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EC Measures Concerning Meat and Meat Products (Hormones)
Complaint by Canada

Report of the Panel

(Continued)


VI.121 Dr. Ritter indicated that he was unaware of any data or other evidence of adverse human health effects in countries where meat was produced with the aid of the hormones in question, when compared to countries where the hormones were not utilized for meat production.

Question 10:

How do the potential adverse effects on human health from residues in food in general, and meat in particular, from pesticides administered in accordance with good agricultural practice compare with potential adverse effects from residues of the six hormones in question, when the meat is from animals to which have been administered these hormones for growth-promotion in accordance with good animal husbandry practice and/or good veterinary practice?

VI.122 Dr.  André noted that these parameters were not developed with the aim of comparing the potential health risk of compounds. Each compound with potential adverse effects on human health was submitted to individual evaluations, so as to determine specific ADIs and MRLs (in food of concern). With regards to pesticides, Dr. André pointed out that some of the pesticides might facilitate adverse effects of oestrogens on human health.

VI.123 Dr. Arnold responded that pesticides had biocidal properties and were frequently also otherwise very potent chemicals. Certain groups of pesticides were also used as veterinary drugs, e.g. as ectoparasiticides. These substances might have a significant potential to harm human health if not used according to good agricultural practices. The MRLs established in the EU and elsewhere provided sufficient consumer protection. It appeared that the margin of safety applied when establishing Codex MRLs for residues of veterinary drugs might be somewhat higher if the food baskets used and the calculated Theoretical Maximum Daily Intakes (TMDIs) were compared. JECFA/JMPR and CRVDF/CCPR had started harmonising MRLs for substances which were used in both agriculture and animal production.

VI.124 Dr. Lucier replied that the tools of risk assessment were not sufficiently accurate to determine if pesticide residues or residues of anti-microbial agents posed a greater risk than residues of growth promoting agents. In each case, the risk was somewhere between zero and a small number.

VI.125 Dr. McLean observed that there have been very few documented cases of adverse effects caused by pesticide residues in food, when they were administered in accordance with "good practice". There did not appear to be any proven cases linked to hormonal growth promotants. The use of the word "potential" implied hypothetical cases. Given that hormones had effects on sexual characteristics and metabolic processes, then potentially these would change, if the changes could be perceived or detected.

VI.126 Dr. Ritter indicated that MRLs need not be established for the natural hormones, when used in accordance with good veterinary and/or agricultural practice (see response to question 5). In the case of the synthetic hormones, the nature of the studies used to establish their safety, and the methodological approach for the establishment of MRLs, including determination of a NOEL, calculation of an ADI, establishing a withdrawal period and proposing MRLs, was virtually identical for both pesticide residues and hormone residues. As a result, one would not expect that potential adverse effects on human health would be lesser or greater for hormone residues than might be the case for pesticide residues.

Question 11:

How do the potential adverse effects on human health from residues of carbadox (used in swine production) differ from the potential adverse effects arising from residues of the six hormones in question when used for growth-promotion in accordance with good animal husbandry practice and/or good veterinary practice? Question 30: Further to question 11 and 26, would you consider that the potential adverse effects on human health and/ or animal health from residues of carbadox, monensin, olaquindox, avoparcin, benzylpenicillin, carazolol, ivermectin and organophosphorous compounds are comparable to the potential adverse effects arising from residues of the six hormones at issue when used for growth­promotion in accordance with good animal husbandry practice and/ or good veterinary practice? Are any of the above mentioned substances carcinogenic? If any one of these substances or a combination thereof is administered to the animal, would there always be a residue of that substance in the meat of that animal, even if it is so small that it cannot be detected?

VI.127 Dr. André indicated that carbadox proved to be a genotoxic compound, and consequently no ADI value had been proposed by JECFA (see also response to question 10). Olaquindox was known to be carcinogenic. Dr. André was not familiar with the others.

VI.128 Dr. Arnold noted that as long as the "good practices" were observed, there was no relevant difference. If the lengthy withdrawal time was not observed in the case of carbadox, potentially genotoxic carcinogenic residues of the parent drug and another carcinogenic metabolite were likely to be present in meat of treated animals. In the case of the hormones, only the frequent consumption of injection sites or implants would potentially cause effects on human health.

VI.129 Olaquindox was genotoxic in a number of tests. However the parent drug was extensively metabolised and was not present as a residue if "good practices" were applied. Ivermectin was extremely potent against parasites, but it was safely used in humans for the treatment of e.g. "river blindness" at much higher than residue levels. Carazolol was a hazardous substance for humans with chronic bronchitis which was a substantial part of the general population. In addition, carazolol was administered to the target animals by injection. Benzylpenicillin was absolutely harmless for the general population but could provoke allergic reactions in some sensitized people even at the level of the MRL. Avoparcin was not registered as feed additive on the American continent; its use in the EU had recently been withdrawn. Strict adherence to the identified "good practices" was an absolute requirement for the use of some of these substances. Nearly all of these substances left detectable residues in meat of treated animals under conditions of "good practice in the use of veterinary drugs". At the oral hearing Dr. Arnold added that there is a commercially available alternative for carbadox mainly oxytetracycline.

