Expert 4

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

Expert 12

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.

Expert 10

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.

Expert 13

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.
2 votes 2 0 votes
Expert 13
04/17/2019 11:39

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

0
Expert 2
04/18/2019 10:00

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.

0
Expert 12
04/23/2019 06:34

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.

0
Expert 12
04/23/2019 06:43

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.

0
Expert 10
04/23/2019 10:51

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

2 votes 2 0 votes
Expert 2
04/23/2019 10:58

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.

0
Expert 4
04/24/2019 04:57

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

0
Expert 4
04/24/2019 04:58

1 vote 1 0 votes
Expert 2
04/24/2019 08:00

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.

1 vote 1 0 votes
Expert 10
04/24/2019 09:22

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 ?

1 vote 1 0 votes
Expert 12
04/24/2019 09:50

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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