TSEs) in the United States. We believe that USDA’s efforts related to swine and cattle need to be restructured and expanded in significant ways to assure meat safety. The following represents our views on the kind of research and monitoring that is needed.
Follow Up on 1979 study
First, the USDA should reopen the 1979 study of 106 pigs with Central Nervous System (CNS) disease at the Tobin Packing plant in Albany, NY and try to determine the cause of that outbreak. Was a TSE involved or was it some other neurologic disease(s)? This case should be reopened for a number of reasons. So far, USDA has focused on only one pig, case #2709. Visible spongiform damage to brain was seen only in that animal. However, there is reason to believe that others may have been affected. Similar clinical behaviors were seen in 106 pigs. Dr. Doi, the vet who did the initial study at the plant, and Dr. Langheinrich, the pathologist who examined the tissues, both felt that the syndrome they were looking at was a single entity, i.e. one disease. When Dr. Clarence Gibbs, the leading expert at NIH on TSEs, looked at the video of 13 affected pigs, he also felt that all were suffering from the same disease (Gibbs, pers. com., March 28, 1997).
Last November, Dr. William Hadlow examined one slide from the suspect TSE pig (case #2709). Dr. Hadlow had been sent only one slide because it was the only one that exhibited spongiform damage; USDA considered such damage to be evidence of a TSE. He concluded that the slide showed subtle symptoms (changes in the astrocytes) of a TSE, but he couldn’t say more without looking at slides from other sections of the brain (Hadlow, 1996).
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. 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). Nevertheless, Dr. Hadlow continues to find the evidence suggestive of a TSE. He 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 this finding alone is not enough to conclusively state that the pig had a TSE. 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).
Given Dr. Hadlow’s findings, we feel that the USDA should attempt to locate the brain blocks from pig #2709, if they exist. If the brain blocks can be located, fresh sections can be taken for microscopic analysis, as well as testing for PrPres (or PrP27-30). In addition, material from the brain blocks could be used in inoculation studies with other pigs. If the brain blocks cannot be found, then the USDA should attempt to re-stain the original slides in order to make morphological structures affected by TSEs more prominent or to look for presence of the infectious agent. If the re-staining is not feasible, USDA should determine what further analysis the slides could go through to glean more information from them.
As noted above, Dr. Hadlow pointed out that pigs could have a TSE, with the only morphological evidence being the subtle changes, such as diffuse astrocytosis and other glial alterations, seen in pig brain #2709. This is an important point as the pathologist and others associated with the 1979 study had focused on the one brain that showed evidence of spongiform damage, which in their minds was the main indicator of a TSE. But they were not thinking of the subtle symptomology (i.e. the glial changes) as evidence of a TSE. Thus, CU feels the USDA should check the pathology reports from the other 105 cases and look more carefully at all the cases where the pathology report mentions any glial changes such as “gliosis,” “multi-focus gliosis,” “increase in glial elements,” etc. From our analysis of the 106 pathology reports, it appears that there are 42 such cases. CU urges the FDA to find slides and/or brain blocks (if they still exist) from these 42 cases and have them examined by an expert TSE pathologist, such as Dr. Hadlow. These brain blocks should also be tested for the presence of PrPres (or PrP27-30) and perhaps used in pig inoculation studies. If the brain blocks cannot be found, and if the slides are poorly stained, the USDA should consider re-staining them or taking other action to extract more information from the slides.
Improve Antemortem Surveillance
The 1979 study showed a high rate of CNS disease at one packing plant, where .01628% of all the hogs were condemned for CNS symptoms; this rate, extrapolated to the national level of 83 million hogs slaughtered annually, translates into 13,500 hogs with CNS symptoms. However USDA condemned only 79 hogs for CNS symptoms in 1979, suggesting that 99.5% of the hogs with CNS symptoms would be escaping detection. Thus, in addition to reopening the 1979 pig case, the USDA should take a number of other steps to investigate the possibility of a TSE occurring in pigs.
