Bovine Spongiform Encephalopathy: Hypothetical Risk of Emergence As a Zoonotic Foodborne Epidemic

1106

Bovine Spongiform Encephalopathy: Hypothetical Risk of Emergence as a Zoonotic Foodborne Epidemic

HARLEY w. MOON*

Plum Island Animal Disease Center, Agricultural Research Service, U.S. Department of Agriculture, P.O. Box 848, Greenport, New York 11944, USA

(MS# 95-505: Received 20 December 1995/Accepted 29 March 1996)

ABSTRACT much lower incidence in other countries. Cases outside Great Britain have been attributed to cattle or meat and bone Bovine spongiform encephalopathy (BSE) is a fatal neurologi- meal imported from Great Britain. Imports of British cattle cal disease of cattle, recognized in Great Britain in 1986. Cases in and meat and bone meal into the U.S. are prohibited. The other countries have been attributed to imports from Great Britain. USDA has been conducting active surveillance for BSE The disease has not occurred in the U.S. BSE is one of a group of among U.S. cattle. The disease has not been detected and diseases (other examples are scrapie of sheep and Creutzfeld-Jacob apparently has not occurred in the U.S. (25). disease of humans) referred to as prion diseases or transmissible spongiform encephalopathies. Under some circumstances prion BSE is the most recently emerged disease in a group of diseases can be transmitted by injection or by feeding infected diseases of animals and people that are referred to as (abnormal prion protein-containing) tissue to susceptible hosts. transmissible spongiform encephalopathies (TSE) or more BSE was disseminated by feeding meat and bone meal containing frequently in recent years as prion diseases. Among animals, BSE agent which was not completely inactivated by rendering. these diseases include BSE in cattle, scrapie in sheep and BSE is hypothesized to have emerged from scrapie via recycling of goats, chronic wasting disease in deer and elk, and transmis- rendered by-products in cattle. There is also evidence of spontane- sible mink encephalopathy; the human diseases are kuru, ous feed-borne transmission of BSE to wild ruminants in zoologi- Creutzfeldt Jakob disease, and Gerstmann-Straussler- cal parks and to domestic cats. It has been hypothesized that Scheinker syndrome. Sheep scrapie has been used as a foodborne transmission of BSE to humans has occurred or could model to determine how spongiform encephalopathies are occur, This hypothesis can neither be definitively refuted nor transmitted and to define mechanisms of disease. supported. However, it seems unlikely. In spite of hundreds of years of human exposure to scrapie, there is no evidence of transmission of scrapie to humans. Even if BSE is ultimately found CHARACTERISTICS OF TSE DISEASES to be somehow transmissible to humans, the risk of foodborne transmission appears to be low for several reasons: (i) The oral route is several orders of magnitude less sensitive than the The major characteristics of the prion diseases are, first parenteral route for transmission of prion diseases; (ii) the BSE and foremost, that they are slow diseases. They have an agent is only detectable in brain, spinal cord, and intestine of incubation period of years. The diseases are characterized by infected cattle, tissues infrequently used for human food; and (iii) progressive neurologic degeneration and histologically by a Great Britain (where the disease occurs) destroys and bans the use spongelike degeneration of the brain, which gives the group of all tissues from BSE-infected cattle as well as the brains, spinal one of its names (spongiform encephalopathies). The accu- cords, and intestinal tracts from clinically normal cattle. mulation of an abnormal form of prion protein in the brain is Key words: BSE, foodborne risk, zoonosis, epidemic a characteristic that gives the group another of its names (prion diseases). Although prion diseases can arise in a number of ways, Bovine spongiform encephalopathy (BSE) is a fatal including by genetic mutation and inheritance, they have all neurological disease of cattle (22, 32, 36). BSE has been been shown to be infectious and transmissible (1, 10, 26, recognized in Great Britain since 1986, where it has affected 32). By and large, however, in the ordinary context they are more than 150,000 head of cattle. It has also occurred at a not contagious. Discrete and substantial species barriers exist for transmission across species lines. The agents tend to be more readily transmissible in their original host species than in other species. They tend to adapt to a new (suscep- * Author for correspondence. Current address: Iowa State University, Veterinary Medical Research Institute, 1802 Elwood Drive, Ames, IA tible) species during serial passage in that new species. 50011, USA. Tel: 515-294-9327; Fax: 515-294-1401. However, some species barriers have not been breached in BOVINE SPONGIFORM ENCEPHALOPATHY: FOODBORNE RISK? 1107

