CAUSAL-MODELING OF MULTIVARIATE OUTCOMES FROM DEVELOPMENTAL TOXICITY EXPERIMENTS

Exposure to developmental toxicants may cause foetal malformations, in crease foetal death or resorption and reduce foetal weight. The correl ations among these developmental endpoints have been reported, but the ir causal relationships have not been investigated. Structural equatio n models (path models) were applied to study the patterns of causation among the four developmental outcomes, number of viable foetuses, num ber of malformations, number of deaths/resorptions, and average foetal weight; these outcomes were modelled as response variables with the d ose level and number of implants (litter size) modelled as independent variables. Three hypothesized path models were fitted to developmenta l toxicity data from a study of the herbicide 2,4,5-T exposure in mice . One model, which hypothesized that foetal weight, implicitly a mecha nism such as cellular growth, affects both malformations and death/res orption (equivalently, viability) with no causation relationship betwe en malformation and death/resorption, described data consistently well for three strains of mice. The most consistent relationship found was a strong direct effect of foetal weight on malformations, and the cor relation between malformations and death/resorption (or reduced viabil ity) was likely spurious.