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Blood donations to be treated against CJD

July 18 1998 Times Ian Murray 
Government takes experts' advice and goes for 'better safe than sorry' approach

Blood donations to be treated against CJD ALL blood supplies are to be treated to reduce even further the remote risk of patients being infected with new variant Creutzfeldt-Jakob disease (nvCJD). Donations are to be put through a process called leucodepletion, which removes the white cells that are theoretically the likeliest part of the blood in which the infection could exist.

The treatment will cost #80 million a year in addition to the #70 million needed to protect plasma for the treatment of conditions such as burns and haemophilia. The Government decided yesterday to introduce the change on the recommendation of the Spongiform Encephalopathy Advisory Committee (Seac), a panel of experts that directs policy for controlling BSE and CJD.

To date, there have been 27 cases of nvCJD, but there is no evidence that it can be transmitted via blood or blood products [absence of evidence is not evidence of absence -- webmaster]. However, the committee has now agreed that the risk exists and action should be taken to reduce it even further. Announcing the move, Frank Dobson, the Secretary of State for Health, said: "We will do whatever we are advised to reduce the theoretical risk to the blood supply of the transmission of new variant CJD. Although the risks are still theoretical, it is better to be safe than sorry."

Jeremy Metters, the Deputy Chief Medical Officer, said: "I should stress that this is a purely precautionary measure. Blood in the UK remains very safe and leucodepletion will make it even safer. Leucodepletion will be rolled out in a systematic way, so that blood supplies are not interrupted and patients will continue to get blood when they need it."

Dr Metters said it was more important than ever that blood donors continue to come forward to give blood regularly to enable more patients to be treated in the NHS. "I should emphasise that there is no risk of new variant CJD whatsoever to those who donate blood."

He said that apart from reducing the risk of CJD, there are a variety of benefits for patients given leucodepleted blood. It avoids the risk of fever in those who require repeated transfusions, reduces the risk of graft rejection in patients requiring bone marrow transplants, and prevents infections in babies younger than a year.

The Government has already accepted earlier advice from Seac to abandon the use of British blood for plasma products, such as those used in the treatment of haemohiliacs. All plasma now has to be obtained outside Britain.

The Government's move does not, however, satisfy Stephen Dealler, a microbiologist and outspoken critic of government policy on CJD. He said: "Although leucodepletion would take a large amount of infectivity away there would be enough left to transmit the disease."

He said that scientists had estimated that 80,000 people might be infected with new variant CJD, assuming an incubation period of 25 years. If this was true, as many as one in 250 blood donors might be infected. Since the average patient received two units of blood from different donors, it meant that new variant CJD could possibly be transmitted to one in 125 recipients.

"The danger was heightened by the fact that new variant CJD affected people in the right age bracket for giving blood.

Dr Dealler said: "This is information that's been available for 18 months, but the trouble is the Government has been taking advice from the national blood service who know absolutely nothing about CJD."

Plan to screen blood for CJD

Saturday 18 July By Roger Highfield, Science Editor
DONATED blood is to be treated to lessen the risk of transfusion patients being infected with the human form of mad cow disease, it was announced yesterday.

In future, supplies will go through a process of leucodepletion - the removal of white blood cells which could harbour the infective agent - even though Government advisers admit it is possible that the measure may be ineffective.

The scheme, which will cost ?70 million a year, offers other health benefits. It follows advice from the Spongiform Encephalopathy Advisory Committee, SEAC, which helps to shape Government policy on BSE and its human equivalent, new variant CJD. Importing blood for transfusion was out of the question, given the enormous impact on the national blood supply. Prof Sir John Pattison, chairman of SEAC, said that it would be a "catastrophe - we could not maintain the stocks and the risks would far outweigh those we are trying to prevent".

Including the move to use imported plasma, introduced in February, the Government will now spend ?100 million annually safeguarding the nation's blood supply from CJD. There have been 27 confirmed cases of the disease and although leucodepletion is not 100 per cent effective, the risk is serious enough to warrant action, said Prof Jeffrey Almond of Reading University, a SEAC member. There is no good evidence that the old form of CJD can be transmitted by blood but "there is a reason to be a little more concerned about new variant CJD", said Prof Almond. "The disease process seems to be different."

The human BSE disease process involves the tonsils, spleen and lymph node. "These tissues are packed full of white blood cell types," said Prof Almond. "You can't see any in the old-style CJD." White cells in mice can transmit disease, as can lymph node, spleen and tonsils of sheep. This led SEAC to suspect that white blood cells may carry the disease in patients.

The risk to the blood supply depends on how long an individual has been infected and how much infectivity resides in blood, for instance is a single drop or two pints enough to transfer the disease? "We don't know the answer to that," said Prof Almond.

The second risk factor depends on another unknown, that of receiving a unit of blood donated by an infected person. A rough calculation suggests that one in 125 transfusion patients could be at risk from blood contaminated with human BSE. In reality, despite a risk assessment launched last November, "we don't know", said Sir John. "We don't have enough information to give a useful quantitative risk assessment."

Leucodepletion, which is carried out in four other European countries, removes up to 95 per cent of white blood cells and would therefore reduce risk so long as the white cells are not highly infectious. The move would offer other potential health benefits: white cells transmit other infections, are a cause of fevers in patients who receive transfusions, and are linked to rejection in bone marrow transplants.

Frank Dobson, the Health Secretary, said yesterday: "Although the risks are still theoretical, it is better to be safe than sorry."

Dobson acts on CJD blood threat

by Jo Revill
Evening Standard ... Friday 17 July 1998
The Government today took urgent action to minimise the risk of CJD being passed on to patients through donated blood. Health Secretary Frank Dobson has instructed the National Blood Authority to start removing white blood cells from the blood supply, a process known as leucodepletion.

The move came as the Government's advisers warned that it is impossible to be sure that blood transfusions are safe. One report which was put to the Spongiform Encephalopathy Advisory Committee suggests that up to 80,000 donors could be carrying CJD , the human equivalent of mad cow disease. Leucodepletion is known to be effective at minimising the risk of passing on the infection. So far Britain has had 27 cases of new variant CJD, the form which is believed to arise from eating contaminated beef. Earlier this year, the Government decided to start buying in blood plasma from non-British sources as a precautionary measure.

Mr Dobson said today: "We will do whatever we are advised to reduce the theoretical risk to the blood supply of the transmission of new variant CJD. Although the risks are still theoretical, it is better to be safe than sorry."

Jeremy Metters, the Deputy Chief Medical Officer, said: "Leucodepletion will be rolled out in a systematic way, so that blood supplies are not interrupted and patients will continue to get blood when they need it." He added that it was more important than ever that blood donors continued to come forward to give blood, as an increasing number of patients were needing it. Claire Rayner, of the Patients' Association, called for greater use of autologous blood transfusions , in which patients donate blood before an operation and receive it back during surgery.

CJD risk threatens ban on British blood

by Ian Murray, Medical Correspondent
Times ... Friday 17 July 1998
Ministers are considering banning blood transfusions from British donors because of the remote risk that they might spread Creutzfeldt-Jakob disease, the human form of "mad cow" disease. Such a ban would cost the health service millions of pounds, since British blood is free, while foreign supplies would have to be paid for.

