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Quantitive Assessment of the Residual BSE Risk in Bovine-Derived Products [21 December 2005] http://www.efsa.eu.int Quantitive Assessment of the Residual BSE Risk in Bovine-Derived Products Quantitative risk assessment of food-borne pathogens has emerged as a powerful methodology for estimating how likely, and at what level, an individual or population will be exposed to a microbial hazard. The output of risk models is relatively complex and, ideally, its interpretation and significance requires an integrated understanding of mathematics, statistics, biology and systems knowledge. Elements of the methodology are given here in the context of the quantitative assessment of residual BSE risk. Further general details of different approaches can be found in “Risk assessment of food-borne bacterial pathogens: quantitative methodology relevant for human exposure assessment (EC SSC Preliminary report, February 21-22nd, 2002). http://www.efsa.eu.int/science/biohaz/biohaz_documents/1280_en.html The EFSA Journal (2005)307,1 135 EFSA QRA report 2004 - working document www.efsa.eu.int 1 of 135 QUANTITATIVE ASSESSMENT OF THE RESIDUAL BSE RISK IN BOVINE-DERIVED PRODUCTS EFSA QRA REPORT 2004 WORKING DOCUMENT snip... III.2. The infectious load of the cattle by-products A) The UK Veterinary Laboratory Agency have carried out experimental oral challenge studies in cattle to determine the attack rate and incubation period for a range of amounts of BSE infected cattle brain. In the first of two experiments, groups of 10 calves were dosed orally with 3x100g (100g on 3 successive days), 100g, 10g or 1g of brain tissue from clinically sick animals(titre of inoculum: 103.5 mouse i.c/i.p LD50/g). All animals in the two higher dose categories (3x100 and 100gr, respectively), 7 out of 9 in the 10 g and 7 out of 10 in the 1g trial groups developed BSE. The remaining animals in this experiment were killed at 110 months after exposure and showed no pathological evidence of disease. A second experiment is extending these findings with lower doses of the same inoculum (1g- 1mg), but the final outcome of the study will not be available for at least 5 years. Interim results, at approximately 6 years post exposure, have confirmed 2 of 5 in the 1g trial group, 3 out of 15 animals in the 0.1g group, 1 out of 15 in the 0.01g group, and 1 out of 15 in the 0.001g group, positive for BSE (G. A. H. Wells & S. A. C. Hawkins, VLA, unpublished, updated 7th April, 2004). The combined results of these two experiments give a working estimate of the oral ID50 of this clinically affected BSE brain pool for cattle of 0.58g with a confidence interval of 0.20g to 1.93g. No null effect dose level will be seen in this experiment as 1 mg was the lowest amount used to challenge the second group of cattle. However, on the basis of these data, the range of cattle oral ID50’s in 1g could be approximately 0.52 to 5 although with higher titres of BSE affected brain, the range could extend to 300, as titres of 105 mouse i.c./i.p. ID50/g, have been recorded. Taking this into account, as well as EC (2000), it was decided to take a precautionary view and to assume that the infectivity titre in brain of a clinically BSE infected cow follows the following distribution: Log normal distribution with Median (50 percentile): 5 cattle oral ID50/gram Higher 99 percentile: 100 cattle oral ID50 (CoID50)/gram B) The infectious load of the cattle by-products varies with the type of tissue, the titre of infectivity, its weight and with the age of the animal, relative to incubation period. Table 1 provides, as an example, estimated levels of infectivity of the tissues of animals at the end of the incubation and for an infectivity titre in brain and skull of 2.5 CoID50 per gram. These apply when SRM or whole cadavers of clinically diseased animals would be used. As reference, a beef cattle of 550 kg live weight is used. The table was compiled from various sources (e.g., Simoens 1998; LFRA & MLC 1997; Berends 2000, 2002). Whereas the indicated average weights should be as good as possible estimates, it should be noted, as The EFSA Journal (2005)307,11 135 EFSA QRA report 2004 - working document www.efsa.eu.int 11 of 135 proven by sensitivity analysis of the model, that minor errors would not significantly affect the outcome of the risk assessment. snip... Table 1: Estimated tissue weights and infectivity levels from adult beef cattle, for an infectivity titre of 5 CoID50 per gram in brain of a clinical case Tissue Total mass (g) Titre: CoID50/g Total inf. load Brain 500 5 2500 Trigeminal Nerve Ganglia (TRG) 20 5 100 Spinal cord 200 5 1000 Dorsal Root Ganglia (DRG) 30 5 150 Ileum 800** 0.5 400 Spleen* 800 0.0005 0.4 Rest of head, excl. skull and brain**** 6,500 6.6 All bones, total: 58,000 All bones, without skull 50,000 Bones, excl. skull and vertebrae 37,000 Bone marrow (10% ww)6 2,900 0.0005 1.5 Bone adnexa (20% ww) 5,800 0.0005 2.9 Manure, gut content, … 80,000 Hooves, hide, horns, … 50,000 Other by-products / offals 129,450 Consumed (excl. bones) 215,000 Totals 550,000*** ~4160 CoID50 * No BSE infectivity has so far been found in the spleen of bovines. As a prudent view, bovine spleen is considered to be possibly infectious, but the infectivity level attributed corresponds to the current limit of detection. ** 800g may be excessive for the anatomical region strictly termed ileum (without content), which in an adult bovine represents about 1 meter of bowel. *** It should be noted that, in practice, these weights can vary largely between different animals, depending on age and race. Area dependent there can also be large differences. In the Netherlands for instance the average weight might be considerably lower because of the very large proportion of calves which are slaughtered there. **** The rest of head is assumed to include the eyes (100g) and the tonsil (50g) both with an infectivity assumed to be 4 logs less than brain from the result for tonsil (0.0005 CoID50/g) plus 1.3g of CNS contamination from captive bolt slaughter (Cooper & Bird 2002). 6 Estimates vary largely, but little measured data are available; The here chosen values are based on Koolmees et al (2002), who measured the weight of bones, bone marrow and adnexa of 20 sheep. The EFSA Journal (2005)307,12 135 EFSA QRA report 2004 - working document www.efsa.eu.int 12 of 135 III.3. Assumptions regarding the total infectious load of the cattle by-products annually entering a country’s recycling chains The estimation of total infectious load of the cattle by-products annually entering a country’s recycling chain is a complex issue. It depends upon the BSE prevalence and whether that is increasing or decreasing, the quality of the surveillance system and case ascertainment, the age at slaughter, the removal of certain specified risk materials, etc. Under certain conditions, the infectious load of the cattle entering a by-product recycling chain could be lower in a GBR IV country (e.g., if the epidemic is decreasing and only animals born after an effective feed ban are used) than in a GBR III country (e.g., with an unreliable surveillance system or inappropriate risk management measures.) Modelling can here thus not be reduced to only testing a number of simple BSE incidence scenarios such as, for example: less than 1 or more than 100 BSE cases per million adult cattle. Ideally one would need to consider a continuum of possible “total national infectious loads” ranging from zero (GBR I countries) to very high levels for GBR countries in a increasing phase of an epidemic. To structure this continuum into a number of scenarios that are exploitable by the regulator, the Working Group started from the assumptions presented below in sections III.3.1.- III.3.4. III.3.1. The BSE incidence (detected numbers of BSE positives) On the basis of currently available data, the following BSE incidence classes can be proposed: 1) GBR I countries: BSE is highly unlikely and the incidence is assumed to be zero. The residual BSE risk in products derived from animals sourced from such countries is therefore negligible. 2) GBR II countries: No BSE has been detected and a surveillance system is in place. The presence of one or more cattle clinically or pre-clinically infected with the BSE agent in a region or country is considered highly unlikely but not excluded. The possible BSE risk in products would therefore result from the incubating animals going into the re-cycling/food chain prior to the detection of a first BSE case. This number of pre-clinical animals is estimated to be 2-4 animals, with 3 as most likely value (see below). 