NR ARWY
AU Tyler,K.L.
TI Risk of human exposure to bovine spongiform encephalopathy
QU British Medical Journal 1995 Nov 25; 311(7017): 1420-1
IA http://bmj.bmjjournals.com/cgi/content/full/311/7017/1420
PT Article
VT
Recent reports of prion disease developing in four dairy farmers and two teenagers in Britain have raised renewed concerns about the potential health risk of bovine spongiform encephalopathy to humans. Documented transmission of bovine spongiform encephalopathy to non-human primates indicates that such concerns are not without foundation.[i] Although prions are not conventional pathogens, many of the basic principles governing microbial pathogenesis seem to apply to the infectious forms of prion diseases. In this context human risk of infection after exposure to bovine spongiform encephalopathy can be considered in terms of the size of the infecting inoculum, the potential routes of entry into the host, and factors of host susceptibility.
Inoculum size
Infectivity in human prion diseases is concentrated primarily in neural (brain, spinal cord, eye) and Iymphoreticular (liver, spleen, Iymph nodes) tissues.[ii] Human brain material has been estimated to contain 10 cubed to 10 to the power of five infectious units per gram of tissue,[ii] and bioassay in mice has shown brain material from cattle with bovine spongiform encephalopathy to contain 10 to the power of five to 10 power six infectious units per gram.[iii] In both human prion diseases and bovine spongiform encephalopathy, infectivity is not found in skeletal muscle, adipose tissue, or body fluids (blood, saliva, urine, faeces, semen, milk).[ii-v] Fortunately, with the exception of people occupationally exposed to cattle (farmers, veterinary surgeons, abattoir workers), potential human exposure to bovine spongiform encephalopathy is primarily through beef or milk products, neither of which are likely to contain high infectivity. If infectivity were present in these tissues, conventional methods of food preparation might reduce infectivity but presumably would not fully destroy it given the resistance of prions to decontamination.[vi]
Route of inoculation
Transmission studies on prion diseases have consistently shown that both route and dose of inoculum affect disease transmission. Studies indicate that intracerebral inoculation is the most efficient route of transmission, followed in descending order by intravenous, intraperitoneal, subcutaneous, and intragastric or oral inoculation.[iii,v-ix] Nonetheless, kuru provides an instructive example that ingestion - in this case of highly infectious brain material - can be the source of transmission of human prion diseases.7 In experimental models, bovine spongiform encephalopathy has been transmitted by the oral route to mice by infected bovine brain material but not by blood, milk, muscle, or Iymphoreticular tissues.[iv,v] Potential human exposure to material infected with bovine spongiform encephalopathy would predominantly involve oral exposure to tissues of low infectivity (such as beef or milk products). People working in animal husbandry, health care, and slaughter would be at additional risk of inadvertent subcutaneous or intramuscular inoculation with material of high infectivity.
Host factors
Experiments on the transmission of prion diseases between different types of animals have shown the existence of a "species barrier." The inoculum required to transmit disease between animals of different species is considerably higher than that required for intra species transmission. Such a barrier has been found during experiments of transmission of bovine spongiform encephalopathy to mice,[x,xi] and would be expected to exist for transmission of bovine spongiform encephalopathy to humans. The species barrier should be viewed as an additional impediment, rather than an absolute obstacle, to disease transmission. It would be expected to increase the minimal dose of contaminated material required for human infection.
Susceptibility to the development of sporadic and iatrogenic human prion diseases is probably modulated by polymorphisms in the human prion gene (PrP gene). The prevalence of homozygosity for methionine or valine at PrP codon 129 has been reported to be significantly increased in people with sporadic Creutzfeldt-Jakob disease.[xii] Polymorphisms at this codon may also modulate the phenotypic expression of inherited prion diseases.[xiii] About 50 people have developed Creutzfeldt-Jakob disease after having been treated with growth hormone or gonadotropins derived from pools of human cadaveric pituitary glands. These people also show an increased prevalence of methionine or valine homozygosity at PrP codon 129.[xiv] Large numbers of people exposed to similar doses of the same lots of pituitary hormones for the same period of time and by similar routes as those who subsequently developed iatrogenic Creutzfeldt-Jakob disease have remained disease free. This would suggest that host factors may be a critical determinant of human susceptibility to infectious prion diseases. Different inbred strains of mice have been shown to vary in their susceptibility to bovine spongiform encephalopathy and other prion diseases,[xi]which is consistent with previous identification of genetic determinants of susceptibility to prion disease in a wide variety of animal species. It might be predicted that similar host factors might dramatically influence the risk of the disease developing in a person exposed to bovine spongiform encephalopathy.
Implications for disease prevention
Since no effective treatment of prion diseases currently exists, the emphasis of public health measures must be on preventing disease. Animals known to have bovine spongiform encephalopathy should be immediately destroyed, and their tissues should not be used as food for humans or other animals. The long incubation period between exposure and development of symptomatic bovine spongiform encephalopathy poses a considerable problem, as people might be inadvertently exposed to tissues of presymptomatic cattle harbouring bovine spongiform encephalopathy. Development of reliable tests for presymptomatic detection of bovine spongiform encephalopathy would obviously alleviate this problem and should remain a high research priority. The risk to people can be minimised by preventing human exposure to bovine tissue known to harbour the highest levels of bovine spongiform encephalopathy infectivity, including all neural and Iymphoreticular tissue. Beef and milk are not known to harbour important infectivity, and consumption of these items does not seem to pose an important health hazard. Reducing the incidence of bovine spongiform encephalopathy in cattle would also substantially decrease the risk of human exposure. Current statutory measures designed to prevent contamination of cattle feed with bovine spongiform encephalopathy and its continued transmission within herds should be maintained and modified as needed on the basis of ongoing scientific and epidemiological studies. Research should continue into reliable, practical, and economically efficient measures for the decontamination of potentially infective bovine tissues. Finally, much of the potential increased risk of developing human prion disease in farmers and workers with occupational exposure to bovine spongiform encephalopathy can be reduced or eliminated by preventing accidental inoculation with infected tissues. The use of appropriate protective clothing and specific safety training and education would be expected to diminish risk for these people.
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xi. Fraser H, Bruce ME, Chree A, McConnell I, Wells GA. Transmission of bovine spongiform encephalopathy and scrapie to mice. J Gen Virol 1992;73:1891-7.
xii. Palmer MS, Dryden AJ, Hughes JT, Collinge J. Homozygous prion protein genotype predisposes to sporadic Creutzfeldt-Jakob disease [letter]. Nature 1991;352:340-2
xiii. Goldfarb LG, Petersen RB, Tabaton M, Brown P, LeBlanc A, Montagna P, et al. Fatal familial insomnia and familial Creutzfeldt-Jakob disease: disease phenotype determined by a DNA polymorphism.Science 1992;258:806-8.
xiv. Collinge J, Palmer MS, Dryden AJ. Genetic predisposition to iatrogenic Creutzfeldt-Jakob disease.Lancet 1991;337:1441-2.
ZR 14
AD University of Colorado Health Sciences Center Denver VA Medical Center Denver CO 80220 USA Kenneth L Tyler professor of neurology, medicine, microbiology, and immunology
SP englisch
OR Prion-Krankheiten 8