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Executive Summary Humans live in a complex environment and are often exposed to sequences or mixtures of toxic materials. The science of dealing with the toxicity of mixtures is relatively new and is still developing. Most experimental data relate to the toxic effects of exposures to single materials, yet exposure to two or more toxic materials might produce greater deleterious effects than would be anticipated from knowledge of the effects of each of the materials considered separately. Even as few as two materials can be present in infinite dose combinations, and relative doses might affect toxicity of the mixture. Experimental strategies for testing a manageable sample of the infinite com- binations are obviously needed. Even if the proportions of the constituents are not of consequence (i.e., if only presence or absence is important), many combinations can be made from a few constituents. For example, if each mixture were treated as a separate material, testing all combinations of tox- icants would be physically and economically impossible. Testing all possible mixtures of 10 substances (i.e., 2 at a time, 3 at a time, etc.) would require more than 1,000 tests, even if each substance were tested at only one dose (present or absent). An awareness of these problems and the recognition that the biological mechanisms of toxicity of even single materials are often not known led the Environmental Protection Agency (EPA) to ask the Board on Environmental Studies and Toxicology of the National Research Council, through its Safe Drinking Water Committee, to convene a workshop (1) to review the sci- entific and experimental issues associated with estimating the toxicity of mixtures in drinking water, (2) to suggest possible modifications of the current approaches, and (3) to recommend subjects for future research. This report 95

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96 DRINKING WATER AND HEALTH is the product of the workshop. Because the study of the toxicity of mixtures is relatively new, the Subcommittee on Mixtures, which prepared the report, confined its considerations to a small number of issues. APPROACHES FOR PROBLEM RESOLUTION Several possibilities exist for attacking the problems of testing (and reg- ulating) mixtures. Research on mechanisms could lead to theoretical modeling that would exploit data on the toxicity of single materials; that is a desirable long-term goal. In the absence of knowledge of mechanisms and of accepted models for combining the toxicities of single materials, some mixtures will have to be tested. If the numbers of such mixtures can be kept small, testing might become both operationally and economically possible. GROUPING CHEMICALS FOR ESTIMATION OF COMBINED RISK . A prudent first step in assessing and managing the health risks associated with exposure to mixtures in drinking water is to reduce the apparent number of mixtures by developing appropriate methods for grouping the substances found in water. This report examines two such groups based on similarities of biologic effects: volatile organic chemicals (VOCs), of which several are suspected human carcinogens, and organophosphorus compounds and car- bamates, which inhibit acetylcholinesterase. In addition, this report suggests some ways to make other logical classifications and thus reduce the testing needed. Except for the trihalomethanes (a class of volatile organic chemicals that are by-products of disinfection), the EPA Office of Drinking Water has promulgated standards only for single components of drinking water. It is unlikely that each agent present in drinking water will act in biologic isolation of every other agent present. Where the mechanisms of toxicity of two or more toxicants are the same or similar, exposure to several materials, each at a below-threshold dose (i.e., a dose with a zero response), could amount to exposure to an above-threshold dose and produce a response. EPA's general guidelines for evaluating the health risk associated with exposure to a chemical mixture recommend that, if data are not available on the complete mixture or a toxicologically similar mixture, a dose-additive method be used to define a "hazard index" (in effect, an exposure index) based on measured concentrations and reference doses. The subcommittee recommends using a modified hazard index that sums similar toxicities, incorporates multiple toxic manifestations, and suggests, under some cir- cumstances, the use of an uncertainty factor to allow for possible synergisms. The subcommittee reviewed earlier schemes for the arbitrary grouping of substances in its efforts to devise some classification schemes that could

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Executive Summary 97 facilitate control of mixtures in drinking water. In light of EPA's general guidelines, the subcommittee suggested the following as possible ways for EPA to group substances for assessing their combined risk when they are found in drinking water. Groupings that are more rational for regulatory purposes might be found. ~ Substances can be grouped according to carcinogenicity. According to the currently preferred dose-extrapolation models, additivity of response or risk can usually be assumed for low-dose exposure to a mixture of carcinogens (at doses with relative risks of less than 1.01~. The subcommittee cautions that additivity might not apply for carcinogens at high doses, when some dose extrapolation models are considered, or when one agent is a "pure" initiator and another a promoter. Substances can be grouped according to other toxic end points (such as specific organ toxicity, peripheral nerve damage, etc.~. It is likely that not all members of a group will affect an end point via the same mode of action. When toxic end points are unknown, substances can be grouped on the basis of their transformation into similar metabolites with similar reactivity and stability, although it must be kept in mind that their toxic end points might differ. Substances can be grouped according to structural properties. For toxic materials that fall into any of these groups, a toxic-equivalence approach that estimates the combined toxicity of the members of a single chemical class on the basis of the toxicity of a representative of the class has substantial appeal. In this approach, one estimates the potencies of the contaminants belonging to a given class relative to the potency of a representative of the class. (That is already done for some classes of compounds, such as polycyclic aromatic hydrocarbons, dibenzo-p-dioxins, and dibenzofurans). Toxic doses can then be combined according to some weighting procedure using a dose- additive model. . USING PHYSIOLOGICALLY BASED PHARMACOKINETIC MODELl NG The new field of physiologically based pharmacokinetics warrants attention as a first step in applying existing knowledge of mechanisms of toxicity. (In the realm of toxicity modeling, the term "toxicokinetics" might be more appropriate.) Unfortunately, little is known about how pharmacokinetic vari- ables are affected by simultaneous or sequential exposure to multiple chem- icals. Improved understanding and modeling of the pharmacokinetics of mixtures should lead to improved methods for estimating the risks associated with exposure to multiple chemicals in drinking water. Development of appropriate

