Food Additives & Contaminants
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The concept of the acceptable daily intake: An historical review R. Truhaut To cite this article: R. Truhaut (1991) The concept of the acceptable daily intake: An historical review , Food Additives & Contaminants, 8:2, 151-162, DOI: 10.1080/02652039109373965 To link to this article: https://doi.org/10.1080/02652039109373965
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FOOD ADDITIVES AND CONTAMINANTS, 1991, VOL. 8, NO. 2, 151-162
Symposium Paper The concept of the acceptable daily intake: an historical review* R. TRUHAUT Member of the Academy of Sciences and the Academy of Medicine (Received 25 July 1990, accepted 18 October 1990)
In the first section the sequence of events is outlined which leads to the author's proposal to consider the concept of acceptable daily intake (ADI) for pesticide residues. He developed his theory referring to specific aspects during meetings with experts on the toxicological evaluation of chemical agents which become introduced into foodstuffs intentionally or unintentionally. These meetings were organized periodically by the European Council or Joint FAO/WHO Expert Committees on food additives (JECFA) or pesticide residues (JMPR). The general principles of the ADI evaluation are briefly described as being based on the determination (after extended absorption) of a no-effect dose level in an appropriate animal species; followed by the application, for the extrapolation of the results in animals to humans, of safety factors taking into account the interspecies sensitivity variations and individual sensitivity variations in the groups of essentially heterogeneous human consumers. It is pointed out that the ADI value, which depends on a series of factors, is not a constant, but a guide serving to calculate the admissible limits of diverse chemical agents incorporated in foodstuffs. It must take into account the usual normalities between medium terms of consumption varying a lot with the countries and the various consumer groups. It is clearly noted that, because of the fluctuations in the type and the quantities of absorbed diets, the ADI is in reality an integrated value with regard to the time, a notion that is often forgotten. Other ideas are developed, in particular on the adoption of a temporary ADI and on the concept of a non-specified ADI. Keywords: toxicology, safety evaluation, acceptable daily intake My position is relatively unassailable, I believe, in claiming to be the true instigator of the concept of the acceptable daily intake (ADI)—as, indeed, has been acknowledged in numerous articles (Dois 1977, Elias 1977, Van Esch and Kroes 1984) written by experts who, like myself, were actively involved in the field during the period from 1950 to 1962, at the time when the policy trend among leading international agencies, such as the World Health Organization, Food and Agriculture Organization, International Union Against Cancer, Council of Europe and the European Committee for the Protection of the Population Against the Hazards of Chronic Toxicity, more commonly known as EUROTOXf, founded in 1953, was towards developing principles for the toxicological evaluation of substances included in foodstuffs by accident or design in a bid to protect the health of consumers. It was during this period—in September 1955 to be exact—that a joint * All translated quotations from official reports are the translator's own free translation. † In June 1989, EUROTOX became the Federation of European Societies of Toxicology. 0265-203X/91 $3.00 © 1991 Taylor & Francis Ltd.
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FAO/WHO conference was staged in Geneva, the main conclusion of which was to recommend to the Directors General of the two agencies that regular meetings be called of a joint committee of FAO/WHO experts to study the toxicological problems raised by the use of additives in foods (known by the English abbreviation of JECFA). Unfortunately, and paradoxically, I had published nothing in the scientific journals at this time. I shall not dwell further on the developments in this area which I reviewed extensively on 18 March 1977 in my address to the Symposium 'In Memorium Professor E. J. Bigwood' (Truhaut 1977), or on likewise unpublished voluminous working documents reposing in the WHO archives, which my esteemed friend Professor Gaston Vettorazzi, then Secretary of JECFA for the WHO, asked me to present to the 25th session of JECFA as a summary of that body's first 25 years'work, 24 of whose meetings I was privileged to attend (Truhaut 1981). What I should like to do, on the other hand, to aid with the understanding of later sections, is to note that, at its inaugural meeting in Rome in December 1956, JECFA was concerned to define the broad general principles by which any permission to use additives in food should be governed, and in particular to emphasize the primacy of the principle of positive lists for protecting the health of consumers. Unlike the negative list principle, the effect of this is to prohibit the use of any substance not authorized on sufficient toxicological grounds. Permission is to be granted only after qualitative and quantitative data have been produced establishing that, when ingested regularly, on a daily basis for the greater part of one's life, the additive is unlikely to have a deleterious effect on the health of consumers. Let me say that since we cannot prove absolute non-toxicity, but only a very high degree of innocuousness: positive lists must be constantly open to revision in both directions. Let me add that we must also pay constant attention to the technological usefulness of the additive being toxicologically evaluated, and to the existence of strictly defined identity and purity criteria. Let me repeat my contention that I believe I was truly the first expert of the time to talk in terms of an acceptable daily intake for humans, based on the result of toxicological investigations, and to have insisted on defining the concept with sufficient precision for it to be applicable. I could certainly never have done so without help and constant input from certain other particularly eminent specialists. I cannot mention them all by name, numerous as they are. I will limit myself to mentioning, together with the Secretaries of JECFA, in particular, Nir Grossfeld, Frank Lu and Gaston Vettorazzi, Dr J. Barnes (United Kingdom); Prof. M. J. Dois (Netherlands); Prof. H. Druckrey (Germany); Prof. P. Elias (United Kingdom); Dr G. Fitzhugh (United States); Prof. A. C. Frazer (United Kingdom); Dr G. van Genderen (Netherlands); Dr G. van Esch (Netherlands). Dr. van Esch had the extreme kindness to say in an article co-authored with R. Kroes, entitled 'Acceptable daily intake: Truhaut's concept, still accepted today', that between 1957 and 1962 'Professor Truhaut was present in all the different crucial joint FAO/WHO meetings. It is therefore not inappropriate to say that Professor Truhaut can be considered as the Nestor of the ADI concept, as the basis for the estimation of safety, for the introduction of chemical substances in food and drinking water'. As I said earlier, instead of publishing, I confined myself to promoting my approach to the JECFA meetings and in other forums such as the Council of Europe and, from 1974 onwards, in the Scientific Committee for Food of the European Communities, confining myself to
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the development of working documents, some of which must presumably still be lying in the archives of the WHO and Council of Europe. The consequence of my failure to publish at the time is that, of the many published articles on the ADI, few refer to my role as instigator or, in the words of my eminent colleague and friend Peter Elias, the 'obstetrician of the concept of ADI' (Elias 1977). In accepting that I was indeed the initiator and promoter of the concept, it behoves me to explain in what conditions. Engaged since the very outset of my career in the toxicological evaluation of the prolonged ingestion of chemicals to which humans are exposed in various areas of life, I have always taken as a golden rule the principle enunciated by Paracelsus five centuries ago: 'Sola dosis fecit venenum'—it is only the dose which makes a chemical a poison. This led me to accord paramount importance to the establishing of dose/effect relationships in the methodology of toxicological evaluation with a view to fixing admissible limits. From my appointment in 1950 as an expert to the Scientific Committee for Health Controls on Food under the Partial Agreement, then to the Western European Union and, from 1959, to the Council of Europe, I have never lost sight of that Golden Rule in any discussion in which I have taken part. It was when the Committee set up a Working Party on Pesticides, later elevated to the status of a Scientific Committee in its own right that, having to consider the setting of maximal limits for pesticide residues or their metabolites in treated plants subsequently sold for human consumption, I swiftly came to realize that account had to be taken not only of toxicological data, but also of the nature of the foods likely to contain residues, as well as of the average consumption of those foods, which varies by country, region and even population group. That led me to conclude that we needed to establish a basic concept consisting in the evaluation, on the basis of toxicological data extrapolated to humans, of an acceptable dose for repeated absorption by humans, from which to deduce, having regard to the use of pesticides on certain staple crops and, above all, average rates of consumption of foods derived from them, limits which should not be exceeded. I consistently referred to this in Council of Europe meetings from 1956 onwards. I was therefore prepared to discuss the matter also at JECFA meetings and, during its second session in Geneva from 17 top 24 June 1957 chaired by Professor R. Blackwell Smith of the United States, concerned with the study of methods of toxicological investigation of food additives, I was instrumental in having a new chapter included in the final report on 'Evaluation of concentrations probably harmless to man', including the following words: 'From these various investigations a dosage level can be established that causes no demonstrable effect in the animals used. In the extrapolation of this figure to man, some margin of safety is desirable'. This was as yet somewhat nebulous. Some months later (in November 1957) when taking part in the 3rd meeting of the FAO Working Party on control of the olive fly—the olive being, as you know, a key crop in the Mediterranean economy—chaired by my fellow countryman Michel Féron, Director of the Zoological Station at the Montfavet Research Centre in the French department of Vaucluse, I was confronted with the problem of fixing maximum residue limits for certain organophosphorus insecticides—notably parathion—in olive oil for human consumption. The generally accepted concentration limit for olive oil worldwide was 1 mg/kg oil. Toxicologically speaking, however, the decisive factor is the daily quantity of oil consumed. The Greek shepherd, surrounded by olives, dips his bread into the oil and can ingest up
