Toxicological Risk Assessment of Worker Exposure to Pesticides: Some General Principles

Toxicological Risk Assessment of Worker Exposure to Pesticides: Some General Principles

REGULATORY TOXICOLOGY AND PHARMACOLOGY ARTICLE NO. 25, 204–210 (1997) RT971086 Toxicological Risk Assessment of Worker Exposure to Pesticides: Some...

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REGULATORY TOXICOLOGY AND PHARMACOLOGY ARTICLE NO.

25, 204–210 (1997)

RT971086

Toxicological Risk Assessment of Worker Exposure to Pesticides: Some General Principles W. K. de Raat, H. Stevenson, B. C. Hakkert, and J. J. van Hemmen Department of Occupational Toxicology, TNO Nutrition and Food Research Institute, P.O. Box 360, 3700 AJ Zeist, The Netherlands Received November 27, 1996

1. INTRODUCTION

The worker involved in the application of pesticides will in most cases be exposed to some extent to these substances. Whether this exposure represents a health risk depends on: —the toxicity of the pesticide in humans, —the prevailing occupational exposure conditions, and —the prevailing occupational exposure levels. If the exposure levels exceed the levels which may give rise to toxic effects, a health risk exists. The subject of this paper is the assessment whether this risk may occur. It is in particular concerned with: —the composition of the toxicological data set which is used as a starting point for risk assessment; —the assessment of the critical effect, i.e., the adverse effect which is expected to occur at the lowest exposure levels; —the assessment of the highest level to which the worker can be exposed without adverse health effects; —the comparison of this level with actual occupational exposure levels, to obtain a quantitative impression of risk. The paper does not comprise a presentation of the development of toxicological risk assessment in the foregoing decades (starting with the ADI concept (Lehman and Fitzugh, 1954)), or a critical presentation of various approaches and methodologies proposed and used. For this, the reader is referred to Calabrese (1983), Dourson and Stara (1983), NAS (1983), Royal Society (1983), Clayson et al. (1985), DHC (1985), HSE (1989), Lu and Sielken (1991), Renwick (1991, 1993), Zielhuis and Van der Kreek (1979a,b), and WHO (1987). The paper presents general principles which can be applied when the occupational health risks of pesticide application must be assessed. It is restricted to effects which are supposed to have a reference exposure level, i.e., an exposure level below which the adverse effect

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2. THE TOXICOLOGICAL STARTING POINT

2.1. Limitations The available set of data on the toxicological properties of the pesticide forms the toxicological starting point of risk assessment. Ideally, this set should cover all adverse effects that might arise in the worker under occupational exposure conditions. Moreover, it should allow the risk assessor to establish the dose dependence of these effects, to be able to establish an experimental threshold dose, i.e., the highest dose level at which no adverse effects are observed in the experiment (NOAEL). It is an illusion to think that all possible adverse effects can be detected with any practically and economically feasible toxicological data set. The most important and inevitable limitations of the data set are concerned with: —lack of agreement between experimental and occupational exposure conditions; —limited number of species, animals, and doses that can be applied; —limited number of effects that are sought after. Important limiting aspects of exposure conditions are exposure route, duration and frequency of exposure, and the presence of compounds which alter the effect of the active agent by interactions. The agreement between experiment and occupational situation is further affected by the fact that one active ingredient may be applied in different pesticides, against different pests, and on different crops, variations which can thoroughly influence occupational exposure. Moreover, occupational conditions will depend on the task of the worker. Some workers prepare the formula-

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0273-2300/97 $25.00 Copyright q 1997 by Academic Press All rights of reproduction in any form reserved.

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is not expected to occur. This implies that the present considerations do not apply to pesticides which are genotoxic carcinogens because these are supposed to present a health risk at every exposure level (see for instance Moolgavkar et al., 1988).

