A multidisciplinary approach to toxicological screening: II. Developmental toxicity

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Abstract
As part of the validation of an integrated bioassay for systemic toxicity, neurotoxicity, and developmental toxicity, we evaluated the effects of four pesticides, four chlorinated solvents, and two other industrial chemicals in Fischer 344 rats. The pesticides included carbaryl, triadimefon, chlordane, and heptachlor; the solvents included dichloromethane (DCM), carbon tetrachloride, tricbloroethylene (TCE), and tetrachloroethylene (per‐chloroethylene, PER); and the industrial chemicals were di(2‐ethylhexyl)phthalate (DEHP) and phenol. In the developmental toxicity studies, timed‐pregnant rats were treated by gavage with vehicle or 1 of 2 dose levels of each compound on gestation d 6–19. The dams were allowed to deliver and their litters were examined on postnatal d 1, 3, and 6. Litter weights were determined on postnatal d 1 and 6. Implants were also counted to determine prenatal loss. Maternal toxicity was evidenced by dose‐related alterations in weight gain for all 10 compounds. Clinical signs of maternal toxicity were present for all chemicals except chlordane and heptachlor. DEHP exposure resulted in the most pronounced developmental toxicity (high levels of pre‐ and postnatal mortality), whereas chlordane induced extensive postnatal loss. Of the solvents, only DCM did not cause a high incidence of full‐litter resorption. Phenol, heptachlor, triadimefon, and carbaryl showed only slight potential for developmental toxicity. Malformations suggestive of teratogenicity included kinked tail (phenol), microphthalmia (TCE, PER, DEHP), and cleft palate with renal agenesis (DEHP). Although several findings (eye defects caused by TCE and PER, full‐litter resorption and delayed parturition caused by PER, and delayed parturition/dystocia associated with triadimefon) have not been previously reported, the results are generally consistent with previous reports and highlight the importance and relative ease of incorporation of developmental evaluations into a multidisciplinary screening battery.