Do new hypotheses on the mechanism of action of dioxins help in risk evaluation?
The mechanism of action of chlorinated dibenzodioxins such as 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) is not known, but the prevailing hypothesis is the binding to a specific protein, the Ah-receptor, and subsequent alteration of the expression of specific genes. This Ah-receptor hypothesis does not explain all aspects of toxicity, notably the extreme variation of toxicity between different animal species. We have found two rat strains that differ widely in their sensitivity to TCDD. The resistant Han/Wistar (H/W) rat tolerates doses up to 3000 micrograms kg-1, while 20 micrograms kg-1 is lethal to Long-Evans (L-E) rats. Several morphological, biochemical and endocrinological parameters as well as pharmacokinetics have been screened, but the strains behave by and large similarly. However, there is a clear behavioural difference: TCDD causes anorexia in both strains, but H/W rats start eating again in 1-2 weeks, whereas the reduction of feed intake is permanent in L-E rats until they die in about 3 weeks. Han/Wistar rats, which recover after a single large dose of TCDD, behave aberrantly for months; they seem to have a supersensitive satiety response while they do not respond normally to energy deficiency. Therefore the regulation of feed intake or of body weight seem to be altered permanently by TCDD. It is also of interest that TCDD is more toxic after a central than after a peripheral administration. These findings may be of importance for the risk evaluation of dioxins, because they might help to explain the wide species/strain variation which complicates the assessment of dioxin risk to humans.
Tuomisto
J
J
Department of Environmental Hygiene and Toxicology, National Public Health Institute, Kuopio, Finland.
Pohjanvirta
R
R
D000818:Animals; D000855:Anorexia / Q000503:physiopathology; D001835:Body Weight / Q000187:drug effects; D002149:Energy Intake; D000072317:Polychlorinated Dibenzodioxins / Q000633:toxicity*; D051381:Rats; D011919:Rats, Inbred Strains; D012307:Risk Factors; D013045:Species Specificity
D000072317:Polychlorinated Dibenzodioxins