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tion (mixing and loading), while others carry out the actual application (spraying, fogging, misting, etc.). Many will combine these tasks on one working day or over different working days (Van Hemmen, 1992). Obviously, resources are always too limited to allow all these situations to be adequately taken into account when the toxicological data set must be established. Another aspect which affects the agreement between experiment and occupational situation is the fact that tailor-made toxicity tests, i.e., tests in which the exposure conditions are maximally tuned to the occupational situation, are inherently hard to standardize and to validate. Standardization and validation are, however, prerequisites for the indispensable transparency and comparability of data sets (Dayan, 1992). The other aforementioned limitations scarcely need any further elucidation. Evidently, the number of adverse effects that can be detected depends on the number of species and the techniques used for their detection, while the sensitivity with which they can be detected depends on the number of experimental animals and doses that can be applied.

ity, developmental toxicity, immunotoxicity, and genotoxicity. Special tests are developed to prevent them from being missed.

2.2. Minimal Requirements

Toxicodynamic studies I. In these studies (further referred to as first-category studies) experimental animals are subjected to different exposure regimens. Exposure duration and exposure route are varied. Acute, subacute, semichronic, and chronic studies are discerned. The animals can be exposed via the food or drinking water, by gavage, via inhalation, and via the skin. Acute and semichronic oral studies are nearly always carried out, often supplemented with subacute dermal, oral, and respiratory studies. Most studies are carried out with rats, rabbits, or mice. Sometimes they are supplemented with dog studies or studies with other nonrodent species. First-category studies are not aimed at the detection of specific effects. Various observation methods are applied to detect as many disturbances of functioning and structure of the organism as possible, on the macroscopic, microscopic, and biochemical level. Nearly all are carried out according to strict and often detailed guidelines, which are established by various national and international organizations, e.g., OECD and EU. These are the studies which must provide the link with occupational conditions. Although the experimental setup is virtually fixed by the guidelines, combination of different studies leaves, to a certain extent, room for adaptation to the conditions under which the worker is exposed. Two variables are of utmost importance in this respect: exposure route and duration. As the worker is exposed via the skin or the respiratory tract, these routes should somehow be accounted for. The worker may also be exposed for a substantial part of his occupational life, which means that acute or subacute exposures do not suffice; the data set should at least include a semichronic study.

From the foregoing section it can be concluded that the toxicological data set will always be a compromise between, on one hand, the degree of protection of the worker aimed at and, on the other, the available resources, and the need for standardization and validation. This compromise is formalized by national and supranational competent authorities in the form of guidelines and regulations. As an example Directive 91/414/EC of the European Union can be mentioned. The database required for active ingredients and formulations by the EU is described in the Annex II and Annex III of this directive. Meaningful risk assessment implies certain minimal requirements. The obvious and basic minimal requirement is that data should be generated which are really relevant to the worker and his exposure conditions. This statement is less trivial than it seems. Some data sets simply do not allow the health hazard for the worker to be assessed. For instance, when only oral experiments are carried out (which is by no means unthinkable), and the effects observed are strictly route dependent (they are local or they are influenced by first-pass metabolism), the data tell us nothing at all about the health hazard for the worker who is exposed via the respiratory or the dermal route. This example shows that the basic requirement is in fact concerned with possibility of extrapolation. Data should be generated which can be extrapolated to the worker and his exposure conditions. Some effects may be deemed so important as to lead to minimal requirements. The following may be considered: carcinogenicity, neurotoxicity, reproduction toxic-

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2.3. Currently Used Toxicological Starting Points Currently used toxicological starting points for occupational health-risk assessment comprise basically three categories of studies: —toxicodynamic studies with experimental animals aimed at the detection of a broad range of effects under different exposure regimens, by means of a series of standard behavioral, morphological, clinical, biochemical, and histopathological observations; —toxicodynamic studies with experimental animals or in vitro systems (which make use of cells, tissues, or organs) aimed at the detection of specific effects which cannot adequately be detected with the aforementioned studies; —toxicokinetic studies with experimental animals or in vitro systems. These studies provide information which is in many cases indispensable for extrapolation.

