U. S. Department of health and human services public health service food and drug administration

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Similarly, in the scrapie run, this was one of the most inactivating procedures as far as finding infectivity in meat and bone meal was concerned, but we found nothing in tallow. So, I would venture to suggest that these rather simple test tube studies are probably still relevant in drawing some conclusion about solvent extraction.

I'll finish just with letting you see the results of these studies which have just been completed. We have a starting titre here for both the mouse precise scrapie agent and mouse -- BSE agent. In all cases, there is some deduction if you look at the starting titre compared to the finishing titre after hot solvent -- in this case, heptane -- dry heat followed by wet heat. However, throughout the next three and final slides, you'll see that there are some trends.

Although it's probably not statistically significant here, the titre after exposure, even if the hot saline is actually slightly lower than after exposure to hot solvent and probably significantly so here. There are also suggestions here that the dry heat and wet heat process would combine with solvent at actually slightly less inactivating than the dry heat the processes -- now this would be compatible, in fact, with what I was hinting at earlier on. That procedures such as solvent extraction which can have a fixing effect on protein can protect the modified form of the scrapie agent from the damaging effects of heat.

I think in the next slide, you'll see that the same trend continues whether we're using hexane -- yes, heptane similar trends. Again, very little difference here. Again, that's a greater reduction than that. Again, the big pictures, the difference between here and here, certainly not very impressive. Same trends with the petroleum treatment. And again, these trends that I'm talking about here persist and the same for perchlorethylene.

So, collectively, the simple bottom line from these data is that the amount of inactivation achieved generally by a complete solvent extraction process seems to be on the order of one log. That would be insufficient to explain, per se, the role of the abandonment of solvent extraction as the big trigger for BSE. But of course, if, as seems much more likely, BSE and its origins was multi-factorial -- and we've already touched on some possible factors today -- then this may, of course, have contributed.

There have been suggestions that "oh, it's big changes in the UK rendering process that triggers BSE." Well, there have been big changes in the UK rendering industry like the introduction of the new continuous systems, but I'm reliably informed that that occurred much more commonly during the early to mid-'70s. So, that doesn't fit with being the villain of the piece which triggered the whole thing. But in terms of conspiring as an additional factor, if you add that to what I just said about solvent extraction, what we know about increasing sheep populations, et cetera, et cetera in the UK, then I think the probability that BSE -- the precipitation of the disease was multi-factorial is more likely than not.

Thank you very much.


CHAIRMAN BROWN: Thank you, David.

Now we'll hear from another representative from the United Kingdom, Dr. Raymond Bradley, who has been for a good part of his career -- perhaps all of it -- associated with the Central Veterinary Laboratory in the Ministry of Agriculture, Fisheries & Food, and has been a major player in the analysis and critique of BSE in the United Kingdom.


DR. BRADLEY: Good morning, ladies and gentlemen. It's a pleasure to be here. I would like particularly to thank the FDA for the invitation. I always enjoy coming to the United States, my second visit in the last two weeks.

Like my busy life, there's a lot to say in a short time. The title of the talk is an update on BSE, the epidemic status controls, and tissue distribution of infectivity. I will deal with the controls last because it's more logical to have the update and the tissue distribution knowledge before we deal with how we control the disease in the UK and in Europe.

I can skip quite quickly over some of my slides, and some I've already taken out because the points have already been covered. This is a simple graph of the epidemic which started windtop and came down, hopefully, to hit the bottom line. But this is an uncertainty at the present time. The point of prediction when it will hit that bottom line is somewhere in the region 2001 at the current rate.

I want to draw attention to specific points. Firstly, the total number of confirmed cases is over 170,000. The early stage at which the feed ban preventing the feeding of ruminant protein to ruminant animals was put in -- the delay, as David Taylor mentioned, of the down turn, as a result of this ban is due to the average incubation period of five years -- looked at more scientifically on the epidemic curve which represents all the confirmed cases of BSE.

It's important to look at some of the milestones. The first, histopathological confirmation in November 1986. The feed ban in July 1988, the SBO ban for animals in September 1990, but it had been previously put in to protect public health one year previously. After the announcement of the ten cases of new variant CJD, there was no mammalian meat and bone marrow fed to any species of food animal, horses or fish in the UK. Absolutely none. So, the previous use of this for other species was eliminated at that point. In order to get the export of our materials including meats and live animals agreed with the European Commission, we undertook to clean out all feed mills which had meat and bone marrow or feed containing it, to clean and sterilize them. This was done by the first of August 1996, which was the date after which any cattle born would be unexpected to be exposed to meat and bone marrow feed, or to BSE even by feed.

