History of Toxicology
Dioscorides, a Greek physician in the court of the Roman emperor Nero, made the first attept to classify plants according to their toxic and therapeutic effect. Paracelsus, a Swiss born in 1493, is often referred to as the father of toxicology. He is known for the famous quote "The Dose Makes the Poison" (Dosis facit venenum).
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Example of a Toxicology Monograph
FAO Meeting Report No. PL/1965/10/1 WHO/Food Add./27.65 EVALUATION OF THE TOXICITY OF PESTICIDE RESIDUES IN FOOD The content of this document is the result of the deliberations of the Joint Meeting of the FAO Committee on Pesticides in Agriculture and the WHO Expert Committee on Pesticide Residues, which met in Rome, 15-22 March 1965
Food and Agriculture Organization of the United Nations World Health Organization 1965
Report of the second joint meeting of the FAO Committee on Pesticides in Agriculture and the WHO Expert Committee on Pesticide Residues, FAO Meeting Report No. PL/1965/10; WHO/Food Add./26.65 CONTENTS General considerations The concept of acceptable daily intakes as applied to pesticides Re-evaluation of consumer hazards of pesticides Additional pesticides Biological data presented in the monographs Note to the reader Monographs: Aldrin Allethrin Azinphos-Methyl BHC Capan Carbaryl Chlorbenside Chlordane Chlorfenson Chlorobenzilate Chlorpropham Chlorthion DDT Demeton Demeton-S-Methyl Sulfoxide Diazinon Dichlorvos Dieldrin Dimethoate Dimethrin DNOC Endosulfan Endrin Ferbam Heptachlor Lead arsenate Lindane Malathion Maneb Methoxychlor Mevinphos Nabam Parathion Methyl Parathion Phenylmercuric Acetate Piperonyl Butoxide Phosphamidon Propham Pyrethrins Thiram Triphenyltin compounds Zineb Ziram GENERAL CONSIDERATIONS At the present time, to feed the people of the world, recourse must be had to pesticides to protect the crops both during growth and during their subsequent storage and transport. While some of the chemicals used for this purpose will not contaminate the final crop, others, even when used in accordance with good agricultural or food storage practice, will leave residues which will be present in the food at the time of consumption. This meeting was concerned, as were the previous ones, with the protection of the consumer against the hazards that might result from the presence of these residues, and its aim was to give guidance to authorities responsible for the health, nutrition and welfare of people from this point of view. In carrying out this task, the participants were mainly guided by the principles governing consumer safety in relation to pesticide residues enunciated at the 1961 joint meeting of the WHO Expert Committee on Pesticide Residues and the FAO Panel of Experts on the Use of Pesticides in Agriculture.
The following definitions of the terms used in work on pesticide residues are reproduced from that report. Residue: A pesticide chemical, its derivatives and adjuvants in or on plant or animal. Residues are expressed as parts per million (ppm) based on the fresh weight of the sample. Food factor: The average fraction of the total diet made up by the food or class of foods under discussion. Details of the diet of a country may be obtained from the FAO Food Balance Sheets or other similar data. Acceptable daily intake: The daily dosage of a chemical which, during an entire lifetime, appears to be without appreciable risk on the basis of all the facts known at the time. "Without appreciable risk" is taken to mean the practical certainty that injury will not result even after a lifetime of exposure. The acceptable daily intake is expressed in milligrams of the chemical, as it appears in the food, per kilogram of body-weight (mg/kg/day). Permissible level: The permissible concentration of a residue in or on a food when first offered for consumption, calculated from the acceptable daily intake, the food factor, and the average weight of the consumer. The permissible level is expressed in ppm of the fresh weight of the food.
FAO Plant Production and Protection Division Report No. PL/1961/11; Wld Hlth Org. techn. Rep. Ser., 1962, 240. Tolerance: The permitted concentration of a residue in or on a food, derived by taking into account both the range of residue actually remaining when the food is first offered for consumption (following good agricultural practice) and the permissible level. The tolerance is also expressed in ppm. It is never greater than the permissible level for the food in question and is usually smaller. The meeting was not concerned with tolerances and it wished to re-emphasize the fundamental difference between a tolerance and an acceptable daily intake. Only acceptable daily intakes are based entirely on toxicological evidence. A tolerance is then the smallest residue consistent with control of the pest, but to be toxicologically acceptable it must not exceed the permissible level. In the report on principles governing consumer safety in relation to pesticide residues,
the method outlined for calculating a permissible level is most useful for a pesticide which is used on a single article or class of articles of the diet, if these form the only source of that substance for the consumer. In many cases, a pesticide is used on a number of different types of foodstuff and may also have non-agricultural uses, as in public health programmes. DDT is a good example of this type of pesticide. Account must be taken of such multiple uses of pesticides and in these cases it may be preferable to adopt an alternative method of calculation based on that advocated for food additives.
