Dr. Ritter

430. I think only to say that unless we were to spend a great deal of time strictly defining what we mean by the phrase "risk assessment" we could continue to go around this circle, I think, all night. The point that I was trying to make that, in the opinion of the scientists that were gathered at the Conference, it was their collective wisdom, for whatever reasons they considered. I think, as Professor Bridges has already quite correctly indicated that it did not include extensive examination of some of the evidence which was presented today. But for all the totality of reasons that they considered, at that time, they came to conclusions which have already been made clear. One may raise the question if they were redoing it tomorrow, would they come to the same conclusion? I think this is speculation. One could raise the question, if they were doing it again a year from now, would they come to a different conclusion? I don't know.

Dr. Lucier

431. Were the acceptable levels, or the acceptable daily intakes, were they derived, primarily, from the tests of hormonal activity in non-human primates? Is that correct?

Dr. Ritter

432. No, I don't think that's correct. I think there were extensive carcinogenicity data that were available to the JECFA Committee. These data have been described, the assessments provided, at least in the case of two of the xenobiotic hormones. To the best of my recollection, monographs on the three natural hormones are not available, but they are available for the two synthetics, and certainly they were based on chronic toxicity carcinogenicity studies that had been conducted in a very classical, NTP kind of methodology.

433. No, the naturals were evaluated, what I indicated, to the best of my knowledge, monographs are not available on the naturals. But data was evaluated by the Committee, on which they drew their conclusions, I have not been privy to that data. But then again, I have to be candid, I have not re-evaluated the carcinogenicity data for any of these compounds, in order to prepare this session. This would have been neither practical or arguably even necessary. I would never pretend to suggest that I have greater wisdom in this area than the collective wisdom of the JECFA Panel.

Chairman

434. Dr. Randell, please.

Dr. Randell (Codex)

435. Mr. Chairman, just perhaps to clarify that point.

436. In the case of zeranol, for example, the JECFA Committee did evaluate carcinogenicity studies, in rats and in mice, and so forth, but the conclusion that JECFA came to in this substance and in the other substances, that the carcinogenicity was linked with the hormonal effect, and therefore the establishment of the "no hormonal effect" level was the point at which the evaluation hinged, it hinged around that point.

437. This is why the new data, which we're hearing about today, is of interest because it would supplement that evaluation and help us considerably. However, the information which was available to JECFA definitely did include carcinogenicity studies for all of the substances concerned.

Chairman

438. I'm looking at my watch. It's about 7.30. Could you come to a close for today?

Mr. Christoforou (EC)

439. Mr. Chairman, I will come to a close on this particular point, if you allow me.

440. I will read from what the response of Dr. Ritter was to Question No. 5, because that is what we are discussing now.

441. I quote page 12 of his reply to Question 5, at the end of the first big paragraph:

442. For progesterone:

"The report was silent on the results of mutagenicity studies which were available to the Committee for review."


For testosterone:


"Results from mutagenicity studies, although available to the Committee, were not described in the report."


For the synergy:


"The issue of potential synergy has been addressed, at least in part, through the context of biochemical studies, directed at the effect of excretion of hormone combinations when compared to single hormones alone."


This is on page 14.

"It is, however, clear, that definitive studies relating to genotoxicity or carcinogenicity of hormone combinations have not been carried out even though this is frequently the preferred method of use."

443. I'm slightly puzzled by the positive terms in which Dr. Ritter is now phrasing his replies for the review of the, in the JECFA report. All issues we have been discussing here now about the genotoxicity, not only due to the hormonal effects, as has been rightly pointed by Dr. Lucier but all the other possible sources of risks we have identified.

444. At least the way I understand his replies is that these studies have not been carried out. They might have been available but they have not been reported in the report. We don't know if they were real studies.