3) GBR III countries: The average BSE incidence observed by testing of healthy stock in the EU’s GBR III countries is 30 per million. Therefore, even if BSE has yet to be confirmed in a GBR III The EFSA Journal (2005)307,13 135 EFSA QRA report 2004 - working document www.efsa.eu.int 13 of 135 country, a conservative, estimated incidence range for that country is 1 to 99 per million adult cattle, with 30 as average value. Depending upon the surveillance and screening systems in place, these cases will be detected and disposed of, or will remain undetected and eventually serve as possible raw materials for recycling and further use. In the first case, only the estimated number of undetected cases (see further) will constitute a possible risk; in the second case, the undetected BSE positives also contribute to the risk. 4) GBR IV countries with BSE confirmed : In these countries, the incidence of detected cases is at least 100 per million adult cattle. Depending upon the surveillance and screening systems in place7, these cases will be detected and disposed of, or will remain undetected and eventually serve as possible raw materials for recycling and further use. In the first case, only the estimated number of undetected cases (see further) will constitute a possible risk; in the second case, the undetected BSE positives also contribute to the risk. No distinction is made between a country in GBR IV going into and coming out of a BSE epidemic. If the incidence is clearly falling there is a considerable difference in risk from that in a country where it is rising, especially if control measures are not in place or not well enforced. Regulators may therefore decide that countries classified as GBR IV, for the purposes of the assessment of the residual risk in certain bovine derived products, could be treated under one of the other scenarios. For example, the regulator may well decide that bones for gelatine sourced from animals from a GBR IV country, but born after the comprehensive implementation of risk management measures, could be treated as bones sourced from GBR III countries with an optimal surveillance system. III.3.2. The ratio of sub-clinical non-detected to detected BSE positives A) For countries with an optimal BSE surveillance system: the clinical cases and animals that tested positive with one of the currently available rapid BSE tests are taken out of the food chain. But for each detected BSE case, there are 2 - 4 animals incubating (most likely value: 3), including young calves and adult animals of various ages. The basis for this estimate is the following (C. Ducrot, personal communication, 7 February 2003): If the surveillance and systematic screening programs at the slaughter house run correctly, the BSE positive animals are removed from the food chain. It remains nevertheless necessary to estimate the number / or percentage of slaughtered animals that are infected with BSE but still not detected (e.g., with a rapid test). That question can be partly answered in the following way: 1) From the survival curve of cattle, removed animals due to death, euthanasia or culling (French data), as well as the distribution of the age at contamination and the length of the 7 It may be reasonably assumed that in the currently existing GBR IV countries an optimal surveillance system is in place. The EFSA Journal (2005)307,14 135 EFSA QRA report 2004 - working document www.efsa.eu.int 14 of 135 incubation period (British estimates), a model has shown that only 29% of infected cattle reached the end of the incubation period. The others die or are culled before the clinical phase is reached. If a rapid screening test detects infected animals 3, 6 or 9 months before the end of the incubation, the percentage of infected cattle that can be detected (by test or clinical surveillance) increases to 31%, 34% and 40% respectively. 2) If one accurately knows the number or percentage of animals that are positive with the rapid test, one can extrapolate to the number of animals that were infected but removed (by death or culling) before they can be tested positive. In the table hereafter, a simulation is made for the following situations: - detection with a test at the end of the incubation period and up to 6 months before the end of incubation; - evolution of contamination: increase (x2 per year), constant over time and decrease (x0.5 per year). Table 2: Number of animals not detectable at death or culling per one positive detected Evolution of contamination pressure with time Increase (x2/year) Constant over time Decrease (x0.5 per year) Test positive: At the end of incubation 9.0 2.5 0.7 Test positive: 6 months before the end of incubation 7.2 2.0 0.5 3) One can approximate that 10% of the removed animals were dead or submitted to euthanasia, and 90% culled and slaughtered for consumption. 4) If there is a comprehensive surveillance programme in a given country, one can estimate the number of infected animals that were not detected and entered the food chain from the number of animals detected positive (clinical or by test): - Make hypothesis on period of detection with the test (for example: 6 months before the end of incubation) and the expected evolution of the contamination pressure (epidemic (for example, constant over time) - Multiply the total number of cases detected during a year (abattoir + fallen stock + clinical) by the figure in the table above; this gives the number of positive animals at death or culling that would not be detected during the year. - Multiply by 0.9 to estimate the number of them that entered the food chain. The EFSA Journal (2005)307,15 135 EFSA QRA report 2004 - working document www.efsa.eu.int 15 of 135 Summary A) Depending upon the situation, the number of infected animals not detectable at death or culling per one positive detected per year varies between 0.5 and 10. In the context of a global decrease of contamination in Europe, a number of 2 to 3 seems reasonable. The prerequisite is a good and comprehensive surveillance programme. This estimate could be further refined or made country-specific if sufficient data are available. B) For countries where the ability to detect all cases is not optimal, the ratio of sub-clinical, non-detected animals to detected BSE positives will be higher and this ratio will vary according to the quality of the surveillance and screening systems. As the number of such animals detected is not reliable in itself, it may be preferable for modelling purposes to represent the uncertainty of this ratio by a higher estimate for the BSE incidence. III.3.3. Infectious load per animal A) If specified risk materials are removed. Specified Risk Materials (SRM) are estimated to account for approximately 95% of the total infectious load present in adult animals reaching the clinical stage of disease. This load can be deduced from the risk represented by BSE positives that would enter a recycling chain due to lack of detection by surveillance or screening. B) The currently available tests are able to detect a positive case a few months before clinical onset (Grassi et al., 2001). Under laboratory conditions these tests have shown to perform well on the specific CNS material collected for testing from clinically suspect animals diluted up to 10 times. Thus, under such conditions, only incubating animals with an infective load in the specific CNS material collected for testing below 10% of the total possible brain infectious load would therefore not be detected by the tests. Under field conditions, tests may perform less optimally and animals below a given age may not be tested. It can therefore be assumed that the total infectious loads of rapid-BSE-tested animals (including tissues other than brain and spinal cord) from infected animals (all ages but excluding clinical cases) are estimated to range from 1% to 100% of the maximum possible load, but for 90% of these animals the infective load is below 10% of the maximum possible load. C) We need to take into account that post mortem rapid BSE tests may not be applied in all countries. About half of all cattle slaughtered for food and from which by-products may be sourced are below 24 months and most of these animals are several months if not years before the onset of clinical disease would be expected. Hence, it’s reasonable to say that in such countries the total infectious loads of untested, infected, pre-clinical animals will be in the range from 1% to 100% of the maximum possible load, but that for 50% of these animals the infective load is below 10% of that maximum level. The EFSA Journal (2005)307,16 135 EFSA QRA report 2004 - working document www.efsa.eu.int 16 of 135 III.3.4. Infectious load and age Simulation of the building-up of BSE infectivity with age is possible and models have been proposed of exponential growth with a total infectious load at clinical stage of 100%, corresponding to approx. 5%, at 1/2 of the incubation and approx. 25% at 2/3 of the incubation. However, these models are not yet sufficiently developed to allow the quantitation of the infectious load in animals of various ages. Moreover, the age distribution at slaughter and the incubation period are both (highly) variable and this leads to a complexity that is difficult to model. Therefore, if an age-criterion is required in risk management strategies, the recommendations in the above paragraphs ( III.3.1., III.3.2. and III.3.3) should be applied assuming a BSE incidence corresponding to the incidence below the age under consideration. For example, to decide whether cattle materials could be safely sourced from cattle below 30 months from a given country, the BSE incidence in the age class 0-30 months should be considered. III.4. Assumptions regarding the yield per animal of certain by-products Animals vary in weight and the yield of by-products will vary according to slaughterhouse and cutting practices. For the purpose of the risk assessments presented in this report, it was assumed that all slaughtered animals are adults of approx. 550 kg live weight. The average by-product yields per animal are (see also Table 1): Bones for gelatine, DCP and fats: * 37 kg, if both the skull and the vertebral column are removed; * 50 kg, if only the skull is removed, but the vertebral column is used; * 58 kg, if no specified risk materials (skull, vertebral column) are removed; Mixtures of tissues (by-products) for fats: * 167 kg, if both the skull and the vertebral column are removed * 180 kg, if only the skull is removed, but the vertebral column is used; * 188 kg, if no specified risk materials (skull, vertebral column) are removed Discrete adipose tissues for bovine fats. In Europe, there are significant differences in the quantities of fat tissues collected per animal between the various Member States. An explanation for this difference can be found in the fact that the farmer is paid according to the weight of the carcass. In each Member State, national regulations define the quantity of fat tissues that can be removed in the abattoir. The yield of fat tissues varies according to the source consulted (approx. 8Kg of mesenteric fats not included): 1) According to EFPRA (2002, pers. comm.), the yield of carcass fats collected before splitting the carcass is 16 kg (11 kg omental fat +5 kg kidney fat). The EFSA Journal (2005)307,17 135 EFSA QRA report 2004 - working document www.efsa.eu.int 17 of 135 2) According to FNICGV (2003, pers. comm.), the average weight in France8 in the abattoir is approx. 