RESIDUES PESTICIDE RESIDUES AND CONSUMER RISK ASSESSMENTS

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1 PESTICIDE AND CONSUMER RISK ASSESSMENTS Ray Bates 1 summarises the main issues involved in assessing the risks from pesticides in food Introduction The control of risks from the use of pesticides for the protection of crops from pests and diseases is normally achieved nationally through the widely-used pesticide registration procedures which identify and authorise the maximum registered use of a pesticide which will satisfy the need for effective and reliable crop protection and, at the same time, offer minimum risk to users and leave only residues in food and the environment that are toxicologically acceptable. This article summarises the main issues involved in the risk assessment of pesticide residues in crops and food, emphasising the major role of registration procedures in the complete evaluation. Initial deposits and subsequent residues in crops The application of an agricultural pesticide can lead to deposits of the pesticide formulation on the target crop, the applicator, passers-by or other third parties, and the environment in general. In assessing any risk from a pesticide application a regulatory authority is concerned with the site and size of all deposits and their fate and effects. These deposits may also be considered in relation to exposure from other sources of the pesticide and to other relevant pesticides, but not usually to other chemicals in food and the environment. Thus it is vital to study these initial deposits and the residues that may occur in the environment, in crops and food, and even in human tissues. Although analytical determinations of residues are carried out for many purposes, the phrase residues data is more commonly associated with the analysis of crops and food for the evaluation of risks to the consumer. Pesticide residues in crops at harvest depend mainly on two factors: The initial deposit on the crop, its distribution and coverage Its disappearance after application, both apparent through dilution by crop growth and real, through the effects of a variety of physical, chemical and biological processes The rate of application dictates the upper limits of a deposit and the theoretical maximum residue level in the harvested crop can be anticipated by relating rates of 1 Address: 5 Manor Park Drive, Westoning, MK45 5LS, UK application to average commodity yields per hectare from treated crops. For example, assuming total uniform transfer to the harvested commodity itself, deposits from an application of a pesticide at 1 kg ha 1 to an orchard yielding 10 tonnes apples per hectare could lead to a maximum deposit of about 100 mg kg 1, although deposits are never achieved in practice for many reasons. It is difficult, if not impossible, to isolate and determine the significance of all the individual factors influencing a pesticide deposit but the following will all affect the initial deposit: The rate of application The ratio of surface area to weight of the crop The nature of the crop surface The application equipment Prevailing meteorological conditions The factors affecting deposits and their disappearance are considered by Bates (1991). Detailed supervised residues studies, measuring deposits and following their disappearance until harvest are carried out by pesticide manufacturers, both for their own needs in planning a proposed pesticide use as well as to satisfy the requirements of regulatory authorities when applying for registration of the use. Residues requirements for the registration / authorisation of pesticides For many years national requirements for residues studies to support an application for registration contained significant differences but following the FAO Consultation in Rome on the International Harmonisation of Pesticide Registration Requirements (FAO, 1982) and the long-awaited standardisation of registration procedures within the EU, uniform requirements are now a reality in the EU and some other regional markets for pesticides (FAO, 1986; EU Directive 91/414). In summary, these requirements are: Plant metabolism studies to characterise the chemical nature of the residue which may occur in treated crops An analytical method to identify, quantify and confirm all the components included in the residue definition, in all the crops that may be treated Residue field trials to determine the rate of decline of pesticide deposits and to establish the highest levels of residues in treated crops at harvest 142 Pesticide Outlook August 2002 DOI: /b206513b This journal is The Royal Society of Chemistry 2002

