The EU precautionary bans of animal feed additive antibiotics

Toxicology Letters 128 (2002) 35 – 44 www.elsevier.com/locate/toxlet

The EU precautionary bans of animal feed additive antibiotics D. Michael Pugh Casas Cortijo 247, 11310 Sotogrande, San Roque, Cadiz, Spain Dedicated to the late Philip Chambers

Abstract Toxicologists, with good reason, will feel that the biological safety of chemical products across the market sectors rests largely on their efforts. However, one sector has received much adverse attention from the media, consumers, politicians, legislators and advisory groups in recent years. It is food animal production in intensive systems and, within those, various types of chemical additives included in the compound diets fed. No additive class received more adverse comment than those antibiotics used for the purpose of enhancing the efficiency of animal production. This paper considers the safety of the antibiotic feed additives (AFAs) against the background of the regulatory measures in place, defines their role and describes the relevant concerns. It closes with comment on the microbiologically-based health risk which underpinned the AFA bans and sounds a warning over the precedent created by the use of the precautionary principle in the recent banning of six of their number. © 2002 Elsevier Science Ireland Ltd. All rights reserved. Keywords: Antibiotic feed additives; Safety assurance; Banning; Socio-economic factors; The precautionary principle

1. Introduction Increasingly we live in a world in which the consumer expects absolute safety from his purchases and in which politicians and others attempt to achieve that unreal level of expectation. Seem The author wishes to make plain that although he was a member of the Council working party which drafted the 6th Amendment Directive, of the SCAN when it adopted the Opinions cited above, of the scientific consultant team which assisted Pfizer’s lawyers and was present for the hearings of Case T-13/99 at Luxembourg, the speculations made, opinions offered or questions asked in the above paper are to be ascribed only to himself. E-mail address: [email protected] (D.M. Pugh).

ingly, consumers prefer to believe that absolute safety-in-use of their purchases is deliverable and they press for the provisions by which it could be delivered. Reflecting also the ambitions of the legislators, legislative provisions are sometimes specified beyond the then-existing capability of science. The so-called Sixth Amendment (Council Directive, 1979) in that way obliged toxicologists to agree a standard set of safety test methods which were first used for the regulation of dangerous substances within the EU. Further legislation lead to their use across several other regulated sectors of the EU market, including the animal feed additives which are the topic of this paper.

0378-4274/02/$ - see front matter © 2002 Elsevier Science Ireland Ltd. All rights reserved. PII: S 0 3 7 8 - 4 2 7 4 ( 0 1 ) 0 0 5 3 1 - 8

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The sudden banning of 6 of the 13 authorized AFAs from the European Community suggested to some a failure of that system, or a worrying departure from the science-based rationality which had previously been determinant in the regulation of chemical risk. To others it was a principled stand against the drugs industry and factory farming methods and a necessary, urgent action against a serious health risk. This paper provides some insights into those views, but begins, using medicines as the example, with a brief reminder of the routes to today’s chemical products of assured safety.

2. The safety of medicines In Britain, limiting the points of sale and of access to poisons and medicines was an early approach to safety rooted in the various Pharmacy, Dangerous Drugs and Poisons Acts. From them began the tradition of joint contributions from health-care professionals, science, and legislators to the supply and use of medicines which were safe, efficacious and of a constant quality. A detailed review of the evolution of the safety of medicines is not the aim of this paper. Suffice it to say that the legislation in those areas has reached its present level of sophistication inter alia by progressively raising the standards which drug manufacturers had to meet if they were to continue to market their products, or were to continue to be allowed to bring new products to the market. Commonly, that legislation required that manufacturers provide to regulatory authorities extensive safety data prior to marketing. In Britain, the Medicines Act (1968) founded the requirements for product quality, safety and efficacy as understood today following their incorporation into Community law. Later, industry came to call those pre-marketing requirements ‘‘the three hurdles’’.