40 kg depending of the category of animal, and approx. 40 kg collected after splitting the carcass in the abattoir or in the cutting plant. The following scenarios can thus be considered: For most EU countries: * Mesenteric fat tissues (possibly removed as SRM): 8 kg * Total other fats collected both before and after splitting as non-dedicated processes 32 kg * Total other fats collected both before and after splitting, partly as a dedicated process: 32 kg Including, for most countries: * Fats collected before splitting, removed as a dedicated process: 16 kg * Cutting fats collected after splitting (abattoir and cutting plants): 16 kg For certain countries (e.g., France), under certain conditions: * Mesenteric fat tissues (possibly removed as SRM): 8 kg * Total other fats collected both before and after splitting as non-dedicated processes 80 kg * Total other fats collected both before and after splitting, partly as a dedicated process: 80 kg Including, for certain countries (e.g., France): * Fat collected before splitting, removed as a dedicated process (e.g., France) 40 kg * Cutting fats collected after splitting (e.g., France): 40 kg III.5. Possible sources of BSE infectivity in cattle tissues and by-products III.5.1. Possible sources of BSE infectivity in cattle tissues and by-products The sources of BSE infectivity in cattle by-products are listed below. The likelihood that tissues come from a BSE positive animal is proportional to the BSE prevalence. The possible 8 When in certain French abattoirs abattoir fats are collected before splitting within a dedicated process, procedures are in place on the slaughter line which optimize the quantity of fat tissues collected before splitting. When a process is in place for the dedicated collection of fats before splitting, the ratio is as follows : - 90% before splitting; 10% after splitting. When the abattoir does not apply a dedicated process, the ratio is as follows : - 60% before splitting; 40% after splitting. The EFSA Journal (2005)307,18 135 EFSA QRA report 2004 - working document www.efsa.eu.int 18 of 135 inclusion in the raw materials of tissues infected with BSE will be specified in the various risk scenarios developed in this report. A) Entire organs (e.g., brains, spinal cord, …) resulting from the non-removal of specified risk materials. This corresponds with a scenario of no rules for the removal of SRMs being in place or failure of their enforcement. B) Entire specified risk materials. 'Perfect' slaughtering, separation and cutting processes do not exist and as a reasonable scenario one has to assume at least some contamination. In certain cases, entire organs may be accidentally included in the raw material, in spite of SRM bans being in place. This probability will be different for different types of organs related to specified risks and depends on the slaughter process, cutting process, etc. Provided slaughterhouses and cutting plants respect the standards of good manufacturing practice, the probability of such inclusion may be considered to be very low. Furthermore, the likelihood that an SRM exactly from an infected animal in included in a raw material batch is proportional to prevalence of BSE in the animals that passed the pre-slaughter controls and this needs to be integrated in the calculations. C) Contamination with brain and trigeminal ganglia and with spinal cord, vertebrae (excluding tail vertebrae) and dorsal root ganglia. The brain and the spinal cord have an estimated weight of approx. 500 g (LFRA, 1997) and 170-260g (LFRA, 1997; Nickel et al., 1992), respectively. Most of it would be washed away or removed (e.g., with the waste water), or would not pose a risk (e.g. if the vertebral column is removed without splitting and/or if the spinal cord and skull are removed without risk of contamination of bones that in fact are protected by the meat and other tissues). However, under a worst case scenario, a fraction may be spread over limited areas of the carcass, vertebral column bones, etc. For brain and trigeminal ganglia (TRG), some brain and trigeminal ganglia tissue may be scattered during stunning, slaughter or removal of heads/skulls9. This may contaminate head meat, but is unlikely to contaminate other parts of the carcass. Contamination of bone material is even more unlikely because the bones are covered by other tissues. In the case of spinal cord and dorsal root ganglia (DRG), it has been estimated that 10% or 20 grams on average can remain attached to vertebral column bones(LFRA, 1997, data for the UK in 1997 and prior to the EU-wide obligation to remove the spinal cord in countries where BSE cannot be excluded). In France, residues of spinal cord were found for 10% out of 10,000 bovine carcasses inspected by the French Veterinary Services, with a quantity of spinal cord residues found in all failures being below 2% (below 1% for 90% of the failures).(Press Release of 18 July 2002, AFP). This survey was carried out before 1 January 2002 when in France the removal of spinal cord by aspiration became obligatory. 9 Experts judgements with the SSC’s working group yielded spillage estimates ranging from [0.1% - 1%] to [0.5 - 5%] of the brain material. The lower value would correspond with conditions where brain remains in the skull, SRMs are removed as a dedicated action and knives are cleaned and heat treated in hot water (c. 85ºC) after this use. (Knives are not sterilised in regard to TSE agents). The EFSA Journal (2005)307,19 135 EFSA QRA report 2004 - working document www.efsa.eu.int 19 of 135 In Great-Britain, the State Veterinary Service reported that between 1996 and 2001 no spinal cord was found in any carcass of an animal slaughtered in the UK. (See the UK BSE Enforcement Bulletins). However, spinal cord has been found in a proportion of carcasses imported into the UK from some other EU Member States. For current slaughterhouse practices in the EU, the above risks of contamination are likely to be overestimates because now SRM removal is under supervision and subject to possible controls, the evacuation techniques for the removal of the spinal cord have improved, the spinal canal may be cleaned before further processing, etc. The Working Group and Stakeholders considered the following assumptions as reasonable for modelling the possible spinal cord contamination of vertebrae: - Possible contamination with Dorsal Root Ganglia (DRG) is assumed to be proportional to the contamination of vertebrae with spinal cord and the failure of sorting out vertebrae. - In approx. 1% of the slaughters with removal of the spinal cord, approx. 2.5% of the spinal cord may remain attached to vertebrae when it is removed. This corresponds to approximately 5 grams for a spinal cord of 200 grams, for 1% of the vertebral columns. - If no vertebrae are removed (vertebrae are not an SRM), the above spinal infectivity would enter the production process, plus the entire weight of all the dorsal root ganglia (30 grams). - If vertebrae are removed, a failure in sorting out the pieces of vertebrae of a total of 1% of the quantity can be assumed. - The fraction of it that may eventually contaminate other, non-vertebral column bone material can be considered to be negligible, because other tissues protect the bones. - However, spinal cord material and fluids may contaminate other tissues during the splitting and/or removal process, e.g., during sawing and as aerosols. This is important for the residual risk possibly present in rendered mixture of tissues or fats melted from such mixtures or cutting fats removed after splitting the carcass (see further). snip...full text 135 pages http://www.efsa.eu.int/science/biohaz/biohaz_documents/1280/efsaqrareport2004_final20dec051.pdf BSE GBR III Working Group Report on the Assessment of the Geographical BSE-Risk (GBR) of CANADA 2004 snip... - 2 - 2. EXTERNAL CHALLENGES 2.1 Import of cattle from BSE-Risk2 countries An overview of the data on live cattle imports is presented in table 1 and is based on data as provided in the country dossier (CD) and corresponding data on relevant exports as available from BSE risk countries that exported to Canada. Only data from risk periods are indicated, i.e. those periods when exports from a BSE risk country already represented an external challenge, according to the SSC opinion on the GBR (SSC July 2000 and updated January 2002). • According to the CD, 231 cattle were imported from UK during the years 1980 to 1990 and no cattle imports from UK were recorded after 1990. • According to Eurostat, altogether 198 cattle have been imported from the UK during the years 1980 to 1990, Additionally 500 were recorded in 1993; this import is 1 For the purpose of the GBR assessment the abbreviation "MBM" refers to rendering products, in particular the commodities Meat and Bone Meal as such; Meat Meal; Bone Meal; and Greaves. With regard to imports it refers to the customs code 230110 "flours, meals and pellets, made from meat or offal, not fit for human 2 BSE-Risk countries are all countries already assessed as GBR III or IV or with at least one confirmed Annex to the EFSA Scientific Report (2004) 2, 1-14 on the Assessment of the Geographical BSE Risk of Canada - 3 - mentioned in Eurostat and the updated UK export statistic as male calves, but not mentioned in the original UK export statistics. According to the CD, detailed investigations were carried out and it is very unlikely that the 500 calves have been imported. Therefore, they were not taken into account. • According to the CD, in 1990 all cattle imported from UK and Ireland since 1982 were placed in a monitoring program. • Following the occurrence of the BSE index case in 1993 (imported from UK in 1987 at the age of 6 months), an attempt was made to trace all other cattle imported from UK between 1982 and 1990. • Of the 231 cattle imported from the UK between 1980 and 1990, 108 animals had been slaughtered and 9 had died. From the remaining, 37 were