How do you interpret the cancer bioassays conducted for 1,3-D?

Study 1 in F344 rats observed hepatocellular adenomas in male and female mice in the highest dose. It was positive, but only in the highest dose (25 mg/kg/day, microencapsulated 1,3-D). In this study, the material was given to rats in the diet, and when compared to Study 2, in which the material was given to rats by gavage, with clearly negative results, we can conclude that these studies are not consistent. Studies 2, 3 and 4 are clearly negative. Study 5 and Study 6 were INADEQUATE because of the presence of epichlorohydrin, but showed some evidence of carcinogenicity (SLIGHTLY POSITIVE) : The dosing regimen (two dose levels by gavage three times/week) was not well designed to study chronic toxicity and does not meet test guidelines. Tumors were found, but stomach squamous papillomas and carcinomas are local effects after gavage with 1,3-D containing epichlorohydrin, and other tumor findings are not consistent; moreover, many control mice died during the study due to myocarditis.

As indicated above the non-NTP studies were negative and the NTP studeis cannot be evaluated because of the contamination with epichlorohydrin.

Scott (1995): Increase in liver tumors (combined adenoma/carcinoma) in both male and female rats, indication of dose-response in males. However, most of the tumors were adenomas (only 1 carcinoma) and incidences are within or sligthly higher as compared to historical controls in the performing lab. Is it known if the material tested was identical to that in both the Kelly and the Redmond study regarding the unaccounted impurities ? In addition, there was dosing above MTD due to body weight gain reductions > 10 % in high dose males, but little indications of liver toxicity.
Kelly (1998): no increase in tumor incidences seen, same for Redmond 1995
Kelly (1997): My conclusion is negative, would be even better supported if historical controls for the lesion in the performing lab would be available.
Both NTP studies show an increase in tumor responses, but the interpretaion of the data is problematic as indicated above due to study design and conduct and testing of a material with significant impurities.

There were no clearly positive bioassays. Study 1 presented the strongest evidence of a tumorigenic effect,, with the statistically significant increase in hepatocellular adenoma incidence in high-dose males. Although this increase may be real, it was not accompanied by an increase in malignant hepatocellular tumors. The remaining studies were considered equivocal because of the presence of a carcinogenic contaminant or because of questionable histological nomenclature.