But first the Health Department must decide which poses the greater danger: the 40 million-to-one chance of a donor having CJD, or imported blood which may be contaminated with other infections, such as HIV. A decision is expected next week .

The dilemma arises because the Government's advisers on "mad cow" disease and CJD have concluded after studying a series of reports that it is impossible to be sure that blood transfusions are safe. Three of the 25 known victims of CJD - all of whom died - were blood donors , although it is not known if they were carrying the disease when they gave blood.

One report considered by the Spongiform Encephalopathy Advisory Committee (Seac) suggests that up to 80,000 donors could be carrying CJD , in which case one in every 125 patients given a transfusion could receive blood contaminated with new variant CJD . And some patients who receive several different blood products would be at greater risk.

Seac said that one report showed that a blood purification system known as leukodepletion - which removes white cells - could not be guaranteed to clear the infection from blood, as had been hoped. The report, based on studies in America, found that the system was effective but not perfect.

Seac has now sent the reports to the Government, coupled with the advice that it must decide whether the CJD risk is greater than that of unknown infections in foreign blood . Blood donors in Britain are carefully screened, but other countries - especially those where donors are paid - are not always so scrupulous.

Previous Seac recommendations have been accepted by the Government, including one in February that blood from British donors should not be used in the manufacture of plasma products because of the possibility of infection. From September, all plasma will be bought from the United States, where new variant CJD is unknown.

Because plasma products can be kept for long periods and individual donations are mixed together, it cannot be guaranteed that some of the contaminated blood is not present in some of the products, so they are being phased out. However, blood used in transfusions can be kept only for a month, and since there is no known test for CJD until it is in an advanced state , it is impossible to know if a donor is suffering from it until after the blood has been used.

Stephen Dealler, a microbiologist who was one of the first to raise fears about new variant CJD, last night called on the Government to take urgent action. "This is the news that a lot of people feared," he said. "The official line has always been to play down the risk, but now we have firm evidence that a significant number of people could develop new variant CJD from blood. There may be thousands of people who have become infected while the experts have been aware of the seriousness of the situation."

A Health Department spokesman confirmed that the Seac advice was being considered and that a decision would be taken shortly. "If there is a risk, it is minute and people who need blood would be in infinitely greater danger of dying without a transfusion than from catching CJD from it," he said.

CJD risk threatens ban on British blood

20 July 98 BY IAN MURRAY, medical correspondent, The Times
MINISTERS are considering banning blood transfusions from British donors because of the remote risk that they might spread Creutzfeldt-Jakob disease, the human form of "mad cow" disease. Such a ban would cost the health service millions of pounds, since British blood is free, while foreign supplies would have to be paid for.

But first the Health Department must decide which poses the greater danger: the 40 million-to-one chance of a donor having CJD, or imported blood which may be contaminated with other infections, such as HIV. A decision is expected next week.

The dilemma arises because the Government's advisers on "mad cow" disease and CJD have concluded after studying a series of reports that it is impossible to be sure that blood transfusions are safe. Three of the 25 known victims of CJD - all of whom died - were blood donors, although it is not known if they were carrying the disease when they gave blood.

One report considered by the Spongiform Encephalopathy Advisory Committee (Seac) suggests that up to 80,000 donors could be carrying CJD, in which case one in every 125 patients given a transfusion could receive blood contaminated with new variant CJD. And some patients who receive several different blood products would be at greater risk.

Seac said that one report showed that a blood purification system known as leukodepletion - which removes white cells - could not be guaranteed to clear the infection from blood, as had been hoped. The report, based on studies in America, found that the system was effective but not perfect.

Seac has now sent the reports to the Government, coupled with the advice that it must decide whether the CJD risk is greater than that of unknown infections in foreign blood. Blood donors in Britain are carefully screened, but other countries - especially those where donors are paid - are not always so scrupulous.

Previous Seac recommendations have been accepted by the Government, including one in February that blood from British donors should not be used in the manufacture of plasma products because of the possibility of infection. From September, all plasma will be bought from the United States, where new variant CJD is unknown.

Because plasma products can be kept for long periods and individual donations are mixed together, it cannot be guaranteed that some of the contaminated blood is not present in some of the products, so they are being phased out. However, blood used in transfusions can be kept only for a month, and since there is no known test for CJD until it is in an advanced state, it is impossible to know if a donor is suffering from it until after the blood has been used.

Stephen Dealler, a microbiologist who was one of the first to raise fears about new variant CJD, last night called on the Government to take urgent action. "This is the news that a lot of people feared," he said. "The official line has always been to play down the risk, but now we have firm evidence that a significant number of people could develop new variant CJD from blood. There may be thousands of people who have become infected while the experts have been aware of the seriousness of the situation."

A Health Department spokesman confirmed that the Seac advice was being considered and that a decision would be taken shortly. "If there is a risk, it is minute and people who need blood would be in infinitely greater danger of dying without a transfusion than from catching CJD from it," he said.

80m to cut CJD blood risk

PA News Fri, Jul 17, 1998
By John von Radowitz, Medical Correspondent, PA News

A huge 80 million clean-up operation funded by the taxpayer to cut the risk from blood infected with CJD was announced today. In future white blood cells, which theoretically could harbour the agent that transmits the disease, will have to be filtered out of all donated blood. But critics maintain that the process, leucodepletion, is not efficient enough to ensure that all blood used in transfusions is safe.

The Government was urged to take the decision by the Spongiform Encephalopathy Advisory Committee (Seac), which advises it on BSE and CJD. Since last November, Seac scientists have been assessing the CJD blood risk. During this time, secret contingency plans for a leucodepletion programme were drawn up in case the threat proved real.

Seac has now told the Government that the risk, although small, is serious enough to warrant action. The move will add 80 million to the 70 million-a-year already being spent to protect plasma-based blood products, used to treat haemophiliacs, burns victims and people with weak immune systems, from new variant CJD - the form of the disease linked to BSE in cattle.

In May the Government ruled that all plasma - the fluid serum derived from blood, which is used to make the products - must be imported from abroad. The decision came after advice from the Committee on Safety of Medicines two months earlier. Blood products were thought to pose a significant risk because they are made from plasma collected from thousands of different donors.

Scientists now think that if any CJD infectious agents exist in human blood they are most likely to be found in the white blood cells called lymphocytes. These are produced in the lymph glands and are a vital part of the immune system. No one knows the extent of the danger, but according to one estimate one in 125 transfusion patients could be at risk from blood contaminated with the new strain of CJD.

Making the announcement today, Health Secretary Frank Dobson said: "Although the risks are still theoretical, it is better to be safe than sorry."

Deputy Chief Medical Officer Dr Jeremy Metters stressed that the move was a "purely precautionary measure". Dr Metters added: "Leucodepletion will be rolled out in a systematic way, so that blood supplies are not interrupted and patients will continue to get blood when they need it."

