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

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The specified risk materials have already been mentioned: the skull including brains and eyes, tonsils, spinal cord from cattle, sheep, goats over 12 months of age. The sheep and goats is to protect from the possible risk, total hypothetical risk of there being BSE in sheep as distinct from scrapie in sheep. But it also has an animal health protection measure in regard to meat and bone meal in other member states because if there was scrapie infectivity in brain and the meat and bone meal was getting into pig and poultry feed, there's clear evidence that there must be cross contamination of ruminant rations and theoretically, the scrapie could get back to sheep. We wouldn't want that either. So, this was to adopt a risk reduction rather than a risk elimination policy from the European Union's point of view. The spleen was taken too because that is known to be infected both in scrapie and BSE, or experimental BSE in sheep. The vertebral column of these three species was prohibited to make MRN.

The last summary slide -- and I'll take you through it if you'll just bear in mind that I picked up the wrong slide. I have altered this. This should read "affected" here, not just "infected." How we start is with cattle of all ages which are healthy, susceptible and uninfected with the TSE agent of any sort. Calves and all products present no hazard and therefore, no risk. Everything would be safe in common parlance. If we feed infected feed, cattle could become infected but remain healthy. The problem is determining which ones are infected and which ones are not, and we can not do that. From such cattle, milk and meat is regarded as safe and present a negligible risk providing there are various controls in place.

In regard to the specified bovine materials, there is a hazard, a high risk. These need to be rendered or incinerated or buried. They then present a negligible risk. If the healthy cattle develop clinical disease and become affected, then there is compulsory slaughter and incineration, thereby converting them into the green for go, negligible risk category. In this way, the problem that you start with here, hopefully, disappears.

With that, I finish. Thank you very much for your attention.



We now have up to a half-hour to query and question anything we have heard this morning from the committee.


DR. ROOS: I had a question for Dr. Bradley.

CHAIRMAN BROWN: Oh, incidentally, let me reiterate that David Taylor and Ray Bradley position themselves behind microphones around the Committee table.

Yes, Ray?

DR. ROOS: Yes, I wasn't quite sure how tallow fit into the ban with respect to animal feed.

DR. BRADLEY: There is no ban on the use of tallow.


Other questions? Yes?

DR. FRANCO: Ray, I wonder whether or not you would consider -- and I know how cumbersome it is -- using some comparative analogies based on ILSAs that are less than 100 grams?

DR. BRADLEY: Right. We have done some attack rate studies in cattle. In this study, we had 40 cattle, ten in each of four groups. One group was challenged orally with three times 100 grams. That's 100 grams on three occasions. One group with a 100 grams, the third group with ten grams, and the last group with one gram. I can tell you that although this study is incomplete, that all four challenged groups have succumbed to BSE.

The important message from this study, remembering that it was brain material that was used rather than meat and bone meal, that assuming the rendering procedure produced -- or the drawing procedure produced no reduction in titre, the actual amount, the physical volume to look at, of the amount of tissue necessary to produce BSE in about three years, or three to four years after all dosage of, let's say, about .1 of a gram of the dried brain material -- well, it is .1 of a gram. In other words, if you reckon that brain when you dry it weighs about -- nine-tenths of it is gone and reduced to .1 of a gram of dried product, this very small amount is not something that anybody could control under farming conditions. When you would be talking about we need 2.5 kilograms to infect a cow, then this would be readily possible to control. But such a small amount which is presumed from the study showing that one gram will produce BSE three to four years later, it's quite a remarkable piece of information. Of course, we don't know the dose of meat and bone meal that will do that, only raw brain material.

CHAIRMAN BROWN: Yes, Leon, go ahead.

MR. FAITEK: In one of Dr. Taylor's slides, you showed various temperatures and various titres, and the numbers were something like 109 and 108. Were the titres remaining after subjecting the sample to those temperatures? Those weren't reductions in titre, were they?