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FIGURE 1. Number of new cases of BSE in Great Britain, September 1966 to March 1995 (36). Reproduced with permission.

spite of experimental serial blind passage of the agent in that Prolonged exposures to moist heat or sodium hypochlorite new species. Susceptible host species are characterized by a are considered to be among the most effective practical striking intraspecies genetic predisposition. Some genetic means of inactivation. However, they cannot be considered lines of sheep are much more susceptible to scrapie than absolutely effective, because the agents have skewed inacti- others. Different genetic lines of laboratory mice are more or vation curves such that treatments which reduce their less susceptible to one or another strain of a TSE agent. infectivity by several orders of magnitude leave some residual infectivity. CHARACTERISTICS OF TSE AGENTS EPIDEMIOLOGY Prion disease agents exhibit strain behavior (1, 10, 26, 32, 34). For example, one strain of scrapie agent may have its greatest pathogenicity in one genetic line of mice, whiie The origin of BSE is not known. There is consensus another strain of scrapie agent has its greatest pathogenicity support for the hypothesis that BSE arose from scrapie, in another genetic line of mice. The incubation periods for which became adapted to cattle by the agent being recycled different strains of agent also vary with genetic line within a in rendered ruminant (sheep and cattle) meat and bone meal, susceptible host species. There is evidence that strain by-products used as cattle feed (5, 6, 22, 23, 30). An behavior and species barriers depend at least in part on the alternative hypothesis is that it arose de novo in cattle. degree of homology in prion genes between the hosts The mechanism of dissemination is much more clear. producing and receiving the agent. BSE has been disseminated in Great Britain and elsewhere There are several extraordinary characteristics of TSE through the feeding of rendered meat and bone meal (22, 30, agents. There is controversy as to their fundamental nature, 32). In 1988, the British authorities concluded that BSE whether they are viruses or whether prions are the ultimate probably was a strain of sheep scrapie that had adapted to infectious disease agent (32). Abundant evidence supports cattle, and a ban on feeding rendered ruminant by-products the infectious prion hypothesis (26, 34). This hypothesis back to cattle was put in place. Recognizing that it was a involves a posttranslational change in the prion protein to an TSE, the authorities predicted that there would be a lag abnormal conformation, which causes accumulation of period of years before the ruminant feed ban would have an additional abnormally conformed prion protein. The abnor- impact. Indeed, following the peak in the number of new mally conformed protein is, according to this hypothesis, the cases in 1992, there has been a falloff, and the epidemic self-replicating, transmissible, infectious agent. appears to be abating (Figure 1) (36). Whatever the nature of the causative agents, what is In addition to cattle, BSE has been transmitted spontane- important in managing them and understanding their epide- ously (in feed) to captive wild bovidae in zoos. Epidemio- miology is their extraordinary resistance to inactivation (9, logic evidence indicates that it has also been transmitted 19, 30). Resistance to inactivation during rendering allowed spontaneously to domestic cats and in zoos to captive wild dissemination of BSE in meat and bone meal and is thought felidae that have been fed either raw BSE-infected brain or to have allowed BSE to emerge (adapt) from scrapie. processed cat food (7, 32, 36). 1108 MOON

