Toxicological Sciences, Vol 49, 102-109, Copyright © 1999 by Society of Toxicology
KK Rozman
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.
ARTICLES
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
Department of Pharmacology, Toxicology, and Therapeutics, University of Kansas Medical Center, Kansas City 66160, USA. krozman@kumc.edu
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