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to 60 g/day. He therefore absorbs far more parathion than consumers whose olive oil intake comes only from salad dressing. Reasoning from this example, my line of thought found further support in the idea that we needed to turn the problem on its head and fix an intake which could be used to calculate the tolerances to be fixed for any given food according to the average quantity consumed in a particular region. This line of thinking led me to develop the concept of the acceptable daily intake, which I elaborated further in a working paper presented to the 6th JECFA meeting held in Geneva from 5 to 12 June 1961, chaired by Dr H. C. Spencer, with myself as Vice-Chairman. The report of this session clearly states that it was recommended that the dose which induced no effect of toxicological significance in experimental animals should be expressed in mgjkg body weight per day. The method of extrapolation to humans was discussed in detail. It was emphasized, however, that the maximum ingestion level admitted unconditionally was not the same as the maximum quantity which could be admitted as acceptable on toxicological bases. Considering that agri-food specialists in many countries are confronted with special problems (different consumption patterns, sharply differentiated consumer groups, etc.), all of which need to be taken into consideration, the Committee thought it desirable also to consider the possibility, after consultation with national groups of experts including at least one toxicologist, of establishing a conditionally acceptable dose. It seems appropriate at this juncture to note the Committee's support for expressing the ADI in mg/kg body weight. In that respect I must stress that, at the time when I first began to moot the ADI concept, I had been talking to my eminent Belgian colleague, Professor E. J. Bigwood, who would have far preferred to have expressed ADI as a ratio of mg/body surface area. I, along with many other specialists, must acknowledge the merits of his arguments from the scientific point of view. In point of fact, the metabolism of small animals in particular—and, in the human population, young children—ultimately does bear a proportional relationship to the body surface area to be taken into consideration. For all practical purposes, however, it is easier to express the ratio in terms of weight. That is what JECFA and the other international bodies decided to do. This, I think, is an appropriate juncture to cite the words contained in the report of the 17th JECFA meeting, held in Geneva from 25 June to 4 July 1973, chaired by Professor M. J. Rand (Australia), with Professor F. Berglund as Rapporteur. I shall refer in more detail to this report later in the light of the importance I attach to it; for the agenda of the meeting not only included the toxicological evaluation of certain food additives, but also a discussion of general principles and standards. 'It was recognized by the Committee that the expression of the ADI in terms of body weight (b.wt.) does not reflect the relative exposure of animals of different size as accurately as would the metabolic mass, which is equal to WbO-75. However, in practice the method of expressing the dose in terms of mg/kg body weight has proved satisfactory.' Over series of JECFA sessions between 1961 and the most recent—35th, Rome, 29 May to 7 June 1989—the definition of ADI has been discussed and, to some extent, made more precise still. Let me quote the definition as it was enunciated after study by a scientific committee of WHO experts and JECFA in a 1987 report in the Environmental Health Criteria series (WHO 1987): 'Acceptable daily intake: an estimate by JECFA of the amount of a food additive expressed on
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a body weight basis that can be ingested daily over a lifetime without appreciable health risk (standard man = 60 kg).' I wholly agree with this definition in which I, together with many other experts, had a hand, and which is completely in line with the scientific rationale which impelled my thinking from 1956/1957 onwards. I was instrumental in having them applied to the specific case of pesticides at the joint meeting of a WHO Committee of Experts in pesticide residues with the FAO Group of Experts on the use of antiparasitic products in agriculture on the principles governing health protection for consumers with regard to pesticide residues (WHO 1962). I also attended this meeting, held in Rome from 9 to 16 October 1961 under the chairmanship of Dr W. J. Hayes (United States) (WHO/FAO 1961), which also marked the starting point for the regular meetings of a new Joint Committee of FAO/WHO experts on pesticide residues in foods, known by its English abbreviation JMPR. Its inaugural meeting, which I was privileged to attend, along with many others which followed it, was held in Geneva from 30 September to 7 October 1963 under the chairmanship of Dr Roy Goulding (United Kingdom). Where sufficient toxicological information was available on a pesticide on the agenda, ADIs were established and formed the basis for the calculation of maximum residue limits in foods obtained from pesticide-treated crops, taking account of average quantities consumed. In the lecture I delivered to the Symposium 'In Memoriam Professor E. J. Bigwood' (Truhaut 1977), I expounded the broad lines of the methodology of the toxicological evaluation of chemical compounds included by accident or design in food. I also critically examined the interpretation of results obtained on laboratory animals and in vitro systems, together with observations on humans. I was thus led to study the determination of toxicologically ineffective doses and the often thorny problems posed by their extrapolation to humans with the application of safety factors. I shall not dwell further on this, particularly as the programme for this Colloquium to the development of which it has been both an honour and pleasure for me to contribute, together with my friends Mrs Gunna Wirtzen and Professor Michel Fondu, includes papers by eminent specialists in these very topics. But in a talk on the history of how the ADI concept can to be established, presented as an introduction to this Colloquium, it behoves me, without encroaching too far on the territory to be covered by my colleagues after me, to pass in review at least a few key ideas which are manifestly central to an understanding of what I have to say on the matter. When speaking of toxicologically ineffective doses in experimentation we must never forget that only a zero dose is truly without effect; all other doses do have an effect, be it ever so little. There is a French proverb which says: 'Spit in the port at Le Havre and the sea level rises in San Francisco.' Obviously, effects on that scale are devoid of practical significance, in the sense that a rise of that order in the sea level at San Francisco has no injurious consequences—it will not capsize the boats at anchor in the Bay. What, in my opinion, the toxicologist must understand by ineffective dose is one which induces no toxic effects. The question then arises, however, as to what is a toxicologically significant effect. Can we say, for example, that a fall in body weight induced by a diet to which a test substance has been added at a certain concentration administered to the experimental animal who rejects some of it from lack of craving is toxicologically significant if unaccompanied by
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other signs of possible toxicity? My answer is a categorical 'No'. But things are not always so clear-cut. Toxicology has become a typically multi-disciplinary science in which the methodological approaches of rapidly developing fundamental sciences such as chemsitry, physics and even mathematics, and biological sciences—not only physiology, pathology and histology, but also biochemistry, molecular biology, immunology and genetics—are applied to the study of toxic effects. The result of that multi-disciplinarity is a consequent advance in our knowledge in these different fields, more productive methods of toxicological evaluation clarifying the morphological, functional and biochemical effects which condition the mechanisms of toxic action. Some of the effects thus elucidated do not lend themselves easily to interpretation, and may be considered either as early signs of aggression or reactions of physiological adaptation. What, for instance, is the significance of mitochondrial swelling with an increase in oxidative phosphorylation, or a slight proliferation of the endoplasmic reticulum revealed under electron microscopy? What toxicological significance can we attribute without difficulty to the action of this or that enzyme on the hepatic microsomes until the resulting metabolites have been identified and their toxicity studied? It is a paradox that increasingly high-powered methodologies do not always produce easily interprétable results. In my view, the toxicologist must interpret the results of a particular approach in an integrated context, by which I mean in conjunction with those obtained by other approaches and factoring in such parameters as physiochemical properties, structure/activity ratios, conditions of use and exposure, and toxicokinetic data, notably bioavailability, metabolic conversion, distribution in body fluids and tissues, and the rate of excretion. Interpretation of that order naturally requires great skill based on much accumulated experience, but it also calls for intelligence and the sound common sense essential to worthwhile judgement ('jugement de valeur'). This is a theory I developed in a talk given at Bilthoven in the Netherlands on the retirement of my respected colleague and fellow toxicologist, Dr G. F. Van Esch, on 28 March 1985 (Truhaut 1986). Returning, after that brief aside, to the concept of the acceptable daily intake, I emphasized from the very first that, calculated on the basis of far from mathematically precise data (concentration without effect in the most sensitive animal species and their extrapolation to humans applying a safety factor of variable value), it could not, per se, have a correspondingly high degree of precision. As the definition makes abundantly clear (Truhaut 1986) therefore, it must be considered as a guide to be applied with some flexibility, not as a hard-andfast rule. Nor must it be forgotten that the definition of ADI posits daily exposure over a lifetime. In reality, however, humans do not ingest day after day each of the chemicals (additives, pesticides, residual metabolites, contaminants) likely to be encountered in certain types of foodstuff, the proportion of which in the diet varies over time, and, in any event, certainly practically never attains the upper limit of the acceptable intake. The quantities initially present in the basic commodities, moreover, are most often found to diminish during storage and particularly during the preparation process prior to being eaten—particularly when cooked. There are also circumstances in which the ADI concept is simply not applicable per se. The ADI may be manifestly exceeded in particular dietetic circumstances, such as where modified celluloses are employed to reduce the available energy value