3. The three hurdles; quality, safety and efficacy The earliest aim in improving the quality of

medicines was to provide to the medical practitioner under an agreed name, a product which would always contain the same amount of the same chemical substance which would itself be of the same designated standard of chemical purity. This, the chemical safety of medicines, was addressed by the pharmacists and their means was the inclusion in official pharmacopoeias for each named medicament of a monograph describing the minimal compositional criteria with which the medicine must comply. Importantly, the tests, which should be used to ensure that compliance were also defined. By a succession of agreements, the early city-based pharmacopoeias were amalgamated into regional, national and, later, international publications, which underpinned the universal standards of purity and composition which the prescribing professions enjoyed throughout much of the last century. This ensuring of the constancy of drug quality allowed dose/effect predictability and aided patient safety by ensuring that medicines were free of unacceptable levels of chemical contamination. However, ensuring dose/effect constancy presented a different challenge when the medicines were batches of crude plant preparations or animal tissue extracts because, while their effects were known, most were of unknown chemical composition. Pharmacologists responded by developing a procedure which could quantify the potency of each batch of a natural-product derived medicine by describing it in terms of the potency of a standard preparation. This biological effect-based procedure, quantitative bioassay, allowed biological preparations of variable or unknown composition to be used in clinical medicine with acceptable reliability. The gradual replacement of preparations whose dosages were expressed in arbitrary biological units of activity reflected later successes in identifying and synthesizing their active principles. It was the thalidomide experience which then drove legislators to ensure the biological safety of medicines. This required their toxicological properties to be evaluated pre-marketing in a battery of studies sufficient to reveal all then-known manifestations of toxicity. Those studies yielded find-

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ings, which could be used either to exclude, or to predict the nature and frequency of occurrence of unwanted effects following the clinical use of the product. They established safety by identifying the threshold dosage or exposure conditions above which adverse effects began to be seen in acute and long-term studies. To exclude an unwanted effect, it was necessary not to exceed the experimental animal lowest threshold dose as extrapolated to other target animals, including man. Using that ADI/TDI approach, toxicology contributed also in the many other sectors in which chemical products could be used with benefit, even benefits sometimes accompanied by risk, as with pesticides, herbicides and industrial chemicals. For many of these products, toxicological safety evaluations provided the basis for risk assessments, providing as they did data on hazard identification and characterization. By adding data on human exposure assessments, toxicologists could move to the heart of risk assessment by confirming or rejecting the adequacy of the exposure-determining, manufacturer-proposed, user recommendations for the product, as was the case for the animal feed additives. This sometimes brought toxicologists into conflict with those who believed that while risk assessment was a proper role for scientists, risk management decisions should be voiced only by risk regulators. Efficacy was for many years established on the basis of anecdotal accounts obtained by and from clinicians. The efficacy hurdle was more rigorously addressed when the second half of the last century saw the introduction and adoption of extensive, well-designed and well-controlled clinical trials for establishing and/or comparatively evaluating the efficacy of medicines. This period accelerated the disappearance of some older remedies over whose efficacy there had perhaps long been some doubt.

4. Extra-sectorial inputs The above overview confirms the founding role of those professions which supplied and/or

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used medicines, emphasizes the refining contributions of analytical chemistry, pharmacology and toxicology and the defining role of the legislature. However, the political process, which appoints the legislators is, by its nature, also open to inputs from others. More recently consumer organizations have voiced concerns, rational or otherwise and they too have come to influence the content, interpretation and application of chemical safety legislation. The environmentalists, either as scientists, economists or simply just as enthusiasts have also had impact. As attitudes to the rights of animals have been ever more forcibly expressed, so have campaigners put the conduct of adequate animal-dependent safety studies under increasing pressure. A related concern for farm animal welfare, again largely driven from outside the sector, has been brought to bear in a campaign for a more natural approach than intensive systems in animal production, irrespective of economic considerations. For many consumers, in a time of plenty, the need for food has changed to a demand for choice between foods and for some that choice includes the methods used in the production of animal products. The raising of food animals in intensive systems has received much media, consumer, welfarist and legislator attention in recent years. Farm animal welfare considerations and the practice inherent in intensive systems of including various classes of chemical additives in the diets to be fed to such animals have driven that attention. No additives have received more adverse publicity than the antibiotics added to animal feed for the purpose of enhancing the efficiency of animal production. The remainder of this paper, after a brief justification of intensive production, using pigs as the example, will focus the safety themes of the earlier sections on the feed additive antibiotics. It will offer comment on the present controversy over their use, a controversy so intense that not only have several already EU-approved additives been banned within the EU, (Commission Directive 1997; Council Regulation, 1998) but that ban is itself under challenge at the European Court (Case 1999).

