Using Exposomics to Assess Cumulative Risks from Multiple Environmental Stressors

  • Martyn T. SmithEmail author
  • Cliona M. McHale
  • Rosemarie de la Rosa


Humans are exposed to a milieu of environmental stressors of a chemical, physical, and social nature that may change over time. Interaction of these stressors with various intrinsic factors such as genetics, sex, life stage, and health status determines susceptibility to related diseases. Cumulative risk assessment seeks to determine the combined risks to health from exposures to multiple agents or stressors. This can be achieved by expanding beyond a G × E approach—where “G” represents genetic susceptibility and “E” (environment) represents a limited range of exposures—to an I × E approach—where “I” (intrinsic) represents the many inter-related biological factors that contribute to disease susceptibility and “E” (extrinsic) represents all nongenetic factors including the exposome. Exposomics is poised to advance this concept and make significant advances in environmental health science and our understanding of the causes of chronic diseases. The internal exposome can be assessed using targeted and untargeted exposomics tools to measure individual chemicals, groups of chemicals, or the totality of chemicals acting on a particular receptor or biological pathway in a functional assay. Comprehensive data on the internal, external, and public health components of the exposome together could inform risk assessment and ultimately guide risk management. These approaches could be applied in vulnerable populations such as migrants or those burdened with multiple types of stressor simultaneously as identified through map- or indicator-based approaches. Development and refinement of additional exposomics tools that can be applied in prospective human epidemiology studies should be a focus of future studies.


Cumulative risk Environmental stressors Internal exposome Stressogens 



We thank our lab colleagues Sarah Daniels, Sylvia Sanchez, Fenna Sille, Phum Tachachartvanich, Luoping Zhang, and Felicia Castriota and collaborators Laura Fejerman, Stephen Rappaport, Esther John, Anthony Macherone, Paul Elliott, Jaspal Kooner, John Chambers, Michele La Merrill, Craig Steinmaus, Allan Smith, Daniel Nomura, Jen-Chywan Wang, Kurt Pennell, Michael Denison, and Catherine Thomsen for their collaboration in pursuing exposomics. This work was supported by NIH grant P42 ES004705 from the National Institute of Environmental Health Sciences and award 21UB-8009 from the California Breast Cancer Research Program.


  1. Aldini G, Vistoli G, Regazzoni L, Gamberoni L, Facino RM, Yamaguchi S, Uchida K, Carini M (2008) Albumin is the main nucleophilic target of human plasma: a protective role against pro-atherogenic electrophilic reactive carbonyl species? Chem Res Toxicol 21(4):824–835CrossRefGoogle Scholar
  2. Bakker LE, Sleddering MA, Schoones JW, Meinders AE, Jazet IM (2013) Pathogenesis of type 2 diabetes in South Asians. Eur J Endocrinol 169(5):R99–R114. Scholar
  3. Barker DJ (2004) The developmental origins of adult disease. J Am Coll Nutr 23(6 Suppl):588S–595SCrossRefGoogle Scholar
  4. Bessonneau V, Pawliszyn J, Rappaport SM (2017) The saliva exposome for monitoring of individuals’ health trajectories. Environ Health Perspect 125(7):077014. Scholar
  5. Blackburn EH, Epel ES (2012) Telomeres and adversity: too toxic to ignore. Nature 490(7419):169–171. Scholar
  6. Brouwers MM, Besselink H, Bretveld RW, Anzion R, Scheepers PT, Brouwer A, Roeleveld N (2011) Estrogenic and androgenic activities in total plasma measured with reporter-gene bioassays: relevant exposure measures for endocrine disruptors in epidemiologic studies? Environ Int 37(3):557–564. Scholar