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TABLE 1 Effects Investigated in Separate Tests Effect

Conditions and extrapolatibility (see text)

Lethality Irritation

Tests Tests Tests Tests Tests Tests Tests Tests Tests

Sensitization Genotoxicity Reproduction Developmental Carcinogenicity

carried carried carried carried carried carried carried carried carried

out out out out out out out out out

in in in in in in in in in

vivo: qualitative and quantitative extrapolation vitro: no extrapolation vivo: only qualitative extrapolation vivo: only qualitative extrapolation vitro with microorganisms or tissue-culture cells: no vivo: only qualitative extrapolation; in most cases, no vivo: qualitative and quantitative extrapolation, in most cases vivo: qualitative and quantitative extrapolation, in most cases vivo: qualitative and quantitative extrapolation, in most cases

This is not to say that the semichronic study should always be a dermal or a respiratory study. It is often deemed too costly and too inhumane to subject experimental animals to semichronic dermal or respiratory exposure, in addition to oral experiments. Instead, subacute exposure may suffice for these routes. However, it can be stated that, in practice, the route via which the worker is exposed is still not sufficiently accounted for by most first-category sets of studies. Dermal or respiratory subacute studies are often missing. This has an historical reason, as originally, the data sets were aimed at the protection of the general population, which is virtually exclusively exposed via the oral route, through the consumption of treated crops (Bigwood, 1973; Lu, 1988). Toxicodynamic studies II. Although first-category studies are aimed at the detection of a broad range of effects, it goes without saying that the detection of all possibly relevant adverse effects is beyond the possibilities of any economically and practically feasible firstcategory set. A number of obviously unacceptable effects are, therefore, investigated with studies which are specifically aimed at their detection (further referred to as second-category studies). This means that broadness with regard to the range of effects and similarity with occupational exposure conditions may be sacrificed to assure the detection of one type of effect. A number of effects which are investigated in secondcategory studies are listed in Table 1. The table indicates to what extent their results can be extrapolated to the occupational situation. Three ‘‘levels’’ of extrapolatibility may be discerned: —tests which only point to basic toxicological properties, but do not indicate whether these properties are expressed in vivo; —tests which allow only qualitative extrapolation, i.e., indicate whether the effects can be expressed in humans, without providing information about effective dose levels; —tests which allow qualitative as well as quantitative extrapolation, i.e., indicate whether the effects can

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be expressed in humans, and provide information about effective dose levels. Toxicokinetic studies. Toxicokinetic information is often indispensable for an optimal extrapolation from the experimental to the occupational situation. It allows a more reliable prediction of effects under other exposure conditions and in other animals. Several extrapolation bottlenecks can be thought of, which can be solved by toxicokinetic information. Here, we only refer to a very important one: the bottleneck of routeto-route extrapolation (RtR extrapolation). Occupational risk assessment can be hampered by the lack of studies in which animals are exposed via the relevant route. Sometimes effects to be expected after dermal or respiratory exposure must be predicted from the results of oral experiments. This means that RtR extrapolation must be carried out. As will be elaborated upon further in Section 3, toxicokinetic information may help to answer the question of the validity of RtR extrapolation. Furthermore, RtR extrapolation is facilitated very much by information about the absorption (bioavailability) of the compounds for the routes with which the extrapolation is concerned. 3. EXTRAPOLATION

3.1. The Critical Effect When the set of toxicological data has been established, the next phase of risk assessment is concerned with the establishment of the critical effect. According to an operational definition, this is the adverse effect, the NOAEL of which will serve as a starting point for extrapolation. For two reasons, the critical effect is not necessarily the effect which occurs at the overall lowest effective dose of the complete toxicological data set. —It may be an effect observed at a higher dose than the overall lowest effective dose because the study in which it is observed reflects the occupational conditions better than the study with the overall lowest effective dose. For instance, a higher dermal dose (in terms of

