Subchronic/chronic toxicity of a mixture of four chlorinated dibenzo-p-dioxins in rats. I. Design, general observations, hematology,and liver concentrations.

Groups of 20 male and 20 female rats were administered five different doses of a mixture of 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD), 1,2,3,7,8-pentaCDD (PCDD), 1,2,3,4,7,8-hexaCDD (HxCDD), and 1,2,3,4,6,7,8-heptaCDD (HpCDD). Doses were selected based on relative potency factors derived from acute toxicity data and a previous subchronic study with HpCDD. The mixture was constituted such that each of the congeners contributed one fourth to total toxic equivalency. Total doses were divided into four daily loading doses and six biweekly maintenance doses. The highest total dose for males was 17.5 microg/kg of TCDD, 87.5 microg/kg of PCDD, 350 microg/kg of HxCDD, and 2500 microg/kg of HpCDD. Positive controls were administered PCDD (350 microg/kg) or HxCDD (1400 microg/kg). Females were given 1.5 times lower doses than males. The dosing period was 13 weeks, after which half of the rats were necropsied and the rest provided with an off-dose period of another 13 weeks. Liver concentrations as determined by GC-MS reflected the doses administered. Body weight gain was dose-dependently reduced throughout the study. Mortality rates at the end of the off-dose period were 80 and 60% for the two highest dosages (mixture) in males and 70 and 10% for females. Clinical signs and necropsy findings suggested that the cause of death was related to wasting, hemorrhage, and anemia. Prothrombin times were prolonged and platelet counts were decreased in some rats receiving high doses. This study provides in vivo support for the validity of the assumption of additive toxicity of CDDs as currently used in the toxicity equivalency factor approach to assess the toxicity of mixtures of CDDs.