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Leveraging human genetic and adverse outcome pathway (AOP) data to inform susceptibility in human health risk assessment

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A Data Descriptor to this article was published on 12 July 2021

Abstract

Estimation of susceptibility differences in human health risk assessment (HHRA) has been challenged by a lack of available susceptibility and variability data after exposure to a specific environmental chemical or pharmaceutical. With the increasingly large number of available data sources that contain polymorphism and other genetic data, human genetic variability that informs susceptibility can be better incorporated into HHRA. A recent policy, the 2016 The Frank R. Lautenberg Chemical Safety for the twenty-first Century Act, requires the US Environmental Protection Agency to evaluate new and existing toxic chemicals with explicit consideration of susceptible populations of all types (life stage, exposure, genetic, etc.). We propose using the adverse outcome pathway (AOP) construct to organize, identify, and characterize human genetic susceptibility in HHRA. We explore how publicly available human genetic datasets can be used to gain mechanistic understanding of molecular events and characterize human susceptibility for an adverse outcome. We present a computational method that implements publicly available human genetic data to prioritize AOPs with potential for human genetic variability. We describe the application of this approach across multiple described AOPs for health outcomes of interest, and by focusing on a single molecular initiating event. This contributes to a long-term goal to improve estimates of human susceptibility for use in HHRA for single and multiple chemicals.

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References

  • Abdo N, Wetmore BA, Chappell GA, Shea D, Wright FA, Rusyn I (2015a) In vitro screening for population variability in toxicity of pesticide-containing mixtures. Environ Int 85:147–155

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Abdo N, Xia M, Brown CC, Kosyk O, Huang R, Sakamuru S, Zhou YH, Jack JR, Gallins P, Xia K, Li Y, Chiu WA, Motsinger-Reif AA, Austin CP, Tice RR, Rusyn I, Wright FA (2015b) Population-based in vitro hazard and concentration-response assessment of chemicals: the 1000 genomes high-throughput screening study. Environ Health Perspect 123(5):458–466

    CAS  PubMed  PubMed Central  Google Scholar 

  • Adzhubei IA, Schmidt S, Peshkin L, Ramensky VE, Gerasimova A, Bork P, Kondrashov AS, Sunyaev SR (2010) A method and server for predicting damaging missense mutations. Nat Methods 7(4):248–249

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Akula N, Baranova A, Seto D, Solka J, Nalls MA, Singleton A, Ferrucci L, Tanaka T, Bandinelli S, Cho YS, Kim YJ, Lee J-Y, Han B-G, McMahon FJ (2011) A network-based approach to prioritize results from genome-wide association studies. PLoS ONE 6(9):e24220

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Ankley GT, Bennett RS, Erickson RJ, Hoff DJ, Hornung MW, Johnson RD, Mount DR, Nichols JW, Russom CL, Schmieder PK, Serrrano JA, Tietge JE, Villeneuve DL (2010) Adverse outcome pathways: a conceptual framework to support ecotoxicology research and risk assessment. Environ Toxicol Chem 29(3):730–741

    Article  CAS  PubMed  Google Scholar 

  • Ayati M, Koyuturk M (2016) PoCos: population covering locus sets for risk assessment in complex diseases. PLoS Comput Biol 12(11):e1005195

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Azencott CA, Grimm D, Sugiyama M, Kawahara Y, Borgwardt KM (2013) Efficient network-guided multi-locus association mapping with graph cuts. Bioinformatics 29(13):i171–i179

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Barabasi AL, Gulbahce N, Loscalzo J (2011) Network medicine: a network-based approach to human disease. Nat Rev Genet 12(1):56–68

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Bar-Joseph Z, Gerber GK, Lee TI, Rinaldi NJ, Yoo JY, Robert F, Gordon DB, Fraenkel E, Jaakkola TS, Young RA, Gifford DK (2003) Computational discovery of gene modules and regulatory networks. Nat Biotechnol 21(11):1337–1342

    Article  CAS  PubMed  Google Scholar 

  • Bradford BU, Lock EF, Kosyk O, Kim S, Uehara T, Harbourt D, DeSimone M, Threadgill DW, Tryndyak V, Pogribny IP, Bleyle L, Koop DR, Rusyn I (2011) Interstrain differences in the liver effects of trichloroethylene in a multistrain panel of inbred mice. Toxicol Sci 120(1):206–217

    Article  CAS  PubMed  Google Scholar 

  • Cauchi S, Del Guerra S, Choquet H, D’Aleo V, Groves CJ, Lupi R, McCarthy MI, Froguel P, Marchetti P (2010) Meta-analysis and functional effects of the SLC30A8 rs13266634 polymorphism on isolated human pancreatic islets. Mol Genet Metab 100(1):77–82

    Article  CAS  PubMed  Google Scholar 

  • Chiu WA, Wright FA, Rusyn I (2016). A tiered, Bayesian approach to estimating of population variability for regulatory decision-making. ALTEX 34:377