DR. TAYLOR: These were the starting titres. We customarily, in the types of processes, describe -- lose five, six, maybe even seven logs to infectivity. We would lose in these scrapie base studies about five or six logs of infectivity by the autoclaving procedures described.

One thing to say is that the titres quoted, which at its highest 109.something may seem extraordinarily high in view of the titres of BSE infectivity we talk about when measured in mice, which can be up to maximum, say, 104.5. But of course, what studies have shown at the Central Veterinary Laboratory is that the differential between the cattle and a mouse biopsy is about 1000-fold. So, when we talk about 4.5 logs of BSE infectivity measured in mice, that's probably 7.5 to 8 logs if measured in cattle. And the scrapie data I was talking about were from hamster-to-hamster with no species barrier.

MR. FAITEK: And you say that reduction was about four to five logs from those levels after subjecting them to those temperatures?

DR. TAYLOR: Yes, about five-plus logs would be the customary experience in these types of autoclaving experiments, yes.

CHAIRMAN BROWN: I think this would be a good point for me to interject one point that I have always considered important and that is the mental set that we adopt for discussing results that indicate reduction of infectivity. That is to say, demonstrating that you start with a certain level of infectivity and then you detect a certain lower level of infectivity. That is to say detectable infectivity. That mental set and that experimental design as opposed to being able to conclude that there is no infectivity.

I use as an illustration of this, David's paper on the BSE rendering. If my arithmetic is correct -- and David, you'll have to keep me honest in this -- I see that you, in various of the rendering processes, rendered a total of 250 kilograms of material. That is a process that was tested was 250 kilograms of material. The total amount of that material that was assayed in any given batch was somewhere between one and two grams. So that, if you found infectivity, that is a very satisfactory result in terms of having something precise. If you did not find infectivity, which was the case in at least four of the processes, the amount of the total sample that was actually assayed was one-millionth.

Well, if you assay one-millionth, it gives you a certain leeway to imagine that that "absence" of infectivity in that one-millionth leaves some room for the possibility that in the other 999,000 of the total specimen, there could turn up a few infectious units that you would not detect. This is not a critique, or I should say a criticism of these experiments which were excellent experiments, but you must not just cavalierly conclude that from these experiments you have shown the absence of infectivity in any specimen that you have sampled.

Further questions? Ray? Wait a second. Larry, you had a question before, did you?

DR. SCHONBERGER: Basically, just a point of clarification on David Taylor's point about the stopping of solvent extraction in the UK.

Did I understand you to say that solvents can fix the BSE agent to protect it from heat, but that your assessment of the overall effect of stopping solvent in the UK was to possibly increase the titres in the end product by one log, or something like that? Could you clarify that again?

DR. TAYLOR: Yes. The overall conclusion was not that the titre was actually enhanced as opposed to reduced, but that on average, we lost about one log through the whole process. But rather interestingly, there were hints and I would suggest some bits of evidence that on some parts of the process, you could show the use of heat, per se, was actually causing the degree of inactivation that you had measured rather than heat plus solvent. There was even a suggestion that the effect of solvent was sometimes sparing the agent from inactivating effects of heat. Nevertheless, overall, there was about a one log loss of infectivity for most of the processes.


DR. ROOS: Yes, just to follow up on a comment that you made about Dr. Taylor's studies and the potential limitations here. I got the feeling that a number of the transmissions involved rather long incubation periods. So, the other issue that is a somewhat unavoidable one is, if you don't get infectivity and the animal doesn't come down, does that mean that there isn't infectivity? Or does it just mean that the incubation period is in excess of the life span of these animals, since it certainly was being approached? So, this is another issue with respect to these assays.

DR. TAYLOR: The questions which you ask, we were certainly aware of when we started not only these experiments but a large number of studies relating to BSE. With the fullness of time, we have come to appreciate that there does seem to be pretty well a maximum incubation period that you can get under various circumstances on which we can usually measure. But as you rightly comment that as experiments progress further and further into time, you do suffer from increasing intercurrent losses of animals which, of course, reduces the sensitivity of your assay.

