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.
Expert 12
04/17/2019 11:12No 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).
Expert 3
04/20/2019 15:21The 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
Expert 10
04/23/2019 10:22There 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.