But BSE isn't just a UK problem. It's actually a European problem. On this map which shows no reference to sizes of the epidemic -- I'll deal with that in a moment -- we see that in Western Europe, we have cases in indigenous animals, the ones in red and in pink. In some countries we have cases in imported animals from the UK, presumptively in the incubating stage of BSE whilst they were completely still healthy and could not be identified.

The full range of countries which have reported cases of BSE is here. Those in red are those which have had cases in indigenous native born animals. Those in green, which have only had cases imported from the UK. Such cases do not present a risk providing they are identified, completely destroyed so they can enter no food and feed chain, and for practical purposes, can be discounted. That includes, actually, the Sultanate of Oman. The majority of the cases being reported, including all of those in Netherlands, Belgium and Luxembourg in the ones being reported currently, each one was born after their feed bans, their respective feed bans were in place. So, this cross contamination that David mentioned earlier is a feature in all countries.

It's just interesting to note that these feed bans down on this left side, and the dates upon which they were introduced in the different countries. For the most part, they were put in outside of Great Britain and Northern Ireland in 1990 in the countries which have had BSE. So that, it was two years later. The reason for that was that no other country developed a case until 1990. So, you can see that even the Netherlands and Denmark and so on, they had their bans in position.

The European Union didn't respond completely until 1994 when all countries in the Union had to adopt this ban.

In regard to the offals, a similar situation existed but much fewer countries adopted offals bans. Switzerland was the other important one behind the UK and I'll show you the importance of that in just one moment. Just interesting in passing in this rather old slide that in Iceland, they had a sheep offals ban from scrapie affected areas to all species in 1978. So, this was not something new to us.

If we look at the much smaller epidemics in the other countries outside of the UK, we can see, looking first of all at Switzerland, that the shape of the graph is very similar to the one I showed you first of all. It is rising and then declining in response to the feed ban, and presumptively also, in part, due to the offals ban. None of the other countries put in offals bans until much later on. In fact, quite recently in some cases. You see their epidemics, instead of declining, despite the ban has been in existence since 1990, they're actually on the rise. At this moment, we don't know whether they're close to the top or they're going to be coming down as it has in the UK.

I want now to pass on to the cattle tissues in which infectivity has been found by bioassay. I'm talking now about field cases of BSE. This is not experimental. These are actual field cases of BSE. Infectivity has been found only in the brain, the cervical spinal cord, terminal spinal cord, and the retina. I don't want you to read all the tissues here, but I want to put this slide up to impress you of the large number of other tissues from these same cattle which have been bioassayed in the same animals to show that none of these tissues listed contain infectivity. If this had been sheep with scrapie, we would have been expecting to find infectivity in spleen, in lymph nodes, possibly in peripheral nodes that in the clinical phase of disease and cerebrospinal fluid.

But in the context of tallow, I want to draw particular attention to some issues and also in regard, for tomorrow, to gelatin. Midrum fat, which is the actual fat around the mesentery which is a high quality fat, was tested and shown to contain no detectible infectivity. It would equate with one of the depots of fat mentioned in the Scientific Steering Committee's judgment that that kind of fat is okay.

I draw attention to the fact that skeletal muscle, mammary gland, blood and blood components do not show detectable infectivity. Neither do semen or embryos. In the context of gelatin, neither does skin, neither does bone -- oh, bone marrow. Here we are, bone marrow. None of those tissues have shown detectable infectivity in clinical cases of BSE.

This summarizes what David has just spoken about, that with rendering processes you can have effective processes and ineffective processes. The ineffective ones produce infected meat and bone marrow if they're spiked with BSE brain material, but the tallow derived from them or from the effective processes shows no detectable infectivity under experimental conditions. And once we're at it, it's convenient to get it out of the way for the purpose of a summary at the end that in 1994, as David mentioned to us, in regard to BSE spiked rendering material and rendering processes, continuous vacuum and one form of continuous atmospheric rendering system was banned in the European Union. Now, as a result from the scrapie study, the only system available for rendering waste in the Union is 133 degrees Centigrade, three bar for 20 minutes or equivalent.

The important part of the tissue infectivity studies relate to what happens during the incubation period of BSE. We were fortunate in having the results of the work of Dr. Bill Hadlow, internationally famous veterinary neuropathologist, who did studies in sheep scrapie in regard to natural disease in Suffolk sheep and in goats. It's from that data that we first constructed our offal bans in the UK, but that's now been overtaken by results that we have from conducted pathogenesis studies in cattle. The objective is listed here.