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5. The intensive production of animals Classically, and preferably, in the green minds of those who assume that anything natural has to be the healthiest option, animals should live and feed in a habitat which approximates closely to what nature intended. In Britain, what is remembered as traditional agriculture had its cows in fields (if only for part of the year), its sty-housed pigs enjoyed at best a brief period in the farmer’s orchard, while those chickens lucky enough to escape the fox scratched noisily around the farmyard. By the 1950s, even that style of animal production was changing as farmers strove to produce more meat for an ever more affluent public and strove, in the UK under the government’s cheap food policy, to keep production costs low. That effort resulted in a move from extensive to high-density production systems. Worldwide, it was intensivization which allowed farmers to meet the consumer’s demands for more meat, stable quality and lower prices. Through intensivization production efficiency improved, evident as a reduction in the time taken to achieve slaughter weight and by the use of less feed to produce a unit quantity of meat. The Danes realized early that energy wasted by pigs wandering and rooting naturally was energy better used for growth. They realized that energy used in maintaining body temperature was also energy lost to meat production. Their solution was to raise in the one large house groups of pigs from weaning until boarding the lorry for the slaughterhouse. In those houses pigs would live, sleep, be fed a standard, complete diet, take minimal exercise, be warm and fatten more economically. Rapidly, the Danish Pig House became a must for competitive pig farmers. Such is still the norm for much of Europe’s pig-meat production, but the system has long been recognized as bringing problems as well as advantages. In a small space, animal to animal contact and a shared airspace ensure that infectious diseases can spread very efficiently. Disease control became essential to the continuous production of pigs in intensive systems and disease prevention was the ideal. Happily, the 1950s were also the period which saw the greatest increase in the availability of antibi-

otics. Soon, strategic medication of pigs and other species to prevent disease was an accepted cost in intensive production systems.

6. Antibiotics in animal production At that time there was also much research into dietary factors which could increase the efficiency with which animals gained weight. Among the novel additions to animal feed found to be advantageous in that context was the dried waste material from antibiotic fermentation tanks. Most of the benefit was shown to arise from the trace amounts of antibiotic contained in these novel feeds. So began the soon to become widespread practice of adding antibiotics to feed solely to enhance production efficiency. It is helpful at this point to distinguish clearly between the various strategies for using in-feed antibiotics in intensive production systems. Antibiotics are used in full therapeutic doses for periods of up to a few days in the treatment of disease in those animals, which are sick. The same antibiotics can also be used in exposed but still healthy animals in full, therapeutic doses for the prevention of disease. Originally, some of the same antibiotics were used daily by inclusion in the diet in very small doses solely to enhance the efficiency of production in intensive systems. There were always those who saw danger in one or more of those practices. Microbial resistance to antibiotics was first recognized soon after the introduction of penicillin into clinical medicine. It was then already known that some bacteria capable of causing disease in animals could move to humans and cause the same disease, a zoonotic infection. It was, therefore, suggested that the non-essential use of antibiotics as mere adjuncts to animal production was to risk their devaluation for treating zoonoses. The subsequent recognition of infectious drug resistance as a means for the dissemination of resistance determinants among gut pathogens reinforced the concern of some physicians over the wisdom of allowing any use of antibiotics in veterinary medicine, let alone in animal production. In Britain, that debate saw the publication of the Swann Report (1969). That

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document made a number of recommendations, among which were that no antibiotic which was used for therapeutic purposes in human or veterinary medicine should continue to be used for the enhancement of animal production. The consequence was the development of novel antibiotics, whose commercial exploitation was solely as additives for incorporation in the compounded feeds dominant in intensive production systems. In this way it was presumed that any resultant resistance would be of no consequence to animal or human therapy.

7. Feed-additive regulation in the EU Shortly, the recommendations of the Swann Committee were to influence the microbiological safety content of Council Directive 70/524, which was to regulate the marketing and use of all additives to animal feeds in the EEC (Council Directive, 1970). Unlike the situation for medicines and veterinary medicines, the regulation of animal feed additives was to be fully harmonized from its inception. Directive 70/524 had, therefore, in 1970 provided also for the establishment of the Standing Committee for Feedingstuffs (SCF) to maintain the additive authorization and registration scheme. As a further provision, in 1976 the Commission established, to advise it, a Scientific Committee for Animal Nutrition (SCAN) composed of independent experts (Commission Decision, 1976). The SCF could then refer to SCAN for an Opinion, any additive question over which it had doubt, but routinely referred every submission which concerned an antibiotic. Directive 70/524 brings to bear on the feed additives the standards of quality, safety and efficacy described earlier in the case of medicines. However, the safety concerns are not only for the animal which consumes the additive with its diet, but also for the human who consumes unknowingly any residue of the additive which might be present in food of animal origin. Animals are fed the additive daily for the greater part of their production lives and the consumer could be exposed to residues for the greater part of a lifetime.

