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?

To extrapolate a KMD based on the information obtained from non-linearities observed in mice is difficult. If the non-linearity is due to GSH depletion, we would have to know the basal levels of human lung GSH, the rate of conjugation by 1,3-D and the rate of GSH replenishment in lungs, and consider the distribution of these values in the human population. If the non-linearity is due to GST saturation, then a lower bound KMD could be around the lowest human Km value for 1,3-D conjugation via the GST. Information on disease state and GST variability/polymorphisms may help in predicting interinvidual variability.

In view of inherent interspecies variability it is difficult to provide a definite “lower bound” for the KMD in human population based on the kinetic (KMD) data available in animal species. However, 1,3-Dichloropropene toxicokinetics in humans appear to be similar to those observed in rodents. Inhalation studies with both humans and animals have shown that 1,3-dichloropropene vapors are readily absorbed, conjugated with glutathione (GSH) via glutathione S-transferase (GST), and rapidly excreted in the urine as N-acetyl-(S-3-chloroprop-2-enyl) cysteine (3CNAC), a mercapturic acid metabolite.
Waechter et al. (1992) also found that blood concentrations plateaued rapidly at low exposures for most subjects. In five of the six subjects, blood levels of 1,3-dichloropropene reached an apparent plateau within 1 hour of exposure to 4.54 mg/m2. In terms of uptake, detoxification and formations of major metabolites.

Overall, because the conducted toxicological risk assessment is not robust enough this open the way to several debates on the KMD and resulting calculated MOEs. There is still some uncertainty in the mouse-to-human extrapolation that is not covered by the current uncertainty factors used to calculate the MOE from the KMD value. For example, additional uncertainty factors might be needed for (i) intermittent versus repetitive dosing scenario versus the GSH depletion recuperation, (ii) the toxicity of the isomer cis versus trans close to saturation, the species difference in the plasma protein binding to define which species have more unbound (and active) compound in plasma. These data (informations) are not available, unfortunately. Therefore, for more precaution, the KMD should be the lowest we can estimate. Somewhere between 10 and 20 ppm, probably 10 ppm, since the non-linearity seems to start already to a dose close to 10 ppm for both the cis and trans isomers based on the Figure 5 of the white paper. There is some accordance with the whiter paper: ''the KMD should be at or below 30 ppm.'' Overall, using a lower bound of 10 ppm (that is probable based on Figure 5) should also cover better the remaining uncertainty and variability effects, as mentioned above. Nevertheless, 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. More explanations are provided in the following items 7.2, 7.3. 7.4 and 7.6.