Featured Report:
Risk of Transmission of Bovine Spongiform Encephalopathy to Humans in the United States (A-98) Full Text

NOTE: This report was presented as Council on Scientific Affairs Report 6 at the 1998 American Medical Association Annual Meeting. A revised version of this report has been published: Tan L, Williams MA, Khan MK, Champion HC, Nielsen NH, for the Council on Scientific Affairs. Risk of transmission of bovine spongiform encephalopathy to humans in the United States. JAMA. 1999;281:2330-2339. (June 23/30)  (Available on-line to AMA members only.)

 Introduction

The transmissible spongiform encephalopathies (TSEs) are a group of chronic, progressive and always fatal neurodegenerative disorders of both animals and humans.^1-3The transmissibility of these diseases is due to a slow-replicating agent that requires long incubation periods before achieving levels within the body sufficient for disease
expression.^4-6 In animals, these diseases include, but are not limited to, the sheep disease, scrapie⁷; the cat disease, feline spongiform encephalopathy⁸; and the cow disease, BSE.⁹ In humans, diseases such as Creutzfeldt-Jakob disease (CJD), fatal familial insomnia (FFI), kuru and Gerstmann-Straussler-Scheinker disease (GSS) also fall into this category.^10,11 In 1995, a novel form of CJD named "new variant CJD" (nv-CJD, vCJD in the UK) was described in the UK. Several scientific studies have suggested that nv-CJD may be due to the transmission of BSE to humans, and this has caused significant concern about the potential that many humans may be infected with this disease but are currently asymptomatic.¹²

This possibility has been brought before the public in a dramatic fashion by the "mad cow" scare in Europe, the subsequent economic downturn of the British beef industry, and by the popular press, and two recently published books, Deadly Feasts by Richard Rhodes, 1997,¹³ and Mad Cow U.S.A by Sheldon Rampton and John Stauber, 1997.¹⁴ The sensationalistic discussion in these books of the possibility of an outbreak of BSE in the United States and transmission of the disease to Americans was the impetus for this CSA report. Back to Top

 Methods

To assess the risk of transmission of BSE to humans in the United States, the following information was required:

1. Background on the nature of prion diseases and current information on BSE and its outbreak in the United Kingdom (UK) and Europe.               
2. Status of the transmission of BSE to humans in the UK and Europe.              
3. Measures adopted by the UK and European Union governments to control, prevent, and eradicate BSE.              
4. Status of BSE in the United States and measures taken by the US government.

The research strategy was designed to obtain information that would allow the assessment of risk of transmission of BSE to humans in the United States. As this is an emerging public health threat involving a controversial disease agent, the research strategy spanned several data sources, including published scientific literature and current awareness services.

Literature searches were conducted in the MEDLINE and EMBASE databases for English-language articles on bovine spongiform encephalopathies, prion diseases, prions, and Creutzfeldt-Jakob syndrome. Lexis/Nexis news databases were searched for current developments in bovine spongiform encephalopathies, prion diseases, prions, and Creutzfeldt-Jakob syndrome.

The World Wide Web was used to determine regulatory actions and health surveillance.

European/international:
World Health Organization (WHO), http:/www.who.ch/
Office for International Epizootics (OIE), http://www.oie.org/
European Union, http://europa.eu.int/index-en.htm
Commonwealth Agricultural Bureaux (CAB) International, http://www.cabi.org/
Ministry of Agriculture, Fisheries and Food, United Kingdom, http://www.maff.gov.uk/maffhome.htm
CCTA Government Information Services, United Kingdom, http://www.open.gov.uk/

United States:
Food and Drug Administration, http://www.fda.gov/
Animal and Plant Health Inspection Service, United States Department of Agriculture, http://www.aphis.usda.gov/
Centers for Disease Control, http://www.cdc.gov/
Proceedings of the National Managed Health Care Congress (NMHCC) 2nd International Conference on Transmissible Spongiform Encephalopathies held on November 17-18, 1997, at the Sheraton City Centre Hotel in Washington, DC was used for more information.

Inclusion Criteria: Primary journal articles and 23 review articles were selected based on their ability to provide information pertinent to the risk assessment issues: (1) identification of the hazard; (2) assessment of the risk; (3) management of the risk; and (4) communication of the risk, where the hazard/risk was BSE and its transmission. Following reading of the 23 review articles, further relevant primary articles were selected from the reference listings using the same inclusion criteria. Back to Top

 Nature of the Infectious Agent

Several hypotheses have been advanced by the scientific community to explain the pathogenesis of TSEs. Some researchers have proposed that a slow-acting virus^6,15,16 or a naked nucleic acid particle wrapped in host protein called a "virino" is responsible.¹⁷ Others believe a unique microbe called a spiroplasma is involved.^18,19 The most widely accepted hypothesis has gained increasing support over the last 10 years. Once highly controversial, the "prion hypothesis" proposes the TSE agent to be composed only of protein. This hypothesis was initially suggested by J.S. Griffith in 1967²⁰ and has been strongly supported by Drs. Stanley Prusiner, David Bolton, and Paul Bendheim.^7,21 This hypothesis ultimately led to the 1997 Nobel Prize for medicine for Dr. Prusiner.²² Supporters of the "prion hypothesis" maintain that the agent responsible for TSEs is an infectious protein commonly called a prion (PrP).^7,23,24 This protein normally exists as a protease-sensitive, glycosylphosphatidyl inositol-anchored cell surface protein in neurons (designated in the literature as PrP^c or PrP^sen).²⁵ Disease occurs when an abnormal, protease-resistant isoform of this protein (PrP^sc or PrP^res) accumulates within the brain.^{7,10,23,24,26} There is now considerable evidence to support the prion hypothesis including transgenic mouse, physical, and biochemical studies.^27-32 Furthermore, the remarkable ability of this infectious agent to survive ultraviolet radiation and other procedures designed to hydrolyze and destroy nucleic acids has provided additional support for the prion hypothesis.^33-38

The Prion Protein: All prion diseases involve the participation of the prion protein, which is coded for by a gene within the host (on chromosome 20 in humans).^7,39-42 This has been demonstrated by the observation that transgenic mice not expressing the cellular PrP gene, PrP^c, are resistant to prion disease.^32,43 In another study, when wild-type brain grafts were placed in the gene-ablated mice, these grafts were the only portions to develop pathology following infection of the mice with PrP^res.44 Interestingly, these transgenic mice did not appear to suffer any neurological deficit as a consequence of the gene disruption. Thus, the role that the normal prion protein plays in the central nervous system (CNS) remains to be elucidated,⁴⁵ but some data suggest that the prion protein might be important for the survival of cerebellar Purkinje cells and GABA-mediated fast neuronal inhibition in older mice.⁴⁶ However, this 254 amino acid-long protein is highly conserved across species, suggesting an important function.^36,47

 The conversion of the normal PrP^sen into the abnormal PrP^res is the precipitating event for disease. Infection with, or perhaps the spontaneous development via somatic mutation of, an abnormal prion protein catalyzes a slow conversion of existing PrP^sen into the abnormal PrP^res.^7,23 As the conversion progresses, PrP^res accumulates in the brain and is resistant to breakdown. When sufficient particles of PrP^res are present, the host begins to develop the classical symptoms of spongiform encephalopathies.^38,48 Transmission of the disease, however, can occur before the appearance of clinical signs.^38,48 In some cases, the aggregates of PrP^res can be seen as amyloid fibrils and plaques within the brain.^7,49