    PubMed  PubMed Central  Google Scholar 

  • Churchill GA, Airey DC, Allayee H, Angel JM, Attie AD, Beatty J, Beavis WD, Belknap JK, Bennett B, Berrettini W, Bleich A, Bogue M, Broman KW, Buck KJ, Buckler E, Burmeister M, Chesler EJ, Cheverud JM, Clapcote S, Cook MN, Cox RD, Crabbe JC, Crusio WE, Darvasi A, Deschepper CF, Doerge RW, Farber CR, Forejt J, Gaile D, Garlow SJ, Geiger H, Gershenfeld H, Gordon T, Gu J, Gu W, de Haan G, Hayes NL, Heller C, Himmelbauer H, Hitzemann R, Hunter K, Hsu HC, Iraqi FA, Ivandic B, Jacob HJ, Jansen RC, Jepsen KJ, Johnson DK, Johnson TE, Kempermann G, Kendziorski C, Kotb M, Kooy RF, Llamas B, Lammert F, Lassalle JM, Lowenstein PR, Lu L, Lusis A, Manly KF, Marcucio R, Matthews D, Medrano JF, Miller DR, Mittleman G, Mock BA, Mogil JS, Montagutelli X, Morahan G, Morris DG, Mott R, Nadeau JH, Nagase H, Nowakowski RS, O’Hara BF, Osadchuk AV, Page GP, Paigen B, Paigen K, Palmer AA, Pan HJ, Peltonen-Palotie L, Peirce J, Pomp D, Pravenec M, Prows DR, Qi Z, Reeves RH, Roder J, Rosen GD, Schadt EE, Schalkwyk LC, Seltzer Z, Shimomura K, Shou S, Sillanpaa MJ, Siracusa LD, Snoeck HW, Spearow JL, Svenson K, Tarantino LM, Threadgill D, Toth LA, Valdar W, de Villena FP, Warden C, Whatley S, Williams RW, Wiltshire T, Yi N, Zhang D, Zhang M, Zou F (2004). The Collaborative Cross, a community resource for the genetic analysis of complex traits. Nat Genet 36:1133–1137

    Article  CAS  PubMed  Google Scholar 

  • Churchill GA, Gatti DM, Munger SC, Svenson KL (2012) The diversity outbred mouse population. Mamm Genome 23(9–10):713–718

    Article  PubMed  PubMed Central  Google Scholar 

  • Cichocki JA, Furuya S, Venkatratnam A, McDonald TJ, Knap AH, Wade T, Sweet S, Chiu WA, Threadgill DW, Rusyn I (2017) Characterization of variability in toxicokinetics and toxicodynamics of tetrachloroethylene using the collaborative cross mouse population. Environ Health Perspect 125(5):057006

    Article  PubMed  PubMed Central  Google Scholar 

  • Clewell HJ, Andersen ME (1996) Use of physiologically based pharmacokinetic modeling to investigate individual versus population risk. Toxicology 111(1–3):315–329

    Article  CAS  PubMed  Google Scholar 

  • Clewell HJ, Teeguarden J, McDonald T, Sarangapani R, Lawrence G, Covington T, Gentry R, Shipp A (2002) Review and evaluation of the potential impact of age- and gender-specific pharmacokinetic differences on tissue dosimetry. Crit Rev Toxicol 32(5):329–389

    Article  CAS  PubMed  Google Scholar 

  • Collins FS, Gray GM, Bucher JR (2008). TOXICOLOGY: transforming environmental health protection. Science 319(5865):906–907

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Corton JC (2008) Evaluation of the role of peroxisome proliferator-activated receptor alpha (PPARalpha) in mouse liver tumor induction by trichloroethylene and metabolites. Crit Rev Toxicol 38:857–875

    Article  CAS  PubMed  Google Scholar 

  • Cote I, McCullough SD, Hines RN, Vandenberg JJ (2017) Application of epigenetic data in human health risk assessment. Curr Opin Toxicol 6:71–78

    Article  PubMed  Google Scholar 

  • Croteau-Chonka DC, Rogers AJ, Raj T, McGeachie MJ, Qiu W, Ziniti JP, Stubbs BJ, Liang L, Martinez FD, Strunk RC, Lemanske RF, Liu AH, Stranger BE, Carey VJ, Raby BA (2015) Expression quantitative trait loci information improves predictive modeling of disease relevance of non-coding genetic variation. PLoS ONE 10(10):e0140758

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Davis JA, Burgoon LD (2015) Can data science inform environmental justice and community risk screening for type 2 diabetes? PLoS ONE 10(4):e0121855

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Davis AP, Grondin CJ, Johnson RJ, Sciaky D, King BL, McMorran R, Wiegers J, Wiegers TC, Mattingly CJ (2016) The comparative toxicogenomics database: update 2017. Nucleic Acids Res 45(D1):D972–D978