The roll-out programme is expected to take several months. Microbiologist Dr Stephen Dealler, one of the first to warn of the danger from new variant CJD, said leucodepletion was not the answer.

"Although leucodepletion would take a large amount of infectivity away, there would be enough left to transmit the disease," he said. He said scientists had estimated that 80,000 people may be infected with new variant CJD, assuming an incubation period of 25 years.

If this were true, as many as one in 250 blood donors might be infected. Since the average patient received two units of blood from different donors, it meant new variant CJD could be transmitted to one in 125 recipients. The danger was heightened because new variant CJD affected people in the right age bracket for giving blood. The classical form of sporadic CJD generally affected the elderly, who would not normally qualify as donors.

Dr Dealler said: "This is information that's been available for 18 months, but the trouble is the Government has been taking advice from the national blood service, who know absolutely nothing about CJD. "Infectivity in mixed plasma might be quite low, but for blood transfusions it could be relatively high. When you work out the figures it is quite unacceptable."

A spokeswoman for the National Blood Authority, which runs the blood service, said the Government had promised to pay for the first year of the leucodepletion programme from central funds. Thereafter, hospital trusts would probably have to pay more for blood - currently costing between 35 and 40 per unit. This would have to come out of the NHS budget.

Dr Lorna Williamson, a lecturer and consultant in transfusion medicine who chairs the UK Standing Advisory Committee on Blood Components, said the leucodepletion filters would remove 99.9% of the white cells.

She said: "I think the people who have done the risk assessment have done a very good job. "The take home message is that people are not transfused unless they are in need of it. For an individual, the benefits of a transfusion which might allow them to have a life-saving operation far outweigh any tiny residual risk from any infective agent, whether CJD or anything else."

It has been suggested that autologous blood transfusions - whereby a patient donates his or her own blood before an operation and is then given it back again - might be another solution.

But the blood authority said this was both expensive and impractical. The spokeswoman said: "The basic problem is that most people who receive blood during operations are not well enough to donate blood in advance. This applies to routine surgery as well as accident and emergency. It could only be of use to about 5% of patients." Autologous transfusions are available on the NHS if patients request it, but only at the discretion of the doctor in charge.

Claire Rayner, who chairs the Patients' Association, called for greater use of autologous blood transfusions. She said that in the US it was now common practice for people preparing for elective surgery to receive their own blood through ABT.

"Wider use of autologous transfusions would resolve a lot of the problems," she said. "But under the present situation that is not permitted in the NHS. "One of the things about blood is that it is a tremendous source of paranoia. There has always been unease about it and it is easy to frighten people. "However, it is life-saving and many people would not be alive today without it. You have to measure the risks against the benefits and I personally took it."

Dr Dealler said a third possible solution lay in a class of drugs which were able to halt infection by CJD-type diseases. Experiments on these drugs were carried out in the 1980s but never properly concluded. However one drug, pentosan polysulphate, was currently available in the US for treating an obscure bladder disease. It had no serious side effects, and was cheap.

Responses collected by CJD Voice on early symptoms of CJD

20 July 1998 CJD Voice

What initial diagnosis did CJD victims get from their doctors?

20 July 98
Data compiled from 99 cases by CJD Voice
       
       Acquired epilepsy = 1 
       Athritis in cerebral zone = 1 
       Alzheimer's = 5 
       Ataxia(OPCA) = 1 
       Benign essential tumor = 1 
       CJD = 8 
       CNS vasculitis = 1 
       Conversion reaction disorder = 2 
       Degenerative brain disorder = 1 
       Dementia = 10 
       Depression = 13 
       Focal seizures = 1 
       Guillain Barre = 1 
       Hardening of arteries to brain = 1 
       Heart problem, CNS = 1 
       Herpes simplex encephalitis = 1 
       Influenza = 1 
       Inner Ear infection = 2 
       Multiple Sclerosis = 3 
       Nervous breakdown = 1 
       NONE (doctors didn't know) = 6 
       Neurodegenerative disorder = 1 
       Parkinson's = 5 
       Prion Disease = 1 
       Seizures = 1 
       Sensory neuropathy = 1 
       Stress = 4 
       Stroke = 18 
              TIA and low blood sugar = 1 

EU Scientific Steering Committee on phosmet


 

Opinion on possible links between BSE and Organophosphates used as pesticides against ecto- and endoparasites in cattle

Report and opinion adopted at the Scientific  Steering Committee meeting of 25-26 June 1998
Members of the Scientific Steering Commitee: Prof. Michael J.Gibney (Head of the Unit of Nutrition and Dietetics, Department of Clinical Medicine, Trinity College Medical School, Dublin, Ireland), Prof. W. Philip James (Director of the Rowett Research Institute, Aberdeen, United Kingdom), Prof. Werner Klein (Direktor of the Fraunhofer Institute for Umweltchemie und Okotoxikologie, Schmallenberg, Germany), Prof. Robert Kroes (Directeur van het Onderzoeksinstituut voor Toxicologie (RITOX), Universiteit Utrecht, Nederland), Prof. Gerard Pascal (Directeur du Centre National d"Etudes et de Recommandations sur la Nutrition et l"Alimentation (C.N.E.R.N.A.), France), Prof.Vittorio Silano (Direttore Generale del Servizio Farmaceutico, Ministerio della Sanita, Roma, Italia), Prof. Marcel Vanbelle: Professeur a l"Universite Catholique de Louvain, Belgique) and Prof. Per Jonas F.M. Wierup (Head of the Swedish Animal Health Service, Stockholm, Sverige)

In January 1998, the Scientific Steering Committee (SSC) was requested to evaluate and possibly amend the MDSC's opinion of 16 May 1997 in the light of possible additional evidence and scientific literature that meanwhile may have become available. More precisely, it was invited to provide its opinion on the hypothesis that there is a link between the use of some organophosphates, especially Phosmet, and the initiation of BSE by the formation of delayed neuro-excitatoric proteins as a consequence of the phosphorylation of the PrP in the foetuses of the treated cows to the toxic PrPSc protein.

The Committee carefully analysed the available evidence [but see below]. It confirmed the opinion of the MDSC that there is no evidence for such link to exist.

I. Framework and mandate

In its opinion on Organophosphates and TSE's of 16 May 1997, the Multidisciplinary Scientific Committee (MDSC) concluded that no relation existed between the use of and exposure to organophosphates and the occurrence of BSE.

The hypothesis of a link between the use of and exposure to organophosphates and the occurrence of BSE was forwarded in two papers by Purdey (1996) (22; 23) on "The UK-epidemic of BSE: Slow Virus or Chronic-Pesticide-Initiated Modification of the Prion-Protein? Part 1: Mechanism for a Chemically-Induced Pathogenesis / Transmissibility. Part 2: An Epidemiological Perspective".

In January 1998, the Scientific Steering Committee (SSC) was requested to evaluate and possibly amend the MDSC's opinion of 16 May 1997 in the light of possible additional evidence and scientific literature that meanwhile may have become available. More precisely, it was invited to provide its opinion on the hypothesis that there is a link between the use of some organophosphates, especially Phosmet, and the initiation of BSE by the formation of delayed neuro-excitatoric proteins as a consequence of the phosphorylation of the PrP in the foetuses of the treated cows to the toxic PrPSc protein.