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mg/kg body wt) may determine the critical effect instead of a lower oral dose because occupational exposure occurs via the dermal route. According to another example, a higher dermal dose may determine the critical effect instead of a lower dermal dose if the former is applied under occupationally more relevant conditions. —It may be an effect observed at a higher dose because extrapolation reveals that this dose results in a lower occupational reference exposure level than the overall lowest effective dose (Renwick, 1991, 1993). For instance, a higher dose observed with mice may determine the critical effect instead of a lower dose observed with dogs because the former gives rise to a lower occupational reference level after extrapolation. Furthermore, a higher dose may determine the critical effect because the effect observed is deemed so serious as to give rise to a lower occupational reference level. It is impossible to formulate general rules for the selection of the critical effect. It is often a question of balancing, on one hand, relevance with regard to occupational conditions and, on the other hand, difference between occupational reference levels after extrapolation. It thus relies heavily on expert judgment, considering the whole toxicological database. It is not always possible or justified to select a critical effect. Obviously, this is the case when the toxicological database does not fulfill the requirements which were touched upon in Section 2.2 of this paper. Furthermore, a database that does fulfill these requirements may yield indications for important effects which are themselves not critical in a quantitative sense, but are deemed particularly important for the worker (for instance, immunotoxicity or neurotoxicity). When the database is regarded to be not sensitive enough for the detection of these effects, it may be required to perform additional studies. These studies should then make clear whether or not the the effect in question should be taken as a starting point for extrapolation. 3.2. Definition of Extrapolation Extrapolation can simply be defined as dividing an experimental threshold dose (NOAEL) by certain factors, often referred to as ‘‘assessment factors,’’ to compensate for: —differences between experiment and occupational situation; —differences in sensitivity between experimental animals and the occupational population; —uncertainty caused by limitations of the toxicological data set. In general, it can be stated that extrapolation deals with the lack of compound-specific toxicological knowledge which remains after an exhaustive evaluation of the available toxicological data. This lack of knowledge

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cannot be completely dealt with during the extrapolation phase because not all possible adverse effects may be detected with a practically and economically feasible toxicological data set (see Section 2). Extrapolation can only start with observed effects and tries to predict the exposure levels which should be maintained under occupational conditions to prevent these effects in the worker. 3.3 Different Types of Assessment Factors Extrapolation should in the first instance be based on an exhaustive use of general toxicological knowledge, i.e., knowledge based on general toxicokinetic and toxicodynamic principles. Compound-specific knowledge can be used to adapt assessment factors based on general knowledge. The factors based on general toxicological knowledge can be denoted as adjustment factors because they compensate for real known and quantifiable mechanistic differences. General toxicological knowledge can be formalized with quantitative mechanistic models. So far, physiology-based pharmacokinetic models (PBPK models) are most promising in this respect (see, for instance, Zwart et al., 1992; and Urtuzberea et al., 1992). To some extent they can predict absorption, distribution, and elimination of the compound in animal and human and may, thereby, yield well-founded adjustment factors which can be applied for extrapolation purposes. Extrapolation can also have a purely statistical basis; i.e., it can be devoid of any mechanistic considerations. The factors are then derived from distributions of effects observed with other compounds under different conditions. However, these factors can be adapted by using compound-specific knowledge. In a way, the statistically based factors may be regarded as the real uncertainty factors because they quantify uncertainty and, thereby, prevent us from unnecessary overestimation of risk. It is a disappointing fact that the factors we have touched upon so far are seldom used in extrapolation. The only real mechanistically based factor known to the authors is concerned with allometry (DHC, 1985). It has been long known that a dose per unit of body weight for an animal is not directly applicable to humans. Comparison of large and small mammals for their sensitivity has shown that, on a per kilogram of body weight basis, the former are more sensitive than the latter. This phenomenon is regarded to reflect the fact that larger mammals need less energy per kilogram. This in turn is related to a smaller food intake and thereby a slower elimination. Slower elimination means longer internal residence time and thus longer internal exposure. So, a better agreement on a per kilogram of body weight basis of threshold doses is achieved if food intake or caloric demand is taken into account.