The design of the study was to have 30 calves dosed orally at four months of age with 100 grams of brain and there were ten undosed controls. Two points to make about this. Firstly, the dose was very large, and secondly, this was unprocessed brain material, not rendered brain material. So, the challenge was enormous. Three challenged calves and one control were killed at four monthly intervals approximately commencing at six months of age. There was some slight adjustment as the experiment went on to that interval. From each of the kills, we collected a range of tissues, some frozen for inoculation and others for other purposes.

This is the current result of this study which is still incomplete. The interval post-challenge is listed in months here. The green period, no kills were done at this time but this was the first time that we saw onset of clinical disease. Any animals that lived up to this age, every single one -- in the experiment had clinical disease. Remember that the incubation period in the natural disease is on average five years and this was two years quicker. So, I think that also tells us something about the infectivity of the brain compared with the meat and bone marrow.

Now, clinical signs, as I say, were detected from 35 months onwards. As with the other TSEs, it's not unexpected that you find infectivity in CNS tissue shortly before or around the time of clinical disease occurrence. You see this is shown -- this brain pathology, there is brain infectivity in the caudal medulla, in the spinal cord. The dorsal root ganglia, I'll come to in just a moment, and various other ganglia. Importantly, and we'd recognize this in 1994 in the study conducted by Gerald Wells and colleagues at CVL, that the distal ileum showed infectivity from six months post dosing up to 18 months post dosing and again, from 38 to 40. This gap in the middle is not yet fully explained.

What was important was this recent result of finding infectivity in the dorsal root ganglia which resulted subsequently in the British Government removing bone in meat for consumption. That meant such things as T-bone steaks and rib steaks could no longer be consumed in the UK, not even from imported meat from any country in the world. That was really for control purposes. It was not the advice of the SEAC. We provided options for the government to take, one of which was the one they adopted. But we also provided lesser options because we considered the risk was extremely small. Tomorrow -- and I'll show this slide again tomorrow -- we noted that there was infectivity found in bone marrow, but this experiment is not possible to interpret at the present time.

So, we now come to control. The principles of the control, firstly in regard to protecting animals and man from BSE, is to eliminate or reduce exposure to a level below which disease can not occur. We can not prove a zero risk. This is a very important concept.

It's convenient to consider controls in the context of animal health and also separately, in regard to public health. I'll deal with animal health first. I'm not going into any detail in some of the less important points relevant to today, but concentrating on the major control measures. In 1988, the disease was made notifiable. Suspect animals had to be restricted to farms and pregnant cattle imminently parturient had to be isolated in case there was any potential for maternal transmission. The main control, perhaps the only one, if it could have been effectively adopted from the word go, would be to have no ruminant protein in ruminant feed with certain obvious exceptions such as milk. So, this was the control which was hoped to be effective from a very short time after its introduction.

The second control was applied after we discovered that we could transmit BSE to pigs when we inoculated them intracerebrally. This would protect other species other than man, who is already protected because this ban had been in place since 1989 for human consumption purposes. As David has shown, the animals that were born after the ban, at this point, none of these cases that are over here should have actually existed should that ban have been perfect. Unfortunately, it wasn't. The first short period probably was due to feed still in the supply chain, that the others were still being exposed right up until 1994, the so-called "born off the ban animals."

This histogram is for just six months because the ban only came in July of that year and it's conveniently and happily declining, but it's still noteworthy. We've had six cases of BSE in that cattle born in 1994. That's quite a long time after the ban. I won't go into the detail, but this was attributed to the cross contamination of ruminant rations first of all by porcine and poultry rations which, up until 1990, could legitimately and legally have contained meats and bone meal potentially carrying infectivity, and subsequently by cross contamination as a result of the offals ban, itself not working 100 percent either.

The feed ban has been amended and adjusted and refined over the period of time. It started as a ruminant protein-to-ruminants ban. Then in 1994, it is a mammalian protein-to-ruminants ban which was already operative, actually, in the UK because we had mixed species raw materials. But this was applied by the European Commission to all member states. In 1996 in the UK alone, mammalian meat and bone meal was forbidden to be fed to all farmed animals, horses and fish -- a very, very severe ban. The question is, how do we police it?

I don't want to go into the detail here, but this summarizes amendments and adjustments and dates when they took place for various things. I want to draw your attention to this particular item here, the ELISA test which had been developed in one of our veterinary investigation centers to identify specie-specific materials in imported meats and so on originally to stop people selling imported kangaroo as beef and so on. We had to check it. So, this ELISA test was adopted for use to detect mammalian species protein in meat and bone meal.

Now, this is currently done. We do several thousand tests a year and all these tests are reported to the public -- if you could just show this to the audience, please? Please, just show it to the audience -- in our BSE Enforcement Bulletin which gives a description of many of the things I've already told you about and the results of those ELISA tests. Any positive tests are investigated very thoroughly and none has been reported this February to be positive in any case. Some of the positives are false positives due to particular cross reactions resulting from plant protein. So, there's a lot of research required to get this test to work well, but we're very happy with it now. It does demonstrate to the public that there is safety in cattle feed.

