Chronic toxicity and carcinogenicity of 1,2,3,4,6,7,8-heptachlorodibenzo-p-dioxin displays a distinct dose/time toxicity threshold (c × t = k) and a life-prolonging subthreshold effect

Chronic toxicity of 1,2,3,4,6,7,8-heptachlorodibenzo-p-dioxin (HpCDD) including its carcinogenicity was studied in female Sprague-Dawley rats in lifetime experiments. Six single dose and three multiple dose rate experiments were conducted with a single dose corn oil control group and a multiple dose rate corn oil control group, respectively. The lowest dose (1.0 mg/kg) of HpCDD and multiple dose rates of corn oil (4.0 ml/kg every other week) both prolonged the life of rats by about 2 months over that of single dose corn oil controls. Higher doses resulted in a predictable shortening of the life of rats after single dose administrations as well as after multiple dose rate administrations. The c × t = k paradigm previously validated for acute toxicity [Toxicol. Sci. 49 (1999) 102] was confirmed for chronic toxicity including carcinogenicity of HpCDD. The c × t = k product was independent of dosing regimen. Anemia and squamous cell carcinoma of the lungs were the earliest and most prevalent endpoints of toxicity. A dose of 2.1 mg/kg and 3.1 mg/kg of HpCDD caused 16.6% and 73.3% lung cancer, respectively. Liver cancer had a low prevalence and was a very late effect occurring only at doses lethal acutely for most rats in the three highest dosage groups. There was no correlation in the dose-dependence of non-malignant hepatic lesions and liver cancer.