First, USDA should train inspectors and veterinarians on CNS symptoms they should be on the lookout for. For such training, the USDA should use films of pigs exhibiting CNS symptoms. In addition to the film of affected pigs from the 1979 incident, the USDA should consult 3-4 experts on clinical observations of pig diseases to see if other films on animals exhibiting CNS symptoms exist.
Second, USDA should beef up antemortem inspection (or at least not decrease it). Further, at present, as pointed out by the March 27, 1997 letter from the Government Accountability Project et al. to Secretary Dan Glickman, only 5-10% of the antemortem inspections take place when the pigs are in motion (Devine et al., 1997). USDA should extend the antemortem observation period long enough to ensure that all animals are observed while they are in motion. This is a critical requirement as subtle CNS symptoms can and will be missed if inspectors and/or vets observe animals that are not moving. Pigs exhibiting any CNS symptoms should be condemned.
Conduct New TSE Studies in Swine
At a minimum, the USDA should replicate the Doi et al. study but include more (say at least 10) packing facilities/slaughter-houses, chosen in a scientific fashion, taking into account such factors as geographical location, extent of refeeding of pig protein, etc. Inspectors trained in recognizing CNS symptoms should observe all the animals coming into a facility while they are moving so that subtle CNS symptoms can be seen. Any suspect pigs should be removed and examined clinically; if necessary, pathology samples should be taken and sent out for analysis. The brains of suspect animals should be examined for morphological and biochemical evidence of TSEs and tested for PrPres (or PrP27-30). Any brains that turn up positive should be used for pig inoculation studies.
The USDA should also do a neurologic survey and actively look for pig TSEs by targeting those populations of pigs where TSEs would most likely be found. Given the biology of TSEs in other organisms, we would expect a TSE to show up in older animals and in animals exhibiting neurological symptoms. Consequently, the study could try to focus on the longest living pigs, such as breeding sows, which tend to live for 3+ years. Also, one could locate facilities/slaughterhouses that specialize in diseased and “downed” animals. In both populations, one should have a higher chance of finding an animal with TSE symptoms, if it existed, than in animals chosen at random. Any suspect animals should be observed for clinical symptoms and, if need be, samples taken for pathological and immunohistochemical testing.
Finally, USDA should ensure that a proper feeding experiment be done to see if pigs can get BSE through the oral route. Experiments in the United Kingdom have shown that pigs are susceptible to BSE. Pigs inoculated via intracranial, intravenous and intraperitoneal routes with BSE develop a TSE (Dawson et al., 1990). A feeding experiment is currently underway in the UK to see if BSE can be orally transmitted to pigs; as of March, 1997, some 6.5+ years after the start of the experiment, none of the pigs fed BSE brain have come down with a TSE.
Unfortunately, the design of this experiment severely limits what we will learn from it, and will most likely not tell us conclusively if pigs can get BSE from feed. It turns out that the pigs were not fed BSE brain continuously. Rather, the pigs ate BSE-infected brains on only 3 occasions, each one to two weeks apart, during their lives. On each occasion 4 kg of brain from BSE-infected cows was divided up in the rations and fed to 10 pigs. The total amount of infective material given to each pig for its entire lifetime was only .4 kg X 3 = 1.2 kg. Consequently, a negative finding would be hard to interpret and would not mean that BSE is not orally active in pigs.
The rationale for the dose of brain fed to the pigs at each feeding was that .4 kg was roughly the amount of brain that one would expect a pig to be fed during a 3 month period (assuming that about 15% of a pig’s diet is animal protein). It is therefore obvious that this experiment is designed to answer the narrower question — “Can pigs fed brains from BSE-infected animals at about, or slightly higher than, the level that occurs in their normal diet develop BSE symptoms?” — and not the broader question — “Can BSE be orally transmitted to pigs, regardless of the dosage?” A proper feeding study would be designed to answer the latter question. Animals can be infected and possibly be infective to humans without showing any symptoms. A proper feeding study would entail continuous feeding of as much BSE-infected brains as the pigs could eat. In our view, USDA should ensure that such a feeding study be done.