In 1967, J.S. Griffith proposed the following mechanism for conversion of a normal protein to an abnormal protein.²⁰ PrP^res physically associates with its normal homologue PrP^sen. This contact allows the formation of various heteromers (conformations that involve multiple units of both PrP^sen and PrP^res). These heteromers are subject to catalysis by the abnormal PrP^res within the heteromer yielding several monomers of the abnormal PrP^res. These new PrP^res molecules can then continue to multimerize with and convert additional normal PrP^sen protein into abnormal PrP^res.^7,20,50

Since this mechanism was originally proposed, the molecular biology of disease pathogenesis has been well elucidated. The aforementioned physical association has been demonstrated experimentally, and substances that inhibit protein aggregation, or that hydrolyze proteins, also inhibit disease pathogenesis.^28,38,51,52 Additionally, due to the requirement for physical association of the prion proteins, differences between the infecting PrP^res and the host PrP^sen proteins ultimately determine the efficiency of conversion of the host PrP^sen by the infecting PrP^res.^23,53,54 Thus, if the infecting PrP^res is dramatically different from the host PrP^sen, then there is less likelihood that disease will occur because the two proteins are less likely to associate productively. This is seen as a "species barrier" between prion proteins from one species and another,^7,55,56 and has been demonstrated in transgenic mice systems.^54,57,58 Further experiments have shown that if transgenic mice expressing hamster PrP^sen are infected with mouse PrP^res, the resulting prions are of mouse origin. Hence, the new synthesis of prions is species-specific and dependent on the origin of the infecting prion.⁵⁴ The conversion of normal PrP^sen into PrP^res also has been demonstrated in-vitro.⁵⁹

The conversion of PrP^sen into PrP^res causes the protein to lose a -helical structure and to have increased b -sheet properties.⁶⁰ With this structural transition come several profound alterations in the properties of the protein. PrP^res is no longer soluble in nondenaturing detergents or readily hydrolyzed by proteases.⁶¹ In fact, proteinase K completely hydrolyzes PrP^sen, but results in a truncated isoform of PrP^res (PrP^27-30) that retains infectivity.^29,41,61,62 The normal PrP^sen does not readily aggregate, but PrP^27-30 polymerizes into amyloid rods.⁶³ Finally, with disease initiation, PrP^res now copurifies with infectious brain matter, whereas it has never been found in normal brain.^29,62,64,65 Other studies have also shown that the appearance of PrP^res precedes the onset of clinical disease, sometimes by a significantly long time period.^66-70 Much research still is needed to identify how the replication and accumulation of the PrP^res causes disease and how the disease can be treated. Back to Top

 Prion Diseases

 Bovine Spongiform Encephalopathy (BSE): This new disease of cattle was first diagnosed in 1986. Skeptics question the characterization of BSE as a completely new disease, maintaining that it has occurred in cattle for a long time but remained undetected. However, the remarkably unique and previously undescribed clinical and neuropathologic signs of BSE suggest otherwise, and most experts agree that BSE represents a newly discovered spongiform encephalopathy of cattle.

Clinically, BSE begins with signs of anxiety, restlessness, and aggressive behavior, thus leading to the descriptor "mad cow disease."^9,71 The age of affected cattle ranges from 20 months to 18 years, with most cases appearing between 2 to 8 years of age.^72,73 As the disease progresses, the cow becomes unable to rise from a lying position, posterior ataxia develops, and the cow loses body weight despite normal appetite. Death usually occurs between 2 weeks and 6 months after the onset of clinical symptoms.⁵ Confirmation of disease is based on postmortem examination of brain tissue. Currently, no test to detect the disease in live cattle has been validated.

Postmortem examinations of BSE-infected cows reveal distinct vacuolation confined to the CNS, giving the appearance of spongiform changes in the gray matter.⁷⁴ These vacuolations typically have a systematic and bilateral distribution pattern and are most severe in the dorsal horn of the spinal cord and intermediate gray matter. Degenerative changes in the basal ganglia are more striking than those seen in the cerebellum.^5,9 These unique pathological changes never occur in normal healthy cattle. 

Ultrastructural examination reveals that the pathological findings in BSE-infected cows also resemble those found in scrapie and in nv-CJD-infected animals. Specifically, the vacuoles may contain many membrane bodies and tubulofilamentous particles and scrapie-associated fibrils also may be present.⁷⁵

Finally, immunohistochemistry has revealed distinct formations in the diseased animal brain composed of protease-resistant prions. These are similar to prion protein plaques seen in kuru, nv-CJD, and many of the other TSEs.^5,76 Back to Top

 Creutzfeldt-Jakob Disease (CJD): CJD is a rare and fatal human TSE. Similar to the other TSEs, it is transmissible to mammals and between humans, although there are limited ways by which this can occur. It is not a new disease, having first been described by Dr. H. Creutzfeldt in 1920 and Dr. A. Jakob in 1921.¹⁰ CJD has a stable world-wide incidence of about 1 case/million/year, an equal male:female incidence ratio, and does not appear to have a definable geographic or ethnic distribution.^77,78 There are four known types of CJD: sporadic, inherited, iatrogenic, and variant. The only types of CJD documented as transmissible to humans are the iatrogenic and the new variant forms. Kuru, another human prion disease, is transmitted between humans by oral consumption of infected human brains (discussed later).⁷⁹ The sporadic form of CJD comprises about 85% of all cases, whereas 10% to 15% are inherited as an autosomal dominant trait.^10,55,78 In all types of CJD, there is little or no immunologic activity directed against the disease agent within the patient.⁸⁰

While many epidemiologic risk factors have been proposed for sporadic CJD, none are definitive. It is suggested that either a rare infection with prions, a rare misfolding of the normal PrP^sen protein, or a somatic mutation of the PrP gene is responsible for the bulk of these cases.²³ Interestingly, a large number of the patients with sporadic CJD were homozygous for either methionine or valine at codon 129 of the PrP protein.⁸¹

The inherited CJDs have been linked to several different mutations in the human PrP gene that lead to nonconservative substitutions in the protein. The first such described linkage was a proline-to-leucine substitution at position 102. This mutation has been shown to segregate with many cases of GSS around the world.⁸² In transgenic mice, genetic mutations that result in changes to the coding region of the PrP protein have been shown to result in neurodegenerative disease, and now, in addition to the mutation described above, genetic linkage has been demonstrated for several other mutations.^23,83-86

Iatrogenic CJD has been traced to corneal transplantation, contaminated electroencephalographic electrode implantation and surgical operations with contaminated surgical equipment.^7,87-89 Cases also have been traced to patients receiving human pituitary growth hormone or gonadotrophin.^90-92 Finally, dura mater grafts have been implicated, most recently in Japan where over 40 cases have been linked to contaminated dura mater.⁹³

Clinically, CJD presents a wide spectrum of symptoms. Early in the disease course, most CJD patients exhibit rapidly progressive dementia, myoclonus, and pyramidal tract dysfunction. Electroencephalograms are characterized by distinctive periodic sharp wave activity. Only 10% to 20% of patients present with an ataxic illness.^7,10,55 It is important to realize that almost any combination of cortical, subcortical, cerebellar, and spinal-cord findings is possible, and thus the rapid progression of the disease is often the characteristic that suggests a diagnosis of CJD.⁵⁵ Death may be caused by the neurological dysfunction itself, or by complications of the dementia such as pneumonia and dehydration.

