"Mad Cow Disease" or Bovine Spongiform
Encephalopathy: Scientific and Regulatory Issues

Judith A. Johnson and Donna U. Vogt
Science Policy Research Division

Update July 9, 1997

96-641 SPR

SUMMARY

In March 1996, the British government announced a possible link between a deadly cattle disease, bovine spongiform encephalopathy (BSE), and a rare, fatal human illness, Creutzfeldt-Jakob disease (CJD). The announcement was prompted by the discovery of 10 atypical cases of CJD; the current total is 20 cases. The possible link between CJD and BSE caused a loss in public confidence in beef in Europe; the economic impact has been severe. No BSE cases have been reported in the United States. Because of the potential risk to U.S. public health and the economic well-being of the beef industry, federal agencies are: monitoring the situation in Europe; supporting research on CJD and BSE; and prohibiting imports of cattle and beef products from BSE-affected countries. On June 5, 1997, the Food and Drug Administration published a final rule designed to prevent the spread of BSE through animal feed in the United States.

BACKGROUND

BSE, or "mad cow disease," is an incurable degenerative neurological disease of cattle. On post mortem examination, the diseased brain is permeated with holes like a sponge, hence the name "spongiform." BSE is one of a group of diseases called transmissible spongiform encephalopathies (TSEs). These diseases are transmitted by feeding, injecting or transplanting tissues containing the agent. TSEs are not new and are known to affect several other species besides cattle. The TSE that affects sheep (i.e., scrapie) has been known for over 250 years. TSEs have also been found to affect goats, mink, deer, elk, domestic cats as well as various antelope and feline species in zoos. There is a long incubation period (2-8 years in cattle) during which no symptoms are apparent. Length of the incubation period depends on the species affected, the dose and the mode of infection. Unlike scrapie, the BSE agent seems to be easily transmissible orally to some animal of other species. The oral dose can be minute: in one study, 500 milligrams (.02 ounces) of brain tissue from cattle with BSE produced disease in one out of six sheep. There is no immune system response; this has hindered efforts to develop a test to detect disease in live animals and rendered a protective vaccine unfeasible.

In humans, a group of four related spongiform encephalopathies has been identified. These diseases appear similar to each other on post mortem examination of the brain, but may differ in the way they are acquired, their clinical symptoms (dementia, insomnia, ataxi a), or their pattern of distribution throughout the world. Kuru is found only in one tribe in Papua New Guinea. Affected individuals contract the disease either through cannibalism or preparation of the dead for burial. Fatal famllialinsonmia (FF1) and Gerstmann-Straussler-Scheinkerdisease (GSS) are inherited (familial) with cases occurring in families; symptoms appear in mid-life.

The fourth disease, Creutzfeldt-Jakob disease (CJD), usually strikes people over 65. It occurs worldwide at an estimated annual rate of one case per million population. About 10-15% of CJD cases are inherited. Less than 1% of CJD cases are iatrogenic: they occurred as the result of various medical treatments or procedures which inadvertently transferred the CJD agent (e.g., neurosurgical procedures, corneal eye transplant, injection of growth hormone derived from the pituitary glands of human cadavers). The incubation period ranges from 15 months to 30 years for iatrogenic CJD cases. Although they do not have an inherited mutation, individuals who have developed iatrogenic CJD have a genetic "feature" which may make them more susceptible to developing the disease following exposure to the disease agent; 49% of Caucasians have this same genetic "feature."

Most (85-90%) CJD cases are sporadic: cases occur randomly and their cause is unknown. A large majority of sporadic GJD cases have the same genetic "feature" associated with iatrogenic CJD cases. Scientists speculate that sporadic CJD may be caused by non-inherited mutations or other unidentified iatrogenic routes, such as oral surgery or eye exams. Speculation includes the possibility that a new atypical form of CJD, called new variant CJD (nv-CJD), may have been caused by consuming meat contaminated with the BSE agent. Ten cases of nv-GJD were first reported in April 1996 in the United Kingdom (UK); the current total is 19 nv-CJD cases in the UK and 1 in France. The nv-CJD cases are atypical because the patients are young (all under age 42, average age 27) and their clinical symptoms and brain pathology are different than common CJD cases. Although the BSE agent has not been found in milk or muscle tissue such as steak, contamination of meat may occur during slaughter or grinding of meat for sausage or hamburger (through a process called advanced meat recovery) via tissues with high levels of the agent, such as brain, spinal cord, retina. The small amounts of tissue necessary to produce disease in experimental animals is within the range of brain tissue present in commercial food products for human consumption before successive control measures were implemented in the UK.

