Evaluating the MoA/human relevance framework for F-344 rat liver epithelioid granulomas with mineral oil hydrocarbons

Abstract

Toxicology feeding studies of mineral oil hydrocarbons (MOHs), within the carbon number range C₂₂–C₂₈, results in species-specific epithelioid granulomas in the liver of F-344 rats but not in other rat strains, or species. While MOH has been detected, and some pathological effects have been shown to occur in other organs/tissues of F-344 rats and other rat strains/species, it is generally accepted that the effect of toxicological concern is species-specific inflammatory liver granuloma. As oil retention and other MOH-related nontoxic pathological changes in the liver are observed in humans, some have hypothesized that the potential for oil accumulation over a lifetime, through dietary sources, may predispose humans to similar liver effects as observed in F-344 rats. To address this concern, a mode of action/human relevance framework (MoA/HRF) analysis for MOH-induced epithelioid granuloma in the F-344 rat model was developed. The key events for the development of liver epithelioid granulomas were identified as increased MOH intestinal absorption, preferential tissue retention and ultimately formation of necrotic granulomas encased by infiltrating inflammatory lymphocytes. The hypothesized MoA was evaluated using the modified Bradford Hill considerations for causality and was considered to be established in the F-344 rodent model. However, key strain/species differences in the rate of intestinal absorption, tissue retention of MOH and inflammatory response to MOH in the liver were identified. Overall, the F-344 rat MoA was not considered to be relevant to humans, consistent with data showing no evidence for the formation of epithelioid granulomas with humans even in cases of massive ingestion of MOHs.

Keywords:

• Mode of action
• aliphatic hydrocarbons
• lipogranuloma
• white oil
• adverse outcome pathway
• human relevance
• weight of evidence

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Erratum

Acknowledgements

The authors would like to acknowledge the CONCAWE STF-33 panel for helpful comments on the initial draft of this manuscript. The authors would like to specifically thank Christine Palermo for assistance with reviewing the manuscript and providing comments that significantly improved the manuscript. The authors gratefully acknowledge the insightful comments of reviewers selected by the Editor and anonymous to the authors.

Declaration of interest

The company affiliations of the authors are indicated on the cover page. The authors are employed by companies that manufacture mineral oils, waxes, and lubricants. The manuscript was written as part of their normal employment and was the sole responsibility of the authors. No external funding was obtained for manuscript preparation. None of the authors has appeared during the past 5 years in any legal or regulatory proceedings related to the contents of this paper.