Population-based in vitro hazard and concentration-response assessment of chemicals: The 1000 genomes high-throughput screening study

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Abstract

BACKGROUND: Understanding of human variation in toxicity to environmental chemicals remains limited, so human health risk assessments still largely rely on a generic 10-fold factor (10(½) each for toxicokinetics and toxicodynamics) to account for sensitive individuals or subpopulations.<br /><br />OBJECTIVES: We tested a hypothesis that population-wide in vitro cytotoxicity screening can rapidly inform both the magnitude of and molecular causes for inter-individual toxicodynamic variability.<br /><br />METHODS: We used 1086 lymphoblastoid cell lines from the 1000 Genomes Project, representing 9 populations from 5 continents, to assess variation in cytotoxic response to 179 chemicals. Analysis included assessments of population variation and heritability, and genome-wide association mapping, with attention to phenotypic relevance to human exposures.<br /><br />RESULTS: For about half the tested compounds, cytotoxic response in the 1% most "sensitive" individual occurred at concentration within a factor of 10(½) (i.e., approximately 3) of that in the median individual; however, for some compounds, this factor was >10. Genetic mapping suggested important roles for variation in membrane and trans-membrane genes, with a number of chemicals showing association with SNP rs13120371 in the solute carrier SLC7A11, previously implicated in chemoresistance.<br /><br />CONCLUSIONS: This experimental approach fills critical gaps unaddressed by recent large-scale toxicity testing programs, providing quantitative, experimentally based estimates of human toxicodynamic variability, and also testable hypotheses about mechanisms contributing to inter-individual variation.

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Abdo, N., Xia, M., Brown, C. C., Kosyk, O., Huang, R., Sakamuru, S., … Wright, F. A. (2015). Population-based in vitro hazard and concentration-response assessment of chemicals: The 1000 genomes high-throughput screening study. Environmental Health Perspectives, 123(5), 458–466. https://doi.org/10.1289/ehp.1408775

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