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While most patients accept medicinal risk because of the expectation of benefit, feed additive residues would be without benefit and always unwanted by the consumer. As a zero residue remains an ideal, AFAs, unlike medicines, were always subject to long term, including carcinogenicity, testing. Additionally, their dossiers must always contain analytical methods, which would enable their mandatory monitoring in premixtures, finished feeds and animal tissues. Finally, all additive-derived excreted material is to be identified and subject to studies of its fate within and impact upon the environment. It was of course over the microbiological safety of those feed additives which were antibiotics that the Swann Report influenced 70/524. No antibiotic could be used as a feed additive if it should ‘‘for serious reasons concerning human or animal health…be restricted to medical or veterinary purposes’’. Also ‘‘at the level permitted in feedingstuffs, treatment or prevention of animal disease is excluded’’. Proof of microbiological safety later included an ‘‘investigation of spectrum of action by means of MIC determinations in a selection of pathogenic and non-pathogenic organisms, both Gram positive and negative; a search for cross-resistance to therapeutic antibiotics in mutants chromosomally resistant to the additive; field tests to investigate the ability to select for resistance and to monitor the proportion of resistant organisms over time; an investigation of the transmissibility and multiplicity of that resistance; determination of the effect of the additive on the intestinal flora, including the excretion of pathogens’’. The same test guidelines also required additives to undergo the full rigour of specified studies performed in compliance with good laboratory practice and with due observance of the protection of animals used for experimental purposes when establishing the attributes of quality, safety and efficacy (Council Directive, 1987). Partial re-evaluations have been performed whenever a manufacturer sought a new use or a change of use for an already authorized additive. A 1996 directive, amending 70/524 for the fifth time, provided for a 10-yearly full re-evaluation of all AFAs (Council Directive, 1996).

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8. AFA banning provisions Given that the systems developed to ensure medicinal substance safety have been applied to the other classes of regulated chemicals in the EU; given that for animal feed additives, and for the group of antibiotics especially, safety studies are more extensively specified; given the extent of the risk-managing controls over the use of the additives during feed-compounding and in animal feeding; and given their confirmatory monitoring both in feed and in animal produce within each Member State, it is reasonable to ask what could have caused the Commission to ignore the contrary advice of the SCAN and move for the banning of avoparcin, ardacin (Commission Directive, 1997), bacitracin, spiramycin, tylosin and virginiamycin (Council Regulation, 1998) when all had enjoyed decades of beneficial and seemingly problem-free use. The means for the temporary removal from the market of approved feed additives was provided in Article 11 of Council Directive 70/524. Any Member State could institute a temporary ban within its territory if ‘‘as a result of new information or a re-assessment of existing information’’ it ‘‘has detailed grounds’’ … that its use ‘‘constitutes a danger to animal or human health or the environment. It shall immediately inform the other Member States and the Commission thereof, giving reasons for its decision. The Commission shall, as soon as possible, examine the grounds cited … and consult the Member States within the SCF; it shall then deliver its opinion without delay and take appropriate measures’’. Note that the Commission is given discretion and a duty to act. Bases for terminating authorization were evident from Art 7 of 70/524. The health grounds remain today ‘‘an adverse effect on human or animal health or the environment; harming the consumer by alteration of the characteristics of livestock product; when, for serious reasons concerning human or animal health its use must be restricted to medical or veterinary purposes’’. Presumably, then, the bans followed from the contravention of one of these conditions, a Member State had the detailed grounds to substantiate