There are three distinct neuropathologic characteristics of TSEs⁷: (1) spongiform degeneration of neurons^94,95; (2) severe astrocytic gliosis that is out of proportion with the degree of cell loss^96,97; and (3) amyloid plaque formation.^98,99 With CJD, there is obvious astrogliosis and usually spongiform degeneration.^7,10 Plaque deposition occurs in 5% to 10% of cases.¹⁰⁰ While astrogliosis is a prominent feature, it is not unique to CJD. However, in CJD, widespread proliferation of fibrous astrocytes in the gray matter is obvious. Generally, spongiform changes are seen in the cerebral cortex, putamen, caudate nucleus, thalamus, and the molecular layer of the cerebellum. These are characterized by 1 to 5m m vacuoles within nerve cell bodies and processes of neurons and glia cells.¹⁰¹ Under electron microscopy, the vacuoles appear as swollen neuronal processes surrounded by a membrane. Amyloid plaques, when present, stain with antisera raised against PrP^res.⁴⁹ Additionally, prions purified from CJD brains demonstrate the ultrastructural and histochemical properties of the amyloid plaques.¹⁰² Back to Top

 Kuru Disease: Kuru, another human prion disease, is transmitted between humans by oral consumption of infected human brains.⁷⁹ Kuru probably originated around the turn of the century from a case of sporadic CJD in the Fore people of New Guinea that was recycled back into the population by ritualistic cannibalism.¹⁰³

Because of the large amount of homology between the infecting PrP^res and the host PrP^sen, a prion agent produces the most consistent disease in terms of symptoms and incubation period when transmitted within a species.⁷ Thus, kuru presents a remarkable consistency in its clinical and pathological profile.⁷⁹ Usually 6 to 12 weeks elapse between the appearance of prodromal symptoms like headache and joint pain and ambulatory dysfunction. Other eventual symptoms include progressive ataxia, a loss of balance, tremors leading to an inability to sit or stand, incontinence, and an inability to swallow. All patients die within 2 years of onset with an average illness duration of 16 months.¹⁰⁴ Clinical signs of cerebellar dysfunction occur throughout the disease, and there is evidence of dementia in late stages of disease.^79,105

Neuropathologically, kuru consistently shows cerebellar and brainstem involvement. The grey matter shows spongiform changes and amyloid plaque formation. Typically, kuru plaques are densely unicentric. They have homogenous centers with radiating spikes or small granules, and also stain for PrP^res.^106,107 With the cessation of cannibalism, kuru has all but disappeared. Back to Top

 New Variant CJD (nv-CJD): New variant CJD (nv-CJD) presents very different clinical and pathologic features from sporadic CJD.^12,108 The first obvious difference is the age of onset of disease. While most cases of sporadic CJD occur in late middle age, typically between the ages of 60 and 65, patients with nv-CJD have a mean age of onset of 29 years.¹⁰⁹ nv-CJD cases have a more protracted clinical course than sporadic CJD. Thus, while most sporadic CJD cases run a clinical course of less than 1 year, the average clinical course of nv-CJD usually is 14 months.^109,110

Second, nv-CJD presents clinical symptoms that are more in line with kuru than traditional CJD.^23,110,111 Two early clinical features are sensory disturbance and behavioral changes (such as withdrawal, anxiety, and depression) that typically result in referral to a psychiatrist; these progress to neurological abnormalities.¹¹² Ataxia develops early in the course of disease and is present in the majority of cases, unlike the 10% to 20% seen in sporadic CJD.^12,109 Within weeks of presentation, a progressive cerebellar syndrome with forgetfulness and other memory impairment develops. A number of patients are apathetic and have weight loss and mild insomnia. Progressive dementia is present in all cases, but memory impairment may not be an early sign accompanying the dementia. Late in the disease, most patients develop myoclonus. None of the patients had the electroencephalographic changes associated with sporadic CJD. Just before death, most patients had akinetic mutism and some developed cortical blindness. It is important to note that according to the classical clinical diagnostic criteria described above, none of these nv-CJD cases would have been classified as probable CJD.¹⁰⁹ Genetically, all cases were methionine homozygotes at codon 129 of the PrP gene¹⁰⁹ suggesting a possible genetic susceptibility for methionine homozygotes at codon 129.

The third distinction between nv-CJD and sporadic CJD is in neuropathology. nv-CJD patients had significant PrP plaques and uniform spongiform changes sparsely distributed throughout the cerebral cortex.^{12,55,109,110} The spongiform changes, neuronal loss, and astrocytosis are most visible in the basal ganglia and thalamus. However, the most striking neuropathologic feature was the presence of the PrP plaques in all the brains examined.^12,23 These plaques were distributed throughout the cerebrum and in particular, the cerebellum, and less so in the basal ganglia, thalamus, and hypothalamus. They resembled kuru plaques, with their dense eosinophilic centers and pale periphery. A region of spongiform change surrounds the plaques. Finally, immunohistochemistry demonstrated that the plaques all stained well for PrP.^12,113

While there are clinical and neuropathological similarities between nv-CJD and kuru, there is little doubt that the two diseases are distinct. Back to Top

 Confirmation of Probable CJD Diagnosis: Unfortunately at this time there is no method to confirm a probable case of CJD unless a postmortem examination is performed.¹⁰ However, at least two antemortem techniques have been proposed. One involves detecting the appearance of the 14.3.3 brain protein marker in the CSF of CJD patients by ELISA.^114-116 The other involves detecting the prion protein itself in the tonsils of affected individuals.^117,118 However, there is controversy as to the overall sensitivity and accuracy of these tests. For example, while the 14.3.3 test appears to be fairly accurate for sporadic CJD cases, it has not yet been proven reliable for nv-CJD cases. The recent availability of a monoclonal antibody that distinguishes the PrP^sen isoform from the PrP^res isoform may allow the development of a diagnostic antemortem test.¹¹⁹  Back to Top

 Transmission of Prion Diseases

By definition, the TSEs can be transmitted from mammal to mammal, from human to human, and potentially, from mammal to human. Between mammals, transmission of TSEs has occurred from cattle to cats, sheep, goats, pigs, marmosets, mice, and other cattle.^5,120 Human TSEs can be transferred into chimpanzees, squirrel monkeys, and marmosets.^7,23 Human TSEs have also been transferred to other humans such as in iatrogenic CJD cases and in kuru where oral ingestion of infected high-risk material is the path of infection.⁷⁹

 Conditions Governing Transmission of Prion Diseases: It is important to realize that certain conditions have to exist for transmission to occur. Many studies have documented the existence of a "species barrier" with respect to transmission of disease from one species to another.^7,55,56 This barrier is due to the conformational differences between the PrP proteins in different species. Thus, if the differences between the donor PrP and the host PrP were substantial, the incubation period for disease (when conversion of host PrP occurs) would be so long that disease could never be detected. If the differences between donor and host PrP proteins are too great, the conversion may not occur, in which case there would be no possibility of disease. The strain of PrP responsible for scrapie differs substantially from human PrP in conformation and this may be why scrapie has never been shown to transfer to humans.^78 23 77 On the other hand, the strain of PrP responsible for BSE does not appear to have a highly rigorous species barrier and hence can be transferred to many species.^5,120,121 It must be noted that a species barrier may be circumvented via prior passage of the prion protein into another species.^23,122 For example, the passage of the sheep scrapie PrP^res into cattle may result in a cattle-adapted PrP^res that causes BSE, which in turn may now infect humans.

Another important condition for transmission is the tissue source of the PrP^res. Certain organs contain significantly more infectious prions than other organs.^123,124 The World Health Organization (WHO) in conjunction with the Office International Des Epizootics (OIE) has categorized organs into four risk groups (Table 1).^125,126 These classifications are now used internationally in policies concerning BSE and CJD. Thus, the WHO and IOE consider Category I organs as possessing a high titer of infectivity and to be avoided. Specified Bovine Offals (SBO; the heads and spinal cords) fall into this category. On the other hand, Category IV materials (such as milk and skeletal muscle) have not been demonstrated to contain titers of infectivity and are therefore currently deemed safe.