  7. Carballal S, Radi R, Kirk MC, Barnes S, Freeman BA, Alvarez B (2003) Sulfenic acid formation in human serum albumin by hydrogen peroxide and peroxynitrite. Biochemistry 42(33):9906–9914. Scholar
  8. Chen E, Schreier HM, Strunk RC, Brauer M (2008) Chronic traffic-related air pollution and stress interact to predict biologic and clinical outcomes in asthma. Environ Health Perspect 116(7):970–975. Scholar
  9. Chen Y, Yao H, Thompson EJ, Tannir NM, Weinstein JN, Su X (2013) VirusSeq: software to identify viruses and their integration sites using next-generation sequencing of human cancer tissue. Bioinformatics 29(2):266–267. Scholar
  10. Clougherty JE, Levy JI, Kubzansky LD, Ryan PB, Suglia SF, Canner MJ, Wright RJ (2007) Synergistic effects of traffic-related air pollution and exposure to violence on urban asthma etiology. Environ Health Perspect 115(8):1140–1146. Scholar
  11. Cox S, Niskar AS, Narayan KM, Marcus M (2007) Prevalence of self-reported diabetes and exposure to organochlorine pesticides among Mexican Americans: Hispanic health and nutrition examination survey, 1982–1984. Environ Health Perspect 115(12):1747–1752. Scholar
  12. Cushing L, Faust J, August LM, Cendak R, Wieland W, Alexeeff G (2015) Racial/ethnic disparities in cumulative environmental health impacts in California: evidence from a statewide environmental justice screening tool (CalEnviroScreen 1.1). Am J Public Health 105(11):2341–2348. Scholar
  13. Dossus L, Becker S, Achaintre D, Kaaks R, Rinaldi S (2009) Validity of multiplex-based assays for cytokine measurements in serum and plasma from “non-diseased” subjects: comparison with ELISA. J Immunol Methods 350(1–2):125–132. Scholar
  14. Dupont NC, Wang K, Wadhwa PD, Culhane JF, Nelson EL (2005) Validation and comparison of luminex multiplex cytokine analysis kits with ELISA: determinations of a panel of nine cytokines in clinical sample culture supernatants. J Reprod Immunol 66(2):175–191 Scholar
  15. Ehrenberg L, Granath F, Tornqvist M (1996) Macromolecule adducts as biomarkers of exposure to environmental mutagens in human populations. [Review] [38 refs]. Environ Health Perspect 104(Suppl 3):423–428CrossRefGoogle Scholar
  16. Elshal MF, McCoy JP (2006) Multiplex bead array assays: performance evaluation and comparison of sensitivity to ELISA. Methods 38(4):317–323. Scholar
  17. Feil R, Fraga MF (2012) Epigenetics and the environment: emerging patterns and implications. Nat Rev Genet 13(2):97–109. Scholar
  18. Fejerman L, Sanchez SS, Thomas R, Tachachartvanich P, Riby J, Gomez SL, John EM, Smith MT (2016) Association of lifestyle and demographic factors with estrogenic and glucocorticogenic activity in Mexican American women. Carcinogenesis 37(9):904–911. Scholar
  19. Feng H, Taylor JL, Benos PV, Newton R, Waddell K, Lucas SB, Chang Y, Moore PS (2007) Human transcriptome subtraction by using short sequence tags to search for tumor viruses in conjunctival carcinoma. J Virol 81(20):11332–11340. Scholar
  20. Finkelstein MM, Jerrett M, DeLuca P, Finkelstein N, Verma DK, Chapman K, Sears MR (2003) Relation between income, air pollution and mortality: a cohort study. CMAJ 169(5):397–402Google Scholar
  21. Gonzalez-Bulnes A, Astiz S, Ovilo C, Garcia-Contreras C, Vazquez-Gomez M (2016) Nature and nurture in the early-life origins of metabolic syndrome. Curr Pharm Biotechnol 17(7):573–586CrossRefGoogle Scholar
  22. Granath F, Ehrenberg L, Tornqvist M (1992) Degree of alkylation of macromolecules in vivo from variable exposure. Mutat Res 284:297–306CrossRefGoogle Scholar
