Integrating mechanistic and polymorphism data to characterize human genetic susceptibility for environmental chemical risk assessment in the 21st century

Abstract

Response to environmental chemicals can vary widely among individuals and between population groups. In human health risk assessment, data on susceptibility can be utilized by deriving risk levels based on a study of a susceptible population and/or an uncertainty factor may be applied to account for the lack of information about susceptibility. Defining genetic susceptibility in response to environmental chemicals across human populations is an area of interest in the NAS' new paradigm of toxicity pathway-based risk assessment. Data from high-throughput/high content (HT/HC), including -omics (e.g., genomics, transcriptomics, proteomics, metabolomics) technologies, have been integral to the identification and characterization of drug target and disease loci, and have been successfully utilized to inform the mechanism of action for numerous environmental chemicals. Large-scale population genotyping studies may help to characterize levels of variability across human populations at identified target loci implicated in response to environmental chemicals. By combining mechanistic data for a given environmental chemical with next generation sequencing data that provides human population variation information, one can begin to characterize differential susceptibility due to genetic variability to environmental chemicals within and across genetically heterogeneous human populations. The integration of such data sources will be informative to human health risk assessment.

Keywords: -omics; ACToR; Aggregated Computational Toxicology Resources; Bioinformatics; CNV; Copy Number Variant; Diabetes Type 2; EGP; EPA's chemical prioritization research program; EWAS; Environment-Wide Association Study; GWAS; Genome-Wide Association Study; HT/HC; HTS; HapMap; High-throughput screening; High-throughput/High content; Human genetic variation; IRIS; Integrated Risk Information System; International Haplotype Map (HapMap) Project; MOA; Mode of action; NAS; NCBI; NIEHS; NIEHS-Environmental Genome Project; NR; National Academy of Sciences; National Center for Biotechnology; National Institute of Environmental Health Sciences; Nuclear Receptor; PDR; Polymorphism Discovery Resource; Reference Concentration; Reference Dose; RfC; RfD; SNP; Single Nucleotide Polymorphism; Single Nucleotide Polymorphism Database; Susceptibility; TD; TD2; TK; TSS; ToxCast; Toxicity pathway; Toxicodynamics; Toxicokinetics; Transcription Start Site; UF; US EPA; US Environmental Protection Agency; Uncertainty/Variability Factor; dbSNP; neologism relating multiple fields in biology that end in -omics (e.g., genomics, transciptomics, proteomics, metabolomics).