The inherited forms of human spongiform encephalopathy (CJD, GSS, FF1) all are caused by mutation of the "prion" protein gene.1 Prions, or "proteinaceous infectious particles," are also involved in the non-inherited TSEs. Many scientists believe prions are the infectious agents of TSEs. Initially it was thought that a "slow virus" was the cause of such TSEs. When the prion theory was first proposed, the idea that a protein, not a DNA or RNA containing virus, is the infectious agent was viewed as heretical. Further studies have provided additional evidence for the prion theory, and the prevailing view is that a prion, and not a virus, is the agent causing TSEs. The debate continues, however, and the heart of the controversy is the role of the prion protein in causing BSE and the other related TSEs: is it the transmissible agent, or just a pawn in a viral-mediated disease?

BSE was first recognized in British cattle in late 1986. Through a process of elimination, British epidemiologists have pinpointed the probable source: a protein supplement in animal feed called "meat and bone meal" (MBM). MBM is made by rendering offal, the animal parts (internal organs, residual meat and bones) left over when an animal is butchered. Rendering is a cooking process in which water is removed from the offal (which sometimes includes whole carcasses of diseased animals and road kill), leaving behind fats and solids; the solids are made into MBM. Unlike viruses and bacteria, aberrant prions are resistant to inactivation by radiation, chemicals, and heat, even at temperatures much higher than that used during the rendering process. Scientists believe that the BSE outbreak was caused by MBM containing aberrant prions from either: (1) sheep infected with scrapie; or, (2) cattle infected with a previously undetected TSE. Experiments performed in Iowa involving the inoculation of cattle with sheep scrapie resulted in a disease quite distinct from BSE, leading some scientists to theorize that scrapie is not the source of BSE. However, there are various strains of scrapie, and the strain used in the US experiments may not be the same as the strains present in the UK. Similar experiments have not been performed in the UK. BSE surveillance information from Northern Ireland and Switzerland lends support the second hypothesis.

There are many remaining unknowns in the route by which aberrant prions in animal feed may cause BSE and how this may have led to nv-GJD. Scientists do not understand how prions enter the body. The possible pathways identified to date include: (1) the lymphatic system in the digestive tract; (2) cuts in the mouth; or, (3) MBM dust in the eye or nose. Prions might then be carried via blood or lymph to the brain, where they induce the host's prions to change into the aberrant form. According to reports in the Apr. 6, 1996, issue of The Lancet, scientists have determined that the nv-GJD patients did not inherit the disease and did not receive medical treatments associated with causing CJD; all had the same genetic "feature" as found in sporadic and iatrogenic CJD cases. The unique pathology of the nv-GJD cases as well as the experimental transfer of BSE to monkeys and scientific evidence consistent with the transmission of BSE to humans, as reported in the June 27 and October 24, 1996, issues ofNature, are reasons for the speculation that these human prion disease cases were caused by exposure to the BSE agent.

BSE IN THE UNITED KINGDOM AND EUROPE

According to the UK Ministry of Agriculture, Fisheries and Food (MAFF), from 1988 through Jan.10, 1997, the UK reported a total of 167,089 confirmed cases of BSE. The disease has been detected in 59% of all dairy herds and 15% of all beef herds in Great Britain.2 In Northern Ireland, the figures are 12% of dairy herds and 2% of beef herds. Cases of BSE have also occurred in native cattle in France, Portugal, Switzerland and the Republic of Ireland. Cases have been reported in Denmark, Germany, Italy, Canada, Oman and the Falkland Islands in cattle imported from the UK. However, only the UK is reporting a high incidence of BSE.

To prevent further cases of BSE, legislation was introduced in the UK in 1988 making BSE a notifiable disease and banning the feeding of ruminant (cattle, sheep, goats, deer) derived MBM to ruminants. Since the ruminant-to-ruminant ban was implemented, the number of BSE cases has declined sharply from 1000 suspected cases reported per week (end of 1992/beginning of 1993) to 200 suspect cases per week (May 1996). However, BSE has continued to occur in cattle born after the ban; these currently account for 60% of cases being confirmed. According to a May 1996 MAFF report, continued exposure to contaminated feed is the most likely explanation for these post-ban cases. Other transmission modes have been proposed: maternal (cow to calf); horizontal (animal to animal); and grazing in fields contaminated with the prion agent. Scrapie is passed from ewe to lamb and scrapiefree sheep have acquired scrapie by grazing in fields once used by a scrapie-infected flock. Maternal transmission of BSE may occur at very low levels; there is no significant evidence of horizontal BSE transmission.