But the other point I would make is that all animals, not just those displaying clinical science -- this is mice -- even those negative at the end of an experiment are subjected to histological examination of the brain. Now, the perfect situation would be to take those that are negative and passage their brains and spleens back into new animals to absolutely prove there's nothing hanging around there. But we just have too many experiments to afford ourselves that luxury.

CHAIRMAN BROWN: And of course, you'd have to do that with 24 million mice.


DR. BRADLEY: If I may, Mr. Chairman, I'd just like to come back on the reply I gave to the question on tallow. I said that there wasn't a restriction on tallow. By that I meant that tallow coming from our currently under 30 month old animals, of which have been caused fit for human consumption, no problem, that there is no restriction. But I need to emphasize the fact that tallow prepared from specified risk materials, number one, or all the cattle that are over 30 months of age, that is forbidden to be used.

I want to give you some figures to show the extreme importance of the economics of this. To date, we've killed over two million cattle over 30 months and of their productive life, whatever that may be. This has produced something like a quarter to a third of a million tons of meat and bone meal from those which were rendered, and something of the order of 158,000 tons of tallow which is currently stored pending disposal. This can not be used for anything and it has to eventually be incinerated. We've got ideas of how to do this, but it's not actually yet been done.

So, just to clarify, tallow from the animals under 30 months, no problem except we can't export it. There is no European Union ban on tallow. It's purely on meat and bone meal.

CHAIRMAN BROWN: There are rumors that this tallow will wind up as heating fuel for Windsor Palace. Is there anything to that?

DR. BRADLEY: Correct. We have done studies to, I'd say collectively weigh -- this is not my institute, but collectively in the UK, have done studies to demonstrate the risk factor from burning this as a fuel in power stations. The risk factor is extraordinarily low, much lower than we would normally experience in anything that we do in normal life. I think it suggested -- I heard quoted that you might have to consume 2.5 kilos of the flu ash from a chimney from these in one go to get one potential lethal mouse dose, or something of that order.

So, it's safe. For practical purpose, it is safe to do this and the best way to get rid of it. Unfortunately, the power stations want an indemnity from the government to make sure that that statement is correct in actual practical terms, and there's an impasse at the minute.


DR. BURKE: A question and clarification from Dr. Bradley.

You mentioned that bone marrow and skin has not been found to be infectious from the BSE, where it is in scrapie. How were those assayed? Were they assayed back by passage into susceptible bovines, or were those assayed in a mouse assay?

DR. BRADLEY: Into mice.

DR. BURKE: So that, that may well reflect the fact that it's an insensitive assay for detecting the presence of the agent?

DR. BRADLEY: All it can tell you is that the titre that is present is at least 1,000 times lower than it is in the brain.

DR. BURKE: But in the comparison of scrapie to bovine, it doesn't really say that there's any significant tissue distribution difference between the two species?

DR. BRADLEY: Well, I would beg to differ there.

DR. BURKE: Okay, well, that's the clarification I'm after.

DR. BRADLEY: Yes, because in BSE -- and there's another experiment I need to just mention briefly. We haven't been able to find any infectivity in the spleen, not even by bioassay in cattle and equally with lymph nodes as well. I have to say that those studies are incomplete. In other words, the cattle are still alive well after the incubation period for the brain tissue from the same source and which, of course, did transmit to the cattle very quickly. I think it's now about six years.

The question is, when do you draw the line and say it's a negative study. We haven't got a dose response curve for cattle yet, even from brain tissue. So, it's difficult to come to a conclusion. But I think we've generally accepted that seven years is an acceptable, reasonable time limit if no disease has occurred in that time, particularly by an IC route. This was not an oral route.

DR. BURKE: Sure.

