I'd like to suggest more than one question, but my priority would be this one: "What would you consider to be a reasonable **lower bound** for the KMD in an outbred population of humans, given what we know and what is reasonably foreseeable about both human interindividual variability in GSH kinetics and temporal variability in shorter-term exposures that must be averaged?"
Bearing in mind that EPA's goal is to ensure there is sufficient information to reliably support registration decisions that are protective of human health and the environment, while avoiding the generation and evaluation of data that do not materially influence the scientific certainty of a regulatory decision, to what extent are the toxicokinetics of 1,3-D adequately characterized to conclude: 1) that 1,3-D is rapidly eliminated from the body; 2) that it does not accumulate; 3) that the toxicokinetics of 1,3-D following inhalation exposure is essentially the same as that following oral exposures; 4) that the toxicokinetics of 1,3-D in humans is essentially the same as that in rodents; 5) that GSH based metabolic clearance of 1,3-D seems to be saturated in the 10-30 ppm range 6) that there is sufficient evidence for a kinetically-derived maximum dose for repeated exposures at or below 30 ppm
Please confirm that the Big Blue mutation and 32P DNA adduct mouse inhalation studies (Gollapudi 1997 and Stott 1997) used doses (60 and 150 ppm) that would have exceeded the KMD, and thus the protective mechanism of GSH conjugation. Please confirm there are similar metabolic profiles across routes, species and sexes, and thus, it can be reasonably concluded that the negative findings from the mouse inhalation and rat oral studies (genotoxicity and cancer) are generally supportive of each other. Please point out any caveats.
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?
What is the biological significance of the changes in cis and trans ratio noted at higher levels of exposure?
What can be said regarding species extrapolation of TK based on the comparative levels of glutathione and elimination kinetics in tissues of experimental animals and humans, particularly in the cases of human diseases where severe glutathione depletion is observed?