An extended evaluation of an in vivo teratology screen utilizing postnatal growth and viability in the mouse

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Abstract
A teratology test system proposed by Chernoff and Kavlock [3,4] utilizes growth and viability for 3 days after birth to prioritize chemicals for standard teratology testing. The present study is an extended observation of the growth and viability of Chernoff and Kavlock's animals from 41 treatments for 250 days to determine if neonatal weight reductions persisted throughout life, if mortality occurred later in life or, if other serious abnormalities developed that could not be anticipated from the neonatal data. One chemical which was positive in the present study would be a false negative in the standard teratology test and the Chernoff/Kavlock Assay (CKA). Congo red did not cause frank malformations or mortality but it specifically altered reproductive function in the offspring. Two chemicals produced a variety of unusual abnormalities that were not apparent in the neonates, indicating that postnatal testing is necessary to determine the full teratogenic potential of some compounds. Mice exposed prenatally to cytosine arabinoside became hydrocephalic and 30% of them lacked lower incisors. Nitrofen caused hydrocephaly, the age of eye‐opening was delayed, a few of the mice had no eyes, and most of the mice lacked Harderian glands. Eighteen of the 41 treatments caused mortality of 15%, or greater, by day 3, and four of these treatments resulted in additional mortality past the neonatal period. No compound caused a decrease in viability after the neonatal period without also reducing days 1 or 3 litter sizes, validating the use of this measurement in the CKA. Cytosine arabinoside was administered later in gestation than the CKA dosing regime and caused a marginally significant increase in mortality near birth but killed over 50% of the pups after weaning. Altering the duration or period of exposure in the CKA may necessitate a longer postnatal evaluation than presently recommended [3,4]. Neonatal weight, the second parameter used in the CKA to prioritize chemicals for additional testing, appears to be less useful than viability. It was a poor predictor of subsequent growth, some early weight effects persisted, while most of those concurrent with maternal weight reductions were transient. A correlation analysis of the parameters measured in the CKA and in the present study, excluding the compounds that produce frank malformations, indicated that compounds that reduced maternal weight gain during dosing had fewer live pups and growth was transiently retarded. Compounds could be tested in the CKA at a dose that result in less than a 20% reduction in maternal weight gain during dosing without confounding maternal toxicity with postnatal effects.