Expert 6

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.

Expert 9

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.

Expert 11

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 ?
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Expert 6
04/17/2019 19:33

What is the concentration of 1,3 D in Telone II and in DD-92? Are they the same?

1 vote 1 0 votes
Expert 11
04/18/2019 03:15

I agree that information on possible differences in composition of the test material in the two oral rat studies is crucial

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Expert 2
04/18/2019 15:16

I'm not sure where any further discussion of historical controls should go (here or on some other page), but I continue to be somewhat skeptical of Table 16 in the White Paper. As I wrote under topic 5.5 in the prior round, "Table 16 in the white paper represents extreme cherry-picking. The historical control rate for male F344 rats at Dow in the year of the study is 2% (pooled 5/250). The complete control rate in Table 16, for all years, is 4.6% (40/865). Only by picking the highest possible control rate for males (16% in one year) and adding an irrelevant value for females (8%) was the white paper able to inflate the control rate by an amount large enough to make the 18% incidence at 25 MKD seem POSSIBLY not significant."

So comments above to the effect that the liver tumor incidence in mid-dose males (12%) was within historical control rates is not really fair-- and of course that says nothing about the 18% incidence in the high-dose males. If these tumors are to be ignored for biological reasons, so be it, but I don't think it's appropriate to ignore them as "elevated in the experiment but not elevated if you happen to compare them to either of 2 hand-picked prior experiments out of the 17 that we have data for..."

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Expert 11
04/19/2019 01:09

Somewhat agree with user-37600 [Expert 2] , but it is strange that the same dose, but a much lower Cmax causes tumors in one study. Same dose, but much higher Cmax does not do anything in a 2nd study ? Again emphasize that detailed information on the composition of the materials tested could help explain the complex dataset. It is not known what other impurities except epichlorohydrin were/are present and if variable impurities contribute to the inconsistent results.

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Expert 2
04/19/2019 08:52

I agree with 477751 [Expert 11] immediately above-- just flagging that my comment above was about historical controls GENERALLY, and I'm not sure if any of the pages on this site have a discusssion of the way the White Paper (mis?)uses historical control data to suggest that statistically significant increases are not what they seem. I'm happy to move this comment and my prior one to a different page if asked.

0 votes -1 1 vote
Expert 9
04/19/2019 10:21

This comment pertains to the comment by user-37600 [Expert 2] above questioning the use of historical control data as described in the White Paper with reference to Table 16. In my experience , historical control tumor data are often used to aid in the interpretation of tumor data from a specific study. The historical control incidences represent a range of incidences that may occur in a control group by chance alone. If the tumor incidence in a specific study falls within the range of historical control incidences, it is fair to conclude that this tumor incidence may have occurred by chance alone and may not be treatment-related. Application of HCD in this way is fairly standard and is not considered to be "cherry picking". At the same time, application of HCD in this way does not "prove" that a specific tumor incidence was not treatment-related. This is true for the liver adenoma incidences in the Scott, 1995 study. We should also note that whereas Table 16 lists HCD on liver tumors over a 21 year interval (1991-2012), the highest HCD incidence in males (16%) occurred in 1992 and the highest incidence in females (8%) occurred in 1997. Since the Scott study was completed in 1995, the highest HCD incidences occurred within a few years of the completion of the Scott study. The time frame of these HCD data in relation to the Scott study increases their relevance in terms of interpreting the tumor data from the Scott study.

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Expert 2
04/19/2019 18:28

In response to user-750802 [Expert 9] : I agree that historical controls are relevant; my problem is with the non-statistical handwaving inherent in Table 16 and the accompanying narrative. The historical control rate is 4.6%. This number has some uncertainty around it, but the right way to portray the uncertainty is not to choose the single highest experiment out of about 20 different experiments and call that the "upper bound" in order to say that 18% (four times the pooled historical control rate) is "within the range."

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Expert 2
04/20/2019 08:01

(PS: the simplest formula for the uncertainty in the pooled historical control rate of 40/865 (4.6%) gives 95% confidence limits that extend from 3.2% to 6.0%, both very far below 18%. This formula assumes that there is not some systematic effect making the individual experiments non-random, so if in fact the control rate was changing from year to year not by chance, these limits would be too narrow. But the White Paper makes no attempt to posit any factor that would make some control rates relevant to the experiment being analyzed and others not, let alone to posit some model for pooling the rates in some non-uniform way).

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