VI.130 Dr. Lucier indicated that it was difficult to accurately compare risks from carbadox residues to risks from residues of growth-promoting substances (see also response to question 10). However, he expressed concerns about carbadox residues and that the risks from these residues were likely greater than the risks associated with the use of growth promoters.

VI.131 Dr. McLean replied that carbadox and its metabolite desoxycarbadox were not permitted in meat, because the latter compound was carcinogenic. In the case of carbadox, a withholding period was set to achieve the situation where there were no detectable residues in food. The three naturally occurring hormones were normally found in animals and humans. The data supporting the use of trenbolone and zeranol was extensive, with toxicological end-points related to their hormonal effects. Finite residues were permitted for trenbolone and zeranol. In this way any risk of adverse effects was managed through the MRL and safety to consumers was assured.

VI.132 Dr. McLean further noted that olaquindox was considered to be genotoxic and no toxicity studies were available on its metabolites, therefore JECFA was unable to determine an ADI or MRL. Benzylpenicillin was widely used as an antimicrobial agent in animals and humans. Allergenic potential was the major toxic effect and it was recommended that the total intake be kept below 30 micrograms per day for a human. Benzylpenicillin showed no carcinogenic potential. While carazolol showed no genotoxic or carcinogenic potential, it was a potent beta-adrenoceptor blocking agent. MRLs had been established for pig tissues. However, if carazolol was used in pigs to prevent stress during transport to slaughter, there was concern that residues at the site of injection could result in consumers receiving a pharmacologically active dose of the drug. The toxicity and residue data base for ivermectin and related compounds was extensive and the drug was also used in humans. The compound did not show genotoxic or carcinogenic potential and an ADI and an MRL had been established.

VI.133 The organophosphorus compounds (OP) were described by Dr. McLean as powerful neurotoxins, and most of the untoward effects were related to the direct exposure of operators and others. There was a new syndrome of organophosphate - induced delayed polyneuropathy - which was of concern when there was acute exposure.299 The OP had been associated with carcinogenicity and there were reports of acute poisoning associated with the consumption of treated food. Very low levels of the parent compound and/or metabolites might remain, although they could not be detected by sensitive analytical techniques. Dr. McLean did not comment on monensin or avoparcin because of the limited amount of registration data available which was in public domain.

VI.134 Dr. Ritter observed that carbadox was reviewed by the JECFA in 1990. In its review, the JECFA considered data from short-term and long-term carcinogenicity, mutagenicity and reproduction studies with carbadox, and data from mutagenicity and long term studies of its metabolites. JECFA noted that results from several long term feeding studies in rats demonstrated dose-related increases in both benign and malignant tumours at doses above 1.0 mg/kg BW/day. Positive findings were also noted in 14 of the 15 mutagenicity studies reported. JECFA concluded that carbadox appeared to be both genotoxic and carcinogenic. Results from additional studies carried out with quinoxaline-µ-carboxylic acid, an important metabolite of carbadox, indicated that there were no effects on incidence of tumours, even at doses of 100 mg/kg BW/day. In view of the carcinogenic and genotoxic nature of carbadox and desoxycarbadox, a metabolite of carbadox, JECFA was not able to establish an ADI. Notwithstanding, the JECFA recommended MRLs of 0.03 mg/kg in liver and 0.005 mg/kg in muscle of pigs, based on and expressed as quinoxaline-µ-carboxylic acid.

VI.135 The establishment of an ADI and recommendation of an MRL reflected scientific confidence in the expressed residue levels being essentially devoid of risk to humans exposed to dietary residues on a lifetime basis. Therefore, neither carbadox nor the growth promoting hormones should pose potential adverse human health effects as a result of exposure to dietary residues at or below the MRLs specified by JECFA. Notwithstanding, it was noteworthy that carbadox and at least one of its metabolites was both carcinogenic and mutagenic, while the hormones were not considered carcinogenic or mutagenic at biologically relevant doses. In addition, reliable residue monitoring and risk estimation of carbadox residues was somewhat complicated by the presence of bound residues, while residues of the hormones either fell within normal physiological range or could be reliably and easily measured.