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of a diet for a restricted period. Or in the opposite case of certain high-risk groups such as newborns and very young children between, say the age of 3 and 6 months, who are generally more sensitive for a host of reasons (including undeveloped metabolism, different intestinal flora to adults, slow development of barriers against certain receptors, such as the central nervous system, etc.) whose food should be permitted to contain additives. The ADI concept is not applied to the general population indiscriminately, therefore. But I leave it to subsequent speakers to develop this point further. Let me, however, stress that the variations in daily diets caused by eating habits do give rise to fluctuations in the daily quantities absorbed. Consequently, the fact of exceeding the ADI in food consumed over a very short period, notably on one particular day, does not entail a health risk, since it will be subsequently compensated for by underexposures through the consumption of far lower quantities. This leads me to consider cumulative chemicals, where fluctuations in the quantities absorbed require close attention. The problem here is the same as that in fixing maximum admissible limits for chemicals which find their way into the air of towns and, more particularly, workplaces. Some of these are maximum limits, valid for exposures of short duration to substances whose main danger lies in their acute toxicity, but mostly referring to substances which tend to accumulate in the body. Considering that workplace exposure is generally from 7 to 8 hours daily and 35 to 40 hours a week, repeated over relatively long periods of time, these values are time-weighted averages, which take account of compensating fluctuations in exposure rates. A comparable rationale to this guided the JECFA experts at their 16th meeting in Geneva from 4 to 12 April 1972 (WHO 1972), which I had the privilege of chairing. Considering the case of cumulative heavy metals (mercury, lead and cadmium) which may contaminate food, their conclusion was that the continuous variations in the daily quantities likely to be absorbed could best be taken into account by fixing 'provisionally tolerable weekly intakes'. That brings me to another initiative I took in the form of a working document for the meeting of a Scientific Committee of WHO experts organized in Geneva from 12 to 18 July 1986, chaired by Dr L. Golberg, then Director of the British Industrial Biological Research Association (BIBRA) in Carshalton (United Kingdom), with myself as Vice-Chairman and Dr Ahlmark (Canada) as Rapporteur. The purpose of the meeting was to study the methods of toxicological evaluation of substances incorporated, intentionally or otherwise, in food (WHO 1967a). Given that certain additives and pesticides had a real technological value, but the highly detailed toxicological information required on them for positive listing had not been forthcoming in an ideally satisfactory way, albeit the available information gave no grounds for fearing a significant health risk, I proposed that the concept of the temporarily acceptable daily intake should be adopted. Sensitive to my responsibilities, I made my proposal contingent on the following conditions: 1. the toxicological information had to be sufficient to rule out any appreciable risk of toxicity for consumers for the period of temporary authorization; 2. the value of the safety factor to be applied to the results obtained in experimentation on laboratory animals, for extrapolation to humans, should be notably higher (at least double) that for the calculation of a normal ADI;
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3. the temporarily acceptable daily intake would be valid only for a limited period of 3 to 5 years; 4. the toxicological and biochemical data judged essential for fixing a regular ADI at a later date had to be clearly indicated; 5. the situation should be reviewed before the temporary ADI period expired, comparing all the initial data with all that which had subsequently become available; 6. if the additional data required were not forthcoming by the expiry of the period fixed, the JECFA Committee would have power to cancel the temporary ADI. After, I must confess, extensive discussion, the Committee agreed to my proposal. I contended that it was, to a certain extent, in the interest of consumers to have the measure adopted; for, provided the principle of sufficient information to protect consumers' health was complied with, and at the same time affording manufacturers the opportunity to put on the market products in which they had invested heavily, toxicologists also had greater powers to demand more detailed toxicological information from them, the interpretation of which would be facilitated by the observations on humans allowed by the use of those products during the temporary authorization period. That seemed to me a very major consideration, given the steady pace of advance in our toxicological knowledge. The recommendation to allow a temporary ADI materialized almost immediately at the 10th meeting of the JECFA Committee in Geneva 3 months later, from 11 to 18 October 1966, chaired by Dr G. Fitzhugh, then Deputy Director of the Division of Toxicological Evaluation of the US Food and Drug Administration, with Dr W. A. Mannel (Canada) and myself as Rapporteurs (WHO 1967b). In this regard it seems to me important from the historical point of view, to cite verbatim Annex 4 of the report of that meeting: 'It will be observed from the above that the acceptable daily intake is only an estimate and depends upon a great number of factors, all of which should be taken into consideration. Therefore an exact maximum acceptable daily intake cannot be calculated. This is one of the reasons why, in some cases, the zone of acceptability is divided into two parts, 'conditional' and 'unconditional'. Although the whole zone of acceptability may be safely used, obviously the smaller the amount of a given chemical consumed, the smaller the risk. However, there are circumstances where one has to weight one risk against another. For a food colour, for instance, one would be inclined to make the acceptable risk smaller than for an antimicrobial used to preserve food that is scarce in many parts of the world. The conditional zone is one that can be safely used under certain conditions, which are specified where appropriate. Thus, in some cases, the use of the chemical might also be permitted for a limited length of time in order to obtain information from further work. In cases where the conditions are not specified, a final decision on whether intakes that fall within the range of conditional acceptance may be considered acceptable in particular circumstances should be taken by a group of scientists including a toxicologist, experienced in this field'. Remaining on the historical plane, I feel it appropriate to state that, at the following JECFA meeting—the 11th—held in Geneva 21-28 August 1967 (WHO
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1968) chaired by Professor G. Brownlee (United Kingdom), with Dr G. J. van Esch as Rapporteur, the above text was reproduced retaining the concepts of conditional ADI and unconditional ADI, despite certain objections which I raised. But the report of this meeting was even more specific than that of its predecessor in setting forth the 1966 recommendation of the WHO Scientific Committee concerning the adoption of a temporarily acceptable daily intake applied, incidentally, for the first time to certain additives under evaluation such as, for example, the aromatics ethylmethylphenylglycidate and maltol, and the nonnutritive synthetic sweeteners sodium- and calcium-cyclohexylsulphamate. That brings me to a more detailed consideration of the report of the 17th JECFA meeting, the importance of which I emphasized earlier due to the critical examination of general principles and standards it contains (WHO 1973). It was at this meeting which, due to some confusion born out of the variety of implementing rules for ADI subject to reservations, that it was considered—to my considerable satisfaction, I must admit—that it would be best to forgo setting any. In the critical review of the general principles governing toxicological evaluation, a number of extremely important points were emphasized. Without trying to cover them all, let me simply mention a few. The first relates to the establishment of a group ADI for chemically and toxicologically related additives. At the 7th meeting held in Rome from 18 to 25 February 1963 under the chairmanship of Professor A. C. Frazer (United Kingdom), the JECFA Committee had adopted an additive grouping system to facilitate evaluation: phenol antioxidants, emulsifiers in the polyoxyethylenesorbitan polyglyceride ester series, modified celluloses and propyleneglycol derivatives. According to the report of the 17th meeting the ADI should then cover all the members of the groups capable of inclusion under the arrangement. Additives falling in two group could not have a content higher than the lower of the two maximum admissible doses. This problem is less complex that it might appear at first sight, since each group of additives contains many substances with similar technological functions and probably thus interchangeable. A second extremely important point relates to the proposal to set an ADI with no express limit ('unlimited ADF) for substances with very low toxicity, notably those used as ingredients in foods or substances which were normal metabolites in humans. It was specified that, as in all other cases, an additive granted an unlimited ADI must still comply with criteria of good manufacturing practice. For example, it must have proven technological effectiveness and be used at the minimum effective dose and also not mask inferior quality or lead to nutritional imbalance (WHO 1973). The description unlimited acceptable daily intake was severely criticised at the 3rd Joint FAO/WHO Conference on food additives and contaminants held in Geneva in October 1973 (FAO 1974) on the grounds that any chemical becomes toxic past a certain dose level. For that reason the 18th JECFA meeting held in Rome from 4 to 13 June 1974 (WHO 1974), which I was privileged to chair, with Dr W. A. Mannel of Canada as Rapporteur, resolved to replace that expression with 'ADI not specified', attaching to it the following definition: 'The statement 'ADI not specified' means that, on the basis of the available data (toxicological, biochemical, and other), the total daily intake of the
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R. Truhaut substance, arising from its use or uses at the levels necessary to achieve the desired effect and from its acceptable background in food, does not, in the opinion of the Committee, represent a hazard to health. For this reason, and for the reasons stated in individual evaluations, the establishment of an acceptable daily intake (ADI) in mg per kg of body weight is not deemed necessary'.
