Dr. Lucier

336. Thank you, Mr. Chairman. I just wanted to make a few comments regarding Dr. Epstein's presentation. One regarding the presence of the oestrogen receptor in various tissues of the body. He had made the point that there were oestrogen caused tumours in numerous sites. It is also true that oestrogen receptors are found in every tissue of the body, so there is no reason to think that oestrogen action isn't occurring through a normal receptor mediated pathway. That doesn't mean genotoxic events aren't also occurring, but it's clear that classical receptor mediated events would be occurring as well. The other point relates to the increased incidences of some tumours occurring in various countries in the world. Regarding testicular cancer, I think that it's probably true that there is a real increase in testicular cancer and this increase appears to be predominant in young men which is especially disturbing. Why this is occurring, no one really knows, but as a public health person it is very disturbing. There is no reason however to think that this has to be associated with oestrogen, there are a lot of other kinds of things that could be causing that, so there is not a direct link to it, although that increase is in fact a real one. Regarding breast cancer, that is also likely increasing. However, one can't necessarily attribute that to exposure to exogenous external oestrogens. There are several studies in the literature which suggest that or demonstrate that exposure to genotoxic agents during the time that a woman is a teenager causes a dramatic increase in breast cancer. This was shown in atomic bomb survivors from Japan. Those women who survived the atomic bomb, who were teenagers at the time, had very elevated risk of breast cancer later in life, women who survived who were in their 20s or 30s had no increase in risk and there is very plausible biology for this which I won't go into. It's also been shown now in three publications that women who start smoking as teenagers have a higher increase in breast cancer later in life, whereas if they start smoking later, they do not. So there are a lot of reasons why exposure to genotoxic agents could be accounting for the rise in breast cancer rates that are seen throughout the world. So we need to be cognisant of other factors and not just blame the exogenous oestrogens for everything. Regarding the oral contraceptive issue, I think Dr. Epstein is probably right that there would be an increase in breast cancer risk for women who start taking the pill very young because that extends the period of time in which they are exposed to high levels of oestrogen and this is a known risk factor for breast cancer. The same exposures a little bit later probably wouldn't have an increase, so when you average everything out together you don't get a statistically significant increase in breast cancer from oral contraceptives. I don't think that anyone is challenging the fact that oestrogens are carcinogenic, IARC is classified conjugated oestrogens as a known human carcinogen, they have classified oral contraceptives as an ... [tape ends]

... carcinogen based on an increase of liver cancer not on the increase in breast cancer. They have also classified tamoxifen as a known human carcinogen because of its oestrogenic activity in the uterus. I don't think that anyone is disputing that fact that oestrogens do cause cancer.

Chairman

337. Thank you.

Dr. McLean

338. Just by way of explanation, I did not mean to mislead and I can see how that appeared. I was talking in the context of tumours relating to the use of hormones as growth promotants, and I just make one observation that the increase in tumours occurs in those countries where the use of growth promotant is not widespread and the increase began before the hormonal growth promotants received widespread use. But it was in the context of the hormonal growth promotants rather than an increase in cancer per se that I meant to convey, and if I misled then I apologise.

Chairman

339. Thank you. Mr. Christoforou can I come back to you. Oh Dr. Arnold, you wanted to speak as well, sorry.

Dr. Arnold

340. Just a short remark, Mr. Chairman. Dr. Liehr and Dr. Cavalieri have proposed interesting mechanisms how oestrogens could induce cancer by genotoxic mechanisms. The Panel should know that other well-known people working with other models came to different views. For example, I mentioned Dr. Schulte-Hermann who is a well-known expert in rodent liver carcinogenesis. He says for the hormones to exert their action, there must be some pre-neoplastic lesions already present in the animals, and although his evidence is also not complete, he has quite a lot of data supporting his ideas. He for example has shown that the incidence of tumours after oestrogen treatment depends on the age of the animals at the time they start the treatment. And he has developed experimental techniques to reduce the number of pre-neoplastic lesions by restricting the diet, and he could show that under these conditions the incidence of tumour formation was lower when he started with old animals he kept on the restricted diet and then administered oestrogens. So there is some evidence in other models that perhaps there is no need that oestrogens are complete carcinogens but the first step could be an unknown initiation, the formation of pre-neoplastic lesions and then in addition the hormone promotes the further development. Thank you.

Chairman

341. Thank you very much. Can we go to your next comment and question?

Mr. Christoforou (EC)

342. We have been addressing until now, the potential at least genotoxic effects of the natural hormones. But three of the hormones in dispute in this case also are synthetic. They don't occur naturally by the other animals. So we would like also to address the potential genotoxic and carcinogenic effects of the synthetic hormones. I would give the floor with your permission to Dr. Metzler who has produced a paper and who will after this short presentation conclude by framing a question to the scientists. Thank you.

