What is a best estimate for KMD in humans? Based on this estimate, is there any evidence that certain individuals (e.g., with occupational or proximity) exposure?

Again concur with user # 850922 [Expert 10] . This question is almost the same as Q.1 and the later part is difficult to answer.

The comment from user-292467 [Expert 12] has a lot of good information in it, but the notion that 10 ppm is a lower bound on the 30 ppm has NOTHING to inform it with respect to humans-- all the "should be sufficient" conclusion comes from data (such as it is) on rodents. I also don't fully understand how at the same time this user can claim that (1) exposures below the KMD (whatever that value is) are OK because detoxification proceeds faster than damage; AND (2) intermittent exposures above the KMD are OK because GSH can "recuperate." It would seem to me that "recuperation" only happens after depletion, which is exactly why I (and others?) have concern about intermittent high doses.

Yes, based on my previous comments you may have two choices: 1. used the lowest 10 ppm to cover some uncertainty and variability effect, or 2. used 30 ppm but adjust the interspecies and/or inter individual scaling factors for differences in the unbound fraction in plasma (amount of active form) and differences in the amount of Gluthatione. However, as said the current MOE are already large (safe). No additional correction is probably not needed for the current human exposure.

intermittent exposures above the KMD are OK because GSH can "recuperate...Yes after depletion (but it depends of the dosing interval; we still not know since no intermittent dosing scenario has been made), the GSH may recuperate for a higher elimination effect of the compound. This may be on the safe side and hence a higher KMD could be considered. However, this is only be true when the metabolite is not toxic....if the metabolite is also toxic this should be of concern since more metabolite could be produced if the Glutathione is less saturated ; this should be considered with scaling factor to correct the dosing scenario. Information in that domain are missing. From my side the current scaling factors used in their risk assessment are not conservative enough. Overall, using more robust scaling factors may stop our discussions on the uncertainty for the extrapolation to human.

the current available data does not allow make any estimation of a human KMD value.

I don't disagree with user-292467 [Expert 12] 's point that given what we know about current human exposures, the MOEs are "large" and it is therefore not that important to actually consider what the human TK are and the inter-individual variability therein. However, I have seen too many cases where an advocate uses this "logic": (1) chemical X might be a human *risk* if exposures were not currently very low; (2) therefore, chemical X is not a human carcinogen.

There's nothing wrong with combining hazard classification and risk assessment, but it has to be understood that "no significant risk" is a function of exposure, and cannot *by itself* determine the hazard classification. This becomes very worrisome in cases where exposures change and are no longer small relative to the level of concern.

Yes and for pesticide assessments EPA controls for this possibility by specifying the amounts of the pesticide to be used under each type of application and user group that may be exposed, including personal protective equipment requirements, field entry delays, etc. so that the exposure levels don’t change. Pesticides. Must be used as specified on the label. Not doing so is a violation of Fededral law and it is taken very seriously

User-125195 [Expert 4] : I agree with you that labelilng requirements are "serious"-- but all I'm saying is that, as a logical matter, if the current "very small" exposures are *illogically* used to conclude that the pesticide is not carcinogenic AT ALL (a classification matter), THEN it is possible that the EPA requirements could change-- after all, why not allow more exposure for a "non-carcinogenic" substance. The hazard classification and the risk assessment are two separate exercises and must not be conflated.

The question is if we can estimate a human KMD. I don't understand why MOE are brought up in this discussion. Are we assessing risk or are we determining a kinetically derived value ?

We are determining a KMD, but the MOE depends of the KMD. Thus, either we decrease or increase the KMD (e.g., 10 or 100 ppm); this will have not real impact since the MOE will still be high then safe. In other words, the human exposure is very low compared to any KMD we may derive from the white paper. .
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