The possible consumer hazards arising from the intake of a pesticide could then be assessed by adopting the follow procedure: (1) Determine the residue in each type of food and drink liable to contain the pesticide in question. (2) Calculate the daily intake level of the pesticide that might occur if it had been used on all the foodstuffs for which it might be used, working on the basis of the average daily diet. (3) Knowing the average body-weight, calculate the daily intake of the pesticide, expressed as mg per kg per day. (4) Check this figure against the acceptable daily intake for that pesticide. (5) If the figure does not exceed the acceptable daily intake, the proposed was of the pesticide are acceptable. If the figure exceeds the acceptable daily intake, one or more of the proposed uses will have to be reconsidered with a view to reducing the residues resulting from such use (or uses) or abandoning one or more uses entirely.
FAO Plant Production and Protection Division Report No. PL/1961/11; Wld Hlth Org. techn. Rep. Ser., 1962, 240.
See the Sixth Report of the Joint FAO/WHO Expert Committee on Food Additives, FAO Nutrition Meetings Report Series, 1962, 31; Wld Hlth Org. techn. Rep. Ser., 1962, 228. (6) When there is a margin between the figure and the acceptable daily intake, proposals for further uses of that pesticide on foodstuffs can be considered. THE CONCEPT OF ACCEPTABLE DAILY INTAKE AS APPLIED TO PESTICIDES Since pesticides are, from their very nature, poisonous to some forms of life, any intake by man in the food may be considered undesirable. For this reason the rate of application of the pesticide to the crop should be as low as possible, and the interval between its last application and the consumption of the crop should be as long as possible so that the residue is reduced to a minimum. Nevertheless, if pesticides are to be used, as they must be, some ingestion will occur. It would help in the assessment of any possible hazards arising from the consumption of these tiny amounts of pesticides if it were known how much could be consumed daily without risk. In order to determine an acceptable daily intake the following information should be available. (a) The chemical nature of the residue in food as presented for consumption. Pesticides may undergo chemical changes and are frequently metabolized by the tissues of the plants and animals that have been treated with them. Even when a single substance has been applied, the residue may consist of a number of substances with distinct properties, the exact nature of which may differ in animals and plants and in different crops and products. (b) The toxicities of the substances forming the residue, as judged by acute, short-term and long-term studies in animals. In addition, knowledge is required of the metabolism, mechanism of action, and the possible carcinogenicity of pesticide residues when consumed. (c) A sufficient knowledge of the effects of these residues on man. Information on this scale is not often available at the present time, but if it is, a daily level of intake having no observable effect on a sensitive species of animal can be determined. In some cases, this level has been determined for man himself. From this starting point an acceptable daily intake for man can be proposed by employing a suitable factor. When an acceptable human daily intake of a residue has been proposed, the nature of the food bearing the residue is probably immaterial. The amount of data available varies considerably for the different pesticides. Nevertheless, even when the information about a particular pesticide appears very complete and an acceptable intake is proposed, it must be realized that, however carefully the data are evaluated, the statement that x mg/kg body-weight can be eaten every day for a lifetime without appreciable risk remains an expression of opinion which carries no guarantee of "absolute" safety. Such a guarantee would be impossible.