Dr. Metzler (EC)

343. Thank you Mr. Chairman. Although the synthetic oestrogens or I would rather call them xenobiotic oestrogens and androgens, trenbolone and zeranol have been far less thoroughly studied in terms of their genotoxicity, they have most been subject to routine toxicological testing which is difficult to pick up the genotoxicity of hormonal carcinogens. Nevertheless, there is some evidence that these xenobiotic hormones also are genotoxic and I'd just briefly summarize the evidence. There are data from three different laboratories showing that there is DNA binding at a low but significant amount or degree with a covalent index of about 10. There is induction of chromosomal damage in mammalian cells by trenbolone and other by the non-hormonally active isomer diethyl trenbolone and there is evidence for cell transformation in vitro in different laboratories. For zeranol there is also evidence for DNA binding with a similar covalent binding index and for closely related compounds, zeralenone there is recent evidence of DNA adducts in vivo in mice in different organs. So although there are not many studies available, the few studies indicate that there is also genotoxic potential for these xenobiotic hormones and I would like to finish this brief presentation by addressing a question to Dr. Lucier. Dr. Lucier has indicated that for the natural hormones it does not make much sense or he called it irrelevant to discriminate between genotoxic and non-genotoxic compounds. How would you view this issue for the xenobiotic compounds?

Dr. Lucier

344. Before I answer, you have to answer one of mine before I answer your question Manfred. What is, at the risk of getting too technical, what is the evidence for the DNA adduct formation for zeralenone or zeranol? Is this simple binding of radioactivity to a DNA fraction or has altered nucleoside isolated and characterized?

Dr. Metzler (EC)

345. For zeralenone or the microtoxin, or the micro-oestrogen I should probably say, there has been a recent study with the post-labelling assay indicating in vivo in mice both in the kidney and in the liver a level of adducts, of various adducts as shown by the post-labelling assay at the level of about 1,000 nucleitides, modified nucleitides per 10(?) nucleitides. So it's such a spining of discrete adducts that shown for zeralenone. No such study has been done for zeranol to my knowledge, for the growth promotant.

Dr. Lucier

346. One other quick question. Is it possible that P-30 post-labelling which doesn't characterize an individual adduct, is it possible that that is just arising because a change in self-proliferation rates because when a cell divides, of course, it loses its DNA adduct, or if it doesn't divide it keeps its adducts. So a measurement of the endogenously occurring adducts could lead to an alteration in the apparent number but not be related to the zeranol itself. In other words, so that adduct hasn't been characterized it's just been seen as a spot on a TLC plate?

Dr. Metzler (EC)

347. Well these adducts have been seen as spots but there were controls on untreated animals of course and there were also species differences like in rats. None of these adducts were seen with zeralenone, they were only seen in mice. So there is a species difference which also is in favour of real adduct.

Dr. Lucier

348. Sorry Mr. Chairman for that digression, but I needed that information to answer Dr. Metzler's question. The adducts that may arise from synthetic materials are likely different and of more concern than the ones, in terms of a risk assessment, than the ones that arise from the naturally-occurring ones, because we already know that there is a given body burden of the naturally-occurring oestrogens. So whether DNA adduct formation is occurring or whether its cell replication you are just adding a very small amount to an existing burden, whether it be genotoxic or whether it be non-genotoxic so that mechanism is irrelevant as Manfred said for the naturally-occurring oestrogens. That is not necessarily true for the synthetic materials and in fact an adduct or DNA damage has been characterized and identified this may be starting out from ground zero. We have no kind of damage like that is currently in the body, so there the issue of a threshold versus linear models becomes much more important in terms of a hazard identification. So that in fact an adduct has been characterized and I would probably say at this point the data is suggestive of that. That a DNA adduct is occurring that's related to the zeranol itself or zeralenone, but not convincing because that adduct has not been identified in terms of the altered nucleoside. In other words it could be just be altering the occurrence of naturally­occurring adducts is a possibility. Although the date the Dr. Metzler has briefly presented is suggestive that such an adduct independent of the naturally-occurring adducts is in fact being formed.