that, the Commission discussed the matter at the SCF and the SCF voted to adopt the Commission’s draft measure. However, had all of the above steps been uncontroversial, Pfizer, the manufacturer of the banned antibiotic Virginiamycin, acting with the support of the European Animal Health and Feed Additive Industry Associations, would hardly have spent two and a half years contesting the ban at the European Court. In essence, Pfizer claims that the Commission acted with unnecessary haste, with insufficient proof, failed to observe its own circulated draft Precautionary Principle Guidelines, acted contrary to the written Opinion which it sought from SCAN and without a re-consultation, cited sometimes inappropriately from that Opinion in the recitals to Council Directive 2821/98 and was motivated, at least in part, by considerations other than a health risk. Alpharma, the company which marketed bacitracin, is also in dispute with Commission and Council. For its part, the Commission rejects the cases and claims that its over-riding duty is to act to ensure a high standard of human health throughout the Community. Judgements are pending at the time of writing.

9. The issue For each banned antibiotic, toxicologists can comfort themselves that the debate arose over a novel question, and one of microbiological safety. It was claimed that when used in production animal diets, the AFAs selected for resistance in Enterococcus faecium, a gut commensal found in animals and man and used in the manufacture of some health foods. Resistant examples were recovered from pig and poultry faeces in a high proportion of samples and could also be shown to occur on uncooked meats at the point of sale and even within hospital kitchens. Those findings lead to the proposal of a possible role for the commensal E. faecium in resistance gene dissemination both within and between bacterial and animal species. During the late 1980s, clinical medical interest in E. faecium rose when its status changed from contaminant to pathogen, especially in intensive

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care units and in immune-impaired patients. For some E. faecium infections, vancomycin was the last-remaining effective antibiotic. The public was hearing ever more frequently about such ‘‘antibiotics of last resort’’. It was, therefore, of concern when it was shown that the AFA avoparcin, a member of the same glycopeptide family as vancomycin, lead in animals to the selection of E. faecium resistant not only to avoparcin, but also to vancomycin. It was shown also that the high level resistance mechanism of avoparcin-selected animal isolates depended on possession of the same gene, vanA, as that found in vancomycin-resistant human isolates. It was suggested that the symptomless carriage of vanA-bearing E. faecium in the non-hospitalized community could depend on exposure to raw meats, or environmental sources. Carriers could later be admitted to hospital with a condition which might require vancomycin. That, by selecting in favour of the resident vancomycin-resistant strain, could unwittingly transform the previous symptomless carrier state into an overwhelming infection. Clonal spread of glycopeptide-resistant E. faecium (GREF) within hospital intensive care units was demonstrated also. This lead to media scares over ‘super-bugs’ and the prospect of a ‘‘return to the pre-antibiotic era’’, should the vanA gene transfer into MRSA or other human pathogens still sensitive to glycopeptides. The argument against avoparcin was that its continued non-essential use in agriculture could spread resistance to vancomycin in man. Avoparcin, and the glycopeptide ardacin, were, therefore, removed from the EU market as a precautionary measure aimed at preserving vancomycin’s clinical utility. Following the announcement of the Danish ban on avoparcin, and the subsequent German ban, the Commission had consulted both the SCF and the SCAN. The Danish claim that avoparcin use was followed by the detection of GREF in a significant number of herds and flocks were upheld. Importantly, however, the finding of some E. faecium ribotypes in common was not accepted by SCAN as evidence implying animal to man transfer when ribotyping was then shown to be insufficiently discriminating to support the claim of common identity.

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For SCAN, the fact that GREF infection and fatality levels in patients were worse in the USA, where avoparcin had never been licensed for animal use, than they were in Europe, where it had seen around 30 years of very extensive use, was of major importance. Both territories used vancomycin, America more so than Europe. That seemed to suggest that although vancomycin resistance was plainly a problem to human medicine, its occurrence was not of necessity avoparcin-dependent. Furthermore, there was no evidence provided to SCAN which showed that GREF of animal origin had ever colonized man, or had ever transferred its resistance determinant while in transit through the human gut, or had ever caused a health problem in people. Surely if GREF were to move from animals to man by the means suggested by Denmark, then it would not have been impossible to have provided confirmation of its having occurred. At the time of the Danish ban on avoparcin, about 20 000 kg of avoparcin were used per year in animal production in Denmark, a country with more pigs than people. Sufficient opportunity for human exposure to animal GREF must, therefore, have existed, could have occurred by the routes and with the consequences proposed, were those proposals correct. At the time of the Danish ban of Avoparcin, not a single case of GREF disease, or GREF-induced worsening of disease in man nor even a single instance GREF carriage had been reported in a Dane. For SCAN, Denmark had, therefore, revealed the existence of the hazard of GREF carriage in animals, but had failed to show any sign of a dependent risk in the human population. SCAN concluded that the evidence against avoparcin was insufficient to justify national bans based on the terms of Directive 70/524. Properly, however, SCAN recommended studies, other measures (including resistance surveillance) and a full review within 2 years (SCAN, 1996). A 2-year, industryfinanced, resistance surveillance scheme was initiated by the Commission. Unfortunately, it was later vitiated when the 1998 bans of AFAs then under surveillance invalidated the scheme’s study plan. Since 1996, international meetings and highlevel committees have found it easy to agree on

