LACK OF CHEMOPREVENTION EFFECTS OF THE MONOTERPENE D-LIMONENE IN A RAT MULTIORGAN CARCINOGENESIS MODEL

Modifying effects of dietary administration of the monoterpene d-limon ene were examined using a multi-organ carcinogenesis model. Groups of twenty F344 male rats were treated sequentially with N-diethylnitrosam ine (DEN, i.p.), N-methyl-N-nitrosourea (MNU, i.p.), 1,2-dimethylhydra zine (DMH, s.c.), N-butyl-N-(4-hydroxybutyl)nitrosamine (BBN, in drink ing water) and dihydroxy-di-N-propylnitrosamine (DHPN, in drinking wat er) during the first 4 weeks (DMBDD treatment), and then d-limonene wa s administered in the diet, at the dose of 2.0, 1.0 or 0.5%. The maxim al tolerable dose was 2.0% under the present conditions. Further group s were treated with DMBDD or 2.0% d-limonene alone as controls. All su rviving animals were killed at week 28, and major organs were examined histopathologically for development of preneoplastic and neoplastic l esions. The incidences and/or multiplicities of renal atypical tubules and adenomas were increased in animals fed 2.0% d-limonene. The immun ohistochemical reactivity for alpha(2a)-globulin in the proximal tubul es was greater in rats fed d-limonene than in the carcinogen alone gro up. No enhancing or inhibitory effect was noted for tumor development in other organs. The present results indicate a lack of any chemopreve ntive effect of d-limonene in any organ of male rats under the present experimental conditions.