On the other hand, the desire to use the most sensitive criteria for the determination of the threshold effect levels, coupled with the natural conservatism of an international body, inevitably leads to great caution in the proposals for acceptable daily intakes. This should be taken into account when these values are used. At the meeting, a single set of acceptable daily intake figures was proposed. It was recognized, however, that exceptional situations might arise when the possibility of exceeding these figures would have to be considered, e.g., in the event of serious food shortage. The meeting was not in a position to offer guidance to cover all such circumstances; each case will have to be decided on its merits by the national authorities responsible, who should take expert advice on the risks to health from excess intake of pesticides and the medical consequences arising from the loss of the crop. There are obviously conditions in which it would be unrealistic to adhere to these levels. The only advice which can be given to those faced with making this type of decision is to consider the nature of the criterion used to determine the level. Obviously, when the criterion used is a minimal change in cholinesterase activity of the blood, the level can be more safely exceeded than when the criterion is some more serious functional change. Only a limited number of the many pesticides now available have been considered. The omission of a pesticide from the monographs does not imply criticism of that pesticide, nor does it suggest that it can be used without restraint. The meeting strongly emphasized that new data or new knowledge could always lead to a re-evaluation of an acceptable daily intake. Values of this nature are always provisional. It is the duty of all who use the material contained in the monographs to ensure that they possess the latest information. RE-EVALUATION OF CONSUMER HAZARDS OF PESTICIDES The 37 pesticides evaluated in 1963 were reconsidered by the meeting, not only on the basis of the information contained in the previous report,
but also in the light of further data that have since become available. For 21 substances the monographs remain unchanged. For 11 substances (aldrin, dieldrin, endrin, heptachlor, dimethoate, malathion, parathion, carbaryl, captan, triphenyltin compounds and lead arsenate) new information was added to the monographs without affecting the evaluation of the hazard to man.
Stoner, H. B. (1964) J. Food Cosmet. Toxicol., 2, 457.
FAO Meeting Report No. PL/1963/13 (mimeographed); WHO/Food Add./23/1964 (mimeographed). A re-evaluation was made for chlordane, propham and chlorpropham. For chlordane, new data have demonstrated a maximum no-effect level in the rat, and the meeting was informed that the suggestion that propham and chlorpropham possessed co-carcinogenic activity had not been substantiated. Nevertheless, the information about these compounds was still insufficient to allow an acceptable daily intake for man to be established. In the case of DDT, the meeting considered that in view of the vast amount of information on the metabolism, fate and toxic effects of this compound in man obtained from observations on large numbers of people in many countries, a wider range could be accepted for the "acceptable daily intake" for man. This has now been set at 0-0.01 mg/kg/day. Finally, in the case of diazinon it was considered on re-evaluation of new data that an "acceptable daily intake" for man could be estimated to be 0.0002 mg/kg/day. This was based on the threshold level for the dog which is very sensitive to this pesticide. The meeting re-emphasized the lack of information on the toxicity of diazinon to man. The meeting found that there was still insufficient knowledge for complete assessment of the possible consumer hazards from these pesticides. An attempt has been made in the monographs to indicate in a little more detail than in the previous monographs what information is still missing. The heading "Further work required" indicates a higher priority than "Further work considered desirable". In some cases it has been possible, under the heading "Comments on experimental studies reported", to draw attention to the absence of a specific piece of information which would materially assist in setting an "acceptable daily intake" value. It is hoped that such work will be forthcoming for consideration at future meetings. The meeting still felt concern about some results indicating that certain organo-chlorine compounds could evoke the formation of tumours in susceptible strains of laboratory animals. Since it was realized that a precipitate withdrawal of these pesticides would create difficulties in agriculture and public health in some countries, the meeting urged that serious attempts should be made to remove the doubts concerning the significance of these findings. ADDITIONAL PESTICIDES The meeting also considered five additional pesticides - dichlorvos, pyrethrins, allethrin, dimethrin and piperonyl butoxide - using the same criteria for their evaluation as were used in the previous report.