445. He was not part of the JECFA committee, in that particular case. So I don't know where he has got this information. Whereas Dr. McLean was part of this report and also he might have an interest to explain to us whether this has been done. From the reports we have in front of us, Dr. Arnold has provided a table, where there are some black holes where things which have not been examined. I see there is, at least some, contradiction between what our scientists are saying on this particular issue. If one reads the entire report of JECFA, it is clear that only the hormonal effects of those substances have been studied for the potential carcinogenic effect. So what is the exact scientific basis on which Dr. Ritter is making these comments?

446. One more comment.

447. I think Dr. André, because he was part of the Organizing Committee of the 1995 Conference, he has, in my view, direct inside information on how this conference was organized. The Community only funded the Conference and left the scientists entirely to address some issues.

448. In the report of Dr. Ritter, it is frequently referred to as the EC Conference. It is not the EC Conference. It is a conference funded, but no more than that. It was entirely left to the Steering Committee who to invite and what to discuss in this conference.

Chairman

449. I would propose that we have a final round on this question and then we will close the meeting for today, and I would give the opportunity to respond to the scientific experts.

450. Maybe Dr. Ritter would speak at the end.

451. I'll start with Dr. McLean.

Dr. McLean

452. I thoroughly concur with the comments of Dr. Randell. We were trying to put a positive view on the availability of JECFA, if people wanted to take that opportunity, rather than forcing people to do it.

453. In relation to the mutagenicity data for the naturally-occurring substances, the mutagenicity data that was reviewed is referenced in the report, in each case, and so therefore, not so much that is was silent but it referred to mutagenicity data that was in the open literature. So, in the case of progesterone, testosterone and oestradiol 17 beta, there were a number of published documents that the Committee did look at, and they are referenced in the report.

Chairman

454. Dr. Arnold.

Dr. Arnold

455. Mr. Chairman, I have two points.

456. The first point is I have difficulty understanding how it could happen, but the legally competent authorities of the EEC, on the advice of the competent advisory scientific body, have established no MRL for oestradiol and this happened two years ago.

457. The public summary report states, inter alia, "The conclusion of the FAO/WHO Expert Committee on Food Additives, JECFA, that no ADI and MRL for oestradiol need to be established, as adopted." And then all the other things I mentioned this morning, this is what I have difficulty in understanding, this happened in 1994. And this Regulation has been implemented, it has passed all the EC institutions and the result has been published in the Official Journal. I refer to this in my answers to the question of the Panel.

458. My second point is I was rapporteur of the Codex for five consecutive years. That means I had jointly, with the secretaries of the two agencies of the United Nations and with the US Secretariat of the Committee, to prepare the report. I was in a really difficult situation because it's true that the EC objected to move these MRLs to the next step in the procedure, but without raising any health issues. So, I was really in trouble and you can find the result in the report. I finally got a written statement and the arguments you will find there are, inter alia, the EC is opposing because they have specific legislation prohibiting the use and the EC consumer doesn't wish to receive meat from animals treated.

459. These were the arguments, so I'm a little disappointed that these questions have not been raised earlier, first of all, in earlier years during the Codex discussions. It could have happened, for example, to refer the whole matter back to JECFA with new health arguments for re-evaluation, at that time, but this proposal was not made.

460. And that secondly, two years ago it happened that we came to the same conclusions by the competent authorities of the EC regarding oestradiol. Progesterone has also been finished but not yet published in the Official Journal, and testosterone is still under evaluation.

Chairman

461. I think we will reserve this for tomorrow.

462. I'd like to conclude and if anybody of you would like to speak?

Dr. André

463. Just to say a little more about this Conference because I have been asked to do so.

464. It's clear that the EC has just asked four experts to organize this Conference: Sir John Maddocks is the Head Director of the Nature Review, a scientific paper, an Irish colleague, Bergen colleagues and myself.

465. I can witness that we were very, very free of our to our choices, in terms of selecting scientific people. And we organized this with a first group of two people for the three Work Shops, and they proposed that we invite scientific people and we agreed, on the basis of the publication and the famous of these people.

466. But, I think, and I personally regret now that we didn't take enough care with the scientific publication. I discovered this morning a lot of publications on this topic and some of them were available and the scientific were also available, and maybe we have not done our best. We have done our best but maybe it was not good enough, and that will explain also the missing of some information in this Conference.

