Expert 9

The TK data are helpful for interpretation of the increased incidence of benign lung tumors in B6C3F1 male mice (Stott, 1987). At the highest exposure level of 60 ppm, the TK data indicate that the plasma exposure to 1,3-D is supralinear due to depletion of glutathione at that exposure level. Since the primary metabolic clearance mechanism was depleted at that exposure level, it is very difficult to extrapolate the tumor incidence observed at 60 ppm to humans even if we assume that the increased tumor incidence was real and treatment-related.

Expert 6

TK information is important because it allows better extrapolation of the results obtained in rodents to humans. It has been shown that oral and inhalation administration of 1,3-D in rodents and humans are similar in terms of uptake, detoxification and formations of major metabolites. Following rapid uptake, 1,3-D is primarily metabolized and detoxified by conjugation with GSH to form mercapturic acid metabolites. A study in which human volunteers were exposed by inhalation for 6 hours to 1 ppm cis/trans 1,3-D showed rapid and complete uptake through the lung and subsequent metabolism to excretable mercapturic acid metabolites in humans.

Expert 11

The inconsistencies in Cmax after oral administration with diet or by gavage with the tumor response are further supporting the conclusion that the tumors seen in Scott et al., 1995 in rats are due to confounding. On the other hand, why are there reductions in body weight gain if Cmax is much lower after dietary administration as compared to gavage ? Cmax not relevant to outcome ? This weakens the argument that an MTD was exceeded in Scott et al., 1995 where there seems to be no apparent toxicity at the same dose levels, but much higher Cmax. Tumors and toxicity in Scott due to a contaminant in the test material or other factors such as rat strain used ? Non-linear kinetics are not relevant for effects on the lung since the effect is unlikely treatment-related (see response to 8.1) . More detailed investigations on lung metabolism of 1,3-D in male mice may be helpful if kinetics are used as a central argument in case the tumors are considered as treatment related. Effects such as cytotox by GSH-depletion and/or formation of a toxic metabolite of 1,3-D could be assessed in such studies. There is GSH depletion after inhalation of 1,3-D in mice, but little indications of lung toxicity. Arguments against using this specific tumor type for human risk characterization are better based on variability in background incidences.
1 vote 1 0 votes
Expert 6
04/17/2019 19:27

to users-477751 [Expert 11] and 750802 [Expert 9] - agree with you -

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Expert 11
04/18/2019 03:01

All, any conclusion if the lung tumors are related to treatment or just an artifact due to variable background ?

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Expert 11
04/18/2019 03:21

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Expert 9
04/18/2019 20:44

The TK data indicate that the 1.3-D plasma exposures were higher than expected (linear) at the highest exposure of 60 ppm due to saturation of the clearance mechanism (glutathione conjugation). This fact does not rule out the possibility that the tumors were treatment-related. However, saturation of the clearance mechanism in the mice makes it very difficult to extrapolate this effect to humans because we don't know how to estimate the clearance of the compound in exposed humans. A linear extrapolation of the tumor incidence to lower human exposures is likely to yield erroneous results.

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