I fully agree with the White paper interpretation of the inhalation chronic bioassays by Stott 1987 (in mice) and Lomax 1987 (in rats). Of the two carcinogenicity studies conducted via inhalation exposure, increased lung tumors were observed in male B6C3F1 mice only, and in the highest dose animals. Two sets of historical control data by EPA indicate that male B6C3F1 mice are uniquely predisposed to developing lung tumors at a high rate. In addition, I agree that 1,3-D inhalation-induced lung tumors appears to be a local (portal-of-entry) effect, as no treatment-related lung tumors were identified in the 4 oral carcinogenicity studies (therefore it is not a lung specific carcinogen). Moreover, further examinations of lung effects in the second inhalation study in F344 rats were conducted to fully evaluate 1,3-D’s lung toxicity via the inhalation route. 1,3-D neither induced lung tumor formation, nor caused any preneoplastic lung effects in rats, as indicated by no effects on clinical chemistry or histopathology at the tumorigenic concentration in mice. The increased lung tumors (bronchioloalveolar adenoma) were characterized as benign, and restricted to high-concentration, and in male mice only. Male mice are usually more prone to the development of neoplasia in carcinogenesis models when compared to female mice. This response (development of lung adenomas in male mice only, and in highest dose) should not be considered relevant for human health risk assessment. No lung tumors were observed with the same inhalation doses in rats.
In general, I agree with the White paper interpretation of the Stott, 1987 study. While the lung tumor incidence in high-dose male mice was significantly higher than that of concurrent controls, the incidence was only a little higher than that seen in historical control data from Dow and NTP studies (44% vs. 36%). We cannot rule out the possibility that this increase was treatment-related, but we must also consider the fact that the 60 ppm exposure concentration caused a higher than proportional plasma exposure due to saturation of clearance mechanisms (depletion of glutathione). This observation does not mean that the increased tumor incidence was not real for B6C3F1 mice, but that extrapolation of this result to humans is very problematic. In contrast to the Stott, 1987 study, the Lomax, 1987 study showed no evidence of an increase in any tumor type in the rat. The observation of reduced weight gain (5%) and local changes in respiratory tissues (portal of entry, local effects) suggest that the exposures were adequate. It would have been nice to have TK data for the rats similar to the data presented for the mice but the absence of such data should not disqualify the rat study from consideration as a valid, negative bioassay.
As said above, not treatment related weak response in one sex and one species. Absence of human relevance of the mouse lung tumors in combination with gentox and TK arguments permit to conclude on non-relevance for human risk assessment. Outcome of several studies are somewhat puzzling when trying to put them into context