467. On the last point, I would like to say that the conclusions are a reflection of a common discussion, and it is not a complete reflection of the majority of people. It is not a total opinion of the members of the Committee and it cannot be taken into account as something coming from an official body. Our objective was just to put some light, some knowledge, on these hormones in order to inform politicians preparing new regulations and no more. It is not the same thing as to establish an official MRL. The responsibility was not exactly the same order.

Chairman

468. Dr. Lucier.

Dr. Lucier

469. I'm just surprised in reading through this report that, given the fact that oestradiol is a known human carcinogen, that an ADI was considered unnecessary for it. There is a tolerance but not an ADI, if I'm reading the report correctly.

Chairman

470. What page?

Dr. Lucier

471. 19.

Chairman

472. The JECFA Report. This was the 1988 JECFA Report. Is that correct?

Dr. Lucier

473. In the middle of page 19 it said the Committee considered an ADI unnecessary for a hormone that is produced endogenously in human beings and shows great variation and level according to age and sex.

Dr. McLean

474. The difficulty that JECFA had of setting any ADI was the problem of the increase that one saw upon treatment, against a background of very large levels that occurred naturally. And so therefore it meant that the setting of the ADI really wasn't possible, because the treatment altered the levels by such a small amount when compared with the endogenous levels in cattle to make any ADI meaningless, and that was the difficulty we had.

475. I would suggest, today, that is not possible to regulate the use of the three naturally-occurring hormones by the setting of an ADI because you can't tell the difference between treated animals and untreated animals, by a method that is suitable for regulatory purposes.

476. It's a practical consideration, a real and practical consideration. I don't quarrel with what you say, but in practise there's no way of regulating it.

Dr. Lucier

477. But if one knew, which we do know, what are given body burden in the cattle would be produced by the use of growth promoters, we can certainly estimate various eating habits of people, what they would take in their body from those agents that were exogenously administered.

478. One could come up with reasonable estimates on that and establish an ADI. In my mind, that could be done. From my comments this morning, I don't argue with your point that it's a very small number of molecules, one in 28,000 I came up with in my calculations, not taking into account the fact that it is poorly absorbed and that would make it one in 280,000.

479. But nevertheless, some sort of an assessment should have been made, in my mind, of what that risk was, as low as it is. I'm not saying that the risk is high but I believe the risk is extraordinarily low or zero. That's not my point. I am just surprised that that exercise was not done.

Chairman

480. If more points on this are to be discussed, I would like to discuss them tomorrow because I think we are a little tired.

481. Would you like to make statements tonight?

482. I apologise for the length of the meeting but it has been, in my view, very informative and I would like to thank the experts and also the delegations for their support.

483. As agreed, we will meet tomorrow at 2 o'clock, hopefully sharp, and we will open discussions with the statements and questions by the Canadian Delegation.

484. Thank you very much and good night.

485. The meeting is closed.

Second day - 18 February 1997

Chairman

486. As announced yesterday, we shall proceed in the following manner. We will go first to Canada for their comments and questions to the experts. We will then turn again to the European Communities and I would urge the Community to limit their interventions to the utmost necessary in order to save time. We will see how much time can be allocated when the Canadians have made their statements and questions and then there will be final questions from the Panel to the experts and then the final statements by the experts in the end. I have to be able to conclude this meeting by around 6 o'clock. I am not able to say whether we will be able to do so. It depends on you and I am in your hands to a large extent.

Mr. Christoforou (EC)

487. We would really do our best to respect what you have indicated, but our delegation has a serious problem in the sense that the planes of two of our scientists are leaving at 6 o'clock and we consider their testimony and their presentation very important. It is just a request and we hope we have the understanding of the Panel in this room. If it is possible by 4 o'clock, Canada does not finish, I do not know how many questions they have, if we can stop for a while they can make their presentations and if there are any questions or answers and then they could probably be able to take their taxis and get to the airport in time. That is the request.

