Establishment of Multi-Organ Carcinogenesis Bioassay Using Rats Treated With A Combination of Five Different Carcinogens.

Abstract

Two initiation protocols for multi-organ carcinogenesis bioassays for detection of modifying effects of chemicals were investigated and compared in F344 male rats. Animals in group 1 were treated sequentially with N-diethylnitrosamine (DEN, i.p.), N-methyl-N-nitrosourea (MNU, i.p.), N-butyl-N-(4-hydroxybutyl) nitrosamine (BBN, drinking water), MNU (i.g.), and dihydroxy-di-N-propyl-nitrosamine (DHPN, drinking water) during the first 4 weeks (DMBMD treatment). Rats in group 2 were treated in the same manner as group 1 except that N, N'-dimethylhydrazine (DMH, s.c.) was administered instead of MNU (i.g.) (DMBDD treatment). Surviving animals were killed at 20 and 28 weeks after the commencement, seven rats in group 1 and one rat in group 2 being found dead during the experiment. Immunohistochemical examination revealed quantitative values for glutathione S-transfer-ase placental form positive liver foci to be significantly higher in group 2 than in group 1, especially at the week 28 time point. In the case of pepsinogen 1 altered pyloric gland (PAPG) induction in the glandular stomach, quantitative values for group 1 were higher than for group 2. Complete histopathological assessment of hyperplastic and neoplastic lesion yields revealed relatively high incidences in the lung, gastrointestinal tract, kidney, urinary bladder, thyroid, and other organs in both groups at week 28. We conclude that the present DMBDD protocol is superior for introduction in multi-organ carcinogenesis bioassays because of its wide spectrum initiation. The present results suggest the probability of detecting not only carcinogens and tumor promoters but also tumor inhibitors within a relative short period.