Effect of exposure route on potency of carcinogens

To compare the effectiveness of different exposure routes for the induction of cancer in experimental animals, the estimated dose associated with a 25% additional risk of cancer (RRD(25)) was calculated using a group of carcinogenic agents for which both inhalation and oral ingestion cancer bioassays were available. Comparisons were made of 14 agents in rats and 9 in mice. Seven of the nine compared in mice were also compared in rats. Among rats, 8 of 14 agents were more effective via the oral route, while 7 of 9 were more effective via the oral route in mice. The variation in RRD(25) values with route, however, was less than 10-fold for all the agents tested in mice and for 11 of 14 tested in rats. An overall difference in potency with route could not be detected statistically. In rats, differences in potency greater than 10-fold were found for asbestos, vinyl chloride, and hydrazine. In the case of asbestos, the agent was in the form of relatively insoluble particulate matter. The greater potency via inhalation is likely due to longer residence time of the particles in the deep lung than in the gut, allowing for a greater degree of particle dissolution with an accompanying increase in bioavailability. Vinyl chloride was generally tested by inhalation at doses high enough to saturate activation pathways, resulting in underestimates of low-dose potency. Many of the smaller potency differences with route, as well as those for hydrazine, were considered likely to be the result of variability in the design and/or quality of studies. It was concluded that, if the design and conduct of the experiments were adequate, if agents in the form of relatively insoluble particulate matter are eliminated, and if corrections are made to account for incomplete activation, then large errors during route extrapolation are unlikely to occur.