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 (10½ each for toxicokinetics and toxicodynamics) to account for sensitive individuals or subpopulations.
Objectives: We tested a hypothesis that population-wide in vitro cytotoxicity screening can rapidly inform both the magnitude of and molecular causes for interindividual toxicodynamic variability.
Methods: We used 1,086 lymphoblastoid cell lines from the 1000 Genomes Project, representing nine populations from five 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.
Results: For about half the tested compounds, cytotoxic response in the 1% most “sensitive” individual occurred at concentrations within a factor of 10½ (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 transmembrane genes, with a number of chemicals showing association with SNP rs13120371 in the solute carrier SLC7A11, previously implicated in chemoresistance.
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 interindividual variation.
1Department of Environmental Sciences and Engineering, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, USA; 2National Center for Advancing Translational Sciences, National Institutes of Health (NIH), Department of Health and Human Services (DHHS), Bethesda, Maryland, USA; 3Bioinformatics Research Center, and 4Department of Statistics, North Carolina State University, Raleigh, North Carolina, USA; 5Department of Genetics, 6Department of Psychiatry, and 7Department of Biostatistics, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, USA; 8National Center for Environmental Assessment, U.S. Environmental Protection Agency, Washington, DC, USA; 9National Institute of Environmental Health Sciences, NIH, DHHS, Research Triangle Park, North Carolina, USA
Recommended Citation:
Nour Abdo,1 Menghang Xia,2 Chad C. Brown,et al. Population-Based in Vitro Hazard and Concentration–Response Assessment of Chemicals: The 1000 Genomes High-Throughput Screening Study[J]. Environmental Health Perspectives,2015-01-01,Volume 123(Issue 5):458