Teratology of 2,3,7,8-tetrachlorodibenzo- p-dioxin in a complex environmental mixture from the Love Canal

Abstract

The organic phase of a leachate (OPL) from the Love Canal chemical dump site contains more than 100 organic compounds including 2,3,7,8-Tetrachlorodibenzo- p-dioxin (TCDD). The teratogenic potential of OPL was determined in two inbred and one hybrid mouse strain which differ in their sensitivity to aromatic hydrocarbon ( Ah) receptor-mediated toxicity. OPL was orally administered in corn oil on Days 6–15 of gestation to C57BL 6 J mice ( Ah b Ah b ) at doses of 0, 0.1, 0.3, 0.5, and 0.7 g kg −1 day −1 and to DBA 2 J ( Ah d Ah d ) females, which were mated with either DBA 2 J or C57BL 6 J males, at 0, 0.5, 1, and 2.0 g kg −1 day −1. In C57BL 6 J mice, which express a high-affinity Ah receptor that avidly binds TCDD, the ED50's of OPL for cleft palate and hydronephrosis were 0.44 and 0.11 g OPL kg −1 day −1, respectively. Maternal mortality was 5% at the highest dose. In DBA 2 J fetuses, which express a low-affinity receptor, neither treatment-related cleft palate nor hydronephrosis was induced by dose levels that caused 36% maternal mortality. In hybrid D2B6F1 fetuses, the incidence of cleft palate reached only 8% at 2 g OPL kg −1 day −1 but the ED50 for hydronephrosis was 0.76 g OPL kg −1 day −1. TCDD was similarly administered to pregnant C57BL 6 J mice at 0, 0.5, 1, 2, and 4 μg kg −1 day −1 and to DBA 2 J mice at 0, 0.5, 2, 4, and 8 μg kg −1 day −1. In C57BL 6 J fetuses, the ED50's for cleft palate and hydronephrosis were 4.6 and 0.73 μg TCDD kg −1 day −1, respectively. In DBA 2 J fetuses the ED50's for cleft palate and hydronephrosis were 15.0 and 6.4 μg TCDD kg −1 day −1, respectively. Both the OPL and TCDD caused maternal hepatomegaly and thymic atrophy in all strains, but increased only C57BL 6 J fetal weights. OPL decreased the number of fetuses per C57BL 6 J dam at the two highest doses but there were no other reproductive effects in any of the groups. It was concluded that the OPL is teratogenic and that hydronephrosis is a sensitive measure of TCDD toxicity in a complex organic mixture. Based on the ED50's of OPL- and TCDD-induced cleft palate and hydronephrosis in the C57BL 6 J strain, the OPL had TCDD equivalence of 6.6 and 10.5 ppm, respectively. These values compare closely with the chemical analysis of 3 ppm. The results suggest that the teratologic effects are due primarily to the TCDD in the OPL and that these effects are mediated through the Ah receptor, but that the maternal thymic atrophy and hepatomegaly were due primarily to the non-TCDD components of the OPL.