Chairman

349. Thank you very much.

Mr. Christoforou (EC)

350. Mr. Chairman, I think we have reviewed the potential to toxic and carcinogenic effects of now all the substances in question. The next question is related to the response the distinguished experts gave to the question whether the JECFA report of 1987 and 1988 is taken into account this type of evidence which you have been hearing this afternoon. As you already noticed, this evidence has started appearing quite late, I would rather put it roughly, mid 1980s and it is growing very fast in this area. The scientists have replied that all these aspects of genotoxicity, synergistic effect, long-term exposure to these substances have indeed been taken into account in the JECFA report. But there were very strong differences in my views. For example Dr. Ritter would say that they have not addressed mutagenicity for all hormones, they have not addressed definitive studies for genotoxicity or carcinogenicity of combinations although this is the preferred method for use. The other scientist, Dr. Arnold for example, would say that genotoxicity and carcinogenicity have been examined and Dr. André would say that synergistic effects have not been taken into account. I would appreciate if all the scientists could summarize once again whether this synergistic effect, the long-term exposure and the potential effects or increased effect from the use of combinations have indeed been taken into account in the JECFA report. And if they have not been taken into effect what is the consequences of that? Do we have to review that report now in view of that evidence? Dr. Ritter has said there is no compelling evidence that we need to review it today. In his written reply he said the weight of evidence would not appear to suggest that there is no, that they are genotoxic and carcinogenic. So there are some variations and slight nuances in the expression. So I would appreciate if we can come back on this issue by hearing the five experts on this.

Chairman

351. Did you get the question and could you, who would like to start? Dr. Ritter.

Dr. Ritter

352. Thank you Mr. Chairman. In the written comments which I offered with regard to the xenobiotic hormones, I think that it will be evident to all that MGA for example, has not been subjected to a JECFA evaluation. As I indicated earlier on in the day, my assessments were drawn primarily, let me go further, they were drawn entirely from information which was published in the open literature and obviously dominated by JECFA reports and other ones. It is clear that MGA has not been subjected to such an evaluation and consequently, I have no information other than of a proprietary nature which I did not use, from these evaluations to offer any public opinion on MGA. In so far as the carcinogenicity testing of the combinations are concerned it will also be evident to any reader of the JECFA reports, that the assessments and conclusions offered therein are based on the single compound that were evaluated by the Committee and it was in that context that I offered those views. When I concluded that there is no compelling evidence to suggest that these compounds should be immediately re-evaluated, it was on the basis again of my understanding not only of the historical reviews which have been carried out by JECFA and other organizations, but indeed how much more recent reviews, including those published as a result of the European Conference on Growth Promotion in late 1995, early 1996, and indeed on the basis of the statements presented by our colleagues here today, Dr. Liehr, Dr. Metzler and others. I think as Dr. Liehr indicated, the work which he has carried out recently the work which others made out recently, the work which others have presented recently, suggest that there are circumstances under which adverse effects may be demonstrated in association with the multitude of these compounds. But I think the scientists in my view have quite correctly noted that their relevance to the doses at which this debate focuses is unknown, and I'm simply suggesting that that is not in my view necessarily a reason to argue that it should therefore be immediately redone. In other words, let me put it another way, if Mr. Chairman, an organization like JECFA or indeed a national regulatory authority, were to immediately conclude that every evaluation that it had carried out should always be subject to an immediate re-evaluation at any time that a report indicating that there are circumstances under which an adverse condition can be demonstrated with a particular compound, then I would respectfully submit we will always be re-evaluating everything that we had ever done. Because work goes on, not only on these hormones but indeed on every substance that we can think of. But as scientists, I think we are compelled to look at the totality of the evidence as it's available. I think that totality of evidence, certainly recognizing the information that has been presented here today as well as the historical information, suggest to me that the assessments that were provided then continue to assure a reasonable degree of safety to consumers of these commodities. As I say this is not only my opinion but in fact it was the conclusion of a conference held very recently and sponsored by the European Commission on exactly this issue. That these compound when used in accordance with accepted practice, I should perhaps use a phrase that we have all been using, good veterinary practice, good practice in the use of veterinary drugs, whichever acronym you would like to use. I think this has been the consensus view of this Conference if you like. I use the word consensus because clearly in any scientific endeavour of this sort one can quite properly and realistically anticipate that there will be a divergence of opinion. The nature of scientific interpretation is that legitimate bona fide knowledgeable scientists may reach different conclusions from the same set of data. But I think the consensus opinion of that Conference Mr. Chairman, was that the weight of evidence used then continues to prevail now, and that the assessments and conclusions drawn then are still consistent with the available information now. I think as Dr. Arnold has indicated, this in no way is intended to cast any doubt or validity on the work which others such as Dr. Liehr have performed. And certainly this sort of work should continue, and I don't think anybody can assure you that in some time down the road, that it will not require or dictate that there be a re-evaluation. But as we sit here in this room today, I continue to be of a view that those assessments served the community well then, the international community, and they continue to do so now. And that there has not been compelling evidence that has been provided to suggest that those assessments have been in serious error.

