Answer Explanations 3

8
Expert 5
Other than strand breakage assays, I see no evidence that 1,3-D is genotoxic in vivo. The strand break assays used doses well above the kinetically-derived maximum dose, likely indicating their mechanisms of action were not relevant to human exposure conditions. However, full dose responses were not carried out, so results at exposure-relevant doses are unknown. In a weight of evidence approach, these considerations lead me to conclude with a fairly high degree of confidence the 1,3-D is not genotoxic to humans at realistic exposure conditions. However, additional state-of-the art assays that show negative results would increase my confidence.
7
Expert 14
Clastogenicity and aneugenicity are not fully covered neither in vitro nor in vivo, due to the limitations/shortcomings of the data set available.
7
Expert 1
some calls were made in absence of original data, confidence would be higher with all data available, historical background ranges, etc.
2 votes 2 0 votes
Expert 5
04/20/2019 11:34

I am confident that 1,3-D has genotoxic potential in vitro, but this greatly reduced when glutathione is present (a realistic scenario). Other than strand breakage assays I see no evidence that 1,3-D is genotoxic in vivo. The strand break assays used doses well above the kinetically-derived maximum dose, likely indicating their mechanisms of action were relevant to human exposure conditions. However, full dose responses were not carried out, so results at exposure-relevant doses are unknown. In a weight of evidence approach, these considerations lead me to conclude with a fairly high degree of confidence the 1,3-D is not genotoxic to humans at realistic exposure conditions.

0
Expert 14
04/20/2019 15:00

For hazard identification the “strand break assays” employed appropriate dose-levels for the individual assays and this is what is needed to establish whether a compound is genotoxic or not. The kinetically-derived maximum dose is a different issue in the context. For the strand break assays and more specifically the in vivo comet assay by Sasaki et al., (1998) where marked and statistically significant increases in DNA breakage in the stomach, liver, kidney, blood, lung, brain and bone marrow three hours after treatment, no signs of cytotoxicity or necrosis were observed by histopathological observation in the organs in which DNA damage was observed. This confirms that the dose-levels used were appropriate. Concerning the last sentence of the above comment, the statement that "1,3 -D is not genotoxic to humans" does not appear to me correct. In terms of hazard identification, genotoxicity of 1,3-D (Mainly clastogenicity) cannot be ruled out based on the available data. So, what is needed is to firmly establish if 1,3-D is genotoxic, as also discussed in previous comments by myself. Once this is achieved the risk characterization for humans at realistic exposure conditions can be performed.

1 vote 1 0 votes
Expert 5
04/20/2019 17:23

Important typo correction in the sentence, "The strand break assays used doses well above the kinetically-derived maximum dose, likely indicating their mechanisms of action were relevant to human exposure conditions". Should read, The strand break assays used doses well above the kinetically-derived maximum dose, likely indicating their mechanisms of action were NOT relevant to human exposure conditions.

1 vote 1 0 votes
Expert 5
04/20/2019 17:49

In response to user 617591 [Expert 14] , more data would certainly be helpful and increase confidence. With respect to strand break assays, I don't necessarily think that a lack of cytotoxicity indicates the dose level was appropriate, as the mechanism of action may not reflect the mechanism that occurs at the lower exposures to which humans are more likely exposed. If the mechanism of action is not relevant, then risk characteristics in humans starting with that dose will not be relevant. A smooth increasing dose-response would address this question, but the data are not available. The closest we have is the kinetically-derived maximum dose, and the strand breakage assays were well above this value.

2 votes 2 0 votes
Expert 1
04/21/2019 19:43

To note, the overall confidence level of all of us with the dataset is similar between 6/10 and 8/10. I would assume that the sponsor of this study would want to increase this closer to '10' - and from what I have seen in the debate so far it seems that we all struggle with coming to a more clear answer for the lack of state-of-the-art data for clastogenicity/aneugenicity

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