  23. Grigoryan H, Edmands WMB, Lan Q, Carlsson H, Vermeulen R, Zhang L, Yin S-N, Li G-L, Smith MT, Rothman N, Rappaport SM (2018) Adductomic signatures of benzene exposure provide insights into cancer induction. Carcinogenesis 39(5):661–668CrossRefGoogle Scholar
  24. Hasmik Grigoryan, William M B Edmands, Qing Lan, Henrik Carlsson, Roel Vermeulen, Luoping Zhang, Song-Nian Yin, Gui-Lan Li, Martyn T Smith, Nathaniel Rothman, Stephen M Rappaport, (2018) Adductomic signatures of benzene exposure provide insights into cancer induction. Carcinogenesis 39 (5):661-668CrossRefGoogle Scholar
  25. Guan C, Dang R, Cui Y, Liu L, Chen X, Wang X, Zhu J, Li D, Li J, Wang D (2017) Characterization of plasma metal profiles in Alzheimer’s disease using multivariate statistical analysis. PLoS One 12(7):e0178271. Scholar
  26. Hattis D, Banati P, Goble R (1999) Distributions of individual susceptibility among humans for toxic effects. How much protection does the traditional tenfold factor provide for what fraction of which kinds of chemicals and effects? Ann N Y Acad Sci 895:286–316CrossRefGoogle Scholar
  27. Haugen AC, Schug TT, Collman G, Heindel JJ (2015) Evolution of DOHaD: the impact of environmental health sciences. J Dev Orig Health Dis 6(2):55–64. Scholar
  28. Herceg Z, Lambert MP, van Veldhoven K, Demetriou C, Vineis P, Smith MT, Straif K, Wild CP (2013) Towards incorporating epigenetic mechanisms into carcinogen identification and evaluation. Carcinogenesis 34(9):1955–1967. Scholar
  29. Jaacks LM, Staimez LR (2015) Association of persistent organic pollutants and non-persistent pesticides with diabetes and diabetes-related health outcomes in Asia: a systematic review. Environ Int 76:57–70. Scholar
  30. Jones DP (2016) Sequencing the exposome: a call to action. Toxicol Rep 3:29–45. Scholar
  31. Juarez PD, Matthews-Juarez P, Hood DB, Im W, Levine RS, Kilbourne BJ, Langston MA, Al-Hamdan MZ, Crosson WL, Estes MG, Estes SM, Agboto VK, Robinson P, Wilson S, Lichtveld MY (2014) The public health exposome: a population-based, exposure science approach to health disparities research. Int J Environ Res Public Health 11(12):12866–12895. Scholar
  32. Khoury JD, Tannir NM, Williams MD, Chen Y, Yao H, Zhang J, Thompson EJ, Network T, Meric-Bernstam F, Medeiros LJ, Weinstein JN, Su X (2013) Landscape of DNA virus associations across human malignant cancers: analysis of 3,775 cases using RNA-Seq. J Virol 87(16):8916–8926. Scholar
  33. Kostic AD, Ojesina AI, Pedamallu CS, Jung J, Verhaak RG, Getz G, Meyerson M (2011) PathSeq: software to identify or discover microbes by deep sequencing of human tissue. Nat Biotechnol 29(5):393–396. Scholar
  34. Lee JT, Son JY, Kim H, Kim SY (2006) Effect of air pollution on asthma-related hospital admissions for children by socioeconomic status associated with area of residence. Arch Environ Occup Health 61(3):123–130. Scholar
  35. Liebler DC (2008) Protein damage by reactive electrophiles: targets and consequences. Chem Res Toxicol 21(1):117–128. Scholar
  36. Lill CM (2016) Genetics of Parkinson’s disease. Mol Cell Probes 30(6):386–396. Scholar
  37. Lin M, Chen Y, Villeneuve PJ, Burnett RT, Lemyre L, Hertzman C, McGrail KM, Krewski D (2004) Gaseous air pollutants and asthma hospitalization of children with low household income in Vancouver, British Columbia, Canada. Am J Epidemiol 159(3):294–303CrossRefGoogle Scholar
  38. Lu SS, Grigoryan H, Edmands WM, Hu W, Iavarone AT, Hubbard A, Rothman N, Vermeulen R, Lan Q, Rappaport SM (2017) Profiling the serum albumin Cys34 adductome of solid fuel users in Xuanwei and Fuyuan, China. Environ Sci Technol 51(1):46–57. Scholar
  39. Macherone A, Daniels S, Maggitti A, Churley M, McMullin M, Smith MT (2015) Measuring a slice of the exposome: targeted GC-MS/MS analysis of persistent organic pollutants POPs) in small violumes of human plasma. In: 63rd AMS conference on mass spectrometry and allied topics, St. Louis, MO, p Abstract TP 309Google Scholar
