Answer Explanations 5
As stated in the White paper, 1,3-D inhalation and oral toxicokinetics is similar. Rodent liver tumors are a common finding in chronic oral studies with a wide range of agrochemicals. The lung tumors are at a port of entry. Port of entry effects are relevant to risk assessment. However, mice of different strains vary markedly in their sensitivity to develop pulmonary tumors, and in this case, B6 male mice are highly prone to the development of these tumors given its genetic susceptibility. Dose - The weight of evidence does not support a low dose linear cancer risk. Exposures exceeding non-linearity TK may result in toxicities which are not relevant to actual human exposures. The issue of dose is further addressed in my response to 5.11.
See explanation in 4.4.
However, the hazard characterization would be strengthened by a statement relative to the level of current human exposures.
A useful classification includes a narrative specifying the conditions of exposure or scenarios under which the material is likely (or not likely) to be carcinogenic in humans. For both oral and inhalation exposure, it appears that cancer is induced at high levels of exposure unlikely to be encountered by humans except in rare, and episodic, instances. Again, in the absence of an established MOA, the potentially carcinogenic scenarios can't really be described. It may be that the lung tumors observed in the mouse inhalation study are portal of entry effects. Discussion of lung toxicity and genotoxicity (lack thereof) would enter into a systematic MOA evaluation.
Some responses of concern were evidenced by both diet and inhalation routes, and while many of the tumor-incidence increases in the mid-dose groups were not elevated to p=.05 levels, the lack of power to detect small effects should not be used to change the hazard classification (though I believe it could be used to relax the assumption of linearity of risk).