The Committee requested that 'whenever the expression appears in a table, it should be accompanied by a reference to a footnote containing the definition'. In the general report published by the WHO in 1987, this definition was extended somewhat. In particular it was specified that an additive meeting the general criteria involved must be used in accordance with the rules of good manufacturing practice. Any relatively major change in the technological conditions of use must, in my opinion, lead to a review of additives granted an unspecified ADI. This rule is followed by the EEC's Scientific Committee for food, whose successive reports— and notably the 10th report on the guidelines for evaluating the safe use of additives in food (Commission of the European Communities 1980)—coincide, with very few exceptions, on all points with the opinions of JECFA as regards the definition of acceptable doses. For that reason I do not intend to labour the point. Another recommendation adopted at the 18th meeting of JECFA, again taking account of the comments of the 3rd Joint FAO/WHO Conference of October 1973 (FAO 1974), was to amend the rule adopted at the 6th session, which resurfaced in the 17th report, by which the ADI need not include levels of the substance being evaluated occurring naturally in food. Since a substance is equally toxic whether natural or synthetically produced, subject of course to strict compliance with purity standards, and since, on the other hand, chemical analysis cannot distinguish from which of the two origins the substance derives, the Committee concluded that the ADI should include the level of the naturally occurring substance as well as the dose of the product added. This is a particularly crucial condition to observe in the case of nitrates. The Committee noted that certain exceptions might exist, however, and that consequently each case had to be evaluated on its particular merits. As a corollary the Committee emphasized the need to test the total quantity of the substance being evaluated in the diet of experimental animals. Furthermore, if the substance was present in food in a different form from that in which it was used as an additive, each form might need to be evaluated separately. By way of example, such was the case with ascorbic acid and benzoic acid. I shall not go any further into that, however. What I cannot do, by contrast, is to omit any mention of the 19th JECFA meeting held in Geneva from 14 to 23 April 1975, chaired by Professor P. Shubik (WHO 1975). Here I feel I must cite directly, but briefly, a few words from the report of this meeting expressing a fundamental approach to the general principles governing the setting of acceptable daily intakes. The Committee reiterated its practice of following the principles stated in its previous reports and in reports of a WHO Scientific Group on Procedures for Investigating Intentional and Unintentional Food Additives and a WHO Scientific Group on the Assessment of the Carcinogenicity and Mutagenicity of Chemicals.
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In this regard I cannot over-emphasize the value to be drawn from reading the successive reports of the Scientific Committee for Food of the European Communities, as well as the 1987 booklet published by the WHO in the 'Environmental Criteria' series (WHO 1987). Having no desire to trespass on the unquestionably rewarding discussions which will round off this Colloquium, I shall bring my review to a close here. That is also the reason for which I voluntarily refrained from launching into a discussion on the concept of the 'potential acceptable daily intake' advanced by our Danish colleague Hansen in 1979, as well as various other approaches. Lack of time also obliged me to omit a consideration of extremely important issues such as the setting of an ADI for certain classes of non-genotoxic carcinogens and that raised by chemical contamination of drinking water—both key issues in regard to food. Despite the things I should have included and have most surely forgotten, for which I apologize, I hope I have managed to do what the organizers of this International Colloquium on the acceptable daily intake wanted, with a review of the milestones in the historical development of the concept. More particularly, I hope I have gone some way to countering some of the criticisms which have been from time to time been levelled at it and which, in my opinion, apply only to poor conditions of application; overlooking, for example, the need when setting tolerances for food and water for human consumption to take into account the nature of those containing the additives or contaminants for evaluation and the average rates of consumption on them in different countries and population groups. But most of all, I hope I have shown how the use of the ADI concept has made a powerful contribution to protecting the health of people the world over, and oiling the wheels of international trade. References COMMISSION OF THE EUROPEAN COMMUNITIES, 1980, Rapport du Comité scientifique de l'alimentation
humaine sur les lignes directrices concernant l'appréciation de la sécurité d'emploi des additifs alimentaires. Opinion, 22 February, Series 1, EUR 6892. DOLS, M. J. L., 1977, Minutes of the discussion of the second day of the round table on the interpretation and use of the concept of acceptable daily intake CAD 8 of food additives on the occasion of the Symposium 'In Memoriam Professor Bigwood', 19 March, pp. E3 and 4. ELIAS, P., 1977, Minutes of the discussion of the second day of the round table on the interpretation and use of the concept of acceptable daily intake CAD 8 of food additives on the occasion of the Symposium 'In Memoriam Professor Bigwood', 19 March, E10. EUROPEAN TOXICOLOGY FORUM, 1984, Proceedings of the Session of the European Toxicology Forum held in the International Conference Center, Geneva, 18-21 October; Remarks. FAO, 1974, FAO Miscellaneous Meetings. Report Series, 1974. Document ESN WHO Food Add/74-43. TRUHAUT, R., 1977, Principes généraux d'évaluation toxicologique des additifs dans les denrées alimentaires. Proceedings of the Symposium 'In Memoriam Professor Bigwood'—Les données de base de l'action communautaire—18-19 March (Brussels: Université Libre de Bruxelles, Institut d'Etudes Européennes), pp Bl-B26. TRUHAUT, R., 1981, 25 Years of JECFA achievements. Report presented to the 25th session of JECFA, WHO, Geneva, 23 March-April. TRUHAUT, R., 1986, Critical remarks on qualitative and quantitative aspects of toxicological evaluation of chemicals: The need for an integrated approach. Lecture given on the occasion of the retirement of Dr G. J. van Esch, 28 March 1985—Report of the Symposium organized by the National Institute of Public Health and Environmental Hygiene, Bilthoven, Netherlands, and the Netherlands Society of Toxicology in honour of J. Van Esch, Bilthoven, 1986, pp. 6-15. VAN ESCH, G. J. KROES, R., 1984, Acceptable daily intake. Truhaut's concept still acceptable today. Homage to Professor René Truhaut, Paris, 19 October 1984, (Imprimerie Tardy, Quercy, Cahors) pp. 1124-1127.
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WHO, 1962, Principes devant régir la protection de la Santé des consommateurs à l'égard des résidus de persticides. Report of a meeting of a joint WHO Committee of experts in pesticide residues and an FAO group of experts on the use of antiparasitic products in agriculture. Rome, 9-16 October 1961. WHO Technical Report Series, No. 240 (Geneva: WHO). WHO, 1967a, Méthode d'évaluation toxicologique des substances ajoutées intentionnellement ou non aux aliments. Report of a WHO scientific group. Technical Report Series, No. 348 (Geneva: WHO). WHO, 1967b, Normes d'identité et de pureté et évaluation toxicologique des additifs alimentaires. Divers émulsifiants et stabilisants et certains autres substances. 10th report of the Joint FAO/WHO Committee of experts on food additives. Technical Report Series, No. 373 (Geneva: WHO). WHO, 1968, Normes d'identité et de pureté et évaluation toxicologique des additifs alimentaires. Divers aromatisants et édulcorants non nutritifs. 11th report of the Joint FAO/WHO Committee of experts on food additives. Technical Report Series, No. 383 (Geneva: WHO). WHO, 1972, Evaluation de certains additifs alimentaires et de contaminants. Mercure, Plomb, Cadmium. 16th report of the Joint FAO/WHO Committee of experts of food additives. Technical Report Series, No. 505 (Geneva: WHO). WHO, 1973, Evaluation toxicologique de certains additifs alimentaires. Examen des principes généraux et des normes. 17th report of the Joint FAO/WHO Committee of experts on food additives. Technical Report Series, No. 539 (Geneva: WHO). WHO, 1974, Evalulation de certains additifs aux aliments. 18th report of the Joint FAO/WHO Committee of experts on food additives. Technical Report Series, No. 557 (Geneva: WHO). WHO, 1975, Evaluation de certains additifs alimentaires colorants, épaississants, condensats de fumée et autres substances. 19th report of the Joint FAO/WHO Committee of experts on food additives. Technical Report Series, No. 576 (Geneva: WHO). WHO, 1987, Principles for the safety assessment of food additives and contaminants in food. Environmental Health Criteria, No. 80 (Geneva: WHO).