Epidemiological Evidence of TSE in Pork
The urgency of further investigating the 1979 incident at the Albany packing plant for the occurrence of a possible TSE is heightened by evidence from other sources. First, there are two epidemiological studies that have linked the consumption of pork to a human TSE, Creutzfeldt-Jakob disease (CJD). Both studies are discussed in our comments to FDA on their proposed draft feeding rule (copy included) so we will only summarize them here.
The first study, involving 38 CJD patients and published in 1973, found that one-third of the CJD patients had eaten brains. Obviously, one-third of the general population does not eat brains. The authors noted that compared to controls who also ate brains, “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).
The second study, involving 26 CJD patients and published in 1985, looked at diet more carefully. Nine out of 45 individual food items studied 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 processed 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). Finally, 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. Thus, the evidence from epidemiology studies on CJD patients pointing to a possible link with pork consumption, plus the possibility that a certain percentage of Alzheimer's disease may turn out to be CJD, points to the crucial necessity of USDA figuring out what neurologic disease caused the outbreak observed at the Albany packing plant in 1979, and conducting new surveillance studies.. CATTLE The two major planks in USDA's strategy to protect the U.S. against BSE in cattle are antemortem inspections (controlled by FSIS) and the BSE Surveillance program (run by APHIS). CU believes that USDA's BSE Surveillance program is flawed in both design and execution. The program is based on the assumption that a native bovine TSE does not exist in the US and that the major threat comes from a British-style BSE. A good deal of indirect evidence, involving studies on transmissible mink encephalopathy as well as on scrapie transmitted to cattle, suggests that a native bovine TSE occurs in the US and may be hiding among the "downer cow" population. We believe the surveillance program should be both larger and more focused on downer cows. The program should have vets trained to recognize more subtle symptoms of TSEs, as well as make better use of the immunohistochemical probe to test for the presence of the infectious agent. Evidence from transmissible mink encephalopathy Transmissible mink encephalopathy (TME) is a rare disease. TME has been seen only in farm-raised mink and was first described in the scientific literature in 1966, in a paper that discussed outbreaks of this disease on 8 or 9 mink farms in Wisconsin over a 16 year period (Hartsough and Burger, 1966a,b). The disease was first recognized on a mink farm in 1947. In 1961, another outbreak of the disease appeared on 5 or 6 mink farms, from three adjoining counties. Since all the farms with affected mink used a ready-mix feed ration which came from the same feed plant, the scientists assumed that the feed was the source of the infectious agent (Hartsough and Burger, 1966a). Two years later, in the summer of 1963, TME appeared again, almost simultaneously, on 2 more mink farms. Suspecting a possible feed-based source of contamination, based on the 1961 outbreak, the scientists went through the two farms' feed records. A striking finding was that, from July through October 1962, meat "from beef carcasses unfit for human consumption (so-called 'downer' cows)" that came from Farm A was fed to minks on both Farms A and B. As the scientists noted, "Since mink on both farms developed the disease almost simultaneously, we believe this feed component has to be incriminated" (Hartsough and Burger, 1966a: 389). Although the authors could not completely rule out the possibility of sheep parts being part of the suspect meat shipment, this was the first suggestion that "downer" cows may be connected to TME. ("Downer" cow is a term that refers to cattle that are killed because they no longer can stand up or have collapsed or died for any of a number of reasons. There are an estimated 100,000 downer cows in the U.S. each year.) The evidence was convincing enough that, at an NIH-sponsored meeting on TSEs in 1964, Drs. Burger and Hartsough hypothesized that sporadic cases of a bovine TSE occurred in the US under the clinical picture of downer cow (Burger and Hartsough, 1965). The next recorded outbreak of TME in the U.S. occurred 22 years later, in 1985, on a mink ranch in Stetsonville, Wisconsin. Dr. Richard Marsh and his colleagues (Marsh et al., 1991) studied