Chronic toxicity and carcinogenicity of 1,2,3,4,6,7,8-heptachlorodibenzo-p-dioxin displays a distinct dose/time toxicity threshold (c x 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 x t = k paradigm previously validated for acute toxicity [Toxicol. Sci. 49 (1999) 102] was confirmed for chronic toxicity including carcinogenicity of HpCDD. The c x 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.
Rozman
Karl K
KK
Department of Pharmacology, Toxicology, and Therapeutics, University of Kansas Medical Center, 3901 Rainbow Boulevard, Kansas City, KS 66160, USA. krozman@kumc.edu
Lebofsky
Margitta
M
Pinson
David M
DM
D000740:Anemia / Q000139:chemically induced* / Q000401:mortality; D000818:Animals; D015197:Carcinogenicity Tests; D002273:Carcinogens / Q000633:toxicity*; D002294:Carcinoma, Squamous Cell / Q000139:chemically induced* / Q000401:mortality; D003314:Corn Oil; D004305:Dose-Response Relationship, Drug; D005260:Female; D008175:Lung Neoplasms / Q000139:chemically induced* / Q000401:mortality; D000072317:Polychlorinated Dibenzodioxins / Q000031:analogs & derivatives* / Q000633:toxicity*; D011897:Random Allocation; D051381:Rats; D017207:Rats, Sprague-Dawley; D013997:Time Factors; D023382:Toxicity Tests, Acute; D036401:Toxicity Tests, Chronic
D002273:Carcinogens; D000072317:Polychlorinated Dibenzodioxins; D003314:Corn Oil; C046839:1,2,3,4,6,7,8-heptachlorodibenzodioxin