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the worrying problem of the increasing levels of resistance in several human pathogens and the resulting increase in the difficulty of managing certain serious infections. All have mentioned the dangers of resistance possibly inherent in the use of AFAs. None has received evidence of an existing adverse health consequence in people as a result of AFA-selected resistance in feed animals having transferred to a human by whatever means. All have recommended the banning or phasing out of the AFAs. In contrast, none has recommended beyond prudent use in the case of the therapeutic or prophylactic use of antibiotics in animals, although that use has been shown to select for resistance, sometimes multiple, in animal pathogens and some of those pathogens are known to transfer into man, causing zoonotic disease resistant to treatment. The mounting Gram-positive resistance problem in man has caused the re-evaluation of antibiotic classes not considered of sufficient interest for development for human use at the time of their discovery. Of those so-called reserve classes, both avilamycin (an orthosomycin) and virginiamycin (a streptogramin) are members which have seen extensive use as AFAs. The EU’s banning of virginiamycin in 1998, again precautionary, was again supported by proof of selection for resistant strains of E. faecium in animals. The ban was justified by virginiamycin’s close chemical relationship to candidate antibiotics already in use in people (pristinamycin), or under development (dalfopristin/quinupristin), and the wish not to jeopardize their utility by further increasing the resistance gene-pool in animals. Once again, there was no direct evidence of the occurrence of damage to human health originating from the AFA at the time of its national or EU ban (SCAN, 1998). What happened to avoparcin and virginiamycin was in many ways new in the regulation of authorized chemical products in the EU. In both cases the ban was described as precautionary and open to review in 2 years. In neither case was the ban sought solely on adverse scientific evidence. Both banning cases cited supporting studies, some of which were from the open scientific literature. That contrasts with the requirement that companies seeking market entry must provide support-

ing data which complies with the OECD Principles of Good Laboratory Practice. The reasonable burden placed on a Member State by Directive 70/524 to provide grounds which substantiate its claim of serious danger to human health from an AFA at the time of its domestic ban was overlooked in favour of seeming to require others (who else but the AFA manufacturer) to provide proof of its freedom from that unproven risk, something which is scientifically impossible. Further, that new safety evidence was to be produced within 2 years of the ban, during which the ban could change resistance patterns and prevalence continuously. Among the recitals to Directive 97/6/EC, the proper scientific caution of SCAN when describing its assessments of the avoparcin national bansupporting data has been used to suggest scientific uncertainty. That then allowed, in the text explaining the need for the ban, the corollary ‘‘that available evidence does not allow the risk to be excluded with certainty’’. That, in turn, leads to the conclusion that ‘‘it is preferable to show extreme caution’’. That it lacked a conclusive scientific base is made plain when it is stated that the ban ‘‘ought to be perceived as an interim protective measure taken as a precaution’’. The Commission claimed also, for both virginiamycin and bacitracin, that it was required to take a decision on the future of eight AFAs before 31 December, 1998, as the Swedish Treaty of Accession derogation which allowed it not to market those AFAs in its territory expired on that date (Council Regulation, 1998).