The key primary question upon interpretation of the mandate is whether there are indications that organophosphates (e.g. Phosmet) bind to brain prions similarly as they do to the acetylcholinesterase (AchE), following by aging which results in a denaturation of the proteins. These denaturated phosphorylated prions would then possibly and hypothetically be precursors of BSE.

II. Scientific background information on organo-phosphorous compounds

II.1. Uses of Organophosphates and Sources of Consumer Exposure

Commercial compounds usually summarized under organophosphates comprise esters, amides or thiol derivatives of phosphoric, phosphonic, thiophophoric and thiophosphonic acids. About one hundred active ingredients are or have been used in several hundred products against arthropode pests. In addition, highly toxic substances out of the group have been developed as chemical warfare agents (Tabun, Soman, Sarin, VX). (1).

The major use of organophosphates is as agricultural insecticides covering the whole range of crop growing and storage. Most commonly known ingredients are e.g. Azinphos-methyl, DDVP, Dimethoate, Fenitrothion, Malathion, Metasystox, Parathion. The insects to be controlled include the whole range of arthropode pests. Organophosphates and carbamates represent the second generation of agricultural insecticides after DDT and Drin-insecticides. Due to the high mammalian toxicity of the organophosphates and resistance development in certain pests to be controlled, they are to some extent followed by the third generation, the pyrethroids.

A further important area of use is in animal husbandry against arthopode exo-and endoparasites. Here only active ingredients at the lower end of the mammalian toxicity can be used (e.g. Bromphenphos, Dichlorvos (DDVP), Chlorvinphos, Fenthion, Phosmet (Fosdan, Imidian, Prolate, is one of the several organophosphates used on cattle against grub, horn fly or others. Their use on cattle is world-wide. Other minor uses of organophosphates, e.g. additives, are of no relevance.

Most organophosphates are of low persistence. Nevertheless, there are residues on crops or stored food as well as in meat and in meat products. These residues require that acceptable daily intakes for the active ingredient and maximum residue limits for food commodities have been set assuring consumer safety. Although lipophylic (water solubilities typically in the range of 25-100 mg/l) organophosphates are not considered to bioaccumulate due to fast range metabolism/low persistence. The bioaccumulation factor of Phosmet e.g. in fish is about 50. Only triesters of phosphoric acid are considered in the present report.

II.2. Toxicodynamics and Toxicokinetics

Both the toxicodynamics (mechanism of action) and toxicokinetics (distribution, metabolism, etc.) of OP's are largely explained by their biochemical characteristic of interacting with esterases and proteases (2). Esterases have been ranked into two main categories: those inhibited by Op's, B-esterases, representing potential targets for toxicity, and A-esterases which hydrolyze OP's, thereby being involved in detoxification. OP's interact with either esterase as substrates: B-esterases after the formation of a Michaelis complex are phophorylated and the reactivation is either very slow or it does not occur at all. A-esterases, on the contrary, hydrolyze OP's and their catalytic center is rapidly restored.

Moreover, a further reaction might occur on phosphorylated B-esterases, a phenomenon called aging, involving the loss of a group attached to phosphorus and leading to the formation of a negatively charged irreversibly phosphorylated enzyme. On a given enzyme, rates of reactions depend on the chemistry as well as on chirality of the inhibitor.

Any given B-esterase is inhibited by various OP's at different rates. Also rates of reactivation and aging of phosphorylated enzymes are variable, depending on the phosphoryl residue which occupies the catalytic center. Therefore, the degree of inhibition of an esterase and its duration at the site depend both on the enzyme itself and on the chemistry of the OP. For instance, while OP's inhibit acetylcholinesterase (AChE) at variable concentrations, both spontaneous reactivation and aging depend on the phosphoryl residue bound to the active site. As a result of AChE phosphorylation by different OP's, this residue can be the same.

II.3. Toxic Mechanisms

II.3.a. Cholinergic Overstimulation

The molecular mechanism of cholinergic toxicity involves the interaction of OP's with AChE (3), an elongated molecular structure formed by heterologous subunits, is localized in the outer basal lamina of the synapse. A single gen encodes the catalytic subunits of AChE and the threedimensional structure of AChE has been determined (4). Both substrate and inhibitor react covalently with the enzyme in essentially the same manner because acetylation of the resine residue in the active center of AChE is analogous to phosphorylation. However, in contrast with the acetylated enzyme, which rapidly gives acetic acid and restores the catalytic center, the phosphorylated enzyme is stable.

Calculated turnover rates, i.e. the number of molecules hydrolyzed per minute by one molecule are as follows: 300.000 for acetylcholine and 0.008 for OP's. Spontaneous reactivation of enzyme may require several hours (dimethoxy) or does not occur at all (secondary, such as DFP, or tertiary alkyl groups). The loss of one alkyl group, occurring through the non-enzymatic process of aging, further enhances the stability of the phosphorylated enzyme.

AChE's crystal structure reveals that the anionic moiety of AChE's, thought to attract the quaternary nitrogen of the substrate, is misnamed because it contains at most one negative charge. It has been proposed instead that the quaternary moiety of acetylcholine binds chiefly through interactions with the aromatic residues which line the walls and floor of the gorge.

When blocked by the phosphoryl residue, the serine group of the catalytic center is no longer able to participate in the hydrolysis of acetylcholine. Thus the neurotransmitter accumulates, its action is enhanced and given the widespread distribution of cholinergic neurotransmission, toxic effects of OP's will involve parasympathetic, sympathetic and somatic motor component of the PNS and also the CNS (5).

Signs and symptoms include lacrimation, hypersalivation, bronchial hypersecretion and bronchoconstriction, urination and defecation, skeletal muscle fasciculation and twitching, ataxia, respiratory failure, convulsions, hypothermia and death. Death is due to respiratory failure resulting from the combination of these effects.

The interaction of acetylcholine with either muscarinic or nicotinic receptors leads to various biochemical effects on second messenger systems (6) and eventually to the toxic response. Single doses of OP's do not affect brain muscarinic receptors (7) whereas repeated exposures may reduce both their density and affinity for specific ligands(8). Reduction in muscarinic receptors shows regional specificity (9), reflecting either differences in duration or intensity of cholinergic stimulation, or a selective access of the inhibitor.

Reductions of high-affinity brain nicotine-binding sites have also been found after chronic cholinergic stimulation (10). Symptoms of excessive cholinergic stimulation are gradually reduced during chronic OP exposure, despite significant inhibition of AChE, the development of this tolerance has been in part associated with down-regulation of muscarinic receptors caused by prolonged AChE inhibition and acetylcholine stimulation (11).

II.3.b. Delayed Polyneuropathy

Single doses of certain OP's cause a central-peripheral distal sensory-motor axonopathy known as organophosphate-induced delayed polyneuropathy (OPIDP) (12,13,14,15,16).