Question 12:

Are residues of the six hormones in question found in milk or milk products? If yes, how do the levels of these residues compare to those found in meat from animals to which hormones have not been administered? How do the residue levels in milk compare to those found in meat from animals which have been administered these hormones for growth-promoting purposes? For therapeutic or zootechnical purposes?

VI.136 Dr. André replied that residues of hormones in general are found in milk. However, the comparison with meat levels was not relevant. Moreover, hormones were not supposed to be used for growth promotion purposes in lactating cows, only in culled cows. For specific therapeutic or zootechnical purposes, only individual animals were allowed to be treated with hormones. In this case, the milk was not to be delivered for human consumption, as was the case for many other drugs.

VI.137 Dr. Arnold noted that after injection of approved products (nature­identical molecules) permitted for use in the EU to lactating cows, residues would be found in milk. Depending on the product it could take several milkings before the residue levels would have returned to physiological values. Residues found in milk could be higher, equal or lower, depending on which tissues were compared and depending on many other factors (dose, route, age, sex, withdrawal time etc.)

VI.138 Dr. Lucier indicated that if residues of the hormones in question existed in the human body, then residues would also be present in human milk.

VI.139 Dr. McLean replied that hormones are lipid soluble and therefore pass into the fat portion of milk. More polar metabolites would also pass into milk, but it must be stressed that the hormones should not be used for growth promotion in lactating animals. When the various hormones were used for therapeutic or zootechnical purposes, the doses were much higher, therefore the levels in the tissues were higher. It had to be expected that the levels in milk would also be higher.

VI.140 Dr. Ritter observed that growth promoting hormones were generally only permitted for use in beef cattle and veal calves, and not in lactating dairy cattle. Foxcroft and Hess (1986) reported that, at least in the case of the natural hormones, the residue levels of the administered compound or it metabolites in animal products were insignificant in comparison to the levels of the same steroids to which human subjects might normally be exposed. This could occur either (i) as a consequence of the endogenous production rate of sex steroids in human subjects or (ii) as a consequence of the steroids in meat and/or milk products derived from untreated animals.

Question 13:

What factors and procedures should scientists consider in establishing an appropriate assessment of the potential adverse effects on human health from the use of the hormones in question?

VI.141 Dr. André responded that an appropriate assessment of the potential adverse effects on human health stemming from the use of the hormones in dispute "should be more rigorous than common veterinary drugs because of the duration of their use and the very limited, if any, health benefits to the target species".300 Scientists should consider all data available at the present time in dealing with the adverse effects of each compound (see response to question 8), their metabolites and their mechanisms of action, including their action at the level of exposure. Species-specific metabolite patterns should be compared, using (as far as possible) a combination of in vivo and in vitro experiments. Studies should include long-term feeding trials to address life time exposure. All studies should be performed with combinations of the hormones in dispute prior to registration, to obtain valuable data. The effects of the treatment on the kinetics of other common drugs had to be assayed. Epidemiological studies in humans concerning cancer incidence and other hormone related diseases had to be initiated.

VI.142 Dr. Arnold indicated the following should be considered: pharmacokinetic data including metabolism in test animals and target animals, where available in humans; data (preferably quantitative data) from adequately designed toxicity studies in suitable animal species, including information on genotoxicity/carcinogenicity, and no hormonal effect levels; target animal safety studies; efficacy trials; epidemiological studies and other relevant observations in humans; kinetic residue studies; natural occurrence and human exposure from all sources, including endogenous production of the same or similarly acting substances; experience from the history of use in human and veterinary medicine (if applicable); and known or proposed conditions of use. A marketing authorization should only be given to strictly formulated products (not to the active substances). Conditions of use should be fixed in a binding manner in the approval process.

VI.143 Dr. Lucier replied that there were several factors that should be systematically studied or evaluated if information was not available for assessment of risks from the hormones in question. Of special concern were potential risks for cancer and non-cancer effects (reproduction, development, cardiovascular disease, etc.). Additionally, information on effects in sensitive sub­population should be considered. Sensitivity could be conferred by genetic predisposition (presence or absence of cancer susceptibility genes), age (fetus, children or the aged), gender, existing disease status, nutrition, and co­exposure to other chemicals. These factors needed to be considered, although it was unlikely that information on them would ever be complete for any given substance.

VI.144 Dr. McLean noted that the testing protocols used in countries such as the United States, Canada, the United Kingdom, Australia and by JECFA were adequate to assess the effects of the use of hormones on human health. In addition, there was a need for residue monitoring programmes to ensure that residues in meat were less than any MRL which had been established.