I mentioned this one earlier. Next slide, please.

Now, human health risks, instead of animal health risk, could potentially arise in respect from BSE from the consumption of specified risk materials, mechanically recovered meat from sheep, from gelatin, collagen, tallow, pharmaceutical, biological, medical, cosmetic products containing bovine material from medical devices in similar way, or from occupation. Clearly, we're not going to discuss many of these things today, just this little group here: tallow and meat and bone meal. So, in regard to public health, it is really quite simple. As a result of the initial committee, the Southwood Committee, advice was given that all animals, cattle, suspected to have BSE should be removed from all food and feed chains. So, they were compulsorily slaughtered. They were compensated for, and the animal was totally destroyed other than the brain which was used for diagnostic purposes. Then the residue was destroyed.

The second control, a very important one, was the specified bovine offals ban, or SBO ban. This was to protect the public from exposure to infected tissues. We did at this time produce this list from the knowledge that we had from Bill Hadlow's studies and his colleagues in scrapie. This offals were regarded as the following. The brain and the spinal cord, the tonsil, thymus, spleen and intestine from all cattle over six months of age, and the intestine was from the duodenum to the rectum. That meant that the tripe organs anterior to that and the tongue and so on were regarded as safe. This ban itself was modified in the light of new information. Firstly, we had the ban for humans in '89, then moved on to all mammals and birds in 1990. Then from 1994 to 1997, there were a number of extensions and I'll deal with those now.

It may surprise you that before BSE, there was already a significant offals ban in regard to use of them in uncooked meat products. So, none of those offals I've just listed, and a whole range of other ones, were permitted in uncooked meat products anyway under the existing law and had nothing whatever to do with BSE. The exclusion was thymus which, curiously, under our law, is regarded as meat. So, you could have it in a sausage if it was thymus and you had a ten percent meat content, it could be theoretically 100 percent thymus and regarded as meat. At that time, we had a potential concern because it is a lymphoreticular tissue.

However, in regard to calves, we did not consider there was a risk factor for calves under six months originally. But as a result of that pathogenesis study where we found infectivity in the distal ileum, in 1994, no intestine or thymus gland was allowed even from calves under six months. So, we had the SBO ban for cattle over six months in '89.

In 1995, we prevented skulls being utilized and this was because what was being done by the industry was to remove the brains. The brains would go for SBO and the residue of the skull would go for rendering and then get back into feed. But if the rendering system did not destroy infectivity, the residual brain material that could have been left in the skull, and of course the eyes which, at that time, we did not recognize as being infected -- and no studies had been done on them in scrapie -- we thought it was a good idea to take the skulls out. We were also concerned from public health issues in regard to spinal cord getting into mechanically recovered meat. Therefore, this was also removed by not allowing vertebral column from cattle to be utilized for manufacture of this commodity.

In March 1996 after the new variant was announced, no cattle over 30 months were decided by the government to be consumed. This was not the advice of the SEAC. SEAC advised that all meat from these animals over this age should be deboned, but the government chose instead to not consume anything. That became the law. There were also, on SEAC's advice, heads excluding the tongue -- unless it was contaminated, the head would be condemned as well. As a result of finding the infectivity in dorsal root ganglia which could be in such things as T-bone steaks, it was decided again by the government that no bones should be used. As I mentioned earlier, the SEAC gave the government three options and this was one of the options. But there were lesser options because we considered the calculated risk to be extraordinarily low.

The question of infectivity in the bone marrow, as I said earlier, was uninterpretable and I think had we only had that study -- but don't forget that that was only found in clinically affected animals anyway -- we probably would have held fire on this. But nevertheless, at present, we're not allowed to eat cattle over 30 months and even from those, not bone-in or meat on the bone.

In the EU, we're subject to various controls which apply to all member states. There's the feed ban I've already mentioned, the rendering changes, the specified risk materials ban which was mentioned by an earlier speaker this morning, Dr. Bailey. This one was to have been applied last July. It was postponed until January, again postponed to April, and it is now postponed for some date into the future with possible modifications. I won't go into the detail. It operates, nevertheless, in the UK and in France at the moment, and possibly in some other countries.

The most important issue which has got nothing to do with science, as you mentioned, for public confidence reasons, export of live cattle and products excluding semen and milk from the UK was established in March 1996 and that is still our current position. We now have the agreement with the Commission and the member states to reestablish exports and it looks very favorable that we can start this with Northern Ireland meat very shortly, and hopefully by the UK sometime soon afterwards.

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