MEMO/99/54
Brussels, 29 October 1999
Opinion of the Scientific Steering Committee
on the Scientific Grounds of the Advice of 30 September 1999 of the French Food Safety Agency (the Agence Française de Sécurité Sanitaire des Aliments, AFSSA), to the French Government on the Draft Decree amending the Decree of 28 October 1998 establishing specific measures applicable to certain products of bovine origin exported from the United Kingdom.
adopted at its meeting of 28-29 october 1999 and edited following an written procedure (30-31.10.99)
(Document subject to further editorial changes)
Abbreviations used in this document (selection):
AFSSA:Agence Française de Sécurité Sanitaire des Aliments (the French Food Safety Agency)
BSE:Bovine Spongiform Encephalopathy
CEA:Commissariat à l’Energie Atomique
CNS:Central Nervous System
DBES:Date Based Export Scheme
ECHS:Export Certified Herd Scheme
GB:Great Britain
MAFF:Ministry of Agriculture, Fisheries and Food (UK)
MBM:Meat-and-bone meal
OIE:Office International des Epizooties (World Organisation for Animal Health – Organisation Mondiale de la Santé Animale)
OTMS: Over Thirty Months Scheme
PrPRes:pathological isoform of the prion protein(PrPSc in part of the scientific literature).
SBO:Specified bovine offals
SEAC:Spongiform Encephalopathy Advisory Committee (UK)
SRM:Specified Risk Materials
SSC:Scientific Steering Committee
TSE:Transmissible Spongiform Encephalopathy
1.Mandate
Following the AFSSA advice, the European Commission’s questions submitted to the SSC were:
1.Do the opinions and documentation provided by the French authorities contain scientific information, epidemiological data or other evidence that has not been taken into account by the SSC?
2.If, in the above documentation, there is new information, data or evidence, or if the SSC has at its disposal any such new information, would this require a re-examination of any of the four SSC Opinions directly related to the scientific rationale of the DBES?
3.In the light of the answers to the above question, could the SSC confirm (or not) its position that the conditions of the DBES, if appropriately respected, are satisfactory with regard to the safety of the meat and meat-products produced?
2.Background
The original UK proposal of 2 October 1997 proposal refers to the OIE Code[1] requiring, in relation to the export of meat (including products derived therefrom) from a country or zone with a high incidence of BSE, that:
a)the meat must come from animals which were born and retained kept in herds in which no case of BSE had been recorded, or,
b)the meat must come from animals born after the ban on the use of ruminant meat-and-bone meal was effectively enforced.
The first option had been applied in the Export Certified Herd Scheme (ECHS), which was previously submitted by the UK for approval and was the subject of a scientific opinion by the Scientific Veterinary Committee in 1997.
The second option was applied in the DBES (see annex 1). The key elements of the scheme were an effective feedban (from 1.08.96) designed to exclude feedborne transmission and an offspring cull combined with confirmation of survival of the dam for 6 months, designed to significantly reduce maternal transmission. As both known routes of transmission were considered to be covered, the DBES did not include a requirement for herd freedom from BSE as originally proposed in the ECHS.
On 9.12.97, the SSC adopted the Report on the UK Date Based Export Scheme (DBES) and the UK proposal on Compulsory Slaughter of the Offspring of BSE Cases (re-edited on 23.01.98), accepting in general the scientific soundness of the Scheme, but making a number of additional requirements.
These were addressed in the SSC Opinion of 20.02.98 On the revised version of the UK Date Based Export Scheme and the UK proposal on compulsory slaughter of the offspring of BSE-cases, submitted on 27.01.98 by the UK Government to the European Commission.
In addition, in relation to the UK Date Based Export Scheme, the SSC adopted the following 2 opinions:
a.Opinion on The safety of bones produced as by-product of the Date Based Export Scheme, adopted, 23.10.98:
b.Opinion on Monitoring Some Important aspects of the evolution of the Epidemic of BSE in Great-Britain (Status, April 1999), adopted, 28.05.99.
Finally, the SSC adopted a number of opinions of indirect relevance, for example on specified risk materials (SRMs), vertical transmission of BSE, safety of products and geographical BSE risk.
As a result of these opinions, the decision to authorise the export of deboned meat and products derived therefrom under the DBES was adopted on 25 November 1998 (Commission Decision N° 98/692/EC) and the date when the export could commence was set at 1 August 1999 by Commission Decision 1999/514/EC, following the favourable outcome of a Community mission, in April 1999.
On 30 September 1999 AFSSA issued an opinion which challenged the EU Decision of 28 October 1998 establishing specific measures applicable to certain products of bovine origin exported from the United Kingdom.
This AFSSA advice of the 30th September is based on the Opinion of 30 September 1999 of the French Group of Experts on Transmissible Sub-acute Spongiform Encephalopathies regarding the lifting of the UK Export ban. This Group of Experts has the same membership as an Inter-ministerial Committee for Transmissible Suc-acute Spongiform Encephalopathies, established in 1996. In addition, the latter Committee adopted on 1 July 1999 an opinion on the BSE Epidemic in the UK.
