in assessing the predictive value of the methods seem not to have been conducted. The guidance document, however, reviews studies of the acute toxicity of all possible binary combinations of more than 50 industrial chemicals in rats (Smyth et al. 1969) and notes that deviations from the assumption of additivity span a factor of about 5 (expected to observed ratios of LD50 values of binary mixtures range from about 0.2 to 5). More recently, Boobis et al. (2011) searched publications on mammalian toxicology from 1990 to 2008 for studies reporting synergy at low sublethal doses. They discerned a maximum magnitude of synergy of about 3.5. The studies suggest that chemical interactions can modify toxicity, typically by less than a factor of 10. Exceptions do exist. PBO was shown to decrease the toxicity of malathion to daphnids (Daphnia magna) by as much as a factor of 100 (Rider and LeBlanc 2005), and the pesticide synergist N-octyl bicycloheptene dicarboximide increased the toxicity of deltamethrin to a snail (Lymnaea acuminate) by as much as a factor of 300 (Sahay and Agarwal 1997).

A Case Study: Assessing Pesticide-Containing Mixtures

Conventional approaches to assessing the risks posed by exposure to chemical mixtures first determine EECs of the mixture components and then estimate the hazard associated with those exposures. The approach is most appropriate for estimating whether the margin of safety for exposed listed species is sufficient. Table 4-1 provides a hypothetical dataset to exemplify how hazard from exposure to a pesticide in combination with other chemicals in the environment could be assessed by using established approaches discussed in this report. The listed species of concern in this exercise is sockeye salmon (Oncorhynchus nerka), and the pesticide of concern is cypermethrin, a pyrethroid. The cypermethrin is in a formulation that also contains the synergist PBO. The formulation will be added to a tank mixture that contains another pyrethroid insecticide, deltamethrin; a surfactant, Polysorbate-20; and a stabilizer, Epoxisoy. Contents of the tank mixture will be used for insect-pest control according to label specifications. And, several chemicals—nonylphenol, ethinyl estradiol, caffeine, acetaminophen, PBO, and cypermethrin—are known or predicted to be present in the exposure environment at measurable concentrations. Thus, the salmon might be exposed simultaneously to nine chemicals that originate from various sources. At issue is whether exposure to the chemical mixture poses a risk to the salmon.

Columns 2, 3, and 4 in Table 4-1 depict the sources of the chemicals and their concentrations in the different sources. Exposure of salmon to the mixture constituents can be estimated from those data. For example, cypermethrin is present in the formulation at a concentration of 0.05%. Once in the tank mixture, cypermethrin is diluted to a concentration of 250 mg/L (ppm), and the predicted concentration in the environment is 0.01 ìg/L (ppb). The concentration of cypermethrin in the formulation can be derived from the label, the concentration in



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