2 The registration authority needs the following information: To estimate the potential exposure to the pesticide from the proposed uses To predict the total dietary intake of a pesticide and assess consumer risk To estimate maximum residue levels to use as legal limits (MRLs) in monitoring compliance with authorised uses Thus the role of supervised residue trials in which residues can be related to applications which are identified and controlled, carried out by the manufacturer to provide this information, is crucial to the estimation of the potential exposure to pesticide residues in food and the subsequent consumer risk assessment. One outcome of about 50 years of escalating collection and collation of residues data for registration purposes is a truly staggering quantity of information available to national governments and international agencies engaged in assessing risks to consumers before authorising the use of a pesticide. The optimum use of this extensive database in predicting residues in crops is discussed in an IUPAC report (Bates, 1990). It is however important to recognise the major role of continued supervised trials to validate, reject or modify the predictions that can be made from the extrapolation from the existing data base. Consumer risk assessments during registration 2001 was the 40th anniversary of a historic joint meeting of a WHO Expert Committee on Pesticide Residues and an FAO Panel of Experts on the Use of Pesticides in Agriculture held in Rome. The outcome, a report entitled Principles Governing Consumer Safety in Relation to Pesticide Residues (WHO/FAO, 1962) set the scene for many years of scientific and political discussion on this controversial topic. The two fundamental principles identified in the report are still presented as the major principles to be followed in assessing consumer risk. THE TWO MAJOR PRINCIPLES IN THE RISK ASSESSMENT OF PESTICIDES IN FOOD The residue resulting from the use of a pesticide should not be higher than that which results from good agricultural practice. The total amount of residue in the daily food (i.e. dietary intake) should not exceed the amount accepted as safe for life-time consumption by man. (WHO/FAO, 1962) The report assessed the use of toxicological studies on animals, the results of which could be extrapolated to man, and defined, as an objective of these studies, the establishment of an acceptable daily intake (ADI) to define the maximum allowable hazard, as had been done earlier for certain food additives (Stoner, 1964). The process of risk assessment of a pesticide residue involves the characterisation of both the hazard (the pesticide s toxicity) and the exposure (the level of the pesticide in the diet) and it is necessary to estimate both the hazard and the exposure separately. The primary consideration in determining whether a compound can induce a toxic effect is the dose of the substance to which an organism is exposed. Every chemical can be toxic at a certain dose and under some conditions of exposure but for every chemical there should be an exposure than can be regarded as without appreciable risk to human health. Hazard The health hazard of a substance is a reflection of its toxicological properties and these can be identified and quantified within experimental limits. Unfortunately, it can be difficult to extrapolate toxic effects observed with the relatively high doses considered necessary to produce an effect in long-term studies on animal test species, to the very low doses to which consumers are normally exposed. There are several reasons why the previously used (selfexplanatory) term no-effect level (NEL) has no real meaning and should be replaced by no-observed-effect level (NOEL). Even further, a distinction may need to be drawn between adverse and non-adverse effects, giving rise to the currently used no-observed-adverse-effect level (NOAEL). A detailed account of the principles, terminology and methods for evaluating the toxicity of chemicals and the toxicological assessment of pesticide residues in food can be found in two publications by the World Health Organisation (WHO, 1978; WHO, 1990). Safety factors In almost all instances, safety factors have been introduced to provide for uncertainties in extrapolation from animals to man. For many years the commonly used empirical approach for the extrapolation of data in the estimation of a NOAEL for man has been to divide the maximum no-effect dietary level from animal experiments by a factor of 100. This 100-fold safety factor can be viewed as two 10-fold factors, one for inter-species and one for intra-species variability. Safety factors may be modified in the light of available data and any concerns that arise when considering these data. In 1996 the Food Quality Protection Act (FQPA) in the USA required the application of a controversial additional 10-fold uncertainty factor to the acute Reference Dose (see below) to take into account the potential vulnerability of infants and children to chemicals in the environment. A recent discussion of this issue led to the conclusion that if the emotive aspects can be stripped away and the hazard and exposure data carefully and objectively evaluated, there is little, if any, evidence that under current regulatory procedures, children are any more at risk than adults (Wilkinson, 2000). Pesticide Outlook August

