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© 1995 Oxford University Press

research-article

Nonadditive Developmental Toxicity in Mixtures of Trichloroethylene, Di(2-ethylhexyl) Phthalate, and Heptachlor in a 5x5x5 Design1

MICHAEL G. NAROTSKY*,2, EDIE A. WELLER{dagger},3, VERNON M. CHINCHILLI{dagger},4 and ROBERT J. KAVLOCK{ddagger}

*ManTech Environmental Technology, Inc., Research Triangle Park North Carolina 27709 {dagger}Department of Biostatistics, Virginia Commonwealth University Richmond, Virginia 23298 {ddagger}Developmental Toxicology Division, Health Effects Research Laboratory, U.S. Environmental Protection Agency, Research Triangle Park North Carolina 27711

Received September 9, 1994; accepted March 21, 1995

In order to identify nonadditive effects on development, three compounds were combined using five dosages of each agent (a 5x5x5 full-factorial 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/day 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 postnatally. Maternal death showed no main effects but DEHP and HEPT were synergistic. For maternal weight gain on Gestational Days 6–8, main effects for all three agents were observed, as well as TCE-DEHP synergism, and DEHP-HEPT antagonism. Maternal weight gain on Gestational Days 6–20 adjusted for litter weight showed main effects for TCE and HEPT, but no interactions. Main effects for all three agents were evident for full-litter resorptions and prenatal loss. The HEPT main effects were unexpected and were interpreted as reflecting potentiation by HEPT of the other agents. For full-litter loss, the TCE-HEPT and DEHP-HEPT interactions were antagonistic, perhaps due to a "ceiling" effect. For prenatal loss, the TCE-DEHP interaction was synergistic. Postnatal loss 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 antagonism, and TCE-DEHP synergism were evident. Microphthalmia and anophthalmia incidences revealed TCE and DEHP main effects but no interactions. This extensive examination of a full-factorial design elucidates the complexities of studying and interpreting mixture toxicity. The data are available for further analysis.


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