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Deplancke B, Alpern D, Gardeux V (2016) The genetics of transcription factor DNA binding variation. Cell 166(3):538–554

    Article  CAS  PubMed  Google Scholar 

  • Dickinson GL, Lennard MS, Tucker GT, Rostami-Hodjegan A (2007) The use of mechanistic DM-PK-PD modelling to assess the power of pharmacogenetic studies ? CYP2C9 and warfarin as an example. Br J Clin Pharmacol 64(1):14–26

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Dix DJ, Houck KA, Martin MT, Richard AM, Setzer RW, Kavlock RJ (2007) The ToxCast program for prioritizing toxicity testing of environmental chemicals. Toxicol Sci 95(1):5–12

    Article  CAS  PubMed  Google Scholar 

  • Dudley JT, Butte AJ (2009). Identification of discriminating biomarkers for human disease using integrative network biology. Pac Symp Biocomput 2009:27–38

    Google Scholar 

  • Eduati F, Mangravite LM, Wang T, Tang H, Bare JC, Huang R, Norman T, Kellen M, Menden MP, Yang J, Zhan X, Zhong R, Xiao G, Xia M, Abdo N, Kosyk O, N.-N.-U. D. T. Collaboration, Friend S, Dearry A, Simeonov A, Tice RR, Rusyn I, Wright FA, Stolovitzky G, Xie Y, Saez-Rodriguez J (2015) Prediction of human population responses to toxic compounds by a collaborative competition. Nat Biotechnol 33(9):933–940

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • ENCODE Project Consortium (2004). The ENCODE (ENCyclopedia of DNA elements) project. Science 306(5696):636–640

    Article  CAS  Google Scholar 

  • ENCODE Project Consortium (2007). Identification and analysis of functional elements in 1% of the human genome by the ENCODE pilot project. Nature 447(7146):799–816

    Article  CAS  Google Scholar 

  • Federal Register (2015). List of environmentally responsive human genes selected for use in screening large numbers of substances using toxicogenomic approaches. D. O. H. A. H. SERVICES. 80:20237–20238

  • Federal Register (2016) 1-Bromopropane (1-BP); availability of TSCA work plan chemical risk assessment for public review and comment. U EPA. 81 FR 12098:12098–12099

    Google Scholar 

  • Fernandez RM, Bleda M, Luzon-Toro B, Garcia-Alonso L, Arnold S, Sribudiani Y, Besmond C, Lantieri F, Doan B, Ceccherini I, Lyonnet S, Hofstra RM, Chakravarti A, Antinolo G, Dopazo J, Borrego S (2013) Pathways systematically associated to Hirschsprung’s disease. Orphanet J Rare Dis 8:187

    Article  PubMed  PubMed Central  Google Scholar 

  • FQPA (1996). Food Quality Protection Act of 1995: hearings before the Subcommittee on Health and Environment of the Committee on Commerce, House of Representatives, One Hundred Fourth Congress, first session, on H.R. 1627, June 7 and 29, 1995. Washington, U.S. G.P.O: for sale by the U.S. G.P.O., Supt. of Docs., Congressional Sales Office

  • Fridley BL, Biernacka JM (2011) Gene set analysis of SNP data: benefits, challenges, and future directions. Eur J Hum Genet 19(8):837–843

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Fu C, Xie B, Zhang S, Wang J, Luo S, Zheng H, Su J, Hu X, Chen R, Fan X, Luo J, Gu X, Chen S (2016) Mutation screening of the TPO gene in a cohort of 192 Chinese patients with congenital hypothyroidism. BMJ Open 6(5):e010719

    Article  PubMed  PubMed Central  Google Scholar 

  • Fujibuchi W, Kim H, Okada Y, Taniguchi T, Sone H (2009). High-performance gene expression module analysis tool and its application to chemical toxicity data. Methods Mol Biol 577: 55–65

    Article  CAS  PubMed  Google Scholar 

  • Garner CE, Sloan C, Sumner SC, Burgess J, Davis J, Etheridge A, Parham A, Ghanayem BI (2007) CYP2E1-catalyzed oxidation contributes to the sperm toxicity of 1-bromopropane in mice. Biol Reprod 76(3):496–505

    Article  CAS  PubMed  Google Scholar 

  • Genomes Project Consortium (2010). A map of human genome variation from population-scale sequencing. Nature 467(7319):1061–1073

    Article  CAS  Google Scholar 

  • Genomes Project Consortium (2012). An integrated map of genetic variation from 1092 human genomes. Nature 491:10

    Google Scholar 

  • Genomes Project Consortium (2015b). An integrated map of structural variation in 2,504 human genomes. Nature 526(7571):75–81

    Article  CAS  Google Scholar 

  • Gertz M, Tsamandouras N, Säll C, Houston JB, Galetin A (2014) Reduced physiologically-based pharmacokinetic model of repaglinide: impact of OATP1B1 and CYP2C8 genotype and source of in vitro data on the prediction of drug-drug interaction risk. Pharm Res 31(9):2367–2382