this outbreak and produced a number of lines of evidence that linked "downer" cows to TME. First, the mink's diet consisted of 95% "downer" cow and 5% horse meat. The minks received no sheep meat, so scrapie can be ruled out as the infectious agent. Dr. Marsh also performed a number of experiments that further supported the notion that cows were the source of the infectious agent. Dr. Marsh injected brains from Stetsonville mink with TME into the brains of 2 Holstein calves. Within 19 months, both calves had developed a fatal spongiform encephalopathy. They did not act like "mad cows" in Britain; rather they just got a bit lethargic and fell over, i.e. they exhibited symptoms of "downer cow." Furthermore, when brains of these cattle were either injected into mink or simply fed to them, the mink developed TME. The authors concluded that "these results suggest the presence of a previously unrecognized scrapie-like infection in cattle in the United States" (Marsh et al., 1991: 589). The evidence is not solely linked to the Stetsonville outbreak. Dr. Marsh's cattle inoculation experiments have been repeated using mink brain isolate from the early 1960s outbreak of TME in Hayward, WI and in Blackfoot, ID. The results of those studies mirror what Dr. Marsh found: the inoculated cattle die of a TSE within two years (Robinson et al., 199?). Furthermore, the cows inoculated with TME do not behave like "mad cows," but exhibit behaviors consistent with "downer cows." Some scientists have tried to argue that TME is caused by feeding scrapie-infested sheep to the ranch mink. To test this possibility, Dr. Marsh has tried feeding brains from scrapie-infested sheep to mink. Since there are believed to be at least 20 different strains of scrapie, Dr. Marsh tried feeding brains from a number of different strains of scrapie-infested sheep. In none of these cases was he able to infect mink with TME (Marsh et al., 1991). Indeed, we know of no studies in the scientific literature which demonstrate that mink fed scrapie-infested sheep develop TME. A second problem with the hypothesis that scrapie is the cause of TME is that the first outbreak of TME in the US could not have involved feeding of scrapie-infested sheep. The first recorded case of scrapie in the US occurred on a ranch in Michigan in 1947, the year of the first TME outbreak in Wisconsin. The infected sheep was a Suffolk that could be traced back to Britain (where scrapie was rampant among the sheep). Indeed, in the first few years after scrapie was identified in the US, virtually all the infested sheep could be shown to have come from Britain (Detwiler, 1992). Thus, when the first case of TME occurred on a farm in Wisconsin in 1947, there were no known scrapie-infested sheep in the state at the time, unless one hypothesizes the existence of a native scrapie that had gone completely undetected. Scrapie-infested cattle studies Drs. Marsh, Hartsough and Burger's work suggested that TME may result from consumption of "downer cows." This raises the question of where a TSE which causes "downer cow" behavior might come from. One obvious possibility is scrapie. Thus, in 1979, at the USDA field station in Mission, Texas, researchers inoculated cattle with scrapie to see if cattle were susceptible to it: "It had earlier been observed that the carcasses of 'downer' (paralyzed) cows had been used as food for mink in which transmissible mink encephalopathy developed. Since natural scrapie had never been described in cattle, the study was designed to determine the susceptibility to experimental transmission of this spongiform encephalopathy" (Gibbs et al., 1990: pg. 1275). Ten animals were injected with scrapie-infested brain homogenates in the brain, muscles and under the skin, as well as fed it. Three of the injected animals developed neurologic symptoms some 2-4 years after inoculation. The clinical symptoms were not those seen in cows with British-style BSE (i.e. the cows did not act "mad"); rather, the symptoms were more similar to those seen in "downer cow" syndrome: "neurological signs 27-48 months after inoculation, consisting of progressive difficulty in rising, a stiff-legged gait, incoordination, abnormal tail position, disorientation, and terminal recumbency" (Gibbs et al., 1990: pg. 1275). More interesting than the clinical symptoms was the fact that Dr. Hadlow's histopathological analysis of the brains of the three affected cows revealed only diffuse gliosis with little or no vacuolization of the neurons. At the time, this was not considered sufficient evidence to conclude that the animals had a TSE: "Histopathological examination of the brains of affected