TRANSMISSIBILITY cause human disease, it would perhaps manifest itself as CJD (3, 4, 22). The occurrence of CJD in 3 British farmers There have been a number of experimental trials, many with occupational exposure to BSE is of concern (28). of them still ongoing, on the transmissibility of BSE (10, 15, However, epidemiologic analysis does not show an in- 20, 21, 24, 27). BSE has been transmitted orally to several creased risk of CJD for any occupation (including farmers) species (mice, sheep, goats, and mink) by feeding raw in Great Britain, and the 1994 incidence of CJD there was BSE-infected brain and spinal cord. It has also been similar to that in other countries where the prevalence of transmitted parenterally to a larger number of species (mice, BSE is much lower or where BSE has not occurred (18, 28). sheep, goats, mink, cattle, pigs, and marmosets). The There is also concern about the possibility of scrapie sensitivity of the parenteral route is characteristically 105 to emerging in cattle in the United States from a U.S. strain of 109 times greater (depending on the strain of the agent and scrapie. Cutlip and colleagues attempted to transmit the U.S. the genetic line of the host) than the oral route for the scrapie agent by feeding a single dose of raw scrapie- transmission ofTSE agents (26,32). BSE has been transmit- infected sheep brain to young calves, or by the daily feeding ted to experimental animals parenterally by direct injection, of other young calves with rendered sheep scrapie material usually into the brain, of raw BSE-infected brain tissue. For for one year (13). All of those cattle, now more than 5 years example, in one experiment 10 pigs were given parenteral after exposure, remain normal (R. Cutlip, personal commu- injections (intracerebral, intravenous, intraperitoneal-com- nication). bined) of raw brain material from cattle with BSE, and one Two groups of investigators have been able to transmit of the pigs developed spongiform encephalopathy (16). the U.S. scrapie agent to cattle by direct injection of infected Another group reported challenge of two primates (marmo- sheep brain into the brains of young calves. After an sets) by the combined intracerebral, intraperitoneal, and incubation period of about a year and a half, many of those subcutaneous injection of raw BSE brain material. Both cattle developed degenerative neurologic disease (11, 14). marmosets developed spongiform encephalopathy about 4 However, the disease that developed was not BSE, being years after challenge (2). expressed as depression rather than mania and hyperesthe- There is no proof that BSE can be transmitted to sia. Moreover, the brains of the diseased cattle did not have humans. Regarding the hypothetical possibility that it could spongiform change. Abnormal prion protein did accumulate be, much of the rationale rests on the abundant experience in the brain of the diseased cattle, but the prion accumulation with scrapie, because BSE is thought to have emerged from was intracellular in neurons; this is different from the scrapie. In spite of centuries of living with scrapie and eating extracellular accumulation which occurs in BSE or scrapie. sheep from flocks with scrapie, there is no evidence that Thus the experimental disease produced was neither scrapie scrapie is transmissible to humans (3-5, 8, 17, 29). The nor BSE. incidence of human spongiform encephalopathies in countries with scrapie, such as Britain, is similar to that in RISK FACTORS countries without scrapie in their sheep, such as Australia. Furthermore, in countries where scrapie occurs, the incidence of human spongiform encephalopathies is similar in It is useful to compare Great Britain and the United groups with and without exposure (occupational or dietary) States with regard to the risk factors that are thought to have to sheep. However, the BSE agent could be a new or unique contributed to the emergence of BSE in Great Britain (Table strain of scrapie which is particularly transmissible to 1). One of the principal risk factors was a change in the humans, or it could be a distinct agent which did not arise rendering process in Great Britain (33). In the early 1980s, from scrapie. there was a switch from batch to continuous-flow rendering It has been hypothesized that transmission of BSE to processes. The time and temperature parameters were humans might have occurred but not yet have been recog- changed and the use of solvent extraction was discontinued. nized, because of the prolonged incubation period for prion These changes are thought to have resulted in incomplete diseases in humans (17). Obviously this hypothesis can inactivation of the scrapie agent, leaving residual infectivity neither be refuted nor supported with existing evidence. in the rendered by-products fed to cattle. Similar rendering Creutzfeld-Jakob disease (CJD) is the most common prion processes (continuous flow, no solvent extraction) have been disease of humans (1, 8). Some think that if BSE were to used in the United States for more than 20 years.

