I think that the results obtained in F344 rat study (incidences of hepatocellular adenomas), with 1,3D by dietary route, are inconsistent, since the numbers of hepatocellular adenomas are within the HCD. There is a difference in rat strain susceptibility (F344 x CD), but also different ways of administering the test compound (conducted via different oral treatments - dietary x gavage). Usually, when dietary exposure is compared to gavage exposure, there is a tendence to get more tumors in the gavage exposure.The effects observed here were on the opposite direction. Cmax values were 14-fold higher via oral gavage, consistent with the slower intake pattern via diet. This confirms the inconsistency of results of studies 1 and 2. However, there is also a difference in the commercial preparation of 1,3D given to rats in both studies (Telone II and DD-92) that should be considered. Table 14 shows that purity and composition of 1,3 D in studies 1 and 2 are quite similar. F344 rat diet study with 1,3 D has been performed by Scott, 1995, and used Telone II. Increased incidences of hepatocellular adenoma were observed in both high dose males and females and in mid-dose males. The combined adenoma and carcinoma were evaluated as well. Statistically increased adenoma (9/50 vs. 2/50), and combined adenomas and carcinomas (10/50 vs. 2/50) were identified only in high-dose males. Sprague Dawley Crl:CD rat gavage study with 1,3 D was performed by Kelly 1998, and used DD-92 formulation with 1,3 D. The tumor incidence of rats administered DD-92 for up to 24 months was not statistically increased relative to controls. A variety of palpable tumors occurred with low incidence in both control and treatment groups. All were considered to be spontaneous occurrences, unrelated to administration of DD-92. (DD92 has a concentration of 1160 1,3D/liter) Additional studies were performed by diet and oral gavage routes in rats. Overall, Cmax values were 14-fold higher via oral gavage, consistent with the slower intake pattern via diet. AUC24hr values for either exposure route were comparable at each of the three dose levels. These data indicate that the same dose administration results in a higher chronic systemic exposure to 1,3-D in the rat following oral gavage dosing than by the dietary administration route (which is usually the case for gavage x dietary studies with the same compound). The fact that lower or comparable systemic exposures led to more severe toxicity (tumors vs. nontumors) further supports that the tumorigenicity only observed in rats via dietary exposure is not consistent. Moreover, the Historical Control Data from Dow demonstrates variable background incidences for hepatocellular adenomas in both male and female F344 rats. The liver tumor incidences in mid- dose males and high-dose females are within the relevant historical control ranges. The lack of statistical significance further supports that the incidences of benign adenomas in the mid-dose male and high-dose females were similar to those of controls.
Whereas the Scott, 1995 dietary study in F344 rats showed an increased incidence of hepatocellular adenomas, the Kelly, 1998 gavage study in CD rats showed no tumor increases. This difference may be explained as a strain difference. However, if the liver tumor increase in F344 rats was real, it is surprising that this difference was not apparent in a gavage study in which higher peak plasma levels should have been present. The TK data discussed in the White paper were apparently based on a gavage study after which modeling was used to predict exposures after dietary administration. As expected, the mean Cmax levels were 14-fold higher after gavage dosing whereas the AUCs were comparable for both routes. The limitation here is that we have no real TK data from dietary administration. I would like to have seen real TK data by both routes if this comparison was important for the interpretation of the liver tumor data. Even if the total AUCs by both routes were comparable, the AUC vs. time curves may be very different which may also contribute to the differences in liver tumor results.
I would expect dose-rate to be a major driver for a response due to a rapid depletion of GSH by 1,3-D after gavage in the liver and can not reasonably justify why an identical daily dose resulting in much lower Cmax results in tumors for a material that is rapidly eliminated. GSH resynthesis is rapid. Could check sensitivity of CD vs F344 regarding liver tumor induction, different sensitivity to GSH depletion ? P450 activities ? Is there anything known regarding effects resulting in the decrease in body weight gain in the F344 study from histopath/clin chem ? Are the materials tested identical/ comparable or are there possible differences in the composition of the byproducts that may explain the difference in outcome ?