The main points on which the Opinion of 30 September 1999 of the French Group of Experts on Sub-acute Spongiform Transmissible Encephalopathies is based, were summarised as follows:
Much more sensitive tests are emerging that allow the finding of PrPRes in tissues in which no infectivity has been detected so far.
The similarity of the number of confirmed cases reported in UK in the period January to end of August 1998 and 1999, suggests an unexplained slow down of the rate of decrease.
The availability of the post-mortem BSE-tests evaluated by the Commission.
The results from additional surveillance programmes (i.e., in the UK: brain histopathology of bovines slaughtered under the Over Thirty Months Scheme (OTMS); in Switzerland: the Prionics test, if necessary confirmed by histology or immunocytochemistry on all adult cows in fallen stock, emergency slaughters and a sample of routinely slaughtered adult cows).
Doubts on the traceability of meat products.
3.Elements of discussion
The 3 questions submitted to the SSC by the EC were first discussed at two meetings of the SSC’s TSE/BSE ad hoc Group (14 October 1999 and 25 October 1999)[2]. The ad hoc Group discussed the following 4 points:
The possibility of verifying the distribution of PrPRes in the various body tissues and fluids of infected (incubating) cattle. Linked to this was the question of the usefulness of increasing sensitivity of the BSE laboratory tests and assays.
The evolution in 1999 of the epidemiology of the disease in the UK and its importance for the DBES, and linked to it, the issue of possible new transmission routes.
The potential of the recently evaluated rapid diagnostic BSE-tests and of new analytical possibilities with regard their use in surveillance and monitoring of TSEs.
The traceability of the meat and meat products.
As to date, the SSC was given detailed information on the analyses and deliberations of the TSE/BSE ad hoc Group, together with the data on the UK epidemic as of mid-October 1999, new input on epidemiological analyses of BSE including projections of cases in the DBES herd and also the most recent data from SEAC from cattle-to-cattle experiments on the possible infectivity of muscle, spleen and lymph nodes. The SSC had also access to other recent scientific material such as the Notes of the Tübingen Conference on Characterisation and Diagnosis of Prion Diseases in Animals and Man (23-25 September 1999) and other recent papers.
3.1.New tests for PrPRes and an assessment of the distribution PrPRes in different organs
The SSC reassessed the usefulness of new methods which promise to provide ever more sensitive ways for documenting the distribution of PrPRes of different TSEs in the organs of different species.
These methods, e.g., the one developed by Schmerr et al (see also: Notes of the Tübingen Conference), use different techniques which may lead ultimately to assays approaching the possibility to even detect single proteins. The question was raised as to how far this would be relevant with respect to the potential infectivity of bovine tissues containing very low concentrations of PrPRes for animals and in particular for man.
It was recognised that some recently published research using sensitive tests has documented the distribution of injected PrPRes into different organs in species which normally do not manifest the clinical disease. Thus, there may be a need to distinguish between the mere presence of PrPRes, its capacity to replicate and its ability to cause disease. The presence of low concentrations of PrPRes can be a feature of the distribution characteristics after parenteral administration or oral exposure and has not necessarily an implication of infectivity.
The sensitivity of current methodologies is such that the failure to find PrPRes of currently detectable concentrations, however, does not necessarily guarantee the true absence of PrPRes. When tests indeed detect the presence of PrPRes aggregates in naturally infected animals, it is reasonable to infer that the TSE transmitted to the particular species has probably replicated and may eventually lead to clinical disease.
Three recent post mortem diagnostic tests evaluated by the EC on material from the brain of BSE clinically diseased animals have been shown to be robust in assessing clinical cases of BSE. Dilution experiments also imply that one or more of these tests may prove valuable in detecting PrPRes replication before the development of the clinical disease. (see also Section 3.4).
The SSC concludes that new and more sensitive tests may well highlight the presence of the BSE agent in different cattle tissues long before clinical disease develops. Whether the presence of extremely low levels of detectable PrPRes indicate infectivity for man is a different issue which is being considered by the SSC.
Until such time as the biological significance of the newly developed, highly sensitive molecular assays becomes clearer, the SSC has no basis for changing its approach, especially as it has accumulated considerable experience and historical control data using established methodologies. The SSC would need to acquire control data for the alternative methodology before changing. The SSC from its first analyses of risk has used data from infection studies in different systems to estimate the relative risk of the BSE agent load in different tissues at different stages of the infection cycle.
3.2.Organ distribution: the importance of considering both the type of TSE agent and the species affected.
The SSC took account of recent studies e.g. by Schmerr et al (1999)[3], Maingien et al (1999)[4], Wells et al (1998, 1999)[5],[6] whichfollow the distribution of different TSE agents in different species. The SSC was also informed of preliminary[7] research found to indicate the presence of PrPRes during the first months of life after birth in lymphoid organs of sheep born to a scrapie infected ewes. Recent analyses show the importance of establishing the specificity of pathogenic processes whereby one TSE e.g. a scrapie strain establishes itself in a particular host, whereas another TSE e.g. BSE or even other scrapie strains either have no effect or induce a different pathological process. Transgenic models are being used to distinguish between the scrapie agents and the BSE agent. These models may eventually prove helpful in distinguishing between the scrapie and BSE agents when examining the basis of spongiform encephalopathies in sheep. Thus, it would be possible to establish whether a scrapie-like illness in sheep is in practice caused by the BSE rather than by a scrapie agent.
