challenge for test design and interpretation to minimize the problems noted above and, thereby, improve the predictiveness of laboratory animal toxicology protocols.


Four approaches have traditionally been used to evaluate human developmental toxicity: (1) case series, (2) randomized controlled trials, (3) cohort studies, and (4) case-control studies.

Case series comprise an important first step in assessing relationships between exposures and adverse pregnancy outcomes. Many developmental toxicants are first recognized by astute clinicians who correlate specific patterns of developmental defects or developmental disabilities with specific exposures during pregnancy. Most notable among agents first identified this way as causing developmental defects are rubella and thalidomide (Gregg 1941; Lenz and Knapp 1962; for a review, see Rosa 1992). Case series can be useful when the outcome is distinctive, the exposed population is large enough that numerous cases are recognized, and the dose and timing are well described. Case series should be interpreted with caution, however, because the association can be due entirely to chance. They rarely permit identification of a causal link between exposure and outcome due to their anecdotal nature and the high background of adverse pregnancy outcomes in humans (see Table 2-1). Their greatest value is in the generation of hypotheses for further investigation.

Randomized controlled trials are the most widely accepted type of epidemiological study for assessing the relationship between an intervention and an outcome. Subjects are enrolled into a randomized trial based on pre-established criteria. They are randomly assigned to a reference group (placebo or alternate treatment) or a test group and administered a test agent under controlled conditions. Because the agent of interest is deliberately administered, this type of study is not appropriate for assessing risk of chemical exposures on pregnancy, or of adverse effects of chemicals in general. Randomized control trials have their widest use in tests of the efficacy of pharmaceuticals and other medical interventions.

Cohort studies are observational epidemiological studies in which individuals are assigned to groups (cohorts) on the basis of pre-existing exposure status and are followed to determine pregnancy outcome. The cohort study approach is limited to the investigation of few exposures, but allows for the assessment of numerous developmental endpoints. Considering the rarity of congenital anomalies, large studies are needed to detect differences between cohorts. For example, spina bifida occurs in 0.1% of most American populations and might not be detected even in a cohort of 1,000 pregnancies. Even though cohort studies allow for the next best determination of a causal association (after randomized controlled trials), they are often not practical. An additional problem is that some

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