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sure that the sum of all the ratios of incurred dose to acceptable dose relevant to a given end point total less than 1 (NRC, 1972a, 1989; OSHA, 1983; ACGIH, 1977, 1988; EPA, 1987a, 1988g; Calabrese, 1991; Pierson et al., 1991). That approach is based on an assumption that doses of different agents can be treated as roughly additive with regard to inducing the end point; this assumption is reasonably consistent with much of the experimental evidence on the joint actions of chemicals in mixtures.

Among the key problems associated with the general strategy is that the procedures currently used for defining acceptable exposures to systemic toxicants are rather crude. Proposals to incorporate more quantitative treatment of data and to focus on risk prediction without reference to thresholds (e.g., Crump, 1984; Dourson et al., 1985; Dourson, 1986) have not been widely adopted. The additivity assumption for systemic toxicants further complicates the crude approaches taken to identifying safe intakes of the components of a complex mixture. As an Environmental Protection Agency (EPA) technical support document (EPA, 1988g) comments, this use of the additivity assumption implies that,

as the acceptable level is approached or exceeded, the level of concern increases linearly … and in the same manner for all mixtures [which is incorrect, because the estimates used to derive such recommended acceptable levels] do not have equal accuracy or precision, and are not based on the same severity of toxic effect. Moreover, slopes of dose-response curves in excess of [such levels] in theory are expected to differ widely. The determinations of accuracy, precision or slope are exceedingly difficult because of the general lack of toxicity data.

Despite its drawbacks, the crude additivity approach to the problem of aggregation of potential threshold effects has had relatively straightforward and uncontroversial regulatory applications.

Much more debate has focused on quantitative risk-assessment methods for end points assumed not to have threshold dose-response relationships, such as cancer. Particularly with regard to environmental exposures to multiple chemicals, risk-management decisions (e.g., cleanup criteria) tend to be driven by the estimated low-dose risk associated with exposure to materials that lead to assumed nonthreshold end points. This chapter focuses on aggregation of different risks and different types of risk attributable to integrated, multiroute exposure to multiple chemicals that are assumed to have nonthreshold effects.

Exposure Routes

Any comprehensive assessment of health risk associated with environmental exposure to any particular compound must consider all possible routes by which people might be exposed to that compound, even if expected applications in risk management are limited to some particular medium, such as air, or partic-

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