3 Estimating an Acceptable Daily Intake (ADI) The toxicological properties of all pesticides must be examined in detail and the minimum data base normally used in estimating an ADI consists of short-term and longterm feeding studies, carcinogenicity studies, multigeneration reproduction studies, teratogenicity studies, and acute and repeated exposure metabolic, toxicokinetic and toxicodynamic data. Where deemed necessary, additional special studies may also be required. e.g., genotoxicity. The NOAEL from the most appropriate animal study divided by an appropriate safety factor determines the proposal from the ADI for man. DEFINITION OF ACCEPTABLE DAILY INTAKE (ADI) 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 (WHO/FAO, 1962) The acute Reference Dose (acute Rfd) In principle, the acceptability of human exposure to a pesticide residue in food is most appropriately derived from animal studies that closely mimic the human exposure pattern of concern usually long-term feeding studies at very low levels. However, the traditional ADI approach may not always be the most appropriate, since some effects may be noted after a relatively short-term, or even a single, exposure. This could happen, for example, with some cholinesterase inhibitors. Since databases normally used for estimating an ADI may not contain the information necessary to derive an acceptable intake for a single exposure, such an intake has been called acute reference dose. The acute RfD would be estimated using the same basic principles and methodology used to estimate the traditional ADI, the same safety factors being applied. Exposure The potential consumer exposure arising from the individual uses being considered by a regulatory authority will depend on the size of the residue and the contribution the treated commodity makes to the diet. Although the intake of a single pesticide on a specific commodity is evaluated separately, it is also an essential part of estimating total consumer intake. Use of residues trials data The importance of data from supervised residues trials and the use of these by regulatory authorities has already been emphasised. Since it is not practicable to carry out supervised trials on all the crop species and varieties on which a pesticide may need to be used, under a wide range of climatic conditions and cultivation practices, the concept of extrapolation is essential to the evaluation of residues data and the estimation of MRLs. However, data from limited trials, even with appropriate expert extrapolation, should not be used for estimates of potential exposure from proposed uses, predictions of total consumer intake or for estimating MRLs without adequate reference to the extensive residues database that is available. Predicting total dietary intakes Since analytical dietary studies refer retrospectively to unknown pesticide use on unspecified commodities, they cannot be incorporated in regulatory decisions on the prospective use of pesticides (see later). Thus it is normally necessary, in the absence of information on actual dietary intake, to make an appraisal of potential risks to consumers from an estimation or prediction of the total dietary intake at the time of registration of a proposed use of a pesticide, or indeed at any later time if required, as an alternative to the analysis of a diet. Such predictions require a knowledge of both the residue levels in a foodstuff and the quantity of that foodstuff consumed and, of course, the validity of the estimate depends on the quality and quantity of the information available. The prediction can be made with different degrees of realism. Since the more realistic estimates involve the consideration of certain information which is often difficult to obtain, such as the known uses of a pesticide on crops in a particular year, the crude theoretical maximum daily intake, or TMDI, is usually chosen as the first approximation. The TMDI was originally calculated on the assumption that a pesticide is used on all the crops for which authorisation is granted and the residues are at the level of the estimated maximum, i.e. the widely publicised MRL. This calculation results in a gross overestimate of the true intake and a modification of this estimate uses the median residue level from supervised residues trials as a measure of exposure instead of the MRL (WHO, 1988, revised 1997) If when the TMDI is compared with the acceptable daily intake (ADI) for the pesticide there is a large safety margin (in addition to the usual safety factor inherent in the estimation of the ADI), then clearly the risk to consumers is minimal. On the other hand, in situations where the TMDI approximates to, or exceeds, the ADI, then there is a need to proceed to more realistic estimates of dietary intake, and information on: known uses of the pesticide (not always the same as the complete registered uses) the contribution that the food commodity makes to the dietary pattern (diet factor) the maximum residue, the mean or most frequent residue that can be expected at harvest the distribution or partition of the residue in the crop and the fate of the residue on cooking or processing should be taken into account, finally arriving at a prediction of the best estimate, the estimated daily intake or EDI. 144 Pesticide Outlook August 2002