A further issue considered was the current bioassay distinction between the infectivity of the BSE agent in sheep and cattle. Using the mouse bioassay system, two sheep, one challenged orally and anither i/c with BSE, were found to have infectivity in the spleen. Tissues other than brain and spleen were not tested, but the distribution of BSE in sheep through the peripheral tissues and the lymphatic system may prove to be similar to scrapie when further studies are undertaken. By contrast, no bioassay – either with mice or with cattle, the most sensitive bioassay system yet devised, i.e. intra-cerebral infection in cattle - has documented BSE infectivity in the spleen of cattle suffering from clinical BSE.
These data might be taken to imply that the pathological process of the BSE agent migration in cattle is different from the spread of the scrapie agent or even of the BSE agent in sheep. However, the SSC had not come to that conclusion because it is possible that more sensitive tests would show that the BSE agent can occur in the lymphatic tissues and blood of cattle orally infected with the BSE agent relatively early in the incubation period, although current bioassays have not revealed infectivity in these tissues.
The SSC notes that its original cautious approach to the designation of BSE infectivity in cattle (9.12.1997) presupposed that the behaviour of the BSE agent in cattle could parallel that of scrapie in sheep. If more sensitive assays can be applied to blood, lymphatic tissues, peripheral nerves and other organs of BSE affected cattle and sheep then a more coherent view can be obtained of whether the BSE agent behaves in the same way in sheep and cattle. The SSC would recommend that this research be promoted.
The SSC - in its various opinions related to tissue infectivity (e.g., on Specified Risk Materials (9.12.97); on the safety of bones as a by of the DBES (23.10.98), on vertical transmission of BSE (March 1999) - also used the most recent results, provided by MAFF, of the still ongoing pathogenesis experiment. This experiment [8],[9] started in April 1992, is based on oral cattle-to-cattle transmission with 100 grams of contaminated bovine brain material, i.e., a test system with no species barrier. Mice were then inoculated i/c with preparations of various tissues taken from the infected but pre-clinical cattle at different intervals after oral exposure. Thus far, none of the tissues which were not already known (in 1998) not to harbour infectivity, have led to clinical disease.
In another bioassay, some of these tissues from orally exposed cattle are also being re-inoculated i/c into cattle. This test is the most sensitive bioassay of infectivity currently available with incubation times for the clinical manifestation of the disease which are shorter than the time for oral dose to induce the clinical state. Thus dilutions of infected brain, diluted 10-3 to 10-7 have average incubation times to disease of 24 to 42 months. Cattle challenged with spleen taken from cattle killed 10 and 26 months post oral exposure now show no disease 15 and 7 months later.
Cattle were also challenged with pooled muscle tissue comprising both white and red fibre muscles, which are closely associated with peripheral nerves close to the brain and spinal cord. The muscles from cattle killed 18 months post challenge, were inoculated i/c into further cattle. These cattle are now, 36 months post inoculation, without clinical disease. Similarly, muscles from cattle killed 32 months post challenge, were inoculated i/c into further cattle. At this stage (32 months), the CNS of the orally infected cattle from which the muscles were taken were shown to contain infectivity in the mouse bioassay. Recipient cattle are now, 35 months post inoculation, and without clinical disease.
In yet another experiment, lymph node and spleen homogenates taken from cattle with confirmed BSE, were inoculated i/c into healthy cattle. Today, 80 months post challenge, they are all free of clinical disease. Given that the average incubation period of naturally exposed, i.e., orally infected cattle is 4 to 5 years, this experimental data with intra-cerebral challenge and an incubation period of 6½ years is strongly suggestive of no infectivity associated with the lymph nodes and spleen in orally infected cattle.
This therefore now provides important evidence in favour of a difference in the routes of spread of both scrapie strains and BSE infectivity in sheep compared with the spread of BSE in cattle.
The SSC notes that muscle tissue has never been found to be infective, even from BSE cattle in the later stages of infection, in spite of the fact that peripheral nerves, lymphatic tissue and blood are associated with muscle.
3.3.Epidemiology
In its opinion of July 1st 1999, the French Inter-Ministerial Committee on Transmissible Sub-acute Spongiform Encephalopathies issued an opinion on the pattern of decline in the UK epidemic of BSE. It compared the number of cases recorded by OIE in 1996, 1997 and 1998 with estimated numbers of cases and estimated range (95% confidence intervals) of cases to the models of Anderson et al (1996) and Donnelley et al (1997). The Expert Group on Transmissible Sub-acute Spongiform Encephalopathies issued a further opinion on September 30th 1999, on this topic. The opinion drew the attention of the AFSSA to the following: “The increasingly limited decline in prevalence in Great Britain, despite measures taken, begs the question as to whether we understand all the possible origins of contamination”. The group also points out that, in this regard, they had access to data on the UK epidemic as of July 1999.