PROMOTION OF N-NITROSODIETHYLAMINE-INITIATED HEPATOCELLULAR TUMORS AND HEPATOBLASTOMAS BY 2,3,7,8-TETRACHLORODIBENZO-P-DIOXIN OR AROCLOR-1254 IN C57BL 6, DBA/2, AND B6D2F1 MICE/

To investigate the hypothesis that tumor promotion by chlorinated arom atic hydrocarbons involves Ah receptor occupation and subsequent induc tion of cytochromes P-450 1a-1, effects of Aroclor 1254 or 2,3,7,8-tet rachlorodibenzo-p-dioxin (TCDD) were examined in N-nitrosodiethylamine -initiated mice with different Ah receptor phenotype. Levels of cytoch romes P-450 1a and 2b were measured by enzyme assay and Western immuno blots. Males of the C57BL/6, DBA/2, or (C57BL/6 x DBA/2)F-1 (hereafter referred to as ''B6D2F1'') strain were initiated with a single i.p. d ose of N-nitrosodiethylamine (90 mg/kg body weight), followed by eithe r multiple doses of TCDD (0.05 mu g/kg) weekly or Aroclor 1254 chronic ally in the diet (100 ppm) for 20 weeks, and then no treatment for 24 weeks. Lung tumor incidence or multiplicity was not altered by either of the promoters. Liver tumor incidence was similar among the three st rains after N-nitrosodiethylamine alone (14, 21, and 21%, respectively ). In DBA/2 mice, TCDD neither induced Cyp 1a nor promoted liver tumor s. Aroclor caused an 8-fold induction of hepatic Cyp 2b, which was its maximum at the 12-week time point but did not promote tumors. Inducti ons of hepatic Cyp 1a by TCDD and la and 2b by Aroclor were similar in C57BL/6 and B6D2F1 mice, but tumor promotion responses were quite dif ferent. Dietary Aroclor significantly promoted Liver tumors in C57BL/6 mice (59 versus 14%) but not in B6D2F1 mice (24 versus 21%). Repeated TCDD promoted only in B6D2F1 mice (52 versus 21%) and not in C57BL/6 mice (19 versus 14%). Thus, whereas these data confirm that a function al Ah receptor is required for Liver tumor promotion, the degree of ac tivation as measured by induction of Cyp 1a is not directly related to the degree of tumor-promoting capability, Other genetic factors must play a role in mediating the final tumor outcome.