The molecular target is thought to be a protein in the nervous system called Neuropathy Target Esterase (NTE). High inhibition of NTE (> 70%) in the nervous system, measured within hours after dosing, correlates with the delayed onset of clinical signs of OPIDP 10-20 days later. OPIDP is caused by certain, but not all OP's, providing they inhibit NTE above the threshold. Doses causing OPIDP depend on the OP, the route of administration, the species and other factors.

However from the practical point of view, it is important how the dose causing OPIDP compares with that causing cholinergic toxicity (17). This concept, represented numerically by the ratio LD50/neurotoxic dose, allows comparisons of the potential of OP's to cause OPIDP. Thus a ratio LD50/neurotoxic > 1 discriminates OP's causing OPIDP at doses which do not cause cholinergic toxicity from those which cause OPIDP only if animals are treated against cholinergic symptoms (ratio < 1). All commercial OP insecticides have a ration of < 1 and most have a ratio < 0.1. Therefore among NTE inhibitors, cholinergic toxicity is the limiting factor for OPIDP development.

Histopathology of OPIDP has been described for several species (18, 19). The morphological hallmark is axonal degeneration of motor and sensory fibers characterized by focal nerve varicosities and paranodal demyelination located in the distal but not terminal axons. There is no evidence of death of corresponding neurons, but varying degrees of chromatolysis occur in proportion to the severity of neuropathy. Ultrastructural studies show aggregation and accumulation of neurofiliments and neurotubules as well as proliferation of smooth endoplasmic reticulum, particularly in proximity to nodes of Ranvier. Lesions are distributed both in the CNS (spinal cord) and PNS (peripheral nerves of legs mostly. The degree of pyramidal involvement predicts the pathogenesis of OPIDP. If only peripheral nerves are involved the neuropathy is reversible within several months whereas if CNS is involved, spasticity is permanent.

II.4. Phosmet Identity and Use

Phosmet is a non-systemic OP insecticide used on both animals and plants. It can be used in the treatment of warble-fly in cattle and also as an active ingredient in some dog collars.

II.4.b. Chemical Structure

The structure of Phosmet is given in the following Figure. Its IUPAC name is O-O-dimethyl-S-phthalimidomethyl- phosphorodithioate.

II.4.c. Metabolism and Fate (20):

In humans and animals:

- Phosmet shows a very rapid kinetism with a very quick absorption, distribution and elimination. Radiolabeled Phosmet was excreted predominantly in the urine: by the time of sacrifice (120 hours after treatment) 79% had been excreted in the urine and 19% in the faeces, while very little was expired as 14CO2. Tissue levels of radiolabel were low, especially in fat and the gonads. In an other labeled study in rats very little label (1-2%) was detected in the carcass 96 hours after treatment. The lowest concentrations of label were found in bone and fat and the highest in the skin. There were no data mentioned for brain levels.

- It crosses the placenta - a single dose of 70mg/kg in goats showed no more residues in the milk after 24 hrs.

- Cattle fed silage with an average residue level of 19 ppm for 2 months showed no residue levels in the milk above the detection limit of 0.01 ppm - dietary levels of 20-100 ppm showed no residues in the tissues higher than 5 ppb.

- Metabolic breakdown in very quick. A proposed metabolic pathway is given in the following figure. Phtalamic acid and phtalic acid and their esters are the most important metabolites. Phtalamic acid would have been deaminated to phtalamic anhydride and hydrolysed to phtalic acid.

Environmental Fate:

- Phosmet is rapidly broken down in soil. The compound persists longer in dry soil than in moist soil. Breakdown is also faster under basic conditions.

- In water it is rapidly broken down by hydrolysis and by sunlight (photolysis). Under alkaline conditions (pH 9) the half-life is as short as 16 hours - in a neutral solution (pH 7) the half-life is 18 hours and under acidic conditions (pH 5) the half-life is within 9 days.

- Plants break down phosmet quickly, primarily by oxidation and hydrolysis. Washing and blanching can reduce residue levels by 50 to 80%.

II.4.d. Effects on Enzymes (20)

Erythrocyte and brain cholinesterases are more sensitive to Phosmet in rats than is plasma cholinesterase. Rat aliesterases are more sensitive to inhibition by Phosmet than is acetylcholinesterase.

A dose of 10 mg/kg orally administered has no effect on plasma or erythrocyte cholinesterase activities at either time or on brain cholinesterase activity at 24h. However 4 hours after treatment with this dose, brain cholinesterase activity was inhibited by 14% in males and 21% in females.

II.4.e. Toxicological Effects (20) - Acute Toxicity:

Moderately toxic by ingestion - moderately to highly toxic through the skin - very high toxic through inhalation. Oral LD50 in rats is 113 - 369 mg/kg bw - in mice 23-50 mg/kg bw.

The compound appears to be more toxic to many domestic animals (cattle, sheep and goats): LD50 from 25-50 mg/kg bw., than for experimental animals.

- Chronic Toxicity: In rats: NOAEL of 1-2 mg/kg/day In dogs: NOAEL of 1 mg/kg/day Cattle: 1-2 mg/kg for 8 weeks provoked a decrease of blood enzyme activity. In rabbits: during 3 weeks applied to their skins showed high mortality at doses of 300-600 mg/kg/day. - Delayed Neurotoxicity was not observed in chickens, the most sensitive animal species known. - Reproductive Effects: In rats: 2.0 mg/kg bw for the first generation -4.0 mg/kg for the second and third generations did not provoke negative reproductive effects.

In rabbits: 10-60 mg/kg dermally and orally 3 weeks before mating and on 18 consecutive days of gestation showed no effects on reproduction parameters.

Conclusion: Phosmet did not shown negative effects on reproduction. - Teratogenic Effects: In rabbits: 10-60 mg/kg for 3 weeks gave no birth defects. A NOAEL was estimated to be 35 mg/kg In monkeys: 8-12/kg for days 22-32 of gestation gave no birth defects. In rats: 30 mg/kg between day 9 and 13 of gestation produced an increase in brain damage (hydrocephaly) in 33 out the 55 embryos examined. With lower doses (1-5 mg/kg) such effect was not seen.

Conclusion: No convincing evidence for teratogenic effects has been found in rabbits or monkeys, whereas in rats only, at high doses of 30 mg, some effect was seen, probably due to maternal toxicity.

- Mutagenic Effects

In bacteria: no any mutation test was positive except in two tests with one strain of Salmonella Typhimurium (reverse mutation).

In animal cells: two mouse lymphoma tests were performed with a positive result, one (forward mutation at the tk locus) in the absence of metabolic activation and one (sister chromatid) in the absence of metabolic activation (< 0.1 mg/ml) and one in the presence of metabolic activation (0.008-0.040 mg/ml).

Conclusion: its mutagenic potential is rather unclear but certainly not proven.

- Carcinogenic Effects:

In rats: 1-20 mg/kg/day for 2 years showed no differences but there were too few rats at the end of the test. In another study no tumours were seen that were attributable to treatment with Phosmet.