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Sometimes factors based on distributions of effects are used to compensate for differences in duration of exposure. A limited study of the distributions for subacute, semichronic, and chronic studies shows that in 95% of the cases the sensitivity of a semichronic test with rats differs no more than a factor of 10 from those of chronic test and subacute tests (Dourson and Stara, 1983). This factor may be used to extrapolate from subacute to semichronic toxicity and from semichronic toxicity to chronic toxicity, at least, if the percentage of 95% is considered to offer enough certainty. However, most factors used for extrapolation have a rather intuitive or even arbitrary foundation. Sometimes these factors can more or less be adapted on the basis of compound-specific knowledge and expert judgment. To assure transparancy and comparability, expert judgment should always be made explicit. 3.4 The Number of Factors Depending on the toxicological starting point of risk assessment and the occupational situation for which the risks must be assessed, various gaps must be bridged during extrapolation. The overall extrapolation gap can be split up in many smaller ones. Many aspects can be identified which determine the difference between the experimental and the occupational situation, and different extrapolations could be carried out for each of these aspects. Obviously, this would be a rather extreme and counterproductive endeavor. It can easily be seen that it would not lead to a more meaningful, i.e., more reliable, prediction of what is really happening in the occupational situation. The number of gaps for which different extrapolation factors are applied should be determined by the following principles. —Together the factors should be aimed at the coverage of the complete extrapolation gap, as far as this can be perceived. —It should be possible to account for the quality of the toxicological starting point. —The number of factors should be kept as low as allowed by the first two principles. —Extrapolation should maximally be based on wellfounded (mechanistically or statistically) factors. —Arbitrary factors should only be used if no wellfounded factors are available. As has been set forth above, current practice makes clear that we are far away from the ideal situation aimed at by the last two principles because extrapolation is still largely based on arbitrary factors. 3.5 Which Factors Can Be Applied? Interspecies variation. Extrapolation must always account for differences in sensitivity between experimental animal and humans. Two factors can be applied

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here: A factor determined by differences in caloric demand between humans and experimental animal, i.e., a well-founded factor representing differences in duration of internal exposure (DHC (1985); see Section 3.3). All remaining, unquantified, or unquantifiable differences can be lumped together in an overall arbitrary uncertainty factor. Intraspecies variation. Sensitivity to a toxicant can vary considerably within a species. Important causes for this variation are age, sex, reproductive status, health status, genetic differences in endpoint sensitivity, genetic differences in biotransformation, previous exposures, etc. In general, intraspecies variation within the experimental species is not accounted for in extrapolation. However, to prevent the underestimation of risk, an arbitrary factor is always applied for the human population (Gelbke, 1992). An arbitrary factor of 3 can be applied in case the protection of the occupational population is aimed at, and a factor of 10 can be applied in case the assessment is dealing with risks for the general population (for additional discussion see Calabrese (1985) and Hattis et al. (1987)). The offspring of the worker must be regarded as a member of the general population. This means that a higher factor must be employed for the intraspecies variation in case embryotoxic or teratogenic effects are starting points of extrapolation. Duration of exposure. In principle, extrapolation should only be based on chronic, semichronic, or subacute experiments. Two steps are required to bridge the gap between chronic and subacute. Maximum factors of 10 may be taken, based on a limited study on the distribution of effects. In the absence of any supporting data, such factors seem to provide a certainty of 95% (DHC, 1985). However, in view of the limited nature of their statistical foundation, also these factors must be regarded as largely arbitrary. There are often additional data available which allow the use of smaller factors. Route of exposure. Preferably, the experimental and the occupational exposure route should be the same. However, the most important shortcoming of many toxicological starting points is the lack of studies in which experimental animals are exposed via the correct route (Gelbke, 1992). In that situation, one cannot but apply route-to-route (RtR) extrapolation. Ideally, RtR extrapolation should only be carried out if experimental data or well-founded estimations are available which give a reliable impression of both the absorption via the experimental exposure route and the absorption via the occupational exposure route. Moreover, the experimental effects should not have a local character, be determined by a first-pass effect or otherwise be route dependent; in other words, they should be fully systemic. Then RtR extrapolation proceeds in two steps.

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—The experimental external threshold dose (NOAEL) is converted to an internal threshold dose by correcting it for the amount of compound which did not enter the body during experimental exposure as a result of incomplete absorption. —The internal threshold dose is converted to an external dose for the occupational exposure route by correcting it for the amount of compound which will not enter the body during occupational exposure as a result of incomplete absorption. Often, no quantitative data or well-founded estimates are available about the absorption via the experimental or the occupational exposure routes. Only worst-case default values can be used then. The validity of RtR extrapolation depends strongly on the qualitative comparability (comparable distribution, elimination, biotransformation) of the internal doses after experimental and occupational exposure. In most cases, no data are available which make it possible to judge the validity of RtR extrapolation on this point. An extra arbitrary uncertainty factor (for instance 2) might be applied to compensate for this source of uncertainty. Other aspects of exposure. The differences between experimental and occupational exposure are not solely determined by the route and the division into subacute, semichronic, or chronic. Many other aspects may play a role as well, which cannot be separately covered with well-founded factors. In addition, a factor might be used to cover differences in exposure duration per day and number of days exposed per week between the experimental and the occupational situation. For the occupational situation, a duration of 8 hr per day and 5 days per week in general may be assumed.