    Article  CAS  PubMed  Google Scholar 

  • Gharib SA, Loth DW, Soler Artigas M, Birkland TP, Wilk JB, Wain LV, Brody JA, Obeidat M, Hancock DB, Tang W, Rawal R, Boezen HM, Imboden M, Huffman JE, Lahousse L, Alves AC, Manichaikul A, Hui J, Morrison AC, Ramasamy A, Smith AV, Gudnason V, Surakka I, Vitart V, Evans DM, Strachan DP, Deary IJ, Hofman A, Glaser S, Wilson JF, North KE, Zhao JH, Heckbert SR, Jarvis DL, Probst-Hensch N, Schulz H, Barr RG, Jarvelin MR, O’Connor GT, Kahonen M, Cassano PA, Hysi PG, Dupuis J, Hayward C, Psaty BM, Hall IP, Parks WC, Tobin MD, London SJ, C. Consortium and C. SpiroMeta (2015) Integrative pathway genomics of lung function and airflow obstruction. Hum Mol Genet 24(23):6836–6848

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Ginsberg G, Smolenski S, Neafsey P, Hattis D, Walker K, Guyton KZ, Johns DO, Sonawane B (2009) The influence of genetic polymorphisms on population variability in six xenobiotic-metabolizing enzymes. J Toxicol Environ Health B 12(5–6):307–333

    Article  CAS  Google Scholar 

  • Graf ME, Sookthai D, Johnson T, Schubel R, Katzke V, Bugert P, Hoffmeister M, Kaaks R, Kuhn T (2017). Biological reproducibility of circulating P-Selectin, Thrombopoietin, GPIIb/IIIa and Thrombomodulin over one year. Clin Biochem 50:942–946

    Article  CAS  PubMed  Google Scholar 

  • Greene CS, Krishnan A, Wong AK, Ricciotti E, Zelaya RA, Himmelstein DS, Zhang R, Hartmann BM, Zaslavsky E, Sealfon SC, Chasman DI, FitzGerald GA, Dolinski K, Grosser T, Troyanskaya OG (2015) Understanding multicellular function and disease with human tissue-specific networks. Nat Genet 47(6):569–576

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Gross-Davis C, Heavner K, Frank A, Newschaffer C, Klotz J, Santella R, Burstyn I (2015) The role of genotypes that modify the toxicity of chemical mutagens in the risk for myeloproliferative neoplasms. Int J Environ Res Public Health 12(3):2465–2485

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • GuhaThakurta D (2006) Computational identification of transcriptional regulatory elements in DNA sequence. Nucleic Acids Res 34(12):3585–3598

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Harrill AM, McAllister KA (2017). New rodent population models may inform human health risk assessment and identification of genetic susceptibility to environmental exposures. Environ Health Perspect 125(8):086002

    Article  PubMed  PubMed Central  Google Scholar 

  • He Q, Cai T, Liu Y, Zhao N, Harmon QE, Almli LM, Binder EB, Engel SM, Ressler KJ, Conneely KN, Lin X, Wu MC (2016) Prioritizing individual genetic variants after kernel machine testing using variable selection. Genet Epidemiol 40(8):722–731

    Article  PubMed  PubMed Central  Google Scholar 

  • Hormozdiari F, Kang EY, Bilow M, Ben-David E, Vulpe C, McLachlan S, Lusis AJ, Han B, Eskin E (2016a) Imputing phenotypes for genome-wide association studies. Am J Hum Genet 99(1):89–103

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Hormozdiari F, van de Bunt M, Segre AV, Li X, Joo JW, Bilow M, Sul JH, Sankararaman S, Pasaniuc B, Eskin E (2016b) Colocalization of GWAS and eQTL signals detects target genes. Am J Hum Genet 99(6):1245–1260

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Ideker T, Ozier O, Schwikowski B, Siegel AF (2002) Discovering regulatory signalling circuits in molecular interaction networks. Bioinformatics 18(Suppl 1):S233–S240

    Article  PubMed  Google Scholar 

  • Inoue S, Howgate EM, Rowland-Yeo K, Shimada T, Yamazaki H, Tucker GT, Rostami-Hodjegan A (2006) Prediction of in vivo drug clearance from in vitro data. II: potential inter-ethnic differences. Xenobiotica 36(6):499–513

    Article  CAS  PubMed  Google Scholar 

  • International HapMap Consortium (2007). A second generation human haplotype map of over 3.1 million SNPs. Nature 449(7164):851–861

    Article  CAS  Google Scholar 

  • IOMC (2017). Revised guidance document on developing and assessing adverse outcome pathways. E. D. O. F. E. C.-O. A. DEVELOPMENT. Paris, OECD Environment, Health and Safety Publications