Chairman

488. Thank you very much. I think we will see where we are with Canada at 4 o'clock.

Mr. Brinza (US)

489. Mr. Chairman, a procedural question. Last night we had left that the Panel was going to deliberate on our question about the follow-up submission. That was requested by the Europeans and I wondered if the Panel had come to a conclusion with respect to the matter we had raised last night. It is important, in part, because as we understand, the procedure that was just described, there would be no more opportunity for comments by either Canada or the United States after the Canadians have finished their questions today (and obviously we finished our questions yesterday), and there are a number of points that have been made that I think it would be appropriate to give us an opportunity to respond to.

Chairman

490. Thank you very much. I intended to take this up at the end of the meeting but since you raise it I can give the answer of the Panel. We have looked into the question and based upon the text which was communicated on 3 February by the Secretariat to the Parties, which I will read in a second, we reviewed the decision I made yesterday and we will not accept any ex-post submissions from the Parties. The United States has submitted some materials, you have submitted some materials yesterday which we took on the file, but we will not take on any more written materials after this day. The text reads "Please find attached the responses of four of the five scientific experts responses to Panel questions. Professor Arnold requested a few more days to submit these responses. [They came later on.] The Parties are informed that their comments to these questions at the 17-18 February meeting with scientific experts should be made available, as is customary with the Parties' oral statements at panel meetings, in the written form and if possible on diskette to the Secretariat". So this means that we expected these comments by today and I think we will conclude the proceedings based on this letter. So if you have additional materials, please hand them in by the end of this meeting.

Mr. Christoforou (EC)

491. Mr. Chairman, the practice though is that we are allowed to submit a document at least the next day after the oral presentation. This has always been the case. We are adjusting the text while we are speaking and I have been doing that for so many years and it is always the next day we are allowed to submit in writing the oral presentation. It is very restricted this time-limit of today. I would appreciate it if tomorrow there is also a chance for us to submit a document. Thank you.

Chairman

492. I think the problem is that then we need to have another go on rebuttals. And I think we stick to this here for the moment because this has been a hearing of experts by a panel and we do record on tape and will transcribe everything which is being said at this meeting so I do not think that we would need another written statement on the side of your part.

Mr. Christoforou (EC)

493. Mr. Chairman, if you apply this rule then the entire text which is in the text that the United States has circulated has not been read out orally. Then I would have unfortunately to request you to exclude all those parts of the documents which have not been read out. I really regret that in this part of the document there are so many things which have not been said yesterday.

Chairman

494. I think it was not required that this be read out because it says that the comments on these questions should be made available to the Secretariat. It is not exactly the same proceeding in my view as in the ordinary first and second substantive meetings here. I do hope that you are able to provide some of the materials as it was done yesterday, today - the statements by the experts and so on.

Mr. Thompson (Canada)

495. Thank you Mr. Chairman. If I am going to get started before my 4 o'clock deadline then I had best get quicker with the finger on the button.

496. It had been Canada's original intention to comment quite briefly on the experts' answers to the Panel's questions. Primarily by noting in point form some seven areas where the experts were in general consensus and then to put what we hoped were a few focused questions. We still intend to do that, however some of the events of yesterday require some broader comments on Canada's understanding of the purpose of this meeting and the rulings that you made on how we were to proceed.

497. We came here prepared to comment on and explore the Panel of Experts' answers to your questions and abide by your ruling that no new evidence would be introduced after 8 February. I believe, Mr. Chairman, that you will recall the purpose of that ruling was intended to provide all participants with an equal opportunity to review relevant material in advance so that informed commentary could be made.

498. Yesterday we all had the privilege to hear some of the world's leading experts comment and debate the properties and characteristics of the substances in issue. Some highly technical and complex issues were discussed with clarity and precision. Unfortunately and unfairly, in Canada's submission, we were sometimes deflected from that very high level of debate by the introduction of new material, some of which was apparently presented out of context and in a selective way. The Panel's experts were asked to make extemporaneous replies on matters they had not had an opportunity to consider in advance. This sometimes led to prolonged discussion clarifying facts on matters of marginal importance to the issues this Panel must decide.