Chairman

353. Thank you very much. Professor McLean.

Dr. McLean

354. Thank Mr. Chairman. I'll be brief. I'd like to highlight the fact that in my submission I made no comment about melengestrol acetate because there hasn't been a large amount of data package available for evaluation and so I restricted my comments to the other five hormones. The only other comment I would make that if any national body or group believe that the time for re-evaluation of some of the hormones previously evaluated by JECFA was upon us, then I would invite them to make an approach to JECFA as has been done on a number of occasions with the number of compound of varying chemical classes. It is interesting that if this information that has concerned some has been so compelling, to ask why an approach to JECFA has not been made.

Chairman

355. Thank you very much. Dr. Arnold.

Dr. Arnold

356. Thank you Chairman. Concerning the table I have presented in my written contribution, I just wanted to facilitate the work of this Panel so that you don't need to read all these documents and so I summarize the kind of information, I was saying information pertaining to the effects have been considered by the study, it's on page 9. I have not stated that I felt that all this evidence was complete at that time, I explicitly mentioned that some data had been completed only at the 34th meeting of the Committee. This was only to facilitate the discussion. What concerns the six substances, I made no statement on melengestrol acetate because I haven't seen the data. The only statement I made was on the availability of analytical methods because this is something I know, but otherwise I have limited my statements on the five endogenous hormones. I did however say that from my point of view, the significant new evidence which has been produced since that Committee did not invalidate the basic conclusions and therefore I still am feeling very comfortable with the conclusions although I admit that a lot of new evidence has been produced by the scientific community. Coming to the question of combinations the synergistic and antagonistic effects of whatever, I had some difficulties to understand this question because every time if we administer fixed combination to animals or humans, it's quite clear and in all countries participating in this dispute there are mechanisms that these fixed combinations are evaluated. But I didn't understand the significance of these questions when we are talking about the residue levels because at those concentrations, all these substances occur simultaneously in human beings of all sexes all ages and it's quite obvious that these substances have both synergistic or antagonistic effects in living animals including human beings. This is their normal physiological function and they can synergize in one tissue in one cell with respect to one effect and they can antagonize each other. Therefore I had difficulties if these substances enter the internal pools of the hormones they are immediately confronted with all kinds of hormones, so I didn't understand what the question meant at the residue level. At pharmacological levels of course they are tested in all states if they are administered as fixed combinations.

Chairman

357. Could you Professor Epstein precise the question?

Dr. Epstein (EC)

358. I am sorry that my point that I raised was so obscure. I would have thought that if you add two carcinogens to an animal or to a human, you stand the risk of interactions of one kind or another. There are data showing that are positive interactive effects whether they be additive or synergistic such as those between oestrogen and progesterone. With oestrogen and progesterone together, produce a far greater increase in mammary cancers in rodents than do either separately. So that is clear what one means by synergism. I'm unaware of any evidence of antagonistic, any experimental evidence of antagonistic effects of any anabolics and would be happy if you could refer me to the appropriate citations.

Dr. Arnold

359. I agree with Dr. Epstein that there are examples of synergistic effects but I could list a number of situations where these hormones counteract. I'm not prepared at the moment to give you such references but I'm sure I can do it tomorrow.

Chairman

360. Dr. Lucier.

Dr. Lucier

361. Probably the best example is the one that you just cited; oestrogen and progesterone in which oestrogen unopposed by progesterone causes an increase in uterine cancer. If progesterone is given at the same time then that effect is blocked. So where as oestrogen and progesterone seem to synergize each other in terms of breast cancer risk, they actually antagonize each other for uterine cancer risk. So it just points to the fact that's very difficult to fully appreciate the complexity of trying to estimate synergistic responses, additive responses or antagonistic responses. Even the same two hormones in different tissues will do exactly the opposite, one synergize, the other antagonize.

Chairman

362. Thank you very much. Can I give you the floor?

Dr. André

363. We will speak about the six hormones and not of MGA, it is clear we are just speaking about the other ones. I think that concerning this question when JECFA has considered these hormones, they have been considered as drugs, as classical drugs and for this reason, all the data concerning toxicological assays has been asked to companies and evaluated by very well scientific expert groups. But I think they have not been evaluated as for the reviews for growth promoters, I mean with a very large scale use. I think interference between this large scale use of hormones and the other drugs used also in animal breeding has never been studied, and its clear that the use of hormones has been demonstrated to longer some withdrawal period and elimination rates of other drugs. The probability to have interference between two drugs when they are used for therapeutic use is very small because you have no opportunity to have at the same time two different illnesses and two drugs at the same time. But when you are using such compounds in large scale as hormones, then you have a higher probability to see on the same animal at the same time the use of these hormones and use of another drug. And I think in this particular case of growth promoting substances, the assay has to be done. And concerning the new scientific evidence we are speaking about very recent data from this morning altogether and I would just make two remarks that many of these data concerning mode of mechanism of action carcinogenicity and other are recent data from '90 to now and most of them have been published during 1995 and 1996, the two last years. So this could also explain in some ways that many of these data, recent data have not been taken into by the EC Conference in '95 because the bibliography and the investigation has been done for this Conference up to the beginning of '95 and not more recently.

