Lack of Chemoprevention Effects of the Monoterpene d-Limonene in a Rat Multi-organ Carcinogenesis Model

Modifying effects of dietary administration of the monoterpene d -limonene were examined using a multi-organ carcinogenesis model. Groups of twenty F344 male rats were treated sequentially with N -diethylnitrosamine (DEN, i.p.), N -methyl- N -nitrosourea (MNU, i.p.), 1,2-dimethylhydrazine (DMH, s.c.), N -butyl- N -(4-hydroxybutyl)nitrosamine (BBN, in drinking water) and dihydroxy-di- N -propylnitrosamine (DHPN, in drinking water) during the first 4 weeks (DMBDD treatment), and then ( d -limonene was administered in the diet, at the dose of 2.0, 1.0 or 0.5%. The maximal tolerable dose was 2.0% under the present conditions. Further groups were treated with DMBDD or 2.0% d -limonene alone as controls. All surviving animals were killed at week 28, and major organs were examined histopathologically for development of preneoplastic and neoplastic lesions. The incidences and/or multiplicities of renal atypical tubules and adenomas were increased in animals fed 2.0% d -limonene. The immunohistochemical reactivity for α_2u-globulin in the proximal tubules was greater in rats fed d -limonene than in the carcinogen alone group. No enhancing or inhibitory effect was noted for tumor development in other organs. The present results indicate a lack of any chemopreventive effect of ( d -limonene in any organ of male rats under the present experimental conditions.