499. An example, no better or worse than many I could choose, is Dr. Epstein's table on oestradiol residues in eight-year olds, which ultimately led to the somewhat surprising assertion that two quarter­pounders or 110 gram whoppers were the equivalent of 500 grams of meat. If I could be permitted a pun, that was a real whopper! With respect, it is important to refocus the issues these experts are here to help elucidate.

500. The complaint before this Panel concerns a measure of the EC which bans the importation of beef or any of the six hormones, alone or in combination, that have been used for growth promotion purposes in the face of properly established international standards of safe use.

501. One goal of the SPS Agreement is to further the use of harmonized sanitary measures between Members so as to protect health but not unnecessarily interfere with trade. The Agreement permits a Member to depart from these standards for certain prescribed circumstances. The relevant one for the issue concerning the Panel's experts, and the only one in my submission, is a scientific justification. Dr. Randell has spoken eloquently of the high standards of JECFA and Codex and the subject matter that was taken into account in establishing the standards of both the natural and synthetic hormones and the very conservative assumptions adopted to ensure safety through the use of ADIs and MRLs where required. It is clear that these organizations are to be commended for their work and nurtured rather than criticized.

502. We have learned that studies have been conducted for more than 12 years to try and prove a hypothesis that oestrogen is genotoxic. Many of these studies were known to and considered by JECFA. Dr. Liehr, in one of his studies, has injected comparatively massive doses of oestrogen in a male Syrian hamster in an experiment designed to produce tumours. The quantities are about twice the dose given to cattle. Dr. Lucier, as I understood him, agreed that in light of this evidence there was a risk, but he puts that risk at a level somewhere between zero, a concept which cannot be achieved in absolute terms, and a factor so small that it cannot be measured.

503. The question for this Panel is this in my submission: is that a risk that justifies departing from an international standard in light of its impact on trade and the objects of the Agreement. One way of testing that, Mr. Chairman, is by comparing other EC sanitary measures where there are similar or greater risks. Canada will pose some questions on the issues of consistency or lack of it in the EC's handling of these and other veterinary drugs.

504. Before turning to those questions I would like to review what Canada submits are the points of consensus between the Panel's experts: (1) good animal husbandry practice is a broad term encompassing good herd health, management practices and includes good practice in the use of veterinary drugs; (2) in the event that good practice in the use of veterinary drugs is not followed, higher residue levels may result.

505. However, given the fact that the MRL was derived from an ADI where a large safety margin has been applied, such an event is unlikely to cause an adverse health effect; (3) consumers are not able to distinguish the meat of an animal treated with growth-promoting hormones and the meat of an untreated animal; (4) observing withdrawal times for the hormones does not guarantee zero residues in meat. No residues detected does not imply that there are no residues present in meat as they may be present at levels that are below detection; (5) following treatment with the natural hormones, for either therapeutic, zootechnical or growth-promoting reasons, hormone levels will fall to those normally associated with untreated animals. There are no differences between the residues of natural hormones that are endogenous to the animal and the residues of the same hormones administered exogenously to the animal. Extensive data relating to genotoxicity and carcinogenicity were available to the JECFA and were considered by the Committee. The Committee concluded that the five compounds evaluated are not genotoxic carcinogens; and (6) growth hormones have been used in animal husbandry for many years; in some cases up to 40 years and there are no human epidemiological data that suggests a hazard. Adverse health effects have not been observed in those countries using growth hormones.

506. I have just one other point I wanted to raise briefly, not for purpose of resolution but rather to alert the Panel to an additional concern that Canada has. It has become apparent that the European Communities intend to present a slide demonstration at some time this afternoon. I have not seen that demonstration and I do not know the contents of it, but I am concerned that it may well be fresh evidence which would be introduced after the February deadline the Panel has set and I am also advised by some people who claim to have seen these slides that it is of little scientific assistance and may well be inflammatory. If and when the EC chooses to present that slideshow I would hopefully have an opportunity to discuss whether it is appropriate or not.