VI.145 Dr. Ritter observed that scientists considered a wide array of toxicological endpoints and risk assessment procedures in estimating potential adverse effects on human health from residues of all chemicals, including anabolic hormones, other veterinary drugs and pesticides. The issue of factors and procedures which were appropriate to the assessment of the potential adverse effects on human health included toxicity studies which established the following: which organs and/or systems were most vulnerable to the toxic effects and under what exposure conditions; the nature of any damage and/or disease produced, and the dose response relationship; the time course for the onset and any progression of the adverse effect; the mechanism responsible for the adverse effect; the relevance of the adverse effect observed in experimental animals to humans; the potential impact of biological mechanisms which led to the adverse effect but which, by virtue of the dose utilized, were not relevant to the assessment of the biological effect in humans (this was particularly important for the hormones in question which were only associated with adverse effects at doses which were not considered to be of relevance to the assessment of human health effects arising from food residues); whether it was appropriate to consider the adverse effects observed as a function of a threshold mechanism, or rather if a genotoxic mechanism was more likely and hence a threshold mechanism would be an inappropriate risk model.

VI.146 In addition, Dr. Ritter noted that it might also be relevant to establish if the nature of the residue was distinguishable from normal endogenous levels - this was particularly relevant for the use of the natural gonadal hormones which resulted in residue levels typically in the range of untreated animals; whether appropriate and reliable methods existed for the estimation and monitoring of residues of the hormones following their use as growth promoting substances; and knowledge of the uncertainty inherent in the hazard and risk assessment paradigm.

Question 14:

What are the potential hazards, if any, to human or animal health of the use of large quantities, or doses higher than those recommended, of any of the six hormones in dispute? And from the administration of these hormones contrary to good animal husbandry practice and/or veterinary practice? Can you think of any incentives or disincentives for farmers to use quantities larger than those specified in the label of the manufacturers or to administer these hormones contrary to good animal husbandry practice and/or veterinary practice? Are you aware of any evidence of such use by farmers?

VI.147 Dr. André indicated that a higher dosage, another route of administration than those recommended for delivery (other location for implants, injectable solutions of hormones, etc.), shorter withdrawal periods, etc., in short, any disrespect of good animal husbandry and/or good veterinary practices, might induce higher levels of residues or changes in metabolite patterns. The first consequence would probably be a modification in animal behaviour and/or health. It was reasonable to think that a higher residue content in meat would enhance the risk of hazards to human health.

VI.148 The anabolic effect of the hormones in question was proportional to the dosage, with a maximum effect. Farmers tried to obtain larger effects through administration of more implants than recommended, although it was not evident that a double dose, even at one time, gave a better response. In some cases, a parenteral administration (e.g. intramuscular injection) produced a more rapid effect than implants, and farmers tried by this mean to obtain faster effects. Disincentives for farmers to use larger quantities would be a decrease of the benefit/cost ratio, but implants were usually cheap. In countries where they were in use for growth promotion purposes, penalties due to higher residue levels detected in meat products compared to the MRLs might also have dissuasive effects on farmers. When five out of the six hormones in dispute were allowed in France, the experience was that farmers tried to give a second dose later. They did not respect the withdrawal period and they injected another dose at half way through the theoretical withdrawal period. Clearly they saw benefit to do this because the effect was longer at the time. Dr. André further reported that during the four to five years when these hormones were allowed as growth promotants in France, the misuse of other hormones continued and the black market was also present.

VI.149 Dr. Arnold noted that there were considerable safety margins built into the established MRLs for the synthetic residues. As long as "good practices" were observed, the calculated theoretical maximum daily intakes of residues would range around 5 per cent of the ADI for both zeranol and trenbolone acetate. It had been shown that the implantation of approximately five times the recommended dose of zeranol would have almost no effect on maximum residue levels in the muscle and liver of steers slaughtered only five days after implantation. When a total dose more than 100­times higher than the recommended dose was intravenously administered as 6 split doses over three days to steers and the animals were slaughtered on the third day after the last dose, consumption of the meat of these animals would still not have caused an above­ADI intake of residues of zeranol.301 The studies available to the 32nd and 34th JECFA showed that residues of trenbolone were highest if heifers were implanted shortly (15 days) before slaughter. With respect to the calculated theoretical maximum intakes, there was no difference whether this implant was the first or the second which the animal had received. From these data, it seemed unlikely that even the frequent use of higher doses, or repeat doses or slaughtering the animals at earlier than recommended times after implantation, could result in residue intakes in excess of the ADI by the consumer. For the three nature­identical hormones, the safety margins (theoretical residue intakes compared with endogenous production rates of the most sensitive sub­population) were much higher than for the synthetic substances.