10. Concluding thoughts Over how many chemical products marketed under regulations which require an authorization containing a safety evaluation could we guarantee the current, let alone future exclusion of a risk to health? Is it not reasonable that when market entry depends on safety studies deemed to have yielded acceptable findings, then market exclusion should require adverse findings, which are at least as well-founded? How should we judge an authorizing institution, which admits of the need for

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risk assessments, but then argues a health concern not within the conventional usage of hazard and risk, but rather in terms of a non-proven danger or threat? Will a persuasively campaigned perception of a possible, future risk to health be enough in the future to ensure the removal from the regulated market of any authorized but targeted product? How should the chemicals industry plan for a future when it has seen the evidence-based conclusions of the Commission’s own-appointed expert scientific committee set aside by the regulators in favor of a more general, contrary perception? These are all questions which merit attention. What is clear is that none of us should expect the best efforts of rational science always to triumph over voter perceptions, consumer preferences (survey-based preference for additive-free food), macro-economic considerations bearing on the market (see the fourth hurdle below), or even simple political expediency (the imminent expiry of the Swedish AFA marketing derogation). After all, risk management does always require a balancing of interests. To return to the three hurdles and animal production, a few years back those who sought to market in the EU products which enhanced the efficiency of animal production began to encounter what they called the fourth hurdle. The regulators were thought to be adding a socio-economic analysis to those of quality, safety and efficacy. It is the case in some sectors that European food production is in excess of consumption. Is it, therefore, not reasonable that the Commission could perhaps wish to limit food production by preventing the sale of products likely to increase a surplus and drive the need for expensive, internal market-correcting measures? Were the earlier exclusions of the hormonal and the b-agonist production enhancers both examples of the fourth hurdle in action? Is the progressive removal of the antibiotic feed additives (AFAs) on incomplete health arguments, as was also the case against the hormones and b-agonists, just another means to contain or downsize animal production in Europe, to move that production away from the intensive and perhaps even to influence the content of the European diet in a direction which

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some consumers would believe to be more healthy? These would all be legitimate political preferences, even if the price were more labour-intense animal production, more expensive meat and an increase in animal health problems for several years. The issue as described above was plainly challenging for the legislators. If a post-marketing review of an approved feed additive suggests a previously unsuspected or undetected health risk attaching to its use, as was the case for the AFAs, plainly that risk requires urgent evaluation. But for the Commission then twice to have acted contrary to the written evaluation of its own, apposite expert committee in the removing of products where there was no proof of existing risk, even if that product was used to support a style of animal production unpopular among consumers and subject to the adverse but speculative comment of some national experts seems at best unbalanced. To have quoted out of context from the SCAN Opinion, misquoted even, when justifying the AFA bans, was at least unfortunate (SCAN, 1998). Then, late in its drafting history to have introduced the precautionary principle as the basis of the 1998 ban, but not always to have applied that principle in compliance with its own circulated draft guidelines on its use, does suggest a singular determination to succeed (European Commission, 1998). The acceptance of the bans by those outside the industry has shown that the regulation of food and health questions using the precautionary principle has extensive support among administrators, legislators and consumers. It is an approach acceptable to all who see hazard identification as a sufficient basis for a risk management decision. The EU’s feed additive antibiotic precautionary bans have established useful precedents for the highly risk-averse. The possibility of further use of the precautionary principle as a preferred tool for urgent action on claimed health risks remains. However, it must remain. A precautionary approach is long-established in health-based regulatory actions. It is a powerful device for use when sufficient evidence indicates urgent action, even though that evidence is incomplete. But over claimed health concerns, is it

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preferable that health scientists should with proper objectivity identify the occasions for its use and so advise the legislators? Or is science content to leave such identifications to risk managers perhaps more influenced by risk perception than risk reality and, perhaps, by tangential administrative problems relevant to the requirement for a balancing of interests? These extreme options, together with the above described bans, seem to suggest that, at the very least, industry’s need for a predictable environment in which to take future, speculative investment decisions requires both toxicologists and those industries which employ them to give urgent consideration to the precautionary principle and to secure formative input into the EU guidelines/regulations which will modulate its future use. I wonder how Philip, my former departmental colleague and good friend of 35 years would have viewed the above complexities. Had he been wearing his second hat, that of Honorary Cellarer to the Trinity College Common Room, and had he been in the cellar performing assiduously his tasting duties at the time of asking, he would probably have smiled his sometimes angelic smile and, eyes twinkling, have said, ‘‘and now let’s open another bottle for no good reason at all!’’

References Case T-13/99, 1999. NV Pfizer Animal Health vs. Council of the European Union. Commission Decision 1976, (76/791/EEC of 24 September, 1976) establishing a Scientific Committee for Animal Nutrition. Off. J. Eur. Comm. L 279 35 –36.

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