the differentiating paw skeleton of the limbs, and exposure causes exencephaly or digit malformations, respectively (Terry et al. 1994). In the case of 2-methoxyethanol, the maternal plasma AUC of 2-methoxyacetic acid was highly indicative of that in the embryo and might serve as a surrogate of separate conceptus toxicokinetic measurements (Welsch et al. 1995, 1996).

Toxicokinetic information could be helpful in judging the extent of the hazard to humans from exposures if human kinetics are known (Yacobi et al. 1993). For example, the anticonvulsant drug valproic acid given to pregnant mice induces exencephaly in their embryos when a certain maternal plasma threshold concentration is surpassed for a very brief duration (Nau 1986). Larger total exposure over time (larger AUC) achieved by constant maternal drug infusion causes a dramatically lower incidence of exencephaly, indicating that the peak concentration (Cmax) rather than total exposure over time (AUC) induces the teratogenic response in mice. In contrast, clinical use of valproic acid for antiepileptic therapy requires the maintenance of valproic acid concentrations in an effective therapeutic range at which the required human doses produce serum Cmax values that are 6-10-fold lower than the teratogenic concentrations in mice (Nau 1986). A similar inference regarding Cmax as a cause of embryotoxic effects was made for caffeine in mice. A large single dose (100 mg/kg) induced a teratogenic response, whereas the same total amount divided into four separate administrations did not cause any malformations (Sullivan et al. 1987).

The embryotoxicity of other agents appears to depend on the total exposure over time (AUC). For example, the developmental toxicity of all-trans retinoic acid and cyclophosphamide (a chemotherapeutic alkylating agent) in the rat correlates best with duration of exposure (Tzimas et al. 1997; Reiners et al. 1987).

Caution in the interpretation of maternal AUC information without concomitant conceptus toxicokinetics is necessary because a single agent might act through both toxicokinetic exposure patterns, depending on the stage of development. 2-Methoxyacetic acid seems to induce mouse digit malformations best correlated with maternal and conceptus AUC (Clarke et al. 1992, 1993; Welsch et al. 1995, 1996). However, additional toxicokinetic data from both the maternal and the conceptus compartments at an earlier stage of mouse embryogenesis indicate that the agent induces neural tube defects that correlate best with Cmax in the conceptus tissues (Terry et al. 1994; Welsch et al. 1996). What is still lacking in these data is information on the toxicodynamic interaction of 2-methoxyacetic acid with a specific and still unknown recognition site (receptor) in the conceptus. The significance of considering both AUC and Cmax measurements for developmental toxicity risk assessment is especially important because of known temporal differences in tissue susceptibility. In cancer risk assessment, Haber’s law (the product of concentration times time is equal to a constant) is used to normalize risk impacts. Such generalizing concepts cannot be applied in developmental toxicity risk assessment. A recent study by Weller et al. (1999) illustrated these differences for ethylene oxide developmental toxicity.



The National Academies | 500 Fifth St. N.W. | Washington, D.C. 20001
Copyright © National Academy of Sciences. All rights reserved.
Terms of Use and Privacy Statement