Characterizing Variability and Uncertainty Associated with Transcriptomic Dose–Response Modeling

Transcriptomics dose–response analysis (TDRA) has emerged as a promising approach for integrating toxicogenomics data into a risk assessment context; however, variability and uncertainty associated with experimental design are not well understood. Here, we evaluated n = 55 RNA-seq profiles derived f...

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Bibliographic Details
Published inEnvironmental science & technology Vol. 56; no. 22; pp. 15960 - 15968
Main Authors Ewald, Jessica D., Basu, Niladri, Crump, Doug, Boulanger, Emily, Head, Jessica
Format Journal Article
LanguageEnglish
Published United States American Chemical Society 15.11.2022
Subjects
Animals
Chlorpyrifos
Coturnix
Datasets
Design of experiments
Dose-Response Relationship, Drug
Ecotoxicology and Public Health
Experimental design
Pesticides
Risk assessment
Risk Assessment - methods
Toxicogenetics - methods
Transcriptome
Transcriptomics
Uncertainty
alternative toxicity testing
chemical risk assessment
avian toxicity testing
toxicogenomics
new approach methods
next generation sequencing
bioinformatics
egg injection
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Summary:Transcriptomics dose–response analysis (TDRA) has emerged as a promising approach for integrating toxicogenomics data into a risk assessment context; however, variability and uncertainty associated with experimental design are not well understood. Here, we evaluated n = 55 RNA-seq profiles derived from Japanese quail liver tissue following exposure to chlorpyrifos (0, 0.04, 0.1, 0.2, 0.4, 1, 2, 4, 10, 20, and 40 μg/g; n = 5 replicates per group) via egg injection. The full dataset was subsampled 637 times to generate smaller datasets with different dose ranges and spacing (designs A–E) and number of replicates (n = 2–5). TDRA of the 637 datasets revealed substantial variability in the gene and pathway benchmark doses, but relative stability in overall transcriptomic point-of-departure (tPOD) values when tPODs were calculated with the “pathway” and “mode” methods. Further, we found that tPOD values were more dependent on the dose range and spacing than on the number of replicates, suggesting that optimal experimental designs should use fewer replicates (n = 2 or 3) and more dose groups to reduce uncertainty in the results. Finally, tPOD values ranged by over ten times for all surveyed experimental designs and tPOD types, suggesting that tPODs should be interpreted as order-of-magnitude estimates.
ISSN:0013-936X
1520-5851
DOI:10.1021/acs.est.2c04665