exported, 76 were sent to incineration and one was buried; these were not entering the rendering system and therefore not taken into account. • According to the CD, 16 cattle were imported from Ireland (according to Eurostat 20), of which 9 were slaughtered, 3 died. The remaining 4 were incinerated and did therefore not enter the rendering system. According to the CD, the 6 animals which were imported in 1990 according to Eurostat, were never imported. • Moreover 22 cattle have been imported from Japan (through USA), of which 4 were exported (excluded from the table) and 14 were destroyed and therefore not entering the rendering system, 4 were slaughtered. • Of 28 imported bovines from Denmark, 1 was destroyed and 1 was exported. Of the 19 buffalos imported in 2000, 1 was incinerated and the others were ordered to be destroyed. • Additionally in total 264 cattle according to the CD (276 according to other sources) were imported from Austria, France, Germany, Hungary, Italy, The Netherlands and Switzerland. • The numbers imported according to the CD and Eurostat are very similar. Some discrepancies in the year of import can be explained by an extended quarantine; therefore it is likely that imports according to Eurostat in 1980 and imports according to the CD in 1981 are referring to the same animals. • Additionally, between 16.000 and 340.000 bovines have annually been imported from US, almost all are steers and heifers. In total, between 1981 and 2003, according to the CD more than 2.3 million, according to other sources 1.5 million cattle have been imported. • According to the CD, feeder/slaughter cattle represent typically more than 90% of the imported cattle from the USA; therefore, only 10% of the imported cattle have been taken into account. snip... Annex to the EFSA Scientific Report (2004) 2, 1-15 on the Assessment of the Geographical BSE Risk of Canada 2.2 Import of MBM or MBM-containing feedstuffs from BSE-Risk countries An overview of the data on MBM imports is presented in table 2 and is based on data provided in the country dossier (CD) and corresponding data on relevant exports as available from BSE risk countries that exported to Canada. Only data from risk periods are indicated, i.e. those periods when exports from a BSE risk country already represented an external challenge, according to the SSC opinion on the GBR (SSC, July 2000 and updated January 2002). According to the CD, no imports of MBM took place from UK since 1978 (initially because of FMD regulations). • According to Eurostat data, Canada imported 149 tons MBM from the UK in the period of 1993 to 2001. According to up-dated MBM statistics from UK (August 2001) no mammalian MBM was exported to Canada from 1993 – 1996. As it was illegal to export mammalian meat meal, bone meal and MBM from UK since 27/03/1996, exports indicated after that date should only have included nonmammalian MBM. Therefore, these imports were not taken into account. • According to the CD, imports of MBM have taken place from Denmark, Germany, France, Japan and US. • According to Eurostat Canada imported MBM from Denmark, Belgium, France and Ireland. • According to the CD further investigations concluded that all imported MBM from Denmark consisted of pork and poultry origin and was directly imported for aquaculture, the imported MBM from France was feather meal, the imported MBM from Germany was poultry meal for aquaculture and the imported MBM from Belgium was haemoglobin; therefore these imports were not taken into account. • The main imports of MBM were of US origin, according to the CD around 250.000 tons, according to other sources around 310.000 tons between 1988 and 2003. snip... 2.3 Overall assessment of the external challenge The level of the external challenge that has to be met by the BSE/cattle system is estimated according to the guidance given by the SSC in its final opinion on the GBR of July 2000 (as updated in January 2002). Live cattle imports: In total the country imported according to the CD more than 2.3 million, according to other data 1.5 million live cattle from BSE risk countries, of which 231 (CD) respectively 698 (other sources) came from the UK. The numbers shown in table 1 are the raw import figures and are not reflecting the adjusted imports for the assessment of the external challenge. Broken down to 5 year periods the resulting external challenge is as given in table 3. This assessment takes into account the different aspects discussed above that allow to assume that certain imported cattle did not enter the domestic BSE/cattle system, i.e. were not rendered into feed. In the case of Canada, the 500 cattle imported from UK according to Eurostat were not taken into account and it is assumed that all incinerated, buried, exported animals and the animals still alive did not enter the rendering system and were therefore excluded from the external challenge. MBM imports: In total the country imported according to the CD around 300.000 tons, according to other sources nearly 360.000 tons of MBM from BSE risk countries, of which 149 tons came from the UK. The majority consisted of MBM imported from the US. The numbers shown in table 2 are the raw import figures and are not reflecting the adjusted imports for the assessment of the external challenge. Broken down to 5 year periods the resulting external challenge is as given in table 3. This assessment takes into account the different aspects discussed above that allow to assume that certain imported MBM did not enter the domestic BSE/cattle system or did not represent an external challenge for other reasons. As it was illegal to export mammalian meat meal, bone meal and MBM from UK since 27/03/1996, exports indicated after that date should only have included non-mammalian MBM. In the case of Canada all imported MBM from UK, Germany, Belgium, Denmark and France was not taken into account. snip... 3. STABILITY 3.1 Overall appreciation of the ability to avoid recycling of BSE infectivity, should it enter processing Feeding The annual Canadian production of MBM is approximately 575,000 tons of which approx. 40,000 tons are exported each year, mainly to USA. Use of MBM in cattle feed • Before the feed ban, dairy cattle received supplementary feed containing MBM during their productive life (maximum 200-400 g MBM per day). Beef cattle in the western part of the country do not usually receive complementary feed. Beef cattle in the eastern part receive normally no supplement protein but the calves could have access to creep feeds containing MBM, after weaning the ratios may have contained supplemental protein containing MBM (100-400 g per day). • According to the CD, MBM is mainly fed to pigs and poultry and included in pet food. • According to the CD, only a proportion of dairy cattle may have received MBM. Feed bans • Before 1997, there was no legal restriction to include MBM into cattle feed. • An MBM-ban was introduced in August 1997; it is forbidden since to feed mammalian MBM to ruminants except if of pure porcine, equine and non mammalian origin, i.e. in practice a ruminant-to-ruminant ban (RMBM-ban). Annex to the EFSA Scientific Report (2004) 2, 1-15 on the Assessment of the Geographical BSE Risk of Canada - 9 - Potential for cross-contamination and measures taken against • Cross-contamination in the about 600 feed mills is assumed to be possible as long as cattle and pig feed is produced in the same production lines, and premises. • Cross-contamination during transport is possible, particularly if the same trucks are used for transporting ruminant MBM (RMBM) and non-ruminant MBM (porcine or poultry MBM which still might be included into cattle feed) or for transporting pig/poultry feed and cattle feed. • On-farm cross-contamination is regarded to be possible. • Cross-contamination of cattle feed with RMBM can not be excluded. Hence, as reasonable worst case scenario, it has to be assumed that cattle, in particular dairy cattle, can still be exposed to RMBM and hence to BSE-infectivity, should it enter the feed chain. Control of Feed bans and cross-contamination • With the introduction of the RMBM ban (1997) the feed mills (approximately 600) were checked for compliance with the ban, including good manufacturing practices (GMP) and record keeping, i.e. the separation in production of MBM containing ruminant material (RMBM) from non-ruminant MBM. • The feed mills had previously – since 1983 – been regularly checked in relation to production of medicated feed. • No examinations are performed to assess cross-contamination with RMBM of the protein (e.g. non ruminant MBM) that enters cattle feed. Differentiation would anyway be difficult. Rendering Raw material used for rendering • Ruminant material is rendered together with material from other species, but according to the CD only in the production of MBM prohibited for use in ruminant feeds. • Slaughter by-products, including specified risk material (SRM) and fallen stock are rendered. • The country expert estimated that 20% of the rendering plants, processing 20% of the total amount of raw material, are connected to slaughterhouses. Their raw material is more than 98 % animal waste from these slaughterhouses while less than 2 % is fallen stock. No estimation was given for the remaining 80% of the rendering capacity. • There are 32 rendering plants of which 3 are processing blood exclusively. Rendering processes • The rendering systems (parameters) were specified for 6 plants producing mixed MBM, none of these fulfilled the 133/20/3 standard. Of these, 5 have dedicated facilities to produce products for use in ruminant feed and products not permitted for use in ruminant feed. • The remaining plants process porcine or poultry material exclusively. SRM and fallen stock • There is an SRM ban for human food in place since 2003. Annex to the EFSA Scientific Report (2004) 2, 1-15 on the Assessment of the Geographical BSE Risk of Canada - 10 - • However, SRM are rendered together with other slaughter waste and fallen stock. However, according to the CD, MBM with SRM is not permitted to be fed to ruminants. Conclusion on the ability to avoid recycling • Between 1980 and 1997 the Canadian system would not have been able to avoid recycling of the BSE-agent to any measurable extent. If the BSE-agent was introduced into the feed chain, it could have reached cattle. • Since 1997 this ability gradually improved with the introduction of the ruminant MBM ban and its implementation. • Since cross-contamination cannot be excluded, and as SRM is still rendered by processes unable to significantly reduce BSE-infectivity, the system is still unable to avoid recycling of BSE-infectivity already present in the system or incoming. 