TABLE 1. Risk factors for ESE emergenceQ

Risk factor

Country Continuous flow Solvent used MBMb/concentrate Calf starter Sheep/cattle (trend) Scrapie (apparent trend)

Great Britain + o 1/780 MBM 3.5/1 (up) High (up) United States + o 1/35,000 Soybean meal 0.1/1 (down) Lower (steady)

Q From Walker et al. (33). b MBM, meat and bone meal. BOVINE SPONGIFORM ENCEPHALOPATHY:FOODBORNE RISK? 1109

Another factor is the use of rendered sheep and cattle been shown to contain the scrapie agent in sheep were by-products (meat and bone meal) in cattle feed. In Great banned from human consumption and from recycling in Britain, prior to the ruminant by-product feed ban, the ratio animal foods (specified bovine offal ban). of meat and bone meal per pound of concentrate (feed There is no proof that BSE is transmissible to people. supplement to grass and hay) fed to adult dairy cattle was However, let us assume for the sake of argument that it can about 1 Ib (ca. 0.45 kg) of meat and bone meal for 780 occur. What would be the risk of the foodbome route of pounds of concentrate. We use much less meat and bone human infection in such a hypothetical situation? First, the meal for that purpose in the U.S., because we have an agent is detectable only in tissues that are infrequently, or abundance of high-quality, low-priced protein supplement in less frequently, used for human food. Britain, where the the form of soybeans. Similarly, meat and bone meal are disease occurs, bans use of those tissues from healthy cattle, commonly used as a protein source in calf starters in Great which have been shown in infected cattle or sheep to contain Britain. We use very little of that in this country, because we the BSE or scrapie agent, respectively. Britain also destroys rely essentially on soybean meal. The ratio of sheep to cattle all tissues from suspected or confirmed BSE cases. Cooking in the two countries is also very different. It was about 3.5 to would reduce the titer of infectivity in any tissue that might 1 in Great Britain in the 1980s at the time BSE was contain the agent. The oral route of infectivity would emerging. The ratio in the United States is about 0.1 to 1. probably be much less sensitive than the parenteral route. This ratio has increased sharply in Great Britain in recent Furthermore the BSE material would not be passaged from years, whereas the sheep population in the United States has human to human. It is important to keep in mind that been declining. recycling of by-products from cattle exposed to the agent, The United States and Great Britain probably also differ back to cattle in the feed, appears to have been necessary for in the prevalence of scrapie. The British have lived with the emergence of BSE in cattle. This continuous serial scrapie for centuries, and they have never had an official passage of the agent in the new host (cattle) is thought to national control program for the disease. We do not know have allowed the scrapie agent to adapt to cattle, causing exactly what the prevalence is in the U.S., but it is probably BSE. In contrast, tissue from humans exposed to the BSE lower than in Great Britain. There have been efforts to agent would not be recycled or serially passaged as human control scrapie nationally since it was first recognized in the food. In the absence of that opportunity for BSE to adapt to a U.S. 40 years ago. new host, the cattle-human barrier would likely be main- The infectivity of tissues from scrapie-infected sheep tained and high infectious doses would likely be required. and BSE-infected cattle are compared in Table 2. The agent Expression of normal human prion protein genes by trans- is detectable only in the brain, spinal cord, and ileum of genic mice resulted in shortened survival times (as com- cattle with BSE (24, 31, 32, 35). Thus, the tissues usually pared to wild-type mice) following inoculation with the CJD used as human food do not have demonstrable levels of agent (12). However, survival times of the transgenic mice infectivity. Distribution of the BSE agent was not known at were not shortened following inoculation with the BSE the time the British authorities had to decide how they were agent, suggesting that the species barrier for transmission of going to deal with the outbreak. Because BSE was thought BSE to humans is substantial. There would be no risk from to come from scrapie, cattle tissues from the organs that had the consumption offoods produced in the U.S. because BSE does not occur in the U.S. In conclusion, the hypothetical risk that BSE could TABLE 2. Infectivity of tissues from BSE-infected cattle and scrapie-infected sheep" emerge as an epidemic foodbome zoonosis appears to be very low. Infectivityb