FAO Meeting Report No. PL/1963/13 (mimeographed); WHO/Food Add./23/1964 (mimeographed). No acceptable daily intake was determined for any of these pesticides. It would have been possible to set a figure for dichlorvos based on inhalation experiments in man. The value would have been an extremely low one. However, it is known, from animal experiments, that dichlorvos is more toxic when inhaled than when taken by mouth, and no data are available on the effects of oral administration in man. Although the available data for the pyrethrins and the related allethrin and dimethrin were insufficient to establish acceptable daily intakes for those substances, there was no reason to question the customary uses of pyrethrins. Piperonyl butoxide was considered because it is often present, as a synergist, in pyrethrin formulations. Although there is no evidence that the uses of piperonyl butoxide as at present approved involve any danger, there is not enough information on the compound to allow the setting of an acceptable daily intake figure for man. BIOLOGICAL DATA PRESENTED IN THE MONOGRAPHS In using the concept of acceptable daily intakes in the control of consumer hazard from pesticides it is not sufficient merely to consult a list of figures. Account must also be taken of the evidence on which the figures are based. As much relevant information as possible has been included in the monographs. Wherever possible this has been obtained from the published literature but other sources of information have also been used. The members of the meeting thanked all those who had made information available to them and offered their apologies to any authors whose work may not have been taken into consideration. They emphasized the need for the early and complete publication of the results of research in this field, particularly of that part which could form the basis of the determination of an acceptable daily intake for man. This is necessary so that the work reported can be the subject of scrutiny and informed criticism by a wider group of scientists covering disciplines not necessarily represented at the Committee meeting. Unpublished data, because they may include more detail than published work, may often be required for the determination of acceptable daily intakes. These data most be complete non-confidential and with an indication of the authorship of the report. The information will not be considered unless it is received by FAO/WHO at least six months before the announced date of the Committee meeting in sufficient copies (at least two) to be distributed to suitable experts. For many substances the amount of information fell short of that required for the setting of an acceptable daily intake for man but not all the substances for which no figure was proposed seem to offer the same hazard. An attempt has been made to indicate the degree of hazard in each case and an indication has also been given of further work needed. When the additional information is forthcoming, the substances in this category will be reconsidered. The figures already set will be reviewed in the light of further knowledge. The biological data are presented under various headings, as in previous reports of this type. Biochemical studies These are important because they reveal the metabolism of the pesticide in the crop during the formation of the residue and subsequently in the animal which consumes it. It is important to know whether a substance is absorbed, its distribution in the body after absorption, its mechanism of action including its influence on enzyme systems, how it is metabolized, and the routes of final elimination. The toxicity of a pesticide may be altered at all these stages. In the crop or - in the case of veterinary pesticides - in the animal, a number of metabolites may be produced, some of which may be the active forms of the pesticides, as in the formation of paraoxon from parathion. After ingestion, these active products may be further broken down to compounds that are excreted. Storage of these or of the parent chemical may occur. The fact that a substance appears to be rapidly broken down and excreted does not necessarily mean that it is more desirable as a residue than one which is stored, say, in the adipose tissue. Short-lived compounds formed during the breakdown might be very poisonous, whereas persistent compounds might be stored in an inactive form. Broadly speaking, the more that is known of the fate and mechanism of action of a pesticide the better should be the understanding of its toxicity and consequently the easier it will be to set an acceptable daily intake for man. Acute toxicity The value of data on acute toxicity is that they give an idea of the inherent toxicity of the material. Where there is information of the acute sensitivity of man to pesticides it has been included under this heading. Short-term studies Investigations covering less than half the animal's life-span, are included under this heading. In the case of some of the pesticides considered, studies have been made in which they have been fed to man. These data are clearly of great value and have also been taken into consideration. In a few instances studies on workers exposed to pesticides have contributed some information or help in arriving at figures for acceptable daily intakes. It is desirable that further careful studies on workers be made because of their prolonged intensive exposure. Long-term studies These studies include tests covering the greater part of the animal's life-span and research on the possible carcinogenicity of the residues. The requirements of the latter tests have been discussed in previous reports.
Long-term studies are important for the determination of the dietary level of the compound which produces no effect, particularly when dealing with compounds that do not produce any measurable biochemical changes. Obviously such tests must be carried out on a species that has been shown by acute and/or short-term studies to be sensitive to the compound. The sensitivity should be as similar as possible to that of man and the metabolism of the compound in the animal should also be similar to that in man. Special studies The Committee again considered the significance of the inhibition of the liver esterases by many organo-phosphorus pesticides at concentrations below those required for the inhibition of cholinesterase. Again, the Committee did not think that it was possible to utilize these effects in the assessment of consumer hazard since the functional importance of these enzymes are not known, no symptoms appear to be attributable to their inhibition and the symptoms of poisoning by organo-phosphorus pesticides can be related to their effect on cholinesterase activity. At the end of the introduction to the last report, the Committee mentioned those additional factors which should be borne in mind when using the acceptable daily intake figures, namely, addition (summation), potentiation and the possibility of genetic differences in the populations at risk. The Committee did not consider that it could amplify its previous remarks on "addition" or "genetic differences". Those remarks are now repeated. (a) Addition. The values given in the monographs have been calculated on the assumption that the diet is contaminated by a single chemical residue. In practice, foodstuffs frequently contain residues of more than one compound, and an additive effect may then occur. The meeting did not feel able to make any specific recommendations under this heading, but emphasized as a general safeguard against these additive effects the importance of always keeping the residues to a minimum.