On March27, 1996, the European Union (EU) imposed an export ban on British beef and beef byproducts. After negotiation, on June 21, 1996, the EU leaders agreed to a plan that would gradually lift the ban. According to Associated Press and Agence France-Presse, the plan does not contain a set timetable, and each phase of lifting the ban must be approved by EU scientific and veterinary expert committees as well as the EU Commission. Reports by Reuter indicate that Germany is opposed to easing the ban and may not abide by the agreement. BSE has had a severe impact on the beef industry in the UK and in Europe. Beef consumption has fallen throughout the EU. At one point, sales dropped by 40% in France and Germany. Cattle producers have suffered a large loss in the value of their animals due to the depressed market. Other industry sectors affected by the BSE scare include slaughterhouse workers, auctioneers, truckers, and beef export firms. All have experienced lay-offs of staff and reduction in income due to the export ban and the loss in confidence in beef.

FEDERAL GOVERNMENT ACTIONS

No cases of BSE have been reported in the United States. Federal agencies are monitoring the situation in Europe to prevent transmission of the disease in the United States via products containing bovine-derived ingredients intended for animal or human use. Various federal agencies have taken actions to: control the use of MBM in animal feed; control imports of live animals and ingredients potentially atrisk for BSE; monitor epidemiology and surveillance information on BSE and CJD; and support research on BSE and CJD at the U.S. Department of Agriculture (USDA), National Institutes of Health (MH), and the Centers for Disease Control and Prevention (CDC).

The Food and Drug Administration (FDA) regulates animal feed ingredients. On June 5, 1997, the FDA published a "final regulation that prohibits the use of mammalian protein (with certain exceptions) in the manufacture of animal feeds given to ruminant animals... The rule will take effect 60 days after its publication.......The final rule allows the use of products believed to pose a minimal risk of BSE transmission. These products include blood, blood products, gelatine, milk, milk products, protein derived solely from swine and equine sources, and inspected meat products which have been offered for human food and further heat processed for food, such as plate waste from restaurants and other institutions." Both CDC and USDA recommended that FDA adopt the feed ban. In addition, the World Health Organization (WHO) has recommended that all countries ban the use of ruminant tissue in ruminant feed.

The Animal Plant Health Inspection Service (APHIS), an agency within USDA, is responsible for safeguarding the health of U.S. livestock. APHIS has banned the importation of live ruminants and the majority of ruminant products in 1989 from countries where BSE exists. The current list of countries is in the Code of Federal Regulations (9 CFR 94.18). They are France, Great Britain, Northern Ireland, Republic of Ireland, Oman, Portugal, and Switzerland. APHIS also has tracked 496 head of cattle imported to the United States from the U.K. between 1981 and 1989; as of February 26, 1997, all but 33 had been located. The 34 still alive have exhibited no signs of BSE. APHIS field personnel examine the animals every 6 months and, when possible, the animals are purchased for research (brain tissue examination) to ensure that they posed no BSE threat. USDA's Food Safety and Inspection Service (FSIS) oversees food safety in meat slaughter and processing plants. Under FSIS's foreign meat inspection program, foreign plants shipping product to this country must be approved as operating under safety requirements that are at least equal to the U.S. system. British beef has not been imported since 1985, and no British establishments are approved by U.S. authorities to ship beef here.

Food, drugs and cosmetics containing bovine-derived material are regulated by FDA. Examples include: gelatin, used in making ice cream, candy and drug capsules; butyl stearate and glycol stearate, used in cosmetics; and Heparin, an anti-coagulant drug derived from the liver and lungs. Between November 1992 and August 1994 FDA sent letters to manufacturers and importers of human and animal drugs, dietary supplements, and cosmetics requesting them not to use bovine-derived materials from cattle that resided in APHIS-designated BSE countries. FDA also requested that the manufacturers keep records on where the animals were born, raised, and slaughtered to ensure that the imported materials were not from APHIS identified BSE countries.