  40. Markides KS, Coreil J (1986) The health of Hispanics in the southwestern United States: an epidemiologic paradox. Public Health Rep 101(3):253–265Google Scholar
  41. Martins MC, Fatigati FL, Vespoli TC, Martins LC, Pereira LA, Martins MA, Saldiva PH, Braga AL (2004) Influence of socioeconomic conditions on air pollution adverse health effects in elderly people: an analysis of six regions in Sao Paulo, Brazil. J Epidemiol Community Health 58(1):41–46CrossRefGoogle Scholar
  42. McEwen BS (1998) Stress, adaptation, and disease. Allostasis and allostatic load. Ann N Y Acad Sci 840:33–44CrossRefGoogle Scholar
  43. McHale CM, Smith MT, Zhang L (2016) Application of toxicogenomics in exposed human populations: benzene as an example. Toxicogenomics in Predictive Carcinogenicity, vol 28, The Royal Society of Chemistry, Cambridge, UKGoogle Scholar
  44. McHale CM, Osborne G, Morello-Frosch R, Salmon AG, Sandy M, Solomon G, Zhang L, Smith MT, Zeise L (2018) Assessing health risks from multiple environmental stressors: a paradigm shift from GxE to IxE. Mutat Res Rev 775:11–20. Scholar
  45. Meehan August L, Faust JB, Cushing L, Zeise L, Alexeeff GV (2012) Methodological considerations in screening for cumulative environmental health impacts: lessons learned from a pilot study in California. Int J Environ Res Public Health 9(9):3069–3084. Scholar
  46. Menzie CA, MacDonell MM, Mumtaz M (2007) A phased approach for assessing combined effects from multiple stressors. Environ Health Perspect 115(5):807–816. Scholar
  47. Moore RA, Warren RL, Freeman JD, Gustavsen JA, Chenard C, Friedman JM, Suttle CA, Zhao Y, Holt RA (2011) The sensitivity of massively parallel sequencing for detecting candidate infectious agents associated with human tissue. PLoS One 6(5):e19838. Scholar
  48. Morello-Frosch R, Shenassa ED (2006) The environmental “riskscape” and social inequality: implications for explaining maternal and child health disparities. Environ Health Perspect 114(8):1150–1153CrossRefGoogle Scholar
  49. Morello-Frosch R, Zuk M, Jerrett M, Shamasunder B, Kyle AD (2011) Understanding the cumulative impacts of inequalities in environmental health: implications for policy. Health Aff 30(5):879–887. Scholar
  50. Moretto A, Bachman A, Boobis A, Solomon KR, Pastoor TP, Wilks MF, Embry MR (2017) A framework for cumulative risk assessment in the 21st century. Crit Rev Toxicol 47(2):85–97. Scholar
  51. Naeem R, Rashid M, Pain A (2013) READSCAN: a fast and scalable pathogen discovery program with accurate genome relative abundance estimation. Bioinformatics 29(3):391–392. Scholar
  52. National Research Council (2008) Phthalates and cumulative risk assessment. National Academy Press, Washington, DCGoogle Scholar
  53. National Research Council (2009) Science and decisions: advancing risk assessment. committee on improving risk analysis approaches used by the U.S. EPA, Board on Environmental Studies and Toxicology, Division on Earth and Life Studies, Washington DCGoogle Scholar
  54. Neidell MJ (2004) Air pollution, health, and socio-economic status: the effect of outdoor air quality on childhood asthma. J Health Econ 23(6):1209–1236. Scholar
  55. Newbold R (1995) Cellular and molecular effects of developmental exposure to diethylstilbestrol: implications for other environmental estrogens. Environ Health Perspect 103(Suppl 7):83–87CrossRefGoogle Scholar
  56. OEHHA (2017) California Communities Environmental Health, Version 3.0 (CalEnviroscreen 3.0) screening tool. OEHHA, California Environmental Protection agency.