DR. BRADLEY: So, it's a very severe challenge. So, I think there is a difference between, first of all, sheep scrapie in cattle. There seems to be a difference which could be reflected for various reasons between the experimental pathogenesis results and the ones in the actual field epidemic. There is also a difference between BSE in cattle and BSE in sheep. If we feed even sheep, does one sheep in the world so far think I'm saying, David, that has been fed BSE after six that came down with BSE. In that animal, there was infectivity detected in the spleen. But no other tissues were examined so we don't know.

DR. BURKE: Can you say how many animals so far have been assayed, or there has been tissues assayed in the bovine bioassay?

DR. BRADLEY: How many tissues?

DR. BURKE: Yes, how many animals where you've looked at bone marrow or skin or some of the other areas that are thought not to have --

DR. BRADLEY: No. Well, those experiments are just being set up or only just started. I couldn't give you figures. But some of the important tissues which your Committee and the SEAC's would advise would be done are being done. I couldn't list them here and now, but that could be given to you.

CHAIRMAN BROWN: A more specific question, Ray, in a given assay in cattle where the bioassay of infectivity from a tissue in a cow, whether experimentally or naturally infected, is assayed in other cattle, how many cattle are inoculated for that bioassay? Let us suppose you want to find out the infectivity in the spleen. How many cattle are inoculated with spleen?

DR. BRADLEY: I think it was a relatively small number like three or five or something of that sort. I can't recall.

CHAIRMAN BROWN: But it would be at least --

DR. BRADLEY: Do you know, Will?

DR. HUESTON: It depends on the tissue, right, because the embryo work is a much larger number, that placenta work was -- I mean, there's a whole range --

CHAIRMAN BROWN: Yes, but it's apart from reproductive tissues or tissues assayed for information about reproductive tissue. It would be three, four, five animals per specimen?

DR. BRADLEY: That sort -- exactly.

DR. ROOS: And would each one of those animals be for a separate spleen? In other words, when you say there's no spleen inactivity, I mean, you're --

DR. BRADLEY: No, we pulled spleens, pulled lymph nodes, and pulled brains from five separate individual cases of field BSE, all of which were confirmed.

CHAIRMAN BROWN: Would you agree that it's a fair summary to say that in view of rather similar, overall tissue distributions of infectivity in most spongiform encephalopathies, that as yet, distinctive differences that seem to be appearing in BSE may or may not in time turn out to be distinctive differences. And that you would be very cautious writing off virtually any tissue in a BSE infected animal as risk free, at the moment?

DR. BRADLEY: I think it's a question not of yes/no, is it there, but how much. I think the how much is a very important question. I'll have to say also that when the studies were done in sheep, from sheep by Bill Hadlow and colleagues, they used mice. There's a species barrier there, too. So, actually, if you assayed those in the requisite kind of sheep of the right PRP genotype, the maximally sensitive animal, it may well be that you would find infectivity in other tissues.

CHAIRMAN BROWN: It might be. It might also be that the species barrier, so-called, between sheep scrapie and mice is considerably lower than that between BSE and mice. I don't think there's any systematic study which shows that species barriers are uniformly -- form uniform barriers.


DR. TAYLOR: Just one comment, Paul, and that's just to say that in some cases where we have clear evidence of clinical scrapie in sheep, classical symptoms, PRP staining in the brain, we do sometimes don't get most transmission.

CHAIRMAN BROWN: Yes, that's true for CJD and some labs have success, some don't. The species barriers are tricky, dicey things.

DR. BRADLEY: I think one of the other interesting features is the recent study that Randall Cutlip has reported in the USA between scrapie in sheep experimentally transmitted to cattle, and then from the cattle again to cattle. The incubation periods, and judged only upon that, were very similar as he points out in his paper between the first and second pathologies.

Now, I think I would hesitate to say that it indicates that there is no species barrier because we don't know the titres of the agent. But nevertheless, there's a possibility that there's a pretty low species barrier between those two species.

CHAIRMAN BROWN: Oh, Larry, okay.