  • Jamei M, Dickinson GL, Rostami-Hodjegan A (2009a) A framework for assessing inter-individual variability in pharmacokinetics using virtual human populations and integrating general knowledge of physical chemistry, biology, anatomy, physiology and genetics: a tale of ‘bottom-up’ vs ‘top-down’ recognition of covariates. Drug Metab Pharmacokinet 24(1):53–75

    Article  CAS  PubMed  Google Scholar 

  • Jamei M, Marciniak S, Feng K, Barnett A, Tucker G, Rostami-Hodjegan A (2009b) The Simcyp®Population-based ADME simulator. Expert Opin Drug Metab Toxicol 5(2):211–223

    Article  CAS  PubMed  Google Scholar 

  • Johanson G, Jonsson F, Bois F (1999) Development of new technique for risk assessment using physiologically based toxicokinetic models. Am J Ind Med Suppl 1:101–103

    Article  Google Scholar 

  • Johnson TN, Rostami-Hodjegan A, Tucker GT (2006) Prediction of the clearance of eleven drugs and associated variability in neonates, infants and children. Clin Pharmacokinet 45(9):931–956

    Article  CAS  PubMed  Google Scholar 

  • Judson RS, Mortensen HM, Shah I, Knudsen TB, Elloumi F (2012) Using pathway modules as targets for assay development in xenobiotic screening. Mol Biosyst 8(2):531–542

    Article  CAS  PubMed  Google Scholar 

  • Kavlock RJ, Austin CP, Tice RR (2009) Toxicity testing in the 21st century: implications for human health risk assessment. Risk Anal 29(4):485–487

    Article  PubMed  Google Scholar 

  • Krewski D, Westphal M, Andersen ME, Paoli GM, Chiu WA, Al-Zoughool M, Croteau MC, Burgoon LD, Cote I (2014) A framework for the next generation of risk science. Environ Health Perspect 122(8):796–805

    PubMed  PubMed Central  Google Scholar 

  • Kumar KK, Pugalenthi G, Suganthan PN (2009) DNA-Prot: identification of DNA binding proteins from protein sequence information using random forest. J Biomol Struct Dyn 26(6):679–686

    Article  CAS  PubMed  Google Scholar 

  • Lamb J, Crawford ED, Peck D, Modell JW, Blat IC, Wrobel MJ, Lerner J, Brunet JP, Subramanian A, Ross KN, Reich M, Hieronymus H, Wei G, Armstrong SA, Haggarty SJ, Clemons PA, Wei R, Carr SA, Lander ES, Golub TR (2006) The Connectivity Map: using gene-expression signatures to connect small molecules, genes, and disease. Science 313(5795):1929–1935

    Article  CAS  PubMed  Google Scholar 

  • Lee MY, Mukherjee N, Pakstis AJ, Khaliq S, Mohyuddin A, Mehdi SQ, Speed WC, Kidd JR, Kidd KK (2008) Global patterns of variation in allele and haplotype frequencies and linkage disequilibrium across the CYP2E1 gene. Pharmacogenomics J 8(5):349–356

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Lee I, Blom UM, Wang PI, Shim JE, Marcotte EM (2011) Prioritizing candidate disease genes by network-based boosting of genome-wide association data. Genome Res 21(7):1109–1121

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Liu F, Ichihara S, Mohideen SS, Sai U, Kitoh J, Ichihara G (2009) Comparative study on susceptibility to 1-bromopropane in three mice strains. Toxicol Sci 112(1):100–110

    Article  CAS  PubMed  Google Scholar 

  • Lonsdale J, Thomas J, Salvatore M, Phillips R, Lo E, Shad S, Hasz R, Walters G, Garcia F, Young N, Foster B, Moser M, Karasik E, Gillard B, Ramsey K, Sullivan S, Bridge J, Magazine H, Syron J, Fleming J, Siminoff L, Traino H, Mosavel M, Barker L, Jewell S, Rohrer D, Maxim D, Filkins D, Harbach P, Cortadillo E, Berghuis B, Turner L, Hudson E, Feenstra K, Sobin L, Robb J, Branton P, Korzeniewski G, Shive C, Tabor D, Qi L, Groch K, Nampally S, Buia S, Zimmerman A, Smith A, Burges R, Robinson K, Valentino K, Bradbury D, Cosentino M, Diaz-Mayoral N, Kennedy M, Engel T, Williams P, Erickson K, Ardlie K, Winckler W, Getz G, DeLuca D, MacArthur D, Kellis M, Thomson A, Young T, Gelfand E, Donovan M, Meng Y, Grant G, Mash D, Marcus Y, Basile M, Liu J, Zhu J, Tu Z, Cox NJ, Nicolae DL, Gamazon ER, Im HK, Konkashbaev A, Pritchard J, Stevens M, Flutre T, Wen X, Dermitzakis ET, Lappalainen T, Guigo R, Monlong J, Sammeth M, Koller D, Battle A, Mostafavi S, McCarthy M, Rivas M, Maller J, Rusyn I, Nobel A, Wright F, Shabalin A, Feolo M, Sharopova N, Sturcke A, Paschal J, Anderson JM, Wilder EL, Derr LK, Green ED, Struewing JP, Temple G, Volpi S, Boyer JT, Thomson EJ, Guyer MS, Ng C, Abdallah A, Colantuoni D, Insel TR, Koester SE, Little AR, Bender PK, Lehner T, Yao Y, Compton CC, Vaught JB, Sawyer S, Lockhart NC, Demchok J, Moore HF (2013) The genotype-tissue expression (GTEx) project. Nat Genet 45(6):580–585