  57. Perera FP, Wang S, Rauh V, Zhou H, Stigter L, Camann D, Jedrychowski W, Mroz E, Majewska R (2013) Prenatal exposure to air pollution, maternal psychological distress, and child behavior. Pediatrics 132(5):e1284–e1294. Scholar
  58. Ponce NA, Hoggatt KJ, Wilhelm M, Ritz B (2005) Preterm birth: the interaction of traffic-related air pollution with economic hardship in Los Angeles neighborhoods. Am J Epidemiol 162(2):140–148. Scholar
  59. Rappaport SM, Smith MT (2010) Epidemiology. Environment and disease risks. Science (New York, NY) 330(6003):460–461. Scholar
  60. Rappaport SM, Li H, Grigoryan H, Funk WE, Williams ER (2012) Adductomics: characterizing exposures to reactive electrophiles. Toxicol Lett 213(1):83–90. Scholar
  61. Rappaport SM, Barupal DK, Wishart D, Vineis P, Scalbert A (2014) The blood exposome and its role in discovering causes of disease. Environ Health Perspect 122(8):769–774. Scholar
  62. Ravelli GP, Stein ZA, Susser MW (1976) Obesity in young men after famine exposure in utero and early infancy. N Engl J Med 295(7):349–353. Scholar
  63. Renwick AG, Lazarus NR (1998) Human variability and noncancer risk assessment—an analysis of the default uncertainty factor. Regul Toxicol Pharmacol 27(1 Pt 1):3–20CrossRefGoogle Scholar
  64. Rider CV, Furr JR, Wilson VS, Gray LE Jr (2010) Cumulative effects of in utero administration of mixtures of reproductive toxicants that disrupt common target tissues via diverse mechanisms of toxicity. Int J Androl 33(2):443–462. Scholar
  65. Roede JR, Uppal K, Park Y, Lee K, Tran V, Walker D, Strobel FH, Rhodes SL, Ritz B, Jones DP (2013) Serum metabolomics of slow vs. rapid motor progression Parkinson’s disease: a pilot study. PLoS One 8(10):e77629. Scholar
  66. Rotroff DM, Motsinger-Reif AA (2016) Embracing integrative multiomics approaches. Int J Genomics 2016:1715985. Scholar
  67. Rubino FM, Pitton M, Di Fabio D, Colombi A (2009) Toward an “omic” physiopathology of reactive chemicals: thirty years of mass spectrometric study of the protein adducts with endogenous and xenobiotic compounds. Mass Spectrom Rev 28(5):725–784. Scholar
  68. Shmool JL, Kubzansky LD, Newman OD, Spengler J, Shepard P, Clougherty JE (2014) Social stressors and air pollution across New York City communities: a spatial approach for assessing correlations among multiple exposures. Environ Health 13:91. Scholar
  69. Simonds NI, Ghazarian AA, Pimentel CB, Schully SD, Ellison GL, Gillanders EM, Mechanic LE (2016) Review of the gene-environment interaction literature in cancer: what do we know? Genet Epidemiol 40(5):356–365. Scholar
  70. Singh GK, Miller BA (2004) Health, life expectancy, and mortality patterns among immigrant populations in the United States. Can J Public Health 95(3):I14–I21Google Scholar
  71. Smith MT, de la Rosa R, Daniels SI (2015) Using exposomics to assess cumulative risks and promote health. Environ Mol Mutagen 56(9):715–723. Scholar
  72. Solomon GM, Morello-Frosch R, Zeise L, Faust JB (2016) Cumulative environmental impacts: science and policy to protect communities. Annu Rev Public Health 37:83–96. Scholar
  73. Stein LJ, Gunier RB, Harley K, Kogut K, Bradman A, Eskenazi B (2016) Early childhood adversity potentiates the adverse association between prenatal organophosphate pesticide exposure and child IQ: the CHAMACOS cohort. Neurotoxicology 56:180–187. Scholar
  74. Steinmaus C, Castriota F, Ferreccio C, Smith AH, Yuan Y, Liaw J, Acevedo J, Perez L, Meza R, Calcagno S, Uauy R, Smith MT (2015) Obesity and excess weight in early adulthood and high risks of arsenic-related cancer in later life. Environ Res 142:594–601. Scholar
  75. Steptoe A, Hamer M, Butcher L, Lin J, Brydon L, Kivimaki M, Marmot M, Blackburn E, Erusalimsky JD (2011) Educational attainment but not measures of current socioeconomic circumstances are associated with leukocyte telomere length in healthy older men and women. Brain Behav Immun 25(7):1292–1298. Scholar