animals revealed mild diffuse gliosis and few vacuoles, changes which were reported as being insufficient to confirm a clinical diagnosis of scrapie. Attempts to transmit the disease by inoculating homogenates of brain from affected cattle to mice were unsuccessful" (Gibbs et al., 1990: pg. 1275). However, Dr. Gibbs believed at the time that the three cows had died of a TSE, in large part due to the animals' behavior (Gibbs, pers. com., March 28, 1997). Ten years later, an immunohistochemical test became available that could detect the supposed infectious agent in scrapie (i.e. PrP27-30). Dr. Gibbs arranged to have the brains of the cattle reexamined using the new probe and found that the three cows with clinical symptoms tested positive while the other cows were negative. Dr. Gibbs et al. published the results of their work in an article entitled "Experimental transmission of scrapie to cattle" in The Lancet (Gibbs et al., 1990). Since publication of the article, another series of mouse inoculation studies using brains from the suspect cows has been done and resulted in passage of disease (Gibbs, pers. com., March 28, 1997). Dr. Gibbs ended the article by stating that the evidence suggested that a bovine TSE was present at a low level in US cattle and that "downer cows" should be tested: "Susceptibility of cattle to scrapie further suggests the possibility that sporadic cases of BSE may have occurred in the United States under the clinical picture of the downer cow syndrome, as suggested by the work of Burger and Hartsough and Marsh. A search for PrP27-30 in the brains of downer cattle should provide useful information for this hypothesis" italics added (Gibbs et al., 1990: 1275). After Gibbs et al. were able to show conclusively in 1990 that the Mission cattle Texas had indeed been infected with scrapie, the USDA repeated the experiment at an ARS (Agricultural Research Service) facility in Ames, Iowa under the direction of Randall Cutlip. Dr. Cutlip's results mirrored those found in the earlier study: some of the cows inoculated with scrapie did die of a TSE, but they did not exhibit behaviors associated with "mad cow" disease in Britain (i.e. British BSE). Rather, the behavior is more subtle and could be mistaken as "downer cow." As Cutlip et al. concluded, "Thus, undiagnosed scrapie infection could contribute to the 'downer-cow' syndrome [in the U.S.]" (Cutlip et al., 1994: 814). BSE Surveillance Program In sum, the indirect evidence from the TME studies, as well as from the scrapie-inoculated cattle studies, points to the existence of a native bovine TSE in downer cows in the U.S. This native BSE could arise spontaneously in cattle; it seems unlikely that all cases are linked to scrapie. But USDA's Surveillance has only recently started looking at downer cows. In 1965, Drs. Burger and Hartsough were hypothesizing the existence of a native BSE strain in the US that could be hiding in the downer cow population. In 1987, Dr. Marsh began hypothesizing the same thing and calling on USDA to look at downer cows for potential TSEs. By 1990, even NIH (in the person of Dr. Clarence Gibbs) was calling for testing of downer cows for the presence of the mutant prion using an immunohistochemical probe (Gibbs et al., 1990). The same year, USDA set up an advisory committee called the Scrapie/BSE consultants committee. Dr. Richard Marsh was one of the members. This committee designed and began the BSE monitoring program done by the USDA. At the start, the BSE Monitoring program did not look at brains from downer cows. There were two selection criteria for animals to be chosen for testing. First were rabies-suspect but rabies negative cattle. Second were animals that had gotten at least two years worth of animal protein (energy-dense feeds) in the diet and had died of obvious neurologic symptoms. Dr. Marsh argued that the CNS symptomology exhibited by "downer cows" would go unrecognized by these two selection screens and therefore argued that downer cows be added to the selection criteria. For at least two years, 1991 and 1992, the committee declined to follow Dr. Marsh's suggestion. At approximately the same time, Dr. Marsh was trying to secure funding to sample downer cows and test them, both pathologically and imuunohistologically, for evidence of a TSE. In the early 1990s, Dr. Marsh submitted grant proposals for two years in a row to USDA; both proposals were turned down. The net result has been that very few downer cows have been included in the BSE Surveillance program. They were first included in the program in 1996. As of January 23, 1997, some 5,342 cattle brains had been tested. Yet only a couple