Analysis of Clustered Multivariate Data from Developmental Toxicity Studies

Abstract

Society is becoming increasingly concerned about problems related to fertility and pregnancy, birth defects, and developmental abnormalities. Consequently, regulatory agencies such as the U.S. Environmental Protection Agency (EPA) and the Food and Drug Administration (FDA) have placed an increased priority on protecting the public from drugs, chemicals and other environmental exposures that may contribute to these risks. Because human data are generally limited, data from controlled animal experiments are generally used as the basis for regulation. This work is motivated by data collected from studies with a segment II design that involve exposing pregnant animals (rats, mice or rabbits) during the period of major organogenesis and structural development. Dose levels for the Segment II design consist of a control group and 3 or 4 dose groups, each with 20 to 30 pregnant dams. The dams are sacrificed just prior to normal delivery, at which time the uterus is removed and examined for resorptions and fetal deaths. The viable fetuses are examined carefully for many different types of malformations, which are commonly classified into three broad categories: external malformations are those visible by naked eye, for instance missing limbs; skeletal malformations might include missing or malformed bones; visceral malformations affect internal organs such as the heart, the brain, the lungs etc.