NONADDITIVE DEVELOPMENTAL TOXICITY IN MIXTURES OF TRICHLOROETHYLENE, DI(2-ETHYLHEXYL) PHTHALATE, AND HEPTACHLOR IN A 5X5X5 DESIGN

In order to identify nonadditive effects on development, three compoun ds were combined using five dosages of each agent (a 5 x 5 x 5 full-fa ctorial design). Trichloroethylene (TCE), di(2-ethylhexyl) phthalate ( DEHP), and heptachlor (HEPT), in corn oil, were administered by gavage to Fischer-344 rats on Gestation Days 6-15. Dose levels were 0, 10.1, 32, 101, and 320 mg/kg/day for TCE; 0, 24.7, 78, 247, and 780 mg/kg/d ay for DEHP; and 0, 0.25, 0.8, 2.5, and 8 mg/kg/day for HEPT. The dams were allowed to deliver and their pups were weighed and examined post natally. Maternal death showed no main effects but DEHP and HEPT were synergistic. For maternal weight gain on Gestational Days 6-8, main ef fects for all three agents were observed, as well as TCE-DEHP synergis m, and DEHP-HEPT antagonism. Maternal weight gain on Gestational Days 6-20 adjusted for lifter weight showed main effects for TCE and HEPT, but no interactions. Main effects for all three agents were evident fo r full-litter resorptions and prenatal loss. The HEPT main effects wer e unexpected and were interpreted as reflecting potentiation by HEPT o f the other agents. For full-litter loss, the TCE-HEPT and DEHP-HEPT i nteractions were antagonistic, perhaps due to a ''ceiling'' effect. Fo r prenatal loss, the TCE-DEHP interaction was synergistic. Postnatal l oss showed DEHP and HEPT main effects but no interactions. Analysis of pup weights on Day 1 revealed TCE and DEHP main effects and DEHP-HEPT antagonism; on Day 6, DEHP and HEPT main effects, DEHP-HEPT antagonis m, and TCE-DEHP synergism were evident. Microphthalmia and anophthalmi a incidences revealed TCE and DEHP main effects but no interactions. T his extensive examination of a full-factorial design elucidates the co mplexities of studying and interpreting mixture toxicity. The data are available for further analysis. (C) 1995 Society of Toxicology