Wld Hlth Org. techn. Rep. Ser., 1958, 144; FAO Nutrition Meetings Report Series, 1958, 17.
Wld Hlth Org. techn. Rep. Ser., 1961, 220; FAO Nutrition Meetings Report Series, 1961, 29.
Wld Hlth Org. techn. Rep. Ser., 1962, 240; FAO Plant Production and Protection Division Report No. PL/1961/11 (b) Genetic differences. The increasing appreciation that genetically determined differences in the enzymic pattern of man can affect his reaction to toxic agents is a further indication that acceptable daily intakes should not be applied too rigidly. Regarding the possibility of the potentiation of the effect of one pesticide residue by the residue of another pesticide, the Committee considered that the evidence which was available indicated that potentiation was unlikely to occur at the concentrations for pesticide residues found in food. Since the last report more information
has come to hand on the results of the use of behavioural tests in the investigation of the toxicity of pesticides. These tests offer additional ways of investigating the actions of pesticides on mammals and the results have been taken into account in the evaluation of the toxicity of the pesticides considered in these monographs. At the present time it would appear that for some substances behavioural tests are not more sensitive than other tests (biochemical, etc.) used to detect toxicity and the information obtained must be considered together with all the other available information. Comments on experimental studies reported Under this heading is given a short commentary summarizing the available evidence and leading to its evaluation from the point of view of the determination of a maximum acceptable daily intake for man. Evaluation In evaluating the toxicological information, the meeting was mainly concerned to establish the maximum dose of the compound that could be given over a long period without producing ill effects. In most cases this was a dose level for some animal species. For some compounds this level had been determined in man, and such human data, although often covering a relatively short period, naturally took precedence. When human data of this type were not available and in the absence of evidence to the contrary, human sensitivity in principle was equated with that of the most sensitive animal species.
Medved, L. I., Spyn, E. I. & Kagan, I. S. (1964) Residue Reviews, 6, 42.
Goldberg, M. E. & Johnson, H. E. (1964) J. Pharm. (Lond.), 16, 60.
Goldberg, M. E. & Johnson, H. E. (1964) J. Pharmacol. exp. Ther., 145, 367.
Goldberg, M. E., Johnson, H. E. & Knaak, J. B., Psychopharma (In press).
Goldberg, M. E., Johnson, H. E. & Knaak, J. B., Biochem. Phamacol. (In press). It is unfortunate that only crude criteria exist for estimating the mammalian toxicity of many pesticides. It was felt that a cautious attitude should be adopted towards compounds whose mechanism of action was unknown. The meeting wished to draw the attention of research workers to the need for more sensitive criteria for use in this type of work. Increasing sensitivity is not valuable of itself unless it is significant from the point of view of toxicity. The sensitivity of those tests used to measure the toxicity of the pesticide at high dosage levels should be increased so that proper dose-response curves can be determined. Extrapolation to man Where a maximum no-effect level of dietary intake has been established in a sensitive animal species and where there are no comparable data for man, the animal dose rate must be taken as a basis for calculating an acceptable daily intake for man. This can be done in several ways.
Unfortunately the more scientific methods of making this adjustment require an amount of information that is seldom available, and was certainly lacking for the compounds studied in the present report. Accordingly the meeting adopted the commonly used empirical method: the maximum no-effect dietary level obtained by animal experiment, expressed in mg/kg bodyweight per day, was divided by a "factor", generally 100. Where the maximum no-effect level for oral intake in man was known, a smaller factor was used - in certain cases as low as 10. The acceptable daily intake figures in the monographs that follow are intended to be of value as a check to ensure that tolerances are toxicologically acceptable. Note to the reader Any comments on chemical and physical information and agricultural data should be addressed to: Crop Protection Branch Plant Production and Protection Division Food and Agriculture Organization Rome, Italy Any comments on biological data and their evaluation should be addressed to: Nutrition Unit World Health Organization Geneva, Switzerland
Gaddum, J. H. (1956) Brit. J. Pharmacol., 11, 156.
Mantel, N. & Bryan, W. R. (1961) J. nat. Cancer Inst., 27, 455
See Also: Toxicological Abbreviations
- Household Products Database
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American Journal of Pharmacology and Toxicology -
American Journal of Pharmacology and Toxicology is a peer-reviewed open access journal that publishes original research/review articles on drug section in all the areas of pharmacology and toxicology in vivo and in vitro metabolism, intracellular metabolism and intercellular regulation.