In mice: no treatment -related changes in organ-weights or macroscopic or microscopic appearance were seen, except in the liver. There was an increase in the incidence of liver adenomas (25/50) in males at a dose of 100 ppm. Liver adenomas were found in 13/60 controls, 10/60 at 5 ppm., 14/60 at 25 ppm and 27/60 at 100 ppm. The prevalence of liver adenomas in the group given the highest dose was reported to be comparable to that in historical controls. No increase in the incidence of liver tumours was seen in females.

III.1. Paper 1. The mechanism for the pathogenesis / transmissibility

The author proposes a hypothesis in which it is said that exposure of the bovine embryo to specific high-dose lipophylic formulations of organophosphate insecticides was the primary trigger that initiated the UK's Bovine Spongiform Encephalopathy epidemy. The mechanism should be a covalent binding with phosphorylating and aging serine, tyrosine or histidine active sites on fetal CNS prion protein. Once this abnormal prion protein isoform agent is initiated, any stress event ensuing in adult life induces a nerve-growth-factor-mediated synthesis of normal cellular prion protein isoform that aggregates to abnormally phosphorylated isoform. The abnormally phosphorylated isoform PrPSc is left corrupted by an extra charged phosphate group. In so far the summary of the hypothesis.

Comments from the SSC:

Purdey (1996a, 1996b) combines a series of hypotheses with proven and unproven biochemical and biophysical features. Some criticisms are formulated hereafter:

- Phosmet is very quickly metabolized and eliminated with no significant tissue accumulation except in fish. Moreover it has been proven that Phosmet residues have no delayed neurotoxicity in chickens, the most sensitive animal species. Such a proof is not demonstrated in the paper.

- No mention is made of any reference or study which proves the presence of a receptor site on the surface (membrane) of the prion protein. It is not enough to speculate on the presence of a serine molecule in order to propose also a covalent binding of OP's on a prion protein. The whole hypothesis is speculative.

- According to the paper, the hypothesis for the trigger effect on brain prion proteins by Phosmet is supported by its structure-relationship with Thalidomide, a very well known teratogen.

- Thalidomide:

This product is very intensively hydrolysed in vivo to form secundary, tertiary and quaternary hydrolysis products. These hydrolysis products however do not appear to possess significant teratogenic activity.

There is also a very different sensitivity to Thalidomide between the different animal species. So the teratogenic effects of Thalidomide are not still proven in cattle.

An intact Phtalimide or Phtalimidine group appears to be essential for teratogenic activity. Thalidomide teratogenicity was dominantly restricted to skeletal malformations mostly of the limbs.

- Phosmet

It seems indeed that Phosmet contains a phtalimide moiety. Hence the conclusion that Phosmet may have identical toxicological properties as Thalidomide and that this gives an explanation for the so-said CNS protein toxicity.

However extensive structure-activity studies have been carried out with over 60 compounds stereochemically related to Thalidomide (under which Phosmet (21). Only Thalidomide itself and three other analogs (See figure) are clearly teratogenic in rabbit, the most sensitive experimental animal.

- Finally before the whole proposed hypothesis can scientifically be accepted as real and the link between the use of OP's and BSE can scientifically be accepted in the pathogenesis of TSE's, the possible affinity and convalent binding of OP's for PrP protein should be shown. Therefore real studies are lacking in his paper.

Conclusion: DFP (di-iso-propyl fluorophosphate) is an OP which causes both cholinergic toxicity and delayed polyneuropathy), approximately at the same dose. It has been used as a model OP to ascertain if these chemicals, including phosmet, might bind to prion proteins. Since no binding was detected it is unlikely that OP's would be capable of modifying this protein, either directly or with a mechnism other than phosphorylation.

III.2. Paper 2: An epidemiological perspective

This paper tries to elucidate the flaws in the hypothesis that BSE originated from alterations in the way that scrapie-contaminated cattlefeeds were manufactured in the UK. The whole epidemiological evolution of BSE is explained in the frame of the hypothesis already described in the first paper.

His conclusion is that both timing, distribution and dynamics of usage of these specific OP's (a.o. Phosmet) correlates with the epidemiology of BSE.

Comments from the SSC:

The first paper provides a scenario in which the use of Phosmet as treatment for warbles and the epidemiology of BSE are put in relation with each other. But data and numbers are lacking and the scenario is rather speculative and anecdotal. The exact number of farms where Phosmet was indeed applied in cattle and the exact number of really diagnozed BSE cases in the same farms are not provided.

Conclusion:

The SSC concludes that the paper is not a true epidemiological study as it is not scientifically founded.

IV. Opinion

On the basis of the elements and evaluations presented in the above report, the Scientific Steering Committee confirms the opinion of 16 May 1997 of the Multidisciplinary Scientific Committee and concludes that there is at present no scientific evidence of possible links between BSE and organophosphates used as pesticides against ecto- and endoparasites in cattle.
VI. Literature

1. Ecobichon D.J., 1991. Toxic Effects of Pesticides. In: Toxicology,
the Basic Science of Poisons, 5th ed. Casaretti L. Doulls J. Mc
Graw-Hill ed. New York p. 643-665

2. Aldridge W.N. and Reiner E., 1972. Enzyme Inhibitors as Substrates.
North-Holland Publ. Co. Amsterdam-London.

3. Taylor P. 1990. Anticholinesterase Agents. In Goodman and Gillmans.
The Pharmacoiogical Basis of Therapeutics. 8th Ed. Goodman Gilman A.,
Rall T.W., Nies A.S. Taylor P.eds. Pergamon Press NY p. 131-149.

4. Sussman J.L. Harel M. Frolow F. et al., 1991. Atomic Structure of
Acetycholinesterase from Torpede California: a prototypic
Acetylcholine- binding Protein .Science, 253, 872-879.

5. Lotti M., 1995. Cholinesterase Inhibition: Complexities in
Interpretation Clinical Chemistry, 69, 705-711.

6. Costa L.G., 1992. Role of Second-Messenger Systems in Response to
Organophosphorus Compounds. In: Organophosphates, Chemistry, Fate and
Effects. Chambers J.E., Levi P.E. eds.
Academic Press, San Diego p. 271-284.

7. Sivam S.P. Norris J.C., Kim D.K. et al., 1993. Effect of Acute and
Chronic Cholinesterase Inhibition with Diisopropyfluorophosphate on
Muscarinic, Dopamine and GABA Receptors of the Rat
Striatum. J. Neurochem, 40, 1414-1422.

8. Ehlert F.I., Kokka N., Fairhurst A.S., 1980. Altered (H)
quinuclidinyl benzilate binding in the Striatum of Rats following
chronic Cholinesterase Inhibition by Diisopropylfluorophosphate. Mol
Pharmacol. 17, 24-30.

9. Churchill L., Pazdemik T.L., Jackson I.L. et al., Topographical
Distribution of Decrements and Recovery in Muscarinic Receptors from
Rat Brains repeatedly exposed to sublethal Doses of Soman. J.
Neurosci., 4., 2069-2079.

10. Costa L.G. Murphy S.D., 1993. (H) Nicotinic binding in Rat Brain:
Alteration after chronic Acetylcholinesterase Inhibition. J.
Pharmacol. Exp. Ther. 226, 392-397.

