ENHANCEMENT OF THYROID AND HEPATOCARCINOGENESIS BY 1,4-BIS[2-(3,5-DICHLOROPYRIDYLOXY)]BENZENE IN RATS AT DOSES THAT CAUSE MAXIMAL INDUCTIONOF CYP2B

To investigate the promoting effects of 1,4-bis[2-(3,5-dichlorspyridyl oxy)]benzene (TCPOBOP) on liver and thyroid carcinogenesis of rats at doses that cause maximal induction of hepatic CYP2B, 5-week-old male F 344 rats were given either a single i.p. dose of 75 mg N-nitrosodiethy lamine (NDEA)/kg body wt in saline or saline alone. After 2 weeks the rats were fed control diet or a diet containing 330 or 1000 p.p.m. TCP OBOP or 500 p.p.m. phenobarbital (PB; a positive control group). A tot al of four sequential sacrifices (9, 30, 52 and 79 weeks of age) was p erformed. At 30 weeks the mean volume (mm(3)) of hepatocellular foci i n NDEA-initiated rats exposed to either dose of TCPOBOP or to PB was s ignificantly increased as compared with rats exposed to NDEA followed by control diet (P < 0.05). In addition, the volume percentage of live r occupied by foci was significantly greater in NDEA-initiated/1000 p. p.m. TCPOBOP-promoted rats as compared with rats exposed to NDEA alone (P < 0.05, n = 6). At 52 weeks of age the incidences (and multiplicit ies, in units of tumors per tumor-bearing rat) of hepatocellular adeno mas were 0, 83 (2.6 +/- 1.3), 100 (3.4 +/- 2.1) or 67% (2.5 +/- 1.9) i n rats exposed to NDEA alone or NDEA followed by 330 or 1000 p.p.m. TC POBOP or 500 p.p.m. PB respectively (n = 12). Hepatocellular carcinoma s were found only in rats given 1000 p.p.m. TCPOBOP (17% incidence) or PB (8% incidence) following NDEA initiation. The incidences of thyroi d follicular cell adenomas were 0, 17, 33 or 8% in rats exposed to NDE A alone or NDEA followed by 330 or 1000 p.p.m. TCPOBOP or 500 p.p.m. P B respectively. Between 53 and 79 weeks of age 38% of rats treated wit h NDEA alone developed multiple (1.5 +/- 0.8) hepatocellular adenomas. This incidence was enhanced to 100% in rats exposed to NDEA followed by either 330 or 1000 p.p.m. TCPOBOP. Multiplicities of hepatocellular adenomas were also increased significantly (10.5 +/- 3.9, 10.4 +/- 7. 0 and 10.1 +/- 6.7 respectively) in rats promoted with 330 or 1000 p.p .m. TCPOBOP or 500 p.p.m. PB. None of the rats exposed to NDEA alone d eveloped hepatocellular carcinomas, while multiple hepatocellular carc inomas occurred in 38% of the rats exposed to 330 p.p.m. and 78% of th e rats given 1000 p.p.m. TCPOBOP following NDEA initiation. Thyroid fo llicular cell tumors occurred at 79 weeks in more than 40 and 50% inci dences in rats exposed to NDEA followed by 330 or 1000 p.p.m. TCPOBOP respectively. Also, a significant decrease in serum levels of triiodot hyronine and thyroxine were observed in non-initiated 79-week-old rats fed 1000 p.p.m. TCPOBOP, compared with age-matched untreated controls (n = 6). Increases in hepatic CYP2B-mediated benzyloxy-resorufin O-de alkylase activity detected in rats exposed to 330 and 1000 p.p.m. TCPO BOP for 2 or 23 weeks were similar in magnitude to those caused by 500 p.p.m. PB. Thus TCPOBOP at maximal CYP2B induction doses exhibits a s trong promoting activity for both liver and thyroid of rats.