VI.150 Dr. Arnold had no information with regard to melengestrol acetate, nor regarding incentives or disincentives for farmers to use combinations or illegal "cocktails" of these hormones. Although these pellets and another devices had been developed to give optimum results when the dose was respected, this did not necessarily prevent some farmers using more implants. But this did not necessarily cause higher residue levels in the carcass. On the other side, it was clear that if twice the amount was injected directly, all levels increased in plasma and in tissues, not necessarily in a linear way, but significantly. That was the difference between a slow release device (like ear implant) and a direct injection. On the other hand, the long term release of high doses might influence the pattern of hormone excretion in the animal's body and this was the intention of using such compounds.

VI.151 Dr. Lucier indicated that any increase in the magnitude of exposure would likely increase any potential risks, but he did not consider himself qualified to answer the rest of this question.

VI.152 Dr. McLean responded that the hormones in question, with the exception of MGA, were not well absorbed when administered orally. Grossly excessive doses might have an effect on consumers of meat, but these effects were likely to be mild and transient and could pass without being noticed. The dose prescribed under "good practice" was sufficient to exert a commercially satisfactory response, and there was no advantage in exceeding this dose. The dose suggested by the sponsor gave the optimum response and therefore, within limits, there was no need or benefit in administering more than was suggested. The regulatory authorities also examined the effects of overdosing during the registration process. Most regulatory authorities, including JECFA, required that data for residues setting did take into account dose rates that were in excess of what was normally used (generally at least twice and sometimes more) so that the effect of overdosing or variations in uptake could be seen. In countries where the use of these compounds was permitted, there were good educational campaigns for farmers as to the correct use and the reasons why the prescribed dose should not be exceeded, and the penalties that existed if one did. The results from residues surveys showed that, by and large, there was no exceeding of the MRL. In Australia, trenbolone and zeranol had been targeted in residue surveys very specifically looking for violations, and to all intents and purposes violations did not occur. Even if there was misuse, and that was difficult to prove, there were still no residues that exceeded the MRL. A similar situation existed with the naturally occurring hormones, where it was not possible to determine whether or not a violation had occurred because the levels that were found in the carcass fall within the normal range.

VI.153 Dr. McLean observed, however, that in countries where the use was not controlled and there was no farmer education campaign and where it was difficult to apply a penalty, then the MRL was significantly exceeded. One of the important factors of legalizing these compounds was to conduct an education campaign and to put in place monitoring procedures to ensure that the MRL is not exceeded. What was important with the maximum residue limit is to understand that it was a legal limit and not a health limit. In other words, exceeding of the MRL did not represent a hazard to health but rather a limit at which the authorities took action. However, to exceed the MRL would not be considered to be good practice.

VI.154 Dr. Ritter noted that it was very difficult, if not impossible, to estimate potential hazards which might be associated with the administration of the hormones contrary to good practice, as the magnitude of the potential hazard would be related to the nature, extent, frequency and magnitude of the inappropriate administration. It had been reported that in the case of the anabolic hormones and using commercially available implants, repetitive implantation had only little influence on the residue profile.302 Similarly, full and half-dosages led to similar hormone levels in edible tissues which, in the case of the endogenous hormones, were within the physiological range. Further, unlawful and improper use of oestradiol might result in residue levels some 300-fold in excess of established tolerance limits, and yet it was virtually impossible to visualize any hazard to humans ingesting meat from animals treated with zeranol.303 Similarly, when steer calves were implanted with zeranol in accordance with recommended procedures, the margin of safety for consumption of edible products was greater than 25,000 and 150,000 for liver and muscle, respectively. While this work did not specifically address the issue of potential abuse, the large margins of safety postulated by the authors suggested that even under limited circumstances of abuse, it was unlikely that consumers would be exposed to unacceptable risks.304 In countries where use of these hormones, the six hormones in particular, had been permitted for a very extended period of time, most notably Canada and the United States, monitoring and compliance programmes which had been conducted for many years consistently demonstrated that residue levels were entirely within recommended limits and that instances of violative residues, that was residues which would indicate abuses taking place, had almost never been reported. It seemed that at least in those jurisdictions where use was lawful, the practicality of abuse had never become a reality. There were few and isolated examples of violative residues in those countries where use had been permitted.

Question 15:

What are the consequences in terms of potential hazards to human or animal health from the use of legally marketed combinations, if they exist, or illegal "cocktails" of the six hormones in dispute for animal growth promotion? Have legally marketed combinations been subject to the same testing regime as each of their individual components? Is there any evidence of synergistic effects of combinations of hormones? Can you think of any incentives or disincentives for farmers to use combinations or illegal "cocktails" of these hormones?

