Yp. Dragan et D. Schrenk, Animal studies addressing the carcinogenicity of TCDD (or related compounds) with an emphasis on tumour promotion, FOOD ADDIT, 17(4), 2000, pp. 289-302
Dioxin and certain structurally related compounds increase the incidence of
liver neoplasms in rodents upon chronic bioassay,. Short-term studies indi
cate the lack of direct DNA-damaging effects including covalent binding To
DNA; however, secondary, mechanisms may be important in the observed carcin
ogenicity as these chemicals affect a number of pathways necessary for main
tenance of normal growth control and differentiation status. Studies with T
CDD in the mouse skin support a lack of initiating activity but an ability
to promote the growth of previously initiated lesions indicative of a promo
ting agent. Mouse skin tumour promotion studies indicate that Ah receptor a
ctivation may be involved in promotion by TCDD and selected structurally re
lated compounds. While the mechanism of carcinogenicity induced by TCDD is
unknown, the processes involved have a no-effect level, which in the rat li
ver is at an exposure level below 10 ng TCDD/kg/ day. At least for the rode
nt liver, the relative effective dose for cytochrome P450 induction is not
a good indicator of promotion potency. Studies on liver tumour promotion in
the female rat liver support a nongenotoxic mechanism for the induction of
neoplasms by TCDD. The ability of TCDD to enhance proliferation and inhibi
t apoptotic processes in focal hepatic lesions further supports an indirect
mechanism of carcinogenicity.