Collaborative Behavioral Teratology Study of Phenytoin: A Test Battery for Neurobehavioral Developmental Toxicity in Rats.

Abstract: At the Behavioral Teratology Meeting (BTM) of the Japanese Teratology Society in 1992, a core test battery was proposed from a practical and simple point of view as an estimation of developmental neurobehavioral toxicity for use in pharmaceutical drug screening. The validity of the core test battery is being examined in a new series of collaborative studies. The present study is the first such study; phenytoin, a well-known behavioral teratogen, was selected as the test compound, and 32 laboratories took part in a behavioral teratology study of phenytoin using the new test battery. Sprague-Dawley strain rats from four breeds were used. Phenytoin (200 mg/kg) was administered orally to pregnant rats from days 10 to 14 of gestation (sperm detection = day 0), and in the male offspring, the survival rate, development of physical landmarks, functional developments, open field test scores, and Biel water maze test results were assessed and the brain weights were measured. The shuttle box conditioned avoidance test was also performed in some laboratories. In the present collaborative study, by taking an aggregate of the relative values converted from the measured values of each breed (providing a much larger sample size than that recommended by reproduction toxicity study guidelines), a high detectability level for phenytoin's effects was established. Under these conditions, the effects of phenytoin on eye opening, incisor eruption, the surface righting reflex, the negative geotaxis reflex, and performance of the open field test, Biel water maze test and shuttle box conditioned avoidance test were observed. It was found that present collaborative study made it possible to evaluate the detectable capacity of each of these test battery items. In addition, the critical period of abnormalities demonstrated in many test items was identified, and the results of several previous reports were confirmed. Furthermore, a breed difference in the effect of phenytoin for several test items was found. The present results established that the core test battery accurately detected the effects of phenytoin.