The route by which the source material is introduced into the host is also an important determinant of transmissibility.^55,123 Direct administration into the CNS is the most infectious route.^123,127 The next most efficient route of administration is into blood vessels and into open wounds, followed by intraperitoneal, intramuscular, and subcutaneous exposure. Oral ingestion is considered less efficient than the parenteral routes.^55,123,125

Finally, the dose of infectious material is an extremely important determinant of transmissibility.¹²³ Unfortunately, this has not been extensively studied. In BSE, it is hypothesized that once the sheep scrapie agent had adapted in the cow, a dose as low as 14 oral LD₅₀ per metric tonne of feed was sufficient for infection.¹²³ This hypothesis would explain the longer incubation times in the earlier cases of BSE (when a sheep PrP was responsible for disease) compared with the later cases when a cattle-adapted PrP was the primary contaminating agent in the animal.^123,128 There has been little work to establish minimum infectious doses for humans because of the species barrier effect. There is no ethical way to compare the lethal dose in humans with an equivalent titer in animals, but as illustrated by the iatrogenic transmission of CJD via incompletely decontaminated stereotactic electrodes, the minimum infectious dose is likely to be small.⁸⁸ Of course, the dose administered will also be critically dependent upon the route of administration with high infectivity routes most likely requiring smaller inoculum. Back to Top

 Mammal-to-Human Transmission: Is nv-CJD BSE in Humans? As described above, scrapie has never been shown to infect humans and thus initially, there was little concern regarding the transfer of BSE to humans. When nv-CJD first appeared, it was difficult to absolutely link the disease to infection with the BSE prion. There is now evidence demonstrating that the PrP responsible for BSE may be the same PrP responsible for nv-CJD.^113,129-131 Bruce et al have previously shown that infection of certain lines of inbred mice with different strains of the PrP^res agent will give distinct reproducible incubation times and pathology. Using 4 to 5 mouse lines, the effects of disease caused by a certain PrP^res strain, as measured by the above criteria, can usually be summarized into a "signature" for the strain that is reproducible and characteristic of that given strain.¹³² In their most recent study, they demonstrated that the PrP^res strain was the same in the 3 nv-CJD cases they examined; were different from the strains identified in sporadic cases of CJD; and most significantly, indistinguishable from the strain that causes BSE.¹²⁹ PrP^res strains can also be distinguished by glycoform profiles. Hill and coworkers had earlier established that different strains of PrP have unique fragment size and ratio of non-, mono-, and diglycosylated forms after treatment with proteinase K¹³³. They have found no difference in glycoform profile between the BSE PrP^res and the nv-CJD PrP^res. Most significantly, they demonstrated that transgenic mice expressing human PrP^sen, following a long incubation period, developed a similar disease when infected with either the cattle BSE PrP^res or nv-CJD PrP^res.¹³⁰ These results have led to the currently accepted hypothesis that nv-CJD is a new variant of CJD and that it is the result of the transmission of the BSE PrP^res from infected cattle into humans.

As of January 1998, there have been 23 cases of nv-CJD in the UK and 1 case in France.^108,134 The first 3 cases were described in 1995; 11 cases occurred in 1996 and 10 more in 1997.¹³⁴ These individuals probably contracted the disease agent via oral ingestion (probably of processed beef) prior to the UK Specified Bovine Offals (SBO) ban in 1989.^{40,55,113,129-131} This ban prohibited the entry of high-risk bovine tissues such as brain and spinal cord into the human food chain at any point.^120,135 Thus, if human exposure theoretically began in 1983 with the entry of BSE-infected but undiagnosed cattle into the human food chain, nv-CJD appears to have at least a 10-year incubation period prior to the appearance of symptoms. Therefore, the extent to which the human population might be affected by nv-CJD is still unknown. Using several different assumptions for risk analysis, Cousens et al¹³⁶ have estimated as few as 75 to as many as 85,000 total human infections. The current pattern would predict hundreds of human infections, assuming a 10-year incubation period.¹³⁶ It is believed that following the SBO ban in 1989, the chance of continued human infection with the BSE prion is low. Back to Top

 The BSE Epidemic in the United Kingdom

Given the current data about the transmission dynamics of the prion diseases, it is reasonable to assume that certain conditions were in place for the outbreak of BSE to have occurred in the UK. This is further supported by the fact that there are no detected cases of BSE in the US, Australia, and New Zealand, and that Switzerland, a major importer of British meat and bone meal (MBM), has the highest number of reported BSE cases in Europe.^5,120,137 The total number of BSE cases in the whole of Europe (626) is almost 3 orders of magnitude less than the total number of BSE cases reported in the UK (170,845).¹³⁷ Thus, what were the existing factors present in the UK that allowed BSE to become such a major health and economic issue?

In a major epidemiological study of BSE in the UK, Wilesmith and co-workers surveyed all UK herds with at least one case of BSE. They collected data ranging from the origin of the cow(s), offspring, and clinical signs and progression of the disease, to information on the use of therapeutics, pharmaceutical products, vaccines, pesticides, herbicides, and all feeding practices prior to and after the occurrence of BSE.⁷¹ When the authors compiled all their data and performed computer simulations, they determined that BSE is an extended common source epidemic.⁷¹ That is, each case of BSE is due to exposure to a single common-source of infection. The only identifiable common factor in the BSE-infected cows was the consumption of cattle feed manufactured from meat and bone meal (MBM) that contained ruminant-derived protein.⁷¹ It is suspected that MBM contaminated by a TSE agent was the source of the BSE. The original TSE agent is believed to be scrapie itself or a cattle-adapted strain of scrapie.⁷¹ Back to Top

Meat and Bone Meal (MBM): The Rendering Process: The production of MBM involves a rendering process whereby raw material composed of any animal byproducts including offal, fat trimmings, and bones from slaughterhouses and dead carcasses from farms are cooked to produce fats (called tallow) and an incompletely processed, protein-rich solid residue called greaves. In the 1970s, greaves were further processed by hydrocarbon solvent extraction and steam desolventizing to yield MBM containing about 1% fat.¹²⁸ This MBM is used as a protein source in the manufacture of animal, and in particular, cattle feed. Between 1977 and 1982, the solvent extraction process was replaced with centrifugation and pressing, resulting in MBM that contained 7% to 14% fat.¹³⁸ Some rendering plants resold the greaves to other animal-feed plants that reprocessed it by a complete cooking process while mixing it with more raw materials to produce their MBM. Thus, at the start of the BSE epidemic, there were two forms of MBM in use: MBM derived directly from the centrifugation of greaves containing 7% to 14% fat, and MBM derived from the reprocessing of greaves. Back to Top

 Risk Factors Leading to the BSE Outbreak in the UK: The USDA and other epidemiological studies have identified 5 risk factors in the UK that led to the BSE problem.^138-140

1. There is a large sheep population relative to the cattle population in the UK.              
2. There is a large, uncontrolled scrapie incidence rate in these sheep. As a consequence, there was a large reservoir of TSE prions that could potentially make their way into cattle. Specifically, prior to 1988, the carcasses of sheep that died from scrapie and other causes constituted a significant part of the raw material used by UK rendering plants for production of animal feed.¹³⁸ Thus, over 14% of UK rendered animal protein is sheep-derived.¹¹⁰              
3. The reduced use of hydrocarbon solvent extraction in the production of MBM from greaves resulted in significant amounts of MBM contaminated with the BSE agent.^5,120,128 However, if greaves are reprocessed by complete cooking into MBM, there is significant deactivation of the BSE agent. Thus cattle herds fed MBM derived from the reprocessing of greaves had a significantly reduced incidence of BSE when compared to cattle herds fed MBM derived directly from greaves derived via centrifugation and pressing.^128,138              
4. The extensive production of MBM from greaves and its use as a protein source in animal feed.¹²⁸ These greaves contain large concentrated amounts of the BSE/scrapie prion due to the partial rendering of the raw material. In contrast, the US derives most of its protein for animal feed from plant-derived proteins.¹³⁹              
5. Four to five percent of the diet of young dairy calves was composed of MBM derived directly from greaves. In this way, 60% of the UK s dairy herds have been affected with at least one case of BSE.⁷²