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enough but points to a factor exceeding a prefixed value (for instance 10). When it does exceed this factor, it should not be used, but instead, additional experiments should be carried out. From concentration in the air to amount per kilogram of body weight and vice versa. In case of RtR extrapolation, concentrations in the air may have to be converted to amounts per kilogram of body weight or vice versa. In the first case, the amount per kilogram of body weight must be estimated from the respiration rate of the experimental animal, its body weight, duration of exposure, and the experimental concentration in the air. In the second case, extrapolation is aimed at a per-kilogram-body weight dose, which is subsequently converted into a concentration in the air on the basis of human respiration rate, duration of exposure, and human body weight. Quality of the database. In some cases the available database is characterized by specific limitations which affect the reliability of the extrapolation process too much, compared to what is deemed generally acceptable. An extra assessment factor may then be applied to compensate for the uncertainty following from this lack of quality. Obviously, the choice (when and which) of such a factor is highly arbitrary, which implies that it should be clearly specified. Furthermore, it should be applied with utmost reluctancy; i.e., if possible, additional experiments should be carried out to make it superfluous. 3.6. Final Integration In principle, the experimental threshold simply must be divided by all the relevant assessment factors to obtain the occupational reference value which finally must be compared with the actual occupational exposure. However, before this is done, an integrative evaluation should be carried out to establish the overall factor. An important aspect of this evaluation is the interdependence of the factors used. In principle, simple multiplication of the factors is not allowed if interdependence is probable. No general rules are available for this evaluation; at present, it depends completely on expert judgment, considering all available data in the light of general toxicological knowledge. This integration may only lead to a reduction of the final factor. If it does, the use of expert judgement should be made explicit and transparant.

From LOAEL to NOAEL. In some cases the lowest effective dose causing the critical effect is also the lowest dose investigated. Then no NOAEL can be established, and the lowest observed adverse effect level or LOAEL might be the starting point of extrapolation. However, the extrapolation should deal with the uncertainty about the effects which may occur at lower doses by means of an extra factor (EPA, 1993). This factor should as much as possible be determined by the dose – effect relation observed in the experiment (Renwick, 1991, 1993; Crump, 1984). It should be the result of an extrapolation of this relation to doses lower than the LOAEL (the benchmark dose is proposed as an alternative; see Crump, 1984). If the dose – 4. THE FINAL STEP OF RISK ASSESSMENT effect relation is too unclear for such an extrapolation to lower doses, then no factor should be determined. This means that no occupational reference value can The final step of risk assessment is the comparison be assessed without additional experiments which ei- of the occupational reference value with the estimated ther yield an unambiguous NOAEL or support the ex- or measured actual exposure of the worker. The actual trapolation to lower doses for the critical effect. The exposure can, for instance, be divided by the occupasame holds when the dose – effect relation is clear tional reference value to obtain a risk ratio. If this ratio

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exceeds 1, then a risk is indicated; i.e., there is a chance that unacceptable effects may occur. This chance needs not to be reckoned with if the ratio is smaller than 1 because the extrapolation process should alway tend to the safe side. Obviously, the whole process of risk assessment is so laden with uncertainties that the border between risk and no risk cannot be so sharp. A gray area exists. No general rules can be established as to how risk ratio’s lying within this area should be used, or as to how the upper limit of this area should be defined (the lower limit equals 1). Evaluation of risk may only be based solely on the risk ratio if this value is clearly lying outside the gray area. ACKNOWLEDGMENTS The authors thank V. J. Feron, J. Kruse, W. J. A. Meuling, and M. I. Willems for critically reading the manuscript. The stimulating cooperation with the Dutch Ministry of Social Affairs and Employment in the field covered by this article is gratefully acknowledged.

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