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The concept of the acceptable daily intake: An historical review R. Truhaut To cite this article: R. Truhaut (1991) The concept of the acceptable daily intake: An historical review , Food Additives & Contaminants, 8:2, 151-162, DOI: 10.1080/02652039109373965 To link to this article: https://doi.org/10.1080/02652039109373965
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FOOD ADDITIVES AND CONTAMINANTS, 1991, VOL. 8, NO. 2, 151-162
Symposium Paper The concept of the acceptable daily intake: an historical review* R. TRUHAUT Member of the Academy of Sciences and the Academy of Medicine (Received 25 July 1990, accepted 18 October 1990)
In the first section the sequence of events is outlined which leads to the author's proposal to consider the concept of acceptable daily intake (ADI) for pesticide residues. He developed his theory referring to specific aspects during meetings with experts on the toxicological evaluation of chemical agents which become introduced into foodstuffs intentionally or unintentionally. These meetings were organized periodically by the European Council or Joint FAO/WHO Expert Committees on food additives (JECFA) or pesticide residues (JMPR). The general principles of the ADI evaluation are briefly described as being based on the determination (after extended absorption) of a no-effect dose level in an appropriate animal species; followed by the application, for the extrapolation of the results in animals to humans, of safety factors taking into account the interspecies sensitivity variations and individual sensitivity variations in the groups of essentially heterogeneous human consumers. It is pointed out that the ADI value, which depends on a series of factors, is not a constant, but a guide serving to calculate the admissible limits of diverse chemical agents incorporated in foodstuffs. It must take into account the usual normalities between medium terms of consumption varying a lot with the countries and the various consumer groups. It is clearly noted that, because of the fluctuations in the type and the quantities of absorbed diets, the ADI is in reality an integrated value with regard to the time, a notion that is often forgotten. Other ideas are developed, in particular on the adoption of a temporary ADI and on the concept of a non-specified ADI. Keywords: toxicology, safety evaluation, acceptable daily intake My position is relatively unassailable, I believe, in claiming to be the true instigator of the concept of the acceptable daily intake (ADI)—as, indeed, has been acknowledged in numerous articles (Dois 1977, Elias 1977, Van Esch and Kroes 1984) written by experts who, like myself, were actively involved in the field during the period from 1950 to 1962, at the time when the policy trend among leading international agencies, such as the World Health Organization, Food and Agriculture Organization, International Union Against Cancer, Council of Europe and the European Committee for the Protection of the Population Against the Hazards of Chronic Toxicity, more commonly known as EUROTOXf, founded in 1953, was towards developing principles for the toxicological evaluation of substances included in foodstuffs by accident or design in a bid to protect the health of consumers. It was during this period—in September 1955 to be exact—that a joint * All translated quotations from official reports are the translator's own free translation. † In June 1989, EUROTOX became the Federation of European Societies of Toxicology. 0265-203X/91 $3.00 © 1991 Taylor & Francis Ltd.
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FAO/WHO conference was staged in Geneva, the main conclusion of which was to recommend to the Directors General of the two agencies that regular meetings be called of a joint committee of FAO/WHO experts to study the toxicological problems raised by the use of additives in foods (known by the English abbreviation of JECFA). Unfortunately, and paradoxically, I had published nothing in the scientific journals at this time. I shall not dwell further on the developments in this area which I reviewed extensively on 18 March 1977 in my address to the Symposium 'In Memorium Professor E. J. Bigwood' (Truhaut 1977), or on likewise unpublished voluminous working documents reposing in the WHO archives, which my esteemed friend Professor Gaston Vettorazzi, then Secretary of JECFA for the WHO, asked me to present to the 25th session of JECFA as a summary of that body's first 25 years'work, 24 of whose meetings I was privileged to attend (Truhaut 1981). What I should like to do, on the other hand, to aid with the understanding of later sections, is to note that, at its inaugural meeting in Rome in December 1956, JECFA was concerned to define the broad general principles by which any permission to use additives in food should be governed, and in particular to emphasize the primacy of the principle of positive lists for protecting the health of consumers. Unlike the negative list principle, the effect of this is to prohibit the use of any substance not authorized on sufficient toxicological grounds. Permission is to be granted only after qualitative and quantitative data have been produced establishing that, when ingested regularly, on a daily basis for the greater part of one's life, the additive is unlikely to have a deleterious effect on the health of consumers. Let me say that since we cannot prove absolute non-toxicity, but only a very high degree of innocuousness: positive lists must be constantly open to revision in both directions. Let me add that we must also pay constant attention to the technological usefulness of the additive being toxicologically evaluated, and to the existence of strictly defined identity and purity criteria. Let me repeat my contention that I believe I was truly the first expert of the time to talk in terms of an acceptable daily intake for humans, based on the result of toxicological investigations, and to have insisted on defining the concept with sufficient precision for it to be applicable. I could certainly never have done so without help and constant input from certain other particularly eminent specialists. I cannot mention them all by name, numerous as they are. I will limit myself to mentioning, together with the Secretaries of JECFA, in particular, Nir Grossfeld, Frank Lu and Gaston Vettorazzi, Dr J. Barnes (United Kingdom); Prof. M. J. Dois (Netherlands); Prof. H. Druckrey (Germany); Prof. P. Elias (United Kingdom); Dr G. Fitzhugh (United States); Prof. A. C. Frazer (United Kingdom); Dr G. van Genderen (Netherlands); Dr G. van Esch (Netherlands). Dr. van Esch had the extreme kindness to say in an article co-authored with R. Kroes, entitled 'Acceptable daily intake: Truhaut's concept, still accepted today', that between 1957 and 1962 'Professor Truhaut was present in all the different crucial joint FAO/WHO meetings. It is therefore not inappropriate to say that Professor Truhaut can be considered as the Nestor of the ADI concept, as the basis for the estimation of safety, for the introduction of chemical substances in food and drinking water'. As I said earlier, instead of publishing, I confined myself to promoting my approach to the JECFA meetings and in other forums such as the Council of Europe and, from 1974 onwards, in the Scientific Committee for Food of the European Communities, confining myself to
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the development of working documents, some of which must presumably still be lying in the archives of the WHO and Council of Europe. The consequence of my failure to publish at the time is that, of the many published articles on the ADI, few refer to my role as instigator or, in the words of my eminent colleague and friend Peter Elias, the 'obstetrician of the concept of ADI' (Elias 1977). In accepting that I was indeed the initiator and promoter of the concept, it behoves me to explain in what conditions. Engaged since the very outset of my career in the toxicological evaluation of the prolonged ingestion of chemicals to which humans are exposed in various areas of life, I have always taken as a golden rule the principle enunciated by Paracelsus five centuries ago: 'Sola dosis fecit venenum'—it is only the dose which makes a chemical a poison. This led me to accord paramount importance to the establishing of dose/effect relationships in the methodology of toxicological evaluation with a view to fixing admissible limits. From my appointment in 1950 as an expert to the Scientific Committee for Health Controls on Food under the Partial Agreement, then to the Western European Union and, from 1959, to the Council of Europe, I have never lost sight of that Golden Rule in any discussion in which I have taken part. It was when the Committee set up a Working Party on Pesticides, later elevated to the status of a Scientific Committee in its own right that, having to consider the setting of maximal limits for pesticide residues or their metabolites in treated plants subsequently sold for human consumption, I swiftly came to realize that account had to be taken not only of toxicological data, but also of the nature of the foods likely to contain residues, as well as of the average consumption of those foods, which varies by country, region and even population group. That led me to conclude that we needed to establish a basic concept consisting in the evaluation, on the basis of toxicological data extrapolated to humans, of an acceptable dose for repeated absorption by humans, from which to deduce, having regard to the use of pesticides on certain staple crops and, above all, average rates of consumption of foods derived from them, limits which should not be exceeded. I consistently referred to this in Council of Europe meetings from 1956 onwards. I was therefore prepared to discuss the matter also at JECFA meetings and, during its second session in Geneva from 17 top 24 June 1957 chaired by Professor R. Blackwell Smith of the United States, concerned with the study of methods of toxicological investigation of food additives, I was instrumental in having a new chapter included in the final report on 'Evaluation of concentrations probably harmless to man', including the following words: 'From these various investigations a dosage level can be established that causes no demonstrable effect in the animals used. In the extrapolation of this figure to man, some margin of safety is desirable'. This was as yet somewhat nebulous. Some months later (in November 1957) when taking part in the 3rd meeting of the FAO Working Party on control of the olive fly—the olive being, as you know, a key crop in the Mediterranean economy—chaired by my fellow countryman Michel Féron, Director of the Zoological Station at the Montfavet Research Centre in the French department of Vaucluse, I was confronted with the problem of fixing maximum residue limits for certain organophosphorus insecticides—notably parathion—in olive oil for human consumption. The generally accepted concentration limit for olive oil worldwide was 1 mg/kg oil. Toxicologically speaking, however, the decisive factor is the daily quantity of oil consumed. The Greek shepherd, surrounded by olives, dips his bread into the oil and can ingest up