DR. SCHONBERGER: I wanted to clarify the testing on the various rendering procedures. One of the rendering procedures you found was better than the others, is that right, because you had negative tests? This was at pressure cooking at 133, three bars, 20 minutes, is that right? But didn't we hear before that that process would denature the proteins and that you wouldn't end up with a satisfactory product?

CHAIRMAN BROWN: Yes, I inferred the same thing, that that particular procedure which, of course, the experiment was done primarily for meat and bone meal rather than for tallow, is incompatible with quality tallow. Is that correct?

DR. SCHONBERGER: Is that correct? That's what we want to find out.

CHAIRMAN BROWN: That's the implication.

DR. TAYLOR: My understanding is that the meat and bone meal is okay, but tallow subjected to that sort of process is certainly not high quality tallow. It doesn't end up as a high quality tallow.


DR. DETWILER: On that same -- you had said that the European Union had put into place that rendering process of 133, three bar, 20 minutes, but there's reports out of the Commission that not all countries have implemented. What would be the percentage that have actually gone ahead and changed their whole rendering system over to that? Do you have any idea?

DR. TAYLOR: Well, the UK has not, simply because as Ray explained, we're now banning protein feeding to all farm species. I had heard that, for instance, the French were digging their heels in. But perhaps Ray knows more about the European reaction to this, or you may not want to tell it.

DR. BRADLEY: I think in France at the time when the ban was coming forward, they did have plants that were not operating on that basis. What I think that they have done -- but I would reserve judgment. You have to clarify with the French authorities that they've used those plants that do not operate at 133, three bar, 20 minutes for processing poultry material.

DR. DETWILER: Would you say that this -- I mean, it's supposed to be throughout the whole of the Union. Has that been done, do you know? To your knowledge?

DR. BRADLEY: Well, yes, it's Commission decision --

DR. DETWILER: No, no, no, not the decision, the actual implementation.

DR. BRADLEY: Yes, it's got to be enacted in each individual country. I've found it personally very difficult to get extract from countries, even notable countries, the date upon which -- and the document which says "here is our law." I have it for France. France has been first class in this, but I haven't had it from some other countries. You could see in my list of dates down there, they just had the year but I haven't got firm, legal evidence in the form of a document saying it's an article or a law.

CHAIRMAN BROWN: Clarification back -- yes?

MR. LANGENHORST: Yes, just a little point of clarity. When I was asked a question earlier, my response was with the current cooking systems, you can't always accomplish that specific process. The batch cooking system is the only one under which you can have all three of those happen. Or you can go through a continuous cooking process and then treat the meal afterwards. There is degradation to the amino acids in the proteins also. That was just done in the US and that has been shown. So, there is degradation of both the tallow and the protein.

As far as Linda's question, "has it been implemented throughout the EU?", the answer is no, it has not.

CHAIRMAN BROWN: But I still don't understand. You're not disagreeing with the notion that 134 degrees Centigrade degrades tallow?


CHAIRMAN BROWN: It does. So, it's simply not a practical thing even to think about with respect to processing tallow?

MR. LANGENHORST: I'd leave that up to the people that buy our tallow to tell you, probably. We're not going further than that, you know, in our part of it, but the people that would use tallow could be able to answer that question much better.

CHAIRMAN BROWN: Are they here? Are the tallow users here?

MR. LANGENHORST: The people this afternoon will be speaking on that, yes.

CHAIRMAN BROWN: You might want to answer that specific question, "have you ever used", "do you know about the qualities of tallow subjected to temperatures of at least 132 degrees Centigrade?" Not just an opinion, but evidence.


MR. FAITEK: Even more than that, bearing in mind the difference between attenuation and elimination -- and we're talking about 130 or 140 degrees C here, at one of our previous presentations we were told that the infectious agent was heated to some phenomenal number like 300, over 300 degrees C and there was still infectious agents present after heating to that temperature. In view of that, how effective does the Committee feel that 130 degree heating would be providing adequate safety?

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