3.2 Overall appreciation of the ability to identify BSE-cases and to eliminate animals at risk of being infected before they are processed Cattle population structure • Cattle population: 12.15 Million in 1988 increasing to 14.6 Million in 2001; • Of the total cattle population, 2.2 million are dairy cattle and 12.4 million are beef. • The cattle population above 24 months of age: approx. 6.0 Million. • Of the approximately 2.2 Million dairy cattle 2 Million are located in the two eastern provinces Ontario and Quebec. • Mixed farming (cattle and mono-gastric species) is usually not practiced; the country expert estimated the proportion of mixed farming to be less than 1%. • Individual regions traditionally have ID systems under provincial authorities. Brand inspectors are present when cattle are assembled. It is estimated by the Canadians that the level of a national, uniform ID for cattle is less than 10%; most of those individual pedigree animals. Mandatory ID for the milk-fed veal sector was implemented in Quebec in 1996, but does not contain information on the herd of origin. An agreement of the relevant industries to develop a national cattle ID and trace back strategy was reached on 1 May 1998 (starting in 2001).Since 2002, a national identification program is existing. Al cattle leaving any farm premises must be uniquely identified by ear tag. BSE surveillance • BSE was made notifiable in 1990. • Every cow over one year of age exhibiting central nervous system signs suggestive of BSE submitted to a laboratory or presented at an abattoir is subjected to a BSE laboratory diagnostic test (histology and over the past years also PrPSc-based laboratory tests). • In addition, cattle submitted for rabies examination and found rabies negative are examined for BSE. Samples are prepared immediately upon arrival to the federal laboratory responsible for the rabies diagnostic for possible later BSE examination, i.e. formalin fixation. • Since the 1940’s, a rabies control program has been in place, where farmers, veterinarians and the general public are well educated about this neurological Annex to the EFSA Scientific Report (2004) 2, 1-15 on the Assessment of the Geographical BSE Risk of Canada - 11 - disease. In 1990, when BSE was made notifiable, this awareness was extended to suspicions of BSE. • Since 1993 the number of brains examined per year did exceed the number recommended by OIE (300 - 336 for countries with a cattle population over 24 months of age of 5.0 to 7.0 Million) in all years, except in 1995 (table 4). year 1992 1993 1994 1995 1996 1997 1998 1999 2000 2001 2002 2003 samples 225 645 426 269 454 759 940 895 1´020 1´581 3´377 3´361 Table 4: Number of bovine brains annually examined for CNS diseases, including BSE. • According to the CD approx. 98% of the examined cattle were older than 24 months and approx. 90% exhibited neurological symptoms. Although the identification system of Canada does not document the birth date or age of the animals, according to the CD, examination of the dentition is used to ascertain the maturity of the animals. • The list of neurological differential diagnoses for the 754 brains examined in 1997 included encephalitis (70 cases), encephalomalacia (19), hemophilus (7), hemorrhage (2), listeriosis (38), meningoencephalitis (36), rabies (22), tumors (2), other conditions (135) and no significant findings (423). • Compensation is paid for suspect BSE cases as well as for animals ordered to be destroyed (90-95% of market value with a maximum of 2,500 Can$ per cow). • Diagnostic criteria developed in the United Kingdom are followed at ADRI, Nepean. According to the very detailed protocol for the collection, fixation and submission of Bovine Spongiform Encephalopathy (BSE) specimens at abattoirs under inspection by the Canadian Food Inspection Agency, the specimen shall be shipped to National Center for Foreign Animal Disease, Winnipeg, Manitoba. • In 2003, around 3000 animals from risk populations have been tested. • According to the CD, it is aimed to test a minimum of 8000 risk animals (animals with clinical signs consistent with BSE, downer cows, animals died on farm animals diseased or euthanized because of serious illness) in 2004 and then continue to progressively increase the level of testing to 30,000. • In May 2003, Canada reported its first case of domestic BSE. A second case was detected in the US on 23 December 2003 and traced back to Canadian origin. Both were born before the feed ban and originated from Western Canada. 3.3 Overall assessment of the stability For the overall assessment of the stability, the impact of the three main stability factors (i.e. feeding, rendering and SRM-removal) and of the additional stability factor, surveillance, has to be estimated. Again, the guidance provided by the SSC in its opinion on the GBR of July 2000 (as updated January 2002) is applied. Feeding Until 1997, it was legally possible to feed ruminant MBM to cattle and a certain fraction of cattle feed (for calves and dairy cattle) is assumed to have contained MBM. Therefore feeding was "Not OK". In August 1997 a ruminant MBM ban was introduced but feeding of non-ruminant MBM to cattle remained legal as well as feeding of ruminant MBM to non-ruminant animals. This makes control of the feed ban very difficult because laboratory differentiation between ruminant and non ruminant MBM is difficult if not impossible. Annex to the EFSA Scientific Report (2004) 2, 1-15 on the Assessment of the Geographical BSE Risk of Canada Due to the highly specialised production system in Canada, various mammalian MBM streams can be separated. Such a feed ban would therefore be assessed as "reasonably OK", for all regions where this highly specialised system exists. However, several areas in Canada do have mixed farming and mixed feed mills, and in such regions, an RMBM ban would not suffice. Additionally, official controls for cattle feeds to control for the compliance with the ban were not started until the end of 2003. Thus, for the whole country, the assessment of the feeding after 1997 remains "Not OK". Rendering The rendering industry is operating with processes that are not known to reduce infectivity. It is therefore concluded that the rendering was and is "Not OK". SRM-removal SRM and fallen stock were and are rendered for feed. Therefore SRM-removal is assessed as "Not OK" snip... 4.2 Risk that BSE infectivity entered processing A certain risk that BSE-infected cattle entered processing in Canada, and were at least partly rendered for feed, occurred in the early 1990s when cattle imported from UK in the mid 80s could have been slaughtered. This risk continued to exist, and grew significantly in the mid 90’s when domestic cattle, infected by imported MBM, reached processing. Given the low stability of the system, the risk increased over the years with continued imports of cattle and MBM from BSE risk countries. 4.3 Risk that BSE infectivity was recycled and propagated A risk that BSE-infectivity was recycled and propagated exists since a processing risk first appeared; i.e. in the early 90s. Until today this risk persists and increases fast because of the extremely unstable BSE/cattle system in Canada. 5. CONCLUSION ON THE GEOGRAPHICAL BSE-RISK 5.1 The current GBR as function of the past stability and challenge The current geographical BSE-risk (GBR) level is III, i.e. it is confirmed at a lower level that domestic cattle are (clinically or pre-clinically) infected with the BSE-agent. This assessment deviates from the previous assessment (SSC opinion, 2000) because at that time several exporting countries were not considered a potential risk. snip... full text; Report Summary The European Food Safety Authority and its Scientific Expert Working Group on the Assessment of the Geographical Bovine Spongiform Encephalopathy (BSE) Risk (GBR) were asked by the European Commission (EC) to provide an up-to-date scientific report on the GBR in the United States of America, i.e. the likelihood of the presence of one or more cattle being infected with BSE, pre-clinically as well as clinically, in USA. This scientific report addresses the GBR of USA as assessed in 2004 based on data covering the period 1980-2003. The BSE agent was probably imported into USA and could have reached domestic cattle in the middle of the eighties. These cattle imported in the mid eighties could have been rendered in the late eighties and therefore led to an internal challenge in the early nineties. It is possible that imported meat and bone meal (MBM) into the USA reached domestic cattle and leads to an internal challenge in the early nineties. A processing risk developed in the late 80s/early 90s when cattle imports from BSE risk countries were slaughtered or died and were processed (partly) into feed, together with some imports of MBM. This risk continued to exist, and grew significantly in the mid 90’s when domestic cattle, infected by imported MBM, reached processing. Given the low stability of the system, the risk increased over the years with continued imports of cattle and MBM from BSE risk countries. EFSA concludes that the current GBR level of USA is III, i.e. it is likely but not confirmed that domestic cattle are (clinically or pre-clinically) infected with the BSE-agent. As long as there are no significant changes in rendering or feeding, the