507. If I may I would like to turn to my questions.

508. Dr. Arnold, on pages 10 to 12 of your written answers you described the evaluations conducted by the EC for oestradiol and progesterone pursuant to Regulation 2377/90. As a result of the evaluation oestradiol has been put into Annex 2 of that Regulation and progesterone is pending I understand. Could you describe the significance of putting these substances in Annex 2 and could you contrast it with the significance of putting a substance in the accompanying Annex 4 and perhaps describe some of the substances that are in Annex 4?

Dr. Arnold

509. I should perhaps spend the first minute describing the working relationships between JECFA Codex and the competent bodies of the Community because I think then you would better understand how this happened.

510. We have set up in the Community a working party obliged to propose maximum residue limits for residues of veterinary drugs in 1984. We started at the beginning without having a true legal basis so it was a big advantage when Regulation 2377/90 became effective on 1 January 1992. If you look, for example, at the Official Journal, or maybe at Volume 6 of the Rules Governing Medicinal Products in the European Community, you will see a whole volume devoted to this issue. You will see the regulation, you will see guidelines, what the requirements are for the evaluation and you will see an annex to that regulation with a list of studies required in order to scientifically evaluate the substances. This list is absolutely identical with the list of JECFA requirements because it has practically been copied from JECFA.

511. I was the Chairman of this Safety Group at this critical time for more than three years and was helping drafting these rules and regulations at that time. This was also an interesting time because JECFA had just started doing reviews and we quickly realized that this could be of great help to us in the European Community.

512. If I look back at the time between 1984 and 1988-90 we had not achieved to set any MRL because it is really a tedious procedure, and as soon as we were able to cooperate with JECFA and Codex and harmonized our procedures with a system, we also harmonized with the Food and Drug Administration we had regular meetings the EC Commission and various experts with the Food and Drug Administration, there was an exponential growth. If you check the list of MRLs we have so far adopted it is quite a considerable list. But you will find the exposure limits, the ADI, are almost every time identical, those proposed by JECFA with those used in the EC. There are slight differences in the MRLs and this can be readily explained because veterinary practices are not the same in all countries.

513. Coming to the hormones, when JECFA has proposed MRLs and ADIs for hormones it was impossible to discuss this issue in this Safety Group and in the Committee of Veterinary Medicinal Products because it is well known that we have had already at that time the specific agricultural policies and the specific rules. Therefore it was surprising to me, and I told you yesterday, that six years after JECFA had discussed these substances, a Committee of the EC came to the same conclusions that the JECFA position is adopted and they also felt it was unnecessary to set an amount in ADI for oestradiol and was unnecessary to set an MRL and this has been signed by the competent authorities of DGIII, of DGVI, it has been published in the Official Journal. And this demonstrates that, scientifically spoken, what JECFA produces, what the JECFA Codex system produces, even if the results have not been officially accepted in the Codex procedure they are used everyday and to the benefit of the consumer protection in Europe.

514. I wanted to say this at length because otherwise you could have the impression that we feel very uncomfortable with JECFA. In fact the opposite is true.

515. Coming back more specifically to your question Annex 2 is meant for substances which no MRL is needed. I give you maybe two examples. If you use sometimes a local anaesthetic on a horse it might be necessary to set a withdrawal time but this is a ridiculous problem in view of setting MRLs for consumer safety in a community like the EC. This could be a candidate for such a substance, or if the substance absolutely harmless after the evaluation had been done. The usual procedure is that the company has to apply for inclusion in Annex 2 and they have to submit scientific evidence. Harmless substances, mainly harmless substances, for which there is no need to set an MRL, for example, elements which endogenously occur in the body. It is a rather long list and they are put into Annex 2.

516. In Annex 4 it is a little bit more difficult. Originally this Annex had been developed to include substances for which it is impossible to develop any conditions of safe use. This means for real hazardous substances, this was the original meaning. But what then occurred that later we had substances for which there were indications that they could be hazardous and gaps in our knowledge missing information. Since these were all out of patent substances and since no sponsor applied to prolong the presence of these substances on the market in order to be able to develop the missing data, some of these substances have also been included in Annex 4. That means we find there substances for which it is quite sure that they are hazardous under all circumstances and other substances for which there is a strong indication that they might be hazardous and no sponsor could be identified who is willing to produce the missing data. Maybe this is enough for the moment from my point of view.

