Answer Explanations 4

4 - high confidence
Expert 12
It is clear that there is a dose-non linearity after about 20 ppm. However, studying also a lower specific dose of 15 ppm and higher dose of 30 ppm would help to define the curve better, i.e., the real starting dose where the non-linearity really becomes relevant. This is because in the Figure 5, we may observe that the non-linearity may be observed relatively below 20 ppm (i.e., between 10 and 20 ppm instead). Based on this Figure 5 we may get the impression that at about 15 ppm the non-linearity appeared by contrast to about 20 ppm, which is a dose 1.3-fold lower. This could become statistically relevant. Overall, it is clear that there is a dose non-linearity in the blood kinetics whether this appeared at 10, 15 or 20 ppm.
3 - equivocal
Expert 10
Metabolic saturation (chemcial free concentrations well above the Km) and Gluthatione depletion (cofactor depletion) are two different mechanisms leading to the same results (lower metabolic rates). With the given information, I cannot exclude one or the other, but pre treatment to DEM highly impacts kinetics at 300 ppm exposure (Yang 1989). Hence, I would tend to think that a cofactor depletion explanation does not fully explain the non-linearity.
4 - high confidence
Expert 5
same as above
4 - high confidence
Expert 13
With the lower dose range expanded, it is clear to see that supra-linear increases in 1,3-D concentrations are evident even at exposures of 20 ppm but certainly above 20 ppm inhaled exposure. This nonlinearity is quite consistent with the depletion of glutathione between 10-30 ppm reported (Lung GSH levels following repeated 6hr exposures to B6C3F1 mice). In addition to 1,3-D AUC and blood level data, additional 2 pieces of evidence support metabolic clearance changes of 1,3-D beyond 30 ppm.
2 votes 2 0 votes
Expert 12
04/17/2019 11:12

No more comment from my side since everybody agree about the possibility of the non-linearity above 20 ppm. However, 3 reviewers also suggested that non-linearity could be as low as 20 ppm or slightly lower to 20 ppm. Overall, all discussions suggested a non-linearity close to 20 ppm. The effect of DEM is an indication that the metabolic rate becomes lower (even if there is a depletion effect).

2 votes 2 0 votes
Expert 3
04/20/2019 15:21

The question suggests metabolic saturation above 20 ppm. Several colleagues suggest that the data support a level (slightly) below 20 ppm for the start of the non-linearity. I think that is a more accurate interpretation of the available data

0
Expert 10
04/23/2019 10:22

There is definitely a non-linear phenomenon occurring . This is clearly the results of a diminishing clearance at exposure levels above 10 ppm (first measured occurence at 20 ppm). It remains to be determined if GSH depletion is the sole explanation, or a enzymatic saturation.

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