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98 OR ~ N K! NG WATER AN D H EALTH pharmacokinetic models will require considerable theoretical and experi- mental work. STATISTICAL APPROACHES FOR REDUCING EXPERIMENTATION (RESPONSE-SURFACE DESIGNS AND FRACTIONAL FACTORIALS) Response-surface methods are mathematical-statistical techniques that per- mit the estimation of the effects of each component of a mixture and the effects of interactions (i.e., departures from additivity) on the basis of a small number of experimental points. The 2k factorial approach permits the esti- mation of possible interactions: each of the k factors (elements in the mixture) is assumed to be present at two concentrations (one of which may be zero), and each concentration of each factor is combined with each concentration of every other factor. Usually, some interactions are of less interest, and that permits the use of fractional factorial designs, which require still fewer experimental groups. The availability of modern computer graphics has per- mitted the plotting of the data, both observed and fitted, in ways that lead to easier identification of nonadditivity, if there is any. ASSESSING EXPOSURE To develop a risk assessment of a drinking water mixture, exposure needs to be estimated. Drinking water is often not the sole source of exposure to many of its contaminants. Exposures due to contact with other media and by other routes must be considered, because they have the potential for raising total body burden to levels that could be of concern and for providing sub- stances critical for synergistic interaction with waterborne substances. In- halation of volatilized drinking water contaminants during cooking, showering, or other activities is another route by which water can contribute additional exposure, as is dermal contact in swimming and bathing. The subcommittee considers it likely that, if a simple analytic process were developed to provide a summary measure of an entire class of toxi- cologically similar constituents in drinking water, it would also detect other, potentially confounding constituents in the water. APPLICATIONS-PROBLEMS OF EXPOSURE On a practical level, ambient exposures to mixtures usually involve low concentrations of the constituents. At concentrations that yield small increases in relative risks, additive and multiplicative responses are essentially indis- tinguishable, and additivity is a satisfactory first approximation. For example, several organophosphorus and carbamate chemicals inhibit acetylcholines

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Executive Summary 99 terase, and their joint action is assumed to be the sum of their separate actions on this end point. The additive approach might need to be modified by incorporating an uncertainty factor (for possible synergism), which would depend in part on the information available and the concentrations of the contaminants. If a great deal of toxicologic information is available on the individual contam- inants, if toxic interactions are not likely (on the basis of the knowledge available), or if the concentrations of the contaminants are low, the uncer- tainty factor might be set at 1 (producing an assumption of simple additivity). If less is known about the toxicity of individual components and the con- centrations of the contaminants are higher, the uncertainty factor might be set at 10. The greater the uncertainty (because of lack of information) and the higher the concentrations of the contaminants, the larger the uncertainty factor required to provide an adequate margin of safety. For example, syn- ergism and antagonism among some anticholinesterases are known to depend on interference with or competition for metabolic mechanisms of detoxifi- cation or activation of the anticholinesterases or their precursors. One might predict that synergism could occur only when the dosages are high enough for metabolic detoxification to be rate-limiting with respect to toxicity. The dosages necessary could be lower when other substances inhibit critical path- ways of detoxification, particularly if the inhibition is of a noncompetitive type. At the (low) concentrations of anticholinesterase compounds found in drinking water, it is probably safe to assume no more than additivity of effect. For such concentrations, the uncertainty factor would be 1. MIXTURES OF CARCINOGENS The subcommittee believes that additivity will usually apply to exposure to carcinogens associated with low risks. However, like the National Research Council Committee on Methods for the In Vivo Toxicity Testing of Complex Mixtures, this subcommittee is aware that large exposures to several carcin- ogens have been shown to produce synergistic interactions-e.g., in a num- ber of studies cigarette-smoking and exposure to asbestos appear to have combined to produce a greater than additive risk of cancer although the mechanisms of carcinogenesis (in this case of asbestos and cigarette smoke- itself a highly complex mixture) might be different. The subcommittee as- sumed that exposures to waterborne toxicants, such as VOCs, at low con- centrations generally are associated with low individual component risks, although the empirical evidence for such an assumption is sparse. Given that assumption, it should be possible to estimate the risk associated with exposure to a mixture of carcinogens by adding the calculated carcinogenic responses to the individual components of the mixture. The current methods and models used by EPA to estimate carcinogenic risks in humans on the basis of ex

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i00 DRINKING WATER AND HEALTH perimental exposures of animals at high doses are derived from the same assumption. Additional research should be conducted to provide a firmer empirical base for the models used. OTHER ISSUES The subcommittee is aware of the possibility of substantially increased risk to some persons associated with even small exposures to chemicals, but it did not address this extensively. Because of the genetic variability of humans or because of earlier sensitizing exposures, what is apparently low- dose exposure for the majority of the population might have serious effects in a small segment of the same population. Providing advice on how to factor these complexities into risk assessment was beyond this subcommittee's charge.