VI.155 Dr. André replied that specific consequences stemming from the use of legally marketed combinations were not known. If they existed potential hazards could be due to synergistic and/or additive effects of the residues. This answer was also valid for illegal "cocktails" of the six hormones in which more than two components could be present. However there was another important potential hazard from the systematic use of these combinations: their use could result in modifications of kinetic parameters of other drugs. For example, trenbolone and testosterone were shown to dramatically decrease the elimination rate of sulfamethazine, trimethoprim and antipyrine in goats, with opposite experimental results in rats. As a consequence, residue levels could be higher than the MRLs at slaughter, even when legal withdrawal periods were respected.305 Recently, the increase of the level of beta agonist residues in liver owing to concomitant oestradiol treatment had been demonstrated in calves.306

VI.156 Dr. André was aware of only one combination (TBA + oestradiol) having been assayed by the JECFA in the context of residue determination in steers. No other combinations had been tested whereas individual components had been tested for toxicological effects. Evidence of synergistic effects of combinations of hormones existed and were well studied mechanisms. For example, concerning endocrinological therapy in humans, combinations of oestrogen and progestin hormones were used; oestrogens induced the synthesis of specific receptors for progestins, which could then exert their specific action. Legally marketed combinations had been developed on the basis of synergistic effects of their components on growth promotion.

VI.157 Incentives for farmers to use combinations (legally marketed) or illegal "cocktails" of these hormones were frequently reported by official control bodies, since farmers tended to think that the more hormones used, the better the anabolic effect. Moreover, interactions between these hormones and other endogenous biochemical parameters (e.g. corticoids, IGF, etc.) were of great importance for human health and could be documented.

VI.158 Dr. Arnold noted that fixed combinations were registered in the form of strictly formulated veterinary medicinal products and were different from illegal mixtures for which the term "cocktail" had been coined in Europe. Fixed combinations were not only used for growth promotion but also for the purposes permitted in the European Union. These combinations were approved and registered by the competent authorities under the respective rules governing veterinary medicinal products. The applicant had to justify the combination and had to demonstrate the quality, efficacy, target animal safety and consumer safety of these products before they could be marketed. For these types of registered products, there was no evidence of a hazard to human health.

VI.159 Dr. Arnold reported that the pharmacodynamic and toxic effects of practically all possible combinations of oestrogens, progestins and androgens had been studied in whole animals, organs, tissue and cell cultures, and other in vitro systems under a great variety of conditions. There was ample evidence of both synergistic and antagonistic effects. Such effects physiologically played important roles in endocrinology and metabolism. The current understanding of these phenomena clearly indicated that concerns over human health hazards arising from combinations of minute amounts of residues in meat were not justified.

VI.160 The flourishing grey market in other veterinary medicines within, for example, Germany showed that farmers tried bypassing official distribution channels when purchasing otherwise licensed high quality products, mainly in order to save costs and prevent having to pay the veterinarian. To what extent "good practices" in the use were otherwise followed remained subject to speculation. It seemed, however, that not all rules were violated at one time. The situation with prohibited substances (e.g. hormones, chloramphenicol) and with abused substances (e.g., clenbuterol) was completely different. There was clearly a black­market where the "dirty products" prevailed. The availability of reasonably priced legal alternative products could be an incentive for many farmers to legalise their practices. Whether this would eliminate illegal cocktails now that the black­market has been well established, remained entirely speculative.

VI.161 Dr. Lucier indicated that there was a definite research need in area of synergistic and/or antagonistic responses to combinations of endogenous or exogenous hormones. Based on current knowledge, it was likely that interactions existed but it was impossible to say with any degree of confidence for a given combination whether the interaction would be synergistic, additive or antagonistic. There was limited evidence to suggest that synergistic responses were occurring although the relevance of these findings to human risks had not been shown. Dr. Lucier noted that the same combinations of hormones, at certain levels, could have both some adverse health effects and some positive ones.

VI.162 Dr. McLean replied that the legally marketed combinations had been examined by regulatory authorities to ensure that residues did not exceed levels seen in normal animals or the prescribed MRL. There were synergistic growth promoting effects seen in treated animals. Illegal "cocktails" were mostly found in countries where the use of hormones was prohibited, resulting in the establishment of an illegal market. They were not normally used where the full range of drugs was available because there was no advantage in the use of illegal drugs, and registered products were usually cheaper and of consistent quality.

VI.163 Dr. Ritter noted that when growth promoting hormones were used as combinations, this use did not alter existing MRLs which had been either recommended internationally or established by national regulatory authorities, and hence the use of hormone combinations was not likely to have any direct adverse consequences in terms of human health. In the case of "illegal" cocktails, it was impossible to speculate on the potential for adverse effects in either humans or animals, as this potential would be a function of the nature of the cocktail, the species of use, the dose, frequency and duration of use, and a range of other factors which could not be assumed.

