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; ) 7 Conclusions and Recommendations for Research In the course of its deliberations the Subcommittee on Mixtures concluded that assessment of the toxic impact of contaminants in drinking water must include consideration of all routes of exposure to the water, such as inhalation and skin contact, as well as the totality of other exposures to the same contaminants through food, air, and soil. The subcommittee also concluded that, in view of the results shown to date, both response-surface models and physiologically based pharmacokinetic models have potential in the risk as- sessment of mixtures in drinking water when a small number of materials are to be considered. These techniques offer promise of substantial progress in experiment design and in describing the dose-response relationships as- sociated with exposure to multiple chemicals. The possibility of synergism cannot be ignored; thus, risk assessment approaches that consider only in- dividual toxic agents are inadequate. and approaches based on (dose) addi- tivity are best applied to groups of agents that have the same or similar mechanisms of action at the same biologic sites. One possible way to incorporate all reported systemic toxicities into a unified measure would be to combine related toxicities and apply weighting factors to the hazard index (and other dose-additive models) currently used by EPA, thus taking into account differences in the toxic spectra of different materials. Current models of carcinogenesis assume no exposure threshold for response, but assume response additivity at low doses, ignoring any potential for synergism. More data are needed to support these models, both to improve estimates of dose-response relationships and risk associated with individual carcinogens in drinking water and to improve understanding of the mechanisms of carcinogenesis. 168

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Conclusions and Recommendations for Research 169 The subcommittee concluded that it would be useful for monitoring pur- poses to have a simple single chemical analytic method that could produce a measure of the total concentration of members of a group (such as the trihalomethanes or all the volatile organic chemicals) whose risk might be assessed jointly. However, it is questionable whether such a method can be developed to determine the sum of the concentrations of a class of toxico- logically similar contaminants in drinking water without potentially con- founding detection of other constituents in the water. The subcommittee proposed the following recommendations for research to improve the assessment of risk associated with exposure to mixtures of chemical contaminants in drinking water. Because of the lack of necessary scientific information, these recommendations are offered as only the be- ginning of what should be a continuing process. Risk assessment methods related to exposure to multiple chemicals in drinking water and their under- lying models and assumptions must be evaluated periodically as more data become available. 1. The usefulness of various indexes used to characterize a mixture of toxicants needs to be studied. For example, can the hazard index be used to predict toxic severity? Specifically: a. The hazard index used by EPA should be modified to take into account the sensitivity of each toxic end point. Modifying the hazard index by using a weighting factor would help to account for differences in the toxic spectra of different materials and avoid the lumping together of unrelated toxicities, but would still permit the incorporation of all re- ported toxicities into a unified measure. b. The additive approach should be modified by incorporating a synergism factor that would vary with the amount and type of information available and the concentrations of contaminants. c. The "toxic-equivalence" approach that estimates the combined toxicity of the members of a class of chemicals on the basis of the toxicity of a representative of the class should be further developed. Toxicities can then be added according to a weighting procedure. d. The usefulness of response-surface methods in describing the relation- ship between concentration and response for a variety of toxicant com- binations should be explored. Relevant experimental designs should be used, and procedures for presenting multidimensional surfaces graph- ically should be developed. 2. The response additivity and dose additivity of multiple compounds at low doses or low concentrations should be tested. For example, clarification is needed as to whether interactions with active acetylcholinesterase inhibitors at a primary biochemical target (e.g., the acetylcholinesterase-active center) produce truly additive responses when multiple chemicals are used. The

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170 DRINKING WATER AND HEALTH resulting knowledge would help to validate the usefulness of summing re- sponses or doses that produce a given response as an approach to recom- mending quality standards. 3. The role of inhibition of carboxyl esterases and the role of noncritical (silent) receptors, whether or not they involve carboxyl ester linkage, should be investigated further. 4. The mechanisms of interaction of carbamate and organophosphorus insecticides need better definition to determine whether new concepts or methods for testing for interaction potential can be developed. 5. Biologic research is needed to improve understanding of the mecha- nisms of cholinesterase inhibition and other actions of the components of mixtures. The results should be used to develop models of these mechanisms; the validity of models should be tested repeatedly as new biologic inflation becomes available, such as that on the formation and persistence of DNA adducts. 6. Potential pharmacokinetic changes of individual representative chem- icals (i.e., chemicals taken to represent classes of chemicals) under the influence of long-term, low-dose intake of a mixture of contaminants in drinking water should be studied. 7. Physiologically based pharmacokinetic models for multiple chemicals in mixtures that represent drinking water contaminants should be developed. 8. Toxicity studies that can help to define the health effects of long-term, low-dose intakes of chemical mixtures in drinking water should be carried out. The assessment of health effects should include immunotoxicologic studies and initiation-promotion studies. 9. The most serious omission in the current literature on mixtures is that of information on dose-response relationships. Some phenomena that prevail at high doses might be absent or attenuated at low doses while others are proportionally strengthened as the statistical models suggest. Some binary combinations are known to produce synergism. It would be reasonable to begin testing the effects of dose by turning to those combinations. Later, observations of the results of largely acute and subchronic exposures could be amplified usefully with longer treatments, inasmuch as environmental problems stem from chronic exposure. Fractional factorial designs could reduce the resource requirements for such tests. 10. The frequency of occurrence of toxic interactions among drinking water contaminants and whether threshold concentrations exist for such in- teractions should be studied. A computerized data base on toxic interactions would be a useful first step in conducting the needed studies.