Wide-spectrum initiation models: possible applications to medium-term multiple organ bioassays for carcinogenesis modifiers.

Two wide-spectrum initiation models were investigated in F344 male rats. Model I: After sequential treatment with diethylnitrosamine (DEN), N-methylnitrosourea (MNU) and dihydroxy-di-N-propylnitrosamine (DHPN), animals were given phenobarbital (PB) or N,N-dibutylnitrosamine (DBN) as a test compound for 14 weeks and sacrificed at week 18. Model II: Animals were treated with DHPN, followed by N-ethyl-N-hydroxyethylnitrosamine (EHEN), and then 3,2'-dimethyl-4-aminobiphenyl (DMAB) as initiators and were subsequently given 3-methylcholanthrene (MCA) or PB as a test compound for 11 weeks. Animals were sacrificed 16 weeks after the commencement. In both models, assessment of lesion yield revealed significant enhancement of carcinogenesis by the test compounds in their respective target organs. Since, in many cases, treatment with PB, DBN and MCA subsequent to the combined initiation procedures brought about a marked increase in lesion development, far greater than a simple sum of the yields given by initiators and test compounds alone, the presently described approach appears promising for development of medium-term bioassay systems for detection of environmental carcinogens.