Since the carcinogenicity of 1,3-D has been in question for more than 30 years, and every one of the 8 lifetime bioassays to date is subject to some degree of controversy, would it not be helpful to conduct a state-of-the-art bioassay, by inhalation (the predominant human exposure route), using a current commercially-available formulation, that could resolve these doubts one way or the other? (for example, with larger sample sizes at doses of 5 and 20 ppm, to have sufficient power to detect small excesses if they exist)

I guess we all agree that the new formulation of Telone II is not genotoxic. Only 2 studies have shown some evidence of carcinogenesis, which are the Scott study (1995) (Increased incidences of hepatocellular adenoma were observed in both high dose males and females and in mid-dose males) and the inhalation study in B6C3F1 Mice, in which statistically identified increase in benign lung tumors (bronchioloalveolar adenomas) was observed in male mice only exposed to high-concentration (60 ppm )1,3-D (22/50 vs. 9/50 in controls).
Carcinogens nowadays must be characterized according to their mode and mechanism of action. What would be the mechanism of action of 1,3D for carcinogenesis? Any evidence?

For lung, the mouse is very susceptible to GSH-depletion, but the MoA for other chemicals causing lung tumors in mice require cytotoxicity and hyperplasia. Based on absence of toxicity in the mouse lung and no lung response in the rat inhalation study, my conclusion is that the lung tumors are not treatment related. Issue with Scott et al, are much lower Cmax as compared to Kelly. Still struggle a little with the indication of a dose-response in Scott ? Mechanisms could be GSH-depletion at high doses/concentrations ? Agree that it is highly unlikely that direct genotoxicity plays a role in the responses.

Most of these responses (those in the prior round and some of the comments to date) sidestep the original question by focusing on genotoxicity. The original question proposed a larger-N bioassay (not necessarily a "mega-mouse" study by any means) so that we wouldn't have to make qualitative ("increases above controls aren't really increases because in some years the control rate would have been greater...") and quantitative ("at this dose there were no statistically significant tumors") pronouncements with low power to make them.

A larger study would allow for slightly lower doses to be used, and for the uncertainty in historical control rates to make far less potential difference.

(separating this from my immediately prior comment, for emphasis)

I remain puzzled by the complete lack of attention, both in the White Paper and in this exercise to date, of one particular positive bioassay finding that seems quite important: the striking and dose-related increase (above a ZERO control rate) of transitional cell carcinomas of the bladder in female mice (NTP 1985-- 16% at 25 ppm and 42% at 50 ppm).

Can anyone explain why we should be completely ignoring these? I know-- "epichlorohydrin." EXCEPT that (1) epichlorohydrin has never to my knowledge been implicated in bladder carcinogenesis; and (2) if you believe the back-of-the-envelope risk assessment (see user-37600 [Expert 2] comment on the WOE topic 5.5 elsewhere on this site) using EPA's cancer potency (slope) factor for epichlorohydrin, it's virtually impossible for 1 PERCENT impurity to cause more than 1 or 2 tumors per 50 rodents at ANY site, let alone one where the impurity does not seem to be active.

Various sections of the White Paper, and various commenters, have at least coherent theories as to why we should ignore the liver adenomas, the forestomach tumors, and the inhalation lung adenomas-- but I've seen no attempt-- other than silence-- to explain away the bladder tumors...

The WOE from reviewers suggests that the extant bioassays provide sufficient data to support a hazard WOE. Rather than require more cancer bioassays, I would recommend more cogent and logical explication of the most probable MOAs.

User-37600 [Expert 2] raises a valid point about the transitional cell carcinomas in female B6C3F1 mice in the NTP gavage study. The tumor incidences of 0, 16 and 42% in control, low and high-dose mice when viewed in isolation are impressive and suggest a carcinogenic effect in the bladder. However,
we need to look at these tumor incidences in the context of all the other relevant data. The presence of 1% epichlorohydrin in the test article is important. User-37600 [Expert 2] states that this 1% impurity is unlikely to have caused this effect based on EPA's data and on the absence of any prior information that epichlorohydrin could produce this effect. These are valid points. However, we have no information on the potential interaction between this impurity and 1,3-D. Is a synergistic effect possible? We don't know. Secondly, The same doses of 1,3-D were given to B6C3F1 mice by gavage in the Redmond, 1995 study with no suggestion of an effect on the bladder. Thirdly, Stott, 1987 reported no bladder tumors in their inhalation exposure study, a route that is more relevant to human exposure to 1,3-D. Finally, there is no evidence of bladder tumors in any of the other bioassays conducted in CD-1 mice mice and in F344 or CD rats. Therefore, looking at all the relevant data, the weight of evidence is that 1.3-D did not cause bladder tumors in multiple oral and inhalation bioassays with the exception of one study in which a potentially confounding impurity was present. Given this data base, I have to conclude that this one result was an outlier that could not be reproduced in multiple additional studies.

My point is that with the variable incidences of lung tumors in mice, it will always be difficult to obtain reliable results no matter how large the groups are. I think that more information on the composition of the materials tested including impurities other then epichlorohydrin may help explain some of the contradictions. I also agree that presence of epichlorohydrin may only explain the forestomach tumors. My conclusion that the NTP study should be set aside is based on issues with study design and conduct. The bladder tumors are somewhat puzzling and there seems to be dose-response. I tend to agree with user 750802 [Expert 9] regarding consitency of the overall database on carcinogenicity

I agree with the comment from user-2441 that the existing bioassays provide sufficient data to support a hazard WOE, and that a more cogent and logical explication of the most probable MOAs would likely shed more light on the issue

I think we should not include the 2 NTP studies in our discussions, because of the contamination with epichlorohydrin. I would like to know the composition of TeloneII used for the other studies, and also the composition of DD92 used for some studies.