Expert 6

I fully agree with the White paper interpretation of the inhalation chronic bioassays by Stott 1987 (in mice) and Lomax 1987 (in rats). Of the two carcinogenicity studies conducted via inhalation exposure, increased lung tumors were observed in male B6C3F1 mice only, and in the highest dose animals. Two sets of historical control data by EPA indicate that male B6C3F1 mice are uniquely predisposed to developing lung tumors at a high rate. In addition, I agree that 1,3-D inhalation-induced lung tumors appears to be a local (portal-of-entry) effect, as no treatment-related lung tumors were identified in the 4 oral carcinogenicity studies (therefore it is not a lung specific carcinogen). Moreover, further examinations of lung effects in the second inhalation study in F344 rats were conducted to fully evaluate 1,3-D’s lung toxicity via the inhalation route. 1,3-D neither induced lung tumor formation, nor caused any preneoplastic lung effects in rats, as indicated by no effects on clinical chemistry or histopathology at the tumorigenic concentration in mice. The increased lung tumors (bronchioloalveolar adenoma) were characterized as benign, and restricted to high-concentration, and in male mice only. Male mice are usually more prone to the development of neoplasia in carcinogenesis models when compared to female mice. This response (development of lung adenomas in male mice only, and in highest dose) should not be considered relevant for human health risk assessment. No lung tumors were observed with the same inhalation doses in rats.

Expert 9

In general, I agree with the White paper interpretation of the Stott, 1987 study. While the lung tumor incidence in high-dose male mice was significantly higher than that of concurrent controls, the incidence was only a little higher than that seen in historical control data from Dow and NTP studies (44% vs. 36%). We cannot rule out the possibility that this increase was treatment-related, but we must also consider the fact that the 60 ppm exposure concentration caused a higher than proportional plasma exposure due to saturation of clearance mechanisms (depletion of glutathione). This observation does not mean that the increased tumor incidence was not real for B6C3F1 mice, but that extrapolation of this result to humans is very problematic. In contrast to the Stott, 1987 study, the Lomax, 1987 study showed no evidence of an increase in any tumor type in the rat. The observation of reduced weight gain (5%) and local changes in respiratory tissues (portal of entry, local effects) suggest that the exposures were adequate. It would have been nice to have TK data for the rats similar to the data presented for the mice but the absence of such data should not disqualify the rat study from consideration as a valid, negative bioassay.

Expert 11

As said above, not treatment related weak response in one sex and one species. Absence of human relevance of the mouse lung tumors in combination with gentox and TK arguments permit to conclude on non-relevance for human risk assessment. Outcome of several studies are somewhat puzzling when trying to put them into context
1 vote 1 0 votes
Expert 11
04/18/2019 03:11

A point to discuss is the conclusion that the lung tumors occur at concentrations that induces non-linear plasma kinetics. I do not think that this argument can be made since plasma concentrations of 1,3-D may not reflect target tissue concentrations in the lung. This should be related to exposure concentration. Metabolism in the target cells could be saturated, but would this would only be reflected in plasma concentrations if there is a significant 1st-pass in the lung ?

0 votes -2 2 votes
Expert 7
04/18/2019 09:02

I am not a PK expert and I hope others contribute to the discussion on this point. But the PK issue would not change my view that the slight increase in lung ademonas via inhalation in a highly susceptible strain/sex does NOT provide a basis for a concern in humans. Also as stated in comments above, there was no evidence of carcinogenicity in female mice and in either sex of the rat in the inhalation bioassays. Slight increase likely due to growth of spontaneous lesions and ability to score as adenomas because of size.

1 vote 1 0 votes
Expert 2
04/18/2019 10:25

An honest question out of possible ignorance: how is it possible to ignore lung tumors **by inhalation** as a "portal of entry effect"? How is this different from ignoring melanoma among lifeguards as a "portal of entry effect"? Naively, perhaps, one would think that the first site of contact with a carcinogen would be more, rather than less, important than distal sites.

3 votes 3 0 votes
Expert 9
04/18/2019 21:14

User-37600 [Expert 2] asks an important question. Should we rule out "portal of entry effects" as irrelevant for human risk assessment? Do we ignore UV-induced melanomas in humans? The answer is no. However, if a compound given by daily oral gavage causes forestomach tumors in a rodent model, should we conclude that the compound would be carcinogenic in humans exposed by inhalation? Not necessarily. Since inhalation is the primary route of human exposure to 1.3-D, I would not rule out the importance of lung tumors in an inhalation study.

1 vote 1 0 votes
Expert 11
04/19/2019 01:01

The point is not ignoring portal of entry effect. I am questioning the arguments regarding relevance of the non-linear plasma kinetics to discuss away the lung effects. I do not think that this is logic since the conc. of 1,3-D in the respiratory tract is depending on the air conc. Plasma kinetics may indicate saturation of liver biotransformation. I would not rule out portal of entry effects in any assessment

5 votes 5 0 votes
Expert 7
04/19/2019 06:27

I agree, simply because a response is port of entry, is not a basis for disregarding. My point is given the high variable background and susceptibility, and that this benign tumor response was slightly outside of HCs, it is not convincing evidence of carcinogenicity. Some of the statements in the White paper should be revised so as not to imply that port of entry is a basis for downplaying or dismissing.

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Expert 11
04/19/2019 07:22

Agree with user-232578 [Expert 7]

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Expert 6
04/19/2019 15:05

agree with user 477751 [Expert 11] and user 232578 [Expert 7]

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Expert 2
04/23/2019 10:51

just flagging that in Section 8.6 below, there is a more complete discussion of the (not-agreed-upon) issue of whether the lung adenomas are in fact "slightly outside" of historical control rates or are completely different from historical control rates.

1 vote 1 0 votes
Expert 6
04/24/2019 08:38

answering to users 37600 [Expert 2] and 750802 [Expert 9] , if to consider portal of entry for respiratory system, the nasal cavity would be the selected one, and not the lungs.

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