Expert 12

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.

Expert 10

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.

Expert 13

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.
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Expert 13
04/17/2019 11:21

I don't think it is possible to make an assumption that that the KMD would probably be about 10 ppm based on limited animal exposure data.

2 votes 2 0 votes
Expert 2
04/18/2019 09:44

User-850922 [Expert 10] says it well: (to paraphrase) "we have no idea what the range of human KMDs are or might be. We would have to know a lot more than we do now about average rates of various human parameters and their interindividual range."

So why are we leaping from a qualitative finding (there appears to be a KMD somewhere) to ANY kind of quantitative conclusion about where the human KMD actually is? Frankly, I find the third comment above (user-292467 [Expert 12] ) to misstate the question, which asks about humans, rather than rodents. It's possible that a factor of 2-3 (from a starting point of 30 ppm) might provide a lower bound for the RODENT KMD, but this provides zero information on what interspecies and intraspecies adjustments would be necessary to declare a human KMD.

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Expert 12
04/23/2019 06:21

Yes, this is why I asked to make at least a plasma protein binding study in rodent and human to define the amount of free drug in human plasma versus rodent plasma. Considering that only the free drug moiety is active, the KMD in rodent would have to be corrected by an additional interspecies scaling factor for an extrapolation to human while the unbound fraction in plasma is not the same in rodent and human.

1 vote 1 0 votes
Expert 10
04/23/2019 10:36

Human data (in vitro or in vivo) are simply lacking and therefore it is impossible to make a quantitative estimation of the sort.

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Expert 12
04/24/2019 09:45

Therefore a lower KMD or higher uncertainty factor should be used for more precaution. Something closer to 10-30 ppm compared to 60 ppm.

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