Chairman

364. Can I give you the floor?

Mr. Christoforou (EC)

365. Mr. Chairman, Dr. Liehr would like to make a comment on the synergistic effects and then Dr. Bridges would like to intervene on the so-called 1995 EC Scientific Conference what was ....... during that Conference. Then if you allow me I will summarize once again what was said I may be making probably slightly legal but directly related question to what is the JECFA standards in this case and what is the legal context in which we are litigating in this case. I think that will be important for our scientists. Thank you.

Dr. Liehr (EC)

366. Mr. Chairman, concerning the synergism of hormones, I agree with Dr. Lucier who stated that the combination of oestrogen plus progestin inhibits uterine tumour formation whereas it appears to enhance mammary tumour formation. It certainly does so in animals and the epidemiological evidence in humans is also quite strong. In this context, I think it is very important for all of us to realise that when several hormones are combined and given as a combination that the balance of hormones within the body, the regulation by various hormones appears to be altered or influenced in ways that we have not sufficiently taken into account. If for instance progestin inhibits uterine tumour formation then and enhances mammary tumour formation, then it is obvious that circulating within all of us are hormones in a quite well-defined balance and as humans proceed through life, through stages, the endocrine regulation is quite well balanced. Once combinations of hormones are added this balance is being destroyed and I think an obvious example of how this, effects, synergistic effects can arise, is the fact that the metabolism of oestrogen is clearly or has clearly been shown to be inhibited by progestins. So combinations of hormones they easily alter the balance between these, between endogenous hormone levels and for the many synthetic progestins, I don't know to what extent this is known. A number of synthetic progestins have been examined but certainly not all of them. Thank you Mr. Chairman.

Chairman

367. Thank you very much.

Mr. Christoforou (EC)

368. Mr. Chairman before giving the floor to Dr. Bridges, I would like to clarify one point and Dr. Stephany will intervene just afterwards. Dr. Ritter has said, JECFA evaluated only single compounds, single substances. From what we know in the market, the implants, there is only one implant that is one substance only marketed. All the others are implant of compounds of similar substances and I think Dr. Stephany would like to say a couple of words about this. So in fact, what it is administered to the animals in this case, they are no single substances except one. The majority of all the rest of the implants are several compounds together. That I think Dr. Stephany would like to say a couple of words on this.

Chairman

369. Yes? Dr. Ritter please.

Dr. Ritter

370. I don't want to pre-empt the comments, but in addressing the issue of combinations, I'm not sure if you are dealing with the issue of animal safety, who presumably would be at greatest risk from the combination, if the combination was to produce synergistic effects? Because I'm left with the impression, perhaps these comments will be addressed, that in terms of human safety, the issue is the exposure to the levels which are present as food residues, which indeed are present in combination with hundreds of other substances, not only these two alone. So I'm not sure if the comments are intended to be more relevant to the issue of safety in the cow, or to the issue of safety to humans who consume commodities from which the residues may indeed be present in combination but at very much reduced levels and again in present in combination not only for the two steroids in question, but indeed present in combination with hundreds of other residues of both natural and exogenous origin.

Mr. Christoforou (EC)

371. Thank you, thank you very much indeed. Because there is one aspect which is not practically discussed in this room but has been argued in the submissions of the parties, especially in submissions of the European Community. This case concerns both the facts on human beings of course, but also on animals, and we did not elaborate because the effects on the animals are even more obvious than what the effects are of this residue for human beings. But Dr. Stephany will also given you some information on animal health also in this case, that is the prostate of animals that are affected. Our question is not only the potential effects of the animals but also the potential effects of those combinations for human beings. And the link that was made, has been explained, is since the implants which are used on the market, apart from one the others are compounds of several substances, this is linked to our question, what are the possible synergistic effects of this combination? Has this been studied by the JECFA Report? That was the aim or the point that we were trying to make. But I give the floor first to Dr. Stephany then will come back to Dr. Bridges. Thank you.

