Much of the literature before 1975 concerning studies of in-utero-induced adverse developmental outcome is troubled by small sample sizes, inappropriate routes and modes of exposure, inconsistent methodology, and excessively high dose or concentration exposures. Many of those deficiencies have been corrected by the regulatory mandate of adhering to Good Laboratory Practices (OECD 1987; FDA 1987; EPA 1990).

Several studies of concordance between the perturbed developmental outcomes in experimental animal studies and the human clinical experience have been made (Nisbet and Karch 1983; Kimmel et al. 1984; Francis et al. 1990; Hemminki and Vineis 1985; Newman et al. 1993). The most rigorous and earliest of those was done in the early 1980s and is contained in a technical report for the National Center for Toxicological Research (NCTR) (C.A. Kimmel, EPA, unpublished report, 1984).1 In general, these studies concluded that there is concordance of developmental effects between animals and humans and that humans are as sensitive or more sensitive than the most sensitive animal species.

The NCTR study was notable because it employed criteria of acceptance for both human and experimental animal reports that included study design and statistical power considerations. Additionally, the authors held to the premise that adverse developmental effects represented a continuum of responses—or at least a number of interrelated effects—including in utero growth retardation, death of the products of conception, frank malformations, and functional deficits that manifest themselves in later stages in life. Hence, an effect on any one of these end points in experimental animals or human studies was considered a basis for concordance. Concordance did not require an exact mimicry of response among species. This was not required because exposure conditions (e.g., timing and duration of exposure and toxicokinetic differences) and tissue sensitivity (e.g., toxicodynamic differences) could differ enough between experimental animals and humans to result in a different type of effect.

Many different agents—mostly chemical agents but also physical agents—have been evaluated to determine their capacity to produce developmental toxicity in experimental animal models, such as the rat, mouse, and rabbit. Most of those studies have been conducted by private industry and federal government-funded research programs and involved test agents that had not yet entered the market. Schwetz and Harris (1993) provide a good review of 50 chemicals that the National Toxicology Program has evaluated for developmental toxicity using rodent bioassays.

As discussed in Chapter 2, humans were never exposed to many of the materials that have been evaluated in rodent bioassays and that have been shown to affect animal prenatal development adversely. Thus, it will never be known

1  

Dr. Kimmel presented this information to the committee during its meeting on October 6, 1997, in Washington, D.C.



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