4 Use of diet factors Dietary patterns vary significantly and there is little justification in adopting mathematically derived dietary factors which suggest a greater accuracy than is realistic. In view of the uncertainty about most figures available to describe the contribution of a commodity to the average diet, national authorities and the WHO have indulged in extensive computer studies aimed at hypothetical global diets as well as hypothetical cultural, regional, age-related and other diets. More appropriate diet factors could be based on practical numerical intervals 0.1, 0.2, 0.5, 1, 2, 5, 10, 20 (as for MRLs) and commodities which contribute less than, say, 0.5% to a diet could be ignored and estimates of dietary intake of pesticides based on identifiable important food commodities only. The majority of human diets are based on no more than about 30 important agricultural commodities (Bates and Gorbach, 1987). Recommendations for legal maximum residues limits (MRLs) Although it is relatively easy to control the availability of pesticides through registration procedures, any attempt at subsequent direct control of use presents quite different problems. The measurement of residues in crops at harvest is considered by many to be the only way to check that the user has followed the instructions on the label and the principles of good agricultural practice. The benchmark for this test is usually the legal maximum residues limit (MRL) based on the estimate of the maximum residue that might occur in use following good agricultural practice. What is rarely explained is that the MRL is not simply the highest residue found, either on a single commodity item or on a composite sample from residue trials where the application is known and controlled. Basically an MRL is estimated from residue trials data by expert groups proposing a figure from the internationally accepted sequence of significant levels : 0.01, 0.02, 0.05, 0.1, 0.2, 0.5, 1, 2, 5, 10 mg kg 1 below which the residue in a standard high percentage of samples of treated crops (say 98%) will be expected to fall (Bates, 1991). DEFINITION OF MRL An MRL is the maximum concentration of a pesticide (mg/kg) to be legally permitted in or on a food commodity MRLs do not directly define health, safety or risk levels for consumers and should not be confused with any estimate of consumer exposure or the evaluation of long-term risk to human health. Unit to unit variations of pesticide residues Since the distribution of a pesticide deposit on a crop during application may vary considerably, this can lead to a wide range in the residues in primary samples at harvest and this has always been a major factor in most residue data evaluations by expert groups. The variability is somewhat reduced in the composite samples from supervised trials which provide the residues data for the estimation of MRLs but a small number of individual units within the crop will always exceed the MRL based on the composite sample. National and international MRLs National MRLs are usually established using residues data from trials in the country concerned and therefore reflect the national registrations, climates and use patterns. Consequently it is not unusual for national MRLs for a pesticide/crop combination to conflict with each other, giving rise to problems in international trade. National MRL enforcement activities also vary according to policy and the resources available to sustain such an activity. The primary objective of the Codex Committee on Pesticide Residues (CCPR), established in 1963 by the FAO/WHO Codex Alimentarius Commission, is to develop internationally acceptable MRLs which would ultimately facilitate international trade and contribute to worldwide safe food. The initial evaluations of hazard and exposure leading to Codex MRLs are made by Joint Meetings of the FAO Panel of Experts on Pesticide Residues and the WHO Expert Committee on Pesticide Residues (JMPR), members of both bodies invited individually as expert scientists. Confirmation of exposure Monitoring and surveillance of residues in food crops For established pesticides, monitoring and surveillance data can be useful to refine intake estimates made during the registration of uses. However, sampling programmes and residues analysis methodologies must be carefully examined, particularly if monitoring is primarily undertaken for administrative reasons to identify compliance with MRLs. It is, of course, helpful if monitoring samples can be related to at least some crop history so that valid comparisons with supervised trials data (and MRLs) can be made. Residues in excess of MRLs in monitoring studies The results of many years of monitoring crops and food commodities for pesticide residues in many countries show that up to about 80% of millions of random samples of agricultural commodities did not contain determinable residues; that is, if a residue existed it was below the analytical level of determination an administrative zero. About 15-18% contained measurable residues below the various legal MRLs and less than 3% often less than 1% for many commodities contained residues above the legal limits. These limits, of course, are agricultural standards and not health standards. The random samples in these monitoring studies are normally prepared according to internationally agreed sampling procedures, involving several commodity units, Pesticide Outlook August