Once BSE was established, the feeding of large amounts of rendered BSE-infected cattle products back to calves further fostered the epidemic. This recycling of BSE agent from adult cattle to calves probably continued until the ruminant-to-ruminant feeding ban was initiated in 1988. Back to Top

 How the nv-CJD Problem Developed in the United Kingdom

Prior to any action taken to contain BSE, there were several points where contaminated bovine products could have entered the human food chain. The most likely was through contamination of processed beef, like ground beef, by the Specified Bovine Offals (SBOs).^40,124 In the early 1980s, there was no reason for the UK government to suspect that beef products were contaminated with a lethal agent that could potentially infect humans. Even so, only products that contain the SBOs, now called Specified Risk Materials (SRM), would be potentially infectious providing they contained enough of the infectious prions.¹²⁴ Additionally, when cases of BSE were first identified, there was no reason to suspect that the BSE prion would be able to cross the species barrier, especially since scrapie has been endemic in sheep for over 200 years and has not been shown to infect humans.^7,40,77,78

It was not possible to predict that the BSE prion would have a less rigorous species barrier. There also was no evidence that the scrapie agent would be capable of causing human infection after passage in cattle. In fact, a report by Raymond and co-workers¹⁴¹ who analyzed the ability of the BSE PrP^res agent to convert human PrP^sen into PrP^res suggested that the risk of transmission was low. However, the authors recognized that this conclusion was limited because their in vitro experiment did not take into account in vivo effects such as dose of inoculum and route of infection, which play a role in transmission.

Thus, it appears that a combination of factors such as the lack of scientific data concerning the species barrier between cattle and humans, the long lag time between consumption of the BSE prion and the appearance of nv-CJD, and perhaps the general failure to respond rapidly to the emerging problem all played roles in the current BSE/nv-CJD problem in the UK. Back to Top

 Why Has BSE Not Been Found in the United States?

No cases of BSE have been detected in US cattle. In fact, on the entire continent of North America, there has been only one case (in Canada) and it was not in native cattle. This cow was imported from Great Britain and was destroyed along with all its herdmates plus other imported cattle deemed to have been potentially exposed.⁵⁵

There are several reasons why US cattle are at minimal risk for BSE (summarized in Table 2). First, the UK has over 40 million sheep compared to 8 million sheep in the US. In addition, the UK had only 12 million head of cattle (prior to the outbreak of BSE) compared to more than 104 million head of cattle in the US. Thus the sheep-to-cattle ratio is much higher in the UK.¹¹⁰ Considering the epidemiological data indicating that BSE probably originated from the feeding of cattle with MBM contaminated with sheep scrapie prions,⁷¹ this significantly reduces the potential reservoir of infective agent in the US. This is actually reflected in the fact that US rendered animal protein has only 0.6% sheep-derived protein.¹¹⁰

Second, while both the US and UK rendering industries were producing ruminant-derived animal protein products, there was a major difference between them in availability of plant-based proteins as an animal feed source. The US is a major provider and user of plant-based protein such as soybean meal, and plant-based proteins are a major part of complete animal feeds in the US.¹³⁹ Conversely, the UK derives a significant portion of its protein for animal feeds from other animals, thus increasing the risk of feeding MBM contaminated with SRMs from infectious sheep or cattle to uninfected animals.

It has also been speculated that the strains of scrapie infecting US sheep (estimated to be as many as 20) may not be capable of overcoming the species barrier as the scrapie strain in the UK may have done in the transmission from sheep into cattle.¹¹⁰ There also may be a lower incidence of scrapie in US sheep because the US has had a scrapie control program in place since 1952.¹¹⁰

There is speculation in the US, as there was in the UK, that BSE already exists at very low levels in US cattle and has simply not been detected yet.¹¹⁰ When cows were experimentally infected with the US scrapie prion they developed an ataxic neurologic illness, albeit without the spongiform neuropathology characteristic of BSE. This disease was diagnosed as BSE only when immunoassays were conducted postmortem that detected the presence of the prion protein in the brain.¹⁴² This implies that BSE cases may be missed if neuropathologic examination does not include immunoassays to detect the PrP protein. However, the lack of spongiform neuropathology in this experimental situation would distinguish this form of disease from the BSE cases in the UK. Despite these concerns, the neuropathologic examinations of more than 6500 US cattle diagnosed with neurologic disorders since 1990 have not revealed a case of BSE, suggesting that BSE does not exist in the US.^5,55,110,143 Back to Top

 Policies and Regulations Adopted to Control BSE and nv-CJD

 The UK and the European Union Response: World organizations as well as individual governments have utilized three approaches to control nv-CJD: (1) minimize the risk of further contamination of cattle with BSE; (2) eradicate any existing BSE cases; and (3) eliminate the exposure of humans to the BSE agent. The UK has implemented several regulations and guidelines. Due to the severity of the UK problem, British policies are obviously the most stringent, although policies of the European Union are similar. 

 Regulation of Animals and Animal Products: Following the appearance of BSE in 1986, the UK implemented legislation in 1988 that made BSE a reportable disease and that required all cattle suspected of suffering from BSE to be destroyed and sent for diagnosis. BSE suspects are incinerated.¹²⁰ Monetary compensation, first at 50% and later at 100%, is provided to cattle farmers to ensure adherence to the rules. This initiates an eradication process of infected animals. The European Union has adopted a more stringent version of this policy whereby the entire herd in which the suspected BSE-infected cow(s) was found is also destroyed.¹⁴⁴ The European Union also instituted a temporary ban on almost all UK bovine products into Europe,¹⁴⁴ which remains in place today. Also, there are detailed guidelines on the sourcing of imported materials into European countries to ensure that no potentially BSE-infected product will enter the country.^144,145

In the UK, all adult animals designated for slaughter are first examined by veterinarians to ensure that no suspected BSE cases are slaughtered for human consumption.¹³⁵ BSE prions have been detected only in certain organs generalized as the SRM.¹³⁵ To prevent possible transmission via these organs into either animals or humans, the head (excluding the tongue), spinal cord, spleen, and tonsils of cows aged 6 months or older and the intestines and thymus of all cows are removed at slaughter and discarded. Brain, spinal cord, tonsils, thymus, spleen, and intestines of cattle over 6 months have been banned from human food since 1989 and from animal feed since 1990.^5,124,135 In addition, the Specified Bovine Material Order has banned the use of SRM in cosmetic, pharmaceutical, and medical products since March 1997.¹⁴⁶ In order to ensure uniformity, similar standards will come into effect in the European Union on April 1, 1998 (Committee Decision 97/534/EC).^145,146

The UK government has also implemented a proposal that prohibits the use of any cattle over 30 months of age for animal or human consumption.¹³⁵ Since cows over 30 months are most likely to develop a significant amount of the BSE prions, this measure effectively removes all the highest risk cows from the human food chain.