    Article  CAS  Google Scholar 

  • Mitra K, Carvunis AR, Ramesh SK, Ideker T (2013) Integrative approaches for finding modular structure in biological networks. Nat Rev Genet 14(10):719–732

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Mooney MA, Wilmot B (2015) Gene set analysis: a step-by-step guide. Am J Med Genet B 168(7):517–527

    Article  Google Scholar 

  • Mortensen HM, Euling SY (2013) Integrating mechanistic and polymorphism data to characterize human genetic susceptibility for environmental chemical risk assessment in the 21st century. Toxicol Appl Pharmacol 271(3):395–404

    Article  CAS  PubMed  Google Scholar 

  • NRC (2009). Science and decisions: advancing risk assessment. The National Academies Press, Washington, DC

    Google Scholar 

  • NRC (2010). Toxicity-pathway-based risk assessment: preparing for paradigm change: a symposium summary. The National Academies Press, Washington, DC

    Google Scholar 

  • NRC (2011a). Review of the environmental protection agency’s draft IRIS assessment of formaldehyde. The National Academies Press, Washington, DC

    Google Scholar 

  • NRC (2014a). Critical aspects of EPA’s IRIS assessment of inorganic arsenic: interim report. The National Academies Press, Washington (DC)

    Google Scholar 

  • NRC (2014b). Review of EPA’s integrated risk information system (IRIS) process. The National Academies Press, Washington, DC

    Google Scholar 

  • NRC (2016). Interindividual variability: new ways to study and implications for decision making: workshop in brief. The National Academies Press, Washington, DC

    Google Scholar 

  • NRC (2017). Using 21st century science to improve risk-related evaluations. The National Academies Press, Washington, DC

    Google Scholar 

  • Oki NO, Nelms MD, Bell SM, Mortensen HM, Edwards SW (2016) Accelerating adverse outcome pathway development using publicly available data sources. Curr Environ Health Rep 3(1):53–63

    Article  PubMed  Google Scholar 

  • Patlewicz G, Simon TW, Rowlands JC, Budinsky RA, Becker RA (2015) Proposing a scientific confidence framework to help support the application of adverse outcome pathways for regulatory purposes. Regul Toxicol Pharmacol 71(3):463–477

    Article  PubMed  Google Scholar 

  • Pearce RG, Setzer RW, Strope CL, Sipes NS, Wambaugh JF (2017). httk: R package for high-throughput toxicokinetics. J Stat Softw 79(4):1–26

    Article  Google Scholar 

  • Piñero J, Bravo À, Queralt-Rosinach N, Gutiérrez-Sacristán A, Deu-Pons J, Centeno E, García-García J, Sanz F, Furlong LI (2016) DisGeNET: a comprehensive platform integrating information on human disease-associated genes and variants. Nucleic Acids Res 45(D1):D833–D839

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Pittman M, Edwards SW, Ives C, Mortensen HM (2017). AOP-DB: a database resource for the exploration of adverse outcome pathways through integrated association networks. Toxicol Appl Pharmacol. https://doi.org/10.1016/j.taap.2018.02.006

    Google Scholar 

  • Polak S, Ghobadi C, Mishra H, Ahamadi M, Patel N, Jamei M, Rostami-Hodjegan A (2012) Prediction of concentration–time profile and its inter-individual variability following the dermal drug absorption. J Pharm Sci 101(7):2584–2595

    Article  CAS  PubMed  Google Scholar 

  • Public Law 114–182 (2016). Frank R. Lautenberg Chemical Safety for the 21st Century Act U. Congres

  • Qi Y, Ge H (2006) Modularity and dynamics of cellular networks. PLoS Comput Biol 2(12):e174

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Reyes-Gibby CC, Melkonian SC, Wang J, Yu RK, Shelburne SA, Lu C, Gunn GB, Chambers MS, Hanna EY, Yeung S-CJ, Shete S (2017) Identifying novel genes and biological processes relevant to the development of cancer therapy-induced mucositis: an informative gene network analysis. PLoS ONE 12(7):e0180396

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Ring CL, Pearce RG, Setzer RW, Wetmore BA, Wambaugh JF (2017) Identifying populations sensitive to environmental chemicals by simulating toxicokinetic variability. Environ Int 106:105–118