CDC has initiated an Emerging Infections Program (EIP) which is conducting disease surveillance in 5 sites around the country. They are California, Minnesota, Oregon, Connecticut, and Atlanta, Georgia. EIP collects data on incidence of all types of emerging disease and will allow clusters of CJD to be identified. CJD is not a notifiable disease and therefore cases are not reported to CDC. CDC officials have examined U.S. death certificates dated 1979 to 1994 for CJD and found the annual incidence remained stable over this 15-year period at one case per million. However, an autopsy is required to confirm a CJD diagnosis, and the number of autopsies performed in the United States has declined over the past 25 years to less than 10% of non-homicide-related deaths. There probably is an under-reporting of CJD in the elderly due to the autopsy decline and the similarity with the symptoms of Alzheimer's disease. One study found that 13% of clinically diagnosed Alzheimer cases were proven to be CJD at autopsy. Younger persons with these neurological symptoms are more likely to be autopsied. Pathologists may be reluctant to perform an autopsy on a CJD victim because of the potential risk of contracting the disease.

BSE is a notifiable disease under Title 9, Code of Federal Regulations, Parts 71 and 161. APHIS's BSE surveillance program coordinates interagency educational and monitoring efforts on BSE. Besides distributing information about BSE to diagnostic laboratories, pathology departments in veterinary schools, private veterinarians, and producers in the beef and dairy industries, APHIS also has trained federal and state veterinarians who conduct field investigations for a number of animal diseases including BSE. APHIS maintains an extensive database on foreign animal diseases and is closely monitoring the BSE outbreak in Britain.

FSIS inspectors examine cattle before slaughter to monitor the safety of the U.S. meat supply. Every year 35 million U.S. cattle are slaughtered, about 130,000 cattle each working day. Those exhibiting neurological symptoms cannot be used for human consumption. APHIS and FSIS have been taking brain samples of cattle at slaughter, cattle exhibiting evidence of neurologic disease on farms, and rabies negative cattle. The samples are examined by APHIS for evidence of BSE. BSE has not been found in 5,342 brains examined from 1990 through January 23, 1997. This monitoring effort rules out a major presence of BSE in the United States. However, it does not rule out a low level presence of BSE. According to an APHIS veterinarian, in order to detect BSE in cattle occurring at the same rate as CJD in humans (one case per million population per year) at a 90% confidence level, approximately 975,000 cow brains per year would have to be examined. Some speculate that a 1985 TSE outbreak on a Wisconsin mink farm indicates a possible low level BSE problem among dairy cows in the United States. According to Dr. Richard Marsh, a Professor of Animal Health and Biomedicine at the University of Wisconsin, Madison, the mink on this farm had been fed "downer" (nonambulatory) dairy cows, but were never fed sheep or animal feed containing MBM.

POLICY ISSUES

There are no reported BSE cases in the United States. Still, a case can be made that the scientific uncertainties suggest action to control feeding practices that may add to the possibility of cattle contracting BSE. Given the uncertainties, many believe it is safest to err on the side of caution until more of the questions on BSE and CJD are answered. This is the current position of European governments and WHO on the ruminant-to-ruminant feed ban. A similar ban will soon be implemented by FDA. Some representatives of the rendering and feed industries and others have voiced opposition to the ban, claiming it will have a severe financial effect on their industries and create a waste disposal problem of animal carcasses, all in pursuit of an unproven remedy. While the ban may cause increased business and production costs for the U.S. rendering and feed industries, it might also safeguard the beef industry from a possible crisis in consumer confidence as occurred in Europe. The beef industry is the largest segment of U.S. agriculture (accounting for more than 20% of all agricultural product marketing and an estimated 1.56 million jobs).

ENDNOTES

1 The prion protein is found in many body cells, especially on the surface of nerve cells in the brain. Its normal function is poorly understood. Prion gene mutation causes the prion protein to become more susceptible to changing into an abnormal shape. The abnormal prion can induce normal prionsto change to the aberrant form, and it is this remarkable ability which allows the prion to replicate and behave as an infectious agent. The aberrant prion is highly resistant to cellular enzymes. Because it is not broken down and elaininated, deposits accumulate within the brain. The loss of normal brain cell prions causes nerve cell death which eventually leads to the characteristic holes that are a trademark of the disease.

2 BSE is a bigger problem in dirry herds due to the long incubation peried: beef cattle are usually slaughtered at 2 years, dairy at 6-8 years. Also, dairy cattle were fed more MBM containing feed and this feed was given at a younger age. Slaughtered dairy cows are often used to make hamburger and pet food.