Enhancing potential of 6 different carcinogens on multi-organ tumorigenesis after initial treatment with N-methyl-N-nitrosourea in rats

Abstract

The advantages of applying a whole-body concept to the assessment of carcinogenic potential of compounds in a two-stage model after initiation by N-methyl-N-nitrosourea (MNU) were investigated. Male, 6-week-old F344 rats were injected with MNU (20 mg/kg, i.p.) twice a week for 4 weeks and they then received 3,2'-dimethyl-4-aminobiphenyl (DMAB) (50 mg/kg, s.c., once a week), N,N'-dibutylnitrosamine (DBN) (0.05%, in drinking water), N-bis(2-hydroxypropyl)nitrosamine (DHPN) (0.1%, in drinking water), diethylstilbestrol (DES) (2.5 ppm, in diet), sodium o-phenylphenate (S.OPP) (2%, in diet) or captafol (0.15%, in diet) for 20 weeks. All six carcinogens enhanced the incidences of preneoplastic and neoplastic lesions in their respective target organs: liver, pancreas, small intestine and urinary bladder with DMAB; liver, esophagus, forestomach and urinary bladder with DBN; thyroid, lung, liver, esophagus, forestomach, small intestine and urinary bladder with DHPN; liver and forestomach with DES; and thyroid, forestomach, kidney and urinary bladder with S.OPP; liver and forestomach with captafol. The results suggested that prior treatment with MNU sensitized the tissues to the organotropic carcinogenic potential of chemicals given thereafter for as short a period as 20 weeks. Thus, this system could be utilized as a whole-body medium-term bioassay system for the screening of environmental carcinogens, bridging the gap between in vitro mutagenicity and long-term carcinogenicity tests.