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to 60 g/day. He therefore absorbs far more parathion than consumers whose olive oil intake comes only from salad dressing. Reasoning from this example, my line of thought found further support in the idea that we needed to turn the problem on its head and fix an intake which could be used to calculate the tolerances to be fixed for any given food according to the average quantity consumed in a particular region. This line of thinking led me to develop the concept of the acceptable daily intake, which I elaborated further in a working paper presented to the 6th JECFA meeting held in Geneva from 5 to 12 June 1961, chaired by Dr H. C. Spencer, with myself as Vice-Chairman. The report of this session clearly states that it was recommended that the dose which induced no effect of toxicological significance in experimental animals should be expressed in mgjkg body weight per day. The method of extrapolation to humans was discussed in detail. It was emphasized, however, that the maximum ingestion level admitted unconditionally was not the same as the maximum quantity which could be admitted as acceptable on toxicological bases. Considering that agri-food specialists in many countries are confronted with special problems (different consumption patterns, sharply differentiated consumer groups, etc.), all of which need to be taken into consideration, the Committee thought it desirable also to consider the possibility, after consultation with national groups of experts including at least one toxicologist, of establishing a conditionally acceptable dose. It seems appropriate at this juncture to note the Committee's support for expressing the ADI in mg/kg body weight. In that respect I must stress that, at the time when I first began to moot the ADI concept, I had been talking to my eminent Belgian colleague, Professor E. J. Bigwood, who would have far preferred to have expressed ADI as a ratio of mg/body surface area. I, along with many other specialists, must acknowledge the merits of his arguments from the scientific point of view. In point of fact, the metabolism of small animals in particular—and, in the human population, young children—ultimately does bear a proportional relationship to the body surface area to be taken into consideration. For all practical purposes, however, it is easier to express the ratio in terms of weight. That is what JECFA and the other international bodies decided to do. This, I think, is an appropriate juncture to cite the words contained in the report of the 17th JECFA meeting, held in Geneva from 25 June to 4 July 1973, chaired by Professor M. J. Rand (Australia), with Professor F. Berglund as Rapporteur. I shall refer in more detail to this report later in the light of the importance I attach to it; for the agenda of the meeting not only included the toxicological evaluation of certain food additives, but also a discussion of general principles and standards. 'It was recognized by the Committee that the expression of the ADI in terms of body weight (b.wt.) does not reflect the relative exposure of animals of different size as accurately as would the metabolic mass, which is equal to WbO-75. However, in practice the method of expressing the dose in terms of mg/kg body weight has proved satisfactory.' Over series of JECFA sessions between 1961 and the most recent—35th, Rome, 29 May to 7 June 1989—the definition of ADI has been discussed and, to some extent, made more precise still. Let me quote the definition as it was enunciated after study by a scientific committee of WHO experts and JECFA in a 1987 report in the Environmental Health Criteria series (WHO 1987): 'Acceptable daily intake: an estimate by JECFA of the amount of a food additive expressed on
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a body weight basis that can be ingested daily over a lifetime without appreciable health risk (standard man = 60 kg).' I wholly agree with this definition in which I, together with many other experts, had a hand, and which is completely in line with the scientific rationale which impelled my thinking from 1956/1957 onwards. I was instrumental in having them applied to the specific case of pesticides at the joint meeting of a WHO Committee of Experts in pesticide residues with the FAO Group of Experts on the use of antiparasitic products in agriculture on the principles governing health protection for consumers with regard to pesticide residues (WHO 1962). I also attended this meeting, held in Rome from 9 to 16 October 1961 under the chairmanship of Dr W. J. Hayes (United States) (WHO/FAO 1961), which also marked the starting point for the regular meetings of a new Joint Committee of FAO/WHO experts on pesticide residues in foods, known by its English abbreviation JMPR. Its inaugural meeting, which I was privileged to attend, along with many others which followed it, was held in Geneva from 30 September to 7 October 1963 under the chairmanship of Dr Roy Goulding (United Kingdom). Where sufficient toxicological information was available on a pesticide on the agenda, ADIs were established and formed the basis for the calculation of maximum residue limits in foods obtained from pesticide-treated crops, taking account of average quantities consumed. In the lecture I delivered to the Symposium 'In Memoriam Professor E. J. Bigwood' (Truhaut 1977), I expounded the broad lines of the methodology of the toxicological evaluation of chemical compounds included by accident or design in food. I also critically examined the interpretation of results obtained on laboratory animals and in vitro systems, together with observations on humans. I was thus led to study the determination of toxicologically ineffective doses and the often thorny problems posed by their extrapolation to humans with the application of safety factors. I shall not dwell further on this, particularly as the programme for this Colloquium to the development of which it has been both an honour and pleasure for me to contribute, together with my friends Mrs Gunna Wirtzen and Professor Michel Fondu, includes papers by eminent specialists in these very topics. But in a talk on the history of how the ADI concept can to be established, presented as an introduction to this Colloquium, it behoves me, without encroaching too far on the territory to be covered by my colleagues after me, to pass in review at least a few key ideas which are manifestly central to an understanding of what I have to say on the matter. When speaking of toxicologically ineffective doses in experimentation we must never forget that only a zero dose is truly without effect; all other doses do have an effect, be it ever so little. There is a French proverb which says: 'Spit in the port at Le Havre and the sea level rises in San Francisco.' Obviously, effects on that scale are devoid of practical significance, in the sense that a rise of that order in the sea level at San Francisco has no injurious consequences—it will not capsize the boats at anchor in the Bay. What, in my opinion, the toxicologist must understand by ineffective dose is one which induces no toxic effects. The question then arises, however, as to what is a toxicologically significant effect. Can we say, for example, that a fall in body weight induced by a diet to which a test substance has been added at a certain concentration administered to the experimental animal who rejects some of it from lack of craving is toxicologically significant if unaccompanied by
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other signs of possible toxicity? My answer is a categorical 'No'. But things are not always so clear-cut. Toxicology has become a typically multi-disciplinary science in which the methodological approaches of rapidly developing fundamental sciences such as chemsitry, physics and even mathematics, and biological sciences—not only physiology, pathology and histology, but also biochemistry, molecular biology, immunology and genetics—are applied to the study of toxic effects. The result of that multi-disciplinarity is a consequent advance in our knowledge in these different fields, more productive methods of toxicological evaluation clarifying the morphological, functional and biochemical effects which condition the mechanisms of toxic action. Some of the effects thus elucidated do not lend themselves easily to interpretation, and may be considered either as early signs of aggression or reactions of physiological adaptation. What, for instance, is the significance of mitochondrial swelling with an increase in oxidative phosphorylation, or a slight proliferation of the endoplasmic reticulum revealed under electron microscopy? What toxicological significance can we attribute without difficulty to the action of this or that enzyme on the hepatic microsomes until the resulting metabolites have been identified and their toxicity studied? It is a paradox that increasingly high-powered methodologies do not always produce easily interprétable results. In my view, the toxicologist must interpret the results of a particular approach in an integrated context, by which I mean in conjunction with those obtained by other approaches and factoring in such parameters as physiochemical properties, structure/activity ratios, conditions of use and exposure, and toxicokinetic data, notably bioavailability, metabolic conversion, distribution in body fluids and tissues, and the rate of excretion. Interpretation of that order naturally requires great skill based on much accumulated experience, but it also calls for intelligence and the sound common sense essential to worthwhile judgement ('jugement de valeur'). This is a theory I developed in a talk given at Bilthoven in the Netherlands on the retirement of my respected colleague and fellow toxicologist, Dr G. F. Van Esch, on 28 March 1985 (Truhaut 1986). Returning, after that brief aside, to the concept of the acceptable daily intake, I emphasized from the very first that, calculated on the basis of far from mathematically precise data (concentration without effect in the most sensitive animal species and their extrapolation to humans applying a safety factor of variable value), it could not, per se, have a correspondingly high degree of precision. As the definition makes abundantly clear (Truhaut 1986) therefore, it must be considered as a guide to be applied with some flexibility, not as a hard-andfast rule. Nor must it be forgotten that the definition of ADI posits daily exposure over a lifetime. In reality, however, humans do not ingest day after day each of the chemicals (additives, pesticides, residual metabolites, contaminants) likely to be encountered in certain types of foodstuff, the proportion of which in the diet varies over time, and, in any event, certainly practically never attains the upper limit of the acceptable intake. The quantities initially present in the basic commodities, moreover, are most often found to diminish during storage and particularly during the preparation process prior to being eaten—particularly when cooked. There are also circumstances in which the ADI concept is simply not applicable per se. The ADI may be manifestly exceeded in particular dietetic circumstances, such as where modified celluloses are employed to reduce the available energy value