Dr. Stephany (EC)

372. Thank you Mr. Chairman. First of all I have to make one very small correction, of the implants that are on the market, there are two having a single active component but only one having oestradiol and the other one is zeranol. So there are two, one is oestradiol the brand name is Compudose and the other one contains zeranol, xenobiotic and the name is Ralgro. All others as far as I am aware are combinations of having at least one xenobiotic hormonal active compound in it. What surprises me a little is that we always talk about, that the implants contain compounds that are identical to the natural ones. That's simply not true because the implants contain either the natural ones in chemical different form like an ester like oestradiol benzoate and or the testosterone as a testosterone propionate. And at least testosterone propionate what is xenobiotic circulates freely in the body as is known from clinical chemical studies, and I'm not aware of any residue studies of testosterone propionate as such and it is certainly not true that all testosterone propionate or all oestradiol benzoate only will hydrolyse and will yield the natural identical hormones. So I think that's one thing and coming or responding to the remarks of Dr. Ritter, if you have two hormonal active components in your implants you will have two at least two hormonal active residues. So the consumer will in his food have, in between a wealth of other things, I fully agree, the probability of being served with two hormonal active hormones or residues at the same time, at least two different ones. Well what's next? Oh the remark on animal health, it's only a small remark. Some recent research in the Netherlands with, picking up old research, we know that if you treat bull-calves with oestrogenic compounds then at least a few organs will change like the prostate and with some new technology based on histo-chemical its a new thing, we found that at least this effect is much more extended than we have found previously. Whether that will effect the health of the animal as such, I can hardly say especially for calves only having a full life of half a year. But at least it's another signal that a lot of things change in the body of the animal, besides that more meat is produced. And also that's an item that is touched in the European Conference, ranging from animal health to animal welfare, but that's completely another thing. I think that's it for the moment, and once again I think the most important thing is that the implants do not contain in most cases natural identical compounds.

Chairman

373. Thank you could. I'm sorry I missed before Dr. Randell he wanted to intervene. May I give you the floor?

Dr. Randell (Codex)

374. Thank you Mr. Chairman. I would not like the Panel to go away with the idea that JECFA did not evaluate the residues present in animals from these mixed implants. The monographs which were prepared by JECFA at the 32nd session clearly indicate that trials were done on mixed implants as well as on single substances implants and exactly the sort of mixtures that we have just heard, that is, oestradiol together with testosterone; oestradiol together with progesterone; oestradiol benzoate together with testosterone propionate and also oestradiol with trenbolone acetate under the oestradiol evaluations. These were known to JECFA at the time and the pharmacokinetics of these substances as they were gradually metabolized and excreted by the animals were studied by the experts at that time. Thank you.

Chairman

375. Sorry, Dr. Arnold.

Dr. Arnold

376. Thank you Mr. Chairman. Dr. Stephany is absolutely right that the esters are administered. However, this is also the case in the European Union. If these substances are legally used for therapeutic purposes because, and I think here the rules are entirely right, it is recognized that the esters are readily hydrolyzed to yield the substances. Therefore it doesn't make a great difference if we have talked about oestradiol, testosterone and progesterone because these esters are in fact readily hydrolyzed. The reason why the esters are used is that the free substances are more slowly released because we discussed this earlier today. The plasma half-life is so short. However, in order to give you an idea how ineffective these substances still are, when testosterone propionate was used in earlier times as androgen substitution therapy, it was necessary to inject 25 mg. every day intra-muscularly, so although he is from an academic viewpoint entirely right, I think we can continue discussing the effects of the free substances. Thank you.

Chairman

377. Thank you very much. I give the floor back to the Community.

Dr. Bridges (EC)

378. Chairman, I'd just like to clarify the nature of the December 1995 Conference because several speakers have referred to it as if it was an up-to-date comprehensive risk assessment on steroids. It wasn't really of that nature at all, it had nearly 400 participants, which is a pretty difficult way of going about risk assessment. It was covering three areas, development of new growth promoters generally, risk assessment across a range of growth promoters and then monitoring and surveillance. So there wasn't and the way the papers were identified was that we had a small organizing committee who chose the speakers. Now in their wisdom or otherwise, they chose not to have any body who was involved in genotoxicity and so as a consequence, and I was a plenary speaker for risk assessment so I remember the brief well, as a consequence this issue of genotoxicity was not addressed at all by the conference and therefore the conclusions of the Conference did not take it into account. So it isn't and was never intended to be a comprehensive risk assessment and it didn't really consider any other mechanism because of the way the speakers were selected other than just to look at the hormonal mechanism and how that may be related to cancer.

Chairman

379. Can I ask you, the fact that you did not invite speakers, was that an indication that this was not part of the mainstream thinking at the time, or?