5 which are compatible with the samples on which MRLs are based. The results of the many monitoring surveys are evidence of the accuracy of these estimates used for MRLs. However, the fact that an average residue in a sample prepared from several units will occasionally exceed an MRL also emphasises the variability of residues found in the commodity units. The consumption of single units containing a residue from the higher end of the distribution range of residues should not present a risk to consumers. Although a high consumption of high residue units by a single consumer is statistically unlikely, it could theoretically lead to the acute reference dose being exceeded but since this includes generous safety margins even such intake is not likely to exceed the NOAEL or offer a risk. Multiple residues in commodities and food Crops often need the application of several pesticides to achieve satisfactory protection and survey data confirm that residues of more than one pesticide may sometimes be detected in food. This could give rise to concern over the possibility of unanticipated interactions The possibility of pesticide interaction was recognised as early as 1961 (WHO/FAO, 1962) and discussed JMPR meetings in 1964, 1967 and 1981, the last of these concluding that Not only could pesticides interact, but so could all compounds (including those in food) to which man could be exposed. This leads to unlimited possibilities and there is no special reason why the interaction of pesticides (which are at very low levels) should be highlighted as being of particular concern. Dietary studies The actual exposure of any consumer to pesticide residues can theoretically be determined by the analysis of the consumer s total diet and, in the past, very large numbers of many average and specific diets have been analysed. However, the complexity of most diets and the varied sources of food commodities containing a variety of pesticide residues has made it difficult, if not impossible, to extrapolate the results of one dietary study to another food intake. Therefore, it must be concluded that since it is not possible to construct an average diet from commercially available commodity units with an average pesticide residues content at any one time, experimental studies to measure intakes of pesticides directly are of limited value individually. Some authorities have now discontinued such dietary studies. However, in spite of their shortcomings the results of such studies are still used regularly by government administrators to reassure the public that their long-term food supply is not excessively contaminated with pesticide residues. Understanding the risk a consumer viewpoint! All human health risk situations are a function of a hazard and exposure to that hazard. If the hazard is small and fixed (an estimated ADI), then the risk will be proportional to the exposure which can be reduced to be low and occasional. When both the hazard and the exposure can be quantified with a considerable degree of confidence then a realistic estimate can be made of the risk involved in consuming foodstuffs containing some pesticide residues. In fact, this confidence can be identified as a main factor in the political judgement to regulate pesticide residues in food. Unfortunately media interest in any information which does not conform to regulatory standards is immediately publicised as demonstrating a health risk. The Precautionary Principle From the relationship RISK = HAZARD EXPOSURE it can be seen that zero risk can be approached only if either the hazard or the exposure approach zero. Since pesticides are widespread in worldwide food production then zero hazard or zero exposure are unrealistic even if either or both can be considerably reduced in practice. Some opponents of the use of pesticides demand zero risk and seek refuge in the precautionary principle, conceptually a variation of the traditional wisdom better safe than sorry. The principle has appeared in a wide range of international and European domestic treaties as a mechanism to deal mainly with environmental situations in which there are unknown consequences, uncertain science and a political climate pressurising policymakers to resolve an issue. However, there is now little uncertain science or few unknown consequences associated with the assessments of health risks from pesticide residues, leaving only a political climate as the main reason to invoke the precautionary principle. Most national governments have detailed regulations on pesticide residues in food suggesting that they have already rejected the precautionary principle as an appropriate response to public concerns over the possible health risks from pesticide residues. A perspective on the risk from pesticide residues Coming to terms with an imaginary risk from pesticide residues in food has provided both governments (politicians, International Agencies and a host of expert committees) and the public with a dilemma. On the one hand those with access to the wealth of data on both the hazard and the exposure have failed dismally in conveying the data and explaining their significance to the public in a meaningful way. Rather they have chosen to present the data in a limited and difficultly available form without the reassurance that the risk truly is minimal to the point of insignificance. The media on the other hand, revel in the publication of selected items of limited information, often out of context, accompanied by scare headlines which reach a vast audience. Governments by their reluctance to explain the lack of risk clearly and the media by their health scares are equally to blame if the public fail to understand the real significance of the risk from pesticide residues in food. When a pesticide is authorised for a particular use through rigorous registration procedures it means that, by definition, any residues that may persist in diets are without appreciable risk to human health even after a lifetime of exposure. 146 Pesticide Outlook August 2002

6 Conclusions The lesson to be learned from the evaluation of the existing extensive database on pesticide residues in commodities and diets is that health risks from residues are minimal when pesticides are used according to authorised uses. Countries wishing to apply legal maximum limits (MRLs) to harvested crops (or foodstuffs) as a means of monitoring authorised uses should recognise that this activity has administrative significance only and has no bearing on the general health of a population. The whole subject of risks from pesticide residues has been, and still is, frequently misrepresented by the media s pseudo-experts and some official activities and depends more on the arousal of emotions than on the meaningful presentation of data. The concern of the public is understandably real but the worries are irrational and not in proportion to the actual risk. References Bates, J. A. R.: Gorbach, S. (1987) Recommended Approach to the Appraisal of Risks to Consumers from Pesticide Residues in Crops and Food Commodities. IUPAC Report on Pesticides No 22., Pure & Applied Chemistry, 59(4), Bates, J. A. R. (1990) The Prediction of Pesticide Residues in Crops by the Optimum Use of Existing Data. IUPAC Report on Pesticides No 26. Pure & Applied Chemistry, 62(2), Bates, J. A. R. (1991) Perspective on Pesticide Residues in Food. In: Pesticide Chemistry Advances in International Research, Development and Legislation. Ed. Helmut Frehse. ISBN (VCH, Weinheim). FAO (1982) Report of the Second Government Consultation on International Harmonisation of Pesticide Registration Requirements Rome, 11th October FAO (1986) Guidelines on Pesticide Residue Trials to provide data for the Registration of Pesticides and the Establishment of Maximum Residue Limits. FAO, Rome. Stoner, H. B. (1964) The Concept of Acceptable Daily Intakes of Pesticides for Man. Food and Cosmetics Toxicology, 2, 457. WHO/FAO, (1962) Principles governing Consumer Safety in relation to Pesticide Residues. WHO Technical Report Series No 240, WHO, Geneva. WHO Environmental Health Criteria No 6. (1978) Principles and Methods for Evaluating the Toxicity of Chemicals. WHO, Geneva. WHO Environmental Health Criteria No 104. (1990) Principles for the Toxicological Assessment of Pesticide Residues in Food. WHO, Geneva. WHO (1988) Guidelines for Predicting Dietary Intake of Pesticide Residues. WHO/EHE/FOS/88.2 and as revised WHO/FSF/FOS97.7 WHO, Geneva. Wilkinson, C. F. (2000) Are infants and children really more vulnerable than adults to the potential adverse effects of pesticides. Pesticide Outlook 11(5), 203. Ray Bates participated for many years in risk assessments of pesticide residues in food in UK, European and other international meetings. He was a member of the FAO/WHO Joint Meeting on Pesticide Residues (JMPR) for 10 years and chaired the IUPAC Commission on Pesticide Chemistry as well as the Codex Committee's Working Group on the Development of Residues Data and Sampling. CROP PROTECTION BOOKS from the Royal Society of Chemistry Metabolic Pathways of Agrochemicals EDITORS-IN-CHIEF : Terry Roberts and David Hutson Part 1 Herbicides and Plant Growth Regulators ISBN Part 2 Insecticides and Fungicides ISBN X Package price (Parts 1 and 2) ISBN Chemistry and Mode of Action of Crop Protection Agents by L. G. Copping and H. G. Hewitt (ISBN ) Crop Protection Agents from Nature. Natural Products and Analogues Edited by L. G. Copping (ISBN ) Pesticide Chemistry and Bioscience. The Food-Environment Challenge Edited by G. T. Brooks and T. Roberts (ISBN ) Progress in Neuropharmacology and Neurotoxicology of Pesticides and Drugs Edited by D. Beadle (ISBN ) Agri-Food Quality II. Quality Management of Fruits and Vegetables Edited by M. Hagg, R. Ahvenainen, A-M Evers and K Tiilikkala (ISBN ) Order to be sent to Sales & Customer Care, Royal Society of Chemistry, Thomas Graham House, Science Park, Milton Road, Cambridge CB4 0WF, UK. Tel: +44 (0) Fax: +44 (0) sales@rsc.org. Pesticide Outlook August