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of a diet for a restricted period. Or in the opposite case of certain high-risk groups such as newborns and very young children between, say the age of 3 and 6 months, who are generally more sensitive for a host of reasons (including undeveloped metabolism, different intestinal flora to adults, slow development of barriers against certain receptors, such as the central nervous system, etc.) whose food should be permitted to contain additives. The ADI concept is not applied to the general population indiscriminately, therefore. But I leave it to subsequent speakers to develop this point further. Let me, however, stress that the variations in daily diets caused by eating habits do give rise to fluctuations in the daily quantities absorbed. Consequently, the fact of exceeding the ADI in food consumed over a very short period, notably on one particular day, does not entail a health risk, since it will be subsequently compensated for by underexposures through the consumption of far lower quantities. This leads me to consider cumulative chemicals, where fluctuations in the quantities absorbed require close attention. The problem here is the same as that in fixing maximum admissible limits for chemicals which find their way into the air of towns and, more particularly, workplaces. Some of these are maximum limits, valid for exposures of short duration to substances whose main danger lies in their acute toxicity, but mostly referring to substances which tend to accumulate in the body. Considering that workplace exposure is generally from 7 to 8 hours daily and 35 to 40 hours a week, repeated over relatively long periods of time, these values are time-weighted averages, which take account of compensating fluctuations in exposure rates. A comparable rationale to this guided the JECFA experts at their 16th meeting in Geneva from 4 to 12 April 1972 (WHO 1972), which I had the privilege of chairing. Considering the case of cumulative heavy metals (mercury, lead and cadmium) which may contaminate food, their conclusion was that the continuous variations in the daily quantities likely to be absorbed could best be taken into account by fixing 'provisionally tolerable weekly intakes'. That brings me to another initiative I took in the form of a working document for the meeting of a Scientific Committee of WHO experts organized in Geneva from 12 to 18 July 1986, chaired by Dr L. Golberg, then Director of the British Industrial Biological Research Association (BIBRA) in Carshalton (United Kingdom), with myself as Vice-Chairman and Dr Ahlmark (Canada) as Rapporteur. The purpose of the meeting was to study the methods of toxicological evaluation of substances incorporated, intentionally or otherwise, in food (WHO 1967a). Given that certain additives and pesticides had a real technological value, but the highly detailed toxicological information required on them for positive listing had not been forthcoming in an ideally satisfactory way, albeit the available information gave no grounds for fearing a significant health risk, I proposed that the concept of the temporarily acceptable daily intake should be adopted. Sensitive to my responsibilities, I made my proposal contingent on the following conditions: 1. the toxicological information had to be sufficient to rule out any appreciable risk of toxicity for consumers for the period of temporary authorization; 2. the value of the safety factor to be applied to the results obtained in experimentation on laboratory animals, for extrapolation to humans, should be notably higher (at least double) that for the calculation of a normal ADI;
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3. the temporarily acceptable daily intake would be valid only for a limited period of 3 to 5 years; 4. the toxicological and biochemical data judged essential for fixing a regular ADI at a later date had to be clearly indicated; 5. the situation should be reviewed before the temporary ADI period expired, comparing all the initial data with all that which had subsequently become available; 6. if the additional data required were not forthcoming by the expiry of the period fixed, the JECFA Committee would have power to cancel the temporary ADI. After, I must confess, extensive discussion, the Committee agreed to my proposal. I contended that it was, to a certain extent, in the interest of consumers to have the measure adopted; for, provided the principle of sufficient information to protect consumers' health was complied with, and at the same time affording manufacturers the opportunity to put on the market products in which they had invested heavily, toxicologists also had greater powers to demand more detailed toxicological information from them, the interpretation of which would be facilitated by the observations on humans allowed by the use of those products during the temporary authorization period. That seemed to me a very major consideration, given the steady pace of advance in our toxicological knowledge. The recommendation to allow a temporary ADI materialized almost immediately at the 10th meeting of the JECFA Committee in Geneva 3 months later, from 11 to 18 October 1966, chaired by Dr G. Fitzhugh, then Deputy Director of the Division of Toxicological Evaluation of the US Food and Drug Administration, with Dr W. A. Mannel (Canada) and myself as Rapporteurs (WHO 1967b). In this regard it seems to me important from the historical point of view, to cite verbatim Annex 4 of the report of that meeting: 'It will be observed from the above that the acceptable daily intake is only an estimate and depends upon a great number of factors, all of which should be taken into consideration. Therefore an exact maximum acceptable daily intake cannot be calculated. This is one of the reasons why, in some cases, the zone of acceptability is divided into two parts, 'conditional' and 'unconditional'. Although the whole zone of acceptability may be safely used, obviously the smaller the amount of a given chemical consumed, the smaller the risk. However, there are circumstances where one has to weight one risk against another. For a food colour, for instance, one would be inclined to make the acceptable risk smaller than for an antimicrobial used to preserve food that is scarce in many parts of the world. The conditional zone is one that can be safely used under certain conditions, which are specified where appropriate. Thus, in some cases, the use of the chemical might also be permitted for a limited length of time in order to obtain information from further work. In cases where the conditions are not specified, a final decision on whether intakes that fall within the range of conditional acceptance may be considered acceptable in particular circumstances should be taken by a group of scientists including a toxicologist, experienced in this field'. Remaining on the historical plane, I feel it appropriate to state that, at the following JECFA meeting—the 11th—held in Geneva 21-28 August 1967 (WHO
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1968) chaired by Professor G. Brownlee (United Kingdom), with Dr G. J. van Esch as Rapporteur, the above text was reproduced retaining the concepts of conditional ADI and unconditional ADI, despite certain objections which I raised. But the report of this meeting was even more specific than that of its predecessor in setting forth the 1966 recommendation of the WHO Scientific Committee concerning the adoption of a temporarily acceptable daily intake applied, incidentally, for the first time to certain additives under evaluation such as, for example, the aromatics ethylmethylphenylglycidate and maltol, and the nonnutritive synthetic sweeteners sodium- and calcium-cyclohexylsulphamate. That brings me to a more detailed consideration of the report of the 17th JECFA meeting, the importance of which I emphasized earlier due to the critical examination of general principles and standards it contains (WHO 1973). It was at this meeting which, due to some confusion born out of the variety of implementing rules for ADI subject to reservations, that it was considered—to my considerable satisfaction, I must admit—that it would be best to forgo setting any. In the critical review of the general principles governing toxicological evaluation, a number of extremely important points were emphasized. Without trying to cover them all, let me simply mention a few. The first relates to the establishment of a group ADI for chemically and toxicologically related additives. At the 7th meeting held in Rome from 18 to 25 February 1963 under the chairmanship of Professor A. C. Frazer (United Kingdom), the JECFA Committee had adopted an additive grouping system to facilitate evaluation: phenol antioxidants, emulsifiers in the polyoxyethylenesorbitan polyglyceride ester series, modified celluloses and propyleneglycol derivatives. According to the report of the 17th meeting the ADI should then cover all the members of the groups capable of inclusion under the arrangement. Additives falling in two group could not have a content higher than the lower of the two maximum admissible doses. This problem is less complex that it might appear at first sight, since each group of additives contains many substances with similar technological functions and probably thus interchangeable. A second extremely important point relates to the proposal to set an ADI with no express limit ('unlimited ADF) for substances with very low toxicity, notably those used as ingredients in foods or substances which were normal metabolites in humans. It was specified that, as in all other cases, an additive granted an unlimited ADI must still comply with criteria of good manufacturing practice. For example, it must have proven technological effectiveness and be used at the minimum effective dose and also not mask inferior quality or lead to nutritional imbalance (WHO 1973). The description unlimited acceptable daily intake was severely criticised at the 3rd Joint FAO/WHO Conference on food additives and contaminants held in Geneva in October 1973 (FAO 1974) on the grounds that any chemical becomes toxic past a certain dose level. For that reason the 18th JECFA meeting held in Rome from 4 to 13 June 1974 (WHO 1974), which I was privileged to chair, with Dr W. A. Mannel of Canada as Rapporteur, resolved to replace that expression with 'ADI not specified', attaching to it the following definition: 'The statement 'ADI not specified' means that, on the basis of the available data (toxicological, biochemical, and other), the total daily intake of the