VI.164 In general, safety (toxicology) evaluations of drugs, pesticides and other food contaminants were carried out on single compounds only, rather than as combinations. There were several reasons for this approach which included prior pharmacological and biochemical knowledge that toxicity associated with combinations was not likely to produce effects greater than the sum of the individual components. On a more practical level, it was difficult to contemplate the broad range of possible combinations which would be the subject of testing. Finally, as different commercial interests might be involved in the production and sale of various growth promoting hormones, proprietary interests would make it unlikely that combinations could be evaluated toxicologically. In some cases, the efficacy of hormone combinations had been evaluated. In the case of combinations of trenbolone with zeranol or oestradiol, for example, it was found that (i) the combinations were equivalent in young bulls and steers, (ii) anabolics containing oestradiol were more effective in veal calves, and (iii) the composition and quality of the meat was not modified by the use of combinations when compared to single use.307 As with any drug or unlawful drug combination, farmers sometimes were under the incorrect impression that combinations which had not been evaluated might provide significantly enhanced efficacy over those which had been approved for use. Such improper use of illegal cocktails could affect withdrawal times and residue limits and might, in some jurisdictions, result in compliance and enforcement as disincentives to the unlawful use of non-approved cocktails. Dr. Ritter noted that it must also be recognized that the quest for ever improved yield could lead some producers to the use of unapproved drug combinations.

VI.165 Dr. Randell indicated that the monographs which were prepared by JECFA at the 32nd session clearly indicated that trials were done on mixed implants as well as on single substance implants. JECFA had considered such mixtures as 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 pharma-kcenetics of these substances as they were gradually metabolized and excreted by the animals were studied by the experts at that time. Moreover, the information which was available to JECFA included carcinogenicity studies for all of the substances concerned.

Question 16:

Which substances in addition to the hormone compounds at issue are present in the commercially available products marketed for animal growth promotion? Are there any potential adverse effects on human or animal health? Question 33: Further to question 16, are there other substances in human implants potentially dangerous to human health?

VI.166 Dr. André noted that if the question referred to the excipient or to potential sub-products of synthesis, these data, as property of manufacturers, remained confidential. Concerning the simultaneous use of other drugs marketed for growth promotion (e.g. antibiotics), their residue levels could be modified by the use of the hormones (see response to question 15), so that a potential adverse effect on human health could appear.

VI.167 Dr. Arnold indicated that other growth promoters (antibacterials) were used under the feed additives legislation of the European Communities (e.g., flavomycin, virginiamycin, zinc bacitracin, salinomycin, monensin, lasalocid). The review process was centralised. There were no known potential adverse effects on human or animal health if these additives are properly used. The use of glycopeptide avoparcin was recently withdrawn as a precautionary measure because of some suspicion that glycopeptid­resistance selected by the use in animal production could be transferred to human­pathogenic enterococci.

VI.168 Dr. Lucier responded that there are many known cases of the presence of oestrogenic substances arising from plant products, pesticides and industrial contaminants. It was likely that the oestrogenic potency of these substances, taken together, exceeded that from meat residues of the six hormones in question.

VI.169 Dr. McLean stated that there were a number of non-active components used in the implants to ensure that the drug was delivered over the life of the implant. These included a carrier for the drug and an inert matrix which made up the implant. The formulation was approved by the regulatory authorities in each country. The components were often used in human and other animal drug formulations and their safety had been established.

VI.170 Dr. Ritter replied that the composition of commercially available products was generally regarded as proprietary information. Consequently, he had no direct knowledge of the identity of the substances other than the hormones which might be present in commercially available hormone preparations.

Question 17:

What are the implications for human or animal health of residues from misplaced implants or improper administration, i.e. when administered differently than indicated in the label of the manufacturer, of any of the six hormones in dispute ?

VI.171 Dr. André indicated that the consumption of meat (or of any meat-containing food preparation) containing a misplaced implant could be a hazard for human health, in particular for children, fetuses, pregnant women or immunodeficient people. Misadministration of any of the six hormones in dispute could change the kinetics of elimination of these hormones and induce a subsequent higher level of residues. This could become a real health hazard if there was systematical misuse.

VI.172 Dr. Arnold observed that there might be a concern only where misplacement (growth promotion) or improper administration (therapy, zootechnical treatment) lead to consumption of a whole implant or injection site. Otherwise, residues remaining in the carcass of the respective animal would have no effects, even if they were higher than would be expected if "good practices" had been applied. The worst case assumption was that a whole fresh implant containing oestradiol or an ester of this hormone is consumed, because the implanted dose was higher than the doses injected for the other purposes and orally active oestradiol­doses were lower than the required doses of the other hormones. If this entire dose was ingested at once, only transient effects on hormonal feedback mechanisms would be expected. Clear hormonal effects would occur if an entire injection site was processed, e.g., into a meat containing product and the same person would eat the whole product in divided portions over a couple of days.

