Bioinformatic Workflows for Deriving Transcriptomic Points of Departure: Current status, Data Gaps, and Research Priorities

Jason O'Brien; Constance Mitchell; Scott Auerbach; Liam Doonan; Jessica Ewald; Logan Everett; Adam Faranda; Kamin Johnson; Anthony Reardon; John Rooney; Kan Shao; Robert Stainforth; Matthew Wheeler; Deidre Dalmas Wilk; Andrew Williams; Carole Yauk; Eduardo Costa

doi:10.1093/toxsci/kfae145

Bioinformatic Workflows for Deriving Transcriptomic Points of Departure: Current status, Data Gaps, and Research Priorities

Toxicol Sci. 2024 Nov 5:kfae145. doi: 10.1093/toxsci/kfae145. Online ahead of print.

Authors

Jason O'Brien¹, Constance Mitchell², Scott Auerbach³, Liam Doonan⁴, Jessica Ewald⁵, Logan Everett⁶, Adam Faranda⁷, Kamin Johnson⁸, Anthony Reardon⁹, John Rooney¹⁰, Kan Shao¹¹, Robert Stainforth¹², Matthew Wheeler³, Deidre Dalmas Wilk¹³, Andrew Williams¹⁴, Carole Yauk¹⁵, Eduardo Costa¹⁶

Affiliations

¹ Ecotoxicology and Wildlife Health Division, Environment and Climate Change Canada, Ottawa, ON, Canada.
² Health and Environmental Sciences Institute, Washington, DC, USA.
³ Predictive Toxicology Branch, Division of Translational Toxicology, NIEHS, RTP, NC.
⁴ Syngenta International Research Centre, Bracknell, Berkshire, United Kingdom.
⁵ Institute of Parasitology, McGill University, Montreal, QC, Canada.
⁶ Center for Computational Toxicology and Exposure, Office of Research and Development, US Environmental Protection Agency, Research Triangle Park, NC, USA.
⁷ FMC Agricultural Solutions, Newark, DE, USA.
⁸ Corteva Agriscience, Indianapolis, IN, USA.
⁹ Healthy Environments and Consumer Safety Branch, Health Canada.
¹⁰ Syngenta Crop Protection, LLC, Greensboro, NC, 27409.
¹¹ Department of Environmental and Occupational Health, School of Public Health-Bloomington, Indiana University, Bloomington, IN, USA.
¹² Radiation Protection Bureau, Health Canada, Ottawa, Canada.
¹³ Investigative Safety, GSK, Collegeville, PA, USA.
¹⁴ Environmental Health Science and Research Bureau, Health Canada, Ottawa, ON, Canada.
¹⁵ Department of Biology, University of Ottawa, Ottawa, ON, Canada.
¹⁶ Corteva Agriscience, Mogi Mirim, Brazil.

PMID: 39499193
DOI: 10.1093/toxsci/kfae145

Abstract

There is a pressing need to increase the efficiency and reliability of toxicological safety assessment for protecting human health and the environment. While conventional toxicology tests rely on measuring apical changes in vertebrate models, there is increasing interest in the use of molecular information from animal and in vitro studies to inform safety assessment. One promising and pragmatic application of molecular information involves the derivation of transcriptomic points of departure (tPODs). Transcriptomic analyses provide a snapshot of global molecular changes that reflect cellular responses to stressors and progression toward disease. A tPOD identifies the dose level below which a concerted change in gene expression is not expected in a biological system in response to a chemical. A common approach to derive such a tPOD consists of modeling the dose-response behavior for each gene independently and then aggregating the gene-level data into a single tPOD. While different implementations of this approach are possible, as discussed in this manuscript, research strongly supports the overall idea that reference doses produced using tPODs are health protective. An advantage of this approach is that tPODs can be generated in shorter term studies (e.g., days) compared to apical endpoints from conventional tests (e.g., 90-day sub-chronic rodent tests). Moreover, research strongly supports the idea that reference doses produced using tPODs are health protective. Given the potential application of tPODs in regulatory toxicology testing, rigorous and reproducible wet and dry laboratory methodologies for their derivation are required. This review summarizes the current state of the science regarding the study design and bioinformatics workflows for tPOD derivation. We identify standards of practice and sources of variability in tPOD generation, data gaps, and areas of uncertainty. We provide recommendations for research to address barriers and promote adoption in regulatory decision making.

Keywords: POD; Transcriptomics; bioinformatics.