Mr. Thompson (Canada)

517. My second question is also drawn from some of the material in Dr. Arnold's answers. By way of prelude I can let you know it is a compound question and there will be some follow-ups that come with it.

518. In your answer to question 2.2 on page 5 of your written answers there is a table that describes the uses of nature identical hormones and their esters in the European Communities. My first series of compound questions are: How are these substances used? Why are they used for oestrus­synchronization and when used for synchronizing oestrus, are the animals treated because they are sick or for a zootechnical purpose? This question may also venture into the expertise of Professor McLean.

Dr. Arnold

519. I cannot satisfactorily answer all your questions and sub­questions. I wanted to show only a few examples of substances for which I absolutely know that they are used. The list might be longer because a list of substances which are in compliance with our rules in the EC has been set up early on the advice by the Committee for Veterinary Medicinal Products, there are more substances on the market. I am not a veterinarian so I cannot really tell you whether this is justified to use these substances for this purpose. What I wanted to show you was how similar some of these substances are which are used on the one side for growth promotion and on the other side for therapeutic and zootechnical purposes, but there are also differences in the esters, and based on this table I developed my answer so these were just examples and I can as a non-veterinarian not justify their use but I am sure they are used in accordance with the directives in the EC.

Mr. Thompson (Canada)

520. I wonder if Professor McLean or one of the other experts can assist me with that information?

Dr. McLean

521. Thank you Mr. Chairman. Oestrus-synchronization is a commonly-used animal husbandry practice. You synchronize the reproductive activity of your herd for a variety of purposes; it may relate to the availability of feed, it might relate to the availability of markets, etc. It is a relatively common animal husbandry practice.

Mr. Thompson (Canada)

522. After use would residues of these administered substances be present in meat and milk of the treated animal?

Chairman

523. I would suggest that all of the experts may take the floor if they wish to do so. Who would like to go first?

Dr. McLean

524. Yes, the residues would be in meat or milk if the animal was slaughtered. It is interesting that oestrus-synchronization that is often used in dairy cattle in a variety of production circumstances and the residues would be in milk.

Mr. Thompson (Canada)

525. If I could continue with that table and some of the information on it. I wonder if any of the experts who feel confident could help me with the use of these various esters in the EC formulations. What are the chemical differences between the esters and why are different esters used and is there any comparison of persistence in the body of these various esters?

Dr. McLean

526. The esters are generally used to alter the rate of uptake of the drug from either the injection site or if it is in some sort of intravaginal device for example, although generally not there, it alters the rate of uptake. But what generally happens is that the oestradiol ester is actually metabolized either at the site of injection in the blood or in the tissue and the bond between the active substance, the oestradiol, and the side chain to which it is bound is readily broken and the active constituent oestradiol 17 beta, or testosterone in its various forms, is the active constituent.

527. There can be under some circumstances small quantities of the ester appearing in the blood and that is picked up by analysis. But those levels are small and no consideration when it comes to looking at the toxicity because, for example, if there were esters in the meat and someone ingested that meat then the enzymes of the gastrointestinal tract of humans that digests normal food readily cleave the ester bond.

Chairman

528. Mr. Thompson, just for the benefit of the Panel, would you anticipate to draw some conclusions from these statements? I am not in a position to do so myself.

Mr. Thompson (Canada)

529. I thought that was the purpose of tomorrow's meeting when I would be presenting oral argument. But the general purpose of these lines of questions and a few others that I have is to try and demonstrate that the European Communities use some of these hormones either alone or in combination for zootechnical purposes such as in increasing the rate of production in sheep and cattle. Notwithstanding that other alternative means may be available they continue to use these substances for these purposes. What I would be arguing tomorrow in a like manner is that North America and other places use growth hormones.