hundred of the brains came from downer cows. While we applaud USDA for finally deciding to include downer cows in their surveillance, CU believes that USDA needs to focus more strongly on the downer cows. Since the USDA has not publicly admitted that we could have a native bovine TSE already present in the US, the BSE Surveillance program has focused on looking for British-style BSE. Consequently, CU believes that the USDA must admit that there is a strong likelihood that a native TSE exists in US cattle. Once the USDA makes this admission, the other changes needed in the Surveillance program will logically follow. First, the veterinarians and pathologists who are looking at the brain samples have been trained with slides and materials from British cattle with BSE, so that they are looking for the characteristics of the British strain of BSE. The brain damage characterisitic of British style BSE is easily seen as there is lots of vacuolization of the nerves. However, the work of the USDA and ARS on transmission of US scrapie to cattle suggest that a US strain of a TSE in cattle probably could show only subtle changes in brain morphology with very little, if any, vacuolization of nerves. Thus, the U.S. vets may not may not be looking for the right brain characteristics. Consequently, vets should be trained using materials that show TSEs with subtle characteristics, such as the pathology slides from the three affected cattle from the original Mission, Texas studies or from the affected cattle in Dr. Cutlip et al.'s repeat study. Furthermore, USDA should make greater use of the immunohistochemical probe. Indeed, all suspect brains should be examined using the probe. In addition, the USDA needs to focus more heavily on the downer cow population. At present, only a couple of hundred downer cows have been examined. This is completely inadequate. If the disease were occuring at a rate of one in 1,000 animals, it might not show up at all in this sample. Yet this is a rate that would be of great public health concern. Likewise, there are approximately 100,000 downer cows each year in the US (Marsh, 1992). If just one-half of one percent (0.5%) of these cows had a TSE, that would mean 500 infected cows. One would have to look at 5,000 cows just to see 25 cases. Consequently, we believe that USDA should expand the BSE Surveillance Program, modify the selection criteria and focus far more heavily on downer cows. In fact, the major selection criterion should be downer cows. For example, USDA could try to sample at least 500-1,000 downer cows every year. Furthermore, among downer cows, USDA should focus on those that exhibit CNS symptoms and not downer cows that have broken legs, milk fever, etc. The USDA could also focus on states which make the largest use of rendered ruminant protein in their cattle feed and that have some of the oldest cows. This would mean focusing on the larger dairy states such as Wisconsin, California and New York. We hope you will consider these concerns. We particularly urge you and the staff of USDA to consults with the experts at NIH about appropriate design for research efforts. We look forward to discussing these questions further. Sincerely, Michael K. Hansen, Ph.D. Research Associate 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. Detwiler, L.A. 1992. Scrapie, Revue Scientifique et Technique. Office Internationale Epizootics, 11(2): 491-537. Gibbs, C.J., Safar, J., Ceroni, M., Di Martino, A., Clark, W.W. and J.L. Hourrigan. 1990. Experimental transmission of scrapie to cattle. Lancet, 335: 1275. -------------- 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. 1996. Letter to Patrick McCaskey, USDA/FSIS/Eastern Lab, dated November 10, 1996. --------------------1997. Letter to Patrick McCaskey, USDA/FSIS/Eastern Lab, dated April 10, 1997. Hartsough, G.R. and D. Burger. 1966a. Encephalopathy of mink. I. Epizootiologic and clinical observations. Journal of Infectious Diseases 115: 387-392. ----------------------------------------------------b. Encephalopathy of mink. II. Experimental and natural transmission. Journal of Infectious Diseases 115: 393-399. Manuelidis, E.F. 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. Marsh, R.F. 1992. Transmissible mink encephalopathy, scrapie and downer cow disease: potential links. paper presented at the Third International Workshop on Bovine Spongiform Encephalopathy, Bethesda, Maryland, December 9-10, 1992. 7 pp. ----------------, Bessen, R.A., Lehmann, S. and G.R. Hartsough. 1991. Epidemiological and experimental studies on a new incident of transmissible mink encephalopathy. Journal of Genetics and Virology, 72: 589-594.