stability remains extremely/very unstable. Thus, the probability of cattle to be (pre-clinically or clinically) infected with the BSE-agent persistently increases. SUMMARY Summary of Scientific Report http://www.efsa.eu.int/science/efsa_scientific_reports/gbr_assessments/573/sr03_biohaz02_usa_report_summary_en1.pdf REPORT (6 PAGES) snip... EFSA Scientific Report (2004) 3, 1-6 on the Assessment of the Geographical BSE Risk of snip... http://www.efsa.eu.int/science/efsa_scientific_reports/gbr_assessments/573/sr03_biohaz02_usa_report_v2_en1.pdf Report http://www.efsa.eu.int http://www.efsa.eu.int/science/efsa_scientific_reports/gbr_assessments/565/sr04_biohaz02_mexico_report_v2_en1.pdf Summary Summary of Scientific Report The European Food Safety Authority and its Scientific Expert Working Group on the Assessment of the Geographical Bovine Spongiform Encephalopathy (BSE) Risk (GBR) were asked by the European Commission (EC) to provide an up-to-date scientific report on the GBR in Mexico, i.e. the likelihood of the presence of one or more cattle being infected with BSE, pre-clinically as well as clinically, in Mexico. This scientific report addresses the GBR of Mexico as assessed in 2004 based on data covering the period 1980-2003. The BSE agent was probably imported into Mexico and could have reached domestic cattle. These cattle imported could have been rendered and therefore led to an internal challenge in the mid to late 1990s. It is possible that imported meat and bone meal (MBM) into Mexico reached domestic cattle and leads to an internal challenge around 1993. It is likely that BSE infectivity entered processing at the time of imported ‘at - risk’ MBM (1993) and at the time of slaughter of imported live ‘at - risk’ cattle (mid to late 1990s). The high level of external challenge is maintained throughout the reference period, and the system has not been made stable. Thus it is likely that BSE infectivity was recycled and propagated from approximately 1993. The risk has since grown consistently due to a maintained internal and external challenge and lack of a stable system. EFSA concludes that the current geographical BSE risk (GBR) level is III, i.e. it is likely but not confirmed that domestic cattle are (clinically or pre-clinically) infected with the BSE-agent. The GBR is likely to increase due to continued internal and external challenge, coupled with a very unstable system. http://www.efsa.eu.int/science/efsa_scientific_reports/gbr_assessments/565_en.html ONE YEAR PREVIOUSLY ; From: Terry S. Singeltary Sr. [flounder@wt.net] Greetings FDA, snip... PLUS, if the USA continues to flagrantly ignore the _documented_ science to date about the known TSEs in the USA (let alone the undocumented TSEs in cattle), it is my opinion, every other Country that is dealing with BSE/TSE should boycott the USA and demand that the SSC reclassify the USA BSE GBR II risk assessment to BSE/TSE GBR III 'IMMEDIATELY'. for the SSC to _flounder_ any longer on this issue, should also be regarded with great suspicion as well. NOT to leave out the OIE and it's terribly flawed system of disease surveillance. the OIE should make a move on CWD in the USA, and make a risk assessment on this as a threat to human health. the OIE should also change the mathematical formula for testing of disease. this (in my opinion and others) is terribly flawed as well. to think that a sample survey of 400 or so cattle in a population of 100 million, to think this will find anything, especially after seeing how many TSE tests it took Italy and other Countries to find 1 case of BSE (1 million rapid TSE test in less than 2 years, to find 102 BSE cases), should be proof enough to make drastic changes of this system. the OIE criteria for BSE Country classification and it's interpretation is very problematic. a text that is suppose to give guidelines, but is not understandable, cannot be considered satisfactory. the OIE told me 2 years ago that they were concerned with CWD, but said any changes might take years. well, two years have come and gone, and no change in relations with CWD as a human health risk. if we wait for politics and science to finally make this connection, we very well may die before any decisions http://www.bseinquiry.gov.uk/files/yb/1989/02/14010001.pdf http://www.bseinquiry.gov.uk/report/volume7/chapted2.htm http://www.bseinquiry.gov.uk/files/yb/1989/02/14011001.pdf although 176 products do _not_ conform to the CSM/VPC http://www.bseinquiry.gov.uk/files/yb/1989/09/06011001.pdf http://www.mad-cow.org/00/nov00_late_news.html#fff http://www.whale.to/v/singeltary7.html http://www.mad-cow.org/00/may00_news.html http://www.mad-cow.org/00/jul00_dont_eat_sheep.html#hhh STUDY DESIGN AND METHODS: BSE was passaged through macaque monkeys and RESULTS: All three inoculated microcebes became ill after incubation CONCLUSION: Buffy coat from a symptomatic microcebe infected 17 months http://www.blackwell-synergy.com/servlet/useragent?func=synergy&synergyAction=showAbstract&doi=10.1046/j.1537-2995.2002.00098.x http://www.bseinquiry.gov.uk/files/yb/1989/09/06011001.pdf 5.23 This alerted Sir Donald Acheson to the fact that concerns about the http://www.bseinquiry.gov.uk/report/volume7/chapted2.htm TSS For questions and inquiries call: 1-800-835-4709 or 1-301-827-2000. Guidance for Industry: Revised Preventive Measures to Reduce the Possible Risk of Transmission of Creutzfeldt-Jakob Disease (CJD) and Variant Creutzfeldt-Jakob Disease (vCJD) by Blood and Blood Products - 1/9/2002 - (PDF), (Text) MMWR Notice to Readers: PHS Recommendations for the Use of Vaccines Manufactured with Bovine-Derived Materials Table of Contents Introduction: Recommendations for Use of Vaccines Manufactured with Bovine-Derived Materials Transcripts of 27 July, 2000, Joint Meeting of the Transmissible Spongiform Encephalopathy and Vaccines and Related Biologicals Advisory Committees CBER and FDA Guidance Documents on Sourcing of Bovine-Derived Materials Vaccines and Vaccinations: CDC / NIP / NVP Website Overview of Vaccine Manufacturing Estimating Risk for vCJD in Vaccines Using Bovine-Derived Materials Questions and Answers Current list of Vaccines Using Bovine-Derived Materials from countries on the USDA's BSE list or from Unknown Countries Countries/Areas Affected With Bovine Spongiform Encephalophathy [CFR 94.18] - Animal and Plant Health Inspection Service (APHIS), US Department of Agriculture Related Links -------------------------------------------------------------------------------- In 1991 the USDA list included only countries and other regions in which BSE was known to exist, such as France, Great Britain, Northern Ireland, the Republic of Ireland, Oman, and Switzerland. In 1998, the USDA expanded the list to include countries and other regions in which BSE had not been documented but in which import requirements were less restrictive than requirements that would be acceptable for import into the United States or in which surveillance was inadequate. Thus, all European countries, even those that have had no reported BSE cases, are currently on the USDA list, which is published in the Code of Federal Regulations, title 9, part 94 (9 C.F.R. part 94). In 2000, CBER learned that its recommendations regarding the sourcing of bovine materials for the manufacture of vaccines had not been followed in at least one instance. As a result of this finding, CBER requested all vaccine manufacturers to review the source for all bovine-derived materials used in the manufacture of their vaccines. This review identified additional vaccines manufactured with bovine-derived materials that had been obtained from European countries on the USDA list. No evidence exists that any case of vCJD has resulted from the administration of a vaccine product(4), and no cases of vCJD have been reported in the United States. To evaluate the risk of disease that might result from a vaccine manufactured with a process that utilizes bovine materials potentially contaminated with the BSE agent, CBER conducted risk assessments and convened a special joint meeting of the Transmissible Spongiform Encephalopathy Advisory Committee and the Vaccines and Related Biological Products Advisory Committee on July 27, 2000. In assessing the potential risk of vaccines, CBER and the joint Committees considered: (1) the likelihood that any cattle that were used might be infected (i.e., the time period and country of origin) and animal husbandry procedures; (2) the amount of bovine material that might be present in the final vaccine; and (3) the inherent infectivity of the various types of bovine materials that were used. The joint Committees concluded that the risk of vCJD posed by vaccines in the scenarios that were presented was theoretical and remote. They also noted that the benefits of vaccination far outweigh any remote risks of vCJD. The joint Committees made several recommendations. Working bacterial and viral seed banks and working cell banks that were established using bovine-derived materials sourced from countries on the USDA list should be re-derived with bovine-derived materials from countries not on the USDA list. However, master bacterial and viral seed banks established in a similar manner do not need to be re-derived; the potential risk presented by the master seed banks is even more remote than that presented by the working seed banks and is outweighed by the risk of altering the bacterial or viral vaccine through re-derivation. These issues are of public interest and, therefore, the public should be informed about the safety of vaccines that used materials sourced from countries on the USDA list, and the assessment of the nature of any risk of vCJD from such vaccines. The vaccines that use bovine-derived materials from countries on the USDA list include: Aventis Pasteur Inc.’s Diphtheria and Tetanus Toxoids and Acellular Pertussis (DTaP) Vaccine, Tripedia (the pertussis components manufactured by The Research Foundation for Microbial Diseases of Osaka University ("BIKEN") for use in Tripedia are the only components