The UK government has prohibited the use of ruminant-derived protein in any product that is used to feed other ruminants (1988) and has now expanded that ban to include mammalian protein in any ruminant feed (1994).^124,147 The European Union has also adopted the mammalian-to-ruminant ban (1994) .1⁴⁵ Additionally, the incorporation of mammalian MBM in any farmed animal feed (including farmed fish) has been banned in the UK (1996).¹⁴⁷ Since feed produced for pigs and other livestock (which until this ban, contained bovine material) was commonly produced near feed intended for cattle, this ban was intended to eliminate potential cross-contamination. There is also a ban on the use of mammalian MBM on premises where livestock feed is used, produced, or stored and a requirement that all those handling mammalian MBM thoroughly clean and disinfect their premises/equipment and keep comprehensive records.¹⁴⁷ Since the BSE agent does not transmit laterally, that is directly from cow to cow, and the transmission from mother to calf is responsible for no more than 10% of expressed disease in the field, the feed ban measure should result in eventual eradication of the disease in cattle.^73,124 These efforts have been remarkably successful, as the rate of new BSE infections has rapidly declined (40% per annum) in the UK.¹²⁰

When the UK discovered that residual stocks of mammalian MBM were still being used, and hence contamination of healthy cows was still occurring, there was a recall of all residual stocks of mammalian MBM in March 1996.^140,147,148 Unfortunately, this means that the BSE agent was still entering new animals until 1996. Fortunately, the 1989 ban of SRMs in human food probably precluded further human infection from these new infections.¹⁴⁶

To ensure enforcement of these regulations, the UK implemented a rigorous sampling program in February 1996 to examine a large number of premises that handle animal feed for compliance.¹⁴⁷

Most emphasis has been on preventing potentially infected bovine material from being consumed. Along these lines, the European Union has introduced legislation (finalized July 30, 1997, and effective April 1, 1998) that will prohibit the use of SRM for any purpose.¹⁴⁵ This was determined to be necessary to prevent any potential human consumption of the BSE agent. On December 6, 1997, the UK initiated a requirement that all beef be deboned based on data indicating that the BSE agent could be detected in the dorsal root ganglia and bone marrow of cows over 30 months of age.¹⁴⁹

Finally, no infectivity has been detected in cow's milk and thus it has been deemed safe for human consumption.^124,125

The European Union has also initiated preliminary trials (1997) of a new rendering process designed to reduce the infectious BSE prion to undetectable levels.^{145 
Back to Top}

 Regulation of Human Tissues: The National CJD Surveillance Unit headquartered in Edinburgh, Scotland, monitors the appearance of CJD cases in the UK. This unit discovered and described the first cases of nv-CJD in 1995.¹² The existence of this unit allows monitoring of the extent of human disease resulting from the BSE epidemic in cattle. This unit, along with the Spongiform Encephalopathy Advisory committee (SEAC), has advised the UK government on several of the policies on handling of human cases of CJD and nv-CJD. Since the transmission of disease between humans generally has to come from very specific routes (cannibalism, iatrogenic cases) there has not been much concern at this level until recently. The concern that nv-CJD is a result of the transmission of BSE into humans has prompted other studies to determine how to protect the human population from further risk. 

The WHO has determined that human blood products do not carry the infectious prions and are safe for use.¹²⁵ Scientific data thus far would appear to support this conclusion.^150-153 However, the WHO has recommended continued observation and exclusion of people who either have or are at risk for CJD from donating blood.¹²⁵ As for supplies of potentially infected blood or blood products currently on hand, there has been no action recommended by the WHO and legislation has been left to individual countries. No recommendations have yet been made with regard to donors with nv-CJD. However, since there is a higher involvement of lymphoreticular tissue in nv-CJD, studies are under way to examine the risk that nv-CJD might be transferred via white blood cells in blood.^154,155 On October 24, 1997, the SEAC in the UK suggested that until more studies are conducted, new blood supplies should be leukodepleted to remove this potential transmission route.¹⁵⁵ Additionally, the SEAC has suggested that where practical, leukodepleted blood and blood products should be used. This recommendation may be justified in light of a study published in December 1997 implicating the necessity of B cells for the development of clinical scrapie.¹⁵⁶ In Europe, plasma pools containing plasma from CJD-infected donors are not recalled. However, on October 30, 1997, the UK decided to recall all plasma if contamination from nv-CJD-infected donors was present.¹⁵⁷ The differences of opinion and action between Europe and the UK serve to highlight the lack of satisfactory scientific data and the need for continued research on this issue. Back to Top

 The US Response

In the US, the USDA and its associated Animal and Plant Health Inspection Service (APHIS) are responsible for regulations and guidance pertaining to the importation of plant and animal materials into this country. They are involved in educating the agricultural sector about BSE and for the surveillance of BSE in the US. The FDA regulates the content of animal feed as well as the content of any product that will be utilized for human consumption. Although there is shared responsibility for meat, poultry, and egg products (as opposed to shell eggs), the Food Safety Inspection Service (FSIS) of USDA primarily regulates these products. Back to Top

 Regulation of Animals and Animal Products: The lack of BSE cases in US cattle has put the FDA in a bit of a quandary. Why is regulation necessary if there is no BSE in the US? BSE could theoretically occur in US cattle because other TSEs exist in the US (ie, scrapie in sheep and goats, transmissible mink encephalopathy in farmed minks, and chronic wasting disease in deer and elk) that could potentially transfer to cattle.^158-160 If this occurred in the absence of regulation, then the disease agent would be amplified and transmitted throughout US cattle via the feeding of processed ruminant proteins to cattle. The long incubation period for BSE also would mask any undetected amplification, ultimately resulting in greater animal exposure to BSE. This is exactly what transpired in the UK. Thus, the US government has implemented several regulations to prevent this from happening. These regulations are based on risk assessment studies that rely on four basic assumptions of hazard identification, risk assessment, risk management and risk communication.¹⁶¹

As of 1989, APHIS has banned the importation of live ruminants and certain cattle products from the UK and all countries reporting BSE.¹⁶² Of 496 cattle imported from the UK between 1981 and 1989, all have been traced, only 17 remain and have been quarantined.¹⁴³ In 1991, this ban was formalized to include all ruminant meat and edible products and most byproducts of ruminant origin (which include serum, MBM, bone meal, blood meal, offal, fat, glands, and collagen) from all countries identified to have BSE.¹⁶² The FSIS reports that the US has not imported beef from the UK since 1985, and since 1991 APHIS has required that all imported meat and edible products for human or animal consumption from ruminants of the bovine family be deboned and that visible lymph and nervous tissue be removed.¹⁴³ Additionally, the 1991 ban requires that imported meat and edible products be obtained from animals that have undergone a veterinary examination prior to slaughter. These animals also must not have been in any country in which BSE was reported during a period of time when that country permitted the use of ruminant protein in ruminant feed.¹⁶² On December 12, 1997, this ban was expanded to prohibit the importation of all live ruminants and most ruminant products from all European countries¹⁶³ to minimize the chances of BSE entering this country.

Second, the FDA has implemented precautionary regulations directed at preventing amplification of BSE through US cattle should undetected BSE exist at low levels in the cattle population. The FDA regulation instituted in 1997 prohibits the use of protein derived from mammalian tissue, with some exemptions, in feed for ruminant animals.¹⁶⁴ The regulations cover mammalian protein from the renderer to the ruminant feeder and all points in between. The exemptions are for pure swine or pure equine proteins, blood and blood products, gelatin, feeds processed from restaurant waste, and milk and milk products. Pigs and horses have never been identified with a naturally occurring TSE and are thus exempt. Blood and milk were exempted because these substances were never found to contain the infectious prion protein. Additionally, the WHO and the European Union have also exempted swine and equine products, blood, and milk in their policies.^125,144,145 The FDA maintains that the critical element of these regulations is conformance by individuals and establishments that are responsible for feeding ruminants.¹³⁹ Over a 2-year period, the FDA plans to inspect close to 100% of the establishments that produce, process, manufacture, or distribute ruminant-derived protein intended for use in the feeding of animals. These industries include feed mills, renderers, and protein blenders. There will also be some inspections of farms/feedlots/ranches where ruminants are raised to determine whether or not they are being fed prohibited ruminant-derived proteins. The Center for Veterinary Medicine (CVM) of the FDA has redirected one-fourth of its Field resources to accomplish this goal (FDA. Personal communication, March 1997).