    Article  CAS  PubMed  Google Scholar 

  • Rostami-Hodjegan A (2012) Physiologically based pharmacokinetics joined with in vitro–in vivo extrapolation of ADME: a marriage under the arch of systems pharmacology. Clin Pharmacol Ther 92(1):50–61

    Article  CAS  PubMed  Google Scholar 

  • Rostami-Hodjegan A, Tucker GT (2007) Simulation and prediction of in vivo drug metabolism in human populations from in vitro data. Nat Rev Drug Dis 6(2):140–148

    Article  CAS  Google Scholar 

  • Rotroff DM, Wetmore BA, Dix DJ, Ferguson SS, Clewell HJ, Houck KA, LeCluyse EL, Andersen ME, Judson RS, Smith CM, Sochaski MA, Kavlock RJ, Boellmann F, Martin MT, Reif DM, Wambaugh JF, Thomas RS (2010) Incorporating human dosimetry and exposure into high-throughput in vitro toxicity screening. Toxicol Sci 117(2):348–358

    Article  CAS  PubMed  Google Scholar 

  • Sacks JD, Stanek LW, Luben TJ, Johns DO, Buckley BJ, Brown JS, Ross M (2010) Particulate matter-induced health effects: who is susceptible? Environ Health Perspect 119:446–454

    Article  PubMed  PubMed Central  Google Scholar 

  • Sager JE, Yu J, Ragueneau-Majlessi I, Isoherranen N (2015) Physiologically based pharmacokinetic (PBPK) modeling and simulation approaches: a systematic review of published models, applications, and model verification. Drug Metab Dispos 43(11):1823–1837

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • SDWA (1996). Safe Drinking Water Act Amendments of 1995: hearing before the Committee on Environment and Public Works, United States Senate, One Hundred Fourth Congress, first session, on S. 1316, a bill to reauthorize and amend Title XIV of the Public Health Service Act (commonly known as the Safe Drinking Water Act”), and for other purposes, October 19, 1995. Washington: For sale by the U.S. G.P.O. Supt. of Docs., Congressional Sales Office

  • Smalley JL, Gant TW, Zhang S-D (2010) Application of connectivity mapping in predictive toxicology based on gene-expression similarity. Toxicology 268(3):143–146

    Article  CAS  PubMed  Google Scholar 

  • Snel B, Huynen MA (2004) Quantifying modularity in the evolution of biomolecular systems. Genome Res 14(3):391–397

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • The International HapMap Consortium (2005). A haplotype map of the human genome. Nature 437(7063):1299–1320

    Article  PubMed Central  CAS  Google Scholar 

  • Threadgill DW, Churchill GA (2012) Ten years of the collaborative cross. G3 2:153–156

    Article  PubMed  PubMed Central  Google Scholar 

  • Timchalk C, Kousba A, Poet TS (2002) Monte Carlo analysis of the human chlorpyrifos-oxonase (PON1) polymorphism using a physiologically based pharmacokinetic and pharmacodynamic (PBPK/PD) model. Toxicol Lett 135(1–2):51–59

    Article  CAS  PubMed  Google Scholar 

  • Tishkoff SA (2001) Haplotype diversity and linkage disequilibrium at human G6PD: recent origin of alleles that confer malarial resistance. Science 293(5529):455–462

    Article  CAS  PubMed  Google Scholar 

  • Torkamani A, Topol EJ, Schork NJ (2008) Pathway analysis of seven common diseases assessed by genome-wide association. Genomics 92(5):265–272

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • US EPA (2002). Toxicological Review of Benzene (NonCancer Effects) (In Support of Summary Information of the Integrated Risk Information System (IRIS)). US EPA, Washington DC

  • US EPA (2014). TSCA Work Plan for Chemical Assessments: 2014 Update. O. o. P. P. a. Toxics

  • Venkatratnam A, Furuya S, Kosyk O, Gold A, Bodnar W, Konganti K, Threadgill DW, Gillespie KM, Aylor DL, Wright FA, Chiu WA, Rusyn I (2017). Collaborative Cross mouse population enables refinements to characterization of the variability in toxicokinetics of trichloroethylene and provides genetic evidence for the role of PPAR pathway in its oxidative metabolism. Toxicol Sci 158:48–62

    Article  CAS  PubMed  Google Scholar 

  • Villeneuve DL, Crump D, Garcia-Reyero N, Hecker M, Hutchinson TH, LaLone CA, Landesmann B, Lettieri T, Munn S, Nepelska M, Ottinger MA, Vergauwen L, Whelan M (2014a) Adverse outcome pathway (AOP) development I: strategies and principles. Toxicol Sci 142(2):312–320

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Villeneuve DL, Crump D, Garcia-Reyero N, Hecker M, Hutchinson TH, LaLone CA, Landesmann B, Lettieri T, Munn S, Nepelska M, Ottinger MA, Vergauwen L, Whelan M (2014b) Adverse outcome pathway development II: best practices. Toxicol Sci 142(2):321–330