11. Russel R.W., Overstreet D.H., 1987. Mechanisms underlying
Sensitivity to Organophosphorus -abticholinesterase Compounds. Prog.
Neurobiol. 28, 97-129.

12. Abou-Donia M.B. and Lapadula D.M., 1990. Mechanism of
Organophosphorus ester-induced Delayed Neurotoxicity: Type I and Type
II. Ann. Rev. Pharmacol. Toxicol. 30, 405-440.

13. Johnson M.K., 1982. The Target for Initiation of Delayed
Neurotoxicity by Organophosphorus esters: Biochemical Studies and
Toxicilogical Applications. In: Reviews in Biochemical Toxicology.
Hodgson E., Bend J.R. and Philpot R.M. eds. Vol. 4 p. 141-212,
Elsevier New York.

14. Lotti M., 1992. The Pathogenesis of Organophosphate Delayed
Polyneuropathy. Crit. Rev. Toxicol. 21, 465-487.

15. Lotti M. Becker C.E., Aminoff M.J., 1984. Organophosphate
Polyneuropathy Pathogenesis and Prevention. Neurology, 34, 658-662.

16. Lotti M., Moretto A, Capodicasa E., Bertolazzi M, Peraica M.,
Scapellato M.R., 1993. Interactions between neuropathy Target Esterase
and its Inhibitors and the Development of Polyneuropathy. Toxicology
and Applied Pharmacology, 122, 165-171.

17. Lotti M, Johnson M.K., 1978. Neurotoxicity of Organophosphorus
Pesticides: Predictions can be based on in vitro studies with hen and
human enzymes. Arch. Toxicol .41, 215-221.

18. Bouldin T.W. and Cavanagh J.B., 1979. Organophosphorous Neuropathy
II. A fine-structural Study of the early Stages of axonal Degeration.
Am. J. Path.94, 253-270.

19. Bouldin T.W. and Cavanagh J.B., 1979. Organophosphorous Neuropathy
I. A teased-fiber Study of the spatoio-temporal Spread of axonol
Degeneration. Am. J. Path.94, 241-252.20.

20. Marss, T.C., 1994. Phosmet. In: Pesticide Residues in
Food-toxicology Evaluations. JMPR,
P.119-135.

21. Schumacher H.J., 1975. Chemical Structure and teratogenic
Properties. In: Methods for the Detection of Environmental Agents that
produce congenital Defects. Chapter 6 p.65-77. Shephard T.H..,
Miller J.R. and Marois M. eds. North-Holland Publ.Co. Amsterdam-Oxford

22. Purdey, M. 1996a. The UK-epidemic of BSE: Slow Virus or
Chronic-Pesticide-Initiated Modification of the Prion-Protein? Part 1:
Mechanism for a Chemically-Induced Pathogenesis /
Transmissibility. Medical Hypotheses 1996, Vol. 46: pp 429-443.

23. Purdey, M. 1996b. The UK-epidemic of BSE: Slow Virus or
Chronic-Pesticide-Initiated Modification of the Prion-Protein? Part 2:
An Epidemiological Perspective. Medical Hypotheses 1996,
Vol.46: pp. 442-454.

24. European Commission, 1997. Opinion of the Multidisciplinary
Scientific Committee on possibel link between the use of and exposure
to organophosphates and BSE.

25. Kemper, F., 1998. Letter of 8 January 1998 To Dr.E.Vanopdenbosch,
rapporteur of the working group on Possible links between
organophosphates and BSE.

26. King, J.W., 1996. Bovine Spongiform Encephalopathy and
Organophosphates. Published by J.W.King, Buckinhamshire (UK). 42 pages

27. Lotti, M.,1997. Letter to the secretariat of the
Multi-Disciplinary Scientific Committee on the UK epidemic of BSE.

28. Poulsen, E., 1997. Comments on the postulated relation between
effects of organophosphorous compounds and the disease in cattle, BSE.
Note for the attention of the Multi-Disciplinary Scientific Committee.

29. Poulsen, E., 1997. Letter of 3 March 1998 to the Secretariat of
the Scientific Steering Committee on Bovine Spongiform Encephalopathy,
possible links with organophosphates.

Phosmet induces up-regulation of surface levels of the cellular prion protein

Neuroreport 1998 May 11; 9(7): 1391-5).
Gordon,I.; Abdulla,E.M.; Campbell,I.C.; Whatley,S.A.

The committee seems to have overlooked the single most important article with regard to their question: The important article of Gordon et al. was published only on 11 May 1998, after the request to the SSC, but well before its meeting of 25-26 June 1998. Furthermore the article had been acepted by the journal already in February 1998 and Mark Purdey was aware of this article because the authors thank him for helpful discussions and the Mark Purdey research foundation founded this research. Finally this research has done in London, Department of Neuroscience, Institute of Psychiatry, London SE5 8AF, UK.

Mark Purdey [not consulted by committee] refers to this article in his Witness Statement dated 23 March 1998 to the BSE Inquiry. Not only did SSC not consult him, they did not look at his Witness Statement.

Purdey states there (in part)

23. My meeting with SEAC

Prior to February 1997, Lord Lucas, the MAFF spokesman in the House of Lords, gave a written answer to a question from Lord Lester in which he said that the Government had asked SEAC to re-examine my theory. He also indicated that the Government was aware of new research from the Institute of Psychiatry into the effects of Phosmet on prion protein cell cultures. The research in question consisted of experiments commissioned by myself and funded by well-wishers. I was angry that Lord Lucas had erroneously stated that the basis of the OP hypothesis had not been published in peer-reviewed journals, despite the fact that Mrs Gurnhill of MAFF in a letter dated 7 February 1995 acknowledged that one of my articles was peer-reviewed.

24. I was invited to attend the 41st meeting of SEAC, which was held on 15 April 1997 at MAFF, Tolworth. Also present were Sir Colin Berry, Professor Ian Shaw, Professor Tony Dayan, Professor Ian Aitken, Professor Quentin McKellar, Dr Chris Powell from the Veterinary Products Committee, Mr Horton of the Veterinary Medicines Directorate and Dr Tim Marrs of the Department of Health. After the discussion SEAC asked Sir Colin Berry and Professor Shaw to assess my theory on paper. On the basis of their findings, SEAC would decide whether to advise the Government to fund research into my theory. I was concerned that Sir Colin Berry and Professor Shaw were members of the Government's Advisory Committee on Pesticides. Would they be able to act impartially? I felt that their response (SEAC 44/1) was toxicologically naive and full of inaccuracies and misrepresentations of what I had actually said.

For instance, they used data solely from the manufacturers of Phosmet. On the basis of this data, they argued that Phosmet would only contaminate the fat of treated animals and would not get into the liver, kidney and muscles. On the basis of this, they argued that Phosmet would not get inside cells. They said that Phosmet would not make contact with prion protein and therefore interact with it. Thus they argued that Phosmet would be unlikely to play a role in the causation of BSE.