of the vaccine manufactured with bovine-derived materials from a country on the USDA list); Aventis Pasteur, S.A.’s Haemophilus Influenzae Type b Conjugate Vaccine, ActHIB (ActHIB is also marketed as OmniHIB by SmithKline Beecham Pharmaceuticals); North American Vaccine Inc.’s DTaP Vaccine, Certiva (the tetanus toxoid manufactured by Statens Seruminstitut for use in Certiva is the only component of the vaccine manufactured with bovine-derived materials from a country on the USDA list); SmithKline Beecham Biological’s DTaP Vaccine, Infanrix (the diphtheria toxoid manufactured by Chiron Behring GmbH & Co. for use in Infanrix is the only component of the vaccine manufactured with bovine-derived materials from a country on the USDA list), Hepatitis A Vaccine, Havrix, and the Hepatitis A Inactivated and Hepatitis B (Recombinant) Vaccine, TWINRIX. In some other cases, the source of the bovine-derived materials is unknown, in part because manufacturers have not always maintained or had access to records of the source of such materials, particularly in the 1980s and early 1990s, before the connection between BSE and vCJD was first suggested. Vaccines that use bovine-derived material of unknown origin obtained in 1980 or thereafter (the current best estimate is that BSE first emerged in 1980) include: Aventis Pasteur, S.A.’s Polio Vaccine, Inactivated, IPOL and Lederle Laboratories’ Pneumococcal Vaccine, Polyvalent, PNU-IMUNE 23. Vaccines using bovine-derived materials from a country on the USDA list or from an unknown source to manufacture only the master seed are not listed above; the joint Advisory Committees indicated that master seeds need not be re-derived. Additional information on such vaccines can be obtained upon request. The FDA has requested that manufacturers of vaccines using bovine-derived materials obtained from countries on the USDA list or from an unknown source replace these materials with materials from countries not on the USDA list, consistent with the recommendations of the joint Advisory Committees. The manufacturers have agreed to fully implement these changes. Indeed, several manufacturers initiated a number of these changes before the July 27, 2000, joint Advisory Committee meeting. FDA anticipates that the majority of these changes will be completed within one year. The FDA will revise the list of vaccines using bovine-derived materials from countries on the USDA list or from an unknown source as the requested changes are implemented and the vaccines come to market (see section VIII for the current listing). The Public Health Service (PHS) recommends that all children and adults continue to be immunized according to current immunization schedules(5). At the present time, the PHS has no preference for using one licensed vaccine product over another based on the source of bovine-derived materials used in vaccine production. The recommendations of the FDA Advisory Committees and the actions of the FDA are, as described, precautionary and have been taken to reduce even the remote potential of a risk of vCJD and to maintain public confidence in the safety of vaccines. Failure to obtain the recommended vaccinations with licensed vaccines poses a real risk of serious disease. References -------------------------------------------------------------------------------- Table of Contents -------------------------------------------------------------------------------- Transcripts of 27 July, 2000, Joint Meeting of the Transmissible Spongiform Encephalopathy and Vaccines and Related Biologicals Products Advisory Committees Table of Contents -------------------------------------------------------------------------------- CBER and FDA Guidance on Sourcing of Bovine Derived Raw Materials The following is a summary of the guidance documents and letters from FDA and CBER which relate to the potential for contamination of products with the agent that causes BSE. Points to Consider in the Characterization of Cell Lines Used for the Production of Biologics Manufacturers of FDA-regulated Products Letter to Manufacturers of FDA-regulated Drug/Biological/Device Products Guidance for Industry - The Sourcing and Processing of Gelatin to Reduce the Potential Risk Posed by Bovine Spongiform Encephalopathy (BSE) in FDA-Regulated Products for Human Use 1998 USDA Interim Rule on Import Restrictions of Ruminant Material from Europe (FR 63(3):406-408, 1/6/98) Letter to Manufacturers of Biological Products: Recommendations Regarding Bovine Spongiform Encephalopathy - (Text), (PDF) -------------------------------------------------------------------------------- Vaccines and Vaccinations CDC - National Immunization Program Table of Contents Table of Contents -------------------------------------------------------------------------------- http://www.fda.gov/cber/bse/bse.htm Estimating Risks for vCJD in Vaccines Using Bovine-Derived Materials The risk of vCJD from bovine-derived materials CBER’s survey of vaccine manufacturers revealed a number of vaccines that utilized bovine materials that were obtained from countries where BSE or a significant risk for BSE exists. An estimate of the risk that the use of these materials might pose is presented in the following sections. Two examples have been chosen for presentation here, namely, the risk from the use of fetal calf serum sourced from the United Kingdom (UK) in the derivation of a viral working seed that is subsequently used in vaccine manufacture and the use of European-sourced (excluding the UK) beef broth in the production of a bacterial toxoid. Based on CBER’s survey of the use of bovine-derived materials sourced from countries on the USDA BSE-list, the potential risk that would be associated with other uses of bovine-derived materials in vaccine production would be less than might be associated with these two situations. The infectivity of most bovine-derived materials has not been determined experimentally. More is known about the infectivity of various ovine-derived (from sheep) materials. The knowledge of the infectivities of different ovine tissues relative to each other can be used to estimate the relative infectivities of bovine tissues. For example, if we know that, on a gram for gram basis, sheep brain is 100 million times more infective than sheep muscle, we can assume that bovine brain is also 100 million times more infective than bovine muscle. Thus, if the infectivity of bovine brain has been measured, and contains 10 million infective doses per gram, then we can estimate that bovine muscle is 100 million times less infective and contains 0.1 infective dose per gram. Not surprisingly, since BSE and scrapie (the corresponding disease in sheep) are neural diseases, the greatest infectivity is found in neural tissue. Based on experimental studies, infected bovine brain contains approximately ten million infectious units per gram when administered to other cattle (2,3). In other tissues, such as serum or skeletal muscle, no infectivity has been detected. This does not mean that there is no infectivity associated with these materials; only that, if they are infectious, then the infectivity is at a level that is too low to be measured by current tests. Table I presents the estimated infectivity of different bovine-derived tissues as determined by The European Agency for the Evaluation of Medicinal Products (EMEA) The actual infectivity of skeletal muscle or serum, for example, may be well below the values shown; we will, nevertheless, use these values in our risk estimates. It should be noted that these values are based on experiments in which animals were infected by intra-cerebral injection with affected tissue; this is the most effective means of infecting experimental animals. When another route of administration, namely intramuscular injection, is used, infection rates are estimated to be approximately 200 fold lower (4). The risk assessments follow. Fetal calf serum used to derive viral seed and cell banks Fetal calf serum from the United Kingdom was used in the production of certain viral seeds and cell banks. The calf serum that was used was produced in the mid-1980s, when the BSE epidemic was just getting underway in the UK (5). The U.S. Department of Agriculture estimated the incidence of BSE in adult cattle at about 1 in 200 at that time(6). [Although many fewer cattle were observed to suffer from mad cow disease at that time, the long incubation time for the disease means that more cattle were infected than appeared diseased.] Since fetal calf serum was used in the production of the cell and viral seed banks, it is necessary to address the question of maternal-fetal transmission. Whether there is mother to fetus transmission of BSE is still unknown. One study may be interpreted as indicating that maternal-fetal transmission occurs at a rate of approximately 10%; i.e., that the calves of one of ten infected mothers may become infected with the BSE agent (7). However, other data indicate that maternal-fetal transmission does not occur or, if it does occur, it is below this 10% rate (8). As noted above, the U.S. Department of Agriculture estimates that, during the mid 1980s, approximately 1 in 200 cows in the United Kingdom was infected with BSE. Assuming that the rate of transmission from mother to fetus is 10% we would then estimate that 1 in 2000 fetal calves would have been infected. When fetal calf serum is manufactured, the sera from approximately 1500 calves are pooled together. If 1 in 2000 calves is infected, it is likely that any given serum pool is infected. As mentioned above, although no infectivity has been observed with serum, there are limits to detectability. These experiments only rule out an infectivity that is greater than 1 infectious unit per milliliter (mL) of blood (3,9,10). Although serum is listed as category IV, we are using the highest estimate consistent with infectivity experiments. In the following risk estimate, we assume that the serum of an infected fetal calf can contain up to 1 infectious unit per mL. In our risk calculation, we