Dr. Bridges (EC)

380. Chairman, I wasn't a member of the organizing committee but they were clearly very wise because they chose me as a plenary speaker so I couldn't argue with them. I think really the thinking was that they wanted to follow up to the so-called Lamming Report, and the Lamming Report had concentrated very much on hormones acting as hormones or hormonal mechanism. So I think the natural assumption was that they would get an update on those sort of issues rather than look at broader issues and I've taken the opportunity to talk to members of the organizing committee recently to confirm that that was their view.

Chairman

381. But could it be said that if this would be organized today they would probably take a different approach? Is that, I mean these issues we're discussing have they moved into the debate?

Dr. Bridges (EC)

382. I'm sure Chairman that if we were organizing the same conference today, genotoxicity issues would loom very large in the discussion and I'm sure I would have had to refer to it particularly in my paper.

Chairman

383. Thank you very much. Dr. Arnold.

Dr. Arnold

384. Thank you Mr. Chairman. I totally agree with you that this Conference has not produced the slightest element of risk assessment, I totally agree with you. But I have recognized that some important information has been disseminated including your own very important key lecture, but I wanted to underline this Conference has not produced the slightest element of risk assessment.

Chairman

385. Thank you very much. Dr. Ritter please.

Dr. Ritter

386. Thank you Mr. Chairman. I think it may be useful, a number of us have referred to the report, I have the report with me which I brought at the risk of great personal injury to transport it ... [tape ends]

Mr. Christoforou (EC)

387. It is addressed, particularly for Dr. Ritter, Dr. McLean, Dr. Arnold and of course, Dr. Randell.

Chairman

388. Thank you very much. Could I start with you Dr. Randell because the procedural questions are addressed to JECFA.

Dr. Randell (Codex)

389. Thank you, Mr. Chairman.

390. First I'd like to say that the JECFA Secretariat, of which I had the honour to be a part for a period of my career, would feel very disturbed if they were aware that data were available to the scientific community that were not available to JECFA, or were not being proposed to be available to JECFA, in a manner that would render JECFA's advice to FAO and WHO member countries, either obsolete or inappropriate.

391. Therefore, my comment earlier, was really to maintain, what I believe to be the standing excellence of JECFA's evaluations in all of the fields that JECFA deals with, in order that, we could perhaps encourage those scientists that have these data to assemble them and bring them to JECFA for review. It was meant as a positive, not a negative, statement.

392. A few minor corrections to the history which we've just heard. The vote which took place, in which the hormones were failed to be adopted by the Codex Commission, was in 1991, not 1992.

393. The four principles concerning the role of science in Codex decision-making, and the extent to which other factors are taken into account, was never discussed, as far as I am aware, by JECFA. It was not processed through the JECFA system. It is entirely a Codex matter and, therefore, entirely operated by the member governments of Codex and not by the experts in JECFA.

394. Let me put the JECFA material into perspective. JECFA provides advice to FAO and WHO and through them to the members of those two organizations and also to the Codex Alimentarius Commission.

395. The Codex Alimentarius Commission has, as a matter of procedure, taken the JECFA recommendations in a variety of areas and plugged them into the eight-step elaboration system and the result of this, in most cases, is a consensus adoption of these points of view which are then available for countries to apply, if they feel that they wish to. They are not obliged to under the Codex rules.

396. There have been any number of emergency re-evaluations in JECFA which have been initiated in Codex and which have found themselves reflected in Codex opinion.

397. As to the direct question if there is one that has occurred in the nine-month period since the entry into force of the Uruguay Round Agreements, I'd have to check that in but I can't think of one. The most recent one which has similar import would be the decision of JECFA to withdraw previous evaluation in regard to potassium bromate, as a flour-treatment agent, and the subsequent withdrawal by Codex of all approved uses of potassium bromate in flour, primarily because potassium bromate residues remain in the flour at the time of ingestion by the human consumer, and potassium bromate is a carcinogen.

398. The maximum residue limits are not exclusively concerned with trade. They are concerned with the control of good agricultural or good veterinary practice and they are applied in trade. To be quite practical about it, it's definitely beneficial to trade if countries have the same numerical values for maximum residue limits, or at least if you are exporting a product, the level at which you are exporting is lower than the limit applied by your importer.

399. However, the maximum residue level should reflect the good agricultural, or good veterinary practice, on your territory and not be linked exclusively to trade considerations.

400. I would take umbrage at the point that the MRL is a trade-derived figure. It is, in fact, a figure derived from good veterinary or good agricultural practice.

Chairman

401. Can I ask you to go into the question which was put forward?

Dr. Ritter

402. Very quickly, I think the principle that was being elaborated, the philosophy is more popularly referred to as the precautionary principle.

403. As to what is the most appropriate action in the face of the kind of information, for example, that has been presented today, I take that really to be the work of the Panel, and so I will make no attempt to answer that question.

