substantially greater than that in the mature rat. Unlike most other physiological distribution processes that are flow limited, the distribution of trichloroacetic acid to mammary tissue is diffusion limited. The exposure of the pups to trichloroethylene from maternal milk was small, representing only about 2% of the exposure of the dam. Pup plasma levels of trichloroacetic acid, however, were as high as 30 and 15% of the maternal exposure for drinking water and inhalation exposures, respectively.

Neurotoxicity

Two classes of insecticides, the organophosphates and the carbamates, are acetylcholinesterase inhibitors, which interfere with nerve transmission. Chemically induced functional alterations of the nervous system are often assessed with neurobehavioral tests. However, it has been very difficult to integrate observations of behavior with other aspects of neurotoxicological testing (NRC, 1992). This has been especially true for assessing neurodevelopmental effects in young animals. For example, some studies in laboratory animals have shown that exposure to organophosphates and carbamates before or immediately after birth may alter neurological development and cause subtle and long-lasting neurobehavioral impairments. (See Chapter 4 for a discussion of neurotoxicity testing.) Therefore, additional laboratory animal data are needed to evaluate the effects of low-level chronic exposures on subtle neurotoxicities, including alterations of behavior. The recent NRC report Environmental Neurotoxicology (NRC, 1992) describes in detail the research necessary to improve the neurotoxicological testing of chemical substances, including pesticides. There is currently no validated testing system that satisfies all the necessary requirements for a screening program to detect the neurotoxic potential of chemical substances (NRC, 1992).

Multiple Exposures

Because humans are exposed to multiple chemicals simultaneously, the potential risks associated with joint exposures require consideration (Krewski and Thomas, 1992). Factorial experiments with pairs of chemicals have demonstrated both synergistic and antagonistic effects as well as a lack of interaction, depending on the pair of agents used, the tissues in which the cancers appear, and the time of appearance of different primary site tumors (Elashoff et al., 1987; Fears et al., 1988, 1989). Epidemiological studies have also demonstrated the existence of synergism between two agents, such as tobacco and asbestos (NRC, 1988). Brown and Chu (1989) demonstrated that the multistage model can lead to a spectrum of effects, ranging from additive to multiplicative age-specific relative risks, depending



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