Tissue Scrapie BSE SUMMARY

Brain + + BSE is one of a group of diseases (other examples Spinal cord + + include scrapie of sheep and Creutzfeld-Jacob disease of Ileum + + humans) characterized by a prolonged incubation period, Lymph nodes + 0 spongiform degeneration of the brain, and accumulation of Spleen + 0 prion protein in the brain. There is strong (but still emerging Sciatic nerve + 0 Thymus + 0 and controversial) evidence that these diseases are caused by Liver 0 0 the prion protein. Prion diseases can be inherited as the Pancreas 0 0 result of mutations in the prion gene. Under some circum- Kidney 0 0 stances they can be transmitted by injection of, or by Blood 0 0 feeding, infected (prion-containing) tissue to susceptible Heart muscle 0 0 hosts. Infectivity of these "agents" is remarkably resistant to Skeletal muscle 0 0 the chemical and physical treatments used to inactivate Mammary gland 0 0 conventional infectious agents. BSE was disseminated by Milk ? 0 feeding meat and bone meal containing BSE agent which " From references (32) and (31). was not completely inactivated by rendering. BSE is hypoth- b Bioassay in mice. esized to have emerged from a strain of the scrapie agent 1110 MOON which became adapted to cattle via continuous recycling of scrapie to mice: strain variation and the species barrier. Phil. Trans. R. rendered by-products. An alternative hypothesis is that the Soc. Lond. B 343:405-411. 11. Clark, W. w., J. L. Hourrigan, and W. J. Hadlow. 1995. Encephalopa- BSE agent originally arose in cattle. Like other prion thy in cattle experimentally infected with the scrapie agent. Am. J. Vet. diseases, BSE can be transmitted experimentally across Res. 56:606--D12. some species lines by parentenal injection or by feeding 12. Collinge, J., M. S. Palmer, K. C. L. Sidle, A. F. Hill, 1. Gowland, J. some tissues from affected cattle. Bioassays in mice have Meads, E. Asante, R. Bradley, L. 1. Doey, and P. L. Lantos. 1995. Unaltered susceptibility to BSE in transgenic mice expressing human demonstrated the agent in brain, spinal cord, and intestine. In prion protein. Nature 378:779-783. addition to cattle, there is evidence of foodborne transmis- 13. Cutlip, R. C., J. M. Miller, R. E. Race, A. L. Jenny, and J. B. Katz. sion of BSE to wild ruminants in zoological parks and to 1994. Experimental inoculation of cattle with US sources of scrapie. J. domestic cats. BSE has not occurred in the U.S. There is no Am. Vet. Med. Assoc. 204:72. 14. Cutlip, R. C., J. M. Miller, R. E. Race, A. L. Jenny, J. B. Katz, H. D. proof of transmission to humans. Creutzfeld-Jakob disease Lehmkuhl, B. M. DeBey, and M. M. Robinson. 1994. Intracerebral (CJD) has occurred in British farmers who worked with transmission of scrapie to cattle. J. Infect. Dis. 169:814-820. BSE-infected cattle. However the prevalence of CJD among 15. Dawson, M., G. A. H. Wells, and B. N. J. Parker. 1990. Preliminary evidence of the experimental transmissibility of bovine spongiform British farmers is not greater than that among the British encephalopathy. Vet. Rec. 126:112-113. population at large, nor greater among British citizens than 16. Dawson, M., G. A. H. Wells, B. N. J. Parker, and A. C. Scott. 1990. those of European countries where the prevalence of BSE is Primary parenteral transmission of bovine spongiform encephalopa- much lower than it is in Great Britain. thy to the pig. Vet. Rec. 127:338. 17. Dealler, S., and R. Lacey. 1991. Beef and bovine spongiform It has been hypothesized that transmission of BSE to encephalopathy: the risk persists. Nutr. Health 7:117-133. humans might have occurred, but not yet been recognized. 18. Delasnerie-Laupretre, N., S. Poser, M. Pocchiari, D. P. W. M. This hypothesis can neither be refuted nor supported with Wientjens, and R. Will. 1995. Creutzfeldt-Jakob disease in Europe. existing evidence. 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