Third, USDA-APHIS has implemented aggressive active and passive surveillance for BSE in the United States. Immediate detection of any potential case of BSE in US cattle is essential. Regarding active measures, APHIS aggressively educates veterinarians, industry, farmers and producers on the clinical and pathological signs of BSE.¹⁴³ Hundreds of cattle brains are examined each year from animals that displayed neurologic signs either at slaughter or on the farm.¹⁴³ In addition, antemortem examinations are carried out at all federally inspected slaughter establishments, and inspectors are warned to be alert for CNS disorders. Any suspect animal is condemned and tested. As of December 1997, more than 6500 brains have been examined from cattle demonstrating neurologic deficit and not a single case of BSE has been detected.¹⁴³

Regarding passive measures, private veterinarians provide an extensive but informal surveillance system for potential BSE cases. Additionally, databases are maintained of diagnoses submitted by veterinary schools and laboratories around the country; these databases also include histopathologic examinations for BSE.¹⁴³

Finally, an APHIS/FSIS working group has established a USDA Response Plan in the event that BSE is detected in the US.¹⁴³ This 1996 plan provides a step-by-step outline of actions to be taken should BSE be detected, including identification of the suspect animal, confirmation, epidemiological investigation, and animal and herd disposal. Altogether, the US government has taken substantial steps to ensure that BSE will not spread in US cattle should it ever emerge. Despite this, many critics believe the US government should be doing more.^13,14 Criticisms include a failure to act more rapidly, the need for a more stringent ban preventing the feeding of any mammalian protein to any other animal species, and the failure to include blood and milk and their respective products in the 1991 ban. The critics argue that while the scientific evidence suggests that the risk from these failures is minimal, too little is known about the TSEs to be anything but overly cautious. On the other hand, the US government can justify its actions using exactly the same argument. For example, the scientific data on the transmission of TSEs through blood and milk all support the minimal risk of these products. Thus, there is no need to ban them until more data becomes available. Back to Top

 Regulations Regarding Products for Human Consumption: In the US, a panel of experts, the TSE Advisory Committee (TSEAC), provides advice on scientific issues regarding TSEs to the FDA. Based on the advice of this committee, which acts in a similar capacity as the SEAC in the UK, the FDA has implemented several guidelines (described below) to ensure that humans are not infected. The FDA also continues to monitor the efficacy of its policies as new scientific evidence emerges, and adjusts its regulations according to TSEAC recommendations. The lack of BSE in the US implies that there is already minimal risk for the appearance of nv-CJD. This has been further reinforced by the lack of any case of CJD in the US population bearing the distinctive characteristics of nv-CJD either by current surveillance studies or on review of clinical and neuropathologic hospital records.¹⁶⁵

The FDA has issued guidelines that cover the use of gelatin in drugs and biologics, food and medical devices, and the use and handling of blood and blood products.^166,167 Still under consideration are the more than 300 health products derived from bovine sources; these include collagen and bovine pericardium for cardiovascular devices, bone fillers, cortical shields, and even contact lens disinfectants. Additionally, many biologic substitutes and therapy alternatives using human organs, tissues and cells require the use of bovine-derived products. As of January 1998, the FDA has issued no guidelines on these products although evaluation is ongoing.¹⁶⁸ With regard to drugs containing active ingredient(s) derived from cattle, the Center for Drug Evaluation and Research (CDER) of the FDA assures the safety of the these products, related to BSE, through the application approval process (FDA. Personal communication, March 1998). Back to Top

 Gelatin: From 1991 through 1993, the FDA requested that bovine-derived material originating from animals born or living in countries with active BSE not be used in the manufacture of FDA-regulated products intended for humans.¹⁶⁹ However, at that time, the FDA believed that the available scientific evidence did not suggest transmission of TSE by gelatin and that the manufacturing protocol for gelatin would inactivate the TSE agent. Thus, the FDA did not prohibit the use of bovine-derived materials from countries with active BSE in the manufacture of pharmaceutical-grade gelatin, but considered it best if the materials came from a country without BSE.¹⁶⁹

The European Union s 1997 policy now prohibits the use of any SRM in any product destined for human use, including pharmaceutical and cosmetic products with no exception given to gelatin.¹⁴⁵ The US TSE Advisory Committee has advised that the scientific evidence no longer justifies exempting gelatin from restrictions recommended by the FDA for other bovine products because the processing steps in the manufacture of gelatin could not be shown to remove BSE infectivity from the gelatin. There was also concern that some materials for gelatin might contain neural tissues of the cattle from BSE countries. All these factors and the appearance of nv-CJD due to transmission of the BSE agent into humans in the UK have prompted a change in FDA policy.¹⁶⁶

The new 1997 FDA guidelines now require that the tissue, species, and source country of the raw material for gelatin be determined.^166,170 Gelatin derived from the bones and hides of cattle from BSE countries or countries of unknown BSE status is prohibited from use in injectable, implantable, or ophthalmic products. Oral and cosmetic use of gelatin from bones of cattle from BSE countries is acceptable only if the cattle are from herds without BSE and the SRMs are removed immediately after slaughter.

However, with regard to removal of SRM, the FDA has requested the removal of not only the heads and spinal cords, but also the spines of the cattle and has placed the onus for this on slaughterhouses.¹⁶⁶ This has caused concern among gelatin manufacturers and the pharmaceutical industry because the requirement for entire spines to be removed is difficult to comply with, as it would call for slaughterhouses to modify their slaughtering processes. Additionally, since the European Union decision on SRM does not include removal of the spine,¹⁴⁵ European meat houses will not be changing their slaughtering processes. This would in effect cut off significant gelatin supplies to the US pharmaceutical industry because most US capsule gelatin is imported from Europe. The matter has been taken up with the FDA and is currently under discussion (January 1998).¹⁷¹ The recent UK report of BSE in dorsal root ganglia and bone marrow¹⁴⁹ appears to support the FDA position.

Bovine hide gelatin can be used in foods and cosmetics only if hides from cattle with CNS symptoms are excluded and contamination of hides with CNS and eye tissues is avoided. Gelatin derived from raw materials from the US and from countries without BSE can be used. Pig-skin gelatin can be used if uncontaminated with bovine materials from BSE countries or countries of unknown BSE status. No scientific evidence has indicated a risk of transmission of TSEs from pigs. Back to Top

 Blood: As far as the FDA is concerned, there is conflicting and disputed evidence that the blood of subjects with CJD or other TSEs or incubating TSEs is infectious. Epidemiological studies such as those cited by the WHO and the European Union show no evidence that transmission can occur through blood.^{125,144,150-153} Additionally, no cases of transfusion-related CJD have ever been reported in humans, even in humans with hemophilia.¹⁷² However, results of experimental studies are not completely reassuring. For example, the transfer of spleen, liver, or lymph node materials from CJD patients into primates results in disease, while the transfer of blood of CJD patients into primates does not.^152,170 On the other hand, the transfer of TSE-infected rodent blood into rodents definitely causes disease.^152,170 Therefore, the FDA has adopted an extremely conservative approach to guidelines regarding blood and blood products. This reflects a desire to maintain public confidence in the safety of the US blood supply.

