NOTE to SciPi - My only change is to clean up the comment I made on this question: 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 Federal law and it is taken very seriously
As a said in the item 7.1, I do believe that a lower KMD of 10 ppm would cover the effect of both isomers before the saturation and would be more conservative since the mouse-to-human extrapolation still lack some uncertainty factors. Hence, a lower bound equal to 10 ppm should cover better the remaining uncertainty and variability effect. For example, as I said in the item 7.1, if the plasma protein and lipid binding is greater in the animal model of toxicity (mice) than in humans, the available free and active compound concentration in plasma would become higher in humans compared to the animal model; consequently, the human would be at a greater risk of toxicity compared to the animal model at the same dose in mg/kg. Accordingly, the KMD would need to be corrected with a plasma protein binding factor. Since the information on the binding of the pesticide to the lipids and proteins in plasma/blood is not available, we need to consider a lower KMD for more precaution. However, as mentioned in the item 7,1, the current MOEs are very large using a KMD of 30 ppm, which means that the human exposure is safe. Changing the KMD from 10 to 30 ppm would probably not change the conclusion of the present study. Furthermore, the general human population and workers would probably not be exposed on a repetitive daily basis but rather on intermittent dosing (exposure) basis. Intermittent dosing (exposure) may let the time to the Glutathione to recuperate at depletion (i.e., to be reformed in vivo due to less binding between the Glutathione and the compound as function of time) compared to a repetitive and constant dosing scenario in mice; consequently, a higher metabolic clearance of the pesticide would occur during intermittent dosing for a lower accumulation ratio in the body. Thus, in the real life situation with intermittent dosing, we may see a lower KMD value. Furthermore, under a potentially higher elimination of the pesticide due to the GSH recuperation at depletion during intermittent dosing versus repetitive dosing could produce more metabolite(s) that are potentially more toxic than the parent compound. Again, a conservative KMD or additional uncertainty factors are needed; the potentially lower KMD of 10 ppm determined following repetitive exposures in mice would then be more conservative for the general human population and workers. Overall, a KMD of 10 ppm should be used in the absence of more robust uncertainty factors in the calculation of the MOE from the KMD value.
How does the first part of the question differ from question 7.1? If indeed GSH depletion is the mechanism, then I would need a model to simulate the rate of GSH depletion in function of 1,3-D exposure and as well as the GSH replenishment using human parameters. I cannot give a sound estimation simply by looking at rodent data. If enzyme saturation is the mechanism then information on Km for GST and 1,3-D blood levels vs exposure levels would be crucial. The currently available data does not allow make any quantitative estimation of a human KMD value.
The current available data wouldn't permit determination of human KMD and there is no clarity with regards to appropriate scaling factors for a reasonable extrapolation. I agree that the current MOE are already large and therefore no further correction is needed for the human exposure.