404. I think it goes well beyond the jurisdiction that I've been provided here to comment.

405. I will, very quickly, comment on, if you like, the age of the assessment and I've already made comments on this a number of times, but it perhaps bears repeating.

406. I think it is incorrect and I would respectfully submit that it is misleading to suggest that 1988/1989 is the last time that this issue on the safety of the hormones, in question, has been examined.

407. I've already mentioned that certainly in my view, this issue, without going into a lengthy debate as to whether or not the strict definition of risk assessment was made by the European Conference, I think it goes without question that the issue of the safety of the hormones, in the general sense, was most certainly re-evaluated in December 1995, which is a little more than one year ago.

408. Indeed, a number of people who are here today were active participants at that conference.

409. I must say that I disagree with the view that 1989 is the last time that this issue was formally evaluated on an international level. I think that's incorrect and I think it's misleading.

410. More specifically, on the issue of risk assessment, whatever that means. We could spend the rest of the evening debating whether or not risk assessment have, or have not, formally been discussed by the Conference.

411. I would refer the Panel to a specific section entitled, Risk Assessment, on page 3 of the Conference Report, and it falls under the general section of the Report entitled Report and Conclusions of the Steering Committee, specific section entitled, Risk Assessment.

412. Although the Conference was concerned with many technical matters, it is inevitable that general interest should have centred on the risk assessment of different classes of both promoting substances, the subject of discussions of Working Group 2.

413. Then I would refer, Mr. Chairman, the Panel to a number of specific papers which I would respectfully submit, dealt with very much with the issue of risk assessment. I refer to Workshop No. 2 on pages 245-401 and I would refer specifically to a number of papers, including the one presented by Professor Bridges, but also including papers presented by Dr. Miller from the United States, Dr. Hoffmann from Germany, and so on and so forth.

414. If I refer, just by way of example, not to give particular preference to any one of these papers, to the paper presented by Dr. Miller from the USFDA at that Conference, she concluded, at that time, "hormonal growth promoting agents include a variety of compound which very markedly in pharmacology and biochemistry" so on and so forth.

415. "When these animal drug products are used according to label directions, the edible tissues from treated animals, are safe for all consumers."

416. I would respectfully submit, Mr. Chairman, that that is very much an assessment of risk, regardless of whether or not we can come to a formal definition of what constitutes a risk assessment. It's certainly my view that this is most definitely the element of risk assessment. It strikes the heart of what a risk assessment is, because after all the product of a risk assessment, is the statement of safety to the target population. That's why we carry out risk assessments. It's not merely a mathematical exercise.

417. I would suggest to the Panel that there are a number of papers here that deal very much with the issue of risk to human populations, resulting from the use of these compounds, and that the consensus of this Workshop was that the use of these compounds, as recently reviewed as December of 1995, does not constitute any risk.

Dr. André

418. May I add some comments for the Panel? It can also see in the same paper, page 378, conference.

419. I will read what it says:

"New quantitative risk assessment models are needed for the safety evaluation of chemicals with toxic actions, like general carcinogen."

420. It's in the same paper so it's not possible to extract something when you don't extract all the information.

Dr. Ritter

421. I didn't intend to mislead. I mean obviously I'm not going to read into the record the entire Conference Report it is available.

422. There is no question that a number of deficiencies, in terms of our state of knowledge, as identified throughout the report, but those efficiencies, those deficiencies were weighed in the conclusion which the Panel has reached. They weren't weighed by me. But the conclusions of the Working Group was that the present state of knowledge is sufficient to demonstrate the safety, in their view, of the use of these chemicals in contemporary times.

423. I think it would be silly for any scientist to presume that the day will ever come, on this issue or on any other, where we could say we know enough and that there is no need to do any further work. I have never been associated with a scientific issue where I have ever heard a scientist say, there is no need to do any further work on this topic, we know all that we need to know.

424. I agree that there is further work that is indicated. I agree that statements made by scientists, such as Dr. Liehr will continue to contribute to our understanding, but I also agree that the totality of evidence re-evaluated, as recently as December 1995, suggests that the way in which these substances are used and the residues which they produce, do not constitute a risk to human health.

425. I don't find those statements to be contradictory at all.

Chairman

426. Dr. Lucier.

Dr. Lucier

427. My question may show a certain amount of naivety but did JECFA document or the 1995 meeting address the issue of carcinogen risk assessment, in any kind of way?

428. It seemed to me like the risk was based on the hormonal activity of the agents, in primates.

Chairman

429. We discussed that briefly before. Would you like to give your views on this.

TO CONTINUE WITH EC MEASURES ON MEAT - COMPLAINT BY THE U.S.