Quantitative Risk Assessment for Paternally-Mediated Developmental Toxicity

Abstract

This contribution presents a suggested approach for quantitative evaluation of risk to the offspring for developmental toxicity from paternal exposure. This proposed approach is different than the traditional risk assessment method for developmental toxicity which has focused exclusively on maternally mediated toxicity (i.e., toxicity resulting from maternal exposure during pregnancy) to the developing embryo or fetus (Fabro 1985, Fabro et al 1982, Faustman et al 1989, Francis et al 1990, Frankos 1985, Gaylor 1989, Gaylor et al 1988, Hart et al 1988, Hemminki et al 1986, Hemminki and Vineis 1985, Jelovsek et al 1989, Jelovsek et al 1990, Kimmel 1989, Kimmel and Gaylor 1988, Kimmel et al 1989, Koeter 1983, Mattison et al 1989, Schardein et al 1985, Schardein 1993, Shepard 1989,). Over the past decade there has been considerable discussion of a range of approaches to characterize risk to the developing embryo or fetus from maternal exposure, including: (i) statistical approaches for dose response modeling such as the no observed adverse effect level (NOAEL)-safety factor¹ (SF) approach to determine the allowable daily intake (ADI), the benchmark dose (B_mD)-SF approach to determine the reference dose for developmental toxicity (R_fD_dt); and (ii) biologically based approaches including classical pharmacokinetics (PK), physiologically based pharmacokinetics (PBPK), and biologically based dose response modeling (BBDR). These approaches will be reviewed briefly to suggest a strategy to develop risk assessment techniques for male mediated developmental toxicity (MMDT). In general, this analysis suggests that statistical approaches which characterize the dose-response relationship are most economically applied to the problem of risk assessment for MMDT.