Any scientific study may be criticized based on the design, methods, interpretation of results, etc. As long as we accept this reality, I don't agree that all the bioasays are "subject to controversy". This is certainly true of some of the studies such as those that tested the product containing the carcinogen/mutagen contaminant. However, some studies appear to have been well designed and conducted. Therefore, the results are not controversial. I do not agree with the need for additional studies to answer this question.
There are two oral studies with the currently available formulation both using rats and mice. The only tumor response in these studies was in male rats in one study applying doses that induced a 19 % reduction in bw gain. The study used application with diet that resulted in much lower Cmax as compared to a negative gavage study with identical daily doses. Lung tumor incidences were not changed in the oral studies supporting a portal of entry effect as outlined in the white paper. The inhalation studies showed an increased incidence of lung adenomas in mice as the only tumor response with a high incidence of this tumor type present in controls. Highly variable incidences of lung tumors in control mice are evident from the Dow database and from a number of other sources. Increased adenoma incidences in mice have been seen after inhalation of a number of other chemicals (e.g styrene, naphthalene, and trichloroethene) and mode of action studies with these chemicals suggest a high susceptibility of the target cells in the lung of mice to chemical-induced toxicity and GSH depletion. This toxicity and resulting hyperplasia were identified as key steps in lung tumor induction by these compounds. Moreover, there are anatomical differences between mice and rats/humans with respect to the target cells as elucidated for styrene and other chemicals supporting the conclusion that any tumor tumor response induced by thes MoA is not relevant to humans. The observed GSH depletion in mice after inhalation of 1,3-D may not be sufficient to induce toxicity and hyperplasia ? In my opinion, the arguments regarding variability of control incidence and absence of lung toxicity of 1,3-D in the studies, which is key for lung tumor induction in mice by several non-genotoxic chemicals, are supporting the conclusion that the lung tumors are not treatment related. I am not convinced that the argument regarding non-linear kinetics can be used to conclude that the tumors seen are present at doses above a KMD have no relevance based on kinetic analysis. Blood kinetics show non-linearity for parent material, but the blood kinetics may not reflect exposure of the target tissue lung. These are expected to be driven by air concentrations of 1,3-D and should thus be linear. The non-linearity of blood levels of 1,3-D after inhalation would only be relevant if systemic toxicity is to be considered. Any new study, even with higher sample sizes, will still have the issue of variable background of lung tumors in mice and difficulties in data interpretation.
I do not think that another study with 1,3-D by inhalation route is necessary. Results of the available studies are clear to me. The new formulation of 1,3-D is not genotoxic. In a review by Zeiger, 2005, it has been concluded that “the results in the studies that had an appropriate study design and used 1,3-D that did not contain epichlorohydrin should be used. These studies were uniformly negative.” and “1,3-D is not an in vivo genotoxicant”. Moreover, two inhalation carcinogenesis studies were conducted ( Stott, 1987, in mice, and Lomax 1987 in rats). In the mouse inhalation study, a statistically identified increase in benign lung tumors (bronchioloalveolar adenomas) was observed in male mice only exposed to high-concentration (60 ppm )of 1,3-D (22/50 vs. 9/50 in controls). In the rat inhalation study, there were no statistically identified increases in any tumor incidence in rats exposed by inhalation to 1,3-D. All microscopic tumor observations were considered by pathologists to be incidental and/or age-related changes. In addition, no treatment-related lung tumors were identified in the 4 oral carcinogenicity studies, 1,3-D inhalation-induced lung tumors appears to be a portal-of-entry effect. Moreover, toxicokinetic studies indicate that oral and inhalation administration of 1,3-D in rodents and humans are similar in terms of uptake, detoxification and formations of major metabolites. Following rapid uptake, 1,3-D is primarily metabolized and detoxified by conjugation with GSH to form mercapturic acid metabolites. Therefore, the available studies in mice and rats indicate that 1,3D new formulation (without epichlorohydrin) is not carcinogenic by inhalation route, and no new studies are necessary.