Population-Based in Vitro Hazard and Concentration-Response Assessment of Chemicals: The 1000 Genomes High-Throughput Screening Study

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. In the present study, the authors 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. One thousand and eighty-six lymphoblastoid cell lines from the 1000 Genomes Project, representing 9 populations from 5 continents, were used 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. 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. 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.

Authors: Abdo N, Xia M, Brown CC, Kosyk O, Huang R, Sakamuru S, Zhou YH, Jack J, Gallins P, Xia K, Li Y, Chiu WA, Motsinger-Reif A, Austin CP, Tice RR, Rusyn I, Wright FA. ;Full Source: Environmental Health Perspectives. 2015 Jan 13. [fusion_builder_container hundred_percent=”yes” overflow=”visible”][fusion_builder_row][fusion_builder_column type=”1_1″ background_position=”left top” background_color=”” border_size=”” border_color=”” border_style=”solid” spacing=”yes” background_image=”” background_repeat=”no-repeat” padding=”” margin_top=”0px” margin_bottom=”0px” class=”” id=”” animation_type=”” animation_speed=”0.3″ animation_direction=”left” hide_on_mobile=”no” center_content=”no” min_height=”none”][Epub ahead of print] ;[/fusion_builder_column][/fusion_builder_row][/fusion_builder_container]