Tumorigenic effects in Wistar rats orally administeredbenzoa pyrene for two years (gavage studies). Implications for human cancer risks associated with oral exposure topolycyclic aromatic hydrocarbons

摘要

Humans are exposed via the environment and via food to PolycyclicAromatic Hydrocarbons (PAH), mixtures considered carcinogenic by IARC. Aquantitative cancer risk assessment for oral exposure is hampered by theabsence of adequate data. The need for experimental data issubstantiated by the fact that daily oral doses exceed inhaled doses forsome potent carcinogenic PAH compounds, e.g. benzo[a]pyrene (B[a]P), byone order of magnitude, and the fact that epidemiological studies are notexpected to provide useful data in this respect. For this reason we haveperformed a carcinogenicity study in rats; treatment (by gavage) for 2years with the reference PAH B[a]P resulted in tumour-formation in a widespectrum of organs and tissues, with liver and forestomach as majortarget-organs. Liver tumours in female rats were used for estimating aVirtually Safe Dose (VSD), i.e. the daily dose representing a one permillion risk upon lifetime exposure, via methodology adopted by the DutchHealth Council (HCN, 1994-1996). Based on available data on occurrenceand carcinogenic potency of PAH in Dutch diet it is suggested to apply acorrection-factor of 10 for conversion to a VSD for B[a]P as indicatorfor all dietary PAH. With the resulting VSD of 0.5 ng B[a]P/kgbodyweight per day, cancer risks associated with PAH encountered in Dutchdiet are estimated to be around acceptable risk levels. Parallel ratstudies indicated that B[a]P-induced DNA adducts per se are notsufficient for tumour-development; induced local cell proliferationseems an additional critical factor. The possible implications of thesefindings are discussed.