tion of combined effects at low doses of each mixture component. For that reason, the committee scrutinized the evidence in the literature particularly with respect to low-dose combined effects.

After examining the empirical evidence, this chapter considers options for conducting cumulative risk assessment of phthalates and other antiandrogens. First, several questions are addressed to set the stage for considering various approaches. Which phthalates should be subjected to cumulative risk assessment? Should other antiandrogens be included? If so, which ones? What criteria should be used to group phthalates and other antiandrogens for cumulative risk assessment? Next, approaches to quantitative assessments of cumulative effects are discussed. For cumulative risk assessments of dioxins and other chemical classes, the toxicity equivalency (TEQ) concept has gained broad acceptance and is in widespread use. Accordingly, this chapter addresses whether the TEQ concept presents a practicable option for cumulative risk assessment of phthalates and other antiandrogens or whether alternative approaches should be adopted. The chapter concludes with a discussion of possible stepped approaches to cumulative risk assessment of phthalates and other antiandrogens.


Dose addition and independent action (here used synonymously with response addition) provide two possible approaches to dealing with the mixture issue. However, when one is faced with the task of evaluating specific mixtures, the issue arises as to whether either of the two concepts is appropriate for the mixture in question and should be chosen for assessment. That question becomes all the more important when the two concepts produce different predictions of mixture effects. However, in only a few cases have dose addition and independent action been evaluated together against the same set of experimental mixture data with the aim of establishing whether either approach produces valid predictions of combined effects (for a review, see Kortenkamp et al. 2007). As pointed out by the U.S. Environmental Protection Agency (EPA 2000), the empirical basis of choosing between dose addition and independent action as a default approach for risk assessment is not strong. The decision in favor of either approach as a default for mixture risk assessment is based largely on perceptions of whether the scientific assumptions that underpin dose addition or independent action are met. For such purposes, the two concepts have been allied to broad mechanisms of combined toxicity, as described below.

Dose addition is often stated to be applicable to mixtures composed of chemicals that have a similar or common mechanism of action (EPA 1986, 2000, 2002; COT 2002). However, the original paper by Loewe and Muischneck (1926) contains little that roots dose addition in mechanistic considerations; the idea of similar action probably derives from the “dilution” principle, which forms the basis of this approach. Because chemicals are viewed as dilutions of

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