A novel method to derive a human safety limit for PFOA by gene expression profiling and modelling

Arthur de Carvalho e Silva*, George D. Loizou, Kevin McNally, Olivia Osborne, Claire Potter, David Gott, John K. Colbourne, Mark R. Viant

*Corresponding author for this work

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Abstract

Perfluorooctanoic acid (PFOA) is a persistent environmental contaminant that can accumulate in the human body due to its long half-life. This substance has been associated with liver, pancreatic, testicular and breast cancers, liver steatosis and endocrine disruption. PFOA is a member of a large group of substances also known as “forever chemicals” and the vast majority of substances of this group lack toxicological data that would enable their effective risk assessment in terms of human health hazards. This study aimed to derive a health-based guidance value for PFOA intake (ng/kg BW/day) from in vitro transcriptomics data. To this end, we developed an in silico workflow comprising five components: (i) sourcing in vitro hepatic transcriptomics concentration-response data; (ii) deriving molecular points of departure using BMDExpress3 and performing pathway analysis using gene set enrichment analysis (GSEA) to identify the most sensitive molecular pathways to PFOA exposure; (iii) estimating freely-dissolved PFOA concentrations in vitro using a mass balance model; (iv) estimating in vivo doses by reverse dosimetry using a PBK model for PFOA as part of a quantitative in vitro to in vivo extrapolation (QIVIVE) algorithm; and (v) calculating a tolerable daily intake (TDI) for PFOA. Fourteen percent of interrogated genes exhibited in vitro concentration-response relationships. GSEA pathway enrichment analysis revealed that “fatty acid metabolism” was the most sensitive pathway to PFOA exposure. In vitro free PFOA concentrations were calculated to be 2.9% of the nominal applied concentrations, and these free concentrations were input into the QIVIVE workflow. Exposure doses for a virtual population of 3,000 individuals were estimated, from which a TDI of 0.15 ng/kg BW/day for PFOA was calculated using the benchmark dose modelling software, PROAST. This TDI is comparable to previously published values of 1.16, 0.69, and 0.86 ng/kg BW/day by the European Food Safety Authority. In conclusion, this study demonstrates the combined utility of an “omics”-derived molecular point of departure and in silico QIVIVE workflow for setting health-based guidance values in anticipation of the acceptance of in vitro concentration-response molecular measurements in chemical risk assessment.
Original languageEnglish
Article number1368320
Number of pages11
JournalFrontiers in toxicology
Volume6
DOIs
Publication statusPublished - 21 Mar 2024

Bibliographical note

Funding
The author(s) declare that financial support was received for the research, authorship, and/or publication of this article. Funding was provided by the UK Food Standards Agency (project “Advancing in silico methods of assessing toxicological risk, FS900092).”

Acknowledgments
AS acknowledges the UK Food Standards Agency for the fellowship on Computational Toxicology and LUSH for the Young Researcher LUSH Prize 2022. Authors acknowledge Alex Hogg for the technical support provided.

Keywords

  • omics
  • Markov chain Monte Carlo
  • reverse dosimetry
  • PBK
  • NAMs
  • in silico
  • Bayesian
  • PFOA

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