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The Committee requested that 'whenever the expression appears in a table, it should be accompanied by a reference to a footnote containing the definition'. In the general report published by the WHO in 1987, this definition was extended somewhat. In particular it was specified that an additive meeting the general criteria involved must be used in accordance with the rules of good manufacturing practice. Any relatively major change in the technological conditions of use must, in my opinion, lead to a review of additives granted an unspecified ADI. This rule is followed by the EEC's Scientific Committee for food, whose successive reports— and notably the 10th report on the guidelines for evaluating the safe use of additives in food (Commission of the European Communities 1980)—coincide, with very few exceptions, on all points with the opinions of JECFA as regards the definition of acceptable doses. For that reason I do not intend to labour the point. Another recommendation adopted at the 18th meeting of JECFA, again taking account of the comments of the 3rd Joint FAO/WHO Conference of October 1973 (FAO 1974), was to amend the rule adopted at the 6th session, which resurfaced in the 17th report, by which the ADI need not include levels of the substance being evaluated occurring naturally in food. Since a substance is equally toxic whether natural or synthetically produced, subject of course to strict compliance with purity standards, and since, on the other hand, chemical analysis cannot distinguish from which of the two origins the substance derives, the Committee concluded that the ADI should include the level of the naturally occurring substance as well as the dose of the product added. This is a particularly crucial condition to observe in the case of nitrates. The Committee noted that certain exceptions might exist, however, and that consequently each case had to be evaluated on its particular merits. As a corollary the Committee emphasized the need to test the total quantity of the substance being evaluated in the diet of experimental animals. Furthermore, if the substance was present in food in a different form from that in which it was used as an additive, each form might need to be evaluated separately. By way of example, such was the case with ascorbic acid and benzoic acid. I shall not go any further into that, however. What I cannot do, by contrast, is to omit any mention of the 19th JECFA meeting held in Geneva from 14 to 23 April 1975, chaired by Professor P. Shubik (WHO 1975). Here I feel I must cite directly, but briefly, a few words from the report of this meeting expressing a fundamental approach to the general principles governing the setting of acceptable daily intakes. The Committee reiterated its practice of following the principles stated in its previous reports and in reports of a WHO Scientific Group on Procedures for Investigating Intentional and Unintentional Food Additives and a WHO Scientific Group on the Assessment of the Carcinogenicity and Mutagenicity of Chemicals.
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In this regard I cannot over-emphasize the value to be drawn from reading the successive reports of the Scientific Committee for Food of the European Communities, as well as the 1987 booklet published by the WHO in the 'Environmental Criteria' series (WHO 1987). Having no desire to trespass on the unquestionably rewarding discussions which will round off this Colloquium, I shall bring my review to a close here. That is also the reason for which I voluntarily refrained from launching into a discussion on the concept of the 'potential acceptable daily intake' advanced by our Danish colleague Hansen in 1979, as well as various other approaches. Lack of time also obliged me to omit a consideration of extremely important issues such as the setting of an ADI for certain classes of non-genotoxic carcinogens and that raised by chemical contamination of drinking water—both key issues in regard to food. Despite the things I should have included and have most surely forgotten, for which I apologize, I hope I have managed to do what the organizers of this International Colloquium on the acceptable daily intake wanted, with a review of the milestones in the historical development of the concept. More particularly, I hope I have gone some way to countering some of the criticisms which have been from time to time been levelled at it and which, in my opinion, apply only to poor conditions of application; overlooking, for example, the need when setting tolerances for food and water for human consumption to take into account the nature of those containing the additives or contaminants for evaluation and the average rates of consumption on them in different countries and population groups. But most of all, I hope I have shown how the use of the ADI concept has made a powerful contribution to protecting the health of people the world over, and oiling the wheels of international trade. References COMMISSION OF THE EUROPEAN COMMUNITIES, 1980, Rapport du Comité scientifique de l'alimentation
humaine sur les lignes directrices concernant l'appréciation de la sécurité d'emploi des additifs alimentaires. Opinion, 22 February, Series 1, EUR 6892. DOLS, M. J. L., 1977, Minutes of the discussion of the second day of the round table on the interpretation and use of the concept of acceptable daily intake CAD 8 of food additives on the occasion of the Symposium 'In Memoriam Professor Bigwood', 19 March, pp. E3 and 4. ELIAS, P., 1977, Minutes of the discussion of the second day of the round table on the interpretation and use of the concept of acceptable daily intake CAD 8 of food additives on the occasion of the Symposium 'In Memoriam Professor Bigwood', 19 March, E10. EUROPEAN TOXICOLOGY FORUM, 1984, Proceedings of the Session of the European Toxicology Forum held in the International Conference Center, Geneva, 18-21 October; Remarks. FAO, 1974, FAO Miscellaneous Meetings. Report Series, 1974. Document ESN WHO Food Add/74-43. TRUHAUT, R., 1977, Principes généraux d'évaluation toxicologique des additifs dans les denrées alimentaires. Proceedings of the Symposium 'In Memoriam Professor Bigwood'—Les données de base de l'action communautaire—18-19 March (Brussels: Université Libre de Bruxelles, Institut d'Etudes Européennes), pp Bl-B26. TRUHAUT, R., 1981, 25 Years of JECFA achievements. Report presented to the 25th session of JECFA, WHO, Geneva, 23 March-April. TRUHAUT, R., 1986, Critical remarks on qualitative and quantitative aspects of toxicological evaluation of chemicals: The need for an integrated approach. Lecture given on the occasion of the retirement of Dr G. J. van Esch, 28 March 1985—Report of the Symposium organized by the National Institute of Public Health and Environmental Hygiene, Bilthoven, Netherlands, and the Netherlands Society of Toxicology in honour of J. Van Esch, Bilthoven, 1986, pp. 6-15. VAN ESCH, G. J. KROES, R., 1984, Acceptable daily intake. Truhaut's concept still acceptable today. Homage to Professor René Truhaut, Paris, 19 October 1984, (Imprimerie Tardy, Quercy, Cahors) pp. 1124-1127.
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WHO, 1962, Principes devant régir la protection de la Santé des consommateurs à l'égard des résidus de persticides. Report of a meeting of a joint WHO Committee of experts in pesticide residues and an FAO group of experts on the use of antiparasitic products in agriculture. Rome, 9-16 October 1961. WHO Technical Report Series, No. 240 (Geneva: WHO). WHO, 1967a, Méthode d'évaluation toxicologique des substances ajoutées intentionnellement ou non aux aliments. Report of a WHO scientific group. Technical Report Series, No. 348 (Geneva: WHO). WHO, 1967b, Normes d'identité et de pureté et évaluation toxicologique des additifs alimentaires. Divers émulsifiants et stabilisants et certains autres substances. 10th report of the Joint FAO/WHO Committee of experts on food additives. Technical Report Series, No. 373 (Geneva: WHO). WHO, 1968, Normes d'identité et de pureté et évaluation toxicologique des additifs alimentaires. Divers aromatisants et édulcorants non nutritifs. 11th report of the Joint FAO/WHO Committee of experts on food additives. Technical Report Series, No. 383 (Geneva: WHO). WHO, 1972, Evaluation de certains additifs alimentaires et de contaminants. Mercure, Plomb, Cadmium. 16th report of the Joint FAO/WHO Committee of experts of food additives. Technical Report Series, No. 505 (Geneva: WHO). WHO, 1973, Evaluation toxicologique de certains additifs alimentaires. Examen des principes généraux et des normes. 17th report of the Joint FAO/WHO Committee of experts on food additives. Technical Report Series, No. 539 (Geneva: WHO). WHO, 1974, Evalulation de certains additifs aux aliments. 18th report of the Joint FAO/WHO Committee of experts on food additives. Technical Report Series, No. 557 (Geneva: WHO). WHO, 1975, Evaluation de certains additifs alimentaires colorants, épaississants, condensats de fumée et autres substances. 19th report of the Joint FAO/WHO Committee of experts on food additives. Technical Report Series, No. 576 (Geneva: WHO). WHO, 1987, Principles for the safety assessment of food additives and contaminants in food. Environmental Health Criteria, No. 80 (Geneva: WHO).
