Derivation of inhalation toxicity reference values for propylene oxide using mode of action analysis: Example of a threshold carcinogen

Abstract

Propylene oxide (PO) is an important industrial chemical used primarily in the synthesis of other compounds. Inhalation carcinogenesis studies in rodents, with no-observed-adverse-effect levels (NOAELs) of 100 and 200 ppm, have revealed that chronic, high exposure to PO can induce tumors at the site of contact. Despite these characteristics, there is no evidence that typical environmental or occupational exposures to PO constitute a health risk for humans. The nongenotoxic effects of PO (glutathione depletion and cell proliferation) that augment its DNA-reactive and non-DNA-reactive genotoxicity are expected to be similar in humans and rodents. Available evidence on mode-of-action suggests that cancer induction by PO at the site of contact in rodents is characterized by a practical threshold. Human toxicity reference values for potential carcinogenic effects of PO were derived based on nasal tumors identified in rodent studies and specified uncertainty factors. The 95% lower confidence limit on the dose producing a 10% increase in additional tumor risk (LED10) was calculated using the rat and mouse data sets. The human reference values derived from the rat and mouse LED10 values were 0.7 and 0.5 ppm PO, respectively. A similar noncancer reference value, 0.4 ppm, was derived on the basis of non-neoplastic nasal effects in rats.

Keywords::

• Cancer risk assessment
• genotoxicity
• nasal toxicity
• noncancer risk assessment

Acknowledgments

This work was funded by the Propylene Oxide/Propylene Glycol (PO/PG) Panel of the American Chemistry Council (ACC) and the Cefic PO and Glycols Sector Group.

We thank Drs. Jack Harkema, John Morris, and Jim Swenberg, members of the risk assessment review team, for their helpful comments on early drafts of this report. We also thank Annie Jarabek for insights on testing strategy and development of the mode-of-action framework. We thank Drs. Julie Kimbell and Rory Conolly for their technical advice.

Declaration of interest: The authors alone are responsible for the content and writing of the paper.