VI.173 Dr. Lucier stated that improper or misplaced implants could very well increase residues, thereby increasing the potential risk of the hormones in question. Preventive strategies for misuse needed to involve veterinary supervision, educational programmes, monitoring and stiff penalties for abuse.

VI.174 Dr. McLean replied that the implants would likely be detected if they were eaten because the matrix could not be chewed. If swallowed, they would not be digested but would pass through the human gastrointestinal tract largely unchanged. The implications of misplaced implants may not be of great concern because they were often placed under the skin and removed at slaughter or during processing. In order to facilitate correct and easy administration, applicators were generally available from the pharmaceutical companies. One of the features of injections subcutaneously in the ear was that there was no massive reaction at the site. It was specifically designed, and all the residue studies were carried out, with the implant injected in the ear. The aim of injecting it there was to get prolonged and slow release at low levels over a period of time. It was specifically designed to be that way. Moreover, the injections were usually implanted in the ear because it was very easy to palpate a pellet or an implant under the skin of the ear which was a second way of identifying treated animals.

VI.175 Dr. Ritter responded that the growth promoting hormones were generally administered as feed additives or as implants. In the event that implants were implanted at sites other than those recommended, it was possible that these sites contain unacceptably high residue levels if utilized as a source of human food. The selection of the ear as a site of implantation rather than other sites was because it was a tissue which normally did not enter the food chain and it made identification of the source of the material very easy. Injection site residues, which could be much higher than normal tissue residue levels, were thus extremely unlikely to enter the food supply. The extent to which acceptable residue levels might be exceeded would depend on the exact site of implantation and the withdrawal period involved. The implication for human health would in turn be related to these two variables.

VI.176 Dr. Ritter indicated that illegal injection of oestradiol preparation could produce injection site residues which largely exceeded tolerances. In the case of feed additives, improper use might imply use of approved drugs in non-approved species, improper dose, improper combinations, improper duration of use and improper withdrawal periods. However, the provision of human safety was assured through the establishment of maximum residue levels, levels considered to be safe if consumed by humans in the diet for an entire lifespan. In the event that any of the improper use conditions noted above occurred, and to the extent that such improper use would impact on final residue levels, human safety was assured through appropriate monitoring of the food supply for compliance with approved MRLs.

Question 18:

What are the effects on growth promotion of the use of female hormones on male animals and vice-versa? Are there any potential adverse effects on human or animal health from such use?

VI.177 Dr. André said that the effects of hormones on growth promotion was sex-dependent. The use of male hormones associated with female hormones (ratio 10:1) in heifers had the best anabolic effect without sexual behaviour problems and vice-versa. Concerning the human health, the level of residues had to be taken into account, whatever the gender of the meat producing animals. Concerning animal health, the use of oestrogenic compounds in male animals was shown to result in squamous metaplasia, hyperplasia of the collecting ducts and fibromuscular hypertrophy in the prostate and bulbo-urethral gland, fibromuscular hypertrophy and hypoplasia of the epithelium in the seminal vesicles and epididymis and impaired testicular development. In female animals, oestrogen treatment resulted in squamous metaplasia and fibromuscular hypertrophy in the Bartholin's gland, hyperplasia and secretory activity in the vagina and cervix, and impaired follicular developments in the ovaries. The latter could also be observed when females were treated with androgens, impaired follicular developments in the ovaries sometimes resulted in cystic ovaries.

VI.178 Dr. Arnold indicated that supplemental oestrogens in castrated males increased growth rate, presumably through an increase of endogenous levels of growth hormone, improved feed efficiency and reduced aggressive behaviour. Testosterone was mainly used to slow down the release rate of oestradiol because blood levels required for anabolic effects could not be reached with implants. No adverse effects were known on humans. The use in animals of hormonally active growth promoters might have behavioural side­effects in individual animals.

VI.179 Dr. Lucier observed that some effects, possibly adverse, could occur in the animals receiving the growth-promoted substances. These effects could include feminization of male animals and masculinization of female animals based on both molecular and biological endpoints. These effects should not occur in people eating meat containing residues at the MRL of the hormones in question.

TO CONTINUE WITH EC MEASURES CONCERNING MEAT AND MEAT PRODUCTS (HORMONES) COMPLAINT BY CANADA


299 M. Lotti, Toxicology 21, (1992) p.465.

300 Bridges, 1995 EC Scientific Conference Proceedings, p.250.

301 Food and Nutrition Paper 41, pp.44-45, FAO (1988).

302 Hoffman and Evers (1986).

303 Truhaut et al. (1985).

304 Sundlof and Stickland (1986).

305 Van Miert (1988).

306 Kuiper, 1995 EC Scientific Conference Proceedings, p.377.

307 Bouffault and Willemart (1983).