Delayed acute toxicity of 1,2,3,4,6,7,8-heptachlorodibenzo-p-dioxin (HpCDD), after oral administration, Obeys Haber's rule of inhalation toxicology.
Eight different doses (2.5 to 10.0 mg/kg) of 1,2,3,4,6,7,8-heptachlorodibenzo-p-dioxin (HpCDD) were administered acutely to a total of 272 female Sprague-Dawley rats. The doses ranged from a NOAEL for wasting/hemorrhage to supralethal doses. Dose- and time-responses of wasting/hemorrhage, anemia, and cancer were and are being studied as end points of toxicity. The experiments will be continued until the last rat dies. There was a very steep dose- and time-response between the LOAEL for wasting/hemorrhage (2.8 mg/kg) and the third highest dose (4.1 mg/kg) of HpCDD. The dose-and time-responses were nearly symmetrical, obeying Haber's Rule of inhalation toxicology (c x t = constant) even beyond 100% mortality. Introduction of a minimum of 25% body weight loss as a discriminatory criterion to separate wasting from hemorrhage as the primary cause of death reduced variability from 5.8 to 3.2%. An arithmetic plot of the dose and time data resulted in a nearly perfect hyperbola. A logarithmic plot of these data yielded a straight line of similar perfection. Dose-response data at constant times illustrate the shifting of the dose-response curve towards a liminal value, which represents the necessary observation period for this effect. Time-response data at constant doses demonstrate the shifting of the time-response curve towards a liminal value, which represents the LOAEL for the dose-response of this effect. A three-dimensional plot of dose- and time-response data depicts the surface area on which c x t is constant along hyperbolas, in terms of wasting as the end point of toxicity. Surviving rats in all groups started developing anemia 126 days after dosing, but no rat died of wasting/hemorrhage after day 74. Rats surviving anemia began to die of lung cancer as of day 397 after dosing. Thus, although the experiment has been completed as far as dose- and time-responses of wasting/hemorrhage are concerned, it will be about another 2 years before complete dose and time responses will become available for anemia and lung cancer.
Rozman
K K
KK
Department of Pharmacology, Toxicology, and Therapeutics, University of Kansas Medical Center, Kansas City 66160, USA. krozman@kumc.edu
D000740:Anemia / Q000139:chemically induced* / Q000401:mortality; D000818:Animals; D001835:Body Weight / Q000187:drug effects; D002273:Carcinogens / Q000633:toxicity*; D004305:Dose-Response Relationship, Drug; D005260:Female; D006470:Hemorrhage / Q000139:chemically induced* / Q000401:mortality; D008175:Lung Neoplasms / Q000139:chemically induced* / Q000401:mortality; D000072317:Polychlorinated Dibenzodioxins / Q000031:analogs & derivatives* / Q000633:toxicity; D051381:Rats; D017207:Rats, Sprague-Dawley; D013997:Time Factors
D002273:Carcinogens; D000072317:Polychlorinated Dibenzodioxins; C046839:1,2,3,4,6,7,8-heptachlorodibenzodioxin