assume that the number of infectious BSE units that enters the vaccine production process is equal to the number of infectious units that remain in the vaccine at the end; that is, that the risk for vCJD is the input number of infectious units divided by the number of doses of vaccine that is in the batch. Thus, the risk estimate does not account for any purification step that might be present in the viral vaccine manufacturing process; although there are steps that probably remove infectivity, these are not considered in our risk estimate since none of the manufacturing steps have been demonstrated to remove BSE infectivity. We have also assumed that the BSE agent does not replicate during the manufacturing process; this is a reasonable assumption, bolstered by the many failed attempts to propagate the BSE agent in cell culture (11). The BSE infectivities that are estimated in Table I are derived from data using direct intra-cerebral inoculation (direct injection of the material into the brain). Vaccines are given intramuscularly, a less efficient route of transmitting the disease. In our risk estimate, we have allowed a factor of 200 for reduced transmission by the intramuscular route. In general, there is a species barrier for the transmissible spongiform encephalopathies; that is, it is easier to infect the same species of animal than another species (for example, bovine material is more infectious for cows than it is for other animals, such as mice) (3,4). The species barrier from cows to humans is not known; in our calculations, we will therefore assume that there is none. Given these assumptions, we can estimate the risk for vCJD from fetal calf serum (FCS) being used to prepare a viral working seed as the product of four separate risk factors. The level of BSE agent in the serum of an infected calf is estimated at 1 infectious unit per mL. Approximately 1 infected calf is present in each pool, deriving from approximately 1500 calves, of fetal calf serum. The infectivity of the pooled FCS is thus diluted to 1/1500 infectious units per mL (ca. 6.7 x 10-4 infectious units/mL). The amount of FCS that was used to produce a vial of a working viral seed is approximately 4 mL, and the number of doses of vaccine coming from that batch is approximately 500,000. The risk for acquiring vCJD is therefore: This yields a final risk estimate for vCJD of approximately 2.5 per 100 billion or 1 in 40 billion doses of vaccine [(1/1500) x 1 x 4 x (1/500,000) x (1/200)]. This level of risk would correspond to one case of vCJD arising every 5,000 years (assuming two doses per child) when vaccinating the entire birth cohort of the Unites States (four million children). Because of the assumptions that were used, this is an overestimate of the risk, and the true risk is likely to be significantly less. The risk that would be calculated for the use of a master seed that was prepared with fetal calf serum is again considerably less, due to an additional dilution that attends the preparation of the working seed from the master seed. Beef broth used to manufacture a bacterial vaccine: a bacterial toxoid as an example The potential risk of vCJD from a bacterial vaccine that used bovine-derived material in the nutrient broth to grow the bacterial strain during vaccine production is as follows. In the example that we are using, tissue derived from a single cow is used to prepare the fermentation broth. For this estimate, the incidence of BSE in European cows is taken to be 1 in 10,000. This value was derived by multiplying the average BSE rate in this region over the last five years by a factor of ten (1) to account for any uncertainty in the actual rates. The nutrient medium that is used to grow the bacteria for the vaccine contains approximately 750 grams of skeletal muscle (a Category IV material) and 200 grams of a pancreatic extract (a Category III material); see Table I. Because the broth is autoclaved (heated at high temperature), some of its potential infectivity is lost; a reduction factor of 20 is assigned to the autoclaving process(2). The risk, per dose of vaccine, for vCJD from a vaccine using a beef/pancreatic extract can be calculated as the product of the risk of using an infected cow (1 in 10,000) times the inherent risk of the bovine material after correction for the autoclaving process (approximately 1000 units; [200 grams of Category III material is estimated to contain no more than 20,000 infectious units and the 750 grams of Category IV material no more than 75 infectious units (20, 075 units total); the autoclaving process reduces this infectivity to approximately 1000 units]), divided by the number of doses that are in a batch of vaccine (approximately 1 million), corrected for the route of administration (a reduction factor of 200). This yields a risk estimate for vCJD of 1 case in 2 billion doses of vaccine [(1/10,000) x 1,000 x (1/1,000,000) x (1/200)]. A second scenario can also be considered, namely one in which a small amount of neural tissue inadvertently might contaminate the beef broth. We consider a 0.01% contamination with neural tissue. This would increase the amount of infectious material from 1000 units to 50,000 units, raising the total risk to 1 in 40 million. Because of the overestimates that were used in the risk calculation, the true risk is likely to be significantly less. Potential sources of error In estimating the risk of BSE contamination, it is important to note that each risk factor carries its own uncertainty. The overall risk, which is the product of these factors, compounds these uncertainties. For example, we have assumed no species barrier and no purification effect. The actual risk could be 10 to 1,000 fold lower, but probably no greater. On the other hand, we have assumed a 200-fold reduction due to an intramuscular route of administration. In fact, this risk could be 10-fold greater or 10-fold lower. Finally, in the case of viral vaccines, and based on experiments with analogous cell lines, we have assumed that BSE cannot replicate in cell cultures that were used. These uncertainties must be considered in order to correctly interpret the risk of BSE in viral vaccines. These calculations are not a formal risk assessment, but an attempt to estimate risk based on information currently available. It should be noted that for both the viral and bacterial vaccine examples used, the exposure to this risk is temporary. Manufacturing changes have already been implemented which eliminate exposure during vaccine manufacture to bovine materials from countries at risk of BSE contamination. Vaccines made by these procedures are expected to be available in 2001. -------------------------------------------------------------------------------- Estimated infectivity of bovine tissue by category -------------------------------------------------------------------------------- References: Bader F, Davis G, Dinowitz M, Garfinkle B, Harvey J, Kozak R, Lubiniecki A, Rubino M, Schubert D, Wiebe M, and Woollett G, Assessment of risk of bovine spongiform encephalopathy in pharmaceutical products, Biopharm. Jan., 1998. pp. 20-31. http://www.fda.gov/cber/bse/risk.htm -------------------------------------------------------------------------------- Preparation of bacterial and viral master and working seeds; preparation of master and working cell banks (e.g., use of calf serum, fetal calf serum). Formulation of the final products (e.g., use of gelatin, etc.) Additionally, in this discussion, please include risk assessments for bovine materials sourced, at different times, from different European countries (e.g., UK, Germany, France). The committee stated that 1980 was the cut off date previously decided upon regarding the risk of exposure to the BSE agent for blood donations. In light of that decision, the committee agreed that 1980 would be an appropriate cut-off date for concern about BSE risk in bovine-derived material used in vaccines. The committee stated that in light of current scientific knowledge, the risk of bovine-derived materials sourced from BSE-risk countries in currently licensed vaccines is a "theoretical" risk. The risk assessment is dependent on the geographic source, the type of tissue, and the processing. None of the current estimates of risk can be precisely quantified. This theoretical risk must be balanced against the benefits of the vaccination program (or the real risk of not being vaccinated). Committee members agreed that some form of notification to vaccine recipients or "public disclosure" should be made regarding vaccines which may be manufactured with bovine materials sourced from BSE-risk countries. The committee discussed but was not in full agreement on what would be the most appropriate means of disclosure. The options discussed included issuance of a Dear Health Care Provider letter, inclusion of such information in the package insert, a joint statement of the agencies within the Department of Health and Human Services, or publication by journal article. The committee agreed that any disclosure should be carefully worded in order to express the theoretical risk of exposure to the BSE agent versus the benefit of receiving the vaccine. While the theoretical risk of vaccine products under investigation is the same as the theoretical risk of licensed vaccines, committee members agreed that products under investigation do not have a proven benefit as compared to licensed vaccine products. Therefore, investigational vaccines should be considered separately from licensed products. The committee members agreed that participants in clinical trials should be notified through informed consent about the theoretical risk of vaccines produced with bovine-derived materials from a BSE-risk country. -------------------------------------------------------------------------------- Last Updated: 5/7/2002 http://www.fda.gov/cber/advisory/tse/tsesum072700.htm ALSO; W.H.O. http://www.who.int/vaccines-diseases/safety/hottop/bse.shtml TSS
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