FDA guidelines are complicated but in general call for the withdrawal and quarantine of CJD-implicated blood and blood products.^167,170 There is a contingent reinstatement policy for blood products in short supply, but thus far manufacturers have voluntarily withdrawn products and have not attempted to reinstate due to short supply. The FDA has classified blood donors into the following five risk categories: (1) donors who are diagnosed with TSE; (2) donors at increased risk due to familial TSE; (3) donors at increased risk for iatrogenic TSE; (4) donors at possibly increased risk due to the presence of TSE in a single family member (probably sporadic); and (5) donors at no increased risk of TSE. The FDA suggests donors at risk (categories 1-4) for CJD be excluded from donating blood.^167,170 The FDA has also listed several guidelines regarding disclosure to recipients of products from such at-risk donors. The FDA recommends that source plasma and plasma derivatives from donors later diagnosed with CJD or donors at risk of developing CJD be quarantined and destroyed.^167,170 However, if the plasma derivatives are prepared from pools that contain products from one donor with only one family member with CJD (category 4), withdrawal is not recommended.^167,170 The actions suggested by this guidance are distinct from those of the WHO and the European Union mentioned above.^125,144 While additional basic scientific data are required for definitive conclusions on the safety of blood and blood products, it may be prudent to adopt a conservative course of action. Back to Top

 Specified Risk Materials (SRM): The European Union has conservative regulations on the use of SRM in products destined for human consumption. Its regulation prohibits the use of SRM from cattle, sheep, and goats in any product that will be utilized by humans.¹⁴⁵ However, while the guidance for gelatin defines the use of SRM for gelatin manufacture, no restrictions have been issued by the FDA or the USDA on the use of SRM for other forms of human consumption, eg, eating cow brains. In this regard, the WHO has recommended that all countries conduct a BSE risk assessment and develop their own risk management strategy. If the results lead to establishment of laws banning certain bovine materials from human consumption, these laws must be adhered to rigidly.¹²⁵ Back to Top

 Analysis and Summary

Scientific data suggest that the new variant form of CJD is the result of transmission of the BSE prion into humans.^129,130 In the UK, human infection with nv-CJD most likely resulted from the ingestion of BSE-contaminated beef.¹²⁴ In terms of public health, these links are compelling enough to warrant action by the relevant authorities. However, since BSE has not been observed in the US,^5,55,110,143 most government policies are based on the principles of risk management.

Assuming that BSE can be transferred to humans as nv-CJD, the determination of risk to Americans is dependent on whether parts of an infected cow carrying infectious prions can be consumed by humans as food, medication, biological products, biological devices, or cosmetics. The risk of contracting a human TSE, such as nv-CJD, from cattle in the US currently is minimal because:

1. BSE has not been shown to exist in the US.^{5,55,110,143,162} Thus, any potential human contact with the disease agent would have to come from the importation of contaminated cattle products or exposure while travelling in BSE-infected countries.              
2. Adequate preventive guidelines exist in the US to prevent high-risk bovine materials from contaminating products intended for human consumption.^166,167 The only possible exception is the lack of guidelines for the oral consumption of high-risk organs (SRMs).              
3. Adequate regulations exist to prevent undetected cases of BSE (if any) from uncontrolled amplification within the US cattle population.¹⁶⁴              
4. Adequate regulations exist to prevent entry of foreign sources of BSE, either as live cattle or as bovine-derived products, into the US.^143,163 Back to Top

RECOMMENDATIONS (Adopted AMA Policy)

As of January 1998, there have been no detected cases of bovine spongiform encephalopathy (BSE) in the United States, but the potential for BSE or other transmissible spongiform encephalopathies (TSEs) to emerge and gain entry into food, biomedical products, or cosmetics is serious enough to warrant preventive actions. 

The following statements, recommended by the Council on Scientific Affairs, were adopted by the AMA House of Delegates as American Medical Association (AMA) policy in June 1998:

1. The AMA supports the current Food and Drug Administration (FDA) guidance/regulations regarding the treatment of products from bovine sources destined for human utilization, and the treatment of blood products from potential Creutzfeld-Jakob disease (CJD) donors.           
2. The AMA recommends that the FDA and the United States Department of Agriculture (USDA) continue to aggressively enforce regulations in place to prevent the occurrence/transmission of bovine spongiform encephalopathy (BSE) in the United States.           
3. The AMA recommends that the FDA, USDA, and Department of Health and Human Services continue to evaluate scientific data on transmissible spongiform encephalopathies (TSEs) and incorporate this information into their guidance and regulations.           
4. The AMA recognizes that the public may be concerned about BSE risks; therefore, the AMA recommends that physicians become knowledgeable about BSE so they can appropriately advise their patients about routes and risks of BSE transmission, especially that the consumption of brain and spinal cord from infected animals would carry the highest risk of transmission to humans, and that persons who are travelling abroad should refrain from consuming brain and spinal cord from cattle unless they know that the countries in which they are traveling are free of BSE.           
5. The AMA recommends increased surveillance of new CJD cases as they arise in order to monitor for the possible appearance of new variant Creutzfeldt-Jakob disease (nv-CJD) via: (a) referral of all deaths due to suspected CJD to an appropriately qualified pathologist for autopsy, with the submission of autopsy reports of confirmed cases to the Prion Disease Pathology Surveillance Center at Case Western Reserve University, which is collaborating with the CDC; (b) reporting of the diagnosis of CJD on the death certificate in all cases and the strengthening of the current system enabling health authorities to obtain clinical or pathologic data on the CJD cases of greatest public health concern; and (c) prompt notification of any case of new variant Creutzfeldt-Jakob disease to both the appropriate state health department and the CDC.           
6. The AMA recommends that well-controlled research be performed in the following areas: (a) elucidation of the mechanism of disease of TSEs; (b) elucidation of the infectivity, dose requirements, and clearance of the disease agent to provide more data for adequate risk analyses of disease transmission; (c) the risk of transmission via blood and blood products; (d) alternatives to the use of bovine-derived products in drug manufacture and other biologic industries; and (e) antemortem diagnosis of BSE and nv-CJD and the detection and inactivation of the disease agent in blood supplies.

  Back to Top

  Tables

 Table 1: Prion Infectivity of Different Tissue/Organ Types

 Table 2: United States Versus United Kingdom: Risk Factors for BSE

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 References

 1. Brown P. Bovine spongiform encephalopathy and Creutzfeldt-Jakob disease. BMJ. 1996;312:790-791.

2. Prusiner SB, Hsiao KK. Human prion diseases. Ann Neurol. 1994;35:385-395.

3. Prusiner SB. Biology and genetics of prion diseases. Annu Rev Micro. 1994;48:655-686.

4. Gajdusek DC: Unconventional viruses causing subacute spongiform encephalopathies, in Field BN, Melnick L, Chanock R, Shope RF, Roizman B (eds): Human Viral Infections. New York, Raven Press; 1985:1519-1557.

5. Narang H. Origin and implications of bovine spongiform encephalopathy. Proc Soc Exp Biol Med. 1996;211:306-322.

6. Narang H. The nature of the scrapie agent: the virus theory. Proc Soc Exp Biol Med. 1996;212:208-224.

7. Prusiner SB. Genetic and infectious prion diseases. Arch Neurol. 1993;50:1129-1153.

8. Wyatt JM, Pearson GR, Smerdon TN, Gruffydd-Jones TJ, Wells GA, Wilesmith JW. Naturally occurring scrapie-like spongiform encephalopathy in five domestic cats. Vet Rec. 1991;129:233-236.

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