However, in counter evidence I presented data from peer-reviewed published articles by several teams who had carried out experiments with Phosmet. The articles demonstrated that Phosmet does penetrate liver, kidney and muscles, at twice the intensity that it penetrates the fat. Yet the SEAC conclusions took Sir Colin's and Professor Shaw's evidence from the manufacturers as gospel and completely ignored my evidence.

Along with other grievances that I had about SEAC's conclusions on the meeting, I was amazed that they never even considered the findings of the Institute of Psychiatry, which was the prime motivating factor for the SEAC hearing in Lord Lucas's statement. I was also aggrieved that SEAC said that there was no evidence that OPs were involved in causation of nv CJD, when I pointed out that no studies by the CJD Surveillance Unit had ever been carried out to investigate this possibility.

[According to a 4 Jan 96 article of Claire W. Gilbert, Mark Purdey's house was burned down and his lawyer, his veterinarian and the British prion researcher Dr. C. Bruton all died in car crashes. His new lawyer, so she wrote, also had a car crash but survived. There are similar stories from Dr. Narang who also has an alternative BSE theory. Gilbert writes,

"I asked Purdey if he thought the arrest and firing from his research position of the distinguished, US resident, Nobel Award CJD specialist, Dr. D.C. Gajdusek was also related to this mad cow situation. Purdey said that weeks before the arrest of Gajdusek Purdey was told by Ray Bradley of the Ministry of Agriculture that Gajdusek was seeking alternative hypotheses and specifically requested all of Purdey's papers. They were faxed to Gajdusek."]

European body urges safeguards on human tissue use

Reuters World Report Tue, Jul 21, 1998 By Marcel Michelson
PARIS - A European ethics group on Tuesday proposed strict rules on the uses of human tissue as a way of preventing the spread through transplants of such conditions as Creutzfeldt-Jakob disease and AIDS.

The European Commission's Group of Advisers on the ethical implications of biotechnology proposed privacy and hygenic guidelines for tissue banks, which preserve skin, bone, cornea and other human material for later medical use. It also recommended the creation of a European Union hygiene security body to check and evaluate the use of tissue.

"We found that there are regulations for the use of organs and the use of blood, but there is a void concerning the use of human tissue," Noelle Lenoir, president of the group, told a news conference. Lenoir, a member of France's constitutional court and president of UNESCO's international bioethics committee, said the group thought tissue banks should not be run for a profit.

Tissue banks should be able to check, and would be responsible for verifying, the medical history of donors -- either alive or deceased -- and would have to guarantee the privacy of donors and patients. The donor, or the family of a dead donor, must give authorisation for the use of tissue, including after-birth and umbilical cords, the blood from which could be used to treat leukaemia and other blood cancers.

The hygiene checks are vital to avoid the spread of illnesses such as the debilitating Creutzfeldt-Jacob disease, which is the human equivalent of mad cow disease, or AIDS. Lenoir stressed the need for tests for Creutzfeldt-Jakob disease and said tha,t while these could not be performed on the donor, they can be performed on tissue.

Creutzfeldt-Jakob is also at the heart of the mad cow disease scare with the risk that products of affected cows can transmit the disease to humans. Octavi Quintana Trias, a Spanish doctor who is vice-president of the group, said that more than a million patients a year received human tissue as part of their medical treatment.

Lenoir said that, if all tissue banks observed the sames rules, a Europe-wide exchange in tissue supplies could be possible. The group's recommendations will be presented to the European Commission, the EUs Council of Ministers and the European Parliament. It is up to the Commission to turn it into a directive -- a European law.

Saskatchewan elk disease waning?

July 23/98 Western Producer Ed White
According to this story, Saskatchewan's farmed elk are free to move again but mystery still surrounds the animal that caused the elk industry lockdown when it died of chronic wasting disease.

George Luterbach, the Canadian Food Inspection Agency veterinarian who oversaw the investigation, was quoted as saying, "It would have been nice to show a direct link back." said.

Saskatchewan Elk Breeders' Association president Barry Haubrich was quoted as saying, "She's like normal now." [CWD is invariably fatal -- webmaster]

Luterbach was cited as saying the most likely source of infection was the animal's mother, whom had been imported from a part of South Dakota where another sick elk had come from.

There is some evidence chronic wasting disease can be spread within a herd, but Luterbach added that officials feel confident this animal has not spread the disease.

The quarantine on the four farms that contained the infected animal and its relatives has been lifted, but Luterbach said they will be surveyed every six months to see if any animals show signs of disease.

Vache folle-L'ESB aurait contaminé le mouton

13 Juin 1998 - Le Monde Reuters
PARIS , - Des études britanniques ont établi que l'agent de la vache folle avait contaminé le mouton, rapporte samedi Le Monde.

Cette donnée confèrerait une dimension sans précédent à la crise sanitaire et politique provoquée par les maladies à prions, souligne le quotidien sur la foi du témoignage anonyme d'un expert français.

Bruxelles envisage de lever l'embargo qui interdit à la Grande-Bretagne d'exporter depuis mars 1996 ses viandes et produits d'origine bovine.

"Nos collègues viennent d'isoler une souche de prions identique à celle de l'ESB chez des moutons d'élevage que l'on tenait pour être atteints de la tremblante", déclare l'expert interrogé par Le Monde.

Toute la question serait désormais de déterminer les risques encourus par les consommateurs de viandes ovines potentiellement infectées.

"La question est, d'un point de vue sanitaire, d'autant plus importante que cet agent pathologique se dissémine beaucoup plus largement au sein des organismes ovins qu'il ne peut le faire chez le bovin", souligne cet expert.

Le quotidien précise que ces données, encore confidentielles, n'ont pas encore été publiées par la presse spécialisée.

Depuis l'émergence de la crise de la "vache folle", la possibilité que l'ESB puisse franchir la barrière d'espèce et contaminer les ovins était l'une des craintes majeures des responsables politiques européens.

Avant l'annonce en mars 1996 par le gouvernement britannique de la transmission de l'ESB à l'homme, les experts considéraient que la "tremblante du mouton" ne représentait pas de risque particulier pour l'homme.

Des travaux expérimentaux britanniques avaient démontré par la suite que le mouton pouvait, de manière expérimentale et par voie orale, être contaminé par l'ESB.

La France avait alors pris une série de mesures sanitaires préventives. En juillet 1996, la tremblante est devenue une maladie à déclaration obligatoire et la consommation des bêtes malades a été interdite.

France slaughters 127 cattle in mad cow case

Reuters North America Mon, Aug 3, 1998
PARIS, Aug 3 (Reuters) - French officials have slaughtered 127 cattle after a case of mad cow disease was found in the Manche departement in Normandy, the agriculture ministry announced on Monday.

It was the seventh mad cow case this year in France and the 38th since the disease -- offically known as bovine spongiform encephalopathy or BSE -- appeared in 1990. The ministry said the infected animal was a Prim'Holstein milk cow born in July 1989 in the area. The whole herd was destroyed at the end of last week.

Britain has been worst affected by the disease. The European Union slapped a beef export ban on Britain after the government admitted in March 1996 a possible link between BSE and its fatal human equivalent, Creutzfeldt-Jakob Disease (CJD).

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