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Vinikoor-Imler LC, Owens EO, Nichols JL, Ross M, Brown JS, Sacks JD (2014) Evaluating potential response-modifying factors for associations between ozone and health outcomes: a weight-of-evidence approach. Environ Health Perspect 122(11):1166–1176

    CAS  PubMed  PubMed Central  Google Scholar 

  • Wambaugh JF, Wetmore BA, Pearce R, Strope C, Goldsmith R, Sluka JP, Sedykh A, Tropsha A, Bosgra S, Shah I, Judson R, Thomas RS, Setzer RW (2015) Toxicokinetic triage for environmental chemicals. Toxicol Sci 147(1):55–67

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Wetmore BA, Wambaugh JF, Ferguson SS, Sochaski MA, Rotroff DM, Freeman K, Clewell HJ 3rd, Dix DJ, Andersen ME, Houck KA, Allen B, Judson RS, Singh R, Kavlock RJ, Richard AM, Thomas RS (2012). Integration of dosimetry, exposure, and high-throughput screening data in chemical toxicity assessment. Toxicol Sci 125(1):157–174

    Article  CAS  PubMed  Google Scholar 

  • Wetmore BA, Allen B, Clewell HJ, Parker T, Wambaugh JF, Almond LM, Sochaski MA, Thomas RS (2014) Incorporating population variability and susceptible subpopulations into dosimetry for high-throughput toxicity testing. Toxicol Sci 142(1):210–224

    Article  CAS  PubMed  Google Scholar 

  • Wilson SH, Olden K (2004) The environmental genome project: phase i and beyond. Mol Interv 4(3):10

    Google Scholar 

  • Yang C, Zhou X, Wan X, Yang Q, Xue H, Yu W (2011) Identifying disease-associated SNP clusters via contiguous outlier detection. Bioinformatics 27(18):2578–2585

    Article  CAS  PubMed  Google Scholar 

  • Yates A, Akanni W, Amode MR, Barrell D, Billis K, Carvalho-Silva D, Cummins C, Clapham P, Fitzgerald S, Gil L, Girón CG, Gordon L, Hourlier T, Hunt SE, Janacek SH, Johnson N, Juettemann T, Keenan S, Lavidas I, Martin FJ, Maurel T, McLaren W, Murphy DN, Nag R, Nuhn M, Parker A, Patricio M, Pignatelli M, Rahtz M, Riat HS, Sheppard D, Taylor K, Thormann A, Vullo A, Wilder SP, Zadissa A, Birney E, Harrow J, Muffato M, Perry E, Ruffier M, Spudich G, Trevanion SJ, Cunningham F, Aken BL, Zerbino DR, Flicek P (2015) Ensembl 2016. Nucleic Acids Res 44(D1):D710–D716

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Zaghloul NA, Katsanis N (2010) Functional modules, mutational load and human genetic disease. Trends Genet 26(4):168–176

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Zerbino DR, Wilder SP, Johnson N, Juettemann T, Flicek PR (2015) The ensembl regulatory build. Genome Biol 16:56

    Article  PubMed  PubMed Central  Google Scholar 

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Acknowledgements

We would like to acknowledge funding for this project from the EPA’s Office of Research and Development (ORD) Human Health Risk Assessment (HHRA) National Research Program. We would like to thank Debora Segal, Michael Wright, Annie Jarabek, Brian Chorley, Hisham El-Masri for many helpful discussions on the approach, and thoughtful review of the manuscript. We also thank two anonymous reviewers. We thank Ryan Jones and William Griffin at HERO at EPA for assistance with literature searches.

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  1. Susan Y. Euling

    Present address: Office of Children’s Health Protection, US Environmental Protection, Washington, DC, 20460, USA

Authors and Affiliations

  1. NHEERL, US Environmental Protection Agency, Research Triangle Park, NC, 27709, USA

    Holly M. Mortensen

  2. Oak Ridge Associated Universities, Research Triangle Park, NC, 27709, USA

    John Chamberlin

  3. National Institute of Environmental Health Sciences, Research Triangle Park, NC, 27709, USA

    Bonnie Joubert

  4. NCEA, US Environmental Protection Agency, Research Triangle Park, NC, USA

    Michelle Angrish & Janice S. Lee

  5. NTP, National Institute of Environmental Health Sciences, Research Triangle Park, NC, 27709, USA

    Nisha Sipes

  6. NCEA, US Environmental Protection Agency, Washington, DC, 20460, USA

    Susan Y. Euling

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Mortensen, H.M., Chamberlin, J., Joubert, B. et al. Leveraging human genetic and adverse outcome pathway (AOP) data to inform susceptibility in human health risk assessment. Mamm Genome 29, 190–204 (2018). https://doi.org/10.1007/s00335-018-9738-7

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