  76. Szentpetery SE, Forno E, Canino G, Celedon JC (2016) Asthma in Puerto Ricans: lessons from a high-risk population. J Allergy Clin Immunol 138(6):1556–1558. Scholar
  77. Trasande L, Zoeller RT, Hass U, Kortenkamp A, Grandjean P, Myers JP, DiGangi J, Bellanger M, Hauser R, Legler J, Skakkebaek NE, Heindel JJ (2015) Estimating burden and disease costs of exposure to endocrine-disrupting chemicals in the European union. J Clin Endocrinol Metab 100(4):1245–1255. Scholar
  78. Turner MC, Nieuwenhuijsen M, Anderson K, Balshaw D, Cui Y, Dunton G, Hoppin JA, Koutrakis P, Jerrett M (2017) Assessing the exposome with external measures: commentary on the state of the science and research recommendations. Annu Rev Public Health 38:215–239. Scholar
  79. US EPA (2003) Framework for cumulative risk assessment. vol EPA/600/P-02/001F. U.S. Environmental Protection Agency, Office of Research and Development, National Center for Environmental Assessment, Washington, DCGoogle Scholar
  80. Vesterinen HM, Morello-Frosch R, Sen S, Zeise L, Woodruff TJ (2017) Cumulative effects of prenatal-exposure to exogenous chemicals and psychosocial stress on fetal growth: systematic-review of the human and animal evidence. PLoS One 12(7):e0176331. Scholar
  81. Vieira VM, Villanueva C, Chang J, Ziogas A, Bristow RE (2017) Impact of community disadvantage and air pollution burden on geographic disparities of ovarian cancer survival in California. Environ Res 156:388–393. Scholar
  82. Vishnevetsky J, Tang D, Chang HW, Roen EL, Wang Y, Rauh V, Wang S, Miller RL, Herbstman J, Perera FP (2015) Combined effects of prenatal polycyclic aromatic hydrocarbons and material hardship on child IQ. Neurotoxicol Teratol 49:74–80. Scholar
  83. Weber G, Shendure J, Tanenbaum DM, Church GM, Meyerson M (2002) Identification of foreign gene sequences by transcript filtering against the human genome. Nat Genet 30(2):141–142. Scholar
  84. Xu G, Strong MJ, Lacey MR, Baribault C, Flemington EK, Taylor CM (2014) RNA CoMPASS: a dual approach for pathogen and host transcriptome analysis of RNA-seq datasets. PLoS One 9(2):e89445. Scholar
  85. Xu GJ, Kula T, Xu Q, Li MZ, Vernon SD, Ndung’u T, Ruxrungtham K, Sanchez J, Brander C, Chung RT, O’Connor KC, Walker B, Larman HB, Elledge SJ (2015) Viral immunology. Comprehensive serological profiling of human populations using a synthetic human virome. Science 348(6239):aaa0698. Scholar
  86. Xu Y, Stange-Thomann N, Weber G, Bo R, Dodge S, David RG, Foley K, Beheshti J, Harris NL, Birren B, Lander ES, Meyerson M (2003) Pathogen discovery from human tissue by sequence-based computational subtraction. Genomics 81(3):329–335CrossRefGoogle Scholar
  87. Yan J, Risacher SL, Shen L, Saykin AJ (2017) Network approaches to systems biology analysis of complex disease: integrative methods for multi-omics data. Brief Bioinform.
  88. Yong WS, Hsu FM, Chen PY (2016) Profiling genome-wide DNA methylation. Epigenetics Chromatin 9:26. Scholar
  89. Yu LL, Davis WC, Nuevo Ordonez Y, Long SE (2013) Fast and accurate determination of K, Ca, and Mg in human serum by sector field ICP-MS. Anal Bioanal Chem 405(27):8761–8768. Scholar
  90. Zalli A, Carvalho LA, Lin J, Hamer M, Erusalimsky JD, Blackburn EH, Steptoe A (2014) Shorter telomeres with high telomerase activity are associated with raised allostatic load and impoverished psychosocial resources. Proc Natl Acad Sci U S A 111(12):4519–4524. Scholar
  91. Zota AR, Shenassa ED, Morello-Frosch R (2013) Allostatic load amplifies the effect of blood lead levels on elevated blood pressure among middle-aged U.S. adults: a cross-sectional study. Environ Health 12(1):64. Scholar

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© Springer International Publishing AG, part of Springer Nature 2019

Authors and Affiliations

  • Martyn T. Smith
    • 1
    Email author
  • Cliona M. McHale
    • 1
  • Rosemarie de la Rosa
    • 1
  1. 1.Superfund Research Program, Division of Environmental Health SciencesSchool of Public Health, University of CaliforniaBerkeleyUSA

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