Dr. André

530. Mr. Chairman, I think there is a very big difference between the use of such drugs for therapeutical or zootechnical purposes. In very precisely defined animals, as Professor McLean said, and the use of the same hormones or similar hormones in large scale for growth promotion. No scientist has said that it is a bad thing to use these hormones for therapeutical use. The problem is for growth promotion on large scales on all the animals, it is not the same thing as is being discussed now.

Chairman

531. Is it true that for therapeutical reasons this is done under prescription by assistance of the veterinarian, while the growth promotion is not done so? Can I ask this just for my clarification to one of the experts?

Dr. André

532. In Europe it is done under veterinarian control. Directly by veterinarians in some countries or under veterinarian control by prescription in other countries. For growth promotion we have no experience.

Mr. Thompson (Canada)

533. Perhaps I could continue with some of the other parts of my question and it may become clearer as to the reasons I am asking this. My understanding is that it is not so much therapeutic uses as zootechnical uses in order to increase the production of sheep and cattle so that their gestation periods are reduced and happen more frequently.

534. Can the experts help me with whether there are any synthetic hormones used in the European Communities for synchronization of oestrus such as medroxy progesterone acetate or allyltrenbolone, or whether oestradiol is combined with progesterone in some of these proceedings?

Dr. Arnold

535. I would like to ask my colleagues to assist me. What concerns allyltrenbolone there is an exemption in the directives. This substance can be used because, as I said yesterday, it is not suited for growth promotion. Although the name is suggestive, it does not have the properties of trenbolone. Allyltrenbolone is totally different from trenbolone with respect to the biological facts. So this is the first part of my question.

536. The next part I am not so sure. I know that the European Medicines Evaluation Agency and the CVMP has just finished an evaluation of medroxy progesterone acetate under my recommendation and this does not fit into my picture of what is legal in the EC. Maybe you, François, you know?

Dr. André

537. No, I have no information of this regulatory point but in any case this compound is used for zootechnical purposes and not for growth promotion. It will never be evaluated by EC Organization as growth promoters. It is a very different thing. We are speaking about things that are not of concern with growth promotion here.

Dr. Arnold

538. My problem is that it is synthetic and it doesn't yield the natural hormone upon hydrolysis. That is my point. It is certainly not suitable for growth promotion.

Dr. McLean

539. Medroxy progesterone acetate is sometimes included into an intravaginal device along the lines of the second line on table 2.2 of Dr. Arnold's submission. It is used in a number of countries.

540. If I might just add for the sake of clarification, whilst these substances for zootechnical purposes are used in individual animals, it is not unusual in some practices for a significant portion of the herd to be treated over the life of a reproductive season, if I could put it that way.

541. In other words, whilst individual animals are treated you might get 10 or 15 or 20, I am not fully familiar with the production procedures of EU, of the herd treated over one part of the year that is associated with the breeding season.

Dr. André

542. Mr. Chairman, may be you are not very familiar with the reproduction control in farm animals. In this case, may I explain to you that the medroxy progesterone acetate is included in a sponge and the sponge is put into the vagina of the sheep with a small cord. During a period between 10 days, 15 days, two weeks or maybe a little more but it is not a problem. Then the sponge is pulled out with a small cord and then after this treatment the animal comes into oestrus and is then inseminated and becoming pregnant in most cases. Only one per cent fail to be pregnant and this maybe could be a problem for these animals, but usually people try again and it is not really a problem. It is not a problem of residue of synthetic hormones because these animals are bred to have sheep and they will stay a long time in the farm. They will not be slaughtered after such treatment. It is not the objective. It is very different to treating animals for growth promotion and to slaughter them at the end. It should be very clear in your mind.

Chairman

543. Is this a step of preventive medicine or is this a treatment for animals who have difficulties to conceive?

Dr. André

544. It is just a so-called zootechnical practice. That means it is more easy for the farmer to have all the females at the same date on oestrus and to inseminate them at the same time and then to have products at the same time. It is more convenient for management of animals. No more.

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